LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy.

Various low-density lipoprotein receptors (LPRs) have been identified as entry factors for alphaviruses, and structures of the corresponding virion-receptor complexes have been determined. Here, we analyze the similarities and differences in the receptor binding modes of multiple alphaviruses to understand their ability to infect a wide range of hosts. We further discuss the challenges associated with the development of broad-spectrum treatment strategies against a diverse range of alphaviruses.

Biomorphometric and hematobiochemical alterations in the juvenile african catfish Clarias gariepinus exposed to propranolol.

Propranolol (PRO) is a beta-blocker drug used for the treatment of anxiety, chest pain, migraine and tremors. The present study investigated whether sublethal concentrations of PRO have effects on the body condition, biochemistry, and hematology of Clarias gariepinus juveniles. The 96-h median lethal concentration (LC50) of the drug, which was established through an acute toxicity study, was 9.48 mg/L. Based on these values, the fish were exposed for 21 days to the control and sublethal concentrations of 1.90, 0.95, and 0.63 mg/L, which are equivalent to the 1/5th, 1/10th, and 1/20th of the LC50 of PRO, respectively. After 21 days of exposure, the fish were removed from the toxicant and kept in toxicant-free water for 7 days to recover. The standard length and body weight of each fish were measured after each exposure period. The condition factor (CF) and hepatosomatic index (HSI) were not significantly affected by the drug. The red blood cell (RBC) count, hemoglobin (Hb) count and packed cell volume (PCV) decreased from day 7 to 21 at the tested concentrations, while the white blood cell (WBC) count significantly increased. There were alterations in the mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and mean corpuscular hemoglobin (MCH) in the exposed groups compared to those in the control group. When neutrophil counts increased, the lymphocyte counts decreased, but the monocyte, basophil cell and eosinophil cell counts were not affected. Among the liver enzymes, only aspartate aminotransferase was significantly stimulated in the groups that were exposed to the drug. The protein and glucose levels of fish exposed to the drug decreased. Most of the studied parameters returned to their original values after the 7-day recovery period. The information provided in the current study will be helpful in the monitoring of PRO contamination in aquatic environments.

Novel requirements for HAP2/GCS1-mediated gamete fusion in Tetrahymena.

The ancestral gamete fusion protein, HAP2/GCS1, plays an essential role in fertilization in a broad range of taxa. To identify factors that may regulate HAP2/GCS1 activity, we screened mutants of the ciliate Tetrahymena thermophila for behaviors that mimic Δhap2/gcs1 knockout phenotypes in this species. Using this approach, we identified two new genes, GFU1 and GFU2, whose products are necessary for membrane pore formation following mating type recognition and adherence. GFU2 is predicted to be a single-pass transmembrane protein, while GFU1, though lacking obvious transmembrane domains, has the potential to interact directly with membrane phospholipids in the cytoplasm. Like Tetrahymena HAP2/GCS1, expression of GFU1 is required in both cells of a mating pair for efficient fusion to occur. To explain these bilateral requirements, we propose a model that invokes cooperativity between the fusion machinery on apposed membranes of mating cells and accounts for successful fertilization in Tetrahymena's multiple mating type system.

Corrigendum: Survival outcomes and mobilization during venovenous extracorporeal membrane oxygenation: a retrospective cohort study.

[This corrects the article DOI: 10.3389/fmed.2023.1271540.].

Altered dynamics of calcium fluxes and mitochondrial metabolism in platelet activation-related disease and aging.

Understanding the mechanisms controlling platelet function is crucial for exploring potential therapeutic targets related to atherothrombotic pathologies and primary hemostasis disorders. Our research, which focuses on the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis, has significant implications for the development of new therapeutic strategies. Traditionally, Ca2+-dependent cellular signaling has been recognized as a determinant process throughout the platelet activation, controlled primarily by store-operated Ca2+ entry and the PLC-PKC signaling pathway. However, despite the accumulated knowledge of these regulatory mechanisms, the effectiveness of therapy based on various commonly used antiplatelet drugs (such as acetylsalicylic acid and clopidogrel, among others) has faced challenges due to bleeding risks and reduced efficacy associated with the phenomenon of high platelet reactivity. Recent evidence suggests that platelet mitochondria could play a fundamental role in these aspects through Ca2+-dependent mechanisms linked to apoptosis and forming a procoagulant phenotype. In this context, the present review describes the latest advances regarding the role of platelet mitochondria and Ca2+ fluxes in platelet activation, the formation of the procoagulant phenotype, and thrombosis.

Religious coping and delinquent behaviors: Moderated mediation roles of religion affiliation and prosocial moral reasoning.

Religion has been shown to have a positive impact for developing adolescents; however, the processes underlying this relation are not well known. In his almighty prosocial theory, Anazonwu (Conceptualizing and testing almighty prosociality theory for a more peaceful world, SCOA Heritage Nigeria, 2017) proposed that the activation of learnt prosocial moral reasoning through religion enabled performance of prosocial peace behavior that will benefit society. Thus, religion coping enhances the development of prosocial reasoning which in turn propagate prosocial acts while reducing delinquent behaviors. Similarly, developmental system theory (Lerner, Developmental science, developmental systems, and contemporary theories of human development, John Wiley & Sons, 2006) assumed that in every individual three mechanisms: plasticity (potential to change), context (environment), and developmental regulation (learnable principles) interact to describe the direction of the transactions between individuals and their various embedded sociocultural context of development which will also determine other developmental outcomes. Based on these two theoretical assumptions, the present study examined whether prosocial moral reasoning (developmental regulation) was the mechanism in the negative correlation between religious coping (plasticity) and delinquent behaviors (outcome), and if religious affiliation(context) (Christianity and Islam) moderated these paths. We hypothesized that the link from prosocial moral reasoning to lower delinquent behaviors would be stronger for Muslim compared with Christian youth. These questions were tested among Nigerian adolescence, an important sample because of high interreligious and interethnic tension among youth in the country. 298 adolescents (Mean age = 15.03 years, SD = 1.76; male = 176, female = 122; 46.3% Muslim, 53.7% Christian) were sampled using questionnaires in senior secondary schools in Nigeria. Moderated mediation result shows that greater religious coping was linked with higher prosocial moral reasoning, which in turn predicted fewer delinquent behaviors. Religious coping interacted with religion affiliation to influence delinquent behavior; there was a stronger link between these two constructs for Muslim compared to Christian youth. Thus, interventions aiming to reduce youth delinquent behaviors should consider promoting prosocial moral reasoning, particularly among the various religions (i.e., Christian/Muslim) communities.

Assessment of biometrics and stress indicators of the adult Village Weaver birds (Ploceus cucullatus) during breeding and post-breeding seasons in Jos, Nigeria.

In this era of climate change, some biological conservationists' concerns are based on seasonal studies that highlight how wild birds' physiological fitness are interconnected with the immediate environment to avoid population decline. We investigated how seasonal biometrics correlated to stress parameters of the adult Village Weavers (Ploceus cucullatus) during breeding and post-breeding seasons of the Weaver birds in Amurum Forest Reserve. Specifically, we explored the following objectives: (i) the seasonal number of birds captured; (ii) whether seasonal baseline corticosterone (CORT), packed cell volume (PCV), and heterophil to lymphocytes ratio (H:L) were sex-dependent; (iii) whether H:L ratio varied with baseline (CORT); (iv) whether phenotypic condition (post-breeding moult) and brood patch varied with baseline (CORT) and H:L ratio; and (v) how body biometrics co-varied birds' seasonal baseline (CORT), (PCV) and (H:L) ratio. Trapping of birds (May-November) coincided with breeding and post-breeding seasons. The birds (n = 53 males, 39 females) were ringed, morphologically assessed (body mass, wing length, moult, brood patch) and blood collected from their brachial vein was used to assess CORT, PCV and H:L ratio. Although our results indicated more male birds trapped during breeding, the multiple analyses of variance (MANOVA) indicated that the seasonal temperature of the trapping sites correlated (P < 0.05) significantly to baseline (CORT). The general linear mixed model analyses (GLMMs) indicated that the baseline (CORT) also correlated significantly to H:L ratio of the male and female birds. However, PCV correlated significantly to body size of the birds (wing length) and not body mass. Haematological parameters such as the baseline CORT and the H:L ratio as indicators of stress in wild birds. Hence, there is the possibility that the Village Weaver birds suffered from seasonally induced stress under the constrained effect of environmental temperature. Hence, future studies should investigate whether the effect observed is also attributable to other passerine species.

Mitochondrial bioenergetics as a cell fate rheostat for responsive to Bcl-2 drugs: New cues for cancer chemotherapy.

Pro-survival BCL-2 proteins prevent the initiation of intrinsic apoptosis (mitochondria-dependent pathway) by inhibiting the pro-apoptotic proteins BAX and BAK, while BH3-only proteins promote apoptosis by blocking pro-survival BCL-2 proteins. Disruptions in this delicate balance contribute to cancer cell survival and chemoresistance. Recent advances in cancer therapeutics involve a new generation of drugs known as BH3-mimetics, which are small molecules designed to mimic the action of BH3-only proteins. Promising effects have been observed in patients with hematological and solid tumors undergoing treatment with these agents. However, the rapid emergence of mitochondria-dependent resistance to BH3-mimetics has been reported. This resistance involves increased mitochondrial respiration, altered mitophagy, and mitochondria with higher and tighter cristae. Conversely, mutations in isocitrate dehydrogenase 1 and 2, catalyzing R-2-hydroxyglutarate production, promote sensitivity to venetoclax. This evidence underscores the urgency for comprehensive studies on bioenergetics-based adaptive responses in both BH3 mimetics-sensitive and -resistant cancer cells. Ongoing clinical trials are evaluating BH3-mimetics in combination with standard chemotherapeutics. In this article, we discuss the role of mitochondrial bioenergetics in response to BH3-mimetics and explore potential therapeutic opportunities through metabolism-targeting strategies.

Mesenchymal Stem Cell Priming: Potential Benefits of Administration of Molecular Hydrogen.

Stem cell therapy has emerged as a promising avenue for regenerative medicine, offering the potential to treat a wide range of debilitating diseases and injuries. Among the various types of stem cells, mesenchymal stem cells (MSCs) have garnered significant attention due to their unique properties and therapeutic potential. In recent years, researchers have been exploring novel approaches to enhance the effectiveness of MSC-based therapies. One such approach that has gained traction is the priming of MSCs with molecular hydrogen (H2). This article delves into the fascinating world of mesenchymal stem cell priming with molecular hydrogen and the potential benefits it holds for regenerative medicine.

Receptor-recognition and antiviral mechanisms of retrovirus-derived human proteins.

Human syncytin-1 and suppressyn are cellular proteins of retroviral origin involved in cell-cell fusion events to establish the maternal-fetal interface in the placenta. In cell culture, they restrict infections from members of the largest interference group of vertebrate retroviruses, and are regarded as host immunity factors expressed during development. At the core of the syncytin-1 and suppressyn functions are poorly understood mechanisms to recognize a common cellular receptor, the membrane transporter ASCT2. Here, we present cryo-electron microscopy structures of human ASCT2 in complexes with the receptor-binding domains of syncytin-1 and suppressyn. Despite their evolutionary divergence, the two placental proteins occupy similar positions in ASCT2, and are stabilized by the formation of a hybrid ß-sheet or 'clamp' with the receptor. Structural predictions of the receptor-binding domains of extant retroviruses indicate overlapping binding interfaces and clamping sites with ASCT2, revealing a competition mechanism between the placental proteins and the retroviruses. Our work uncovers a common ASCT2 recognition mechanism by a large group of endogenous and disease-causing retroviruses, and provides high-resolution views on how placental human proteins exert morphological and immunological functions.

Food safety and dietary diversity in African urban cities: evidence from Ghana.

BACKGROUND: Food safety is integral to food security and is increasingly becoming a significant concern in the urban areas of Africa, which are rapidly growing in population. In the case of Ghana, many urban households depend on traditional open-air markets for most of their food needs. However, these urban food markets also depend on domestic food supply chains, which are prone to risks, including poor hygiene and sanitation and weather seasonality. Food safety compliance has associated costs which increase the unit cost of food products. Thus, higher food price is a risk factor to food availability and accessibility-fundamental pillars of food security. METHOD: We use food microbial data and food retail data from food market surveys in major cities in Ghana to assess the safety of selected fresh food commodities and how retailers handle the food products they sell. Additionally, based on a two-wave balanced panel household data, we used fixed effects Poisson and Correlated Random Effects (CRE) Probit models to estimate the effect of weather seasonality on the incidence of diarrhoea and urban household dietary diversity score (HDDS). A final sample of 609 households and 565 market respondents participated in the study. RESULTS: Our findings show that selected food samples tested positive for Staphylococcus aureus and E.coli and had aflatoxin B1 levels above 5.0 ppb. Additionally, the household incidence of diarrhoea/vomiting, a proxy for food safety status, is higher in the dry season. In the dry season, the household incidence of diarrhoea/vomiting increases on average by a probability of 38% points compared to the rainy season. Regarding HDDS, the average HDDS is 7.3; however, we did not find the effect of seasonality on HDDS to be significant. CONCLUSIONS: Although urban food availability and household dietary diversity are not challenges for many urban households, food safety is a challenge in the major food markets in Ghanaian cities and is associated with weather seasonality. Foods available in traditional open-air markets are not always safe for consumption, undermining households' food security. Weak enforcement of food safety regulations contributes to the food safety challenges in Ghanaian urban food markets.

Genetic ablation of Lmp2 increases the susceptibility for impaired cardiac function.

Proteasome degradation is an integral part of cellular growth and function. Proteasomal intervention may mitigate adverse myocardial remodeling, but is associated with the onset of heart failure. Previously, we have demonstrated that increasing abundance of cardiac Lmp2 and its incorporation into proteasome complexes is an endogenous mechanism for proteasome regulation during hypertrophic remodeling of the heart induced by chronic ß-adrenoreceptor stimulation. Here, we investigated whether Lmp2 is required for myocardial remodeling not driven by inflammation and show that Lmp2 is a tipping element for growth and function in the heart but not for proteasome insufficiency. While it has no apparent impact under unchallenged conditions, myocardial remodeling without Lmp2 exacerbates hypertrophy and restricts cardiac function. Under chronic ß-adrenoreceptor stimulation, as seen in the development of cardiovascular disease and the manifestation of heart failure, genetic ablation of Lmp2 in mice caused augmented concentric hypertrophy of the left ventricle. While the heart rate was similarly elevated as in wildtype, myocardial contractility was not maintained without Lmp2, and apparently uncoupled of the ß-adrenergic response. Normalized to the exacerbated myocardial mass, contractility was reduced by 41% of the pretreatment level, but would appear preserved at absolute level. The lack of Lmp2 interfered with elevated 26S proteasome activities during early cardiac remodeling reported previously, but did not cause bulk proteasome insufficiency, suggesting the Lmp2 containing proteasome subpopulation is required for a selected group of proteins to be degraded. In the myocardial interstitium, augmented collagen deposition suggested matrix stiffening in the absence of Lmp2. Indeed, echocardiography of left ventricular peak relaxation velocity (circumferential strain rate) was reduced in this treatment group. Overall, targeting Lmp2 in a condition mimicking chronic ß-adrenoreceptor stimulation exhibited the onset of heart failure. Anticancer therapy inhibiting proteasome activity, including Lmp2, is associated with adverse cardiac events, in particular heart failure. Sparing Lmp2 may be an avenue to reduce adverse cardiac events when chronic sympathetic nervous system activation cannot be excluded.

Corrigendum: The role of cholesterol and mitochondrial bioenergetics in activation of the inflammasome in IBD.

[This corrects the article DOI: 10.3389/fimmu.2022.1028953.].

Endothelial cells drive organ fibrosis in mice by inducing expression of the transcription factor SOX9.

Fibrosis is a hallmark of chronic disease. Although fibroblasts are involved, it is unclear to what extent endothelial cells also might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells in several different mouse fibrosis models. These models included systolic heart failure induced by pressure overload, diastolic heart failure induced by high-fat diet and nitric oxide synthase inhibition, pulmonary fibrosis induced by bleomycin treatment, and liver fibrosis due to a choline-deficient diet. We also observed up-regulation of endothelial SOX9 in cardiac tissue from patients with heart failure. To test whether SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which promoted fibrosis in multiple organs and resulted in signs of heart failure. Endothelial Sox9 deletion prevented fibrosis and organ dysfunction in the two mouse models of heart failure as well as in the lung and liver fibrosis mouse models. Bulk and single-cell RNA sequencing of mouse endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory gene expression, leading to matrix deposition by endothelial cells. Moreover, mouse endothelial cells activated neighboring fibroblasts that then migrated and deposited matrix in response to SOX9, a process partly mediated by the secreted growth factor CCN2, a direct SOX9 target; endothelial cell-specific Sox9 deletion reversed these changes. These findings suggest a role for endothelial SOX9 as a fibrosis-promoting factor in different mouse organs during disease and imply that endothelial cells are an important regulator of fibrosis.

An objective measurement approach to quantify the perceived distortions of spectacle lenses.

The eye's natural aging influences our ability to focus on close objects. Without optical correction, all adults will suffer from blurry close vision starting in their 40s. In effect, different optical corrections are necessary for near and far vision. Current state-of-the-art glasses offer a gradual change of correction across the field of view for any distance-using Progressive Addition Lenses (PALs). However, an inevitable side effect of PALs is geometric distortion, which causes the swim effect, a phenomenon of unstable perception of the environment leading to discomfort for many wearers. Unfortunately, little is known about the relationship between lens distortions and their perceptual effects, that is, between the complex physical distortions on the one hand and their subjective severity on the other. We show that perceived distortion can be measured as a psychophysical scaling function using a VR experiment with accurately simulated PAL distortions. Despite the multi-dimensional space of physical distortions, the measured perception is well represented as a 1D scaling function; distortions are perceived less with negative far correction, suggesting an advantage for short-sighted people. Beyond that, our results successfully demonstrate that psychophysical scaling with ordinal embedding methods can investigate complex perceptual phenomena like lens distortions that affect geometry, stereo, and motion perception. Our approach provides a new perspective on lens design based on modeling visual processing that could be applied beyond distortions. We anticipate that future PAL designs could be improved using our method to minimize subjectively discomforting distortions rather than merely optimizing physical parameters.

Aldehyde-mediated inhibition of asparagine biosynthesis has implications for diabetes and alcoholism.

Patients with alcoholism and type 2 diabetes manifest altered metabolism, including elevated aldehyde levels and unusually low asparagine levels. We show that asparagine synthetase B (ASNS), the only human asparagine-forming enzyme, is inhibited by disease-relevant reactive aldehydes, including formaldehyde and acetaldehyde. Cellular studies show non-cytotoxic amounts of reactive aldehydes induce a decrease in asparagine levels. Biochemical analyses reveal inhibition results from reaction of the aldehydes with the catalytically important N-terminal cysteine of ASNS. The combined cellular and biochemical results suggest a possible mechanism underlying the low asparagine levels in alcoholism and diabetes. The results will stimulate research on the biological consequences of the reactions of aldehydes with nucleophilic residues.

Prevalence and risk factors of detectable HIV viral load among pregnant women with HIV infection seeking antenatal care in Southern Malawi.

We evaluated detectable viral load (VL) in pregnant women established on antiretroviral therapy (ART) for at least 6 months before conception and those self-reported as ART naïve at first antenatal care (ANC) at two government clinics in Southern Malawi. We used logistic regression to identify the predictors of detectable viral load (VL), defined as any measure greater than 400 copies/ml. Of 816 women, 67.9% were established on ART and 32.1% self-reported as ART naïve. Among women established on ART, 10.8% had detectable VL and 9.9% had VL >1000 copies/ml (WHO criteria for virological failure). In adjusted analysis, among women established on ART, virological failure was associated with younger age (p = .02), "being single/widowed" (p = 0.001) and no previous deliveries (p = .05). One fifth of women who reported to be ART-naive were found to have an undetectable VL at first ANC. None of the demographic factors could significantly differentiate those with high versus low VL in the ART-naïve sub-sample. In this cohort, approximately 90% of women who had initiated ART prior to conception had an undetectable VL at first ANC. This demonstrates good success of the ART program but identifies high risk populations that require additional support.

Ir(III) Half-Sandwich Photosensitizers with a π-Expansive Ligand for Efficient Anticancer Photodynamic Therapy.

One approach to reduce the side effects of chemotherapy in cancer treatment is photodynamic therapy (PDT), which allows spatiotemporal control of the cytotoxicity. We have used the strategy of coordinating π-expansive ligands to increase the excited state lifetimes of Ir(III) half-sandwich complexes in order to facilitate the generation of 1O2. We have obtained derivatives of formulas [Cp*Ir(C∧N)Cl] and [Cp*Ir(C∧N)L]BF4 with different degrees of π-expansion in the C∧N ligands. Complexes with the more π-expansive ligand are very effective photosensitizers with phototoxic indexes PI > 2000. Furthermore, PI values of 63 were achieved with red light. Time-dependent density functional theory (TD-DFT) calculations nicely explain the effect of the π-expansion. The complexes produce reactive oxygen species (ROS) at the cellular level, causing mitochondrial membrane depolarization, cleavage of DNA, nicotinamide adenine dinucleotide (NADH) oxidation, as well as lysosomal damage. Consequently, cell death by apoptosis and secondary necrosis is activated. Thus, we describe the first class of half-sandwich iridium cyclometalated complexes active in PDT.

Predictive Minisci late stage functionalization with transfer learning.

Structural diversification of lead molecules is a key component of drug discovery to explore chemical space. Late-stage functionalizations (LSFs) are versatile methodologies capable of installing functional handles on richly decorated intermediates to deliver numerous diverse products in a single reaction. Predicting the regioselectivity of LSF is still an open challenge in the field. Numerous efforts from chemoinformatics and machine learning (ML) groups have made strides in this area. However, it is arduous to isolate and characterize the multitude of LSF products generated, limiting available data and hindering pure ML approaches. We report the development of an approach that combines a message passing neural network and 13C NMR-based transfer learning to predict the atom-wise probabilities of functionalization for Minisci and P450-based functionalizations. We validated our model both retrospectively and with a series of prospective experiments, showing that it accurately predicts the outcomes of Minisci-type and P450 transformations and outperforms the well-established Fukui-based reactivity indices and other machine learning reactivity-based algorithms.