Search

Background: The theory of Condition Dependent Sex predicts that – everything else being equal – less fit individuals would outcross at higher rates compared with fitter ones. Here we used the mixed mating plant Lamium amplexicaule, capable of producing both self-pollinating closed flowers (CL), alongside open flowers (CH) that allow cross pollination to test it. We investigated the effects of abiotic stress – salt solution irrigation – on the flowering patterns of plants and their offspring. We monitored several flowering and vegetative parameters, including the number and distribution of flowers, CH fraction, and plant size. Results: We found that stressed plants show an increased tendency for self-pollination and a deficit in floral and vegetative development. However, when parentally primed, stressed plants show a milder response. Un-stressed offspring of stressed parents show reversed responses and exhibit an increased tendency to outcross, and improve floral and vegetative development. Conclusions: In summary, we found that stress affects the reproduction strategy in the plants that experienced the stress and in subsequent offspring through F2 generation. Our results provide experimental evidence supporting a transgenerational extension to the theories of fitness associate sex and dispersal, where an individual's tendency for sex and dispersal may depend on the stress experienced by its parents. [ABSTRACT FROM AUTHOR]

Background: Insufficient trophoblast invasion, culminating in suboptimal uterine spiral artery remodeling, is pinpointed as a pivotal contributor to preeclampsia (PE) development. LINC01410 has been documented to be increased in various neoplasms, and is significantly associated with the invasive capabilities of tumor cells. Nonetheless, its function and the mechanisms in the pathogenesis of PE require further investigation. Methods and results: LINC01410 and methyltransferase-like 3 (METTL3) were ectopically expressed in HTR-8/Svneo cells via lentiviral transduction. Subsequently, the cells' invasive capabilities and apoptosis rates were evaluated employing Transwell assays and flow cytometry, respectively. The interplay between LINC01410 and METTL3, alongside the m6A methylation of FAS, was probed through RNA immunoprecipitation (RIP). Additionally, the association between FAS and METTL3 was elucidated via Coimmunoprecipitation (Co-IP) assays. The protein level of NF-κB, BAX, and BCL-2 in LINC01410-overexpressing cells was detected by Western blot. Our findings revealed that LINC01410 elevation increased the invasive ability of HTR-8/Svneo cells, directly impacting METTL3 then leading to its reduced expression. Conversely, heightened METTL3 expression mitigated invasiveness while enhancing apoptosis in these cells. Moreover, METTL3's interaction with FAS led to increased FAS expression, subject to m6A methylation. A surge in LINC01410 markedly decreased both mRNA and protein levels of FAS. Furthermore, LINC01410 overexpression significantly reduced NF-κB and BAX protein levels while augmenting BCL-2. Conclusions: Upregulation of LINC01410 expression promotes trophoblast cell invasion by inhibiting FAS levels through modified m6A alteration and suppressing the NF-κB pathway. These findings underscore the pivotal role of LINC01410 in regulating trophoblast cell invasion and propose it as a promising therapeutic strategy for preventing or alleviating PE. This offers valuable insights for the clinical treatment of PE, for which definitive targeted therapy methods are currently lacking. [ABSTRACT FROM AUTHOR]

Background: High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. Materials and methods: EZMLD-containing serum was prepared from Sprague–Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. Results: In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. Conclusions: EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis. [ABSTRACT FROM AUTHOR]

Crohn's disease (CD) is a chronic relapsing inflammatory disorder in which defective apoptosis of mucosal T cells is postulated to produce sustained inflammation and reactive oxygen species accumulation. Whether CD T cells are intrinsically resistant to apoptosis or whether this resistance is acquired at the intestinal site needs to be clarified, as the cellular mechanisms modulate the impaired apoptosis in these cells. Here, we analysed peripheral blood T cells from patients naïve to specific CD treatment at the onset and from healthy controls. Non-activated freshly purified lymphocytes were cultured and submitted to in vitro protocols for activation (CD3/CD28 antibodies) and apoptosis (Fas antibody). Cells were analysed by flow cytometry. Caspases (3, 8, and 9) and catalase activity were measured; protein levels of bax, Bcl-2, and NF-kB were detected by western blotting, and cytokines by Luminex-based assays. The results showed that CD4 T cells from CD patients are less prone to apoptosis before they can migrate to the intestinal mucosa. Caspase-9, FasR, sIL-2Rα, IL-17A, IFNγ, IL-6, TNF-α, and IL-10 were shown to be significantly different in CD but not for the rest of the analysed biological elements. Catalase activity was significantly reduced in CD T cells, which was confirmed in ex vivo experiments in which catalase inhibition in T cells from healthy controls triggered apoptosis inhibition in a dose-dependent manner. In conclusion, apoptosis inhibition of CD T cells is a feature of these cells before they can migrate to the intestinal mucosa. Noteworthy, the impaired apoptosis of T cells can be directly influenced by catalase inhibition. Blood T lymphocytes from CD patients are less prone to undergo apoptosis before migrating to the intestinal mucosa. The inhibition of catalase has a direct impact on the apoptotic capacity of blood T lymphocytes, with potential contribution to the pathogenic events in CD. Graphical Abstract [ABSTRACT FROM AUTHOR]

FIRES and NORSE are clinical presentations of disease processes that, to date, remain unexplained without an established etiology in many cases. Neuroinflammation is thought to have paramount importance in the genesis of these conditions. We hereby report the clinical, EEG, brain MRI, and genetic findings of a nuclear family with recurrent febrile‐related encephalopathy with refractory de novo Status Epilepticus. Whole‐exome sequencing (WES) revealed a homozygous p.C105W pathogenic variant of FADD gene (FAS‐associated protein with death domain, FADD), known to cause ultrarare forms of autosomal recessive immunodeficiency that could be associated with variable degrees of lymphoproliferation, cerebral atrophy, and cardiac abnormalities. The FADD‐related conditions disrupt FAS‐mediated apoptosis and can cause a clinical picture with the characteristics of FIRES. This observation is important because, on one hand, it increases the number of reported patients with FADD deficiency, showing that this disorder may present variable expressivity, and on the other hand, it demonstrates a genetic cause of FIRES involving a cell‐mediated inflammation regulatory pathway. This finding supports early treatment with immunomodulatory therapy and could represent a new avenue of research in the field of new onset refractory status epilepticus and related conditions. [ABSTRACT FROM AUTHOR]

Natural killer cells (NK cells) exert cytotoxicity towards target cells in several ways, including the expression of apoptosis-mediating ligands (TRAIL, FasL). In addition, NK cells themselves may be susceptible to apoptosis due to the expression of TRAIL receptors. These receptors include TRAIL-R1 (DR4), TRAIL-R2 (DR5), capable of inducing apoptosis, and TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), the so-called “decoy receptors”, which lack an intracellular domain initiating activation of caspases. Of particular interest is the interaction of uterine NK cells with cells of fetal origin, trophoblasts, which are potential targets for natural killer cells to carry out cytotoxicity. The aim of this work was to evaluate the expression of proapoptotic receptors and their ligands as well as CD107a expression by NK cells in a model of interaction with trophoblast cells. To evaluate NK cells, we used cells of the NK-92 line; cells of the JEG-3 line were used as target cells. The cytokines IL-1β, IL-15, IL-18, TNFα, IL-10, TGFβ and conditioned media (CM) of the first and third trimester chorionic villi explants were used as inducers. We established that cytokines changed the expression of apoptotic receptors by NK cells: in the presence of TNFα, the amount and intensity of Fas expression increased, while in the presence of TGFβ, the amount and intensity of expression of the DR5 receptor decreased. Soluble chorionic villi factors alter the expression of TRAIL and FasL by NK-92 cells, which can reflect the suppression of the TRAIL-dependent mechanism of apoptosis in the first trimester and stimulating the Fas-dependent mechanism in the third trimester. In the presence of trophoblast cells, the expression of TRAIL and DcR1 by NK cells was reduced compared to intact cells, indicating an inhibitory effect of trophoblast cells on NK cell cytotoxicity. In the presence of chorionic villi CM and trophoblast cells, a reduced number of NK-92 cells expressing DR4 and DR5 was found. Therefore, soluble factors secreted by chorionic villi cells regulate the resistance of NK cells to death by binding TRAIL, likely maintaining their activity at a certain level in case of contact with trophoblast cells.

Abstract Background The theory of Condition Dependent Sex predicts that – everything else being equal – less fit individuals would outcross at higher rates compared with fitter ones. Here we used the mixed mating plant Lamium amplexicaule, capable of producing both self-pollinating closed flowers (CL), alongside open flowers (CH) that allow cross pollination to test it. We investigated the effects of abiotic stress – salt solution irrigation – on the flowering patterns of plants and their offspring. We monitored several flowering and vegetative parameters, including the number and distribution of flowers, CH fraction, and plant size. Results We found that stressed plants show an increased tendency for self-pollination and a deficit in floral and vegetative development. However, when parentally primed, stressed plants show a milder response. Un-stressed offspring of stressed parents show reversed responses and exhibit an increased tendency to outcross, and improve floral and vegetative development. Conclusions In summary, we found that stress affects the reproduction strategy in the plants that experienced the stress and in subsequent offspring through F2 generation. Our results provide experimental evidence supporting a transgenerational extension to the theories of fitness associate sex and dispersal, where an individual’s tendency for sex and dispersal may depend on the stress experienced by its parents.

Abstract Background High-grade serous ovarian cancer (HGSOC) is a common gynecologic malignancy with a poor prognosis. The traditional Chinese medicine formula Erzhimaoling decoction (EZMLD) has anticancer potential. This study aims to elucidate the anticancer effects of EZMLD on HGSOC in vitro and in vivo. Materials and methods EZMLD-containing serum was prepared from Sprague–Dawley rats for treating SKOV3 ovarian cancer cells at varying concentrations for 24 h and 48 h to determine the IC50. Concentrations of 0%, 5%, and 10% for 24 h were chosen for subsequent in vitro experiments. The roles of METTL3 and METTL14 in SKOV3 cells were explored by overexpressing these genes and combining EZMLD with METTL3/14 knockdown. Investigations focused on cell viability and apoptosis, apoptosis-related protein expression, and KRT8 mRNA m6A modification. For in vivo studies, 36 BALB/c nude mice were divided into six groups involving EZMLD (6.75, 13.5, and 27 g/kg) and METTL3 or METTL14 knockdowns, with daily EZMLD gavage for two weeks. Results In vitro, EZMLD-containing serum had IC50 values of 8.29% at 24 h and 5.95% at 48 h in SKOV3 cells. EZMLD-containing serum decreased SKOV3 cell viability and increased apoptosis. EZMLD upregulated METTL3/14 and FAS-mediated apoptosis proteins, while downregulating Keratin 8 (KRT8). EZMLD increased KRT8 mRNA m6A methylation. METTL3/14 overexpression reduced SKOV3 cell viability and increased apoptosis, while METTL3/14 knockdown mitigated EZMLD's effects. In vivo, EZMLD suppressed SKOV3 xenografts growth, causing significant apoptosis and modulating protein expression. Conclusions EZMLD has therapeutic potential for ovarian cancer and may be considered for other cancer types. Future research may explore its broader effects beyond cell apoptosis.

Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children’s Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options. [ABSTRACT FROM AUTHOR]

Abstract Fetal alcohol spectrum disorders (FASD) are a severe developmental condition resulting from exposure to alcohol during pregnancy. The aim of this study was to examine the concentrations of hormones involved in appetite regulation—ghrelin, leptin, and putative peptide YY-3 (PYY)—in the serum of individuals with FASD. Additionally, we investigated the relationship between these hormone levels and clinical indicators. We conducted an enzyme-linked immunosorbent assay on samples collected from 62 FASD patients and 23 individuals without the condition. Our results revealed a significant decrease in leptin levels among FASD patients compared to the control group (5.124 vs. 6.838 ng/mL, p = 0.002). We revealed no statistically significant differences in the levels of other hormones studied (ghrelin and PYY). Comparisons of hormone levels were also conducted in three subgroups: FAS, neurobehavioral disorders associated with prenatal alcohol exposure and FASD risk, as well as by sex. Assignment to FASD subgroups indicated changes only for leptin. Sex had no effect on the levels of hormones. Moreover, the levels of leptin showed a negative correlation with cortisol levels and a positive correlation with BMI and proopiomelanocortin. Alterations in appetite regulation can contribute to the improper development of children with FASD, which might be another factor that should be taken into consideration in the proper treatment of patients.

Mexico City, one of the largest cities in the world, experiences frequent, devastating interplate earthquakes that originate on the subduction thrust along the Pacific coast of Mexico more than 250 km away. A notorious example is the 19 September 1985 Michoacán earthquake (Mw 8.0) which killed ~ 10,000 persons and caused wide-spread destruction in the city. The main cause of seismic damage in Mexico City is its subsoil that amplifies the ground motion. In view of the seismic hazard faced by the city, a reliable estimation of ground motion during future earthquakes is of vital importance. We present a new ground motion prediction equation (GMPE) for the Fourier amplitude acceleration spectrum (FAS) from subduction thrust earthquakes along the Pacific coast of Mexico at the reference station, CU, located in the firm zone of Mexico City. The GMPE is derived via Bayesian regression analysis and is based on an enlarged set of recordings (1965-2020; 40 earthquakes; 250 ≤ R≤ 500 km; 5 ≤ Mw ≤ 8.0). An important feature of the new GMPE is that it includes a term to model different attenuation along different ray paths. The inclusion of this term leads to a reduction in the aleatory variability of the GMPE, particularly at high frequencies. Since spectral amplification of seismic waves with respect to CU is known at many sites in the city, the FAS at these sites can be computed if it is known at CU. The new GMPE has been incorporated in a fully Fourier-based probabilistic seismic hazard analysis of Mexico City.

Copyright of BMC Pharmacology & Toxicology is the property of BioMed Central and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a rare primary immune disorder caused by defect of the extrinsic apoptotic pathway. The current diagnostic criteria combine clinical features and typical biomarkers but have not been the object of clear international consensus. Methods: We conducted a retrospective study on pediatric patients who were investigated for autoimmune cytopenia and/or lymphoproliferation at the CHU Sainte‐Justine Hospital over 10 years. Patients were screened using the combination of TCRαβ+ CD4− CD8− "double negative" (DN) T cells and soluble plasmatic FAS ligand (sFASL). Results: Among the 398 tested patients, the median sFASL and DN T cells were 200 ng/mL and 1.8% of TCRαβ+ T cells, respectively. sFASL was highly correlated with vitamin B12 levels. We identified five patients diagnosed with ALPS for whose sFASL and vitamin B12 levels were the more discriminating biomarkers. While ALPS diagnostic criteria had high sensibility, their predictive value remained low. Conclusion: sFASL level can efficiently discriminate patients with ALPS when using the appropriate thresholds. Our study highlights the need for an international consensus to redefine the place and threshold of biological biomarkers for ALPS diagnosis. [ABSTRACT FROM AUTHOR]

Periodontal disease affects more than 80% of dogs over 3 years of age, making it the most common disease in dogs seen in veterinary clinics. Gingivitis, the early-stage of periodontal disease, may be reversible with tooth brushing. Thiol, a sulfuric compound, has previously been shown to correlate with the degree of periodontal disease. In this study, a thiol-detection test was used to investigate daily tooth brushing efficacy in dogs. Twenty-two beagle dogs were subjected to daily tooth brushing for 2 weeks. Gingival index (GI), plaque index (PI), calculus index (CI) and thiol were assessed before treatment (day 1), after 1 week (day 7), after last treatment (day 14), and 2 weeks after treatment finished (day 29). Degree of stress was also assessed using a fear, anxiety and stress (FAS) scale. Both 7 and 14 days of daily tooth brushing showed an improvement in oral health. Thiol decreased significantly and GI and PI improved significantly after 1 and 2 weeks of brushing. No significant improvement in CI was shown. After an additional 2 weeks without brushing, GI and PI had returned to baseline levels. Stress levels decreased from day 1 to day 14. This study suggests that a thiol-detection test can be used to assess tooth brushing efficacy. Tooth brushing has a positive effect on the oral health in dogs as soon as 7 days after commencement. [ABSTRACT FROM AUTHOR]

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors' expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway. [ABSTRACT FROM AUTHOR]

Background/Aims: Youth with prenatal alcohol exposure (PAE) are under‐recognised in the justice system, warranting improved identification. This study aimed to compare neuropsychological profiles of adolescents, with and without PAE and identify neuropsychological tasks predictive of PAE‐group membership. It was hypothesised that participants with PAE would score significantly lower on neuropsychological tests. Methods: Participants included 85 young people sentenced to detention (mean 15.7 years, 78 males), 46 with PAE. A one‐way‐multivariate analysis of variance tested differences in neuropsychological functioning between PAE/No‐PAE groups, while logistic regression determined tests predictive of PAE. Results: No statistically significant difference in test scores emerged between groups, and regression was not indicative of any models predictive of PAE‐group membership. Neuropsychological profiles were characterised by both strengths and weaknesses, with lower verbal and mathematical skills. Conclusion(s): While no statistically significant differences were found between the groups, the results provided a unique insight into the neurocognitive profile of Australian youth in detention. Routine screening assessments were recommended for young people sentenced to detention. [ABSTRACT FROM AUTHOR]

Background: Even though adults with foetal alcohol spectrum disorder (FASD) are at risk of negative life outcomes, there is no published evidence of this in South Africa, which has the highest estimated FASD prevalence rate globally. Objectives: The purpose of the study was to describe and compare the life outcomes of adults with FASD and adults without FASD in a South African rural community, 16 years after diagnosis. Method: Participants were examined and interviewed regarding their biographical information, knowledge of FASD, information on their family, relationships, home circumstances, education, work and medical history. Results: Adults with FASD were less likely to be in a relationship and more likely to have poor educational outcomes and to be exposed to violence as victim or perpetrator than their peers who did not have FASD. None of the participants with FASD completed secondary school successfully. No differences were found for independent living, employment, health, substance use and legal outcomes, between the foetal alcohol syndrome (FAS) or partial foetal alcohol syndrome (PFAS) and control group. Conclusion: While significant differences existed in certain aspects, differences are not as stark as one would expect between individuals with FASD and controls. Contribution: This study highlights the importance of considering the social context in which a FASD diagnosis is made. The comparative negative impact of an FASD diagnosis and the associated challenges on life outcomes may be less pronounced in rural communities where everyone has fewer opportunities and resources. This can also make the unique needs of persons with disabilities less visible.

Introduction and purpose Maternal alcohol consumption during pregnancy is a well-documented risk factor for adverse fetal outcomes, encompassing a spectrum of disorders known as Fetal Alcohol Spectrum Disorders (FASD). Fetal Alcohol Syndrome (FAS), the most severe form of FASD, manifests with craniofacial anomalies, growth retardation, neurological deficits, and cognitive impairments, imposing lifelong challenges on affected individuals. This article presents a case report of a 4-week-old female newborn with suspected Fetal Alcohol Syndrome, highlighting the clinical complexities and diagnostic challenges associated with FAS. The infant exhibited characteristic dysmorphic features and cardiac abnormalities, underscoring the diverse spectrum of health issues linked to maternal alcohol consumption. Conclusion A presented case report illustrating the clinical complexities of FAS underscores the importance of early recognition and multidisciplinary management. Early identification of FAS is imperative to mitigate long-term outcomes, emphasizing the importance of a multidisciplinary and holistic approach to clinical care. Strategies for addressing maternal alcohol consumption include targeted education, preconception counseling, and innovative therapeutic modalities. This case report underscores the need for ongoing research and collaborative efforts to reduce the prevalence and impact of FASD on affected individuals and society.

Poti, Osmanlı idaresinde Kafkas kıyıları ve iç kesimlerin güvenliğinin sağlamasında bir set görevi görmüştür. Bu fonksiyonu, XIX. yüzyılda Rusya’nın genişleme ile uluslararası ticareti Kafkasya’ya çekme yönündeki politikası neticesinde ticari açıdan daha fazla ön plana çıkmaya başlamıştır. Özellikle Poti, Trabzon-Tebriz ticaretinin Rus topraklarına çekilmesi ve sağlanan ticari kolaylıklarla hızlı bir gelişim seyri yakalamış, Kafkasya’nın idari merkezi Tiflis’in ana limanı haline gelmiştir. Bu bağlamda çalışmanın amacı Rusya’nın kuzeyden güneye doğru genişlemesine paralel olarak yeni limanların ortaya çıkışı, gelişimi ve gerileyişi şeklinde yaşanan değişim ile Redut Kale, Sohum, Batum ve Trabzon limanlarıyla rekabet çerçevesinde Poti’nin liman ve kentsel gelişim seyrini Rus ve Osmanlı kaynakları ışığında ele almaktır.

Ummul Khair Imaduddin,1 Afiat Berbudi,2,* Enny Rohmawaty3,* 1Graduate School of Master Program in Anti Aging and Aesthetic Medicine, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 2Parasitology Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia; 3Pharmacology & Therapy Division, Departement of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, Indonesia*These authors contributed equally to this workCorrespondence: Enny Rohmawaty, Pharmacology & Therapy Division, Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang, KM.21, Hegarmanah, Kec. Jatinangor, Kabupaten Sumedang, Bandung, West Java, 45363, Indonesia, Email e.rohmawaty@unpad.ac.idPurpose: To explore the potential therapeutic effects of Physalis angulata L. (Ciplukan) extract on lung fibrosis resolution in a Bleomycin-induced mouse model, researchers conducted a comprehensive study. The study focused on key genes associated with fibrosis progression, including Nox4, Mmp8, Klf4, and FAS, and assessed their mRNA expression levels following the administration of Ciplukan extract.Methods: A Bleomycin-induced mice model was divided into seven groups to investigate the effects of ciplukan extract on fibrosis-related gene expressions. Mice were induced with subcutaneously injected Bleomycin to generate lung fibrosis and given different doses of the Ciplukan extract for four weeks. Lung fibrosis mRNA expression was analyzed by semi-quantitative PCR for Nox4, Klf4, Mmp8, and FAS.Results: The administration of ciplukan extract resulted in a significant decrease in mRNA expression of Nox4 with p-value=0.000, Mmp8 with p-value =0.002, and Klf4 with p-value =0.007, indicating potential antifibrotic effects. However, FAS expression remained unchanged (p-value=0.127).Conclusion: Ciplukan extract exhibited promising effects on fibrosis-related gene expressions, particularly Nox4, Mmp8, and Klf4. This study suggests that the extract has the potential to intervene in fibrosis progression, offering a potential avenue for therapeutic strategies.Keywords: ciplukan, FAS, Klf4, lung fibrosis, Mmp8, Nox4, pulmonary fibrosis, Physalis angulata L

Introduction/Objective Fas ligand (FasL) induces apoptosis when interacting with the Fas-receptor. The aim was to determine the concentration of soluble Fas (sFas) and soluble FasL (sFasL) in the aqueous humor (AH) of open-angle glaucoma patients, and establish a connection between these markers of apoptosis and the parameters of structural and functional glaucoma damage. Methods This study examined 88 AH samples; 35 primary open-angle glaucoma with elevated intraocular pressure (POAG-HTG) patients, 24 open angle pseudoexfoliative glaucoma patients (XFG) and 29 patients with senile cataract (CAT). The concentration of sFas and sFasL was determined by commercial ELISA tests in the AH. Results The conducted study showed that AH sFas concentration was the highest in XFG (720.14 ± 167.39 pg/ml), and slightly lower in POAG-HTG (713.43 ± 162.69 pg/ml), than in cataract patients (632.46 ± 217.11 pg/ml), without statistical significance. There was a significant negative correlation of sFas concentration and thickness of the peripapillary nerve fibers of the retina (RNFL) inferior thickness in POAG-HTG (p < 0.05). The concentration of sFasL was the lowest in POAG-HTG (9.28 ± 0.551 pg/ml), higher in XFG (9.45 ± 0.61 pg/ml; p = 0.0566), and the highest in the cataract group (9.48 ± 0.73 pg/ml). A negative correlation of sFasL and MD in the POAG-HTG, and a negative correlation with RNFL superior in the XFG were significant. Conclusion sFasL has an active role in the regulation of the inflammatory process in glaucoma. sFas and sFasL, as markers of apoptosis, are associated with the parameters of structural, RNFL thinning, and functional glaucoma damage, namely visual field defects.

In recent times, a fluid antenna system (FAS) has gained attention as a potential contender for 6G wireless networks. Fluid antenna multiple access (FAMA) is a new technology that allows each user to constantly move to the position with the strongest signal-to-interference ratio (SIR) by means of a single RF-chain port fluid antenna. Research works in FAMA mainly focus on propose models and solutions linked to the enhancement of FAMA from several aspects, including FAS system, enhancing orthogonal and non-orthogonal multiple access, channel modeling, diversity gain, artificial intelligence (AI) techniques, FAMA with other emerging technologies for 6G such as intelligent reflecting surface (IRS), multiple-input multiple-output (MIMO), terahertz (THz) communication, etc. There is no survey which covers all these important aspects of FAMA. Based on several concerns, a comprehensive taxonomy of FAMA has been presented in this study. First, FAS system is discussed. Then, FAMA mechanism is presented with its channel modeling and diversity gain. After that, FAMA is investigated with other emerging technologies such as IRS, MIMO, THz communication, etc. AI approaches to enhance FAMA are provided. In the end, we cover the potential research directions for further study in all areas. When designing and enhancing the FAS system, facilitating communication via FAMA, and integrating it with other cutting-edge technologies for 6G, this article may serve as a reference or guidance.

ABSTRACTIdentifying tumor-relevant T cell subsets in the peripheral blood (PB) has become a potential strategy for cancer treatment. However, the subset of PB that could be used to treat cancer remains poorly defined. Here, we found that the CX3CR1+ T cell subset in the blood of patients with lung cancer exhibited effector properties and had a higher TCR matching ratio with tumor-infiltrating lymphocytes (TILs) compared to CX3CR1− T cells, as determined by paired single-cell RNA and TCR sequencing. Meanwhile, the anti-tumor activities, effector cytokine production, and mitochondrial function were enhanced in CX3CR1+ T cells both in vitro and in vivo. However, in the co-culture system of H322 cells with T cells, the percentages of apoptotic cells and Fas were substantially higher in CX3CR1+ T cells than those in CX3CR1− T cells. Fas-mediated apoptosis was rescued by treatment with an anti-PD-1 antibody. Accordingly, the combination of adoptive transfer of CX3CR1+ T cells and anti-PD-1 treatment considerably decreased Fas expression and improved the survival of lung xenograft mice. Moreover, an increased frequency of CX3CR1+ T cells in the PB correlated with a better response and prolonged survival of patients with lung cancer who received anti-PD-1 therapy. These findings indicate the promising potential of adoptive transfer of peripheral CX3CR1+ T cells as an individual cancer immunotherapy.

IntroductionThe use of illicitly manufactured synthetic opioids, specifically fentanyl and its analogs, has escalated exponentially in the United States over the last decade. Due to the targeted nature of drug detection methods in clinical laboratories and the ever-evolving list of synthetic opioids of concern, alternative analytical approaches are needed.MethodsUsing the fentanyl analog screening (FAS) kit produced by the Centers for Disease Control and Prevention (CDC), we developed a liquid chromatography-high resolution mass spectrometry (LC-HRMS) synthetic opioid spectral library and data acquisition method using information dependent acquisition of product ion spectra. Chromatographic retention times, limits of detection and matrix effects, in urine and serum, for the synthetic opioids in the FAS kit (n = 150) were established. All urine and serum specimens sent to a clinical toxicology laboratory for comprehensive drug testing in 2019 (n = 856) and 2021 (n = 878) were analyzed with the FAS LC-HRMS library to determine the prevalence of fentanyl analogs and other synthetic opioids, retrospectively (2019) and prospectively (2021).ResultsThe limit of detection (LOD) of each opioid ranged from 1 to 10 ng/mL (median, 2.5 ng/mL) in urine and 0.25-2.5 ng/mL (median, 0.5 ng/mL) in serum. Matrix effects ranged from -79 % to 86 % (median, -37 %) for urine, following dilution and direct analysis, and -80 % to 400 % (median, 0 %) for serum, following protein precipitation. The prevalence of fentanyl/fentanyl analogs in serum samples increased slightly from 2019 to 2021 while it remained the same in urine. There were only 2 samples identified that contained a fentanyl analog without the co-occurrence of fentanyl or fentanyl metabolites. Analysis of the established MS/MS spectral library revealed characteristic fragmentation patterns in most fentanyl analogs, which can be used for structure elucidation and drug identification of future analogs.ConclusionsThe LC-HRMS method was capable of detecting fentanyl analogs in routine samples sent for comprehensive drug testing. The method can be adapted to accommodate testing needs for the evolving opioid epidemic.

Resistance to immunotherapy in colorectal cancer (CRC) is associated with obstruction of FAS (Apo‐1 or CD95)‐dependent apoptosis, a hallmark of cancer. Here it is demonstrated that the upregulation of pirin (PIR) protein in colon cancers promotes tumorigenesis. Knockout or inhibition of PIR dramatically increases FAS expression, FAS‐dependent apoptosis and attenuates colorectal tumor formation in mice. Specifically, NFκB2 is a direct transcriptional activator of FAS and robustly suppressed by PIR in dual mechanisms. One is the disruption of NFκB2 complex (p52‐RELB) association with FAS promoter, the other is the inhibition of NIK‐mediated NFκB2 activation and nuclear translocation, leading to the inability of active NFκB2 complex toward the transcription of FAS. Furthermore, PIR interacts with FAS and recruits it in cytosol, preventing its membrane translocation and assembling. Importantly, knockdown or knockout of PIR dramatically sensitizes cells to FAS mAb‐ or active CD8+ T cells‐triggered cell death. Taken together, a PIR‐NIK‐NFκB2‐FAS survival pathway is established, which plays a key role in supporting CRC survival. [ABSTRACT FROM AUTHOR]

Sucralose is a food additive initially used to mitigate glycemic peaks and calorie intake in patients with diabetes and obesity. Although sucralose has been considered safe for human consumption, the World Health Organization (WHO) issued a global alert in 2023 concerning the potential health implications of this artificial sweetener. This review aims to comprehensively explore the effects of sucralose intake on human health by understanding sucralose absorption, metabolism, and excretion. We also outline the role of the sweet taste 1 receptor 3 (T1R3) in mediating sucralose-dependent signaling pathways that regulate satiety, incretin release, and insulin response. Finally, we discuss the impact of sucralose on microbiome dysbiosis, inflammatory response origin, liver damage, and toxicity. Gaining a deeper understanding of the manifold effects of sucralose on human physiology will help promote further studies to ensure its consumption is deemed safe for a broader population, including children, adolescents, and pregnant women. [ABSTRACT FROM AUTHOR]

One of the main objectives in engineering seismology or in seismic hazard studies is to estimate the possible ground motion for a given earthquake scenario. In the sparse data regions mostly the ground motion models (GMM) are developed using either seismological models or hybrid empirical approaches. However, if these GMMs do not accommodate the regional seismological attributes, a large uncertainty in ground motion estimates is possible. To overcome this concern, scaling 5% damped Pseudo Spectral Acceleration (PSA) from Fourier amplitude spectra (FAS) proves to be physically consistent as it can capture both spatial and temporal characteristics of the ground motion. Hence, the present study aims to develop a GMM for PSA using FAS and significant duration as the predictor variables. However, since there are few GMMs available for FAS, the current study also aims to develop a GMM for FAS using the earthquake parameters as the predictor variables for intraplate regions. This article employs an Artificial Neural Network (ANN) to develop both GMMs using the Next Generation Attenuation (NGA)‐East database for both horizontal (Effective Amplitude spectra for FAS and RotD50 component for PSA) and vertical components. To verify the performance of the developed models, the residuals analysis and parametric studies have been performed. The parametric study shows that the GMMs can capture the magnitude and distance scaling consistent with the observations. Further, the PSA GMM compared with the global GMMs and it is observed that the predictions lie well within the median of all the available models, proving the models' effectiveness in estimating the ground motion predictions for future data. The developed model can be used only within the considered ranges of the predicted variables such as rupture distances between [19.05–1000] km, the Mw ranges from [3.12–5.74] with Vs30 in the range of [209–2000] m/s. [ABSTRACT FROM AUTHOR]

Live prey is characterized by balanced rich nutrients and high palatability and is widely used for the seedling cultivation of freshwater dark sleeper (Odontobutis potamophila) larvae. In this study, we evaluated the effects of four groups of paired feeding regimens (group C (Daphnia magna), group L (Limnodrilus hoffmeisteri), group H (Hypophthalmichthys molitrix fry), and group M (mixed groups C, L, and H)) on glycolipid and energy metabolism in O. potamophila larvae. We observed that fatty acid synthase (FAS) and sterol-regulatory-element-binding protein-1 (SREBP-1) mRNA levels were significantly lower in group H when compared to mRNA levels in the other three groups (p < 0.05) and that carnitine palmitoyltransferase 1α (CPT1-α) mRNA levels were significantly lower in group L when compared to group M (p < 0.05). Relative glucokinase (GK) expression levels were significantly lower in group M when compared to the other three groups (p < 0.05). Using proteomics, we analyzed and compared groups H and L and identified 457 differentially expressed proteins (DEPs), of which 151 were significantly up-regulated and 306 were significantly down-regulated. In the comparison of group M with groups C, L, and H, we found significant enrichment in glycolytic processes, the endoplasmic reticulum lumen, NAD binding, intermediate filaments, and nutrient reservoir activity. Our results provide a theoretical guidance for bait selection during larvae cultivation stages in carnivorous fish. [ABSTRACT FROM AUTHOR]

Introduction: Children with fetal alcohol spectrum disorders (FASD) exhibit behavioral and affective dysregulation, including hyperactivity and depression. The mechanisms are not known, but they could conceivably be due to postnatal social or environmental factors. However, we postulate that, more likely, the affective dysregulation is associated with the effects of EtOH exposure on the development of fetal serotonergic (5-HT) and/or dopaminergic (DA) pathways, i.e., pathways that in postnatal life are believed to regulate mood. Many women who use alcohol (ethanol, EtOH) during pregnancy suffer from depression and take selective serotonin reuptake inhibitors (SSRIs), which might influence these monoaminergic pathways in the fetus. Alternatively, monoaminergic pathway abnormalities might reflect a direct effect of EtOH on the fetal brain. To distinguish between these possibilities, we measured their expressions in fetal brains and in fetal brain-derived exosomes (FB-Es) isolated from the mothers' blood. We hypothesized that maternal use of EtOH and/or SSRIs during pregnancy would be associated with impaired fetal neural development, detectable as abnormal levels of monoaminergic and apoptotic biomarkers in FB-Es. Methods: Fetal brain tissues and maternal blood were collected at 9–23 weeks of pregnancy. EtOH groups were compared with unexposed controls matched for gestational age (GA). The expression of 84 genes associated with the DA and 5-HT pathways was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) on microarrays. FB-Es also were assayed for serotonin transporter protein (SERT) and brain-derived neurotrophic factor (BDNF) by enzyme-linked immunosorbent assay (ELISA). Results: Six EtOH-exposed human fetal brain samples were compared to SSRI- or polydrug-exposed samples and to unexposed controls. EtOH exposure was associated with significant upregulation of DA receptor D3 and 5-HT receptor HTR2C, while HTR3A was downregulated. Monoamine oxidase A (MAOA), MAOB, the serine/threonine kinase AKT3, and caspase-3 were upregulated, while mitogen-activated protein kinase 1 (MAPK1) and AKT2 were downregulated. ETOH was associated with significant upregulation of the DA transporter gene, while SERT was downregulated. There were significant correlations between EtOH exposure and (a) caspase-3 activation, (b) reduced SERT protein levels, and (c) reduced BDNF levels. SSRI exposure independently increased caspase-3 activity and downregulated SERT and BDNF. Early exposure to EtOH and SSRI together was associated synergistically with a significant upregulation of caspase-3 and a significant downregulation of SERT and BDNF. Reduced SERT and BDNF levels were strongly correlated with a reduction in eye diameter, a somatic manifestation of FASD. Conclusions: Maternal use of EtOH and SSRI during pregnancy each was associated with changes in fetal brain monoamine pathways, consistent with potential mechanisms for the affective dysregulation associated with FASD. [ABSTRACT FROM AUTHOR]

To examine the potential protective impact and underlying mechanism of nerve growth factor on brain tissue in hyperbilirubinemia rats through the downregulation of Fas/Fas ligand expression. Thirty six healthy Sprague-Dawley rats were selected as normal control group, and 0.5 ml saline was injected intraperitoneally. The remaining 24 rats were injected intraperitoneally with 50 μg/g bilirubin to establish the model of hyperbilirubinemia. After the model was established successfully, they were divided into hyperbilirubinemia group and nerve growth factor intervention group. The rats in the nerve growth factor intervention group were intraperitoneally injected with 50 μg/kg/d nerve growth factor once a day for 3 d. Rats in each group were killed and their brain tissues were taken to wait for detection. The changes of pathological morphology and the Fas and Fas ligand were compared between the normal control group at 72 h and the hyperbilirubinemia group at 6 h, 24 h, 72 h and the nerve growth factor intervention group. In hyperbilirubinemia group and nerve growth factor intervention group, the brain tissue of rats had different degrees of neurocyto edema. After 6 h, the brain tissue of both groups had degeneration. After 24 h, the neuron necrosis was obvious. After 72 h, the brain tissue of both groups had glial cell proliferation, nuclear pyknosis and fragmentation. However, the severity of brain tissue in nerve growth factor intervention group was less than that in hyperbilirubinemia group, while that in normal control group was not obvious change. At 6 h, 24 h and 72 h, the Fas in the hyperbilirubinemia group was raised than that of the normal control group; while this in the nerve growth factor intervention group was reduced than that of hyperbilirubinemia. At 6 h, 24 h and 72 h, the Fas ligand in hyperbilirubinemia group was raised than that of normal control group; and it in nerve growth factor intervention group was reduced than that of hyperbilirubinemia group. The expression of Fas/Fas ligand can be downregulated by nerve growth factor, thereby providing protection to the brain tissue of rats with hyperbilirubinemia. [ABSTRACT FROM AUTHOR]

Objectives: To examine the relation of corticotropin-releasing hormone (CRH) family peptides with inflammatory processes and oncogenesis, emphasizing in vulvar inflammatory, premalignant and malignant lesions, as well as to investigate the possibility of lesion cells immunoescaping, utilizing FAS/FAS-L complex. Methods: Immunohistochemical expression of CRH, urocortin (UCN), FasL and their receptors CRHR1, CRHR2 and Fas was studied in vulvar tissue sections obtained from patients with histologically confirmed diagnosis of lichen, vulvar intraepithelial neoplasia (VIN) and vulvar squamous cell carcinoma (VSCC). The patient cohort was selected from a tertiary teaching Hospital in Greece, between 2005 and 2015. For each of the disease categories, immunohistochemical staining was evaluated and the results were statistically compared. Results: A progressive increase of the cytoplasmic immunohistochemical expression of CRH and UCN, from precancerous lesions to VSCC was observed. A similar increase was detected for Fas and FasL expression. Nuclear localization of UCN was demonstrated in both premalignant and VSCC lesions, with staining being significantly intensified in carcinomas, particularly in the less differentiated tumor areas or in the areas at invasive tumor front. Conclusions: Stress response system and CRH family peptides seem to have a role in inflammation maintenance and progression of vulvar premalignant lesions to malignancy. It seems that stress peptides may locally modulate the stroma through Fas/FasL upregulation, possibly contributing to vulvar cancer development. [ABSTRACT FROM AUTHOR]

The developing fetus is dependent on the maternal nutritional environment. This study was conducted to determine the effects of a maternal high-fat diet (HFD) applied during pregnancy and/or lactation on the expression levels of some lipid-related genes in rat models. Half of the pregnant rats (n: 6) were fed an HFD (energy from fat: 45%), while the other half (n: 6) were fed a control diet (CD) (energy from fat, 7.7%) during the pregnancy period. During lactation, dams in both groups were divided into two subgroups, with half fed the CD and the other half fed the HFD. Thus, four groups were obtained: CD-CD, CD-HFD, HFD-CD, and HFD-HFD. At the end of lactation, all mothers and half of the offspring were sacrificed. The remaining offspring were fed a CD for five weeks. The average birth weight of the CD group offspring was found to be lower than that of the HFD group (p < 0.05). The amount of adipose tissue was highest in CD-HFD (p < 0.05), while gene expression levels were similar between groups (p > 0.05), and the most degenerative histological changes were observed in the eight-week HFD-HFD (p < 0.05). This study suggests that maternal HFD during pregnancy and lactation may increase adiposity in offspring rats, especially during the weaning period. [ABSTRACT FROM AUTHOR]

With the 2004 reforms on the Moroccan Personal Status Law, the Moroccan Family Code (Mudawwanah) is considered one of the most egalitarian codes in the Muslim World. The reforms was a product of long-lasting public debates for decades in Morocco. Aḥmad al-Khamlīshī has been actively involved in the debate since the beginning of the 1980s and explained that the Personal Status Law is man-made law open to interpretation, revision of which should be undertaken through ijtihād. Shortly after ascending to the throne, in 2001, the King Mohammed VI appointed the Royal Advisory Commission in charge to reform the Moroccan Personal Status Code. The King charged the commission for making a substantial change in the Code by respecting the main objectives of Sharia (maqāsid al-Sharia) and also responding to the necessities of the time and society by means of exercising ijtihād. He encouraged members of the commission to consider the public interest and to strive for consensus and moderation in any proposed changes. The commission worked for around two and a half years on the proposed changes, but could not reach a consensus on many issues. Everyone on the commission has, more or less, had some leaning towards either of the two main groups, namely, the reformists and traditionalists. Aḥmad al-Khamlīshī was one of the members of the Royal Advisory Commission. He was a person who shared views of the reformist group, but also used the language of the traditionalists. He became a reference point for reformist groups with his critical but moderate views that remain within the Islamic legal framework. In this paper, I argue that al-Khamlīshī was the mastermind behind the reforms of 2004. By applying data analysis method, this study primarly uses al-Khamlīshī’s writings, his interviews and speeches. To reveal the difference and similarities of his understanding, the literature was consulted and comparisons were made. Following a brief background, this paper will discuss al-Khamlīshī’s mediating role between text and context, his influence on the debate of family law reforms, and thus his stance on Sharia-state relations. This paper will then focus on his understanding of ijtihād with reference to his views on the concept of the closure of the gate of ijtihād, qualifications of mujtahid (one who is capable to deduce legal rulings from the revealed texts), and his suggestion on collective type of ijtihād (ijtihād jamā’iʻ); as it was exercised by the Advisory Commission. Al-Khamlīshī’s methods of legal reasoning will be examined with regard to family law.

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPARγ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPARγ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPARγ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.

In this study, we report the robust hydrophobicity, lower fouling propensity, and high thermal efficiency of the 1H,1H,2H,2H-perfluorooctyltriethoxysilane (FAS)-coated, carbon nanotube-immobilized membrane (CNIM) when applied to desalination via membrane distillation. Referred to as FAS-CNIM, the membrane was developed through a process that combined the drop-casting of nanotubes flowed by a dip coating of the FAS layer. The membranes were tested for porosity, surface morphology, thermal stability, contact angle, and flux. The static contact angle of the FAS-CNIM was 153 ± 1°, and the modified membrane showed enhancement in water flux by 18% compared to the base PTFE membrane. The flux was tested at different operating conditions and the fouling behavior was investigated under extreme conditions using a CaCO3 as well as a mixture of CaCO3 and CaSO4 solution. The FAS-CNIM showed significantly lower fouling than plain PTFE or the CNIM; the relative flux reduction was 34.4% and 37.6% lower than the control for the CaCO3 and CaCO3/CaSO4 mixed salt solution. The FAS-CNIM exhibited a notable decrease in specific energy consumption (SEC). Specifically, the SEC for the FAS-CNIM measured 311 kwh/m3 compared to 330.5 kwh/m3 for the CNIM and 354 kwh/m3 for PTFE using a mixture of CaCO3/CaSO4. This investigation underscores the significant contribution of the carbon nanotubes’ (CNTs) intermediate layer in creating a durable superhydrophobic membrane, highlighting the potential of utilizing carbon nanotubes for tailored interface engineering to tackle fouling for salt mixtures. The innovative design of a superhydrophobic membrane has the potential to alleviate wetting issues resulting from low surface energy contaminants present in the feed of membrane distillation processes.

Influenza viruses pose a serious threat to public health, with severe cases often characterized by lung damage and inflammation. However, the underlying mechanisms of these processes remain poorly understood. This study aimed to investigate the essential role of megakaryocytes (MKs) and platelets (PLTs) in influenza A virus (IAV) infections. Conducted at the Department of Rare Respiratory Diseases, Cystic Fibrosis, and Pulmonology, Nord University Hospital, Marseille, France, the study collected seventy blood samples between October 2018 and March 2019. Samples were obtained from healthy individuals and patients diagnosed with IAV. Messenger RNA was extracted from isolated PLTs and subjected to quantitative real-time-polymerase chain reaction using sets of primers targeting immune marker genes. Western blot analysis was also performed for confirmation, focusing on Fas Ligand (FasL). Results showed that PLTs from IAV-infected individuals expressed the FasL, tumor necrosis factor-related apoptosis-inducing ligand, and Granulysin (GNLY) receptors when activated. Furthermore, an in vitro assay revealed the presence of FasL receptors on infected CMK cell lines. In vivo investigations demonstrated that activated MKs and PLTs in mice also expressed FasL. Interestingly, none of the immune receptors under investigation were found in both MKs and PLTs in mouse model studies. In conclusion, MKs and PLTs play a significant role in influencing immune responses that may help prevent viral spread during infection. However, further examination of their mechanisms of action is warranted. Understanding the involvement of these cells in influenza pathogenesis could offer valuable insights for developing potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Ligustrum robustum has been not only used as a heat-clearing and detoxicating functional tea (Ku-Ding-Cha) but also consumed as a hypotensive, anti-diabetic, and weight-reducing folk medicine. From the leaves of L. robustum, ten new monoterpenoid glycosides named ligurobustosides T10 (1a), T11 (1b), T12 (2a), T13 (2b), T14 (3a), T15 (3b), F1 (4b), T16 (5a), T17 (5b), and E1 (6b), together with five known ones (4a, 6a, 7, 8a, 8b), were separated and identified using the spectroscopic method and chemical method in this research. The results of biological tests exhibited that the fatty acid synthase (FAS) inhibitory action of compound 5 (IC50: 4.38 ± 0.11 μM) was as strong as orlistat (IC50: 4.46 ± 0.13 μM), a positive control; the α-glucosidase inhibitory actions of compounds 1–4 and 7–8, and the α-amylase inhibitory actions of compounds 1–8 were medium; the ABTS radical scavenging capacities of compounds 1–3 and 5–8 (IC50: 6.27 ± 0.23 ~ 8.59 ± 0.09 μM) were stronger than l-(+)-ascorbic acid (IC50: 10.06 ± 0.19 μM) served as a positive control. This research offered a theoretical foundation for the leaves of L. robustum to prevent diabetes and its complications. [ABSTRACT FROM AUTHOR]

Osteoporosis (OP) is a systemic skeletal disease that primarily affects the elderly population, which greatly increases the risk of fractures. Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass. Kindlin-2 specific deletion (K2KO) controlled by Adipoq-Cre mice or adipose tissue-targeting AAV (AAV-Rec2-CasRx-sgK2) significantly increases bone mass. Mechanistically, Kindlin-2 promotes peroxisome proliferator-activated receptor gamma (PPAR γ) activation and downstream fatty acid binding protein 4 (FABP4) expression through stabilizing fatty acid synthase (FAS), and increased FABP4 inhibits insulin expression and decreases bone mass. Kindlin-2 inhibition results in accelerated FAS degradation, decreased PPAR γ activation and FABP4 expression, and therefore increased insulin expression and bone mass. Interestingly, we find that FABP4 is increased while insulin is decreased in serum of OP patients. Increased FABP4 expression through PPAR γ activation by rosiglitazone reverses the high bone mass phenotype of K2KO mice. Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice. Collectively, our study establishes a novel Kindlin-2/FAS/PPAR γ /FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment. Adipocytes Kindlin-2 enhances Fas stability, which promotes PPAR γ /Fabp4 signaling, leading to reduced insulin level and bone mass. Adipocytes Kindlin-2 and Fas are potential targets for osteoporosis treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim. N6-methyladenosine (m6A) RNA methylation exerts a regulatory effect on endometrioid ovarian cancer (EOC), but the specific m6A regulator genes in EOC remain to be explored. This study investigated that sulforaphene (Sul) is implicated in EOC development by regulating methyltransferase-like 3 (METTL3). Methods. The dysregulated m6A RNA methylation genes in EOC were determined by methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing. The roles of METTL3 and/or Sul on viability, proliferative ability, cell cycle, and apoptosis of EOC cells were determined by MTT, colony formation, flow cytometry, and TUNEL staining assay, respectively. The expression of METTL3 and apoptosis-related proteins in EOC cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays. Results. Five m6A RNA methylation regulators (METTL3, ELF3, IGF2BP2, FTO, and METTL14) were differentially expressed in EOC, among which METTL3 had the highest expression level. Silencing METTL3 reduced the clonal expansion and viability of EOC cells, and caused the cells to arrest in the G0/G1 phase. This also promoted apoptosis in the EOC cells and activated the FAS/FADD and mitochondrial apoptosis pathways. In contrast, overexpressing METTL3 had the opposite effect. Sul, in a dosedependent manner, reduced the viability of EOC cells but promoted their apoptosis. Sul also increased the levels of IGF2BP2 and FAS, while decreasing the levels of KRT8 and METTL3. Furthermore, Sul was able to reverse the effects of METTL3 overexpression on EOC cells. Conclusions. Sul could suppress cell proliferation and promote apoptosis of EOC cells by inhibiting the METTL3 to activate the FAS/FADD and apoptosis-associated pathways. [ABSTRACT FROM AUTHOR]

A common challenge in regression is that for many problems, the degrees of freedom required for a high‐quality solution also allows for overfitting. Regularization is a class of strategies that seek to restrict the range of possible solutions so as to discourage overfitting while still enabling good solutions, and different regularization strategies impose different types of restrictions. In this paper, we present a multilevel regularization strategy that constructs and trains a hierarchy of neural networks, each of which has layers that are wider versions of the previous network's layers. We draw intuition and techniques from the field of Algebraic Multigrid (AMG), traditionally used for solving linear and nonlinear systems of equations, and specifically adapt the Full Approximation Scheme (FAS) for nonlinear systems of equations to the problem of deep learning. Training through V‐cycles then encourage the neural networks to build a hierarchical understanding of the problem. We refer to this approach as multilevel‐in‐width to distinguish from prior multilevel works which hierarchically alter the depth of neural networks. The resulting approach is a highly flexible framework that can be applied to a variety of layer types, which we demonstrate with both fully connected and convolutional layers. We experimentally show with PDE regression problems that our multilevel training approach is an effective regularizer, improving the generalize performance of the neural networks studied. [ABSTRACT FROM AUTHOR]

Abstract Resistance to immunotherapy in colorectal cancer (CRC) is associated with obstruction of FAS (Apo‐1 or CD95)‐dependent apoptosis, a hallmark of cancer. Here it is demonstrated that the upregulation of pirin (PIR) protein in colon cancers promotes tumorigenesis. Knockout or inhibition of PIR dramatically increases FAS expression, FAS‐dependent apoptosis and attenuates colorectal tumor formation in mice. Specifically, NFκB2 is a direct transcriptional activator of FAS and robustly suppressed by PIR in dual mechanisms. One is the disruption of NFκB2 complex (p52‐RELB) association with FAS promoter, the other is the inhibition of NIK‐mediated NFκB2 activation and nuclear translocation, leading to the inability of active NFκB2 complex toward the transcription of FAS. Furthermore, PIR interacts with FAS and recruits it in cytosol, preventing its membrane translocation and assembling. Importantly, knockdown or knockout of PIR dramatically sensitizes cells to FAS mAb‐ or active CD8+ T cells‐triggered cell death. Taken together, a PIR‐NIK‐NFκB2‐FAS survival pathway is established, which plays a key role in supporting CRC survival.

Background and Objective: Isoproterenol (ISO) is a non-selective β-adrenergic receptor agonist. It can be used to treat bradycardia and cardiogenic shock. Despite its usefulness, the overstimulation of β-receptors by ISO can cause “cardiorenal syndrome,” a term used to describe heart and kidney damage. Resveratrol (RES), a natural polyphenol, has marked anti-inflammatory and antioxidant activities. The present work was designed to study the protective efficacy of liposomal resveratrol (L-RES) against ISO-induced kidney injury. Materials and Methods: The kidney injury was induced in rats by administering ISO (50 mg/kg, s.c.) twice a week for 2 weeks. RES and L-RES were administered at a dose (20 mg/kg/ day, p.o.) along with ISO for 2 weeks. Inflammatory and apoptotic biomarkers were analyzed, which were validated using histochemical analysis. Results: ISO caused renal dysfunction, which manifested as elevated urea, creatinine and uric acid, besides cystatin c and MAPK protein overexpression. In addition, ISO induced gene expression of Fas and lipocalin-2 and provoked genomic DNA fragmentation in renal tissues as compared with the control group. Histological examination confirmed morphological alterations of the kidney tissues obtained from the ISO group. Concurrent treatment of either RES or L-RES with ISO significantly ameliorated kidney damage as demonstrated by the improvement of all measured parameters with the best results for L-RES. The histopathological findings were correlated with the above biochemical parameters. Conclusion: L-RES could be a promising approach for the prevention of kidney injury induced by ISO, most likely via the downregulation of MAPK, cystatin c, Fas, and lipocalin-2.

Abstract Metastatic cancer cells can develop anoikis resistance in the absence of substrate attachment and survive to fight tumors. Anoikis is mediated by endogenous mitochondria-dependent and exogenous death receptor pathways, and studies have shown that caspase-8-dependent external pathways appear to be more important than the activity of the intrinsic pathways. This paper reviews the regulation of anoikis by external pathways mediated by death receptors. Different death receptors bind to different ligands to activate downstream caspases. The possible mechanisms of Fas-associated death domain (FADD) recruitment by Fas and TNF receptor 1 associated-death domain (TRADD) recruitment by tumor necrosis factor receptor 1 (TNFR1), and DR4- and DR5-associated FADD to induce downstream caspase activation and regulate anoikis were reviewed. This review highlights the possible mechanism of the death receptor pathway mediation of anoikis and provides new insights and research directions for studying tumor metastasis mechanisms. Video Abstract

Abstract Background Hepatic encephalopathy (HE) is a consequence of chronic or acute liver diseases. This study evaluates the combined effect of gallic acid (GA), and metformin (Met) on the liver and brain damage associated with HE. Methods Acute HE was induced by a single dose of thioacetamide (TAA) (300 mg/kg) as an I.P. injection. Treated groups received GA group (100 mg/kg/day, p.o), Met (200 mg/kg/day, p.o), or their combination for 25 consecutive days before TAA injection. Results The administration of TAA induced various biochemical and histopathological alterations. In contrast, treatment with GA either alone or combined with Met resulted in improved liver functions by the significant reduction in serum ALT, AST, and ALP activities, and ammonia levels. Inflammatory mediators; TNF-α, IL-6, and NFkβ levels were decreased by these treatments as well as apoptotic cascade via down-regulation of FAS and caspase-3 (CASP-3) expression in hepatic tissues. Furthermore, GA and Met either alone or combined protected the liver and brain tissues from damage by increased glutathione concentration while decreasing malondialdehyde. In addition, it was accompanied by the improvement of the brain neurotransmitter profile via the restoration of norepinephrine, dopamine, and serotonin levels. Based on our data, this is the first study to report a novel combined hepatoprotective and cognitive enhancing effect of GA and Met against TAA-induced acute liver and brain injury. Conclusion GA and Met combination resulted in a prominent improvement in HE complications, relative to monotherapy. Both agents potentiated the antioxidant, anti-inflammatory, and anti-apoptotic effects of each other.

Death receptor signalization that triggers the extrinsic apoptotic pathway and TGF-β1 have important roles in urothelial carcinogenesis, with a complex interplay between them. The aim of this research was to assess the association of death receptors DR4, DR5, and FAS as well as TGF-β1 immunohistochemical expression with the clinicopathological characteristics of urothelial bladder cancer (UBC) and to evaluate their prognostic significance. The decrease or loss of death receptors’ expression was significantly associated with muscle-invasive tumors, while non-invasive UBC often retains the expression of death receptors, which are mutually strongly linked. High DR4 expression is a marker of low-grade tumors and UBC associated with exposition to known carcinogens. Conversely, TGF-β1 was significantly associated with high tumor grade and advanced stage. High expression of DR4 and FAS indicates longer overall survival. High TGF-β1 signifies an inferior outcome and is an independent predictor of adverse prognosis in UBC patients. This study reveals the expression profile of death receptors in UBC and their possible interconnection with TGF-β1 and indicates independent prognostic significance of high FAS and TGF-β1 expression in UBC, which may contribute to deciphering the enigma of UBC heterogeneity in light of the rapid development of novel and effective therapeutic approaches, including targeting of the TRAIL-induced apoptotic pathway.

Background: Longer-term consequences after SARS-CoV-2 infection are becoming an important burden to societies and healthcare systems. Long COVID-19 and post COVID-19 conditions are terms used clinically to describe ongoing or new symptoms that occur beyond 12 weeks of recovery from an acute infection, that cannot be explained by an alternative medical diagnosis. It is now understood that COVID-19 can impact on multiple organ systems, which can lead to a diverse range of persistent symptoms including fatigue, breathlessness, cough, loss of taste and/or smell, myalgia, memory issues and gastrointestinal problems. Very few studies have been conducted globally to assess the burden of Long Covid which are in hospital setting and none published in Karnataka state. This community based cross sectional study intends to bridge the gap in existing evidence pool and to influence evidence-based policy decisions at local administrative level. Objectives: To assess the prevalence of Long covid among people infected with COVID-19 in rural community Bengaluru rural district. Methodology: Community based cross sectional study was conducted between October 2023 to November 2023 in Orohalli & Jadigenahalli Panchayaths of Hoskote Taluk. After obtaining written and informed consent from the participants, all adults > 18years of age residing in identified villages, with COVID-19 RTPCR positive status, tested at least 12 weeks/ 3 months prior to the date of interviewed using a prevalidated questionare and Fatigue Assessment Scale. Data is analysed using SPSS trial version 21. Results: 420 participants were interviewed in 17 villages. Mean period between date of COVID positivity to date of interview was 490 days. 27 (6.4%) participants reported residual symptoms from COVID 19 infection suggestive of Long Covid. Majority of them complained of fatigue. Out 25 respondents with fatigue, 18 people had a score > 22 on FAS, indicative of clinical fatigue. Older age >60years, female gender, and ICU admission during infection, were associated with higher prevalence of long covid and are statistically significant (p value< 0.05) Conclusion: It is essential to determine the burden of longer-term consequences of SARS-CoV-2 infection and the needs of affected individuals, to successfully plan healthcare services and efficiently allocate public health resources.