The small-molecule iododiflunisal (IDIF) is a transthyretin (TTR) tetramer stabilizer and acts as a chaperone of the TTR-Amyloid beta interaction. Oral administration of IDIF improves Alzheimer’s Disease (AD)-like pathology in mice, although mechanism of action and pharmacokinetics remain unknown. Radiolabeling IDIF with positron or gamma emitters may aid in the in vivo evaluation of IDIF using non-invasive nuclear imaging techniques. In this work, we report isotopic exchange reaction to obtain IDIF radiolabeled with 18F. [19F/ 18F]exchange reaction over IDIF in dimethylsulfoxide at 160 °C resulted in the formation of [18F]IDIF in 7±3% radiochemical yield in a 20 minutes reaction time, with a final radiochemical purity of >99%. Biodistribution studies after intravenous administration of [18F]IDIF in wild-type mice using positron emission tomography (PET) imaging showed capacity to cross the blood-brain barrier (ca. 1% of injected dose per gram of tissue in the brain at t>10 min post administration), rapid accumulation in the liver, long circulation time and progressive elimination via urine. Our results open opportunities for future studies in larger animal species or human subjects.

This review is focused on synephrine, the principal phytochemical found in bitter orange and other medicinal plants, and widely used as a dietary supplement for weight loss/body fat reduction. We examine different aspects of synephrine biology, delving into its established and potential molecular targets, as well as its mechanisms of action. We present an overview of the origin, chemical composition, receptors, and pharmacological properties of synephrine, including its anti-inflammatory and anti-cancer activity in various in vitro and animal models. Additionally, we conduct a comparative analysis of the molecular targets and effects of synephrine with those of its metabolite, selective glucocorticoid receptor agonist (SEGRA) Compound A (CpdA), which shares a similar chemical structure with synephrine. SEGRA, including CpdA, have been extensively studied as glucocorticoid receptor activators that have a better benefit/risk profile than glucocorticoids due to the reduced adverse effects. We discuss the potential of synephrine usage as a template for the synthesis of new generation of non-steroidal SEGRA. The review also provides insights into the safe pharmacological profile of synephrine.

Acne vulgaris is a prevalent skin condition that affects people of all ages and can have significant physical and psychological impacts. Hydroxy acids, such as alpha-hydroxy acids (AHA) and beta-hydroxy acids (BHA), have demonstrated potential as effective ingredients for topical acne treatments due to their exfoliating and skin-rejuvenating properties. This study assessed the effectiveness of encapsulating AHA and BHA in pullulan-collagen nanofibers as a novel approach to acne treatment. The study involved preparing Pullulan and polyvinyl alcohol (PVA) solutions combined with sodium chloride (NaCl) to create a stable mixture. Collagen and Pullulan were then dissolved in deionized water and mixed to form a collagen-pullulan solution. Various weight ratios of Collagen to Pullulan were tested to optimize nanofiber formation. This research achieved electrospinning of nanofibers, confirmed by scanning electron microscopy (SEM) analysis, which revealed well-formed and continuous nanofiber structures in acidic solutions. Fourier transform infrared spectroscopy (FTIR) analysis provided insights into the chemical composition of the nanofibers, indicating the presence of ester, carboxylic acid, hydroxyl, and phenolic groups. Contact angle measurements demonstrated that the pullulan-collagen nanocomposite exhibited hydrophilic properties, albeit less hydrophilic than pure Collagen. Biocompatibility assays using mesenchymal stem cells (MSCs) and human skin fibroblasts (HSFs) revealed that the pullulan-collagen nanocomposite promoted higher cell viability compared to pure Collagen, suggesting its potential as a supportive matrix for cell growth and tissue regeneration. AHA-BHA-infused nanofiber skin masks hold promise as effective topical treatments for acne vulgaris. The successful encapsulation of hydroxy acids within pullulan-collagen nanofibers, in conjunction with their favourable chemical composition, hydrophilicity, and biocompatibility, positions them as promising candidates for delivering active ingredients and enhancing skin health. Further nanofiber formulation optimisation is necessary to exploit their therapeutic potential in skincare applications.

The paper deals with the Compound Inverse Rayleigh distribution, shown to constitute a proper model for the characterization of the probability distribution of extreme values of wind-speed, a topic which is gaining growing interest in the field of renewable generation assessment, both in view of wind power production evaluation and the wind-tower mechanical reliability and safety. The first part of the paper illustrates such model starting from its origin as a generalization of the Inverse Rayleigh model - already proven to be a valid model for extreme wind-speeds - by means of a continuous mixture generated by a Gamma distribution on the scale parameter, which gives rise to its name. Moreover, its validity to interpret different field data is illustrated, also by means of numerous numerical examples based upon real wind speed measurements. Then, a novel Bayes approach for the estimation of such extreme wind-speed model is proposed. The method relies upon the assessment of prior information in a practical way, that should be easily available to system engineers. In practice, the method allows to express one’s prior beliefs both in terms of parameters, as customary, and/or in terms of probabilities. The results of a large set of numerical simulations – using typical values of wind-speed parameters - are reported to illustrate the efficiency and the accuracy of the proposed method. The validity of the approach is also verified in terms of its robustness with respect to significant differences compared to the assumed prior information.

Zinc cobalt oxide-zinc hydroxide (ZnCo2O4-Zn(OH)2) microspheres were successfully fabricated on carbon cloth via a sample hydrothermal method. The surface morphology of these microspheres and their efficacy in degrading methyl violet were further modulated by varying the thermal annealing temperatures. The manipulation of thermal annealing temperatures was pivotal in adjusting the porosity of ZnCo2O4-Zn(OH)2 microspheres to amplify their photocatalytic performance. Various analytical techniques were utilized to evaluate the physical and chemical properties of the ZnCo2O4-Zn(OH)2 microspheres, including field-emission scanning electron microscopy, energy-dispersive spectroscopy, X-ray diffraction, field-emission transmission electron microscopy, X-ray photoelectron spectroscopy, and UV-vis spectroscopy. Compared to untreated ZnCo2O4-Zn(OH)2 microspheres, those subjected to thermal annealing exhibited increased specific surface area and light absorption capacity, rendering them highly effective photocatalysts under UVC light exposure. Subsequent studies have confirmed the superior performance of ZnCo2O4-Zn(OH)2 microspheres as a reusable photocatalyst for degrading methyl violet and tetracycline. Additionally, trapping experiments during the photodegradation process involving ZnCo2O4-Zn(OH)2 microspheres have identified hydroxyl radicals (·OH) and superoxide radicals (·O2–) as the primary reactive species.

Rett syndrome (RTT), a neurodevelopmental disorder, is mainly caused by mutations in methyl CpG-binding protein 2 (MECP2), which alter the functions of domains to either bind to methylated DNA or interact with a transcriptional co-repressor complex. It has been established that alterations in cyclin-dependent kinase-like 5 (CDKL5) or forkhead box protein G1 (FOXG1) correspond to distinct neurodevelopmental disorders, given that a series of studies have indicated that RTT is also caused by alterations in either one of these genes. We tried to elucidate RTT through evolution and structure assessment of MeCP2, CDKL5, and FOXG1, by focusing on their binding partners and disordered structures. Here, we provide insight into the similarities of the FOXG1 and MECP2 binding partners evolution and function. On the other hand, we suggest that CDKL5 could be a potential candidate for a classical RTT treatment, particularly based on its disordered structure that spans after the catalytic domain to the C-terminus, which shows abundant linear motifs that can bind to molecules with divergent structures of similar affinity. Additionally, we provide insight into the relationship between disordered structure and disease.

Rett syndrome (RTT) is mainly caused by mutations in methyl CpG-binding protein 2, cyclin-dependent kinase-like 5, or forkhead box protein G1. These RTT-causing proteins harbor an intrinsically disordered region (IDR) whose conformation exhibits spatiotemporal heterogeneity, which not only confer versatility to the protein, but also implicates them in diseases. The IDR generally evolves more rapidly than an ordered structure. In this study, we examined the relationship between pathogenic RTT-associated point mutations in RTT-causing proteins and the evolutionary dynamics of sequence features including structural order–disorder, phosphorylation sites, and evolutionary rates. We also analyzed the molecular properties and evolution of proteins that interact with RTT-causing proteins in terms of phylogenetic profiles, tissue specificity, subcellular localization, expression level, and functions. The results indicate that constrained IDRs may function by forming contacts with other regions in the protein sequence causing pathogenic missense mutations likely to arise in the rapidly evolving IDR and affect molecular networks, leading to disease. The results also provide novel insights into the genetic basis for RTT and the evolution of the neocortex in higher vertebrates.

Porous β-tricalcium phosphate (Ca3(PO4)2; β-TCP) was prepared by freeze-drying and the effects of this process on pore shapes and sizes were investigated. Various samples were prepared by freezing β-TCP slurries above a liquid nitrogen surface at −180 °C with subsequent immersion in liquid nitrogen at −196 °C. These materials were then dried under reduced pressure in a freeze-dryer after which they were sintered by heating. Compared with conventional heat-based drying, the resulting pores were more spherical, which increased both the mechanical strength and porosity of the β-TCP. These materials had a wide range of pore sizes from 50 to 200 µm, with the mean and median values both approximately 100 µm regardless of the freeze-drying conditions. Mercury porosimetry data showed that the samples contained small, interconnected pores with sizes of up to 1.24 µm and macroscopic, interconnected pores up to 25.8 µm in size. The effects of non-ionic surfactants having different hydrophilic/lipophilic balance (HLB) values on foaming and pore size were also investigated. Materials made with surfactants having lower HLB values exhibited smaller pores and lower porosity whereas higher HLB surfactants gave higher porosity and slightly larger macropores. Even so, the pore diameter could not be readily controlled solely by adjusting the HLB value. The findings of this work indicated that high porosity (75%) and good compressive strength (>2 MPa) can both be obtained in the same porous material and that foaming agents with HLB values between 12.0 and 13.5 were optimal.

Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae Lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote gut microbiota homeostasis, however, its role in renoprotection remains unknown. This study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8-week 2% NaCl-feeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, PLR significantly alleviated CKD-associated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and down-regulating the canonical Wnt / β-catenin pathway. Further, PLR rescued gut microbiota dysbiosis and protected high salt-induced gut barrier dysfunction. We found enrichment of Akkermansia and Bifidobacterium after PLR intervention, the relative abundance of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was at least partially exerted through gut microbiota reestablishment and down-regulation of the Wnt / β-catenin pathway. Our study provides evidence for new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.

The signal transduction pathways of estrogen receptors (ER) mainly includes gene pathway and non-gene pathway. Studies have shown that the gene pathway of ER is related with the expression of nuclear proteins, and this is the key issue for our current research. With the GEO database analysis, Human centromere protein F (CENPF) is highly expressed in adenocarcinoma of lung (LUAD), and the co-expression of CENPF and ERβ was found in the nucleus of LUAD cells. Meanwhile, CENPF and ERβ2/5 were related with T stage and poor prognosis (P<0.05). Knockdown of CENPF gene significantly inhibited the biological effects of LUAD cells, the tumor growth of mice and the expression of ERβ2/5 (P<0.05). Further, group experiments showed that knockdown CENPF inhibits biological effects of LUAD cells mediated by ERβ pathway. All the results indicated that both CENPF and ERβ2/5 play important roles in the progression of LUAD, and knockdown of CENPF can inhibit the progression of LUAD by inhibiting the expression of ER2/5. Thus, the development of inhibitors against ERβ2/5 subtype and CENPF remained more effective in improving the therapeutic effect of LUAD.

Recently, different extensions of the fractional derivative operator are found in many research papers. The main aim of this paper is to establish an extension of the extended Caputo fractional derivative operator. The extension of an extended fractional derivative of some elementary functions derives by considering an extension of beta function which includes the Mittag-Leffler function in the kernel. Further, an extended fractional derivative of some familiar special functions, the Mellin transforms of newly defined Caputo fractional derivative operator and the generating relations for extension of extended hypergeometric functions also presented in this study.

The main objective of this present paper is to introduce further extension of extended Caputo fractional derivative operator and establish the extension of an extended fractional derivative of some known elementary functions. Also, we investigate the extended fractional derivative of some familiar special functions, the Mellin transforms of newly defined Caputo fractional derivative operator and generating relations for extension of extended hypergeometric functions.

We have successfully measured amyloid beta (Aβ) (1-40) protein added in human serum by a NiCr strain gauge cantilever biosensor immobilized with liposomes incorporating cholesterol. Importantly, we investigated the effect of incorporation of cholesterol in the liposome in order to suppress the interaction between the liposome and many different proteins included in human serum. It was revealed that incorporating cholesterol suppresses the interaction between the proteins other than Aβ in human serum and the liposome. Finally, we detected Aβ(1-40) in human serum with typical chronological behaviors due to Aβ aggregation and fibrillization. Furthermore, as a digital low-pass filtering procedure could reduce external noises, the cantilever sensor immobilized with liposome incorporating cholesterol can detect low-concentrated Aβ in human serum.

A series of novel substituted isoxazolidine derivatives was synthesized through 1,3-dipolar cycloaddition reactions of α-aryl-N-methyl nitrones with various ethylene moieties, resulting in the formation of isoxazolidine derivatives. The structures of the synthesized compounds were characterized using spectroscopic methods. The [3+2] cycloaddition (32CA) reactions of α-aryl-N-methyl nitrones with diverse ethylene substituents were computed employing Density Functional Theory (DFT) at the B3LYP/6–31G(d) level, upgrading bond parameters. An investigation of the electron localization function (ELF) unveiled the zwitterionic nature of α-aryl-N-methyl nitrones, devoid of pseudoradical or carbenoid centers. Utilization of CDFT indices enabled the prediction of global electronic flux from the strongly nucleophilic α-aryl-N-methyl nitrones to the varied electrophilic ethylene functionalities. Molecular docking and molecular dynamics simulations were conducted on the isoxazolidine derivatives against the EGFR receptor (PDB: 4ZAU). In silico assessment of the synthesized isoxazolidines involved molecular docking, wherein the compound with the highest docking score was subjected to molecular dynamics simulations. Compound 11a, out of the thirty isoxazolidine derivatives, displayed the most substantial binding energy, yielding a g score of -6.57 kcal/mol. These observations highlighted the functional role of amide NH2 and NO2 in the binding process with the target protein, influencing its activity. Furthermore, prediction of ADME drug-likeness properties was performed to identify a suitable candidate.

Testosterone holds significant medical and economic importance, with the global market for testosterone replacement therapies valued at approximately $1.9 billion in 2023. This hormone is essential for the development and maintenance of male sexual characteristics as well as bone and muscle health. It plays a key role in conditions such as hypogonadism, muscle disorders, and andropause. However, the industrial production of testosterone often involves complex chemical processes that result in low yields, high costs, and environmental damage. Microbial biotransformation of steroids presents an eco-friendly alternative to traditional chemical synthesis. A knockout strain of Aspergillus nidulans deficient in steroid 11-α-hydroxylase activity was developed, rendering it incapable of hydroxylating androstenedione, progesterone, and testosterone. In this strain, two newly identified CYP450 enzymes—CYP68L1 from A. nidulans and CYP68L8 from Aspergillus ochraceus—were expressed to confirm their roles as steroid 11-α-hydroxylases. These enzymes successfully hydroxylated steroids such as androstenedione, progesterone, and testosterone. The availability of these 11-α-hydroxylases represents significant progress toward achieving efficient single-step steroid fermentation. Furthermore, the A. nidulans knockout strain is proposed as an effective model for studying the conversion of androstenedione to testosterone owing to its inability to hydroxylate the testosterone produced during bioconversion.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with cognitive dysfunction, memory decline, and behavioral disturbance, and pathologically characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Although various hypotheses have been proposed to explain the pathogenesis of AD, including the amyloid beta hypothesis, oxidative stress hypothesis, and abnormal phosphorylation of tau proteins, the exact pathogenic mechanisms underlying AD remain largely undefined. Furthermore, effective curative treatments are very limited. Epidemiologic studies provide convincing evidence for a significant association between type 2 diabetes and AD. Here, we showed energy metabolism using glucose, lactate and ketone bodies and lipids as energy substrates in normal brain, and changes in such energy metabolism due to type 2 diabetes. We also showed the influences of such altered energy metabolism due to type 2 diabetes on the pathology of AD. Furthermore, we comprehensively searched the risk factors related with type 2 diabetes for AD, and showed possible therapeutic interventions based on considering risk factors and altered brain energy metabolism due to type 2 diabetes for the development of AD.

A “watch and wait” strategy, delaying treatment until active disease manifests, is adopted for most CLL cases; however prognostic models incorporating biomarkers have shown to be useful to predict treatment requirement. In our prospective O-CLL1 study including 224 patients, we investigated the predictive role of 513 microRNAs (miRNAs) on time to first treatment (TTFT). In the context of this study six well-established variables (i.e., Rai stage, beta-2-microglobulin levels, IGVH mutational status, del11q, del17p, and NOTCH1 mutations) maintained significant associations with TTFT in a basic multivariable model, collectively yielding a Harrell's C-index of 75% and explaining 45.4% of the variance in the prediction of TTFT. Concerning miRNAs, 73 out of 513 were significantly associated with TTFT in a univariable model; of these, 16 retained an in-dependent relationship with the outcome in a multivariable analysis. For 8 of these (i.e., miR-582-3p, miR-33a-3p, miR-516a-5p, miR-99a-5p, and miR-296-3p, miR-502-5p, miR-625-5p, and miR-29c-3p) a lower expression correlated with a shorter TTFT, whereas in the remaining eight (i.e., miR-150-5p, miR-148a-3p, miR-28-5p, miR-144-5p, miR-671-5p, miR-1-3p, miR-193a-3p, and miR-124-3p) the higher expression was associated with shorter TTFT. Integrating these miRNAs into the basic model significantly enhanced predictive accuracy, raising the Harrell’C index to 81.1% and the explained variation in TTFT to 63.3%. Moreover, the inclusion of the miRNA scores enhanced the Integrated Discrimination Improvement (IDI) and the Net Reclassification Index (NRI), underscoring the potential of miRNAs to refine CLL prognostic models and providing insights for clinical decision-making. In silico analyses on the differently expressed miRNAs revealed their potential regulatory functions of several pathways, including those involved in the therapeutic responses. To add a bio-logical context to the clinical evidence, a miRNA-mRNA correlation analysis revealed at least one significant negative correlation between 15 of the identified miRNAs and a set of 50 Artificial Intelligence (AI) selected genes, previously identified by us as relevant for TTFT prediction in the same cohort of CLL patients. In conclusion, the identification of specific miRNAs as predictors of TTFT holds promise for enhancing risk stratification in CLL to predict therapeutic needs. However, further validation studies and in-depth functional analyses are required to confirm the robustness of these observations and to facilitate their translation into meaningful clinical utility.

In this paper we report the possibility of using the X-ray powder diffraction (XRPD) technique to detect the gamma-hydroxybutyric acid (GHB) as its sodium salt in different beverages but because it is not possible to freely buy them, beta-hydroxybutyric acid (BHB) and its sodium salt (NaBHB) were used as a model to fine tune an X-ray diffraction method for the qualitative analysis of the sodium salt of GHB. The method requires a small quantity of beverage, and an easy sample preparation, that consists only in the NaOH addition to the drink and a subsequent drying step. The dry residue obtained can be easily analyzed with XRPD using a single crystal X-ray diffractometer to exploit its high sensitivity that allows very fast patterns collection. Several beverages with different NaBHB:NaOH molar ratios were tested and the results show that NaBHB is detected in all drinks analyzed when NaBHB:NaOH molar ratio is 1:50 using characteristic peak at very low 2θ values that permits to detect its presence also in complex beverage matrices. Moreover, depending on the NaOH amount added, shifting and/or splitting of the characteristic peak of the NaBHB salt was observed, and the origin of this behavior was investigated.

Vaccine antigens must present the correct conformation of viral fusion glycoproteins to elicit effective immune responses. Virus-like particles (VLPs) serve as promising vaccine platforms because they mimic the membrane-embedded conformations of fusion glycoproteins on native viruses. Here, we employed SARS-CoV-2 VLPs (SMEN) presenting ancestral, Beta, or Omicron spikes to identify the variant that elicits potent and cross-protective immune responses in the highly sensitive K18-hACE2 mouse model. A combined intranasal and intramuscular administration regimen of the SMEN vaccine generated effective immune responses and was predominantly mediated by antibodies with minor contributions from T cells. Immunization with SMEN presenting an ancestral spike resulted in 100, 75, or 0% protection against ancestral, Delta or Beta VOC-induced mortality, respectively, whereas SMEN presenting the most divergent Omicron spike provided only limited protection (50%, 0%, and 25%) against ancestral, Delta, and Beta variants, respectively. By contrast, SMEN with a Beta spike offered 100% protection against the variants used in this study. Thus, the Beta variant not only overcame the immunity produced by other variants, but also elicited diverse and effective immune response. Our findings suggest that leveraging the Beta variant spike protein can enhance SARS-CoV-2 immunity, potentially leading to a more comprehensive vaccine against emerging variants.

The prevalence of multidrug-resistant Gram-negative infections, particularly carbapenem-resistant strains, has become a significant global health concern. Ceftazidime-avibactam (CZA) has emerged as a promising treatment option. However, data on its efficacy and safety in children are scarce, necessitating further investigation. We conducted a retrospective study at a tertiary hospital in Spain from February 2019 to January 2022. Pediatric patients (<16 years) treated with CZA for confirmed or suspected multidrug-resistant Gram-negative infections were included. Clinical and microbiological characteristics, treatment approaches, and outcomes were examined. Eighteen children received CZA treatment. All had complex chronic conditions, with the most frequent underlying main diseases being liver transplantation (n=8) and biliary atresia (n=4). The predominant type of infection for which they received CZA was intra-abdominal infections caused or suspected to be caused by OXA-48-producing Klebsiella pneumoniae. CZA was generally well tolerated. Within the first month of starting CZA therapy, 2 patients died, with one case directly linked to the infection’s fatal outcome. Some patients needed repeated courses of therapy due to recurrent infections, yet no resistance development was noted. In summary, the use of CZA showed effectiveness and safety, while the lack of resistance development highlights CZA’s potential as a primary treatment option against OXA-48-producing infections.

Modern organic synthesis is majorly focused on developing environmentally benign synthetic protocols by employing green chemistry principles. Accordingly, in our recent research work, we herein report the use of modified supramolecular host cyclodextrin as an effective solid based green catalyst for accessing structurally diverse and medicinally relevant pyrimidone architectures. The catalyst and the synthesized compounds 4 (a-r) were characterized using FT-IR, NMR and GC-Mass spectroscopy. Major highlights of the reported work include: atom economical process, extremely milder reaction conditions, operational simplicity, high isolated yields, and excellent catalyst turnover number. The molecular docking studies suggest that the compound 4n has the hydrogen bonding, hydrophobic and π-pair interactions with the active site of active sites of CXT M 15 receptor.

A reduction of melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding molecular processes of melatonin-related signaling is critical for intervention of AD progression. Recently, we synthesized and tested a series of melatonin derivates with donepezil fragments in silico and in vitro. In this study, one of the most potent compounds, 3c, was studied in an in vivo rat model of pinealectomy (pin) and subsequent icvAβ1-42 infusion. Melatonin was used as a referent drug. The treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) exerted a beneficial effect on memory decline and concomitant rise of Aβ1-42 and pTAU in the hippocampus in the pin + icvAβ1-42 rats. Melatonin supplementation facilitated the non-amyloidogenic signaling via a non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c derivate up-regulated the MT1A and MT2B receptors, pERK and pCREB. Our findings strongly support the hypothesis that melatonin-related derivates may become a promising drug candidate in AD therapy.

The role of initial state (ISI) and final state (FSI) ion–ion interactions in heavy ion double charge exchange (DCE) reactions A(Z,N)→A(Z±2,N∓2) are studied in the context of double single charge exchange (DSCE) reactions given by sequential actions of the isovector nucleon–nucleon (NN) T–matrix. The second order DSCE reaction amplitude is investigated in momentum representation in a formulation, focused on the extraction of nuclear matrix elements under the conditions of strong initial state (ISI) and final state (FSI) interactions. In closure approximation and using the momentum representation, the reaction amplitude is finally separated into ISI/FSI distortion coefficients and reaction kernels and nuclear matrix elements. The ISI/FSI reaction kernels emerge as the result of the repeated scattering on the avoided volume, introduced by the imaginary parts of the ion–ion optical potential and acting as sinks for the quantal probability current. The closure approximation allows derive a set of induced effective two–body isotensor interactions, given by products of spin–scalar, spin–vector central and rank–2 spin–tensor interactions. The intermediate propagator plays a key role in establishing correlation between the DCE transitions in the projectile and target nucleus. The presented approach emphasizes the special features of DSCE reaction dynamics as proceeding like a system of two coupled isospin dipoles whose strengths are determined by the momentum-space form factors of the NN isovector interaction. The properties of the DSCE interaction form factors are investigated and the approach is applied to data.

Statistical modeling of lifetime data plays an essential role in a wide range of practical fields, such as health and engineering. There have been a lot of studies done to develop statistical models that can better describe health data than traditional models. For the first time, we pioneer a novel family of continuous probability distributions called the generalized odd beta prime generalized (GOBP-G) family of distributions. The cumulative distribution and probability density functions of the new family are presented. A new generalization of the Weibull distribution called "generalized odd beta prime-Weibull" (GOBPW) is proposed using the pioneered GOBP-G family. The mixture representations of the new distribution are defined and derived. Some formal statistical properties of the GOBPW distribution, such as the moments, moment generating function, incomplete moments, information generating function, entropies, stress-strength function, quantile function, and order statistics, are derived. The estimation of the parameters of the proposed distribution is evaluated using the maximum likelihood estimation approach. Different cancer disease data sets, such as the bladder, head and neck, acute bone, and blood cancers, are used to illustrate the applicability and usefulness of the new model and were compared using several statistical accuracy measures with that of well-established extended Weibull distributions, which are the beta modified Weibull distribution, Kumaraswamy modified Weibull distribution, gamma generalized modified Weibull distribution, gamma log-logistic Weibull distribution, and beta log-logistic Weibull distribution. The results show that the proposed model gives better results than the competitive models. This study could guide the relevant stakeholders in choosing a suitable statistical model for the health data instead of relying on traditional models to enhance decision-making.

Alzheimer's Disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD) - whose causes are not completely understood - and familial (FAD) - with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Ab) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of Antimicrobial Peptides (AMPs) in this pathology. Literature also demonstrates that Ab can be considered itself as an AMP thus representing a type of innate immune defense peptide that protect the host against a variety of pathogens. Beyond Ab, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin β4, LL37, histatin 1 and statherin have been shown to be involved in AD. Here we have summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

There is now considerable evidence that several infectious agents (viruses, bacteria, or parasites) may play a contributing role in the development of Alzheimer’s disease (AD). The six primary suspects are herpes viruses, spirochetal bacteria, Chlamydia pneumoniae, Porphyromonas gingivalis, mycobacteria, and toxoplasma parasites. Also, some of the antimicrobial and antiviral agents that are used to treat them have shown promise for AD interventions. I describe this evidence and assert it is now time to accelerate clinical trials of these existing drugs, already federally approved, to determine if such treatments can delay, halt, or reverse AD.

The i-4-1-Health project is a One Health project on the prevalence and spread of antimicrobial resistance in the human and veterinary domain in the Dutch-Belgian cross-border region. This paper describes the main components of the laboratory protocol that was developed to standardise the microbiological methods used for the detection of intestinal carriage of highly-resistant microorganisms.

Detection of PLA2R and THSD7A among primary membranous glomerulonephritis (MGN) patients transformed the diagnosis, treatment monitoring and prognosis. Anti-PLA2R can be detected in 70-90% of primary MGN patients while anti-THSD7A in 2-3% of anti-PLA2R negative primary MGN patients depending on the technique used. Serum and urine samples are less invasive and non-invasive respectively and can detect the presence of anti-PLA2R and anti-THSD7A with higher sensitivity and specificity, significant in patients’ monitoring and prognosis better than exposing patients to frequent biopsy which is an invasive procedure. Different techniques of detection of PLA2R and THSD7A in patients’ urine and sera were reviewed with the aim of providing newer and alternative techniques. We proposed the use of biomarkers (PLA2R and THSD7A) in making the diagnosis, treatment decision and follow up of patients with primary MGN. We also reviewed other prognostic renal biomarkers like retinol binding protein (RBP) and beta-2 microglobulin in order to detect progression of renal damage for early intervention.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densi- ties and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on dierent set of true values. Some real data sets were employed to show the usefulness and exibility of the model which serves as generalization to many sub-models in the elds of engineering, medical, survival and reliability analysis.

We proposed a so-called Beta Kumaraswamy Burr Type X distribution which gives the extension of the Kumaraswamy-G class of family distribution. Some properties of this proposed model were provided, like: the expansion of densities and quantile function. We considered the Bayes and maximum likelihood methods to estimate the parameters and also simulate the model parameters to validate the methods based on different set of true values. Some real data sets were employed to show the usefulness and flexibility of the model which serves as generalization to many sub-models in the field of engineering, medical, survival and reliability analysis.

In the paper, the authors survey integral representations of the Catalan numbers and the Catalan–Qi function, discuss equivalent relations between these integral representations, supply alternative and new proofs of several integral representations, collect applications of some integral representations, and present sums of several power series whose coefficients involve the Catalan numbers.

Mercury (Hg) is a toxic element impacting on biological systems and ecosystems. Because the toxicity of Hg species is highly dependent on concentration levels and chemical forms, sensitive identification of chemical forms for Hg, i.e., Hg speciation, is of major significance in providing meaningful information about the source of Hg exposure. In this study, a microfluidic-based device made of high clarity poly(methyl methacrylate) (PMMA) was fabricated. Then titanium dioxide nanoparticles (nano-TiO2) were attached to the treated channel interior with the aid of poly(diallyldimethylammonium chloride) (PDADMAC). After coupling the nano-TiO2-coated microfluidic-based photocatalyst-assisted reduction device (the nano-TiO2-coated microfluid-ic-based PCARD) with high-performance liquid chromatography (HPLC) and inductively coupled plasma-mass spectrometry (ICP-MS), a selective and sensitive hyphenated system for Hg specia-tion was established. Validation procedures demonstrated that the method could be satisfactorily applied to the determination of mercuric ion (Hg2+) and methylmercury ion (CH3Hg+) in both human urine and water samples. Remarkably, the zeta potential measured clearly indicated the PDADMAC-capped nano-TiO2 with predominance of positive charges indeed provided steady force for firm attachment to the negatively charged device channel. The cause for the durability of the nano-TiO2-coated microfluidic-based PCARD was clarified thus.

The World Health Organization recently proposed the Tricycle Protocol for harmonized surveillance of extended-spectrum beta lactamase-producing E. coli (ESBL-Ec) as a proxy for AMR among humans, animals, and the environment. We implemented the Tricycle Protocol with ceftriaxone (CRO) to screen for ESBL-Ec using membrane filtration (TBX-CRO) and Colilert Quanti-Tray (CQT-CRO) workflows in parallel applied to water samples collected from four lakes. ESBL-Ec and E. coli abundance and prevalence, and ESBL-Ec to E. coli ratios were significantly higher in the two highly impacted lakes (receiving sewage treatment plant effluent, open defecation site adjacent to informal settlements) compared to less impacted lakes (wildlife sanctuary, recreational site). The cumulative burden of antibiotic compounds was also higher in the highly impacted lakes. Even in the “pristine” lake in a bird sanctuary, ESBL-Ec and an antibiotic compound were present. Overall, the CQT-CRO format yielded reasonable qualitative (K = 0.603) and quantitative agreement (intra-class correlation coefficient = 0.849) and linearity (r² = 0.785) with the TBX-CRO format adapted from the Tricycle Protocol. However, CQT-CRO doubled the prevalence of ESBL-Ec in settings with decreased E. coli abundance. Consistent with observations for other third-generation cephalosporins, CRO performed poorly for screening the ESBL phenotype. Further, confirmed ESBL-Ec isolates were not associated with an increased number of resistance phenotypes compared with non-ESBL isolates. Instead, the number of resistance phenotypes was associated with the lake from which the sample was collected. In high-burden settings, AMR surveillance efficiency could be increased by directly testing generic E. coli isolates for ESBL phenotype and antibiotic susceptibility. Our experience also suggests that sequencing ESBL-Ec will likely be required to determine epidemiologically appropriate risk mitigation strategies where ESBL-Ec are prevalent. Resource limitations could jeopardize the relevance of the Tricycle Protocol for changing the trajectory of AMR in high-burden low-resource settings globally.

This study addresses the gap in methodological guidelines for Neuroergonomic attention assessment in safety-critical tasks, focusing on validating EEG indices including the Engagement Index (EI) and Beta/Alpha ratio alongside subjective ratings. A novel task-embedded reaction time paradigm was developed to evaluate the sensitivity of these metrics to dynamic attentional demands in a more naturalistic multitasking context. By manipulating attention levels through varying secondary tasks in the NASA MATB-II task while maintaining a consistent primary reaction-time task, the study successfully demonstrated the effectiveness of the paradigm. Results indicate that both Beta/Alpha ratio and EI are sensitive to changes in attentional demands, with Beta/Alpha being more responsive to dynamic variations in attention, and EI reflecting more the overall effort required to sustain performance, especially in conditions where maintaining attention is challenging. The potential for predicting the attention lapses through integration of performance metrics, EEG measures, and subjective assessments was demonstrated, providing a more nuanced understanding of dynamic fluctuations of attention in multitasking scenarios, mimicking those in real-world safety-critical tasks. These findings provide a foundation for advancing methods to accurately monitor attention fluctuations and mitigate risks in critical scenarios, such as train-driving or automated vehicle operation, where maintaining high attention level is crucial.

Oxidative stress and chronic inflammation, both at the systemic and central level, are critical early events in atherosclerosis and Alzheimer’s disease (AD). Purpose. To investigate the oxidative stress, inflammatory, and Tau-phosphorylation lowering effects of pomegranate polyphenols (PP) (punicalagin, ellagic acid, peels, and arils extracts). Methods. We used flow cytometry to quantify protein expression of proinflammatory cytokines (IL-1β) and anti-inflammatory mediators (IL-10) in THP-1 macrophages, as well as M1/M2 cell-specific markers (CD86 and CD163) expression in human microglia HMC3 cells. IL-10 protein expression was also quantified in U373-MG human astrocytes. The effect of PP on human amyloid beta 1-42 (Aβ1-42)-induced oxidative stress was assessed in microglia by measuring ROS generation and lipid peroxidation, using respectively two ′,7′-dichlorofluorescein diacetate (DCFH-DA) and thiobarbituric acid reactive substances (TBARS) tests. Neuronal viability and cell apoptotic response to Aβ1-42 toxicity were assayed using the MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay and the annexinV-FITC apoptosis detection kit; respectively. Finally, flow cytometry analysis was also performed to evaluate the ability of PP to modulate Aβ1-42-induced Tau-181 phosphorylation (pTau-181). Results. Our data indicate that PP was significantly (p<0.05) effective in countering Aβ1-42-induced inflammation through increasing the anti-inflammatory cytokines (IL-10) (in U373-MG astrocytes and THP1 macrophages) and decreasing proinflammatory markers (IL-1β) expression in THP1 macrophages. PP was also significantly (p<0.05) effective in inducing the phenotypic transition of THP-1 macrophages and microglial cells from M1 to M2 by decreasing CD86 and increasing CD163 surface receptor expression. Moreover, our treatments have a significant (p<0.05) beneficial impact on oxidative stress, illustrated in the reduction of TBARS and ROS generation. Our treatments have significant (p<0.05) cell viability improvement capacities and anti-apoptotic effects on human H4 neurons. Furthermore, our results suggest that Aβ1-42 significantly (p<0.05) increases pTau-181. This effect was significantly (p<0.05) attenuated by arils, peels, and punicalagin and drastically reduced by ellagic acid treatments. Conclusion. Our results are attributed to PP's anti-inflammatory, antioxidant, anti-apoptotic, and anti-Tau pathology potential. Future studies should aim to extend our knowledge of the potential role of PP on A1-42-induced neurodegeneration, mainly its association with the tauopathy involved in AD.

Carbapenem antibiotics are the drug of choice for treating multidrug-resistant bacterial infections. Metallo-beta-lactamases (MBLs) are carbapenemase capable of hydrolyzing nearly all therapeutically available beta-lactam antibiotics. Consequently, a need to assess the frequency and phenotypic resistance phenomena of two MBL genes in diarrheal and urinary tract infections (UTIs). Samples were collected through a cross-sectional study, with MBLs genes detected via PCR. Two hundred twenty eight diarrheal bacteria were isolated from 240 samples. The most predominant pathogens were Escherichia coli (32%) and Klebsiella spp. (7%). Phenotypic resistance to amoxicillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 50.4%, 65.6%, 66.8%, 80.5%, 54.4%, 41.6%, 25.7%, 41.2%, 37.2%, and 42.9%, respectively.  Total 142 UTI pathogens were obtained from 150 urine samples, with Klebsiella spp. (39%) and Escherichia coli (24%) are the major pathogens. Phenotypic resistance to amoxycillin-clavulanic acid, aztreonam, cefuroxime, cefixime, cefepime, imipenem, meropenem, gentamicin, netilmicin, and amikacin was 93.7%, 75.0%, 91.5%, 93.7%, 88.0%, 72.5%, 13.6%, 44.4%, 71.1%, and 43%, respectively.  Twenty four diarrheal isolates carried either blaNDM-1 or blaVIM genes; the overall MBL gene prevalence was 10.5%. Thirty six UTI pathogens carried either blaNDM-1 or blaVIM genes (25.4%). Seven isolates carried both blaNDM-1 and blaVIM genes.  MBL genes exhibited a strong association with phenotypic carbapenem and other beta-lactam antibiotic resistance. Resistance to carbapenems requires active surveillance and stewardship.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ soluble protofibrils was approved by US FDA for AD therapy thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms are widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7- Aβ) and the α4β2 nicotinic acetylcholine receptor.

Low-lying coastal communities are often threatened by compound flooding (CF), which can be determined through the joint occurrence of storm surges, rainfall and river discharge either successively or in close succession. The trivariate distribution can demonstrate the risk of the compound phenomenon more realistically rather than considering each contributing factor independently or in a pairwise dependency. Recently vine copula has been recognized as the highly flexible approach to constructing a higher dimensional joint density framework. In such construction, parametric class copula with parametric univariate marginal distributions is often involved. Such incorporation can lack flexibility due to parametric functions with prior distribution assumptions about their univariate marginal and/or copula joint density. This study introduces the vine copula approach in a nonparametric setting by introducing Bernstein and Beta kernel copula density in establishing trivariate flood dependence. The proposed model is applied to 46 years of flood characteristics collected on the west coast of Canada. The univariate flood marginal distribution is modelled using nonparametric kernel density estimation (KDE). The 2-D Bernstein estimator and Beta kernel copulas estimator are tested independently in capturing pairwise dependencies to establish D-vine structure in a stage-wise nesting approach in three alternative ways, each by permutating the location of the conditioning variable. The best-fitted vine structure is selected using goodness-of-fit (GOF) test statistics. The performance of the nonparametric vine approach is also compared with the vine constructed in the parametric and semiparametric fitting procedure. Investigation reveals that the D-vine constructed using Bernstein copula with normal KDE marginals nonparametrically performed well in capturing dependence of the compound events. Finally, the derived nonparametric model is used in the estimation of trivariate OR- and AND-joint return periods, further employed in estimating failure probability (FP) statistics. The trivariate return periods for the AND-joint case are higher than for the OR-joint case for the same flood combination. Also, the trivariate flood hazard results in a high-value FP than bivariate and univariate events. Ignoring the trivariate dependence could result in the underestimation of FP

Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular (CVD) disease not only due to multiple shared pathologic elements, but also because changes that develop over decades in CVD disease appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol, however, cholesterol dependent signaling such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase is downregulated indicating a cholesterol deficit with upregulation of cholesterol synthesis and efflux. Hypoxia related signaling in preeclampsia also appears paradoxical with increased Hypoxia Inducible Factors (HIF) in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol dependent signaling may arise from the effects of dietary lipid variance causing the cellular hypoxia which characterizes preeclampsia.

An imbalance between production and excretion of amyloid β peptide (Aβ) in the brain tissues of Alzheimer’s disease (AD) patients leads to Aβ accumulation and formation of noxious Aβ oligomers/plaques. A promising approach to AD prevention is reduction of free Aβ level by directed enhancement of Aβ binding to its natural depot, human serum albumin (HSA). We previously demonstrated the ability of specific low-molecular-weight ligands (LMWLs) of HSA to improve its affinity for Aβ. Here we develop this approach by bioinformatic search for the clinically approved AD-related LMWLs of HSA, followed by classification of the candidates according to the predicted location of their binding sites on HSA surface, ranking of the candidates, and selective experimental validation of their impact on HSA affinity for Aβ. The top 100 candidate LMWLs were classified into the five clusters. The specific representatives of the different clusters exhibit dramatically different behavior, with 3- to 13-fold changes in equilibrium dissociation constants for the HSA-Aβ40 interaction: prednisone favors HSA-Aβ interaction, mefenamic acid shows the opposite effect, while levothyroxine exhibits the bidirectional effects. Overall, the LMWLs of HSA chosen here provide a basis for drug repurposing for AD prevention, and for search for the medications promoting AD progression.

Chronic lymphocytic leukemia (CLL) is characterized by dysfunctional B cells. Immune checkpoint molecules such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and programmed death-1 (PD-1) are upregulated in patients with CLL and may correlate with prognostic markers such as beta-2 microglobulin (B2M). The aim of this study was to evaluate the levels of immune checkpoints on B-cell subsets and to further correlate them with B2M levels in patients with CLL. We recruited 21 patients with CLL and 12 controls. B cell subsets and the levels of immune checkpoint expression were determined using conventional multi-color flowcytometry. Basal levels of B2M in patients with CLL were measured using an Enzyme-linked immunosorbent assay. Patients with CLL had increased levels of activated B cells when compared to the control group, p< 0.001. The expression of PD-1 and CTLA-4 were increased on activated B cells and memory B cells, p< 0.05. There were no associations between B2M levels and the measured immune checkpoints on B cell subsets, after adjusting for sex and age. African patients with CLL express elevated levels of PD-1 and CTLA-4 immune checkpoints on activated and memory B cell subsets. However, there is no correlation between these immune checkpoint expressions and B2M levels.

The cytokine-producing nucleotide-binding domain leucine-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome is generally recognized to play a central role in the immune response to vaccination and NLRP3 activity is known to be increased by both aluminum adjuvants and by oxidative stress. Thus, the presence of oxidative stress may place individuals at higher risk for exaggerated or prolonged inflammatory responses and related side effects from vaccination. We here examine the relationship between oxidative stress and NLRP3 inflammasome activity, particularly in the context of aluminum-adjuvanted vaccines, and its implications for subpopulations of individuals with restricted antioxidant capacity.

How to disentangle the possible genuine quenching of gA caused by scale anomaly of QCD parameterized by the scale-symmetry-breaking quenching factor qssb from nuclear correlation effects is described. This is done by matching the Fermi-liquid xed (FLFP) point theory to the "Extreme Single Particle (shell) Model" (acronym ESPM) in superallowed Gamow-Teller transitions in heavy doubly-magic shell nuclei. The recently experimentally observed indication for (1-qssb) ≠0 - that one might identify as "fundamental quenching (FQ)" - in certain experiments seems to be alarmingly signicant. I present arguments how symmetries hidden in the matter-free vacuum can emerge and suppress such FQ in strong nuclear correlations. How to conrm or refute this observation is discussed in terms of the superallowed Gamow-Teller transition in the doubly-magic nucleus 100Sn and in the spectral shape in the multifold forbidden β decay of 115In.

Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research, and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models are essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models as well as in patients with Alzheimer’s disease, These tools have facilitated our understanding of disease mechanisms, and provided longitudinal monitoring of treatment effect in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes, and discuss outstanding challenges in disease animal models and future outlook in on-chip characterization of imaging biomarkers towards clinical translation.

Obesity-associated metabolic abnormalities comprise of a cluster of conditions including dyslipidemia, insulin resistance, diabetes, and cardiovascular diseases that has affected more than 650 million people all over the globe. Obesity results from accumulation of white adipose tissues mainly due to the chronic imbalance of energy intake and energy expenditure. Variety of approaches to treat or prevent obesity, including lifestyle interventions, surgical weight loss procedures and pharmacological approaches to reduce energy intake and increase energy expenditure have failed to substantially decrease the prevalence of obesity. Brown adipose tissue (BAT), the primary source of thermogenesis in infants and small mammals may represent a promising therapeutic target to treat obesity by promoting energy expenditure through non-shivering thermogenesis mediated by mitochondrial uncoupling protein 1 (UCP1). Since the confirmation of functional BAT in adult humans by several groups, approximately a decade ago and its association with a favorable metabolic phenotype, intense interest on the significance of BAT in adult human physiology and metabolic health has emerged within the scientific community to explore its therapeutic potential for the treatment of obesity and metabolic diseases. Substantially decreased BAT activity in individuals with obesity indicates a role for BAT in setting of human obesity. On the other hand, BAT mass and its prevalence has been reported to correlate with lower body mass index (BMI), decreased age and glucose levels, leading to lower incidence of cardio metabolic diseases. Increased cold exposure in adult humans with undetectable BAT was associated with decreased body fat mass and increased insulin sensitivity. Deeper understanding of the role of BAT in human metabolic health and its inter-relationship with body fat distribution and deciphering proper strategies to increase energy expenditure by either increasing functional BAT mass, or inducing white adipose browning holds the promise for possible therapeutic avenues for the treatment of obesity and associated metabolic disorders.

We investigate new graph characteristics namely total (vertex, edge) face irregularity strength of gen- eralized plane grid graphs Gmn under k-labeling Phi of type (Alpha, Beta, Gamma). The minimum integer k for which a vertex-edge labelled graph has distinct face weights is called the total face irregularity strength of the graph and is denoted by tfs(Gmn). In this article, the graphs G = (V;E; F) under consideration are simple, finite, undirected and planar. We will estimate the exact tight lower bounds for the total face irregularity strength of some families of generalized plane grid graphs.

In this study, we introduce a novel framework for the estimation of residual renal function (RRF), based on the population compartmental kinetic behavior of Beta 2 Microglobulin (B2M) and its dialytic removal. Using this model, we simulated a large cohort of patients with various levels of RRF receiving either conventional high-flux hemodialysis or on-line hemodiafiltration. These simulations were used to estimate a novel population kinetic (PK) equation for RRF (PK-RRF) that was validated in an external public dataset of real patients. We assessed the performance of the resulting equation(s) against their ability to estimate urea clearance using cross-validation. Our equations derived entirely from computer simulations and advanced statistical modeling, and had extremely high discrimination (AUC 0.808 – 0.909) when applied to a human dataset of measurements of RRF. A clearance-based equation that utilized pre and post dialysis B2M measurements, patient weight, treatment duration and ultrafiltration had higher discrimination than an equation previously derived in humans. Furthermore, the derived equations appeared to have higher clinical usefulness as assessed by Decision Curve Analysis, potentially supporting decisions that for individualizing dialysis frequency in patients with preserved RRF.

The present article analyzes the results of recent clinical trials of beta secretase inhibition in sporadic Alzheimer’ disease (SAD), considers the striking dichotomy between successes in tests of BACE1 inhibitors in healthy subjects and familial AD (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of APP-independent, beta secretase inhibition-resistant production of beta amyloid in SAD, previously proposed by us. In the light of this concept, FAD and SAD should be regarded as distinctly different diseases as far as beta-amyloid generation mechanisms are concerned, and whereas beta secretase inhibition would be neither applicable nor effective in treatment of SAD, the BACE1 inhibitor(s) deemed failed in SAD trials could be perfectly suitable for treatment of FAD. Moreover, targeting the aspects of AD other than cleavages of the APP by beta and alpha secretases should have analogous impacts in both FAD and SAD.

German chamomile (Matricaria chamomilla L.) is an essential oil-content medicinal plant widely used worldwidely. The aim of this study was (1) to gain knowledge of the phytochemical composition and the analgesic and soporific activity of M. chamomilla flowers extract and its amino acid preparations, (2) to predict the mechanisms of their effects by molecular docking, and (3) to develop aqueous printing gels and novel 3D-printed oral dosage forms for M. chamomilla flowers extracts. In total 22 phenolics and 14 amino acids were identified and quantified in the M. chamomilla extracts. The in-vivo animal studies with rodents showed that the oral administration of such extracts revealed the potential for treating of sleep disorders and diseases accompanied by pain. Amino acids were found to potentiate these effects. Glycine enhanced the analgesic activity the most, while lysine and β-alanine improved the soporific activity. The molecular docking analysis revealed a high probability of GABAA and NMDA receptor antagonism and COX-1,2 inhibition by the extracts. A polyethylene oxide (PEO) based gel composition with the M. chamomilla extracts were proposed for preparing a novel 3D-printed dosage form for the oral administration. These 3D-printed extract preparations can be used for example in dietary supplement applications.

The role of foods is shifting from focusing on the provision of energy and basic nutrients to also include bioactive compounds that prevent the development of chronic age-related diseases. Mi-croalgae offer a source of nutritional compounds with important health effects, and have the po-tential for production of health-promoting products, without increasing agricultural land use and negatively impacting the environment. Here we investigate the health effects of microalgal ex-tracts with high levels of the colourless carotenoid phytoene. Phytoene is widely available from dietary sources and can be detected across different tissues in the human body. However, it is usually regarded as a precursor for the synthesis of other carotenoids, rather than a bioactive molecule. We utilised the model organism C. elegans to show that phytoene-rich extracts from Chlorella sorokiniana and Dunaliella bardawil have anti-ageing properties. The extracts protect against oxidative damage and amyloid-β42 proteotoxicity (a major pathology of Alzheimer's disease), and extends lifespan. We show that pure phytoene also has these anti-ageing effects, suggesting that phytoene is a bioactive molecule with positive effects on ageing and longevity.

In this paper, we introduce the (ρ,q)-analogue of the p-adic factorial function. By utilizing some properties of (ρ,q)-numbers, we obtain several new and interesting identities and formulas. We then construct the p-adic (ρ,q)-gamma function by means of the mentioned factorial function. We investigate several properties and relationships belonging to the foregoing gamma function, some of which are given for the case p = 2. We also derive more representations of the p-adic (ρ,q)-gamma function in general case. Moreover, we consider the p-adic (ρ,q)-Euler constant derived from the derivation of p-adic (ρ,q)-gamma function at x = 1. Furthermore, we provide a limit representation of aforementioned Euler constant based on (ρ,q)-numbers. Finally, we consider (ρ,q)-extension of the p-adic beta function via the p-adic (ρ,q)-gamma function and we then investigate various formulas and identities.

This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) among non-carbapenemase producing (NCP) and carbapenemase producing (CP) Escherichia coli and Klebsiella pneumoniae. As mutations for ertapenem resistance establish the genetic background for non-carbapenemase meropenem resistance, there is a great need for antibiotic stewards and researchers to understand the determinants of a strain’s propensity to become resistant. Whole genome sequencing was conducted on clinical carbapenem-resistant E. coli (CREC) and K. pneumoniae (CRKP) across 5 hospitals in San Antonio, U.S. from 2012-2018. The majority of carbapenem resistant Enterobacterales (CRE) were NCP (54%; 41/76). The blaCTX-M was found to be most prevalent among NCP isolates (p = 0.02). LC-MS/MS analysis of carbapenem hydrolysis revealed that blaCTX-M-mediated carbapenem hydrolysis, indicating the need to reappraise the term, “non-carbapenemase (NCP)” for quantitatively uncharacterized CRE strains harboring blaCTX-M. Antimicrobial susceptibility results showed that 56% of all NCPE isolates had an ErMs phenotype (NCPE vs. CPE, p &lt; 0.001), with E. coli driving the phenotype (E. coli vs. K. pneumoniae, p &lt; 0.001). ErMs strains carrying blaCTX-M, had approximately 4-fold more copies of blaCTX-M than ceftriaxone-resistant but ertapenem and meropenem susceptible (EsMs) isolates (3.7 v. 0.9, p &lt; 0.001). ErMs also carried more mobile genetic elements (MGEs), particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p &lt; 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, this work provides evidence of a collaborative effort between blaCTX-M and OmpC in NCP strains that confer resistance to ertapenem but not meropenem. To thwart potential mismanagement of CRE infected patients, future efforts should focus on understanding the mechanism(s) underlying OmpC loss, developing rapid methods to detect blaCTX-M copy number variants, and targeted antimicrobials for NCPE and ErMs strains.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. In this review, we discuss the role of IL-1β in NSCLC, its involvement in inflammatory pathways, and explore its potential role in the treatment of NSCLC.

Finding, safe and reliable alternatives to fungicides is one of the most actual challenges in agriculture. In this regard, our experiment investigated the effectiveness of different elicitors, botanical extracts and essential oils to control grey mould (Botrytis cinerea) and powdery mildew (Podosphaera aphanis) on strawberry plants. Furthermore, the defence mechanisms activated in plants after treatments were investigated. The trial was conducted in field conditions under plastic tunnel with strawberry plants ‘Elsanta’. In the first experiment, a group of strawberry plants was treated before flowering with elicitors [acibenzolar-S-Methyl – (BTH), chitosan], botanical extracts (seaweed extract, alfalfa hydrolysate) and essential oils (thyme and juniper) to evaluate their ability to reduce the incidence of grey mould infection on flowers. In the second experiment, another group of plants was treated before and after experimental inoculation with P. aphanis. Results indicated that the incidence of flower infected by B. cinerea was significantly reduced by thyme and juniper essential oils, showing values that were not significantly different from the commercial fungicide penconazole (positive control). As a consequence, final yield of essential oil-treated plants was +27% higher as compared to control. No significant differences emerged for other tested products against grey mould. However, gene expression analysis showed an up-regulation of FaEDS1, FaLOX and PR gene expression (FaPR1, FaPR5, FaPR10) in leaves treated with BTH. The other tested natural substances also elicited defence-related genes, however at a lower level than BTH. In the experiment, all treatments applied prior inoculation significantly reduced the incidence and severity of powdery mildew as compared to control. At 28 days after inoculation, chitosan and thyme essential oil applications performed similarly to their positive controls (BTH and penconazole, respectively), showing a significant reduction of disease incidence (by -84 and -92%) as compared to control. Post-inoculum application of essential oils showed similar effective action to fungicide (penconazole) in reducing incidence and severity of powdery mildew. These results indicate that the tested substances could be used as alternatives to fungicides for the control of grey mould and powdery mildew in strawberry, therefore representing a valuable tool for the control of these fungal diseases under the framework of the sustainable agriculture.

Much evidence now indicates a direct crosstalk between thyroid hormones (THs) and the immune system. We previously showed that THs behave as anti-inflammatory agents in human leukemic THP-1 monocytes, but a potential neuroprotective effect of THs in microglia have been under-investigated. Microglia, the primary innate immune cells of the brain, play a pivotal role in the regulation of neuroinflammation and nongenomic integrin αvβ3-mediated action of THs appear to be involved. Integrin αvβ3 was highly expressed in activated BV-2 cells, while it was decreased by THs. In addition, THs facilitated wound healing in BV-2 murine microglia cells activated by lipopolysaccharide (LPS), through integrin αvβ3 and reactive oxygen species (ROS), with tetrac (a metabolite of TH) potentiated the inhibition of migration. Nitric oxide (NO) played a role with different mechanisms in the presence of either T3 or T4. Our data showed the capability of TH and analogues to modulate the M1-to-M2 microglial transition and suggest a new spectrum of actions in the central nervous system (CNS).

Due to its application as an anti-cancer drug, pazopanib (1) has attracted the interest of many researchers and several studies on pazopanib synthesis have been reported over the years. This paper provides a novel route for synthesizing N,2,3-trimethyl-2H-indazol-6-amine (5) which is a crucial building block in the synthesis of pazopanib from 3-methyl-6-nitro-1H-indazole (6). By alternating between the reduction and two methylation steps compound 5 was obtained in comparable yield (55.0%) to what has been reported (54%). Noteworthy, the last step of N2-methylation also yielded N,N,2,3-tetramethyl-2H-indazol-6-amine (5’) as a new compound ever reported. Furthermore, the data presented in this paper can serve as instrumental for future research aimed at further refining the synthesis process of pazopanib.

Although there are a large number of databases available for regulatory elements, bottleneck has been created by the lack of bioinformatics tools for predicting types of mechanisms underlying actions of regulatory elements. To reduce the gap, we developed ARabidopsis Transcription regulatory Factor Domain-domain interaction Analysis Tool- Liquid-liquid phase separation (LLPS), Oligomerization, GO analysis (ART FounDATion-LOG), a useful toolkit for protein-nucleic acid interactions (PNI) and protein-protein interactions (PPI) analysis based on domain-domain interaction (DDI). LLPS, protein oligomerization, structural properties of protein domains, and protein modifications are major components in orchestrating spatio-temporal dynamics of PPI and PNI. Our goal is to integrate PPI/PNI information into development of prediction model for identifying important genetic variants in peach. The program unified inter-database relational keys by protein domains for facilitating inference from the model species. Key advantage of the program lies in the integrated information of related features: LOG, structural characterization of domain (e.g. domain linker, intrinsically disordered regions, DDI, domain-motif (peptide) interaction, beta-sheet and transmembrane helices), and post-translational modification. We provided simple tests to demonstrate how to use the program. The program may be applied to other eukaryotic organisms. The program codes and data are freely available for download at and https://sourceforge.net/projects/artfoundation-log/.

Post-COVID-19 bacterial infections are a significant threat to global health, mainly due to the overuse and misuse of antibiotics. The review highlights the importance of using antibiotics judiciously and following appropriate guidelines and recommendations. The article also examines the potential indirect contribution of steroids to antibiotic resistance through immune suppression in severe cases of COVID-19. Anti-microbial resistance (AMR) is one of the leading causes of death worldwide that continues as a silent pandemic caused by the major AMR superbug includes Carbapenem-resistant Acinetobacter baumannii (CRAB), Methicillin-resistant Staphylococcus aureus (MRSA), Carbapenem-resistant Enterobacterales (CRE), Extended-spectrum Beta Lactamase producing Enterobacterales (ESBL) which is resistant to cephalosporin and Multidrug-resistant (MDR) Pseudomonas aeruginosa. Ongoing surveillance and monitoring of antibiotic use and resistance helped to minimize the risk of antibiotic resistance and shrink it from pandemic to endemic.

In the paper, by convolution theorem for the Laplace transforms and analytic techniques, the author finds necessary and sufficient conditions for complete monotonicity, monotonicity, and inequalities of several functions involving polygamma functions. By these results, the author derives a lower bound of a function related to the sectional curvature of the manifold of the beta distributions. Finally, the author poses several guesses and open problems related to monotonicity, complete monotonicity, and inequalities of several functions involving polygamma functions.

Background: developmental dysplasia of the hip (DDH) is a condition characterized by abnormal hip development in infancy. Early diagnosis allows for effective treatment, while late presentation often necessitates complex surgical interventions. Current recommendations advise screening between the 6th and 8th week postnatal using ultrasound, typically employing the Graf method. However, there's no universal consensus on whether ultrasound screening significantly increases treatment compared to clinical examination-guided ultrasound. This study aims to explore the feasibility of prenatal ultrasound for early identification of DDH risk. Methods: This prospective observational study involved 100 pregnant women undergoing fetal hip ultrasound during the second and third trimesters. Using the modified Graf method, alpha and beta angles were calculated on the fetus. Postnatally, alpha and beta angles were compared with prenatal values. Results: Prenatal ultrasound at 24th week showed inconclusive results because of the difficulty in identification of Graf landmarks, while ultrasound at 34th week has proved to be a reliable and safe method for quantitative determination of alpha and beta angles. Significant correlations were found between prenatal and postnatal alpha and beta angles. Moreover, significant differences in prenatal alpha and beta values were observed in patients developing mature/immature hips postnatally. Conclusions: Prenatal diagnostics show promise for predicting infant hip development. Further research is warranted to validate correlation strength and clinical applicability.

Alzheimer’s disease (AD) and the therapies of AD with anti-amyloid1-42 (Aβ) monoclonal antibodies are associated with the vascular complications of brain edema, hemorrhage, and cerebral amyloid angiopathy (CAA) termed amyloid-related imaging abnormalities (ARIAs). The neuropathology of normal and AD brains demonstrates that monocyte/macrophages (MMs) are critical in successful brain clearance in healthy brain by up-loading, transporting, and degrading Aβ but fail degradation and clearance in AD patients by releasing Aβ into vessels at the blood-brain barrier, causing vasculitis and ARIAs. The naturally-formed epoxides (EpFAs) of polyunsaturated fatty acids (PUFA’s), including arachidonic, docosahexaenoic, and eicosapentaenoic fatty acids, may repair degradation of Aβ by regulating Aβ-degrading enzymes, inflammatory cytokines, and unfolded protein response (UPR) to endoplasmic reticulum stress in a homeostatic fashion. EpFAs are, however, degraded by the soluble epoxide hydrolase enzyme (sEH) but are protected by the sEH inhibitor (sEHI) TPPU. In the cultures of AD patients’ macrophages, TPPU with the epoxide EEQ, and the cGAS/STING inhibitor H-151 increased uptake of Aβ at 2 hours and degradation of Aβ at 24 hours. In conclusion, the soluble epoxide hydrolase inhibitor TPPU with omega-3 fatty acids and the cGAS/STING inhibitor H-151 increase Aβ uptake and degradation in macrophages of AD patients, and potentially enhancing Aβ clearance in the AD brain.

This paper introduces extensions H4,p and X8,p of Horn’s double hypergeometric function H4 and Exton’s triple hypergeometric function X8, taking into account recent extensions of Euler’s beta function, hypergeometric function, and confluent hypergeometric function. Among the numerous extended hypergeometric functions, the primary rationale for choosing H4 and X8 is their comparable extension type. Next, we present various integral representations of Euler and Laplace type, Mellin and inverse Mellin transforms, Laguerre polynomial representation, transformation formulae and a recurrence relation for the extended functions. In particular, we provide a generating function for the X8,p and several bounding inequalities for the H4,p and X8,p.

Alzheimer's disease (AD) is the most prevalent form of dementia. With the global aging population, the incidence of AD and related dementias is projected to rise dramatically, posing significant public health challenges. Traditionally, the diagnosis of AD has relied on the detection of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau in the brain, assessed through invasive cerebrospinal fluid (CSF) analysis and costly positron emission tomography scans. However, these methods are not feasible for widespread screening or use in low-resource settings. Recent advances in blood-based biomarkers offer a promising alternative for the early detection and monitoring of AD. These biomarkers provide a minimally invasive, cost-effective means of tracking the pathological progression of AD before the onset of clinical symptoms, potentially enabling earlier and more accurate diagnosis. Blood-based biomarkers, including those related to Aβ, phosphorylated tau, and neurofilament light polypeptide, have demonstrated significant potential in reflecting the underlying neuropathology of AD and correlating with traditional CSF and imaging biomarkers. This review synthesizes the latest research on blood-based biomarkers in AD, highlighting their role in the disease's etiopathogenesis, diagnostic accuracy, and prognostic value. We discuss the emerging evidence on proteinopathies, neuroinflammation, vascular pathology, and bioenergetic profiles, emphasizing the clinical applicability of these biomarkers. Furthermore, we explore the integration of blood-based biomarkers with advanced neuroimaging techniques and their potential to revolutionize the diagnostic landscape of AD, particularly in resource-limited settings. We have integrated protein-protein interaction (PPI) and miRNA network analyses to enhance the analysis. By incorporating these, we can explore the interactions and relationships between different proteomic, genomic, and epigenomic biomarkers, potentially unveiling new insights into the underlying biological mechanisms of AD. The continued development and validation of these biomarkers could lead to more accessible and equitable AD diagnostics, ultimately improving patient outcomes.

Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.

This year marks the 20th anniversary of the discovery that proteins with various cellular functions can be temporarily immobilized in the nucleolus, a process known as nucleolar sequestration. This review reflects on the progress made to understand the physiological roles of nucleolar sequestration and the mechanisms involved in protein immobilization. We discuss how nucleolar sequestration consists of a highly choreographed amyloidogenic liquid-to-solid phase transition that converts the nucleolus into Amyloid bodies (A-bodies). The study of solid condensates A-bodies will offer unique perspectives on cellular assembly of membrane-less compartments and provide alternative insights on pathological amyloidogenesis involved in neurological disorders.

Although the existing paradigm states that CMV reactivation is under control of cellular immune response, the role of humoral counterpart is underestimated. Anti-CMV positive woman after conditioning with Bu-Flu-ATG underwent stem cell transplantation from fully matched, seronegative sibling donor. In immunodeficient recipient fast and significant decrease of specific immune response was observed but reconstitution of marrow-derived B and NK cells was prior thymic origin T cells. The lowest CMV-IgG(89 U/ml) was observed just before CMV viremia. Noteworthy, the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was observed later, but in the first phase immune reconstitution of the PHA-induced IFNγ release was significantly lower than that CMV-induced. It corresponds with NK cells increase at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells by pentamer technique. Most of NK cells are CD16+, thus are stimulated by residual IgG. In immunocompetent donor the cellular and humoral immune response increases in parallel manner but symptoms of CMV mononucleosis were observed till the increase of specific IgG. Our observations shed light on a unique host-CMV interaction: indicate that significant decrease of CMV-IgG is a good predictor for CMV reactivation during secondary immunodeficiency.

With reference to electromagnetic interaction and Abdus Salam’s strong (nuclear) gravity, 1) Square root of ‘reciprocal’ of the strong coupling constant can be considered as the strength of nuclear elementary charge. 2) ‘Reciprocal’ of the strong coupling constant can be considered as the maximum strength of nuclear binding energy. 3) In deuteron, strength of nuclear binding energy is around unity and there exists no strong interaction in between neutron and proton. $G_s\cong 3.32688\times {10}^{28}{\mathrm{m}}^3{\mathrm{kg}}^{-1}{\sec }^{-2}$ being the nuclear gravitational constant, nuclear charge radius can be shown to be, $R_0\cong \frac{2G_s{m}_p}{c^2}\cong 1.24\mathrm{fm}.$ $e_s\cong \left(\frac{G_s{m}_p^2}{\hslash c}\right)e\cong 4.716785\times {10}^{-19}\mathrm{C}$ being the nuclear elementary charge, proton magnetic moment can be shown to be, ${\mu }_p\cong \frac{e_s\hslash }{2m_p}\cong \frac{e{G}_s{m}_p}{2c}\cong 1.48694\times {10}^{-26}\mathrm{J}{.\mathrm{T}}^{-1}.$ ${\alpha }_s\cong {\left(\frac{\hslash c}{G_s{m}_p^2}\right)}^2\cong 0.1153795$ being the strong coupling constant, strong interaction range can be shown to be proportional to $\exp \left(\frac{1}{{\alpha }_s^2}\right).$ Interesting points to be noted are: An increase in the value of ${\alpha }_s$ helps in decreasing the interaction range indicating a more strongly bound nuclear system. A decrease in the value of ${\alpha }_s$ helps in increasing the interaction range indicating a more weakly bound nuclear system. From $Z\cong 30$ onwards, close to stable mass numbers, nuclear binding energy can be addressed with, ${\left(B\right)}_{A_s}\cong Z\times \left\{\left(\frac{1}{{\alpha }_s}+1\right)+\sqrt{\sqrt{30\times 31}}\right\}\left(m_n-m_p\right)c^2\approx Z\times 19.66\mathrm{MeV}.$ With further study, magnitude of the Newtonian gravitational constant can be estimated with nuclear elementary physical constants. One sample relation is, $\left(\frac{G_N}{G_s}\right)\cong \frac{1}{2}{\left(\frac{m_e}{m_p}\right)}^{10}\left[\sqrt{\frac{G_F}{\hslash c}}/\left(\frac{\hslash }{m_{e}c}\right)\right]$ where $G_N$ represents the Newtonian gravitational constant and $G_F$ represents the Fermi’s weak coupling constant. Two interesting coincidences are, ${\left(m_p/m_e\right)}^{10}\cong \exp \left(1/{\alpha }_s^2\right)$ and $2G_s{m}_e/c^2\cong \sqrt{G_F/\hslash c}.$

Waldenstrom’s Macroglobulinemia (WM) is an heterogenous disease, and the majority of patients tends to have a long course. Nevertheless, it is imperative to detect patients who have high risk of progression and who benefit from closer follow up. Many recent studies have displayed the CD163-positive Tumor-associated macrophages (TAMs) contribution in the pathogenesis of various hematological neoplasms and solid tumors. Soluble CD163 (sCD163) can be measured in serum, along with other TAM-chemoattractant cytokines, such as CCL2 and CCL4, and their levels are used to determine macrophage activation. In the current study we investigated the correlation between sCD163, CCL2 and CCL4, with parameters of WM progression and survival. Out of a total 204 WM patients, serum sCD163, CCL2 and CCL4 were measured in 75, 64 and 65, patients’ frozen sera at diagnosis and 30 healthy individuals (HIs) using an enzyme-linked immunosorbent assay (ELISA). We achieved to demonstrate that shorter Time to Treatment (TTT) was observed in 2 years and 7 years intervals in all patients with a ratio of CD163/CCL4 above median (p =0.003 and p=0.024 respectively) and decreased TTT was observed in all asymptomatic WM (AWM) patients with values of CCL4 above the median (p=0.018). Moreover, significantly decreased overall survival (OS) (p=0.033) was observed in all WM patients with CCL2 values above median. Our results indicate that sCD163, CCL2 and CCL4 could be utilized as prognostic markers in WM.

Recently, Shehata et al. [37] introduced the r+1Rs(B;C; z) matrix function and established some properties. The aim of this study established to devote and derive certain basic properties including analytic properties, recurrence matrix relations, dierential properties, new integral representations, k- Beta transform, Laplace transform, fractional k-Fourier transform, fractional integral properties, the k-Riemann{Liouville and k-Weyl fractional integral and derivative operators an extended version of r+1Rs;k matrix function. We establish its relationships with other well known special matrix functions which have some particular cases in the context of three parametric Mittag-Leer matrix function, k- Konhauser and k-Laguerre matrix polynomials. Finally, some special cases of the established formulas are also discussed.