Almond (Prunus dulcis (Mill.) D.A.Webb) is one of the largest nut crops in the world. Recently, phenolic compounds, mostly stored in almond skin, have been associated with much of the health-promoting behavior associated with their intake. The almond skin enriched fraction obtained from cold-pressed oil residues of the endemic Moroccan Beldi ecotypes is particularly rich in chlorogenic acid. In this study, both almond skin extract (AE) and chlorogenic acid (CHL) supplements, similar to traditional positive control resveratrol, significantly increased the replicative life-span of yeast compared to the untreated group. Our results showed that AE and CHL significantly reduced the production of reactive oxygen and nitrogen species (ROS/RNS), most likely due to their ability to maintain mitochondrial function during aging, as indicated by the maintenance of normal mitochondrial membrane potential in treated groups. This may be associated with the observed activation of the anti-oxidative stress response in treated yeast, which results in activation at both gene expression and enzymatic activity levels for SOD2 and SIR2, the latter being an upstream inducer of SOD2 expression. Interestingly, the differential gene expression induction of mitochondrial SOD2 gene at the expense of the cytosolic SOD1 gene confirms the key role of mitochondrial function in this regulation. Furthermore, AE and CHL have contributed to the survival of yeast under UV-C-induced oxidative stress, by reducing the development of ROS / RNS, resulting in a significant reduction in cellular oxidative damage as evidenced by decreased membrane lipid peroxidation, protein carbonyl content and 8-oxo-guanine formation in DNA. Together, these results demonstrate the interest of AE and CHL as new regulators in the replicative life-span and control of the oxidative stress response of yeast.

We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all researches evaluating the effect of GAS use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95% CI) for overall survival (OS) and progression-free survival (PFS) were calculated with fixed-effects or random-effects model. The study population included n=16 retrospective studies and 372,418 patients. Series concerned gastrointestinal tract tumors (n=5 studies), renal cell carcinomas (RCC, n=3 studies), non-small cell lung cancers (NSCLC, n=5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n=3 studies. The pooled HRs for OS and PFS were 1.31 (95% CI: 1.20–1.43; P<01) and 1.3 (95%CI 1.07-1.57; P<0.01) for GAS and no GAS users, respectively. Only studies of EGFR mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.

Marula seed cake (MSC) is a nutritionally-rich natural feed resource that can enhance the healthiness of animal-derived foods (ADFs) for human consumption. This study compared the health-related fatty acid (FA) profiles of MSC products from South Africa and Eswatini. Composite samples monthly collected from both countries were analysed for FAs. MSC products from both countries were found to be dominated by oleic acid (>70%), followed by palmitic, linoleic and stearic acids. Consequently, both products had their FA totals dominated by ƩMUFA followed by ƩSFA, ƩPUFA, Ʃn-6 PUFA and Ʃn-3 PUFA. Both oleic and stearic acids were higher (P < 0.01) whilst linoleic (P < 0.001), α-linolenic (P < 0.05), margaric (P < 0.05), palmitoleic (P < 0.05) and eicosatrienoic (P < 0.05) acids were lower in South African in comparison to Eswatini MSC. Consequently, South African MSC had higher ƩMUFA (P < 0.01) but lower ƩPUFA (P < 0.001), Ʃn-6 PUFA (P < 0.001) and Ʃn-3 PUFA (P < 0.05). Also, Eswatini MSC had higher n-6 : n-3 PUFA, PUFA : SFA (P = 0.001) and PUFA : MUFA (P < 0.05) ratios. Further, MSC products from both countries had similarly (P > 0.05) low atherogenicity and high desaturase indices. In conclusion, both country products are rich particularly in oleic acid and their incorporation into farm animal diets would increase content of the MUFA in ADFs and, consequently, improve health benefits to human consumers.

Many anuran strategies for survival involve hydric regulation, and reproduction is not different. The aquaporin (AQP) family plays an important role in water transport and regulation in many tissues, including the male gonad. The testis undergoes various stages of change during the reproductive cycle, and water balance is an important factor in ensuring reproductive success. Considering the relevance of water control in testicular development in anurans and the lack of research regarding the tissue localization of AQP in the male gonad, the present study investigated the expression of three AQPs (1,2, and 9) in the testis of the neotropical anuran species Leptodactylus podicipinus during two different periods of the reproductive cycle. AQP1 and 2 immunoreactions were found in early germ cells, spermatozoa, Leydig cells, and Sertoli cells, which were strongly associated with the reproductive period. AQP1 was also found in the testicular blood vessels. AQP 9 was identified predominantly in the epithelium of the intratesticular ducts of reproductive period individuals. The study present, for the first time, the localization of AQP1, AQP2, and AQP9 in the testis of an anuran species, and the differences in their location during two distinct periods of the reproductive cycle.

The increasing concern regarding climate change continues to motivate research in the Arctic. Within the delicate cycle of the cryosphere, leads are an important kinematic feature that regulate heat balances in the Arctic. Therefore, it is necessary to quantify the genesis of leads over time to identify when and where changes are occurring. The use of a principal component analysis (PCA) is one such tool that is used to identify the characteristics of seasonal ice variability. The PCA not only identifies “normal” or “dominant” conditions or features, but also extract anomalous spatial features from an archive of long-term sequence of images.

Bananas, a staple food globally and a key agricultural commodity, face a severe threat from the fungus Fusarium oxysporum form specialis cubense (Foc), significantly impacting production. Genetic improvement to develop resistant cultivars stands out as a crucial strategy to mitigate this disease. This study focused on assessing and recommending enhanced diploid banana varieties for resistance against Foc subtropical race 4 (ST4) and Foc race 1 (R1). Twenty-five improved diploids developed by Embrapa, Brazil, underwent evaluation. Utilizing a scale for internal symptoms at 90 days post-inoculation, genotypes were categorized from highly resistant to highly susceptible based on the internal symptom index. The diploid M53 exhibited high resistance to R1 and resistance to Foc ST4, while only the diploid CNPMF 0534 demonstrated complete resistance to both R1 and ST4, with resistance to the latter likely associated with penetration. These findings provide valuable insights for banana and plantain breeding programs, offering selected diploids for crossbreeding with commercial cultivars to develop new, resistant genotypes against Foc.

Incretin effect helps in regulating glucose homeostasis and maintaining glycaemic control within the human body. This effect is achieved by the two naturally occurring incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Such hormones released by specialized entero-endocrine cells of the gastrointestinal tract cause insulin augmentation after food consumption. However, incretin effects are impaired in type 2 diabetic, primarily attributed to the deterioration of GLP-1 function along with decreased GLP-1 receptor expression. Targeting this hormone has, therefore, become an important therapeutic approach to treat this diabetic condition. Native GLP-1’s brief half-life and rapid proteolytic degradation have generated significant enthusiasm in uncovering the long-acting GLP-1 receptor (GLP-1R) agonists to manage type 2 diabetes. These synthetic peptides mimic the natural GLP-1 to activate GLP-1R and effectively exert various physiological benefits in terms of weight management, blood pressure, lipid profile, obesity and major adverse cardiovascular event. This review paper provides insights into the structure, function and expression of GLP-1 and its receptor. It also summarizes existing literature regarding different types of GLP-1 receptor agonists, their effects on blood pressure and how they exert their actions. While animal models have contributed significantly to this area of study, the scarcity of human studies is noted, indicating a need for more investigation in this domain. Expanding research in humans will help in comprehending the impact of GLP-1 receptor agonists on blood pressure regulation and their underlying mechanisms.

Background: Over the past years, there has been a rise in the incidence of type 1 diabetes, partic-ularly among younger individuals. This concerning trend has prompted investigations into po-tential contributing factors, with intestinal dysbiosis emerging as a likely culprit for the escalating annual rates of the disease; (2) Methods: We conducted a retrospective ecologic correlational study involving 37 children from the southern region of Romania between 2019-2021. All participants were within the first six months following the onset of the disease; (3) Results: In the microbiota of the patients we observed a dysbiosis marked by an overabundance of bacteria (Clostridium coccoides, Faecalibacterium, Bacterioides, Enterobacteriaceae) and fungi, compared to the healthy control group. The Spearman correlation revealed a positive association between the presence of Bacteroides (p=0.0442), Butyricicoccus (p=0.0164), and Clostridium leptum (p=0.0023) with recent diabetes onset. Furthermore, a significant correlation was observed between younger age at onset and the pres-ence of Butyricicoccus (p=0.019). The use of antibiotics in the month preceding admission was linked to the presence of fungi in the microbiota (Candida, p=0.0442); (4) Conclusions: The dysbiosis of Romanian type 1 diabetes children correlates with inflammation, more severe onset of the disease and other au-toimmune diseases.

In recent years, numerous approaches have been developed to comprehend the molecular altera-tions underlying thyroid cancer (TC) oncogenesis and explore novel therapeutic strategies for TC. It is now well established that the neurokinin-1 receptor (NK-1R) is overexpressed in cancer cells and that NK-1R is essential for viability of cancer cells. The binding of substance P (SP) to NK-1R in neoplastic cells plays a pivotal role in cancer progression by promoting neoplastic cell growth, protecting tumour cells from apoptosis, triggering invasion and metastasis through enhanced migration of cancer cells, and stimulating endothelial cell proliferation for tumour angiogenesis. Remarkably, all types of human TC (papillary, follicular, medullary, anaplastic), as well as met-astatic lesions, exhibit overexpression of SP and NK-1R compared to the normal thyroid gland. TC cells synthesize and release SP, which exerts its multiple functions through autocrine, para-crine, intracrine, and neuroendocrine processes, including the regulation of tumour burden. Con-sequently, the secretion of SP from TC results in increased SP levels in plasma, which are signifi-cantly higher in TC patients compared to controls. Additionally, NK-1R antagonists have demonstrated a dose-dependent antitumour action. They impair cancer cell proliferation on one side and induce apoptosis of tumour cells on the other side. Furthermore, it has been demonstrat-ed that NK-1R antagonists inhibit neoplastic cell migration, thereby impairing both invasiveness and metastatic abilities, as well as angiogenesis. Given the consistent overexpression of NK-1R in all types of TC, targeting this receptor represents a promising therapeutic approach for TC. Therefore, NK-1R antagonists, such as the drug aprepitant, may represent novel drugs for TC treatment.

Nonalcoholic fatty liver disease (NAFLD) has become a widely studied subject due to its increasing prevalence and links to diseases such as type 2 diabetes and obesity. It has severe complications, including nonalcoholic steatohepatitis, cirrhosis, hepatocellular carcinoma, and portal hypertension that can lead to liver transplantation in some cases. To better prevent and treat this pathology, it is important to understand its underlying physiology. Here, we identify three main factors that play a crucial role in the physiopathology of NAFLD: oxidative stress, insulin resistance, and the key role of carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1). We discuss the pathophysiology linking these factors to NAFLD pathophysiology.

CD39 is involved in adenosine metabolism through conversion of extracellular ATP to adenosine. Because extracellular adenosine plays a critical role in the immune suppression of tumor microenvironment, the inhibition of CD39 activity by monoclonal antibodies (mAbs) is one of the important strategies for tumor therapy. In this study, we developed specific and sensitive mAbs for mouse CD39 (mCD39) using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mCD39 mAbs, which were established by the CBIS method including C₃₉Mab-1 (rat IgG_2a, kappa) and C₃₉Mab-2 (rat IgG_2a, lambda), reacted with not only mCD39-overexpressed Chinese hamster ovary-K1 (CHO/mCD39) but also endogenously mCD39-expressed cell lines, such as L1210 (mouse lymphocytic leukemia) and J774-1 (mouse macrophage-like) cell lines through flow cytometry. Kinetic analyses using flow cytometry indicated that the dissociation constant (K_D) of C₃₉Mab-1 and C₃₉Mab-2 for CHO/mCD39 was 7.3 × 10⁻⁹ M and 5.5 × 10⁻⁹ M, respectively. K_D of C₃₉Mab-1 and C₃₉Mab-2 for L1210 was 3.3 × 10⁻⁹ M and 3.6 × 10⁻¹⁰ M, respectively. Furthermore, C₃₉Mab-1 could detect the lysate of CHO/mCD39 by western blot analysis. These results indicate that C₃₉Mab-1 and C₃₉Mab-2 are useful for the detection of mCD39 in many functional studies.

Iron is the most abundant micronutrient in plant mitochondria and it has a crucial role in biochemical reactions involving electron transfer. It has been described in Oryza sativa that Mitochondrial Iron Transporter (MIT) is an essential gene and that knockdown mutant rice plants have a decreased amount of iron in mitochondria, strongly suggesting that OsMIT is involved in mitochondrial iron uptake. In Arabidopsis thaliana, two genes encode MIT homologues. In this study, we analyzed different AtMIT1 and AtMIT2 mutant alleles, confirming that individually AtMIT1 nor AtMIT2 genes are essential. When we generated crosses between Atmit1 and Atmit2 alleles we were able to isolate homozygous double mutant plants. Interestingly, homozygous double mutant plants were obtained only when mutant alleles of Atmit2 with the T-DNA insertion in the intron region were used for crossings, and in these cases a correctly spliced AtMIT2 mRNA was generated, although at a low level. Atmit1 Atmit2 double homozygous mutant plants, which were knockout for AtMIT1 and knockdown for AtMIT2, were grown and chacterised in iron sufficient conditions. Pleiotropic developmental defects were observed including abnormal seeds, increased number of cotyledons, slow growth rate, pinoid stems, defects in flower structures and reduced seed set. We observed a possible phenomenon of T-DNA suppression in the next generation of Atmit1 Atmit2 double homozygous mutant plants, correlating with an increased splicing of the AtMIT2 intron containing the T-DNA. Molecular analysis of gene expression markers for mitochondrial and oxidative stress showed that Atmit1 Atmit2 double homozygous mutant plants express a degree of mitochondrial perturbation. A RNA-Seq study was performed and we could identify more than 760 genes differentially expressed in Atmit1 Atmit2, including genes involved in iron transport, coumarin metabolism, and hormones metabolism, transport and signaling. Our data suggest that some of the phenotypes observed in Atmit1 Atmit2 double homozygous mutant plants are mediated by defects in auxin homeostasis.

In this research, new setting is introduced for new SuperHyperNotion, namely, 11 Neutrosophic 1-failed SuperHyperForcing. Two different types of SuperHyperDefinitions 12 are debut for them but the research goes further and the SuperHyperNotion, 13 SuperHyperUniform, and SuperHyperClass based on that are well-defined and 14 well-reviewed. The literature review is implemented in the whole of this research. For 15 shining the elegancy and the significancy of this research, the comparison between this 16 SuperHyperNotion with other SuperHyperNotions and fundamental 17 SuperHyperNumbers are featured. The definitions are followed by the examples and the 18 instances thus the clarifications are driven with different tools. The applications are 19 figured out to make sense about the theoretical aspect of this ongoing research. The 20 “Cancer’s Neutrosophic Recognition” are the under research to figure out the challenges 21 make sense about ongoing and upcoming research. The special case is up. The cells are 22 viewed in the deemed ways. There are different types of them. Some of them are 23 individuals and some of them are well-modeled by the group of cells. These types are all 24 officially called “SuperHyperVertex” but the relations amid them all officially called 25 “SuperHyperEdge”. The frameworks “SuperHyperGraph” and “neutrosophic 26 SuperHyperGraph” are chosen and elected to research about “Cancer’s Neutrosophic 27 Recognition”. Thus these complex and dense SuperHyperModels open up some avenues 28 to research on theoretical segments and “Cancer’s Neutrosophic Recognition”. Some 29 avenues are posed to pursue this research. It’s also officially collected in the form of 30 some questions and some problems. Assume a SuperHyperGraph. Then a “1-failed 31 SuperHyperForcing” Z(NSHG) for a neutrosophic SuperHyperGraph NSHG : (V,E) 32 is the maximum cardinality of a SuperHyperSet S of black SuperHyperVertices 33 (whereas SuperHyperVertices in V (G) \ S are colored white) such that V (G) isn’t 34 turned black after finitely many applications of “the color-change rule”: a white 35 SuperHyperVertex is converted to a black SuperHyperVertex if it is the only white 36 SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is referred 37 by “1-” about the usage of any black SuperHyperVertex only once to act on white 38 SuperHyperVertex to be black SuperHyperVertex; a “neutrosophic 1-failed 39 SuperHyperForcing” Zn(NSHG) for a neutrosophic SuperHyperGraph NSHG : (V,E) 40 is the maximum neutrosophic cardinality of a SuperHyperSet S of black 41 SuperHyperVertices (whereas SuperHyperVertices in V (G) \ S are colored white) such 42 that V (G) isn’t turned black after finitely many applications of “the color-change rule”: 43 a white SuperHyperVertex is converted to a black SuperHyperVertex if it is the only 44 1/128 white SuperHyperNeighbor of a black SuperHyperVertex. The additional condition is 45 referred by “1-” about the usage of any black SuperHyperVertex only once to act on 46 white SuperHyperVertex to be black SuperHyperVertex. Assume a SuperHyperGraph. 47 Then an “δ−1-failed SuperHyperForcing” is a maximal 1-failed SuperHyperForcing of 48 SuperHyperVertices with maximum cardinality such that either of the following 49 expressions hold for the (neutrosophic) cardinalities of SuperHyperNeighbors of s ∈ S : 50 |S ∩N(s)| > |S ∩(V \N(s))|+δ, |S ∩N(s)| < |S ∩(V \N(s))|+δ. The first Expression, 51 holds if S is an “δ−SuperHyperOffensive”. And the second Expression, holds if S is an 52 “δ−SuperHyperDefensive”; a“neutrosophic δ−1-failed SuperHyperForcing” is a maximal 53 neutrosophic 1-failed SuperHyperForcing of SuperHyperVertices with maximum 54 neutrosophic cardinality such that either of the following expressions hold for the 55 neutrosophic cardinalities of SuperHyperNeighbors of s ∈ S : |S ∩ N(s)|neutrosophic > 56 |S ∩ (V \ N (s))|neutrosophic + δ, |S ∩ N (s)|neutrosophic < |S ∩ (V \ N (s))|neutrosophic + δ. 57 The first Expression, holds if S is a “neutrosophic δ−SuperHyperOffensive”. And the 58 second Expression, holds if S is a “neutrosophic δ−SuperHyperDefensive”. It’s useful to 59 define “neutrosophic” version of 1-failed SuperHyperForcing. Since there’s more ways to 60 get type-results to make 1-failed SuperHyperForcing more understandable. For the sake 61 of having neutrosophic 1-failed SuperHyperForcing, there’s a need to “redefine” the 62 notion of “1-failed SuperHyperForcing”. The SuperHyperVertices and the 63 SuperHyperEdges are assigned by the labels from the letters of the alphabets. In this 64 procedure, there’s the usage of the position of labels to assign to the values. Assume a 65 1-failed SuperHyperForcing. It’s redefined neutrosophic 1-failed SuperHyperForcing if 66 the mentioned Table holds, concerning, “The Values of Vertices, SuperVertices, Edges, 67 HyperEdges, and SuperHyperEdges Belong to The Neutrosophic SuperHyperGraph” 68 with the key points, “The Values of The Vertices & The Number of Position in 69 Alphabet”, “The Values of The SuperVertices&The maximum Values of Its Vertices”, 70 “The Values of The Edges&The maximum Values of Its Vertices”, “The Values of The 71 HyperEdges&The maximum Values of Its Vertices”, “The Values of The 72 SuperHyperEdges&The maximum Values of Its Endpoints”. To get structural examples 73 and instances, I’m going to introduce the next SuperHyperClass of SuperHyperGraph 74 based on 1-failed SuperHyperForcing. It’s the main. It’ll be disciplinary to have the 75 foundation of previous definition in the kind of SuperHyperClass. If there’s a need to 76 have all SuperHyperConnectivities until the 1-failed SuperHyperForcing, then it’s 77 officially called “1-failed SuperHyperForcing” but otherwise, it isn’t 1-failed 78 SuperHyperForcing. There are some instances about the clarifications for the main 79 definition titled “1-failed SuperHyperForcing”. These two examples get more scrutiny 80 and discernment since there are characterized in the disciplinary ways of the 81 SuperHyperClass based on 1-failed SuperHyperForcing. For the sake of having 82 neutrosophic 1-failed SuperHyperForcing, there’s a need to “redefine” the notion of 83 “neutrosophic 1-failed SuperHyperForcing” and “neutrosophic 1-failed 84 SuperHyperForcing”. The SuperHyperVertices and the SuperHyperEdges are assigned 85 by the labels from the letters of the alphabets. In this procedure, there’s the usage of 86 the position of labels to assign to the values. Assume a neutrosophic SuperHyperGraph. 87 It’s redefined “neutrosophic SuperHyperGraph” if the intended Table holds. And 88 1-failed SuperHyperForcing are redefined “neutrosophic 1-failed SuperHyperForcing” if 89 the intended Table holds. It’s useful to define “neutrosophic” version of 90 SuperHyperClasses. Since there’s more ways to get neutrosophic type-results to make 91 neutrosophic 1-failed SuperHyperForcing more understandable. Assume a neutrosophic 92 SuperHyperGraph. There are some neutrosophic SuperHyperClasses if the intended 93 Table holds. Thus SuperHyperPath, SuperHyperCycle, SuperHyperStar, 94 SuperHyperBipartite, SuperHyperMultiPartite, and SuperHyperWheel, are 95 “neutrosophic SuperHyperPath”, “neutrosophic SuperHyperCycle”, “neutrosophic 96 SuperHyperStar”, “neutrosophic SuperHyperBipartite”, “neutrosophic 97 2/128 SuperHyperMultiPartite”, and “neutrosophic SuperHyperWheel” if the intended Table 98 holds. A SuperHyperGraph has “neutrosophic 1-failed SuperHyperForcing” where it’s 99 the strongest [the maximum neutrosophic value from all 1-failed SuperHyperForcing 100 amid the maximum value amid all SuperHyperVertices from a 1-failed 101 SuperHyperForcing.] 1-failed SuperHyperForcing. A graph is SuperHyperUniform if it’s 102 SuperHyperGraph and the number of elements of SuperHyperEdges are the same. 103 Assume a neutrosophic SuperHyperGraph. There are some SuperHyperClasses as 104 follows. It’s SuperHyperPath if it’s only one SuperVertex as intersection amid two given 105 SuperHyperEdges with two exceptions; it’s SuperHyperCycle if it’s only one 106 SuperVertex as intersection amid two given SuperHyperEdges; it’s SuperHyperStar it’s 107 only one SuperVertex as intersection amid all SuperHyperEdges; it’s 108 SuperHyperBipartite it’s only one SuperVertex as intersection amid two given 109 SuperHyperEdges and these SuperVertices, forming two separate sets, has no 110 SuperHyperEdge in common; it’s SuperHyperMultiPartite it’s only one SuperVertex as 111 intersection amid two given SuperHyperEdges and these SuperVertices, forming multi 112 separate sets, has no SuperHyperEdge in common; it’s SuperHyperWheel if it’s only one 113 SuperVertex as intersection amid two given SuperHyperEdges and one SuperVertex has 114 one SuperHyperEdge with any common SuperVertex. The SuperHyperModel proposes 115 the specific designs and the specific architectures. The SuperHyperModel is officially 116 called “SuperHyperGraph” and “Neutrosophic SuperHyperGraph”. In this 117 SuperHyperModel, The “specific” cells and “specific group” of cells are 118 SuperHyperModeled as “SuperHyperVertices” and the common and intended properties 119 between “specific” cells and “specific group” of cells are SuperHyperModeled as 120 “SuperHyperEdges”. Sometimes, it’s useful to have some degrees of determinacy, 121 indeterminacy, and neutrality to have more precise SuperHyperModel which in this case 122 the SuperHyperModel is called “neutrosophic”. In the future research, the foundation 123 will be based on the “Cancer’s Neutrosophic Recognition” and the results and the 124 definitions will be introduced in redeemed ways. The neutrosophic recognition of the 125 cancer in the long-term function. The specific region has been assigned by the model 126 [it’s called SuperHyperGraph] and the long cycle of the move from the cancer is 127 identified by this research. Sometimes the move of the cancer hasn’t be easily identified 128 since there are some determinacy, indeterminacy and neutrality about the moves and 129 the effects of the cancer on that region; this event leads us to choose another model [it’s 130 said to be neutrosophic SuperHyperGraph] to have convenient perception on what’s 131 happened and what’s done. There are some specific models, which are well-known and 132 they’ve got the names, and some SuperHyperGeneral SuperHyperModels. The moves 133 and the traces of the cancer on the complex tracks and between complicated groups of 134 cells could be fantasized by a neutrosophic SuperHyperPath(-/SuperHyperCycle, 135 SuperHyperStar, SuperHyperBipartite, SuperHyperMultipartite, SuperHyperWheel). 136 The aim is to find either the longest 1-failed SuperHyperForcing or the strongest 137 1-failed SuperHyperForcing in those neutrosophic SuperHyperModels. For the longest 138 1-failed SuperHyperForcing, called 1-failed SuperHyperForcing, and the strongest 139 SuperHyperCycle, called neutrosophic 1-failed SuperHyperForcing, some general results 140 are introduced. Beyond that in SuperHyperStar, all possible SuperHyperPaths have 141 only two SuperHyperEdges but it’s not enough since it’s essential to have at least three 142 SuperHyperEdges to form any style of a SuperHyperCycle. There isn’t any formation of 143 any SuperHyperCycle but literarily, it’s the deformation of any SuperHyperCycle. It, 144 literarily, deforms and it doesn’t form. A basic familiarity with SuperHyperGraph 145 theory and neutrosophic SuperHyperGraph theory are proposed.

In spite of large-scale investigations of homogeneous single-site metallocene catalysts and systems based on them, the problem of controlling their activity, chemo- and stereoselectivity with the aim of developing efficient methods for the preparation of practically useful products of alkenes transformation, such as dimers, oligomers, and polymers, still remains topical. Here we studied catalytic activity of differently structured zirconocenes (10 examples of cyclopentadienyl and indenyl complexes) and co-catalysts activating the system, namely HAlBui2, MMAO-12 or (Ph3C)[B(C6F5)4] at low activator/Zr ratios in 1-hexene oligomerization reaction. The influence of catalyst structure and system composition on alkene conversion, type of products formed and reaction stereoselectivity was investigated. The composition of hydride intermediates forming in the systems L2ZrCl2 (L2= ansa-Me2CCp2)-HAlBui2-activator was studied by NMR and the participation of biszirconium hydride complex as the precursor of catalytically active sites of the alkene dimerization reaction was shown.

When existing at emulsion interface and continuous phase, dispersibility of water-soluble flexible polymer chains has obvious effect on rheology and dielectric properties of whole emulsion. CNF Pickering emulsion is a good system to research these properties with respect to their microscopic phase structure, dielectric and rheological properties by using cellulose nanofibers (CNF) as water-soluble Pickering emulsifier, liquid Paraffin as oil phase and DDAB as a cationic auxiliary surfactant. The CNF- and DDAB-contents were systematically varied while the water to paraffin oil ratio remained constant to discern the influence of the Pickering emulsifiers. Polarized optical microscopic images revealed that the droplets have tendency to become smaller size for higher CNF content, but bigger size for higher DDAB content, which was proved by the fluorescent analysis for CNF dispersibility with varying DDAB content. The dielectric damping exhibits a minimum, whose value decreases with increasing DDAB- and CNF-content. Increasing the DDAB-content promotes solubilization of CNFs in the aqueous phase and will increase the overall viscosity and yield points. Similarly, a higher CNF-content leads to a higher viscosity and yield point, but at high DDAB-contents the viscosity function exhibits an S-shape at intermediate CNF-content. To evaluate the results further they were compared with CNF-dispersions (without oil-phase), which showed a surfactant effect slightly on maximum stress but strongly on yield stress τy, indicating DDAB can promote the formation of CNF network rather than the viscosity of whole system.

A multiscale modeling concept for numerical simulation of multiphysics turbulent flow utilizing map-based advection is described. The approach is outlined with emphasis on its theoretical foundations and physical interpretations in order to establish the context for subsequent presentation of the associated numerical algorithms and the results of validation studies. The model formulation is a synthesis of existing methods, modified and extended in order to obtain a qualitatively new capability. The salient feature of the approach is that time advancement of the flow is fully resolved both spatially and temporally, albeit with modeled advancement processes restricted to one spatial dimension. This one-dimensional advancement is the basis of a bottom-up modeling approach in which three-dimensional space is discretized into under-resolved mesh cells, each of which contains an instantiation of the modeled one-dimensional advancement. Filtering is done only to provide inputs to a pressure correction that enforces continuity and to obtain mesh-scale-filtered outputs if desired. The one-dimensional advancement, the pressure correction, and coupling of one-dimensional instantiations using a Lagrangian implementation of mesh-resolved volume fluxes is sufficient to advance the three-dimensional flow without time advancing coarse-grained equations, a feature that motivates the designation of the approach as autonomous microscale evolution (AME). In this sense, the one-dimensional treatment is not a closure because there are no unclosed terms to evaluate. However, the approach is additionally suitable for use as a subgrid-scale closure of existing large-eddy-simulation methods. The potential capabilities and limitations of both of these implementations of the approach are assessed conceptually and with reference to demonstrated capabilities of related methods.

This study investigated the ability of a HYDRUS 1D model for predicting the vertical distribution of potassium iodine (200 ppm) in soil columns after amendment with five different common remediation materials (gypsum, lime, fly ash, charcoal and sawdust) at a rate of 2.5% (w/w), relative to an unamended control soil. Results shows that relative to the unamended soil, iodine leaching was decreased by all amendments but that the magnitude of the decreases varied with the soil amendment applied. Iodine content was highest in the upper layer of the soil columns and decreased progressively with soil depth. The model was evaluated via comparison of the model simulated values with measured values from the soil column studies. The results showed that the HYDRUS 1D model efficiency was near to 1, indicating that the stimulated results were near to the measured values. Therefore, this study showed that iodine leaching through a soil could be ascertained well using a HYDRUS 1D model. The model over predicted iodine leaching, resulting to a weak correspondence between the simulated and the measured results for iodine leaching. This suggests that the HYDRUS-1D model does not explain accurately different organic and inorganic amended soil and the preferential flow that occurs in these columns. This may be due to the fact that Freundlich isotherm, which is part of the transport equations, does not sufficiently describe the mechanism of iodine adsorption onto the soil particles. This study would help to select amendments for an effective management strategy to reduce exogenous iodine losses from agro-ecosystems. This would also improve understanding of iodine transport in soil profile.

The management of patients with spinal muscular atrophy type 1 (SMA1) is constantly evolving. In just a few decades the medical approach has switched from an exclusively palliative therapy to a targeted therapy, transforming the natural history of the disease, improving survival time and quality of life, and creating new challenges and goals. Many nutritional problems, gastrointesti-nal disorders and metabolic and endocrine alterations are commonly identified in patients af-fected by SMA1 during childhood and adolescence. For this reason, a proper pediatric multidis-ciplinary approach is then required in the clinical care of these patients, with a specific focus on the prevention of most common complications. The purpose of this narrative review is to provide the clinician with a practical and usable tool about SMA1 patients care, through a comprehensive insight into the nutritional, gastroenterological, metabolic and endocrine management of SMA1. Considering the possible horizons opened thanks to new therapeutic frontiers, a nutritional and endo-metabolic surveillance is a crucial element to be considered for a proper clinical care of these patients.

There must exist a reformulation of quantum field theory which does not refer to classical time. We propose a pre-quantum, pre-spacetime theory, which is a matrix-valued Lagrangian dynamics for gravity, Yang-Mills fields, and fermions. The definition of spin in this theory leads us to an eight dimensional octonionic space-time. The algebra of the octonions reveals the standard model; model parameters are determined by roots of the cubic characteristic equation of the exceptional Jordan algebra. We derive the asymptotic low energy value 1/137 of the fine structure constant, and predict the existence of universally interacting spin one Lorentz bosons, which replace the hypothesised graviton. Gravity is not to be quantized, but is an emergent four-dimensional classical phenomenon, precipitated by the spontaneous localisation of highly entangled fermions.

Carnivore protoparvovirus 1 (CPPV-1) is a DNA virus causing gastrointestinal disease and immunosuppression in various terrestrial carnivores. Domestic dogs and cats are considered the primary CPPV-1 reservoirs. The habitat overlaps of wild carnivores and free-roaming dogs increases the threat of CPPV-1 transmission between them. This study explored the CPPV-1 distribution among wild carnivores through PCR screening and compared the DNA sequences of the partial capsid protein (VP2) between wild and domestic carnivores. In total, 181 samples were screened for the CPPV-1 VP2 gene, including 32 masked palm civets (Paguma larvata), 63 Chinese ferret badgers (Melogale moschata), and 86 crab-eating mongooses (Herpestes urva), from 2015 to 2019 in Taiwan. The average prevalence of CPPV-1 was 17.7% (32/181), with the highest prevalence in masked palm civets (37.5%). In addition, a masked palm civet was coinfected with two CPPV-1 strains. Among the 33 partial VP2 gene sequences, 23 were identical to sequences amplified from domestic dogs and cats in Asia and the remaining 10 were identified for the first time. This study demonstrated that CPPV-1 has circulated between domestic and wild carnivores in rural Taiwan. Therefore, further population control and health management of free-roaming domestic carnivores are recommended.

Due to the increasing importance of mangroves in climate change mitigation projects, more accurate and cost-effective aboveground biomass (AGB) monitoring methods are required. However, field measurement of AGB may be a challenge because of its remote location and the difficulty to walk in these areas. This study is based on the Livelihoods Fund’ Oceanium project of 10,000 hectare mangrove plantations monitoring. In a first step, the possibility of replacing traditional field measurements of sample plots in a young mangrove plantation by a semiautomatic processing of UAV-based photogrammetric point clouds was assessed. In a second step, Sentinel-1 radar and Sentinel-2 optical imagery were used as auxiliary information to estimate AGB and its variance for the entire study area under a model-assisted framework. AGB was measured using UAV imagery in a total of 95 sample plots. UAV plot data was used in combination with non-parametric Support Vector Regression (SVR) models for the estimation of the study area AGB using model-assisted estimators. Purely UAV-based AGB estimates and their associated standard error (SE) were compared with model-assisted estimates using (1) Sentinel-1, (2) Sentinel-2 and (3) a combination of Sentinel-1 and Sentinel-2 data as auxiliary information. The validation of the UAV-based individual tree height and crown diameter measurements showed a root mean square error (RMSE) of 0.21 m and 0.32 m respectively. Relative efficiency of the three model-assisted scenarios ranged between 1.61 and 2.15. Although all SVR models improved the efficiency of the monitoring over UAV-based estimates, the best results were achieved when a combination of Sentinel-1 and Sentinel-2 data was used. Results indicated that the methodology used in this research can provide accurate and cost-effective estimates of AGB in mangrove young plantations.

Abstract: Tumor-targeting and blood-brain barrier (BBB)-penetrating are highly desirable for the treatment of glioma. In this study, we developed Pep-1&borneol-bifunctionalized carmustin-loaded micelles (Pep-1/Bor/CMS-M) capable of targeting to IL-13 receptor-overexpressed glioma and penetrating the brain microvascular endothelial cells-associated physiologic barriers. Pep-1/Bor/CMS-M were nearly spherical particles with a dimeter of 32.6 ± 1.1 nm and zeta potential of -21.3 ± 3.1 mV. Carmustine (CMS) released from Pep-1/Bor/CMS-M in pH 7.4 was significantly faster than in acidic environments. In human glioma BT325 cellular studies, Pep-1/Bor/CMS-M remarkably increased the cytotoxicity, notably improved the internalization and effectively induced the cell apoptosis. Likewise, in human brain microvascular endothelial cells (HBMEC) cells, Pep-1/Bor/CMS-M obviously promoted the cellular uptake, rapidly decreased the transepithelial electrical resistance (TEER) and thereby of enhancing the ability of penetration. In orthotopic Luc-BT325 glioma tumor-bearing nude mouse models, the stronger fluorescence signal and longer retention were observed in brain tissues compared with other controls, after single administration of DiD-labelled Pep-1/Bor/M (DiD/Pep-1/Bor/M). Importantly, Pep-1/Bor/CMS-M displayed the strongest inhibition of tumor growth, the longest survival period and low systemic toxicity in treating orthotopic glioma tumor-bearing nude mice. Simultaneous functionalization of Pep-1 and borneol offers a novel strategy for designing CMS-based nanomedicine and precisely treating glioma.

It is well known that the primes and prime powers have a deep relationship with the nontrivial zeros of Riemann’s zeta function. This is a reciprocal relationship. The zeros and the primes are encoded in each other and are reciprocally recoverable. Riemann’s zeta is an extended or continued version of Euler’s zeta function which in turn equates with Euler’s product formula over the primes. This paper shows that the zeros of the converging Dirichlet or Catalan beta function, which requires no continuation to be valid in the critical strip, can be easily determined. The imaginary parts of these zeros have a deep and reciprocal relationship with the odd primes and odd prime powers. This relationship separates the odd primes into those having either 1 or 3 as a remainder after division by 4. The vector pathway of the beta function is such that the real part of its zeros has to be a half.

Exact solutions to conformable time fractional (3+1)- dimensional equations are derived by using the modified form of the Kudryashov method. The compatible wave transformation reduces the equations to an ODE with integer orders. The predicted solution of the finite series of a rational exponential function is substituted into this ODE. The resultant polynomial equation is solved by using algebraic operations. The method works for the Jimbo-Miwa, the Zakharov-Kuznetsov and the modified Zakharov-Kuznetsov equations in conformable time fractional forms. All the solutions are expressed in explicit forms.

Background: This study tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tear (sPTRCT) with fresh, uncultured, unmodified, autologous adipose derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and more effective than corticosteroid injection. Methods: Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy treatments for at least six weeks were randomly assigned to receive a single injection of an average 11.4×10⁶ UA-ADRCs (in 5 mL liquid; mean cell viability: 88%) (n=11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/ml; 2 mL) plus 3 mL of 0.25% bupivacaine (n=5; mITT population), respectively. Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey and pain visual analogue scale (VAS) at baseline (BL) as well as three weeks (W3), W6, W9, W12, W24, W32, W40 and W52 post treatment. Fat-saturated T2 weighted magnetic resonance imaging of the shoulder was performed at BL as well as at W24 and W52 post treatment. Results: No severe adverse events related to the injection of UA-ADRCs were observed in the 12 months post treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, one subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post treatment than those in the corticosteroid group (p < 0.05). Discussion: This pilot study suggests that the use of UA-ADRCs in subjects with sPTRCT is safe and leads to improved shoulder function without adverse effects. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing.

Research efforts toward Philippine biodiversity have increased significantly due to concerns about its natural resources and biodiversity. However, there is an imbalance in the distribution of published studies, with specific territories and organisms receiving more attention. Mindanao, a southern Philippine Island, is known for its high levels of endemism for amphibians and reptiles. Despite this, research on these groups remains unconsolidated. To address this gap, we conducted a biodiversity synthesis focusing on amphibians and reptiles in the faunal region of Mindanao. We found an increasing effort towards herpetofauna over the two decades, yet there is a clear bias in the effort towards amphibians compared to reptiles. In addition, we found that amphibians have a significantly higher species threat index than reptiles and all other vertebrate groups, regardless of ecological status. Yet, threatened herpetofauna species and those facing a greater number of threats are poorly studied, in general. Understanding the factors driving research biases in Mindanao and the Philippines is essential to allow us to redirect research efforts to the most needed areas, particularly to understudied and neglected taxa in Mindanao. This is especially urgent in the face of changing climate, where diverse communities of herpetofauna are at increased risk of extinction. Consequently, by bridging these gaps in biodiversity information, we can effectively contribute to the conservation and understanding of biodiversity in the region.

Background: Antiplatelet medications such as aspirin and clopidogrel are used following thrombotic stroke or transient ischemic attack (TIA) to prevent a recurrent stroke. However, the antiplatelet treatments fail frequently, and patients experience recurrent stroke. One approach to lower the rates of recurrence, may be the individualized antiplatelet therapies (antiplatelet therapy modification (ATM)) based on the results of platelet function analysis (PFA). This review was undertaken to gather and analyse the evidence about the effectiveness of such approaches. Methods: We searched Medline, CINAHL, Embase, Web of Science and Cochrane databases to 7 January 2020. Results: Two observational studies involving 1136 patients were included. The overall effects of PFA-based ATM on recurrent strokes (OR 1.05; 95% CI 0.69 to 1.58), any bleeding risk (OR 1.39; 95% CI 0.92 to 2.10) or death hazard from any cause (OR 1.19; 95% CI 0.62 to 2.29) were not significantly different from the standard antiplatelet therapy without ATM. Conclusions: The two studies showed opposite effects of PFA-guided ATM on the recurrent strokes in aspirin non-responders, leading to an insignificant difference in the subgroup meta-analysis (OR 1.59; 95% CI 0.07 to 33.77), while the rates of any bleeding events (OR 1.04; 95% CI 0.49 to 2.17) or death from any cause (OR 1.17; 95% CI 0.41 to 3.35) were not significantly different between aspirin non-responders with ATM and those without ATM. There is a need for large randomized controlled trials which account for potential confounders such as ischemic stroke subtypes, technical variations in the testing protocols, patient adherence to therapy, and pharmacogenetic differences.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study we aimed to investigate whether abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with COVID-19-induced ARDS. Plasma ET-1 levels were measured in 18 mechanically ventilated COVID-19-induced ARDS patients, with simultaneous central venous and systemic arterial blood sampling on Days 1 and 3 following ICU admission. Two age- and sex-matched non-COVID-19 control groups were also used [mechanically ventilated non-COVID-19 critically ill and ARDS patients]. On ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and venous ET-1 levels compared to non-COVID-19 ARDS and critically ill patients (p< 0.05). The arterial:venous (A:V) ET-1 ratio was higher in the non-COVID-19 ARDS patients [1.06 (0.93-1.20)] compared to the other two groups (p< 0.05). The A:V ratio was 0.63 (0.49-1.02) in the COVID-19-induced ARDS patients and 0.79 (0.52-1.11) in the non-COVID-19 critically ill patients. On Day 3, the A:V ratio in all three groups was < 1. The COVID-19 patient group was then divided based on 28-day ICU mortality. Although arterial and venous levels did not differ, the A:V ratio was statistically significantly higher on ICU admission in the non-survivors [0.95 (0.78-1.34)] vs 0.57 (0.48-0.92), p= 0.027]. Measurement of ET-1 clearance via A:V plasma ET-1 levels on ICU admission may assist in predicting outcomes in COVID-19 critically ill patients.

The ever-increasing demand for seafood-containing diets, especially fish, primarily due to their superior nutritional value, has impacted the availability of wild stocks, necessitating the focus on other underutilised aquaculture species. In this study, the proximate and fatty acid (FA) composition of the indigenous black South African mussel (Choromytilus meridionalis) was investigated. The effects of the hot-smoking as preservation method on the proximate composition for mussels were assessed using the standard AOAC protocols; while gas chromatography-flame ionised detection (GC-FID) was used to determine the FA content. The moisture level in hot-smoked mussels significantly (P

The reaction between 5-acetylbarbituric acid and 4-dimethylthiosemicarbazide or 4-hexamethyleneiminyl thiosemicarbazide produces 5-acetylbarbituric-4-dimethylthiosemicarbazone (H2AcbDM) and 5-acetylbarbituric-4N-hexamethyleneiminyl thiosemicarbazone (H2Acbhexim). Eight new complexes with different cooper (II) salts have been prepared and characterized using elemental analysis, molar conductance, UV–vis, ESI-HRMS, FT-IR, magnetic moment, EPR and cyclic voltammetry. In addition, three-dimensional molecular structures of [Cu(HAcbDM)(H2O)2](NO3)·H2O (3a), [Cu(HAcbDM)(H2O)2]ClO4 (4), and [Cu(HAcbHexim)Cl] (6) were determined by single crystal X-ray crystallography, and was carried out an analysis of their supramolecular structure. The H-bonded assemblies were further studied energetically using DFT calculations, MEP surface and QTAIM analyses. In these complexes, the thiosemicarbazone coordinates to the metal ion in an ONS-tridentate manner, in the O-enolate/S-thione form. The electrochemical behavior of the thiosemicarbazones and their copper(II) complexes has been investigated at room temperature using the cyclic voltammetry technique in DMFA. The Cu(II)/Cu(I) redox system was found to be consistent with the quasi-reversible diffusion-controlled process.

Alcohol abuse can lead to alcoholic liver disease, becoming a major global burden. Hovenia dulcis fruit peduncle polysaccharides (HDPs) has the potential to alleviate alcoholic liver injury may play essential roles in treating for alcohol-exposed liver disease, however, the hepatoprotective effects and mechanisms remain unclear. In this study, the hepatoprotective effects of HDPs and its potential mechanisms were investigated in alcohol-exposed mice by liver metabolomics and gut microbiome. The results found that HDPs reduced medium-dose alcohol-caused dyslipidemia (significantly elevated T-CHO, TG, LDL-C), elevated liver glycogen levels and inhibited intestinal-hepatic inflammation (significantly decreased IL-4, IFN-γ and TNF-α), consequently reversing hepatic pathological changes. By applying gut microbiome analysis, HDPs showed significant decreases in Proteobacteria while significant increases in Firmicutes at the phylum level, and increased Lactobacillus abundance while decreased Enterobacteria abundance, maintaining the composition of gut microbiota. Further hepatic metabolomics analysis revealed that HDPs had a regulatory effect on hepatic fatty acid metabolism, by increasing the major metabolic pathways including arachidonic acid metabolism and glycerophospholipid metabolism and identified two important metabolites C00157 and C04230 involved in the above metabolism. Overall, HDPs reduced intestinal dysbiosis and hepatic fatty acid metabolism disorders in alcohol-exposed mice, suggesting that HDPs has a beneficial effect on alleviating alcohol-induced hepatic metabolic disorders.

APC mutation is the main driver mechanism of CRC development and leads to constitutively activated WNT signaling, overpopulation of ALDH+ stem cells (SCs), and incomplete differentiation. We previously reported that retinoic acid (RA) receptors are selectively expressed in ALDH+ SCs, which provides a way to target cancer SCs with retinoids to induce differentiation. Hypotheses: A functional link exists between WNT and RA pathways, and APC mutation generates a WNT:RA imbalance that decreases retinoid-induced differentiation and increases ALDH+ SCs. Accordingly, to restore parity in WNT:RA signaling, we induced wt-APC expression in APC-mutant CRC cells and assessed the ability of all-trans-retinoic acid (ATRA) to induce differentiation. Notably, ATRA substantially increased expression of the WNT-target gene, CYP26A1, and inducing wt-APC reduced this expression by 50%. Thus, RA and WNT pathways crosstalk to modulate CYP26A1 metabolism of retinoids. We found that inducing wt-APC augments ATRA-induced cell differentiation by: i) decreasing cell proliferation; ii) suppressing ALDH1A1 expression; iii) decreasing ALDH+ SCs; iv) increasing neuroendocrine cell differentiation. Furthermore, NanoString profiling/bioinformatics identified a novel CYP26A1-based network that links WNT and RA signaling. Moreover, CYP26A1 inhibitors sensitized CRC cells to the anti-proliferative effect of drugs that downregulate WNT signaling. Notably. in wt-APC-CRCs, decreased CYP26A1 improves patient survival. These findings have strong potential for clinical translation.

The critical enzyme Dihydrofolate Reductase-Thymidylate Synthase in Leishmania major (LmDHFR-TS) serves a dual-purpose role and is essential for DNA synthesis, a cornerstone of the parasite's reproductive processes. Consequently, the development of inhibitors against LmDHFR-TS is crucial for the creation of novel anti-Leishmania chemotherapies. In this study, we employed an in-house database containing 314 secondary metabolites derived from cinnamic acid that occurred in the Asteraceae family. We conducted a combined ligand/structure-based virtual screening to identify potential inhibitors against LmDHFR-TS. By consensus analysis of both approaches, we identified three compounds, i.e., lithospermic acid (237), diarctigenin (306), and isolappaol A (308), that exhibited a high probability of being inhibitors according to both approaches and were consequently classified as promising hits. Subsequently, we expanded the binding mode examination of these compounds within the active site of the test enzyme through molecular dynamics simulations, revealing a high degree of structural stability and minimal fluctuations in its tertiary structure. The in-silico predictions were then validated through in-vitro assays to examine the inhibitory capacity of the top-ranked naturally-occurring compounds against LmDHFR-TS recombinant protein. The test compounds effectively inhibited the enzyme with IC50 values ranging from 6.1 to 10.1 μM. In contrast, other common cinnamic acid derivatives (i.e., flavonoid glycosides) from the Asteraceae family, such as hesperidin, isovitexin 4′-O-glucoside, and rutin, exhibited low activity against this target. The selective index (SI) for all tested compounds was determined using HsDHFR, with moderate inhibitory effect. Among these hits, lignans 306 and 308 demonstrated the highest selectivity, displaying superior SI values compared to methotrexate, the reference inhibitor of DHFR-TS. Therefore, continued research into the anti-leishmanial potential of these C6C3-hybrid butyrolactone lignans may offer a brighter outlook for combating this neglected tropical disease.

Research conducted on individuals with depression reveals that major depressive disorders (MDDs) coincide with diminished levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain, as well as modifications in the subunit composition of the primary receptors (GABAA receptors) responsible for mediating GABAergic inhibition. Furthermore, there is substantial evidence supporting the significant role of GABA in regulating stress within the brain, which is a pivotal vulnerability factor in mood disorders. Although there is substantial evidence indicating that GABA may be affecting GABA receptors in peripheral tissues, there is comparatively less evidence supporting its direct action within the brain. Emerging evidence highlights that GABA may exert beneficial effects on the brain and psyche through the gut-brain axis. GABA is readily available and approved as a food supplement in many countries. While GABA enjoys wide consumer acceptance in Eastern Asian markets, with many consumers reporting favorable effects on stress regulation, mood, and sleep, rigorous independent research is still largely lacking. Basic research, coupled with initial clinical findings, makes GABA an intriguing neuro-nutritional compound deserving of clinical studies in individuals with depression and other psychological problems.

Zinc, being a part of many proteins and enzymes, plays an important role in the vital processes of the body. Racemic α-lipoic acid (LA) has a wide range of biological activities: antioxidant, antidiabetic, anticancer, and it is also used in diseases such as Parkinson's and Alzheimer's. Nowadays, the synthesis and structural studies of new zinc complexes with biologically active compounds are of great importance for drug discovery. This work shows the studies carried out on the synthesis, structure, identification, also biological activity using in silico methods of a complex compound based on LA and zinc. A complex compound of zinc with LA (ZnLA) was synthesized in the presence of LA and zinc acetate in ethanol. The identification of ZnLA by (FT-IR, XRD and TGA-DTA), also DFT calculations at the B3LYP/def2-TZVPP level of theory was performed. The molecular docking investigation involved docking ZnLA with two different protein receptors such us Glycogen phosphorylase (2GPA) and Kv potassium channel beta subunit (1ZSX) using CB-Dock 2 server and Auto-Dock Vina program to determine the mechanism of action and biological activity. This study reveals potential ligand-protein interactions at the atomic level and suggests that the treatment of diabetes (non-insulin dependent) with ZnLA.

Age-related macular degeneration, a leading cause of visual loss and dysfunction in the devel-oped world, is a disease initiated by genetic polymorphisms that impairs negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of SIGLEC medi-ated glyco-immune checkpoint parainflammatory homeostasis as a main determinant for the vi-sion impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte derived macrophages (PBMDM) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring gly-co-immune checkpoint control with a sialic acid mimetic nanoparticle targeting microgli-al/macrophage SIGLECs to regain retinal para inflammatory homeostasis is a promising thera-peutic that could halt the progression of and improve visual function in all stages of macular de-generation.

Saussurea neoserrata Nakai offers a reliable and efficient source of antioxidants that can help alleviate adverse skin reactions triggered by air pollutants. Air pollutants, such as particulate matter (PM), have the ability to infiltrate the skin and contribute to the higher occurrence of cardiovascular, cerebrovascular, and respiratory ailments. Individuals with compromised skin barriers are particularly susceptible to the impact of PM since it can be absorbed more readily through the skin. This study investigated the impact of protocatechuic acid and syringin, obtained from the n-BuOH extract of S. neoserrata Nakai, on the release of PGE₂ and PGD₂ induced by PM₁₀. Additionally, it examined the gene expression of enzymes involved in the synthesis of PGE₂ and PGD₂ in human keratinocytes. The findings of this research highlight the potential of utilizing safe and efficient plant-derived antioxidants in dermatological and cosmetic applications to mitigate the negative skin reactions caused by exposure to air pollution.

: Exploiting the relationship between the stacking modes of molecules and room-temperature phosphorescence (RTP) performance is of great important to design afterglow materials. A series of coordination polymers base on carbazole–isophtalic acid are synthesized. These compounds exhibit stacking-dependent RTP. It reveals that the phosphorescence efficiency is not proportional to the overlap of p–p stacking, the triplet excited states of discrete dimer mode rather than H-aggregation can dominate the generation of room-temperature phosphorescence. Besides, compounds 1 and 2 exhibit obvious time-dependent RTP with the afterglow color from orange to green, and show white-light emission owing to fluorescence and phosphorescence dual emission. These results indicate that coordination induction is an efficient approach to regulate the aggregation of chromophores, further modulate the room-temperature phosphorescence.

Due to its high specific surface area and rich porous structure, acacia-derived porous activated carbon is the most potentially effective material for wastewater treatment. This research study aimed to prepare activated carbon using Acacia erioloba seedpods as carbonaceous materials and phosphoric acid as an activating agent. The specific surface area of the prepared activated carbon sample was characterised by Brunauer–Emmett–Teller instrument. The specific surface area value was 387 m²/g. The activated carbon prepared was then sieved into three different particle sizes of 50, 100 and 200 micrometres and characterised using various analytical procedures, including proximate analysis to study moisture content, ash content, volatile matter content and fixed carbon content. The bulk density, SEM, power of hydrogen, iodine number and methylene blue number index were also investigated to determine the adsorption properties of the prepared activated carbon. Batch adsorption dynamics for the removal of organic compounds such as methylene blue and unsaturated character of fatty acid from aqueous solution were also carried out at room temperature to evaluate the prepared activated carbon's applicability in water treatment. The iodine number was 528, 638, and 554 mg/g for the 50, 100, and 200 μm activated carbon particles, respectively. From the results, the adsorption of methylene blue favoured the Freundlich adsorption model, showing higher correlation (R²) values than the Langmuir model. The results indicate that methylene blue particles were adsorbed on heterogeneous surfaces.

One of the most interesting groups of fatty acid derivates is the group of conjugated fatty acids, from which the most researched are conjugated linoleic acid (CLA) and conjugated linolenic acid (CLNA), which are associated with countless health benefits. Sex pheromone mixture of some insect species, including tobacco horn-worm (Manduca sexta), are typical for the production of uncommon C16 long conjugated fatty acids with two and three conjugated double bonds, as opposed to C18 long CLA and CLNA. In this study, M. sexta desaturases MsexD2 and MsexD3 were expressed in multiple strains of Y. lipolytica with different genotypes. Experiments with supplementation of fatty acid methyl esters into the medium resulted in production of novel fatty acids. Using GCxGC-MS 20 new fatty acids with two or three double bonds were identified. Fatty acids with conjugated or isolated double bonds or combination of both were produced in trace amounts. Results of this study prove that Y. lipolytica is capable of synthesizing C16 conjugated fatty acids. Further genetic optimization of the Y. lipolytica genome and optimization of the fermentation process could lead to increased production of novel fatty acid derivatives with biotechnologically interesting properties.

Arjunolic acid (AA) is a triterpenoid saponin majorly found in the Terminalia arjuna and is claimed to exert the cardiovascular protective effects as a phytomedicine. However, it is unclear how AA exerts the effects at the molecular level. Hence, this study used an in vitro model using lipopolysaccharide (LPS)-stimulated H9C2 and C2C12 myotubes to investigate the cardioprotective effects of arjunolic acid (AA) via MyD88-dependant TLR4 downstream signaling markers expression. The myotubes were developed by differentiating rat H9C2 and mouse C2C12 myoblast cells. The MTT viability assay was used to assess the cytotoxicity of AA. LPS induced in vitro cardiovascular disease model was developed in H9C2 and C2C12 myotubes. The treatment groups were designed such as control (untreated), LPS control, positive control (LPS+ pyrrolidine dithiocarbamate (PDTC)-25 µM), and treatment groups were co-treated with LPS and three doses of AA (50, 75, and 100 µM). The changes in the expression of TLR4 downstream signaling markers were evaluated through High Content Screening (HCS) and Western Blot (WB) analysis. The outcomes demonstrated that the expression of MyD88, MAPK, JNK, and NFκB markers were significantly upregulated in the LPS-treated groups compared to the untreated control. Evidently, the HCS analysis revealed that MyD88, NF-κB, p38, and JNK were significantly downregulated in the H9C2 myotube in the AA treated groups (50, 75, and 100 µM). For, the C2C12 myotube, the expression of NFκB was downregulated. TLR4 marker expression in H9C2 and C2C12 myotubes was subsequently decreased by AA treatment, suggesting possible cardioprotective effects of AA.

Modern technologies for recycling electronic waste (e-waste) impose high economic efficiency and environmental safety requirements. Among existing technologies, hydrometallurgy is considered the most promising technology for e-waste recycling. Increasing attention to the chlorination method is associated with the complex recycling of low-grade ores containing noble metals and secondary polymetallic raw materials. In this paper, we propose a new scheme for leaching metals from computer printed circuits (PCBs) pre-crushed in a disintegrator: the processes of chlorine production and hydrochlorination are implemented in one reactor under the action of alternating current (AC) of industrial frequency (50 Hz). It was found that complete leaching of gold is achieved from fine fractions of raw materials containing 0.03% and 0.01% of the gold at an experiment duration of 2 hours, a current density of 0.66 A·cm-2, and a solid/liquid ratio of 8.6 g·L-1. Under the same conditions of the electrochemical leaching process from the fraction of raw material with a gold content of 0.08%, the degree of metal leaching is 80.5%. At the same time, with an increase in the copper content in the raw material from 1.40% to 6.13%, an increase in the degree of its leaching from 84.6% to 95.2%, respectively, is observed. These results will serve as a foundation for developing a complex technology for recovering valuable metals from PCBs.

This study focused on the characterization of lactic acid bacteria (LAB) in a renowned traditional Italian cheese, Pecorino di Farindola, to select an autochthonous culture and investigate its po-tential for the improvement of safety and functional properties. Two hundred and six LAB isolated throughout production and maturation from nine cheese lots of three farms were identified by 16S rRNA gene sequencing and tested for the presence of genes encoding virulence factors, vancomycin resistance (for enterococci), biogenic amines (BAs) and bacteriocin production, for antimicrobial activity, and for the capacity to survive in the gastro-intestinal tract (GIT) based on tolerance to low pH and bile salts and adhesion to CaCo-2 cells. A Lacticaseibacillus paracasei isolate was used in cheese making and determined a decline of spiked Listeria monocytogenes and Escherichia coli O157 faster than in control cheese. The autochthonous bacterial groups were numerically unaffected, apart from lactobacilli that were recovered in higher numbers in the cheese with added L. paracasei. Based on Repetitive Extragenic Palyndrome (Rep) PCR profiles, the added strain possibly dominated until day 88 in cheese. Results encourage further trials with autochthonous cultures to efficiently inhibit hazardous bacteria and enrich a functional microbiota in Pecorino di Farindola and similar cheeses.

The experiments were designed to know the function of ascorbic acid against salinity on germination, different biochemical and micronutrients concentrations of Solanum melongena. Ascorbic acid was applied as foliar spray on leaves and given in roots through irrigation at 100 and 200 ppm to the plants growed in non saline, 60mM and 100mM salt stress conditions. Different biochemical parameters i.e. chlorophyll, carotenoids, carbohydratrates, protein and micro nutrients concentrations of Solanum melongena were observed under different salt stress concentrations from control (non-saline), 60mM NaCl and 100mM NaCl solutions. The rates of different biochemical parameters and micro nutrients concentrations exhibited decrease in saline media in comparison with their respective control while ascorbic acid used as a foliar spray and through irrigation in roots at the concentration of 100 ppm and 200 ppm resulted promotion in non saline control as compared with salt concentrations media. It was determined that chlorophyll concentration was decreased considerably under salt stress. Amongst micro nutrients ionic composition of Na, K and Na/K ratio resulted that plants treated with different NaCl concentrations at 60mM NaCl and 100mM salt concentrations showed increase in Na and K ions and ascorbic acid were used as a foliar spray and in roots showed decrease in Na and K ions. Overall from the outcomes of the study it was observed that salinity stress significantly decrease vegetative and reproductive parameters that could be improved with the using of ascorbic acid. Best concentration found were 200 ppm ascorbic acid contributed towards an increase in growth irrespective of non-saline and saline conditions. Based on these findings, ascorbic acid treatment helps in alleviating the negative effects of salinity.

The aim of this study was to investigate the effect of condensed tannin (CTs) with differing molecular weight on their capacity to modify the fatty acid profile in milk. Twenty multiparous crossbred lactating dairy goats were assigned in a randomized complete block design (RCBD), and were subjected to receive the dietary treatments as followings; T1: control (with no CTs supplementation), T2: supplemented with mangosteen peel in a concentrate as a source of low molecular weight CTs at level of 3.0 %DM of CTs equivalent, T3: supplemented with the same diet with T2 but added with polyethylene glycol (PEG, as tannin inactivator) as the control of T2, and T4: supplemented with quebracho CT extract (UNITAN ATO, Buenos Aires, Argentina; 75-77 % tannins) in a concentrate as a source of high molecular weight CTs at level of 3.0 %DM of CTs equivalent, and T5) supplemented with the same diet with T4 but added with PEG as the control of T4. No significant change was detected for feed intake and nutrient digestibility indicate that CTs at level of 3.0 %DM of diet did not showed the detrimental effect to feed intake and nutrient digestibility, however, ruminal fermentation parameters and milk yield and milk compositions did not affected by different source of CT inclusion.

Spike protein is the surface glycoprotein of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) necessary for the entry of the virus via the transmembrane receptors of the human endothelial cells of the respiratoty system for the virus to be engulfed causing COVID-19 disease after priming by type II transmembrane protease TMPRSS2 and then binding with the angiotensin-converting enzyme 2 (ACE2). Therefore, mutations and amino acid variants analysis are essential in understanding the mechanism of binding of spike protein with its receptor to have an insights on possibilities to design a peptide or nucleotide-based vaccine for COVID-19. Here, we employed Iterative Threading Assembly Refinement (I-TASSER) and Multiple Alignment using Fast Fourier Transform (MAFFT) to predict the three-dimensional monomer structure of spike protein of SARS-CoV-2 and to analyze the amino acid variants for protein sequences from GISAID database for samples collected from Jordan in a try to find an explanation for the low confirmed number of COVID-19 in Jordan. Our Protein Homology/analogY Recognition Engine V 2.0 (Phyre2) findings showed four single amino acid variants (SAV) found in 20 samples of SARS-CoV-2. What is equal to 5% of samples showed tyrosine deletion at Y144 located in the SARS-CoV-like_Spike_S1_NTD (N terminal domain), 62% showed aspartate substitution to glycine at D614G located in the SARS-CoV-2_Spike_S1_RBD (spike recognition binding site), 5% showed aspartate substitution to tyrosine at D1139Y and 5% showed glycine substitution to serine at G1167S both located in the Corona_S2 domain. The findings have shown lower mutational sensitivity in all variants that might not affect the function of spike glycoprotein except for D614G, which has the highest mutational sensitivity score (5 out of 9) indicating a higher likelihood to affect the function of the spike protein. This might suggest, in general, a reduced transmitability of SARS-CoV-2 in Jordan.

This study was aimed at investigating the protective effects of glass ionomer cement (GIC) and surface pre-reacted glass ionomer (S-PRG) fillers used as dental restorative materials on demineralization of bovine enamel. GlasIonomer FX ULTRA (FXU), Fuji IX GP Extra (FIXE), CAREDYNE RESTORE (CDR) were used as GICs. PRG Barrier Coat (BC) was used as the S-PRG filler. They were incubated in a lactic acid solution (pH = 4.0) for 6 d at a temperature of 37 °C. The mineral was etched from the enamel surface, and a large number of Ca and P ions were detected in solution. The Al, F, Na, Sr, and Sr ions were released in GICs and S-RPG fillers. The Zn ion was released only in CDR and the B ion was released only in BC. The presence of apparent enamel prism peripheries was observed after 6 d of treatment for the group containing only enamel blocks. pH values for the FXU, FIXE, CDR, BC, and enamel block groups after 6 d were 6.5, 6.6, 6.7, 5.9, and 5.1, respectively. Therefore, the observed pH neutralization effect suppressed progression of caries due to the release of several ions from the restoratives.

Background and objectives: This study were designed to determine uric acid concentration and renal histopathology of M. calabura L. stem bark extract in diabetic rats and to compare the natural product of M. calabura L. stem bark extract with allopurinol. Materials and Methods: A completely randomized design was used for the experiment which consisted of 6 treatment groups, each consisting of 4 rats, as follows: 1) NR, normal rat; 2) KN, diabetic rat (negative control); 3) KP, diabetic rats given allopurinol 10 mg/kg body weight; 4) EM150, diabetic rats given the test extract 150 mg/kg body weight/day; 5) EM300, diabetic rats given the test extract 300 mg/kg body weight/day; and 6) EM450, diabetic rats given the test extract 450 mg/kg body weight/ day. Results: The results showed that M. calabura L. stem bark extract decrease (p<0.05) uric acid levels in diabetic rats and no specific damage to renal proximal tubular cells was seen. Conclusions: It was concluded that M. calabura L. stem bark extract has a potential as an antihyperuricemic in diabetic rats. The recommended does was 300 mg/kg body weight to provide a significant effect on reducing the uric acid level in diabetic rats. Our findings support the use of this plant as a treatment for gout and other inflammatory diseases.

Our study aims to implement a strategy to reduce the carbon steel corrosion rate in sulfuric acid solution, using an expired drug with adsorption affinity on the metal surface. To investigate the corrosion protection efficiency of an environmental friendly inhibitor, namely neomycin sulfate (NMS), the electrochemical measurements were applied on carbon steel immersed in 1.0 M H₂SO₄ solution with and without NMS. The protective layer formed on the steel surface was studied by atomic force microscopy (AFM). The potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) showed that the presence of the neomycin sulfate in acid solution leads to the decrease in corrosion current density (i_corr) and the increase of polarization resistance (R_p). The mixed mechanism between physical and chemical adsorption of NMS molecules on the steel surface was proposed according to the Langmuir adsorption isotherm. The Atomic Force Microscopy (AFM) indicated that the NMS molecules contributed to a protective layer formation by their adsorption on the steel surface. The AFM parameters such as: root-mean-square roughness (R_q); average roughness (R_a) and maximum peak to valley height (R_p-v) revealed that in the presence of NMS a smoother surface of carbon steel was obtained, compared to the steel surface corroded in sulfuric acid blank solution.

Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

Background: Ubiquitination is an important post-transcriptional modification crucial for maintaining cell homeostasis. As a deubiquitination enzyme, ubiquitin-specific protease 1 (USP1) is associated with tumor progression; however, its role in bladder cancer is unknown. This study was aimed to analyze USP1 expression and study its roles in bladder cancer. Methods: The web server GEPIA was used to analyze the USP1 expression. To explore USP1 function in bladder cancer, we constructed USP1-knockout cell lines in UMUC3 cells. A FLAG-USP1 (WT USP1) plasmid and a plasmid FLAG-USP1 C90S (catalytic-inactive mutant) used to overexpress USP1 in T24 cells. CCK8, colony formation, and transwell assays were used to assess cell viability, proliferation and migration. RNA sequencing (RNA-seq) and dual-luciferase reporter assays were performed to screen the pathway. Coimmunoprecipitation and immunofluorescence were used to explore the interaction between USP1 and c-MYC. Xenograft mouse model was used to study the role of USP1 in bladder cancer. Results: USP1 expression is upregulated in human bladder cancer cells and correlated with poor patient prognosis. USP1 overexpression promoted cell proliferation, clone formation, and migration; this was attenuated by genetic ablation of USP1. Furthermore, we observed that USP1- deficiency inhibited tumor formation in vivo. Mechanistically, the c-MYC pathway was remarkably activated compared with the other pathways. Furthermore, USP1 could directly interact with c-MYC. and increase c-MYC stability depending on the catalytic activity of USP1. Conclusions: Our results suggest that high expression of USP1 promotes bladder cancer progression by stabilizing c-MYC; hence, USP1 it may serve as a novel therapeutic target for treating bladder cancer.

This study delves into a unique binary pattern found within the wellknown 3n+1 problem, or Collatz conjecture. Through careful analysis of the steps in the 3n+1 sequence, we have discovered a special binary representation that captures the behavior of all positive integers undergoing this transformation. With this new understanding, we have provided a solid proof confirming the validity of the 3n+1 problem for all positive integers. Our method goes beyond the need for extensive computational confirmation, providing a simple and elegant resolution to a long-standing mathematical mystery.

The C-X-C motif chemokine receptor-1 (CXCR1) is a rhodopsin-like G-protein-coupled receptor, expressed on the cell surface of immune cells and tumors. CXCR1 interacts with some C-X-C chemokines, such as CXCL6, CXCL7, and CXCL8/interleukin-8, which are produced by various cells. Since CXCR1 is involved in several diseases including tumors and diabetes mellitus, drugs targeting CXCR1 has been developed. Therefore, the development of sensitive monoclonal antibodies (mAbs) for CXCR1 has been desired for the diagnosis and treatment. This study established a novel anti-mouse CXCR1 (mCXCR1) mAb; Cx₁Mab-1 (rat IgG₁, kappa), using the Cell-Based Immunization and Screening (CBIS) method. Cx₁Mab-1 reacted with mCXCR1-overexpressed Chinese hamster ovary-K1 (CHO/mCXCR1) and mCXCR1-overexpressed LN229 glioblastoma (LN229/mCXCR1) in flow cytometry. Cx₁Mab-1 demonstrated a high binding affinity for CHO/mCXCR1 and LN229/mCXCR1 with a dissociation constant of 2.6×10^-9 M and 2.1×10^-8 M, respectively. Furthermore, Cx₁Mab-1 could detect mCXCR1 by western blot analysis. These results indicated that Cx₁Mab-1 is useful for detecting mCXCR1, and provides a possibility for targeting mCXCR1-expressing cells in vivo experiments.

Energy efficiency considerations in terms of reduced power dissipation is a significant issue in the design of digital circuits for very large-scale integration (VLSI) systems. Quantum-dot cellular automata (QCA) is an emerging ultra-low power dissipation approach, distinct from the traditional complementary metal-oxide semiconductor (CMOS) technology, for building digital computing circuits. Developing fully reversible QCA circuits has the potential to significantly reduce energy dissipation. The multiplexer is a fundamental element in the construction of useful digital circuits. In this paper, a novel, multilayer, fully reversible QCA 8:1 multiplexer circuit, with ultralow energy dissipation, is introduced. The proposed multiplexer power dissipation is simulated using the QCADesigner-E version 2.2 tool, describing the microscopic physical mechanisms underlying the QCA operation. The results showed that the proposed reversible QCA 8:1 multiplexer consumes 89% less energy than the most energy-efficient 8:1 multiplexer circuit presented previously in the scientific literature.

The Mediterranean diet (MED) is highly recommended. Medical nutrition therapy is the cornerstone of diabetes treatment. We assessed adherence to the MED, and resultant micronutrient intake and glycemic control in youth with type 1 diabetes. Twenty adolescents, median age 18 years (interquartile range: 15.5-21), median diabetes duration 9 years (7-14), using continuous glucose monitoring devices, received personalized diet regimes based on MED. At 6 months post-intervention, the caloric intake remained unchanged; however, the carbohydrate proportion was lower (p=0.058) and the intakes of some monounsaturated fats increased (p=0.049). Sodium intake exceeded the recommended daily allowance by 250% (p=0.653), before and after the intervention. For blood glucose, the percent time-in-range 70-180 mg/dL improved from 52% (38-60) to 63% (47-71) (p=0.047). The total insulin dose decreased marginally, from 0.76 u/kg (0.64-0.97) to 0.72u/kg (0.61-0.89) (p=0.067). BMI z-score and waist circumference did not change (p=0.316 and p=0.161, respectively). Diastolic blood pressure percentile decreased from 73% (68-88) to 69% (50-79) (p=0.028), and LDL cholesterol from 114mg/ dl (105-134) to 104mg/dl (96-124) (p=0.059). The Israeli Mediterranean diet screener score increased, from 8 (7-11) to 13 points (12-14) (p=<0.001). The MED-based intervention demonstrated feasibility and improvements in glycemic outcomes and in certain nutritional parameters.

A new one-pot technique for preparation of polysaccharide-based Pd- and Pd-Ag nanocatalysts by sequential supporting natural polymer (2-hydroxyethyl cellulose (HEC), chitosan (Chit), pectin (Pec)) and metals on zinc oxide was developed. The nanocatalysts based on polysaccharide were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET), infrared spectroscopy (IRS), X-ray powder diffraction (XRD), X-ray photoelectron spectra (XPS) and elemental analysis methods. The catalyst characterization results indicated complete adsorption of polysaccharide and metal ions on zinc oxide, forming polymer-stabilized Pd nanoparticles of ~2 nm in size, evenly distributed on the support surface. The catalysts were studied in the hydrogenation of 2-hexyn-1-ol under mild conditions (0.1 MPa, 40 °C). The catalysts demonstrated nearly the same conversion of 2-hexyn-1-ol. The selectivity to cis-hexen-1-ol of the catalysts decreases in the following order: 0.5%Pd-Ag(3:1)HEC/ZnO>0.5%Pd-Ag(3:1)Pec/ZnO>0.5%Pd-Ag(3:1)Chit/ZnO. The optimum reaction temperature and catalyst loading for the Pd-Ag catalysts modified with HEC and Chit have been determined (40 °C, 0.05 g).

DNA damage repair lies at the core of all cells’ survival strategy, including cancerous. Therefore, targeting such repair mechanisms forms the major goal of cancer therapeutics. The mechanism of DNA repair has been tousled with the discovery of multiple kinases. Recent studies on Tousled like Kinases have brought significant clarity on the effectors of these kinases which stands to regulate DSB repair. In addition to their well-established role in the DDR and cell cycle checkpoint mediation after DNA damage or inhibitors of replication, their suspected involvement in the actual DSB repair process has more recently been strengthened by the important finding that TLK1 phosphorylates RAD54 and regulates some of its activities and localization in the cell. Earlier findings of its regulation of RAD9 during checkpoint deactivation as well as defined steps during NHEJ ends processing were earlier hints of its important involvement broadly in DSB repair. All this has opened up new avenues to target cancer cells in combination therapy with genotoxins and TLK inhibitors.

Ostreid herpesvirus 1 (OsHV-1) is one of the most economically important pathogens of Pacific oysters. Understanding the pathogenesis of this virus is critical to developing tools to control outbreaks on shellfish farms. OsHV-1 is genetically related to vertebrate herpesviruses, which have a lytic and a latent stage, with the latent stage capable of being reactivated to the lytic stage. Here, OsHV-1 latency in Pacific oysters was investigated in experimentally and naturally infected oysters. Lytic infection in one-year-old oysters injected with the Tomales Bay strain of OsHV-1 was detectable between 1 and 4 days post-infection (dpi) but was not detectable after 5 dpi. The infected oysters shed 1102 to 1104 DNA copies/ml during the 4-day acute phase. At 21 dpi, the recovered oysters were temperature and chemically stressed and were found to shed 1104 to 1105 DNA copies/ml over a period of 48 h. Lytic shedding was not detectable in two-year-old oysters injected similarly with the same strain of OsHV-1; however, the OsHV-1 genome was detectable by qPCR in the adductor muscle, gill, mantle, and hemocytes within the first 3 dpi, after which it became undetectable. No OsHV-1 was detectable in the adductor muscle, gill, or mantle from experimentally infected oysters on days 15 and 21 post-infection or from oysters sampled 9 months after surviving an OsHV-1 mortality event; however, OsHV-1 DNA could be detected in hemocytes of both experimentally infected oysters at 21 dpi and naturally infected oysters. In addition, lytic viral gene transcription was detectable in hemocytes of experimentally infected oysters between 1 and 21 dpi and in hemocytes of naturally infected oysters.

Edaravone is a mitochondrially targeted drug with a suggested capability to modify the course of diverse neurological diseases. Nevertheless, edaravone has not been tested yet in the context of spinocerebellar ataxia 1 (SCA1), an incurable neurodegenerative disease characterized mainly by cerebellar disorder with a strong contribution of inflammation and mitochondrial dysfunction. This study aimed to address this gap, exploring the potential of edaravone to slow down SCA1 progression in a mouse knock-in SCA1 model. SCA1154Q/2Q and healthy SCA12Q/2Q mice were getting either edaravone or saline daily for more than 13 weeks. The functional impairments were assessed via a wide spectrum of behavioral assays reflecting motor and cognitive deficits and behavioral abnormalities. Moreover, we used high-resolution respirometry to explore mitochondrial function, and immunohistochemical and biochemical tools to assess the magnitude of neurodegeneration, inflammation and neuroplasticity. Data were analyzed using (hierarchical) Bayesian regression models combined with the methods of multivariate statistics. Our analysis pointed out various previously documented neurological and behavioral deficits of SCA1 mice. However, we did not detect any plausible therapeutic effect of edaravone on either behavioral dysfunctions or other disease hallmarks in SCA1 mice. Thus, our results did not provide support for the therapeutic potential of edaravone in SCA1.

The 3x+1 problem is a problem of continuous iteration for integers. According to the basic theorem of arithmetic and the way of iteration, we derive a general formula for continuous iteration for odd integers. Through this formula, we can construct a loop iteration equation and obtain the result of the equation: the equation has only one positive integer solution. In addition, this general formula can be converted into a linear indeterminate equation. The process of solving this equation shows that the relationship between the iteration result and the odd number being iterated is linear. Extending this result to all positive even numbers, we get the answer to the 3x + 1 question.

Dominance hierarchies are ubiquitous in invertebrates and vertebrates, but little is known on how genes influence dominance rank. Our gaps in knowledge are specifically significant concerning female hierarchies and in insects. To start filling these gaps we studied the social bumble bee Bombus terrestris, in which social hierarchies among females are common and functionally significant. Dominance rank in this bee is influenced by multiple factors, including juvenile hormone (JH) that is a major gonadotropin in this species. We tested the hypothesis that the JH responsive transcription factor Krüppel homologue 1 (Kr-h1) mediates hormonal influence on dominance behavior in the bumble bee. We first developed and validated a perfluorocarbon nanoparticles-based RNA interference protocol for knocking down Kr-h1 expression. We then used this procedure to show that Kr-h1 mediates the influence of JH not only on oogenesis and wax production, but also on aggression and dominance rank. To the best of our knowledge, this is the first study causally linking a gene to dominance rank in social insects, and one of only a few such studies in insects or in female hierarchies. These findings are important for determining whether there are general molecular principles governing dominance rank across gender and taxa.

The incidence of Type 1 Diabetes (T1D) in the Arab world, particularly, oil and gas rich Gulf Cooperative Council (GCC) countries has more than doubled in the last twenty years. Therefore, there is a dire need for careful systematic familial cohort studies, especially in high-risk populations. Several immunogenetic factors affect the pathogenesis of the disease. Genes in the human leukocyte antigen (HLA) account for the major genetic susceptibility to the disease. The triggering agents initiate disease onset by destruction of pancreatic β-cells. The autoantibodies against glutamic acid decarboxylase (GADA), insulinoma antigen-2 (IA-2A), insulin (IAA), and zinc transporter-8 (ZnT-8A) comprise the most reliable biomarkers for T1D in both children and adults. Although three of the GCC countries, namely Kuwait, Saudi Arabia and Qatar are among the top 10 countries with high incidence rate of T1D, no proper diagnostic and prediction tools were applied in the region. Understanding the disease sequelae in a homogenous gene pool with high consanguinity in the GCC could help solve the challenges in understanding pathogenesis, as well as hasten the prevention of T1D. Arab states must incorporate T1D predictive and intervention policies on a war-footing basis to minimize the burden of this serious disease.

Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.

Mangrove forests store and sequester large area-specific quantities of blue carbon (C_org). Except for tundra and peatlands, mangroves store more C_org per unit area than any other ecosystem. Mean mangrove C_org stock is 738.9 Mg C_org ha⁻¹ and mean global stock is 6.17 Pg C_org, which equates to only 0.4–7% of terrestrial ecosystem C_org stocks but 17% of total tropical marine C_org stocks. Seagrasses sequester more C_org per unit area than mangroves (179.6 g C_org m⁻²·a⁻¹) but twice the C_org sequestered by mangroves globally (15 Tg C_org a⁻¹). Mangroves sequester only 4% (range 1.3–8%) of C_org sequestered by terrestrial ecosystems, indicating that mangroves are a minor contributor to global C storage and sequestration. CO₂ emissions from mangrove losses equate to 0.036 Pg CO₂-equivalents a⁻¹ based on rates of C sequestration but 0.088 Pg CO₂-equivalents a⁻¹ based on complete destruction for conversion to aquaculture and agriculture. Mangrove CO₂ emissions account for only 0.2% of total global CO₂ emissions but 18% of CO₂ emissions from the tropical coastal ocean. Despite significant data limitations, the role of mangrove ecosystems in climate change mitigation is globally insignificant but may be more significant and effective at the national and regional scale.

Sentinel-1 (S1) extra-wide (EW) swath data in cross-polarization (horizontal-vertical, HV or vertical-horizontal, VH) are strongly affected by the scalloping effect and thermal noise, particularly over areas with weak backscattered signals, such as sea surfaces. Although noise vectors in both the azimuth and range directions are provided in the standard S1 EW data for subtraction, the residual thermal noise still significantly affects sea ice detection by the EW data. In this paper, we improve the denoising method developed in previous studies to remove the additive noise for the S1 EW data in cross-polarization. Furthermore, we propose a new method for eliminating the residual noise (i.e. multiplicative noise) at the sub-swath boundaries of the EW data, which cannot be well processed by simply subtracting the reconstructed 2-D noise field. The proposed method of removing both the additive and multiplicative noise was applied to EW HV-polarized images processed using different Instrument Processing Facility (IPF) versions. The results suggest that the proposed algorithm significantly improves the quality of EW HV-polarized images under various sea ice conditions and sea states in marginal ice zone (MIZ) of the Arctic. This is of great support for the utilization of cross-polarization SAR images in wide swaths for intensive sea ice monitoring in polar regions.

It has been demonstrated that a decrease in cellular adenosine triphosphate (c-ATP) causes cellular dysfunction. T-cells are not an exception. One of their roles is to properly detect and eliminate cancer cells. These processes occur at the expense of ATP. Therefore, it can be concluded that a decrease in c-ATP can defect T-cell function and promote cancer evolution. In this article, we provide a hypothesis to describe the correlation between the expression of PD-1 protein on T-cells and their c-ATP levels. Moreover, we present the possible predictive factors of Anti–PD(L)-1 therapy which has not yet been determined definitely.

Radio-fluorogenic (RFG) gels become permanently fluorescent when exposed to high-energy radiation with the intensity of the emission proportional to the local dose of radiation absorbed. An apparatus is described, FluoroTome 1, that is capable of taking a series of tomographic images (thin slices) of the fluorescence of such an irradiated RFG gel on-site and within minutes of radiation exposure. These images can then be compiled to construct a 3D movie of the dose distribution within the gel. The historical development via a laboratory-bench prototype to a readily transportable, user-friendly apparatus is described. Instrumental details and performance tests are presented.

Endothelial disorders are related to various diseases. An initial endothelial injury is characterized by endothelial glycocalyx injury. We aimed to evaluate endothelial glycocalyx injury by measuring serum syndecan-1 concentrations in patients during comprehensive medical examinations. A single-center, prospective, observational study was conducted at Asahi University Hospital. The participants enrolled in this study were 1313 patients who underwent comprehensive medical examinations at Asahi University Hospital from January 2018, to June 2018. One patient undergoing hemodialysis was excluded from the study. At enrollment, blood samples were obtained, and study personnel collected demographic and clinical data. No treatments or exposures were conducted except for standard medical examinations and blood sample collection. Laboratory data were obtained by collection of blood samples at the time of study enrolment. According to nonlinear regression, the concentrations of serum syndecan-1 were significantly related to age (p = 0.016), aspartic aminotransferase concentration (AST, p = 0.020), blood urea nitrogen concentration (BUN, p = 0.013), triglyceride concentration (p < 0.001), and hematocrit (p = 0.006). These relationships were independent associations. Endothelial glycocalyx injury, which is reflected by serum syndecan-1 concentrations, is related to age, hematocrit, AST concentration, BUN concentration, and triglyceride concentration.

Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. Using the PRISMA approach, we performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab. Sixty-three publications on 85 patients (mean age 66,9 years (range 34–86); male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3,6 (range 1–28). Symptoms included oculomotor (47%); respiratory (43%), bulbar (35%), and proximal weakness (35%); as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%) and a combination of these (16%). After critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 14% of patients had signs of additional NMDs. PD-1 inhibitor associated myasthenia was associated with cardiac complications in almost 30% of patients and with a more rapid clinical progression compared with idiopathic myasthenia. Mortality was high despite adequate treatment strategies including corticosteroid, IV immunoglobulins and plasmapheresis. In conclusion, clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with significant overlap between myasthenia gravis and myopathy; and cardiac/respiratory complications are common, leading to more severe disease courses than idiopathic myasthenia.

Contrary to optical images, Synthetic Aperture Radar (SAR) images are in different electromagnetic spectrum where the human visual system is not accustomed to. Thus, with more and more SAR applications, the demand for enhanced high-quality SAR images has increased considerably. However, high-quality SAR images entail high costs due to the limitations of current SAR devices and their image processing resources. To improve the quality of SAR images and to reduce the costs of their generation, we propose a Dialectical Generative Adversarial Network (Dialectical GAN) to generate high-quality SAR images. This method is based on the analysis of hierarchical SAR information and the “dialectical” structure of GAN frameworks. As a demonstration, a typical example will be shown where a low-resolution SAR image (e.g., a Sentinel-1 image) with large ground coverage is translated into a high-resolution SAR image (e.g., a TerraSAR-X image). Three traditional algorithms are compared, and a new algorithm is proposed based on a network framework by combining conditional WGAN-GP (Wasserstein Generative Adversarial Network - Gradient Penalty) loss functions and Spatial Gram matrices under the rule of dialectics. Experimental results show that the SAR image translation works very well when we compare the results of our proposed method with the selected traditional methods.

Mesenteric ischemia diagnosis is challenging with an overall mortality in up to 50% of cases despite advances in treatment. The main problem that affects the outcome is the delayed diagnosis because of non-specific clinical presentation. Multi Detector CT Angiography (MDCTA) is the first line investigation for the suspected diagnosis of vascular abdominal pathologies and is the diagnostic test of choice in suspected mesenteric bowel ischemia. MDCTA can accurately detect the presence of arterial and venous thrombosis, determine the extension and the gastrointestinal tract involved, and provide detailed information determining the subtype and the stage progression of the diseases helping clinicians and surgeons for the proper management. CT can differentiate forms that are still susceptible to pharmacological or interventional treatment (NOM= non-operative management) from advanced disease with transmural necrosis in which a surgical approach is required. Knowledge of CT imaging patterns and corresponding vascular pathways is mandatory in Emergency settings to reach a prompt and accurate diagnosis. The aims of this paper are 1. to provide technical information about the optimal CTA protocol; 2. To empathize the CTA arterial and venous supply to gastrointestinal tract and relative ischemic pattern; 3. To describe vascular, bowel and extraintestinal CT findings for the diagnosis of acute mesenteric ischemia.

An exposition is undertaken to reveal the significant impact of the time-dependent root parameter, on the stability of Pointwise Stationary Fluid Flow Approximation (PSFFA) model of the non-stationary queueing system. This opens new grounds to stability analysis of non-stationary queueing systems. Potential PSFFA applications of IoT are highlighted.

Glioblastomas (GBMs) are the most malignant and intractable of all cancers, with an unfavourable clinical prognosis for affected patients. The objective was analysis the sensitivity of GBM cells to the antimicrobial peptides (AMPs) cathelicidin (LL-37) and protegrin-1 (PG-1), both alone and in combination with chemotherapy, to predict overall survival (OS) in the patients. The study was conducted on 27 GBM patients treated in the neurosurgical departments of the Almazov Medical Research Centre (Saint-Petersburg, Russia) from 2021 to 2024. The cytotoxic effects of chemo-therapy, AMPs and their combinations on brain tumor cells were assessed by MTT assay using 50%-inhibitory concentration (IC50). In GBM cells from the patients, LL-37 and PG-1 exhibited strong anticancer effects, surpassing those of chemotherapy drugs. These LL-37 and PG-1 anti-cancer effects were associated with a statistically significant increase in life expectancy and OS in GBM patients. These findings were confirmed by the experiments on rats with C6 glioma, where intranasal administration of LL-37 (300 μM) and PG-1 (600 μM) increased the life expectancy of the animals to 69 and 55 days, respectively, compared to 24 days in the control group (HR=4.139, p=0.0005; HR=2.542, p=0.0759). Additionally, the combination of LL-37 and PG-1 with chemo-therapy drugs showed that a high IC50 of LL-37 with cisplatin (cutoff >800 μM) in GBM cells was associated with increased life expectancy (19 vs 5 months, HR=4.708, p=0.0101) and OS in GBM patients. These combinations could be used in future GBM treatments.

Foliage-feeding fall armyworm (Spodoptera frugiperda) and root-feeding western corn rootworm (Diabrotica virgifera virgifera) are maize (Zea mays L.) pests that cause significant yield losses. Jasmonic acid (JA) play pivotal defense role against insects. 12-oxo-phytodienoic acid (12-OPDA) is converted into JA by peroxisome-localized OPDA reductases (OPR). However, little is known about the physiological functions of cytoplasmic OPRs. Here, we show that disruption of ZmOPR2 reduced wound-induced JA production and defense against FAW while accumulating more JA catabolites. Overexpression of ZmOPR2 in Arabidopsis enhanced JA production and defense against beet armyworm (Spodoptera exigua). In addition, lox10opr2 double mutants were more susceptible than either single mutant, suggesting that ZmOPR2 and ZmLOX10 uniquely and additively contributed to defense. In contrast to the defensive role of ZmOPR2 and ZmLOX10 in leaves, single mutants did not display any alteration in root herbivory defense against WCR. Feeding on lox10opr2 double mutants resulted in increased WCR mortality associated with greater herbivory-induced production of insecticidal death acids and ketols. Thus, ZmOPR2 and ZmLOX10 cooperatively inhibit synthesis of these metabolites during herbivory by WCR. We conclude that ZmOPR2 and ZmLOX10 regulate JA-mediated resistance in leaves against FAW while suppressing insecticidal oxylipin synthesis in roots during WCR infestation.

Acid stress poses a common challenge for bacteria in diverse environments by the presence of inorganic (e.g., mammals’ stomach) or organic acids (e.g., feed additives; acid-based disinfectants). Limited knowledge exists regarding acid-tolerant strains of specific serotypes, clonal lineages, or sources in human/animal pathogens, namely non-typhoidal Salmonella enterica (NTS) and Enterococcus faecium (Efm). This study evaluated acidic pH and peracetic acid (PAA) susceptibility of Efm (n=72) and NTS (n=60) from diverse epidemiological/genetic backgrounds, and with multiple antibiotic resistance profiles. Efm minimum growth/survival-pH was 4,5-5/3-4 and for NTS 4,0-4,5/3,5-4,0. Among Efm, only those of clade-non-A1 (non-hospital associated) or food chain demonstrated greater tolerance to acidic pH compared to clade-A1 (hospital-associated clones) or clinical isolates (P<0.05). MDR (multidrug-resistant) NTS survived better to acidic pH (P<0.05). The MICPAA/MBCPAA was 70-120/80-150mg/L for Efm and 50-70/60-100mg/L for NTS. Efm-clade-A1 or MDR strains exhibited higher PAA tolerance than clade-non-A1 or non-MDR ones (P<0.05). Higher tolerance was found in non-MDR and clinical NTS than in food chain isolates (P<0.05), but not between different serogroups. This unique study identifies specific NTS or Efm populations more tolerant to acidic pH or PAA, emphasizing the need for further research to tailor control measures of public health and food safety within a One Health framework.

Kummerowia striata is a traditional medicine used for the therapy of inflammation-related diseases. Herein, we investigated the anti-melanogenic and antioxidant activities of an ethanolic extract of K. striata (EKS) using a number of in vitro and cell culture model systems. The anti-melanogenic effect was assessed in B16F10 melanoma cells based on melanin synthesis and in vitro tyrosinase inhibitory activity and the anti-oxidant activity assays were performed using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2ʹ-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS); EKS exhibited strong anti-oxidant activities in both the assays. The expression of tyrosinase, tyrosinase-related protein 1, tyrosinase-related protein 2, and microphthalmia-associated transcription factor was decreased in a dose-dependent manner at mRNA and protein levels upon treatment with EKS. Notably, EKS did not affect the cell viability at all the EKS concentrations used in this study, indicating that EKS-mediated inhibition of melanin synthesis is not accompanied with cytotoxicity. Collectively, our findings demonstrate, for the first time, that EKS possesses anti-melanogenic and anti-oxidant activities, and suggest that further evaluation and development of EKS as a functional supplement or cosmetic might be useful for skin whitening and for reduction wrinkles.

Background. Escherichia coli commonly causes catheter-related bloodstream infection (C-RBSI) in specific populations. The differential time to positivity (DTTP) technique is the recommended conservative procedure for diagnosing C-RBSIs. Methods. We conducted a retrospective study of episodes in which E. coli was isolated from catheter lumens obtained using the DTTP technique. We analysed microbiological and clinical data based on the DTTP technique as either catheter colonization, C-RBSI, or non-C-RBSI. Results. We included 89 catheter blood cultures classified as follows: catheter colonization, 33.7%; C-RSBI, 9.0%; and non-C-RBSI, 57,3%. Catheter withdrawal was 15.7% without positive catheter-tip cultures. We found no statistically significant differences in catheter type, antibiotic treatment, or clinical outcome among groups, except for the frequency of catheter lock therapy or in the frequency of successful treatment. Mortality was associated with C-RBSI in only 1 patient. Conclusion. E. coli bacteremia diagnosed by the DTTP technique was non-catheter related in most patients. As the majority of the catheters were retained, E. coli bacteremia could not be microbiologically confirmed or ruled out as catheter related by catheter-tip culture. Future studies are needed to assess the profitability of the DTTP technique for diagnosing E. coli C-RBSIs..

Background: We investigated the tumor immune response in gastric cancer patients receiving third line nivolumab monotherapy to identify immune-related biomarkers for better patient se-lection. Methods: Nineteen patients (10 males, median age 67 years) who received nivolumab as a third or later line therapy were enrolled. We analyzed the tumor immune response in durable clinical benefit (DCB) and non-DCB patients. Pre-treatment and early-on-treatment tumor transcriptomes were examined, and gene expression profiles, immunograms, and T cell receptor (TCR) repertoire were analyzed. Results: DCB was observed in 15.8% of patients, with comparable secondary endpoints (ORR, OS, PFS) to previous trials. Individual immunograms showed no significant changes before and ear-ly-on-treatment, nor consistent alterations among DCB cases. The intratumoral immune response was suppressed by previous treatments in most third or later line nivolumab recipients. TCR repertoire analysis revealed newly emerged clonotypes in on-treatment tumors, but clonal re-placement did not impact efficacy. High T cells/Tregs ratios and a low UV radiation response gene signature were linked to DCB and treatment response. Conclusions: This study emphasizes the tumor immune response's importance in nivolumab ef-ficacy for gastric cancer. High T cells/Tregs ratios and specific gene expression signatures show promise as potential biomarkers for treatment response. Larger cohort validation is crucial to optimize immune checkpoint inhibitors in gastric cancer treatment.

Paratuberculosis (PTB) is a chronic granulomatous enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP) that affects a wide variety of domestic and wild animals. It is considered as one of the diseases with the highest economic impact in the ruminant industry. Despite many efforts and intensive research, PTB control is still controversially discussed and diagnostic and immunoprophylactic tools lack great limitations. Thus, models play a crucial role in understanding the pathogenesis of infection and disease, and in testing novel vaccine candidates. Here, we review the potential and limitations of different experimental approaches currently used in PTB research, focusing on laboratory animals and cell based models. The aim of this review is to offer a vision of the models that have been used and what has been achieved or discovered with each one so that the reader can choose the best model to answer their scientific questions and prove their hypotheses. Also, we bring forward new approaches that we consider worth exploring in the near future.

Soybean are vulnerable to drought and temperature increases potentially induced by climate change. The purpose of this study was to determine if the use of cover crops (CC) can influence the gas exchange potential of glyphosate tolerant soybean when the vapor pressure deficit (Vpd) increases. This two years study was conducted in an open experimental field comprising Direct Seeding plots without CC (DS) or with CC (DSCC). Stomatal conductance (Gs) was measured five times on the same identified leaves following GBH application. These leaves were then collected in order to observe the stomata (size, density and stomatal index) with a scanning electron microscope and to perform measurements on foliar traits (venation density, width of midrib). The Vpd was calculated concomitantly to Gs measurements at the leaf surface. The results suggest that the use of CC promotes phenotypic change in soybean leaves (more elaborate venation and a higher stomatal density), which in turn may enhance their tolerance to drier conditions. In 2019, Gs could be up to 29% higher in DSCC plots compared to DS ones along with similar Vpd values. This study shows that the benefits of using CC can be observed through the morphological development strategies of the crop plants and their higher tolerance to drought.

Human bocavirus (HBoV) is an emerging virus that has been detected worldwide that could be associated with cases of acute gastroenteritis (AGE). However, its contribution to AGE has not been elucidated. This study aimed to describe the frequency, clinical features, and HBoV genotypes circulation in children up to 5 years with or without AGE symptoms in Acre, Northern Brazil. A total of 480 stool samples were collected between January and December 2012. Fecal samples were used for extraction, nested PCR amplification, and sequencing for genotyping. Statistical analysis was applied to verify the association between epidemiological and clinical characteristics. Overall HBoV-positivity was 10% (48/480), being HBoV-positivity rates of 8.4% (19/226) and 11.4% (29/254) recorded among diarrheic and non-diarrheic children, respectively. The most affected age group was between 7 and 24 months (50%). HBoV infection was more frequent in children living in urban areas (85.4%), using water from the public network (56.2%), and living with adequate sewage facilities (50%). Co-infection with other enteric viruses was 16.7% (8/48) and the most prevalent coinfection was RVA+ HBoV (50%, 4/8). HBoV‐1 was the most frequent species detected, responsible for 43.8% (21/48) of cases, followed by HBoV-3 (29.2%, 14/48) and HBoV-2 (25%, 12/48). In the present study, HBoV infections are not associated with AGE, as most HBoV cases belonged to the non-diarrheal group without AGE symptoms. Future studies are warranted to determine the role of HBoV in causing acute diarrhea disease.

Commonly employed methods for reversibly disrupting gene expression, such as those based on RNAi or CRISPRi, are rarely capable of achieving >80-90% downregulation, making them unsuitable for targeting genes that require more complete disruption to elicit a phenotype. Genetic deletion, on the other hand, while enabling complete disruption of target genes, often produces undesirable irreversible consequences such as cytotoxicity or cell death. Here we describe the design, development and detailed characterization of a dual-function "TRE-Lox" system for effecting either (a) doxycycline (Dox)-mediated downregulation or (b) genetic deletion of cathepsin D (CatD), based on targeted insertion of a tetracycline-response element (TRE) and two LoxP sites into the 5' end of the endogenous gene (CTSD). Using an optimized reverse-tetracycline transrepressor (rtTR) variant fused with the Krüppel-associated box (KRAB) domain, we show that CatD expression can be disrupted by as much as 98% in mouse embryonic fibroblasts (MEFs). This system is highly sensitive to Dox (IC50 = 1.46 ng/mL) and results in rapid (t1/2 = 0.57 d) and titratable downregulation of CatD. Notably, even near-total disruption of CatD expression was completely reversed by withdrawal of Dox. As expected, transient expression of Cre recombinase results in complete deletion of the CTSD gene. The dual functionality of this novel system will facilitate future studies of the involvement of CatD in various diseases, particularly those attributable to partial loss of CatD function. In addition, the TRE-Lox approach should be applicable to the regulation of other target genes requiring more complete disruption than can be achieved by traditional methods.

Indirect imaging methods involve at least two steps, namely optical recording, and computational reconstruction. The optical recording process uses an optical modulator that transforms the light from the object into a typical intensity distribution. This distribution is numerically processed to reconstruct the object’s image corresponding to different spatial and spectral dimensions. There have been numerous optical modulation functions and reconstruction methods developed in the past years for different applications. In most cases, a compatible pair of optical modulation function and reconstruction method gives optimal performance. A new reconstruction method termed non-linear reconstruction (NLR) was developed in 2017 to reconstruct the object image in the case of optical scattering modulators. During the years, it was revealed that the NLR could reconstruct an object’s image modulated by an axicons, bifocal lenses and even exotic spiral diffractive elements, which generate deterministic optical fields. Apparently, NLR seems to be a universal reconstruction method for indirect imaging. In this review, the performance of NLR has been investigated for many deterministic and stochastic optical fields. Simulation and experimental results for different cases are presented and discussed.

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

Background: This study aimed to evaluate the burden and impact of cardiac and cerebrovascular disease (CCD) on hospital inpatients with type 1 diabetes mellitus (T1DM). Methods: This is a retrospective nationwide cohort study of people with T1DM with or without CCD in the US National Inpatient Sample between 2016 to 2019. The in-hospital mortality rates, length of stay (LoS) and healthcare costs were determined. Results: A total of 59,860 T1DM patients had a primary diagnosis of CCD and 1,382,934 did not. The median LoS was longer for patients with CCD compared to no CCD (4.6 vs. 3 days). Patients with T1DM and CCD had greater in-hospital mortality compared to those without CCD (4.1% vs. 1.1%, p&lt;0.001). The estimated total care cost for all patients with T1DM with CCD was approximately US $326 million. The adjusted odds of mortality compared to patients with non-CCD admission was greatest for intracranial hemorrhage (OR 17.37, 95%CI 12.68-23.79), pulmonary embolism (OR 4.39, 95%CI 2.70-7.13), endocarditis (OR 3.46, 95%CI 1.22-9.84), acute myocardial infarction (OR 2.31, 95%CI 1.92-2.77) and stroke (OR 1.47, 95%CI 1.04-2.09). Conclusions: The burden of CCD in patients with T1DM is substantial and significantly associated with increased hospital mortality and high healthcare expenditures.

Ozonated sunflower oil (OSO) is an established therapeutic agent and nutraceutical harboring various therapeutic values, including antiallergic, derma-protective, and broad-spectrum antimicrobial activity. Conversely, the medicinal aspects of OSO for wound healing, tissue regeneration, and treatment of inflammation in dyslipidemia have yet to be fully elucidated. Herein, a comparative effect of OSO and sunflower oil (SO) was investigated to heal cutaneous wound and tissue regeneration of zebrafish impediment by carboxymethyllysine (CML) toxicity, following impact on hepatic inflammation and blood lipid profile. After OSO (final 2%, 1 μL) and SO's (final 2%, 1 μL) treatment, substantial healing was elicited by OSO in the cutaneous wound of zebrafish impaired by CML (final 25 mg). As an important event of wound healing, OSO scavenges the reactive oxygen species (ROS), rescues the wound from oxidative injury, and triggers the essential molecular events for the wound closer. Furthermore, the intraperitoneal injection of OSO was noted to counter the CML-induced adversity and prompt tissue regeneration in the amputated tail fin of zebrafish. Additionally, OSO counters the CML-induced neurotoxicity and rescues the zebrafish from acute mortality and paralysis, along with meticulous recovery of hepatic inflammation, fatty liver changes, and diminished ROS and proinflammatory interleukin (IL)-6 production. Besides, OSO efficiently ameliorated CML-induced dyslipidemia by alleviating the total blood cholesterol (TC), triglyceride (TG) and increasing high-density lipoproteins cholesterol (HDL-C). The outcome of multivariate assessment employing principal component analysis and hierarchical cluster analysis supports a superior therapeutic potential of OSO over SO against the clinical manifestation of CML. Conclusively, OSO owing to its antioxidant and anti-inflammatory potential, counters CML-induced toxicity and promotes wound healing, tissue regeneration, hepatoprotection, improved blood lipid profile, and survivability of zebrafish.

Hubble diagrams are examined for SN1a supernovae in the redshift range z = 0.01–1.3 and for gamma ray bursts in the range z = 0.034–8.1. It is shown that in the low redshift range, the Hubble diagram shows an innate equivocality between the ΛCDM and the tired light model. This means that the strong agreement between the z/µ data, calculated with the parameters of the ΛCDM model, and the experimentally measured z/µ values cannot be considered as definite evidence for the expansion hypothesis. The exponential function , which is characteristic of the tired light redshift mechanism, fits the data with similarly high accuracy. Hence, on the premise of low redshift data, a decision for or against either model is completely arbitrary. The Hubble diagram for high redshift gamma ray bursts shows poor agreement with the ΛCDM model, but concurs with the exponential energy decay following from the tired light redshift hypothesis.

Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). Dotinurad selectively inhibits URAT1 and do not inhibit other UA transporters such as GLUT9, ATP-binding cassette transporter G2 (ABCG2) and organic anion transporter1/3 (OAT1/3). We discovered that dotinurad improved metabolic parameters and renal function in hyperuricemic patients. We consider a significance of high selectivity in inhibiting URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dotinurad inhibits selectively URAT1 and increases UA in the proximal tubules, and UA may compete with glucose for GLUT9, reducing glucose reabsorption. The inhibition of UA entry via URAT1 to liver and adipose tissues by dotinurad increased energy expenditure and decrease lipid synthesis and inflammation in rats. The inhibition of URAT1 in kidney, liver and adipose tissues improve metabolic parameters. CKD patients accumulate uremic toxins such as indoxyl sulfate (IS) in the body. ABCG2 regulates renal and intestinal excretion of IS which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into kidney, increasing plasma IS, which produces oxidative stress, inducing vascular endothelial dysfunction in CKD patients. The high-selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD and CVD.

Powder metallurgy is a preferred manufacturing method in various industries because it offers design flexibility, material efficiency and a cost-effective production. In this work, we study the effects of different compaction directions on the strength of parts produced by powder metallurgy. Al–4wt.%Cu alloys are used due to their recyclability, and three distinctive compaction pressures are applied, resulting in two sample groups. One group is air-cooled after sintering, while the other is water-quenched and naturally aged (T4 temper). Both the compressive and tensile strengths are measured and analyzed. The study reveals that both heat treatments and compaction directions significantly influence anisotropic strengths. The novelty of this research lies in the use of powders that can be reused from machining, turning, or foundry rejection. By omitting or reducing the melting stage and employing simple powder metallurgy, the cost-effective and environmentally friendly processes are achieved. The planning of compaction load, compaction direction, and heat treatments is found to play a crucial role in determining the final mechanical performance. Notably, this approach aligns with the environmental, social and governance (ESG) practices that have been increasingly adopted by industry.

A novel group of conjugative plasmids of Pseudomonas is characterized. The prototype plasmid pPPUT-Tik1-1 (153663 bp), isolated from a permafrost strain of P. putida Tik1, carries a defective mercury transposon Tn501 and a streptomycin resistance transposon Tn5393. Ten plasmids and 34 contigs with backbone regions closely related to pPPUT-Tik1-1 have been found in Gene Bank. Two of these plasmids isolated from clinical strains of P. putida and P. fulva are almost identical to the ancient plasmid. A characteristic feature of this group of plasmids is the presence of two genes encoding the initiators of replication (repA1 and repA2). None of these genes has high similarity with plasmid replication genes belonging to known incompatibility groups. It has been demonstrated that while pPPUT-Tik1-1-like plasmids have homologous backbone regions they significantly differ by the molecular structure and the functional burden of their accessory regions. Some of the pPPUT-Tik1-1-related plasmids carry determinants of antibiotic resistance and/or heavy metal salts. Some plasmids are characterized by the ability to degrade xenobiotics. Plasmids related to pPPUT-Tik1-1 are characterized by a narrow host range and are found in various species of Pseudomonas genus. A group of shortened plasmids containing the same replication module, but without conjugation genes, were also found. These plasmids also contain other structural changes that strongly distinguish them from plasmids related to pPPUT-Tik1-1. The data obtained indicate the need for a complex approach to the classification of plasmids.

PSD-95 (Dlg4) is an ionotropic glutamate receptor scaffolding protein essential in synapse stability and neurotransmission. PSD-95 levels are reduced during aging and in neurodegenerative diseases like Huntington’s disease (HD), and it is believed to contribute to synaptic dysfunction and behavioral deficits. However, the mechanism responsible for PSD-95 dysregulation under these conditions is unknown. The Heat Shock transcription Factor 1 (HSF1), canonically known for its role in protein homeostasis, is also depleted in both aging and HD. Synaptic protein levels, including PSD-95, are influenced by alterations in HSF1 levels and activity, but the direct regulatory relationship between PSD-95 and HSF1 has yet to be determined. Here, we showed that HSF1 chronic or acute depletion in cell lines and mice decreased PSD-95 expression. Furthermore, HSF1(+/-) mice had reduced PSD-95 synaptic puncta that paralleled a loss in thalamo-striatal excitatory synapses, an important circuit disrupted early in HD. We demonstrated that HSF1 binds to regulatory elements present in the PSD-95 gene and directly regulates PSD-95 expression. HSF1 DNA-binding on the PSD-95 gene was disrupted in an age-dependent manner in WT mice and worsened in HD cells and mice, leading to reduced PSD-95 levels. These results demonstrate a direct role of HSF1 in synaptic gene regulation that has important implications in synapse maintenance in basal and pathological conditions.

The proportion of area under various crops at a given point in time, known as a cropping pattern, plays an essential role in determining the level of agricultural production. In this study, cropping patterns of three sub-counties in Murang’a County, a typical African smallholder farming area in Kenya, were mapped. Specifically, we compared the performance of eight classification scenarios for mapping cropping patterns; namely using (i) only Sentinel-2 reflectance bands (S2), (ii) S2 and S2 derived vegetation indices (VIs); (iii) S2 and S2 vegetation phenology (VP); (iv) S2 and Sentinel-1 radar backscatter data (S1); (v) S2, VIs, and S1; (vi) S2, VP, and S1; (vii) S2, VIs and VP, and (viii) S2, VIs, VP and S1. Reference data of the dominant cropping patterns and non-croplands were collected. The guided regularized random forest (GRRF) algorithm was used to select the optimum variables and to perform the respective classification for each scenario. The most accurate result of the overall accuracy of 93.16% was attained from the scenario (viii) S2, VIs, VP, and S1. The McNemar’s test of significance did not show significant differences (p≤0.05) among the tested scenarios. Our study demonstrated the strength of GRRF and the synergetic advantage of S2 and S1 derivatives to map cropping patterns in a heterogeneous landscape where high resolution imagery are inaccessible. Our cropping pattern mapping approach can be used in other sites of relatively similar agro-ecological conditions.

Due to the SARS-CoV-2 pandemic a shortage of personal protective equipment, including surgical facemasks and Filtering Facepiece Particle Respirators has occurred. SARS-CoV-2 has a 79,5-82% homology to SARS-CoV. The SARS-CoV UVC sensitivity is described in literature. We have performed UVC transmission measurements of surgical facemasks and respirators. In addition, we performed UVC disinfection experiments of S. aureus with surgical facemasks and respirators. Results show that we can achieve an 8-log reduction of S. aureus in the inner layers of FFP1 respirators and the exterior of surgical facemasks. Furthermore, we showed a 7-log reduction of S. aureus in the inner layers of FFP2 respirators. We conclude that UVC disinfection is an effective, safe and scalable method for reuse of surgical facemask and respirators.

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca²⁺/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca²⁺/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca²⁺] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

To investigate the composition of caproic acid-producing bacterial communities in sub-high-temperature Daqu, we analyzed four different Daqu samples from Sichuan. After enriching the samples with a specialized medium, we performed high-throughput sequencing of 16S rRNA gene amplicons on the metagenomic DNA from both the Daqu samples and the enrichment cultures. Our analysis focused on identifying and characterizing the caproic acid-producing bacterial communities present in Daqu. The results revealed that enrichment increased both the diversity and abundance of potential caproic acid-producing bacteria in Daqu. The predominant caproic acid-producing bacteria, with a relative abundance greater than 1%, included Clostridium sensu stricto 18 (2.19% to 69.00%), Clostridium sensu stricto 15 (1.76% to 7.65%), as well as smaller amounts of Clostridium sensu stricto 12, Clostridium sensu stricto 1, Clostridium sensu stricto 10, Clostridium sensu stricto 7, and Caproiciproducens. Specifically, Q1 Daqu was characterized by the presence of Clostridium sensu stricto 18 and Clostridium sensu stricto 15. Q2 Daqu featured Clostridium sensu stricto 1, Caproiciproducens, and Clostridium sensu stricto 18. Q3 Daqu included Clostridium sensu stricto 18 and Caproiciproducens. Q4 Daqu contained Clostridium sensu stricto 18 and Clostridium sensu stricto 1. These findings indicate that there are variations in the composition of caproic acid-producing bacterial communities among different sub-high-temperature Daqu samples from Sichuan. This preliminary analysis provides a theoretical basis for further studies on caproic acid bacteria in Daqu and offers insights into the development of high-quality Daqu, which may enhance the quality of Nongxiangxing liquor.

Isothermal Nucleic Acid Amplification based-Lateral Flow Testing (INAA-LFT) has emerged as a robust technique for on-site pathogen detection, providing a visible indication of pathogen nucleic acid amplification that rivals or even surpasses the sensitivity of real-time quantitative PCR. The isothermal nature of INAA-LFT ensures consistent conditions for nucleic acid amplification, establishing it as a crucial technology for rapid on-site pathogen detection. However, despite its considerable promise, the widespread application of isothermal INAA amplification-based lateral flow testing faces several challenges. This review provides an overview of the INAA-LFT procedure, highlighting its advancements in detecting plant viruses. Moreover, the review underscores the imperative to address existing limitations and emphasizes ongoing research efforts dedicated to enhancing the applicability and performance of this technology in the realm of rapid on-site testing.

In recent decades, given the important role of gamma-aminobutyric acid (GABA) in human health, scientists have paid great attention to the enrichment of this chemical compound in food using various methods, including microbial fermentation. Moreover, GABA or GABA-rich products have been successfully commercialized as food additives or functional dietary supplements. Several microorganisms can produce GABA, including bacteria, fungi, and yeasts. Among GABA-producing bacteria, lactic acid bacteria (LAB) are commonly used in the production of many fermented foods. Lactiplantibacillus plantarum (previously Lactobacillus plantarum) has a long history of natural occurrence and safe use in a variety of food products. This LAB species provides functional properties to various fermented foods by producing a variety of bioactive compounds, including GABA. The present review aims, after a preliminary excursus on the function and biosynthesis of GABA, to provide an overview on the current uses of microorganisms and in particular of L. plantarum in the production of GABA, with a detailed focus on fermented foods.

The accumulation of loss of function mutations in the uricase gene well explains the high urate levels in hominoids (apes and humans) compared to other mammals. The loss of human uricase activity may have allowed humans to survive environmental stressors, evolution bottlenecks, and life-threatening pathogens. While high urate levels may contribute to developing cardiometabolic disorders such as hypertension and insulin resistance, low urate levels may increase the risk for neurodegenerative diseases. The double-edged sword effect of uric acid has resurrected a growing interest in the antioxidant role of urate and the role of the uricase gene in modulating the risk of obesity. Characterizing both the effect of uric acid levels and the uricase gene in different animal models may provide new insights into the potential therapeutic benefits of uric acid and novel uricase-based therapy.

Polyphenol ellagic acid (EA) possesses anti-oxidant, anti-inflammatory, anti-carcinogenic, anti-diabetic and cardio protection activities, remarking it an interesting multi-targeting profile. EA also controls the central nervous system (CNS) since it was proven to reduce the immobility time of mice in both the forced swimming and the tail-suspension tests, with an efficiency comparable to that of classic antidepressants. Interestingly, the anti-depressant-like effect was almost nulled by the concomitant administration of selective antagonists of the noradrenergic receptors, suggesting the involvement of these cellular targets in the central effects elicited by EA and its derivatives. By in silico and in vitro studies, we discuss how EA engages with human α2A-ARs and α2C-AR catalytic pockets, comparing EA behaviour with those ones of known agonist and antagonist. Structurally, the hydrophobic residues surrounding α2A-AR pocket confer specificity on the intermolecular interactions and hence lead to favourable binding of EA in the α2A-AR, with respect to α2C-AR. Moreover, EA seems to better accommodate within α2A-ARs into TM5 area, closely to S200 and S204 which play a crucial role for activation of aminergic GPCRs such as the α2-AR, highlighting its promising role as a partial agonist. Consistently, EA mimics clonidine in inhibiting noradrenaline exocytosis from hippocampal nerve endings in an yohimbine-sensitive fashion that confirms the engagement of naïve α2-ARs in the EA-mediated effect.

Folic acid, one of the 13 essential vitamins, plays an important role in cardiovascular development. Mutations in folic acid synthesis gene 5,10-methylenetetrahydrofolate reductase (MTHFR) is significantly associated with the occurrence of congenital heart disease. However, the mechanisms underlying the regulation of cardiac development by mthfr gene are poorly understood. Here, we exposed zebrafish embryos to excessive folate or folate metabolism inhibitors. And we established a knock-out mutant of mthfr gene in zebrafish by using CRISPR/Cas9. The zebrafish embryos of insufficient or excessive folic acid, and mthfr-/- mutant all gave rise to early pericardial edema and cardiac defect at 3 days after fertilization(dpf). Furthermore, the folic acid treated embryos showed abnormal movement at 5dpf. The expression levels of cardiac marker genes hand2, gata4 and nppa changed in the abnormality of folate metabolism embryos and mthfr-/- mutant, and there is evidence that they are related to the change of methylation level caused by the change of folate metabolism. In conclusion, our study provides a novel model for the in-depth study of MTHFR gene and folate metabolism. And our results reveal that folic acid has a dose-dependent biphasic effect on early cardiac development.