Sickle cell disease (SCD) is a blood disorder caused by a point mutation on the beta globin gene resulting in the synthesis of abnormal hemoglobin. Fetal hemoglobin (HbF) reduces disease severity, but the levels vary from one individual to another. Most research has focused on common variants which differ across populations and hence do not fully account for HbF variation. To investigate rare and common variants influencing HbF levels in SCD, we performed targeted next generation sequencing covering exonic and other significant fetal hemoglobin-associated loci, including BCL11A, MYB, HOXA9, HBB, HBG1, HBG2, CHD4, KLF1, MBD3, ZBTB7A and PGLYRP1. Results revealed a range of functionally relevant genetic variants. Notably, there were significantly more deletions in individuals with high HbF levels (11% vs 0.9%). We identified frameshift deletion in individuals with high HbF levels and frameshift insertions in individuals with low HbF. CHD4 and MBD3 genes, interacting in the same sub-network, were identified to have a significant number of pathogenic or non-synonymous mutations in individuals with low HbF levels, suggesting an important role of epigenetic pathways in the regulation of HbF synthesis. This study provides new insights in selecting essential variants associated with extreme HbF levels in SCD.

Sickle cell disease (SCD) is an inherited disorder of major health challenge in Nigeria. Micronutrients deficiencies often associated with the disorder may cause inflammation and abnormal metabolisms in the body. The copper-to-zinc ratio is a more important assessment than the concentrations of either of the metals in clinical practice. This study seeks to evaluate serum levels of c-reactive protein (CRP), copper, zinc and copper-to-zinc ratio and to correlate copper-to-zinc ratio with CRP in adult subjects with SCD. Serum copper, zinc, CRP and plasma fibrinogen were assayed in 100 confirmed SCD patients in steady clinical state and 100 age and sex matched subjects with normal haemoglobin. Serum copper and zinc were assayed by colorimetric method using reagents supplied by Centronic, Germany while CRP and fibrinogen were assayed using reagents supplied by Sigma (St. Louis, MO, USA) and Anogen (Ontario, Canada), respectively. The copper to zinc ratio was calculated from serum levels of copper and zinc. The measured parameters were compared between the groups using Students t-test and Pearson correlation coefficient was used to relate CRP with the other parameters. Serum copper, CRP, fibrinogen and copper-to-zinc ratio were significantly higher (p < 0.001) while zinc level was lower in SCD patients than controls. Serum CRP concentration correlated with copper (r = 0.10; p < 0.02), zinc (r = −0.199; p < 0.05) and Copper-to-zinc ratio (r = 0.312; p < 0.002) but the correlation between CRP and fibrinogen was not significant. Inflammatory condition may modulate copper and zinc homeostasis and copper-to-zinc ratio may be used as marker of nutritional deficiency and inflammation in SCD patients.

There are many species of endemic plants from Mexico, without food or commercial use, but with different applications in traditional medicine and valuable for their content of secondary metabolites. In this sense, we found two species of Cucurbitacea family plants natives of southeast and gulf of México, with traditionally use how soap and laundry agent, control of some pests, and it has also been used how infusion for the treatment of different types of dermatitis and stomachache. In the present work, we evaluate the antiproliferative activity in vitro, of six crude organic extracts, tested against six human tumor cell lines, A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon), the results indicated that at least three extracts from both species presents an interesting antiproliferative activity on five tumor cell lines.

Multiple unique environmental factors such as space radiation and microgravity (µG) pose a serious threat to human gene stability during space travel. Recently, we reported that simultaneous exposure of human fibroblasts to simulated µG and radiation results in more chromosomal aberrations than in cells exposed to radiation alone. However, the mechanisms behind this remain unknown. The purpose of this study was thus to obtain comprehensive data on gene expression using a 3D clinostat synchronized to a carbon (C)-ion or X-ray irradiation system. Human fibroblasts (1BR-hTERT) were maintained under standing or rotating conditions for 3 or 24 h after synchronized C-ion or X-ray irradiation at 1 Gy as part of a total culture time of 2 days. Among 57,773 genes analyzed with RNA sequencing, we focused particularly on the expression of 82 cell cycle-related genes after exposure to the radiation and simulated µG. The expression of cell cycle-suppressing genes (ABL1 and CDKN1A) decreased and that of cell cycle-promoting genes (MKI67, KPNA2, CCNB1, STMN1, and MCM4) increased after C-ion irradiation under µG. The cell cycle may pass through the G1/S and G2 checkpoints with DNA damage due to the combined effects of C-ions and µG, suggesting that increased genomic instability might occur in space.

Background: Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is mainly associated with SDHB gene mutation and sometimes with SDHC or SDHD mutation. However, only three case of SDHA-deficient RCC have been reported, and the relation of SDHA mutation to RCC has not been clarified. Methods: We investigated SDHA/B/C/D gene mutations in 72 human RCCs by targeted next-generation sequencing, and also assessed SDHA and nuclear factor erythroid 2–related factor 2 (Nrf2) protein expression in 30 tumors. Results: NGS revealed SDHA gene mutations associated with amino acid sequence variations in 12 tumors, while no tumors had SDHB/C/D mutations. The SDHA gene mutations were identical in somatic and germline DNA of all 12 patients. Tumors with SDHA mutations showed a decrease of SDHA protein (p = 0.0177) and an increase of Nrf2 protein (p = 0.0120), with an inverse correlation between SDHA and Nrf2 protein expression (p = 0.0321). Tumor cells with SDHA mutations characteristically had eosinophilic cytoplasm and showed various patterns of proliferation. Conclusions: Our observations suggested that germline SDHA gene mutations might be linked to hereditary RCC associated with mitochondrial dysfunction.

Steroidal anti-inflammatory drugs are widely used for treatment of chronic cutaneous inflammation, such as atopic dermatitis, although it remains unknown how they modulate cutaneous mast cell functions. Murine connective tissue-type mast cells, which were sensitive to mast cell secretagogues, such as compound 48/80 and substance P, were generated by co-culture of bone marrow-derived mast cells with Swiss 3T3 fibroblasts in the presence of stem cell factor. This process was accompanied by up-regulation of a subunit of a trimeric G protein, G_i1, and several Mas-related G protein-coupled receptor (Mrgpr) subtypes. Secretagogue-induced degranulation and up-regulation of these genes were suppressed when they were cultured in the presence of a synthetic glucocorticoid, dexamethasone. The profiles of granule constituents were drastically altered by dexamethasone. Several Mrgpr subtypes were found to be expressed in the cutaneous tissues and their expression levels were decreased in response to topical application of dexamethasone. The numbers of degranulated cutaneous mast cells in response to compound 48/80 were decreased in mice treated with dexamethasone. These results suggest that mast cell-mediated IgE-independent cutaneous inflammation could be suppressed by steroidal anti-inflammatory drugs through down-regulation of G_ai1 and several Mrgpr subtypes in mast cells.

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S-phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies about the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU-exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients.

Background: Cancer stem cells (CSCs) exhibit self-renewal activity and give rise to other cell types in tumors. Due to the infinite proliferative potential of CSCs, drugs targeting these cells are necessary to completely inhibit cancer development. beta-lapachone (bL) has been widely used to treat cancer development, but its effect on cancer stem cells remain elusive. Thus, we investigated the effect of bL on mammosphere formation using breast cancer stem cell (BCSC) marker positive cells, MDA-MB-231. Methods: MDA-MB-231 Cells, which is negative for NQO1 expression, was constructed to stably express NQO1(NQO1 stable cells) to see the effect of bL. The effect of bL on cells were evaluated by wound healing and Transwell cell culture chambers, and ALDEFLUOR assay. Results: Here, we show that bL inhibited the proliferative ability of mammosphere derived from BCSC marker-positive cells, MDA-MB-231, in an NQO1-dependent manner. bL treatment efficiently downregulated expression level of BCSC markers CD44, ALDH1A1, and DLGAP5 that recently identified as a stem cell proliferation marker in both cultured cells and mammosphered cells. Moreover, bL efficiently downregulates cell proliferation and migration activities. Conclusions: These results strongly suggest that bL could be a therapeutic agent targeting breast cancer stem cells with proper NQO1 expression.

Extracts obtained from leaves of Moringa tree (Moringa oleifera) are a rich source of many bioactive compounds: flavonoids, phenolic acids or carotenoids. It also contains such components as, vitamins (A, C, niacin, pantothenic acid), alkaloids, tannins or saponins. Extracts and plant substances derived from the leaves of Moringa oleifera L. have a strong antioxidant, toning and anti-inflammatory effect. The work attempts to obtain a multifunctional plant extract derived from Moringa tree leaves. Obtained extracts was analyzed for their biochemical and physicochemical properties. The obtained results indicate on a strong antioxidative potential of the tested extracts. The further step was an attempt to apply the extracts in the model body wash cosmetic. The biological activity of extracts and model cosmetic formulation were assayed by in vitro analysis on two human cell lines: keratinocytes (HaCat,) and fibroblasts (BJ). The results showed that the tested extracts may affect on increasing of cell proliferation and reduce oxidative stress in cells. The addition of the tested extracts to the model cosmetic formulation, were contributed to the reduction of their ability to irritate the skin and improve the safety of use of the product.

Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhiza bunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and a reduction in angiogenesis. We further investigated the anti-cancer effects of CTT in A549 and H460 which are NSCLC cell lines. CTT treatment in NSCLC cells reduced cell growth through PI3K/Akt/GSK3β pathway inhibition, G0 / G1 cell cycle arrest, and the activation of apoptosis. CTT induced increase of Bax and cleavage of apoptosis-related signaling such as caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of anti-apoptosis related signaling such as Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. In addition, CTT reduced the protein expression of the PI3K/Akt/GSK3β signaling pathway related to cell proliferation. These results highlight the latent potential of CTT as natural therapeutic agent for NSCLC.

A global revolution in information and communication technologies (ICT) has occurred over the past few decades, emerging first in industrialized countries and then in developing countries. While researchers have examined many facets of the ICT revolution, relatively little work has systematically examined the degree to which ICT has reduced natural disaster vulnerability. In this article we use cross-country data over the 1980-2013 period to estimate the relationship between newly-emerging cell phone access/use and disaster-induced fatalities. Our estimates suggest that a one-standard-deviation increase in cell phone usage reduces disaster fatalities by nearly one half. The estimated effect increases to almost three quarters for geologic events where people are typically afflicted without warning. The largest marginal benefit from cell phones in terms of saving lives come from events where there is typically no warning, thus many are caught by surprise; cell phones are used to call for help and coordinate assistance.

An adaptive operation strategy for on-demand control of DMFC system is proposed as an alternative method to enhance the voltage stability. Based on a single-cell DMFC stack, a newly simplified semi-empirical model is developed from the uniform-designed experimental results to describe the I-V relationship. Integrated with this model, the multi-objective optimization method is utilized to develop an adaptive operation strategy. Although the voltage instability is frequently encountered in unoptimized operations, the voltage deviation is successfully decreased to a required level by adaptive operations with operational adjustments. Moreover, the adaptive operations are also found to be able to extend the range of operating current density or to decrease the voltage deviation according to ones requirements. Numerical simulations are implemented to investigate the underlying mechanisms of the proposed adaptive operation strategy, and experimental adaptive operations are also performed on another DMFC system to validate the adaptive operation strategy. Preliminary experimental study shows a rapid response of DMFC system to the operational adjustment, which further validates the effectiveness and feasibility of the adaptive operation strategy in practical applications. The proposed strategy contributes to a guideline for the better control of output voltage from operating DMFC systems.

Lamin A, B and C, the nuclear intermediate-filament proteins, play a role in epigenetic regulation. While Lamin B is expressed in all nucleated cells studied, Lamin A/C are transcribed in most somatic cell types except mature B lymphocytes. Since Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with tumorigenic processes and is known to alter the epigenotype of its host cells, we studied the expression of the LMNA gene and its epigenetic marks in EBV-carrying human lymphoid cell lines. We observed a high lamin A/C mRNA and protein expression in EBV-immortalized lymphoblastoid cell lines (LCLs) and in group III Burkitt lymphoma (BL) lines where hypomethylated first exons were observed with activating histone marks. In most cell lines with low promoter activity a highly methylated first exon could be detected. Our data showed that methylation of the first exon of LMNA was associated with the downregulation of LMNA expression whereas euchromatic histone marks were enriched at active LMNA promoters in EBV-immortalized LCLs. These data suggest a role for viral latency products to activate LMNAp in EBV-infected latency type III B cells in vitro. Expression of lamin A/C may contribute to the establishment of activated B cell phenotype that needs further explorations.

Electrostatic endothelial cell seeding has evolved as an exceptional technique to improve the efficiency of cell seeding in terms of frequency of attached cells and the amount of cell adhesion for the treatment of vascular diseases. In the recent times, both untreated and superhydrophilic thin film nitinol (TFN) have exhibited strong prospect as substrates for creation of small-diameter endovascular grafts due to their hallmark properties of superelasticity, ultra low-profile character, grown hemocompatible oxide layer with the presence of a uniform endothelial layer on the surface. The purpose of the current study is to understand the effects of endothelial cell seeding parameters (i.e., applied voltage, incubation time, substrate chemistry and cell suspension solution) to investigate the cell seeding phenomenon and to improve the cell adhesion and growth on the TFN surface under electrostatic transplantation. Both parallel plate and cylindrical capacitor models were used along with the Taguchi Design of Experiment (DOE) methods to design in vitro test parameters. A novel in vitro system for cylindrical capacitor model was created using a micro flow pump, micro incubation system, and silicone tubings. The augmented endothelialization on thin film nitinol was developed to determine the effect of cell seeding and deployed in a 6 Fr intravascular catheter setup. Cell viability along with morphology and proliferation of adhered cells were evaluated using fluorescent and scanning electron microscopy. Our results demonstrated that the maximum number of cells attached on STFN in the catheter was observed in 5V with the 2 hr exposure of in the cell culture medium (CCM) solution. The condition showed 5V voltage with 0.68×10-6 µC electrostatic charge and 5.11 V·mm-1 electric field. Our findings have first demonstrated that the electrostatic endothelialization on the superhydrophilic thin film nitinol endograft within the catheter prior to the endovascular procedure could enhance the biocompatibility for low-profile endovascular applications.

Recurrent pregnancy loss (RPL) affects around 2 % of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene polymorphisms have been associated with RPL. Some polymorphisms are increased in women of Asian or Caucasian race. In admixed RPL populations, the information on possible genetic links is scarce and contradictory. The study aimed to assess the frequency of two SNP in different enzymes involved in medical conditions observed during pregnancy. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics. It is present in ovaries, and it is hormonally regulated. The endothelial nitric oxide synthase forms nitric oxide from arginine and is involved in vascular tone. Two SNPs, rs1051740 and rs1799983, were assessed. The study included 26 controls and 63 primary RPL patients. Significant differences were observed in the frequencies of both SNP (p<0.05). The frequency of mutated alleles was higher in patients. Double mutated homozygotes were encountered only in RLP patients (p<0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.

Analysis of complex DNA mixtures is limited by the selected genetic markers characterized and assay technology. Small panels of short tandem repeats (STRs) are the current standards in most countries. Extension of STRs with hundreds of single nucleotide polymorphisms (SNPs) is now commercially available. The current set of extension SNPs focus on phenotypic and biogeographic ancestry informative SNPs. Larger panels with thousands of SNPs have been developed that can identify up to 10 contributors to forensic DNA samples. Herein, multiple sets of SNPs were selected with the focus of increasing the upper limit of detectable contributors. Larger SNP panel sets with lower minor allele frequency (MAF) alleles can detect large numbers of contributors to in silico mixtures of randomly selected profiles from the 1,000 Genomes project. These results provide a path to enable characterization of complex DNA mixtures that are currently impossible to analyse.

Japan has the world’s largest old population ratio, and aging is an urgent societal issue. As global trends seem to be following Japan’s social changes, there is an emphasis on municipalities becoming more age-friendly. Hence, we examine the age-friendliness of 135 Japanese municipalities, selecting 240 resident architectural designers and constructors to assess their municipalities, using the Age-Friendly Cities and Communities Questionnaire (AFCCQ). The findings indicate that Japan lacks “outdoor spaces and buildings.” Additionally, the evaluation of “housing,” “community support and health services,” and “transportation” in populated municipalities in the past five years is significantly higher than those in depopulated ones. Age-friendliness is significantly affected in the AFCCQ total score (hereafter, Score) based on “housing,” “social participation,” “community support and health services,” “transportation” and “financial situation” evaluations. High specificity (0.939) was found when the Score was treated as a marker of depopulation and, therefore, an age-friendly approach is a necessary condition to prevent depopulation. Furthermore, a lack of “communication and information” is observed in municipalities with a higher rate of single-person households aged 65 years and above. Therefore, resident architectural designers’ and constructors’ assessments, combined with the AFCCQ can be a powerful tool in evaluating the age-friendliness of municipalities.

The inverse finite element method (iFEM) is a novel method for reconstructing the full-field displacement of structures by discrete measurement strain. In practical engineering applications, the accuracy of iFEM is reduced due to the positional offset of strain sensors during installation, and errors in structural installation. Therefore, coarse and fine two-stage calibration (CFTSC) method is proposed to enhance the accuracy of the reconstruction of structures. Firstly, the coarse calibration is based on a single-objective particle swarm optimization algorithm to optimize the displacement-strain transformation matrix related to the sensor position. Secondly, as selecting different training data can affect the training effect of self-constructed fuzzy networks, this paper proposes to screen the appropriate training data based on residual analysis. Finally, the experiments of the wing integrated antenna structure verify the efficient of the method on the reconstruction accuracy of the structural body displacement field.

We have shown that lipid-associated loci discovered by genome-wide association studies (GWAS) have pleiotropic effects on lipid metabolism, carotid intima-media thickness (CIMT), and CAD risk. Here, we investigated the impact of lipid-associated GWAS loci on the efficacy of rosuvastatin therapy in terms of changes in plasma lipid levels and CIMT. The study comprised 116 CAD patients with hypercholesterolemia. CIMT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were measured at baseline and after 6 and 12 months of follow-up, respectively. Genotyping of fifteen lipid-associated GWAS loci was performed by the MassArray-4 System. Linear regression analysis adjusted for sex, age, body mass index, and rosuvastatin dose was used to estimate the phenotypic effects of polymorphisms, and P-values were calculated through adaptive permutation tests. Over one-year therapy, a decrease in CIMT was linked to rs1689800, rs4846914, rs12328675, rs55730499, rs9987289, rs11220463, rs16942887, and rs881844 polymorphisms (Pperm&lt;0.05). TC change was associated with rs55730499, rs11220463, and rs6065906; LDL-C change was linked to the rs55730499, rs1689800, and rs16942887 polymorphisms; and TG change was linked to polymorphisms rs838880 and rs1883025 (Pperm&lt;0.05). In conclusion, the polymorphisms rs1689800, rs55730499, rs11220463, and rs16942887 were found to be predictive markers for multiple antiatherogenic effects of rosuvastatin in CAD patients.

Viral infections can endanger public health by causing serious illness, leading to pandemics and burdening healthcare systems. Moreover, in the situation of a global spread, disruptions occur in every aspect of life including business, education, and social life. Fast and accurate diagnosis of viral infections has huge implications for saving people’s lives, preventing spread of the diseases, and minimizing social and economic damages. In the last decades, polymerase chain reaction (PCR) based techniques have been frequently used to detect viruses in the clinic. However, in a situation where rapid virus detection is the primary measure in preventing the spread, as in the case of ongoing COVID-19 pandemic, disadvantages of PCR, such as long processing times and requirement of sophisticated laboratory instruments, have been faced. Due to the urgent need for accurate techniques for virus detection, biosensor systems involved in many applications in biological detection are being developed for rapid, real-time, and high-throughput detection of viruses. Among various sensing platforms, optical devices are of great interest due to their advantages such as high sensitivity and direct readout. In the current review, usability of sensing techniques depending on optical phenomena, such as fluorescence-based sensors, surface plasmon resonance (SPR), surface enhanced Raman scattering (SERS), optical resonators and interferometry-based platforms, is discussed for virus diagnostics applications. Then, we focus on an interferometric biosensor developed by our group, single-particle interferometric reflectance imaging sensor (SP-IRIS), which has the capability to visualize single nanoparticles, to demonstrate its application for digital virus detection.

Biological systems are highly regulated. They are also highly resistant to sudden perturbations enabling them to maintain the dynamic equilibrium essential for sustenance of life. This robustness is conferred by regulatory mechanisms that influence the activity of enzymes/proteins within their cellular context, to adapt to changing environmental conditions. However, the initial rules governing the study of enzyme kinetics were tested and implemented for mostly cytosolic enzyme systems that were easy to isolate and/or recombinantly express. Moreover, these enzymes lacked complex regulatory modalities. Now, with academic labs and pharmaceutical companies turning their attention to more complex systems (for instance, multi-protein complexes, oligomeric assemblies, membrane proteins and post-translationally modified proteins), the initial axioms defined by Michaelis-Menten (MM) kinetics are rendered inadequate and the development of a new kind of kinetic analysis to study these systems is required. The current review strives to present an overview of enzyme kinetic mechanisms that are atypical and, oftentimes, do not conform to the classical MM kinetics. Further, it presents initial ideas on the design and analysis of experiments in early drug-discovery for such systems, to enable effective screening and characterisation of small-molecule inhibitors with desirable physiological outcomes.

Abstract Antibacterial activities can be improved using mixed ligands. Mixed ligands involved in this research are sodium sulfadiazine (Na-sfz) and dithiocarbamate (ai-dtc). One-pot synthesis was used to synthesize ligand of aniline dithiocarbamate (ai-dtc) and the corresponding coordination compounds of [VO(sfz)(ai-dtc)] and [Zn(sfz)(ai-dtc)]. Crystals of ai-dtc, which grew from the solution when refrigerated after five days, were diffracted with technique of single crystal x-ray crystallography to reveal the structure. Other characterization techniques involving physicochemical parameters, FT-IR, UV-Vis and NMR (1H NMR and 13C NMR) were carried out on ligands of ai-dtc, sfz and corresponding coordination compounds. Differences in results of FT-IR, UV-Vis and NMR between ligands and their respective metal ions confirmed the coordination. The in vitro antibacterial studies showed that the ligands (not the metal complexes) had modest activity against Gram negative bacteria: Staphylococcus aureus, whereas, the coordination compounds had modest activities against the Gram negative bacteria: Escherichia coli and Pseudomonas aeruginosa.

Neutrosophic cubic set is the hybridization of the concept of neutrosophic set and interval neutrosophic set. Neutrosophic cubic set has the capacity to express the hybrid information of both the interval neutrosophic set and the single valued neutrosophic set simultaneously. As newly defined, little research on the operations and applications of neutrosophic cubic sets appear in the current literature. In the present paper we propose the score, accuracy functions for neutrosophic cubic sets and prove their basic properties. We firstly develop TODIM method to solve multi attribute group decision making in neutrosophic cubic set environment, which we call NC-TODIM. Also, we solve a MAGDM problem using the proposed NC-TODIM method to show the applicability and effectiveness of the developed method. We also conduct sensitivity analysis to show the impact of ranking order of the alternatives for different values of attenuation factor of losses for multi-attribute group decision making problem.

The biophysical consequences of nanoscale curvature have been challenging to resolve due to size-dependent membrane behavior and the experimental resolution limits imposed by optical diffraction. Recent advances in nanoengineering and super-resolution techniques have enabled new capabilities for creating and observing curvature. In particular, draping supported lipid bilayers over lithographically patterned substrates provides a model system for endocytic pits. The experiments and simulations presented below describe the possible detection of membrane curvature through fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS), single particle tracking (SPT), and polarized localization microscopy (PLM). FRAP and FCS depend on diffraction-limited illumination and detection. In particular, a simulation of FRAP shows no effects on lipids diffusion due to a 50 nm diameter membrane bud at any stage in the budding process. Simulated FCS demonstrated small effects due to a 50 nm radius membrane bud that was amplified with curvature-dependent lipid mobility changes. However, PLM and SPT achieve sub-diffraction-limited resolution of membrane budding and lipid mobility through the identification of the single-lipid positions with ≤15 nm spatial and ≤20 ms temporal resolution. By mapping the single-lipid step lengths to locations on the membrane, the effects of curvature on lipid behavior have been resolved.

The shortage of physicians in rural communities contributes to increased mortality rates among Medicare beneficiaries. This increase in mortality risk is commonly due to diseases such as heart disease and cancer, including melanoma and non-melanoma skin cancer (NMSC). Mohs micrographic surgery (MMS) is considered the gold-standard treatment for NMSC tumors, however, due to a shortage of dermatologists and Mohs surgeons in rural areas, access to MMS is limited. In these areas, image guided superficial radiation therapy (IGSRT) serves as a viable option for the treatment of NMSC lesions, with fewer recurrences and 99% cure rates, which are comparable to MMS cure rates. IGSRT is performed in dermatology clinics with support from a multidisciplinary team, including radiation therapists, medical physicists, radiation oncologists, and dermatologists. As IGSRT is able to be performed by general dermatologists, Medicare beneficiaries in rural communities will have an increase in access to treatment options and a decrease in delayed skin cancer treatment.

The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multiscale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review mathematical modelling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating in vivo cellular dynamics and to reaching a next-generation multiscale picture of T-cell development.

: Image guided superficial radiation therapy (IGSRT) combines superficial radiation therapy (SRT) with full dermal visualization (FDV) via high resolution dermal ultrasound (HRDUS) for the treatment of non-melanoma skin cancer (NMSC). The gold standard for IGSRT delivery includes a comprehensive cancer care model with support for the dermatologists by a multidisciplinary team. When delivered in this model, IGSRT can achieve cure rates of 99% for treatment of NMSC. This paper focuses on the benefits of IGSRT during therapy. Medical records from 7 dermatology clinics of 883 patients with 1,507 cases of NMSC treated with IGSRT be-tween 2017 and 2018 were retrospectively reviewed. 92% of the NMSC lesions showed daily depth fluctuations, 60.32% of lesions did not require changes during therapy, and nearly 40% of lesions required at least one compensatory change during therapy. 83% of NMSC lesions were labeled high-risk based on the 2024 NCCN guidelines. Increasing and decreasing tumor depth measurements during IGSRT inform dermatologists when adaptive changes in energy (kV), TDF and dose will result in more efficacy and less toxicity, respectively.

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a life-long asymptomatic balance between infected cells and host antiviral immunity, but 5–10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides also promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of viral pathogenicity. As CD4+ T cells play a central role in host immunity, deregulation of their function and differentiation by HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs immunological conditions. Various therapeutic approaches have been developed to treat these abnormalities. Allogeneic hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL; however, the patient's immune state may also contribute to its outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, also depends on immune functions, such as antibody-dependent cytotoxicity. In this review, we comprehensively summarize the immunological pathogenesis of HTLV-1 infection in ATL and integrate clinical findings to determine the factors to be considered for developing treatment strategies for ATL.

The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.

The effectiveness of immunotherapy for cervical adenocarcinoma (CA) has not been demonstrated yet. It may be possible for us to use programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and CD8 as biomarkers of response to immune therapy in CA patients. In the present study, we aimed to investigate whether the expression levels of PD-1, PD-L1, and CD8 can predict the prognosis of CA patients and their response to ICI therapy. The levels of the PD-1, PD-L1, and CD8 proteins were analyzed by immunohistochemical analysis from formalin-fixed, paraffin-embedded tumor samples. The correlation between the expression levels and patient prognosis was analyzed by the Kaplan–Meier method and univariate and multivariate Cox proportional hazard regression model. We observed a significant inverse-correlation between the PD-1 and CD8 expression (p=0.001, chi square test). We also found a significant inverse-correlation between the PD-L1 and CD8 expression (p=0.027). The overall survival was significantly worse in patients with positive PD-1 expression (p=0.027). Similarly, the progression-free survival was also worse (p=0.087). Our results demonstrate that a high level of PD-1 expression is associated with a poor prognosis in CA patients. Further research is necessary to identify the molecular mechanisms that mediate this association.

Psoriasis is a chronic immune-mediated skin disease that involves interaction of both immune and skin cells, and is characterized by cytokine-driven epidermal hyperplasia, deviant differentiation, inflammation and angiogenesis. Because available treatments for psoriasis have significant limitations, dietary products are potential natural sources of therapeutic molecules, which can rescind molecular defects associated with psoriasis and could be developed for its management. Fisetin (3,7,3′,4′- tetrahydroxyflavone), a phytochemical naturally found in pigmented fruits and vegetables has demonstrated pro-apoptotic and antioxidant effects in several malignancies. This study utilized biochemical, cellular, pharmacological and tissue-engineering tools to characterize the effects of fisetin on normal human epidermal keratinocytes (NHEKs), peripheral blood mononuclear cells (PBMC) and CD4+ T lymphocytes in 2D and 3D psoriasis-like disease models. Fisetin treatment of NHEKs dose and time-dependently induced differentiation and inhibited interleukin-22-induced proliferation, as well as activation of the PI3K/Akt/mTOR pathway. Fisetin treatment of TNF-α-stimulated NHEKs significantly inhibited the activation of p38 and JNK, but had no effect on ERK1/2. In addition, fisetin treatment significantly decreased the secretion of Th1/Th-17 pro-inflammatory cytokines, particularly IFNγ and IL-17A by 12-O- tetradecanolylphorbol 13-acetate (TPA)-stimulated NHEKs and anti-CD3/CD28-activated human PBMCs. Furthermore, we established the in-vivo relevance of fisetin functions, using a 3D full-thickness human skin model of psoriasis (FTRHSP) that closely mimics in-vivo human psoriatic skin-lesions. Herein, fisetin significantly ameliorated psoriasis-like disease features, and decreased the production of IL-17 by CD4+ T lymphocytes co-cultured with FTRHSP. Collectively, our data identify pro-differentiative, anti-proliferative and anti-inflammatory effects of fisetin, via modulation of PI3K-Akt-mTOR and p38/JNK pathways and the production of cytokines in 2D and 3D human skin model of psoriasis. These results suggest that fisetin has a great potential to be developed as an effective and inexpensive agent for the treatment of psoriasis and other related inflammatory skin disorders.

Ecklonia cava (E.cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.

Taking into consideration the arising resistance towards the currently available antimycobacterial, there is still an unmet need for the development of new chemotherapeutic agents to combat the infectious agent. This study presents the X-ray single-crystal analysis to verify the structure of leading sulfonyl hydrazone 3b, which have proven their potent antimycobacterial activity against Mycobacterium tuberculosis H37Rv with MIC value of 0.0716 μM, respectively, low cytotoxicity and very high selectivity indexes (SI=2216) and fully characterized by NMR and HRMS methods. Furthermore, this study assessed the ex vivo antioxidant activity, acute and subacute toxicity, and in vitro inhibition capacity against enoyl-ACP reductase of hydrazones 3a and 3b, as 3a was identified as the second leading compound in our previous research. Compared to isoniazid, compounds 3a and 3b demonstrated lower acute toxicity for intraperitoneal administration, with LD50 values of 866 and 1224.7 mg/kg, respectively. Subacute toxicity tests, involving the repeated administration of a single dose of the test samples per day, revealed no significant deviations in hematological and biochemical parameters or pathomorphological tissues. The compounds exhibited potent antioxidant capabilities, reducing malondialdehyde (MDA) levels and increasing reduced glutathione (GSH). Enzyme inhibition assays of the sulfonyl hydrazones 3a and 3b with IC50 values of 18.2 µM and 10.7 µM, respectively and molecular docking studies revealed enoyl acyl carrier protein reductase (InhA) as the possible target enzyme of the compounds to show their antitubercular activities. In conclusion, the investigated sulfonyl hydrazones display promising antitubercular drug-like properties and warrant further investigation.

Several studies in computer vision have examined specular removal, which is crucial for object detection and recognition. This research has traditionally been divided into two tasks: specular highlight removal, which focuses on removing specular highlights on object surfaces, and reflection removal, which deals with specular reflections occurring on glass surfaces. In reality, however, both types of specular effects often coexist, making it a fundamental challenge that has not been adequately addressed. Recognizing the necessity of integrating specular components handled in both tasks, we constructed a Specular-Light (S-Light) DB for training single-image-based deep learning models. Moreover, considering the absence of benchmark datasets for quantitative evaluation, the Multi-Scale Normalized Cross Correlation (MS-NCC) metric, which considers the correlation between specular and diffuse components, was introduced to assess the learning outcomes.

Bacteria’s ability to withstand the detrimental effects of antimicrobials may take the form of resistance or tolerance with the minimum inhibitory concentration (MIC), the mutant prevention concentration (MPC), and the mutant selection window as salient concepts. Isolates exposed for 30 days to different concentrations of selected antibiotics, biocides, and heavy metals, singly and in combination, were additionally exposed to very high (15 × MIC) concentrations of ampicillin., and their tolerance was calculated the time to kill 99.9% of the isolate population (MDK99.9). These values were increased by 30 to 50% in test isolates compared to the untreated control. BAC 10-exposed isolates had the highest tolerance increase, and the tolerance appeared to originate from two sources, i.e., stochastic persistence and genetic-induced persistence, involving multiple genes using diverse mechanisms. The mutant selection window of the isolates to ampicillin, amoxicillin, and oxytetracycline also slightly increased compared to the control, indicating the amplification of persister cells during the 30-day exposure. These findings indicate that bacterial exposure to sub-inhibitory concentrations of environmental chemical stressors may not always result in the development of antimicrobial resistance but could initiate this process by selecting for persisters that could evolve into resistant isolates.

The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR=0.56 95%CI 0.35-0.90, Pperm=0.017) and rs2397147 (OR=0.54 95%CI 0.30-0.98, Pperm=0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C×rs17883901-G/G was associated with decreased risk of psoriasis (FDR-adjusted P=0.014), whereas diplotype rs6933870-G/G×rs17883901-G/G (FDR-adjusted P=0.045) showed association with increased disease risk in females. Joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on the risk of psoriasis were observed (Pperm≤0.05). Furthermore, we found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features.

We construct a family of two-step optimal fourth order iterative methods for finding single root of non-linear equations. We generalize these methods to simultaneous iterative methods for determining all the distinct as well as multiple roots of single variable non-linear equations. Convergence analysis is present for both cases to show that the order of convergence is four in case of single root finding method and is twelve for simultaneous determination of all roots of non-linear equation. The computational cost, Basin of attraction, efficiency, log of residual and numerical test examples shows, the newly constructed methods are more efficient as compared to the existing methods in literature.

Pasmo (Septoria linicola) is a fungal disease causing major losses in seed yield and quality, and stem fibre quality in flax. Pasmo resistance (PR) is quantitative and has low heritability. To improve PR breeding efficiency, the accuracy of genomic prediction (GP) was evaluated using a diverse worldwide core collection of 370 accessions. Four marker sets, including three defined by 500, 134, and 67 previously identified quantitative trait loci (QTL) and one of 52,347 PR-correlated genome-wide single nucleotide polymorphisms, were used to build ridge regression best linear unbiased prediction (RR-BLUP) models using pasmo severity (PS) data collected from field experiments performed during five consecutive years. With five-fold random cross-validation, GP accuracy as high as 0.92 was obtained from the models using the 500 QTL when the average PS was used as the training dataset. GP accuracy increased with training population size, reaching values >0.9 with training population size greater than 185. Linear regression of the observed PS with the number of positive-effect QTL in accessions provided an alternative GP approach with an accuracy of 0.86. The results demonstrate the GP models based on marker information from all identified QTL and the 5-year PS average is highly effective for PR prediction.

Weed competitive ability (WCA) is a desirable key trait for the improvement of grain yield under direct-seeded rice (DSR) and the aerobic rice ecosystem. The present study targeted screening of 167 introgression lines (ILs) of a Green Super Rice (GSR) IR2-6 population derived from a cross between Weed Tolerant Rice 1 (WTR1) as the recipient parent and Y134 as the donor parent developed at IRRI for weed competitiveness in screen house conditions (SHC). The ILs were phenotyped for WCA traits such as early seed germination (ESG) and early seedling vigor (ESV) in Petri dishes and pot experiment conditions. The results of phenotypic variance revealed ESG-related traits, especially first germination count (1st GC) that positively correlated with second germination count (2nd GC), germination percentage (GP), total dry weight (TDW), total fresh weight (TFW), and vigor index (VI-1), whereas, in ESV, all the traits were positively correlated with each other except for three traits: root dry weight (RDW), 1st GC, and GP-2. The ESG and ESV traits are vital for weed competitiveness. A 6K SNP array was used to study the genetic association for the WCA traits. Forty-four QTLs for WCA traits were mapped on all chromosomes (except on chromosomes 4 and 8) through single marker analysis (SMA). Out of 44 QTLs, 29 were associated with ESG traits and 15 with ESV traits, with LOD scores of 2.93 to 8.03 and 2.93 to 5.04 and explained phenotypic variance ranging from 7.85% to 19.9% and from 7.85% to 13.2%, respectively. However, 31 QTLs were contributed by a negative additive allele from Y134, whereas a positive additive allele was contributed by WTR1 in 13 QTLs. Among them, two QTL hotspot regions were mapped on chromosome 11 (24.7-27.9 Mb) and chromosome 12 (14.8-17.4 Mb). The majority of the QTLs related to WCA traits were grouped into two QTL hotspots: QTL hotspot-I (qAFW11.1, qFC11.1, qFC11.2, qSC11.1, qGP-111.1, qGP-111.2, qTFGS11.1, qVI-111.1, and qVI-111.2) and QTL hotspot-II (qFC12.1, qFC12.2, qSC12.1, qFC12.2, qGP-112.1, qGP-112.2, qTFGS12.1, qTFGS12.2, qVI-112.1, qIV12.2, qFC12.1, and qGC12.2), and a few of them were co-localized on chromosomes 11 and 12. Further, we fine-tuned in the genomic regions of QTL hotspots and identified a total of 13 putative candidate genes on chromosomes 11 and 12 collectively. The present study is the first report on the genetic basis of WCA-related traits and the co-localized QTLs, which could be highly valuable in future breeding programs aiming to improve WCA in rice.

Abstract: Two novel low-dimensional molecular magnetic materials were prepared by a self-assembling of 3d- and 5d-metal complexes. These are the first neutral heterobimetallic cyanobridged compounds involving one anisotropic Mn(III) Schiff base complex and one octacyanotungstate(V) per molecular unit. A slow diffusion of the constituents’ solutions leads to a formation of the 0D crystalline complex 1 due to coordination of a water molecule to the Mn center prevents a polymer formation. A rapid mixing of reagents results in a precipitation of the microcrystalline powder of the complex 2, which on a totality of experimental data possess 1D polymeric structure. The magnetic studies have shown that antiferromagnetic exchange interactions are dominating in 1 J/k_B= -13.1(7) K, D=-3.0(1.3) K, zJ'= -0.16(20) K and g_av=2.00(1); while the presence of the significant intramolecular Mn(III)–W(V) ferromagnetic couplings through cyanide bridges is characteristic for 2 (J/k_B = 46.1(5) K g_Mn = 2.11(3), fixed g_W = 2.0). Due to the weak interchain interactions, zJ'/k_B = –0.8(2) K, compound 2 is a metamagnet with the Néel temperature of 9.5 K undergoing a spin-flip transition at 2 kOe. The slow magnetization dynamics of 2 was investigated at DС field of 0 and 2 kOe, giving the values of τ₀ 32(15) and 36(15) ps respectively, well within the range typical for SCMs. The respective ∆_τ/k_B values were 48.4(1.2) and 44.9(1.0) K.

The high prevalence of human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) is well-established, with p16 expression being a strong predictor. HPV-related tumors exhibit unique mechanisms targeting p16 and p53 proteins. However, re-search on HPV prevalence and the combined predictive value of p16 and p53 expression in head and neck cutaneous squamous cell carcinomas (HNCSCC), especially in Asian populations, is limited. This retrospective study surveyed 62 HNCSCC patients (2011–2020), excluding those with facial warts or other skin cancers. All patients underwent wide excision and biopsy. Immuno-histochemical staining for HPV, p16, and p53 yielded both positive and negative results. The relevance of each marker was investigated by categorizing the tumor locations into high-risk (Area H) and mid-risk (Area M) zones based on recurrence frequency. Of the 62 patients, 20 (32.26%) were male, with an average age of 82.27 years (26–103). Area H included 19 cases (30.65%), with the eyelid and lip being the most common sites (five cases, 8.06%). Area M in-cluded 43 cases (69.35%), with the cheek being the most common site (29 cases, 46.77%). p16 ex-pression was positive in 24 patients (38.71%), p53 expression in 42 patients (72.58%), and HPV in five patients (8.06%). No significant association was found between p16 expression and HPV presence (p > 0.99), with a positive predictive value of 8.33%. This indicates that p16, a surrogate marker of HPV in OPSCC, is not a reliable marker for HPV in HNCSCC. This study enhances our understanding of the relationship between HPV, p53, and p16 in HNCSCC in Asian populations and offers valuable insights for further research.

EphB2 is a member of the Eph family tyrosine kinase receptors. EphB2 binds to ephrin-B1, ephrin-B2, and ephrin-B3, which are critical regulators of vascular and nervous development through controlling cell migration and axon guidance. EphB2 is overexpressed in tumors, including glioma, breast cancer, hepatocellular carcinoma, and malignant mesothelioma, and it functions as a tumor promoter. Therefore, the development of monoclonal antibodies (mAbs) against EphB2 is essential for tumor diagnosis and therapy for EphB2-positive tumors. In this study, we developed novel mAbs for human EphB2 using the Cell-Based Immunization and Screening (CBIS) method. One of the established anti-EphB2 mAbs, Eb2Mab-3 (mouse IgG1, kappa), reacted with EphB2-overexpressed Chinese hamster ovary-K1 (CHO/EphB2) and an endogenously EphB2-expressing cancer cell line (LS174T) by flow cytometry. Using flow cytometry, the dissociation constant (KD) values of Eb2Mab-3 for CHO/EphB2 and LS174T were determined as 1.1 × 10−9 M and 3.6 × 10−10 M, respectively. These results indicated that Eb2Mab-3 possesses a high affinity for detecting EphB2 and could apply to tumor therapy.

Targeting drugs to the central nervous system (CNS) is challenging due to the presence of the blood-brain barrier. (BBB). The cutting edge in nanotechnology generates optimism to overcome the growing challenges in biomedical sciences through effective engineering of nanogels. The primary objective of the present report was to develop and characterize biocompatible natural chitosan (CS)-based NG that can be tracked thanks to the tricarbocyanine (CNN) fluorescent probe addition of the biopolymer backbone. FTIR shed light on the chemical groups involved in the CS and CNN interactions and between CNN-CS with tripolyphosphate, the cross-linking agent. Both in vitro and in vivo experiments were carried out to determine if CS-NG can be utilized as therapeutic delivery vehicles directed towards the brain. An ionic gelation method was chosen to generate cationic CNN-CS-NG. DLS and TEM confirmed that these entities size fell into nanoscale. CNN-CS-NG was found to be non-cytotoxic as determined in the SH-SY5Y neuroblastoma cell line through biocompatibility assays. After cellular internalization, the occurrence of an endo-lysosomal escape (a crucial event for an efficient drug delivery) of CNN-CS-NG was detected. Furthermore, CNN-CS-NG administered intraperitoneally to female CF-1 mice were detected in different brain regions after 2 h of administration using fluorescence microscopy. To conclude, the obtained findings in the present report can be useful in the field of neuro-nanomedicine when designing drug vehicles with the purpose of delivering drugs to the CNS.

SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to explore the mechanisms behind the vascular and thrombotic events in COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the publicly available Gene Expression Omnibus (GEO) repository. In addition, HUVECs were treated with inactivated protein C before exposure to SARS-CoV-2 infection or a severe COVID-19 serum. An RT-qPCR array containing 84 related genes was used, and the candidate genes obtained were evaluated. Activated protein C levels were measured using an ELISA kit. We identified at the single-cell level the expression of several pro-inflammatory and pro-coagulation genes in endothelial cells from the patients with COVID-19. Furthermore, we demonstrated that exposure to SARS-CoV-2 promoted transcriptional changes in HUVECs that were partly reversed by the activated protein C pretreatment. We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus.

Background: The aim of this study was to investigate a series of complete blood cell count – based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. Methods: Consecutive patients with pathologically diagnosed stage III/IV NSCLC who underwent first-line chemoimmunotherapy were retrospectively enrolled. The clinical outcomes used for biomarker evaluation were Objective Response Rate (ORR) and Overall Survival (OS). Results: Non-responders had significantly higher values of neutrophil to lymphocyte ratio (NLR, median: 5.36; IQR: 2.78–10.82 vs. 3.31; IQR: 2.15–4.12, p = 0.019), neutrophil to monocyte ratio (NMR, median: 14.00; IQR: 8.82–21.20 vs. 9.20; IQR: 7.45–11.20, p = 0.013), and systemic inflammation index (SII, median: 1,395; IQR: 929–3,334 vs. 945; IQR: 552–1,373, p = 0.025), but only NLR and NMR remained independently related with clinical response in multivariate logistic regression. In univariate analysis white blood cells (OR:1.2202; 95% CI: 1.0339 - 1.4400, p=0.019), neutrophils (OR:1.2916; 95% CI: 1.0692 - 1.5604, p=0.008), NLR (OR:1.3601: 95% CI: 1.0949 - 1.6896, p=0.005) and NMR (OR:1.2159; 95% CI: 1.00396 - 1.4221, p=0.015) were significantly associated with survival; Cox regression models confirmed that neutrophils, NLR and MLR were independently associated with survival; NLR at a cut-off value of 4.0 showed the better AUC (0.749) in predicting survival. Conclusions: Baseline complete blood cell count biomarkers, especially the NLR, can predict clinical outcomes in patients with advanced NSCLC treated with first-line chemoimmunotherapy.

In this research work, we describe the preparation process, characterization, and photo-physical studies of an ionic liquid (IL) based semiconductor Zinc Oxide (ZnO) nanoparticles synthesized by an economical wet chemical precipitation method. For the first time, an IL was synthesized with the help of a chemical reaction between triethylamine (TEA) and bromoacetic acid (BAA). A polyamide dye was prepared by a reaction between two monomers, ethylenediamine (EDA) and trimesoylchloride (TMC), under room temperature conditions. The polyamide dye was capped on ZnO nanoparticles, and the final product was divided into three different samples, A, B, and C, according to level of concentrations of IL and Polyamide dye. These samples were characterized with X-Ray Diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Dynamic Light Scattering (DLS) spectra, Ultraviolet-Visible (UV-Vis), and Fluorescence spectroscopies. The formation of polyamide linkages in the ionic liquid has been confirmed by a spectroscopic method using Fourier Transform Infrared (FTIR) spectroscopy. The capping of polyamide dye molecules on the surface of ZnO nanoparticles revealed two things: (i) improved UV absorption spectra and (ii) enhanced luminescence in the photoluminescence spectra. Hence, during investigations, broad absorption bands were observed at peaks 263 nm, 278 nm, and 276 nm respectively for samples A, B, and C. Further, IL was used as an electrolyte or redox mediator and polyamide as a dye material in the fabrication of ZnO Dye-Sensitized Solar Cells (DSSCs). The samples A, B, and C were used in the fabrication of photo-anode assemblies for ZnO DSSCs. The ZnO DSSCs were tested under strong simulated light at Air Mass (AM) 1.5 solar irradiations. The observed photovoltaic results shown that solar cell SCB generated a maximum power conversion efficiency (η) of 5.65%, higher than the power conversion efficiencies of solar cells SCA (3.99%) and SCC (4.46%) respectively. The Incident Photon to Current Conversion Efficiency (IPCE) spectra values of ZnO DSSCs shown a significant improvement in the incident photon to current conversion efficiency of solar cell SCB (IPCE=61%) as compared to SCC (enhanced by 6%) and SCA (enhanced by 4%). Such solar cell assemblies can be suitable for green and clean energy applications.

The DEAD-box RNA helicase DDX3X is a multifunctional protein involved in RNA metabolism and stress responses. In this study, we investigated the role of RG/RGG motifs in the dynamic process of liquid-liquid phase separation (LLPS) of DDX3X using cell-free assays and explored their potential link to cancer development through bioinformatic analysis. Our results demonstrate that the number, location, and composition of RG/RGG motifs significantly influence the ability of DDX3X to undergo phase separation and form self-aggregates. Mutational analysis revealed that the spacing between RG/RGG motifs and the number of glycine residues within each motif are critical factors in determining the extent of phase separation. Bioinformatic analysis of cancer genomic datasets uncovered a significant enrichment of DDX3X mutations in RG/RGG motifs across multiple cancer types, particularly in the N-terminal region of the protein. Furthermore, we found that DDX3X is co-expressed with the stress granule protein G3BP1 in several cancer types and can undergo co-phase separation with G3BP1 in a cell-free system, suggesting a potential functional interaction between these proteins in phase-separated structures. DDX3X and G3BP1 may interact through their RG/RGG domains and subsequently exert important cellular functions under stress situation. Collectively, our findings provide novel insights into the role of RG/RGG motifs in modulating DDX3X phase separation and their potential contribution to cancer pathogenesis.

Galectins are a family of beta-galactoside-binding proteins that are characterised by their carbohydrate recognition domain (CRD) and include galectin-1 and galectin-3. These galectins have been implicated in numerous diseases due to their pleiotropic nature, including cancer and fibrosis, with therapeutic inhibitors being clinically developed to block the CRD. One of the early methods developed to characterise these galectins was hemagglutination of red blood cells. Although insightful this approach has been hampered by a lack of sensitivity and accurate quantification of the agglutination observed. In this study we aimed to validate a more precise and quantitative method to enable further investigation of differences between galectins in respect to agglutination induction in different blood groups as well as characterisation of small molecule inhibitors. Quantification of hemagglutination was shown to be optimal using U-bottom plates imaged and analysed with FIJI ImageJ rather than flat bottom plates read for absorbance on an optical density plate reader. Galectin-3-induced red blood cell agglutination efficacy increased significantly from blood group O to A to B. However, for both the galectin-1 monomer and concatemer a more comparable effect was observed between blood group B and O but with more potent effects than in blood group A. Inhibition assays for both galectin-3 and galectin-1 induced-hemagglutination were able to demonstrate clear concentration-responses and expected selectivity profiles for a set of small molecule glycomimetics, confirming historical profiles obtained in biochemical binding and functional cellular assays.

The refractive index of a liquid serves as a fundamental parameter reflecting its composition, thereby enabling the determination of component concentrations in various fields such as chemical research, food industry, and environmental monitoring. Traditional methods for refractive index (RI) measurement rely on light deflection angles at interfaces between the liquid and a material of known refractive index. In this paper, the authors present a new differential refractometer for highly sensitive measurement of RI differences between two liquid samples. Using a configuration with two cells equipped with flat parallel plates as measuring elements, the instrument facilitates accurate analysis. Namely, the sensor signals from both the solution and the solvent cuvette are generated simultaneously with one laser pulse, reducing the possible fluctuations of the laser radiation intensity. Our evaluation shows the high sensitivity of RI measurements (< 7 · 106), so this differential refractometer can be proposed not only as a high-sensitivity sensing tool that can be used for mobile detection of nanoparticles in solution samples, but also to determine the level of environmental nano-pollution using water (including rain, snow) samples from various natural as well as industrial sources, thus helping to solve some important environmental problems.

According to the ECCB, cancer represents the transition of a genomically damaged multicellular cell to a lower level of cell organization, controlled by the ancestral gene regulatory network (GRN) from the ancestral compartment of human and metazoan genomes. Cancer adopts ancient mechanisms and rules of the common ancestor, similar to those observed in parasitic amoebae. In cancer, the productive cell line generating CSCs is a non-gametogenic cancer germline. This germline proliferates through asymmetric cell division (ACD phenotype). CSCs lack proliferative capacity; they persist in hypoxic niches in a quiescent cell state or transition to an amplifying cell state that performs cyst-like polyploidization cycles, giving rise to precursors and CSCs capable of differentiation. Malignization arises from genomically dysfunctional tetraploid germline cells (DSCD phenotype) that proliferate in a precancerous stage through symmetric cell cycles. DSCD progeny undergo homotypic fusion, forming multinucleated genome repair syncytia (MGRS pathway) driving carcinogenesis. During tumorigenesis, metastasis, and recurrence, subsequent germline clones initiate a cascade of increasingly pathogenic CSCs through mechanisms such as heterotypic cell fusion, soma-to-germ transition, and polyploid giant cell structures (PGCCs). Irradiation and chemotherapies drive some of the very few surviving but dysfunctional CSCs through a PGCC repair pathway homologous to the MGRS pathway of carcinogenesis. The large number of PGCCs during metastasis and recurrence results from the perpetual germline cell damage and CSC poverty induced by oxygen levels above 6.0% O2 (germline hyperoxia).

Introduction: Signet-ring cells are typically associated with mucin-secreting epithelium thus most commonly found in a gastrointestinal tract, however not exclusively. Primary signet ring cell carcinoma of the prostate is a rare and poorly differentiated, aggressive acinar adenocarcinoma variant with a grim prognosis. Clinical case: In June of 2023 a 54-year-old Caucasian male came to the hospital complaining of lower urinary tract obstructive symptoms with occasional macrohematuria, non-specific body aches, and shortness of breath. A prostate specimen obtained in transurethral resection of the prostate was sent for histopathological examination. After a series of extraprostatic diagnostic workups including fibrogastroduodenoscopy, colonoscopy computed tomography imaging, and immunohistochemical studies, the patient was diagnosed with primary prostatic signet-ring cell adenocarcinoma st. IV. Unfortunately, the patient with the disease this advanced, PE, and third-degree thrombocytopenia was not a candidate for chemotherapy and died of cardiopulmonary insufficiency later that week. Discussion: Prostatic signet-ring cell carcinoma accounts for 0.02% of all prostate adenocarcinoma cases. Due to its nature and epidemiology, a diligent extraprostatic investigation has to be carried out. The disease often presents with unremarkable clinical symptoms and variable serum prostate-specific antigen results which may contribute to its late diagnosis which together with inconsistent immunohistochemical findings and unpredictable response to hormonal treatment pose both diagnostic and therapeutic challenges that negatively affect the prognosis. Conclusion: The study highlights the importance of a multidisciplinary approach and the need for diagnostic and therapeutic consensus within the research community in search of the primary site of the disease which may positively influence the prognosis.

Hypertensive diseases of pregnancy (HDP) represent a global clinical challenge, affecting 5-10% of women and leading to complications for both maternal well-being and fetal development. At the heart of these complications is endothelial dysfunction, with oxidative stress emerging as a pivotal causative factor. The reduction in nitric oxide (NO) bioavailability is a vital indicator of this dysfunction, culminating in blood pressure dysregulation. In the therapeutic context, although antihypertensive medications are commonly used, they come with inherent concerns related to maternal-fetal safety, and a percentage of women do not respond to these therapies. Therefore, alternative strategies that directly address the pathophysiology of HDP are required. This article focuses on the potential of the nitrate-nitrite-NO pathway, abundantly present in dark leafy greens and beetroot, as an alternative approach to treating HDP. The objective of this review is to discuss the prospective antioxidant role of nitrate. We hope our discussion paves the way for using nitrate to improve endothelial dysfunction and control oxidative stress, offering a potential therapy for managing HDP.

Diffuse midline gliomas are among the deadliest human cancers and have had little progress in treatment in the last 50 years. Cell cultures of these tumors have been developed recently, but it is unknown the degree to which such cultures retain the characteristics of the source tumors. DNA methylation profiling offers a powerful tool to look at genome-wide epigenetic changes that are biologically meaningful and can help assess the similarity of cultured tumor cells to their in vivo progenitors. Paraffinized diagnostic tissue from three diffuse intrinsic pontine gliomas with H3 K27M mutations was compared with subsequent passages of neurosphere cell cultures from those tumors. Each cell line was passaged 3-4 times and analyzed with DNA methylation arrays and standard algorithms that provided comparison of diagnostic classification and cluster analysis. All samples tested maintained high classifier scores and clustered within the reference group of H3 K27M-mutant diffuse midline gliomas. There was a gain of 1q in all cell lines, with two cell lines initially manifesting the gain of 1q only during culture. In vitro cell cultures of H3 K27M-mutant gliomas maintain high degrees of similarity in DNA methylation profiles to their source tumor, confirming their fidelity even with some chromosomal changes.

Epidemic diseases that arise from infectious RNA viruses, particularly influenza viruses, pose a constant threat to the global economy and public health. Viral evolution has undermined the efficacy of acquired immunity from vaccines and the antiviral effects of FDA-approved drugs. As such, there is an urgent need to develop new antiviral lead agents. Natural compounds, owing to their historical validation of application and safety, have become a promising solution. In this light, a novel marine bacterium, Pseudomonas sp. M20A4R8, has been found to exhibit significant antiviral activity [half maximal inhibitory concentration (IC50) = 1.3 µg/mL, selectivity index (SI) = 919.4] against influenza virus A/Puerto Rico/8/34, surpassing the activity of chloroquine. The antiviral response by M20A4R8 extract was induced during post-entry stages of the influenza virus, indicating suitability for post-application after the establishment of viral infection. Furthermore, post-treatment with M20A4R8 extract protected the host from virus-induced apoptosis, suggesting its potential use in acute respiratory disease complexes resulting from immune effectors' overstimulation and autophagy-mediated self-apoptosis. The extract demonstrated an outstanding therapeutic index against influenza virus A/Wisconsin/15/2009 (IC50 = 8.1 µg/mL, SI = 146.2) and B/Florida/78/2015 Victoria lineage (IC50 = 3.5 µg/mL, SI = 343.8), indicating a broad anti-influenza virus activity with guaranteed safety and effectiveness. This study provides a new perspective on mechanisms for preventing a broad spectrum of viral infections through antiviral agents from novel and natural origins. Future studies on a single or combined compound from the extract hold promise, encouraging its use in preclinical challenge tests with various influenza virus strains.

Redox mediators comprising I–, Co3+, and Ti3C2Tx MXene were applied to dye-sensitized solar cells (DSCs). In the as-prepared DSCs (I-DSCs), wherein hole conduction occurred via the redox reaction of I−/I3− ions, the power conversion efficiency (PCE) was not altered by the addition of Ti3C2Tx MXene. The I-DSCs were exposed to light to produce Co2+/Co3+-based cells (Co-DSCs), wherein the holes were transferred via the redox reaction of Co2+/Co3+ ions. A PCE of 9.01% was achieved in a Co-DSC with Ti3C2Tx MXene (Ti3C2Tx-Co-DSC), which indicated an improvement from the PCE of a bare Co-DSC without Ti3C2Tx MXene (7.27%). It was also found that the presence of Ti3C2Tx MXene in the redox mediator increased the hole collection, dye regeneration, and electron injection efficiencies of the Ti3C2Tx-Co-DSC, leading to an improvement in both the short-circuit current and the PCE when compared with those of the bare Co-DSC without MXene.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (&gt;12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.

Tumor immunotherapy represented by immune target blocking and chimeric antigen receptor cell therapy has developed rapidly. Among them, Natural Killer Cell (NK) is gradually becoming another preferred immunotherapy method after T cell immunotherapy because of its unique killing effect in innate immunity and adaptive immunity. Although NK cell therapy has achieved promising results in clinical trials, there are still some problems, such as low efficacy in solid tumors, insufficient penetration of NK cells and high cost of treatment. Nanomaterials are expected to be an excellent tool to improve the anti-tumor immune response of NK cells due to their advantages such as chemical specificity, biocompatibility and simple synthesis. Nanomaterials can enhance the cytotoxicity of NK cells, participate in the modification and noninvasive cell-tracking patterns of NK cells，and mediate their homing and infiltration, and thus significantly improve the efficiency of NK cell immunotherapy. In this review, we will briefly introduce the methods and mechanisms of tumor immunotherapy, emphasize the research progress of NK cell-based immunotherapy and imaging, and finally summarize the direction and research progress of nanomaterials in NK cell-based immunotherapy.

Although a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) serve as the cleaving protease of vWF-multimers, its role in liver ischemia-reperfusion injury (IRI), as well as partial liver transplantation (pLT), remains unknown. First, ADAMTS13 deficient mice were subjected to IRI to investigate the impact on hepatic IRI. Hepatic IRI significantly decreased serum ADAMTS13 activity, while simultaneously up-regulated intrahepatic vWF expression. Ablation of ADAMTS13 aggravated liver IRI by promoting platelet aggregation and disturbing microcirculation in the liv-er accompanied by exacerbated transaminase release and enhanced pro-inflammatory cytokine/chemokines levels. Adjunctive supplementation of recombinant ADAMTS13 (rADAMTS13) improved hepatic microcirculatory failure observed in ADAMTS13-null mice. Immunohistochemistry revealed massive platelet aggregation within hepatic micro-vasculatures in ADAMTS13-null mice, which was attenuated by rADAMTS13 treatment. Consequently, peripheral platelet counts, transaminase release, and pro-inflammatory cytokines/chemokines levels deteriorated in ADAMTS13-null mice, while ameliorated by rADAMTS13 administration. Notably, rADAMTS13 improved IRI-induced pathologies even in WT mice compared with those without. Next, we tested rADAMTS13 in the rat pLT model. Similarly, in rat pLT, ADAMTS13 supplementation attenuated the aforementioned pathologies observed in the experimental mouse model. In conclusion, ADAMTS13 plays a pivotal role in alleviating both hepatic microcirculation and inflammatory responses, thus providing a novel therapeutic approach against LT-related stress.

Purpose: The aim of the study is an approach to a nanocomposite with copper nanoparticles, constituting a bacteriostatic surface for maintaining the human lung cells' function. Methods: The polyelectrolyte layer coating with copper nanoparticles incorporated was designed. As a bacteriostatic factor, copper nanoparticles were applied as a colloidal solution of copper nanoparticles (ColloidCuNPs) and solution of copper nanoparticles (CuNPs). The influence of polyelectrolytes on selected Gram(+) and Gram(-) strains was examined. The function of the human adenocarcinoma A549 cell line of epithelial human lung cells cultured in the presence of nanocomposite layer coatings was analyzed, as well as their morphology using flow cytometry, fluorescence microscopy, and scanning electron microscopy. In addition, the material of layer coating was assessed using AFM and SEM-EDX characterization. Results: It was observed that polyelectrolytes polyethylenimine and poly-L-lysine do not induce proliferation of E.coli strain. On the other hand, it induces the proliferation of S. aureus strain. Due to CuNPs effectiveness against E.coli strain, CuNPs were selected for further research. The designed coatings at proper NPs share sustained the function of human lung cells cultured within 10 days of culture. The AFM and EDX characterization confirmed copper presence in the layer coating nanomaterial. The presence of CuNPs in polyethyleneimine-based nanocomposite deepens the bacteriostatic effect on E. coli compared with PEI alone. Meanwhile, incorporating CuNPs in PLL at share allowed A549 cell maintenance, did not exert a bacteriostatic influence on the examined strain.Conclusion: The platform based on polyelectrolytes incorporated with copper nanoparticles ensuring the growth and morphology of the human lung epithelial cells can be considered an element of the system components for medical devices for maintaining the human lung cells' function.

Nuclear speckles are compartments enriched in splicing factors present in the nucleoplasm of mammalian cells. Their morphology is linked to the transcriptional and splicing activities of the cell through a recruitment mechanism. Speckles have been studied mostly in mammalian culture cells, and few studies are devoted to speckles in tissue cells. In mammals, speckles are present in different tissues and their morphology also depends on the hormonal cycle in rats. In the present work, we explore whether a similar situation is also present in non-mammalian tissue cells dur-ing the reproductive cycle. We studied the speckled pattern in several tissues of a viviparous rep-tile, the lizard Sceloporous torquatus, during two different stages of reproduction. We used immu-nofluorescence staining against splicing factors in hepatocytes and oviduct epithelium cells and fluorescence and confocal microscopy. The distribution of splicing factors in the nucleoplasm of oviductal cells and hepatocytes coincides with the nuclear speckled pattern described in mam-mals. In addition, the morphology of speckles varies in oviduct cells at the two stages of the re-productive cycle analyzed, paralleling the phenomenon observed in the rat. The results show that the morphology of speckles in reptile cells depends upon the reproductive stage as it occurs in mammals.

Here we explore the emerging role of NKG2D CAR-T cell therapy in the realm of solid tumor treatment. Unique capabilities of NKG2D CAR-T cells to recognize stress-induced ligands on cancer cells are discussed, highlighting the therapy's potential for targeted and precise antitumor responses. We also examine the challenges and opportunities associated with NKG2D CAR-T cell therapy, emphasizing the ongoing advancements and clinical trial progress shaping its future. Ultimately, the discussion underscores the transformative promise of NKG2D CAR-T cell therapy in revolutionizing the landscape of solid tumor treatment and enhancing the prospects for improved patient outcomes.

We investigated the potential genetic variants using whole exome sequencing (WES) and evalu-ated the disease course using T cell receptor (TCR) repertoire analysis in rheumatoid arthritis (RA). Fourteen patients with RA and five healthy controls (HCs) were enrolled. For patients with RA, only naïve patients were recruited before treatment, and data were collected at baseline and 6 and 12 months after the initiation of disease-modifying antirheumatic drug (DMARD) treatment. Laboratory data and disease parameters were also collected. Genetic variants were detected using WES, and the diversity of the TCR repertoire was assessed using Shannon-Weiner diversity. Some variants were detected by WES, but their clinical significance should be confirmed by further studies. The diversity of the TCR repertoire in patients with RA was lower than that in HCs; however, after DMARD treatment, it increased significantly. The diversity was negatively cor-related with laboratory findings and disease measures with statistical significance. Variants with a potential for RA pathogenesis were identified and the clinical significance of TCR repertoire was evaluated in Korean patients with RA. Further studies are required to confirm the findings of the present study.

Claudins are a family of 27 proteins that have an important role in the formation of tight junc-tions. They also have an important function in ions exchange, cell mobility, and in in the epitheli-al-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evi-dence shows improved outcomes when combining monoclonal antibodies against Claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently Chimeric anti-gen receptor T-cells targeting Claudin 18 are under investigation.

The COVID-19 pandemic caused by the RNA virus SARS-CoV-2, has had a significant impact not only on bodily metabolism but also at the genomic level. This study utilizes a bibliometric approach to map and identify the relationship between COVID-19 and DNA damage, genomic instability, and cell cycle deregulation. The research began with the development of in-depth research questions and conducted two rounds of literature search in the Scopus database with stringent filters to ensure relevance and accuracy. From an initial 1098 documents, 576 relevant documents were selected for further analysis. The collected data was then visualized using bibliometric methods, enabling the identification of important patterns, trends, and relationships among the research variables. Key findings indicate that DNA damage, which can induce apoptosis, is the worst impact of the infection on cells. Term frequency analysis and science mapping revealed a close relationship between "DNA damage" and "apoptosis". Furthermore, discussions on genomic instability highlight telomere regulation issues, while cell cycle deregulation during virus replication in mammalian cells indicates the importance of maintaining cell membrane integrity.This study confirms the importance of bibliometric analysis in detecting and understanding the impact of COVID-19 at the genomic level, proposing several potential research targets and enhancing our understanding of the biological response to viral infection.

Silver powder, as the primary component of solar silver paste, significantly influences various aspects of paste performance, including printing, sintering, and conductivity. Silver powders prepared using the liquid-phase reduction method exhibit different microstructures depending on whether the growth process is dominated by aggregation or crystalline growth. This study explores the impact of different silver powder microstructures on packing density and sintering activity. It is observed that polycrystalline aggregated silver powder possesses higher surface energy, lower packing density, and greater sintering activity. Investigation into the influence of different silver powders on the electrical conductivity, adhesion, and structural density of silver paste reveals that polycrystalline aggregated silver powder is more suitable for lower sintering temperature pastes, whereas crystalline growth-type silver powder is better suited for higher sintering temperature pastes, resulting in a denser sintered silver layer. Finally, an analysis of the impact of various silver powders on the aspect ratio and electrical performance of solar cell silver grid lines yields higher aspect ratios (0.40) and photoelectric conversion efficiency (19.26%).

Silkworm ovary-derived BmN4 cells rely on chromatin-induced spindle assembly to form microtubule-based square mitotic spindles that ensure accurate segregation of holocentric chromosomes during cell division. The chromosome passenger protein Aurora B regulates chromosomal condensation and segregation, spindle assembly checkpoint, and cytokinesis; however, its role in holocentric organisms needs further clarification. This study examined the architecture and dynamics of spindle microtubules during prophase and metaphase in BmN4 cells and those with siRNA-mediated BmAurora B knockdown using immunofluorescence labelling. Anti-α-tubulin and anti-γ-tubulin antibodies revealed faint γ-tubulin signals co-localized with α-tubulin in early prophase during nuclear membrane rupture, which intensified as prophase progressed. At this stage, bright regions of α-tubulin around and on the nuclear membrane surrounding the chromatin suggested the start of microtubule assembling in the microtubule organizing centers (MTOCs). In metaphase, the number and size of γ-tubulin foci increased and were detected on both sides of the chromosomes. This resulted in a distinctive multipolar square spindle with holocentric chromosomes aligned at the metaphase plate. siRNA-mediated BmAurora B knockdown significantly reduced the γ-tubulin foci during prophase, impacting microtubule nucleation and spindle structure in metaphase. Spatiotemporal BmAurora B expression analysis provided new insights into the regulation of this mitotic kinase in silkworm larval gonads during gametogenesis. Our results suggest that BmAurora B is crucial for the formation of multipolar square spindles in holocentric insects, possibly through the activation of γ-tubulin ring complexes in multiple centrosome-like MTOCs.

Severe combined immunodeficiency disorders (SCID) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function that lead to a wide spectrum in clinical manifestations. A subgroup of patients presents a disabling and life-threatening clinical course. In these cases, allogeneic hematopoietic stem cell transplant provides a curative approach. The occurrence of SCID-associated lymphoproliferative disorders is rare and occur mostly in adenosine deaminase-deficient severe combined immunodeficiency disorders, after allogeneic hematopoietic stem cell transplant. Epstein Barr virus infection is present in the majority of individuals with primary immunodeficiency developing lymphoma, revealing compromised anti-tumour surveillance of virally transformed cells. Herein, we report a rare case of diffuse large B cell lymphoma occurring in an Epstein Barr virus negative, non-transplanted X-linked severe combined immunodeficiency 4-months-old infant, successfully treated with immunotherapy and allogeneic stem cell transplantation. This case suggests that Epstein Barr virus -independent mechanism of neoplastic transformation must take action in severe combined immunodeficiency associated lymphoma and unveils the curative potential of donor T cells after allogeneic transplantation.

Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. The paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. Treatment of stroke patients with different type of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. Priming or preconditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later phase trials are required to consolidate these findings.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic myelopoietic growth factor and proinflammatory cytokine, clinically used for multiple indications and serving as a promising target for treatment of many disorders, including cancer, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, COVID-19. We have previously shown that dimeric Ca2+-bound forms of S100A6 and S100P proteins, members of the multifunctional S100 protein family, are specific to GM-CSF. To probe selectivity of these interactions, the affinity of recombinant human GM-CSF to dimeric Ca2+-loaded forms of 18 recombinant human S100 proteins was studied by surface plasmon resonance spectroscopy. Of them, only S100A4 protein specifically binds to GM-CSF with equilibrium dissociation constant, Kd, values of 0.3-2 μM, as confirmed by intrinsic fluorescence and chemical crosslinking data. Calcium removal prevents S100A4 binding to GM-CSF, whereas monomerization of S100A4/A6/P proteins disrupts S100A4/A6 interaction with GM-CSF and induces a slight decrease in S100P affinity for GM-CSF. Structural modelling indicates the presence in the GM-CSF molecule of a conserved S100A4/A6/P-binding site, consisting of the residues from its termini, helices I and III, some of which are involved in the interaction with GM-CSF receptors. The predicted involvement of the ‘hinge’ region and F89 residue of S100P in GM-CSF recognition was confirmed by mutagenesis. Examination of S100A4/A6/P ability to affect GM-CSF signaling showed that S100A4/A6 inhibit GM-CSF/S100-induced suppression of viability of monocytic THP-1 cells. The ability of the S100 proteins to modulate GM-CSF activity is relevant to progression of various neoplasms and other diseases, according to bioinformatics analysis. The direct regulation of GM-CSF signaling by extracellular forms of the S100 proteins should be taken into account in the clinical use of GM-CSF and development of the therapeutic interventions targeting GM-CSF or its receptors.

The emergence of antimicrobial resistance remains one of the greatest public health concerns. Biofilm formation has been postulated as a mechanism of microbial pathogens to resist antimicrobial agents. Lactic Acid Bacteria (LAB) and their metabolites have been proposed to combat bacterial biofilms, due to their antimicrobial activity. In this vein, the aim of the present study was to investigate the biofilm removal potential of cell-free supernatant (CFS) of five wild-type Lacticaseibacillus rhamnosus LAB strains, isolated from Greek natural products, in comparison to the commercial available L. rhamnosus GG strain, formed by common foodborne pathogens (Salmonella Enteritidis, Salmonella Typhimurium, Escherichia coli, Listeria monocytogenes, and Staphylococcus aureus). Biofilm removal activity of LAB was assessed on two-days mature biofilm using a microtiter plate-based procedure. Both non-neutralized and neutralized CFSs removed biofilms in a concentration-dependent manner. Biofilm removal activity of the non-neutralized CFSs was significantly higher compared to the neutralized CFSs, as expected, ranging 40 – 90% and 10 – 78%, respectively. Biofilm removal efficiency of L. rhamnosus OLXAL-3 was signifanctly higher among the wild-type L. rhamnosus strains tested (20 – 100% v/v). In conclusion, our results suggested the great potential of application of wild-type Lacticaseibacillus rhamnosus strains CFSs as effective natural agents against pathogenic bacterial biofilms.

Soil cadmium (Cd) contamination has become a serious problem in China. In this study, the goals of the field experiments were to understand how the application of nitrogen fertilizer at the full heading stage and filling stage reduced the uptake of Cd in rice by affecting the distribution of Cd in iron plaques on the root surfaces and subcellular in the root and flag leaf. The hydroponic culture experiments aimed to explore the effect of interaction or deficiency of nitrogen and cadmium on cadmium accumulation in rice at the late growth stage. The results showed that under the condition of having enough nitrogen supply during the early growth stage, applying nitrogen fertilizer during the full heading stage and filling stage resulted in a significant increase in the concentration of Fe and Cd on the root plaques at the milk stage and mature stage. Additionally, it increased the concentration and proportion of Cd in the soluble fraction of subcellular in the flag leaves at the milk stage. On the other hand, when there was a deficiency of nitrogen, the concentration of Fe in the root plaques increased significantly, while the concentration of Cd in the root plaques decreased significantly. Moreover, the proportion of Cd in the flag leaf cell walls increased significantly. Regardless of whether there was sufficient or deficient nitrogen supply during the early growth stage, applying nitrogen at the full heading stage reduced the Cd concentration in brown rice by 35.11% and 57.25%, respectively. Under hydroponic culture conditions with both Cd exposure and later-stage nitrogen supply significantly increased the Cd concentration in brown rice. However, in the absence of Cd, nitrogen supply significantly reduced the Cd concentration in brown rice. The accumulation of Cd in brown rice was significantly correlated with the accumulation of Fe and Mn at the late growth stage. Our findings indicate that when there is sufficient nitrogen nutrition during the early growth stage of rice, topdressing nitrogen fertilizer at the full heading stage combined with lime with mineral element fertilizers such as Fe and Mn is an effective approach to reduce the presence of cadmium in rice grains.

Two new compounds, named aspergilins A (1) and B (2), were isolated from the mangrove endophytic fungus Aspergillus sp. A1E3 associated with the fruit of Rhizophora mucronata, together with averufanin (3). The planar structures and absolute configurations of these compounds were unambiguously established by extensive NMR investigations, quantum-chemical electronic circular dichroism (ECD) calculations, and single-crystal X-ray diffraction analysis. Most notably, the absolute configuration of aspergillin A (1) was determined by single-crystal X-ray diffraction analysis of its tri-pivaloyl derivative 4, conducted with Cu Kα radiation, whereas that of averufanin (3) was first clarified by quantum-chemical ECD calculations. Aspergilin A is the first orsellinic acid–ribose–​pyridazinone-Noxide hybrid containing a unique β-oxo-2,3-dihydropyridazine 1-oxide moiety, whereas aspergilin B and averufanin are the sterigmatocystin and anthraquinone derivative, respectively. From the perspective of biosynthesis, aspergilin A could be originated from the combined assembly of three building blocks, viz., orsellinic acid, β-D-ribofuranose, and L-glutamine. It is an unprecedented alkaloid-Noxide involving biosynthetic pathways of polyketide, pentose, and amino acid. Aspergilin B (2) exhibited potent antiproliferative activity against four cancer cell lines. In addition, Aspergilin B (2) dose-dependently induced G2/M phase arrest in HepG2 cells.

Biological function depends on the composition as well as structure of the organism, that is the organization of interactions between its parts. In multicellular organisms, the complex communication between cells is crucial for the coordination of cellular functions (growth, differentiation, apoptosis), compartmentalization of cellular processes within the organism, and the integration of cells into functioning higher levels of structural organization. Here we focus on the interaction among cells, as the basic level of biological organization, capable of a remarkable degree of autonomy and self-maintenance. While a wealth of data on putative cell interactions has recently become available, its biological interpretation depends on expectations we have for the structure of these interaction networks. This contribution is an attempt at formulating basic questions we may ask about cell interaction data. We build on the understanding that cells fulfill two general functions: the integrity-maintaining and the organismal service function. We derive the expected patterns of cell interactions considering two intertwined aspects: the immediate functional and the evolutionary. Based on these, we propose several guidelines for analysis and interpretation of transcriptional cell-interactome data.

Background: Colorectal cancer (CRC) is one of the major causes of cancer-related death worldwide. Aerobic glycolysis precedes obtainment of oncogenic mutations and loss of tumor suppressors, promoting the progress of CRC. Although numerous biomarkers have been identified to be associated with prognosis and survival, a glycolysis-related gene signature in CRC has not been explored. Methods: mRNA expression profiling data in a group of CRC patients (n = 540) was extracted from the Cancer Genome Atlas (TCGA). Gene set enrichment analysis (GESA) was performed to identify gene sets that were significantly different between CRC tissues and normal tissues. Cox proportional hazards regression models were used to identify genes significantly associated with overall survival. Multivariate Cox regression analysis was used to establish a prognostic risk parameter formula. Kaplan–Meier survival estimates and the log-rank test were used to validate the significance of risk parameters for prognosis prediction. Results: Five glycolysis-related genes (ENO3, GPC1, P4HA1, IDUA, ANKZF1) were identified to be significantly associated with overall survival (AUC=0.754). Based on the five‑gene signature, patients with CRC were divided into high and low‑risk subgroups. CRC patients with a low-risk score had better survival benefits than those with a high one (P &lt; 0.001). Conclusions: A five-gene signature associated with glycolysis for predicting the outcome of CRC patients was generated, serving as a valuable prognosis model with high efficiency and potential targeted therapy of CRC patients.

The paper reports an analytical study of two problems of Rayleigh-Bénard convection(RBC): one in a Newtonian liquid occupying an axi-symmetric cylindrical enclosure(CE) and second in a two-dimensional rectangular enclosure(RE). Linear stability analysis is employed to obtain information on the onset of convection in terms of a critical Rayleigh number, Ra, as a function of the aspect ratio, Ro. The nature and the flow structures of the convective cells, at the onset of convection, are predicted theoretically by plotting the streamlines for different values of Ro. Not so shallow(Ro&lt;1 or Ro≪1), and very shallow enclosures(Ro≫1) are considered. Concepts of cell-width and the wave number are respectively used in these two types of enclosures. An explicit analytical expression for the number of cells as a function of Ro is obtained theoretically. Exact prediction of the critical value of Ra, viz., Rac, as a function of Ro is also made. These are new findings in the case of both CE and RE. The fundamental differences between the problems of CE and RE are also highlighted.

The cancer stem cell hypothesis suggests that neoplastic cells with stem characteristics hierarchically regulate tumor generation and its high cellular heterogeneity. These cells have been detected in all cancer types, and specific signaling pathways give the regulation of self-renewal and differentiation. In prostate cancer, androgen receptor signaling has been extensively studied, and in non-stem cells, it promotes cell proliferation and tumor progression, but in the cancer stem cell population, it negatively regulates processes such as self-renewal. However, in other types of cancer, such as breast and glioblastoma, the androgen receptor seems to favor the maintenance of cancer stem cells, suggesting that androgen signaling has different effects depending on the tumor context. This review discusses the role of androgen receptor in maintaining cancer stem cells by regulating proliferation, self-renewal, and differentiation, as well as the possible signaling pathways involved in these processes.

In the tissue regeneration field, stem cell transplantation and the control of their differentiation represent a promising therapeutic strategy. The second aspect can be achieved using electrical stimulation. This study aims to characterize the effect of a microsecond electrical stimulation on MSCs and iNSCs, in the context of the RISEUP FET-OPEN project (n. 964562) that seeks to control these cells differentiation for the spinal cord injury treatments. Here, the effect of a specific microsecond electric pulses stimulation, characterized by bipolar pulses of 100 µs + 100 µs, delivered for 30 minutes at an intensity of 250 V/cm, on i) cell proliferation, ii) cell cycle, iii) gene expression and iv) apoptosis was evaluated. Results show that the stimulation does not affect cell proliferation, cell cycle, and apoptosis, but induced some variations in gene expression, in particular in EGR1, FOS, and POU5F1. These ob-servations led us to deeply investigate the cell proliferation until 72h from the stimulation observing an increase in the iNSCs. The main outcome of this study is that the chosen stimulation protocol is safe and not toxic for MSCs and iNSCs. The observed variations in the gene expression need to be deeply investigated to assess the molecular mechanisms involved.

Background: The most frequent non-pigmented malignancy of the ocular surface is ocular surface squamous neoplasia (OSSN), which has a frequency of 0.03 to 1.9 per 100,000 people per year. It can be diagnosed histologically as anything from mild dysplasia to aggressive squamous cell carcinoma that affects both the conjunctiva and the cornea. The purpose of this study is to determine the distribution of ocular surface squamous neoplasia at a teaching hospital in South Western Uganda.Methods: In this retrospective study, we reviewed all records of patients with ocular surface squamous neoplasia from the Mbarara University of Science and Technology (MUST)/ Mbarara Regional Referral Hospital (MRRH) pathology laboratory in South Western Uganda, from January 2015- October 2021.Results: Of the 1,133 cases of ocular neoplasia seen during this time, OSSN composed of 26.7% (n=303). OSSN occurred mainly in females (59.1%). The most common OSSN was invasive squamous cell carcinoma (60.4%). The age range was 15-106 years while the mean was 39.99 years. The commonest affected age group was 30-44years (41.3%).Conclusion: The burden of OSSN is high. It primarily affects young adults and is frequently found in women. Squamous cell carcinoma makes up the majority of the disease.

The solar cell industry is a part of the green energy sector, and effectively combining the patents of various manufacturers within the supply chain to collectively create sustainable patent market value is of paramount importance. This study aimed to establish a business strategy framework for Project-based licensing through the analysis of solar cell patents and the integration of supply chain manufacturers' patents, with the goal of collectively creating market value for patents sustainably. The research methodology included literature analysis and focus group discussions. Initially, the study analyzed solar cell industry patents from the past decade using the WIPS Global Patent database to identify projects with the highest patent count. Subsequently, through the use of focus group discussions, the feasibility of a patent pool strategy within the supply chain was explored. Finally, a strategy framework was proposed for Project-based patent pool licensing, focusing on the top 15 projects with the highest count of 5,579 patents. The results indicated that adopting this strategy framework for supply chain manufacturer patents can result in higher commercial patent value.

Still, the most common in vitro model for absorption, distribution, metabolism and excretion (ADME) purposes is the Caco-2 cell line. However, clear differences in gene- and protein expression towards the small intestine and an at best fair prediction accuracy of intestinal drug absorption restrict the usefulness as model for intestinal epithelial cells. To overcome these limitations, we evaluated a panel of low-passaged patient-derived colorectal cancer cell lines of the HROC collection concerning similarities to small intestinal epithelial cells and their potential to predict intestinal drug absorption. After initial screen of a larger panel, ten cell lines with confluent outgrowth and long-lasting barrier forming potential were further characterized in close detail. Tight junctional complexes and microvilli structures were detected in all lines, differentiated epithelial cells were abundant in 7/10. All lines expressed multiple transporter molecules, with expression levels in three lines being close to those of small intestinal epithelial cells. Compared to the Caco-2 model, three HROC lines demonstrated both higher similarity to jejunal epithelial tissue cells and higher regulatory potential of relevant drug transporters. In sum, these lines would be better suited human small intestinal epithelium models for basic and translational research; especially for ADME studies.

Hydrogels can be considered as mimics of extracellular matrix (ECM).Cytoskeleton through integrins is connected with ECM and cytoskeleton tension depends on ECM stiffness.A number of age-related diseases depend on cellular processes related with cytoskeleton function.Some examples of cancer initiation and progression and heart disease in relationship with ECM stiffness has been analysed.Incorporation of rigid particles in ECM can increase ECM stifness and to promote formation of internal residual stresses. Water migration, changes of water binding energy to biomactomolecules, changes of the state of water from tightly bound water to free and loosely bound water changes stiffness of ECM. Risks related with rigid particles incorporation into ECM have been also iscussed.

The advancements achieved in Tissue Engineering are based on a careful and in-depth study of cell-tissue interaction. The choice of a certain biomaterial in Tissue Engineering is fundamental as it represents an interface for adherent cells in the creation of a microenvironment suitable for cell growth and differentiation. The knowledge of the biochemical and biophysical properties of the extracellular matrix is a useful tool for the optimization of polymeric scaffolds. The aim of this re-view is to analyse the chemical, physical and biological parameters on which it is possible to act in Tissue Engineering for the optimization of polymeric scaffolds. Understanding the scaffold impact on cell fate is of paramount importance for the successful advancement of Tissue Engineering.

Yarrowia lipolytica is a widely used microorganism in biotechnology since it is capable of producing a wide range of products. A less studied related strain is Y. divulgata, which is also capable of erythritol production in even higher concenctration then most Y. lipolytica wild strains. Thus the aim of this work was to investigate Y. divulgata’s complex utilisation based on erythritol fermentation to establish a Yarrowia based biorefinery in which both the fermentation broth and separated cells are utilised in high-value products. An important parameter of erythritol fermentation is the adequate oxygen level, so the effect of it was investigated in baffled flasks and fermentor as well. Furthermore, we measured the cosmetic applicability of cell lysates and the efficiency of biodetergent produced during erythritol fermentation. The results were showed that Yarrowia divulagata NCAIM 1485 strain could produce relative high amount of erythritol (44.14±1 g/l) under adequate oxygen supply while its cell lysate could exert good skin moisturizing effect. In all cases, the collected samples had emulsification index above 50% of which stability was also high, above 50% even after 24 hours.Therefore, it can be considered as an effective bioemulsifier. In conclusion, the erythritol fermentation of Y. divulgata is suitable for complex utilisation in a biorefinery, since the fermentation broth can be used for isolation of sweetener and bioemulsifier, meanwhile the cells can be processed for cosmetic application as skin moisturizer.

Rikenella microfusus is an essential intestinal probiotic with great potential. The latest research shows that its imbalance in the intestinal flora is related to the occurrence of various diseases, such as intestinal diseases, immune diseases, and metabolic diseases. Rikenella may be a target or biomarker for some diseases, providing a new possibility for preventing and treating these diseas-es by monitoring and changing the abundance of Rikenella in the intestine. However, the current detection methods have disadvantages such as long detection time, complicated operation, and high cost, which seriously limit the possibility of clinical application of this new treatment method. Therefore, developing rapid and low-cost detection methods has become an urgent problem to be solved. In this study, we used Rikenella as the target bacterium, meanwhile including five other prominent gut bacteria Akkermansia muciniphila, Allobaculum stercoricanis, Blautia producta, Rose-buria intestinalis and Parabacteroides distasonis as control organisms. The aptamer library R.m-R13 was evolved with high specificity and strong affinity (Kd = 9.597 nM) in an iterative Cell-SELEX process after 13 rounds of selection. R. microfusus can efficiently be discriminated from other major gut bacteria in complex mixtures in different analysis techniques including fluorescence micros-copy or fluorometric suspension assays and even in human stool samples. These preliminary re-sults open new avenues towards the development of aptamer-based microbiome bio-sensing ap-plications for fast and reliable R. microfusus monitoring.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and biologically heterogeneous disease. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory (R/R) DLBCL. These agents include anti-CD19 chimeric antigen receptor T-cell therapies (CAR T-cells) and monoclonal antibodies as polatuzumab and tafasitamab. Nevertheless, despite the high efficacy of all these new therapies, there are still patients who do not respond or relapse, representing an unmet clinical need. This review describes new promising therapies that are under investigation to treat R/R DLBCL.

Airway epithelial cells (AECs) play a key role in maintaining lung homeostasis, epithelium regeneration and the initiation of pulmonary immune responses. To isolate and study murine AECs investigators have classically used short and hot (1h 37°C) digestion protocols. Here, we present a workflow for efficient AECs isolation and culture, utilizing long and cold (20h 4°C) dispase II digestion of murine lungs. This protocol yields a greater number of viable AECs compared to an established 1h 37°C dispase II digestion. Using a combination of flow cytometry and immunofluorescent microscopy, we demonstrate that compared to the established method, the cold digestion allows for recovery of a 3-fold higher number of CD45-CD31-EpCAM+ cells from murine lungs. Their viability is increased compared to established protocols, they can be isolated in larger numbers by magnetic-activated cell sorting (MACS), and they result in greater numbers of KRT5+p63+ colonies in vitro. Our findings demonstrate that temperature and duration of murine lung enzymatic digestion have a considerable impact on AEC yield, viability, and ability to form colonies in vitro. We believe this workflow will be helpful for studying lung AECs and their role in the biology of lung.

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer is an important target of monoclonal antibody (mAb) therapy such as trastuzumab. Due to the development of trastuzumab-deruxtecan, an antibody-drug conjugate, the targetable HER2-positive breast cancer patients have been expanded. To evaluate developing modalities using anti-HER2 mAbs, reliable preclinical mouse models are required. Therefore, sensitive mAbs against mouse HER2 (mHER2) should be established. This study developed mHER2 mAbs using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mHER2 mAbs, H2Mab-300 (rat IgG2b, kappa) and H2Mab-304 (rat IgG1, kappa), reacted with mHER2-overexpressed Chinese hamster ovary-K1 (CHO/mHER2) and endogenously mHER2-expressed cell line, NMuMG (a mouse mammary gland epithelial cell) by flow cytometry. Furthermore, these mAbs never recognized mHER2-knockout NMuMG cells. The kinetic analysis using flow cytometry indicated that the dissociation constant (KD) of H2Mab-300 and H2Mab-304 for CHO/mHER2 was 1.2 × 10−9 M and 1.7 × 10−9 M, respectively. The KD of H2Mab-300 and H2Mab-304 for NMuMG was 4.9 × 10−10 M and 9.0 × 10−10 M, respectively. These results indicated that H2Mab-300 and H2Mab-304 could apply to the detection of mHER2 using flow cytometry and may be useful to obtain the proof of concept in preclinical studies.

Solar photovoltaic systems are becoming increasingly popular due to their outstanding environmental, economic, and technical characteristics. To simulate, manage, and control photovoltaic (PV) systems, the primary challenge is identifying unknown parameters accurately and reliably as early as possible using a robust optimization algorithm. This paper proposes a newly developed cheetah optimizer (CO) and improved CO (ICO) to extract parameters from various PV models. This algorithm, inspired by cheetah hunting behavior, includes several basic strategies: searching, sitting, waiting, and attacking. Although this algorithm has shown remarkable capabilities in solving large-scale problems, it needs improvement concerning its convergence speed and computing time. Here, an improved CO (ICO) is presented to identify solar power model parameters for this purpose. Single-, double-, and PV module models are investigated to test ICO's parameter estimation performance. Statistical analysis uses minimum, mean, maximum, and standard deviation. Furthermore, to improve confidence in test results, Wilcoxon and Freidman rank nonparametric tests are also performed. Compared to other state-of-the-art optimization algorithms, the ICO algorithm is proven to be highly reliable and accurate when identifying PV parameters.

Currently, large cell neuroendocrine carcinoma of the lung (LCNEC) is classified as a rare lung cancer subtype, but given the high incidence of lung cancer, the overall number of cases is considerable. The pathologic diagnosis is based on the microscopic appearance of the tumor cells, the amount of intra-tumoral necrosis, the mitotic rate, and the presence of positive neuroendocrine markers identified by immunohistochemistry. Recently, a subdivision into two main categories was proposed based on mutation signatures involving the RB1, TP53, KRAS, and STK11/LKB1 genes, into SCLC-like (small cell lung cancer-like) and NSCLC-like (non-small cell lung cancer-like) LCNEC. In terms of treatment, surgery remains the best option for resectable, stage I–IIIA cases. Chemotherapy and radiotherapy have conflicting evidence. Etoposide/platinum remains the standard chemotherapy regimen. However, based on the newly proposed LCNEC subtypes, some retrospective series report better outcomes using a pathology-driven chemotherapy approach. Encouraging outcomes have also been reported for immunotherapy and targeted therapy, but the real impact of these strategies is still being determined in the absence of adequate prospective clinical trials. The current paper scrutinizes the epidemiology, reviews the reliability of pathologic diagnosis, discusses the need for molecular subtyping, and reviews the heterogeneity of treatment algorithms in LCNEC.

The CRISPR/Cas9 gene editing system has enormous potential in the treatment of multiple genetic disorders. To fully harness this potential, it is essential to deliver CRISPR-Cas9 components safely and effectively into the nuclei of target cells. In this study, we tested the amphipathic cell-penetrating peptide LAH5, previously used for DNA delivery, to intracellularly deliver spCas9: sgRNA ribonucleoprotein (RNP) and RNP/single-stranded homology-directed repair (HDR) template. We discovered that the LAH5 peptide effectively formed nanocomplexes with both RNP and RNP/HDR cargo, and that these nanocomplexes were taken up by cells effectively. Peptide/RNP nanocomplexes were characterized for size and charge, and nanocomplexation with RNP and RNP/HDR cargo was demonstrated via an electrophoretic mobility shift assay. Various ratios of peptide/RNP nanocomplexes were functionally screened on fluorescent reporter cell lines for gene editing and HDR-mediated gene correction. Additionally, targeted gene editing of the CCR5 gene was demonstrated in various cell lines. This LAH5-based delivery strategy paves the way for the development of therapeutic delivery systems for CRISPR/Cas-based genomic engineering.

Thermal safety of lithium-ion traction batteries is a highly concerned issue in the field of electric transportation. The large amount of gas emission during the thermal runaway process of batteries has highly safety hazards such as fire and explosion. Quantitative analysis of emission is one of the important challenges for testing and evaluating battery safety. Focus on quantifying the gas emission through large-scale thermal propagation in battery modules and packs, based on the idea of cell result multiplication, this article conducts thermal runaway emission analysis on single cell and modules, and compares the behavior of thermal runaway and gas emission of the cell and module from the aspects of temperature, pressure, gas composition and battery morphology. The feasibility of the cell result multiplication method was verified from the perspective of experimental data.

Background and Aims: Metabolic Syndrome (MetS), a global problem, predisposes to an increased risk for Type 2 diabetes and premature cardiovascular disease. While MetS is associated with central obesity, there is scanty data on adipocyte hypertrophy, increased fat cell size (FCS), in MetS. The aim of this study was to investigate FCS status in gluteal adipose tissue biopsy of patients with nascent MetS without the confounding of diabetes, cardiovascular disease, smoking or lipid therapy . Methods and Results: Fasting blood and subcutaneous gluteal adipose tissue (SAT) biopsy were obtained in MetS (n=20) and controls (n=19). Cardio metabolic features, FFA levels, hsCRP and HOMA-IR were significantly increased in patients with MetS. Waist-circumference adjusted-FCS was significantly increased in patients with MetS and increased with increasing severity of MetS. Furthermore, there were significant correlations between FCS with glucose, HDL-C and the ratio of TG: HDL-C. There were significant correlations between FCS and FFA, endotoxin and monocyte TLR4 abundance. Also, FCS correlated with readouts of NLRP3 Inflammasome activity. Most importantly, FCS correlated with markers of fibrosis and angiogenesis. Conclusions: In conclusion, in patients with nascent MetS, we demonstrate WC-adjusted increase in FCS from gluteal AT that correlated with cellular inflammation, fibrosis and angiogenesis. While these preliminary observations were in gluteal fat, future studies are warranted to confirm these findings in visceral and other fat depots.

This paper focuses on the impact of defects density and carrier capture cross-section area in the electron transport material (ETM), hole transport material (HTM), and absorber layers on the performance of perovskite solar cells and quantum efficiency (QE). Furthermore, the impact of defects density at the interface between ETM/absorber and absorber/HTM is also studied. SCAPS-1D software is used in the current study in determining solar cell performance. The proposed perovskite solar cell structure is a planar FTO/TiO2/ CH3NH3PbI3/ Cu2O. The results indicated that increasing the defect density in the absorber layer significantly affects cell performance, while in ETM and HTM layers, the cell parameters remain unaffected. It is also found that the defect capture cross-section has a similar behavior to the defect density in the main layers (ETM, absorber, and HTM). In addition, it is observed that by increasing the defects density in the ETM/absorber and absorber/HTM interfaces layer, the cell parameters FF, Jsc, and PCE have been slightly decreased, with no effect on Voc. Moreover, it is also noted that the quantum efficiency QE is sharply reduced. Finally, this paper introduced the correlation between the defect density and the capture cross-section, which is the first attempt to find such a relationship in perovskite solar cells to the knowledge of the authors.

The Epidermal Growth Factor Receptor (EGFR) overexpression or its mutation mediates the sustaining proliferative signaling in cancers. Human EGFR-targeting monoclonal antibody (mAb) therapy such as cetuximab has been approved for clinical use in patients with colorectal cancers and head and neck squamous cell carcinomas. A reliable preclinical mouse model is essential to further develop the mAb therapy against EGFR. However, a mAb against mouse EGFR (mEGFR) for flow cytometry has not been established. In this study, we developed a specific and sensitive mAb for mEGFR using the Cell-Based Immunization and Screening (CBIS) method. The established anti-mEGFR mAb, EMab-300 (rat IgG1, kappa) reacted with mEGFR-overexpressed Chinese hamster ovary-K1 (CHO/mEGFR) and endogenously mEGFR-expressed cell lines, including NMuMG (a mouse mammary gland epithelial cell) and Lewis lung carcinoma cells by flow cytometry. The kinetic analysis using flow cytometry indicated that the dissociation constant (KD) of EMab-300 for CHO/mEGFR and NMuMG was 4.3 × 10−8 M and 1.9 × 10−8 M, respectively. These results indicated that EMab-300 applies to the detection of mEGFR by flow cytometry, and is expected in the use of preclinical study.

The aim of this research was to evaluate the essential oil of Cymbopogon schoenanthus (L.) Spreng. (C. schoenanthus) from Burkina Faso in cytotoxic activity against LNCaP cells, derived from prostate cancer, and HeLa cells, derived from cervical cancer. Antioxidant activities were evaluated in vitro. Essential oil (EO) was extracted by hydrodistillation and analyzed by GC / FID and GC / MS. Thirty-seven compounds were identified, the major compounds being piperitone (49.9%), alpha terpinene isomer (24.02%), elemol (5.79%) and limonene (4.31%). EO exhibited a poor antioxidant activity, as shown by the inhibition of DPPH radicals (IC50 =1730 ± 80 µg/mL) and ABTS+. (IC50 = 2890 ± 26.9 µg/mL). Conversely, EO decreased the proliferation of LNCaP and HeLa cells with respective IC50s of 135.53 ± 5.27 µg/mL and 146.17 ± 11 µg/mL. EO also prevented LNCaP cell migration and led to the arrest of their cell cycle in the G2/M phase. Altogether, this work points out for the first time that EO of C. schoenanthus from Burkina Faso could be an effective natural anticancer agent.

Background: The lymph nodes staging system can predict the prognosis of gastric signet ring cell carcinoma (SRCC), but the optimal system for early and advanced SRCC remains unknown. Methods: This study retrospectively analyzed 693 SRCC patients who underwent radical resection in the Department of Gastrointestinal Surgery, Harbin Medical University Cancer Hospital. The predicted performance of three lymph node staging systems, including pN staging, lymph node metastasis rate (LNR), and log odds of positive lymph nodes (LODDS), was compared using the receiver characteristic operating curve (ROC). The kaplan⁃meier method and the log⁃rank test analyze the overall survival of patients. The Cox risk regression model identifies independent risk factors associated with patient outcomes. The nomogram was made by R studio. Results: The 693 SRCC included 165 early SRCC and 528 advanced SRCC. ROC showed that LODDS had better predictive performance than pN and LNR in predicting prognosis regardless of early or advanced SRCC. LODDS can be used to predict the prognosis of early and advanced SRCC and was an independent risk factor associated with patient outcomes (P=0.002, P<0.001). Furthermore, the nomogram constructed by LODDS and clinicopathological features had good predictive performance. Conclusion: LODDS showed a clear prognostic superiority over both pN and LNR in early and advanced SRCC.

The induction of macrophage death is regarded as a potential mechanism by which components secreted by Clostridium septicum are used to evade the innate immune response and cause tissue damage. This study aimed to determine the effect of partially purified fractions of extracellular proteins secreted by C. septicum on the death of mouse peritoneal macrophages. Elicited mouse peritoneal macrophages were incubated with partially purified fractions of proteins secreted by C. septicum into culture medium. After incubation, we found that the protein fraction with a molecular weight ≥ 100 kDa caused significant cell death in macrophages, changed cell morphology, increased markers of apoptosis and autophagy, and increased the expression (protein and mRNA) of IL-1 and TNFα. Our data suggest that the proteins secreted by C. septicum (MW ≥100kDa) induce cell death in macrophages by promoting autophagy-triggered apoptosis. This may contribute to our understanding of the molecular mechanism of immune evasion by C. septicum at the infection site.

A retrospective study including 49 women with ovarian clear cell carcinoma between January 2009 and December 2021 at Oxford cancer centre was done. The mean age was 63 years, with 78% post-menopausal. All women underwent cytoreductive surgery with no residual disease (R0) in 39 women. The follow-up time ranged between 12-144 months, with mean of 105.5 months. The 3-year OS was 73.4%, and 3-year PFS was 81.3%, with a mean of 101.7months (95%CI, 84.63-118.93). As expected, women with stage 1 disease had the best outcome. In comparing OS in respect to absence or presence of residual disease, the 3-year OS was 88.6% (95% CI 108.6-141.8), compared to 12.5% (95% CI 4.48-32.11) respectively (P<0.001). In multivariant analysis the variables included were CA 125 (< or >200 IU/ml), Hb (< or >115 g/L), albumin (< or >40 g/L), associated endometriosis, ascites, residual disease, and FIGO staging. FIGO stage was the only independent prognostic indicator of OS with (p<0.05). Surgery to achieve no residual tumour is necessary to improve the prognosis in advanced OCCC. At present, the true challenge is to predict which patients with early-stage disease are at higher risk of recurrence and would most benefit from adjuvant treatments.

Solid oxide cells are capable of efficiently converting various chemical energy carriers to electricity and vice versa. The urgent challenge nowadays is the faster degradation rate compared with other fuel cell/electrolyzer technologies. To understand the degradation mechanisms, simulation of a solid oxide cell is helpful. Since most previous research developed models using commercial software, such as COMSOL and ANSYS Fluent, a gap for knowledge transfer is being gradually formed between academia and industry due to licensing issues. This paper introduces a multiphysics model, developed by a computational code, openFuelCell2. The code is implemented with an open-source library, OpenFOAM. It accounts for momentum transfer, mass transfer, electrochemical reactions and metal interconnect oxidation. The model can precisely predict I-V curves under different temperatures, fuel humidity and operation modes. Comparison between OpenFOAM and COMSOL simulations shows good agreement. The metal interconnect oxidation is modelled, which can predict the thickness of the oxide scale under different protective coatings. Simulations are conducted by assuming an ultra-thin film resistance on the rib surface. It is revealed that coatings fabricated by atmospheric plasma spraying can efficiently prevent metal interconnect oxidation, with a contribution of only 0.53 \% to the total degradation rate.

The Chromogranin A (CgA)-derived peptide Catestatin (CST: hCgA352-372) is highly conserved (>90% in 90% species) in mammalian species. The highest-evolved primates show 58.8% similarity with the lowest-evolved monotremes. CST was initially identified as a physiological brake in catecholamine secretion by inhibiting nicotinic-cholinergic signaling. CST also inhibits desensitization of catecholamine secretion, indicating that CST can act both as a cholinergic antagonist (short-term) and as a cholinergic agonist (long-term). The long-term effect sustains catecholamine secretion during stressful situations. CST is now established as a pleiotropic hormone: it affects the cardiovascular system by lowering blood pressure and cardiac contractility, enhancing baroreflex sensitivity, increasing heart rate variability, and promoting angiogenesis; and it increases insulin sensitivity by reducing inflammation, inhibiting hepatic glucose production, attenuating endoplasmic reticulum stress, and inducing glycogen production. The present review will highlight the important direct and indirect effects of CST, CST1-15 (aka cateslytin), D-CST1-15 (where L-amino acids were changed to D-amino acids), and human variants of CST (Gly364Ser-CST and Pro370Leu-CST) on microbial growth inhibition and their potential as therapy for antibiotic-resistant pathogenic microbes.