A lethal mitonuclear incompatibility in complex I of natural hybrids.

The evolution of reproductive barriers is the first step in the formation of new species and can help us understand the diversification of life on Earth. These reproductive barriers often take the form of hybrid incompatibilities, in which alleles derived from two different species no longer interact properly in hybrids1-3. Theory predicts that hybrid incompatibilities may be more likely to arise at rapidly evolving genes4-6 and that incompatibilities involving multiple genes should be common7,8, but there has been sparse empirical data to evaluate these predictions. Here we describe a mitonuclear incompatibility involving three genes whose protein products are in physical contact within respiratory complex I of naturally hybridizing swordtail fish species. Individuals homozygous for mismatched protein combinations do not complete embryonic development or die as juveniles, whereas those heterozygous for the incompatibility have reduced complex I function and unbalanced representation of parental alleles in the mitochondrial proteome. We find that the effects of different genetic interactions on survival are non-additive, highlighting subtle complexity in the genetic architecture of hybrid incompatibilities. Finally, we document the evolutionary history of the genes involved, showing signals of accelerated evolution and evidence that an incompatibility has been transferred between species via hybridization.

Divergent sensory and immune gene evolution in sea turtles with contrasting demographic and life histories.

Sea turtles represent an ancient lineage of marine vertebrates that evolved from terrestrial ancestors over 100 Mya. The genomic basis of the unique physiological and ecological traits enabling these species to thrive in diverse marine habitats remains largely unknown. Additionally, many populations have drastically declined due to anthropogenic activities over the past two centuries, and their recovery is a high global conservation priority. We generated and analyzed high-quality reference genomes for the leatherback (Dermochelys coriacea) and green (Chelonia mydas) turtles, representing the two extant sea turtle families. These genomes are highly syntenic and homologous, but localized regions of noncollinearity were associated with higher copy numbers of immune, zinc-finger, and olfactory receptor (OR) genes in green turtles, with ORs related to waterborne odorants greatly expanded in green turtles. Our findings suggest that divergent evolution of these key gene families may underlie immunological and sensory adaptations assisting navigation, occupancy of neritic versus pelagic environments, and diet specialization. Reduced collinearity was especially prevalent in microchromosomes, with greater gene content, heterozygosity, and genetic distances between species, supporting their critical role in vertebrate evolutionary adaptation. Finally, diversity and demographic histories starkly contrasted between species, indicating that leatherback turtles have had a low yet stable effective population size, exhibit extremely low diversity compared with other reptiles, and harbor a higher genetic load compared with green turtles, reinforcing concern over their persistence under future climate scenarios. These genomes provide invaluable resources for advancing our understanding of evolution and conservation best practices in an imperiled vertebrate lineage.

Predictability and parallelism in the contemporary evolution of hybrid genomes.

Hybridization between species is widespread across the tree of life. As a result, many species, including our own, harbor regions of their genome derived from hybridization. Despite the recognition that this process is widespread, we understand little about how the genome stabilizes following hybridization, and whether the mechanisms driving this stabilization tend to be shared across species. Here, we dissect the drivers of variation in local ancestry across the genome in replicated hybridization events between two species pairs of swordtail fish: Xiphophorus birchmanni × X. cortezi and X. birchmanni × X. malinche. We find unexpectedly high levels of repeatability in local ancestry across the two types of hybrid populations. This repeatability is attributable in part to the fact that the recombination landscape and locations of functionally important elements play a major role in driving variation in local ancestry in both types of hybrid populations. Beyond these broad scale patterns, we identify dozens of regions of the genome where minor parent ancestry is unusually low or high across species pairs. Analysis of these regions points to shared sites under selection across species pairs, and in some cases, shared mechanisms of selection. We show that one such region is a previously unknown hybrid incompatibility that is shared across X. birchmanni × X. cortezi and X. birchmanni × X. malinche hybrid populations.

Riboflavin-Induced DNA Damage and Anticancer Activity in Breast Cancer Cells under Visible Light: A TD-DFT and In Vitro Study.

Targeted treatments for breast cancer that minimize harm to healthy cells are highly sought after. Our study explores the potentiality of riboflavin as a targeted anticancer compound that can be activated by light irradiation. Here, we integrated time-dependent density functional theory (TD-DFT) calculations and an in vitro study under visible light. The TD-DFT calculations revealed that the electronic charge transferred from the DNA base to riboflavin, with the most significant excitation peak occurring within the visible light range. Guided by these insights, an in vitro study was conducted on the breast cancer cell lines MCF-7 and MDA-MB-231. The results revealed substantial growth inhibition in these cell lines when exposed to riboflavin under visible light, with no such impact observed in the absence of light exposure. Interestingly, riboflavin exhibited no/minimal growth-inhibitory effects on the normal cell line L929, irrespective of light conditions. Moreover, through EtBr displacement (DNA-EtBr) and the TUNEL assay, it has been illustrated that, upon exposure to visible light, riboflavin can intercalate within DNA and induce DNA damage. In conclusion, under visible light conditions, riboflavin emerges as a promising candidate with a selective and effective potent anticancer agent against breast cancer while exerting a minimal influence on regular cellular activity.

Gaps and linkages between biometeorological research across the Global South: a call for new efforts to advance biometeorology in the Global South.

Biometeorology research continues to grow and accelerate in terms of productivity (papers produced, studies conducted, etc.) as well as its direct impact on society and policy. Simultaneously, the scientific community is increasingly acknowledging that research has predominantly focused on the Global North. Additionally, work conducted in the Global South often follows extractive practices that primarily advance the careers and scientific knowledge of researchers from the Global North, offering minimal benefit to the communities studied in the Global South. This short communication intends to serve as a call to the biometeorology community to work collaboratively across continents to understand the current knowledge of biometeorology research in the Global South in addition to identifying the gaps, challenges, and opportunities of conducting grounded research in the Global South led by Global South researchers to support societies equitably.

Hypomyelinated vps16 Mutant Zebrafish Exhibit Systemic and Neurodevelopmental Pathologies.

Homotypic Fusion and Protein Sorting (HOPS) and Class C-core Vacuole/Endosome Tethering (CORVET) complexes regulate the correct fusion of endolysosomal bodies. Mutations in core proteins (VPS11, VPS16, VPS18, and VPS33) have been linked with multiple neurological disorders, including mucopolysaccharidosis (MPS), genetic leukoencephalopathy (gLE), and dystonia. Mutations in human Vacuolar Protein Sorting 16 (VPS16) have been associated with MPS and dystonia. In this study, we generated and characterized a zebrafish vps16(-/-) mutant line using immunohistochemical and behavioral approaches. The loss of Vps16 function caused multiple systemic defects, hypomyelination, and increased neuronal cell death. Behavioral analysis showed a progressive loss of visuomotor response and reduced motor response and habituation to acoustic/tap stimuli in mutants. Finally, using a novel multiple-round acoustic/tap stimuli test, mutants showed intermediate memory deficits. Together, these data demonstrate that zebrafish vps16(-/-) mutants show systemic defects, neurological and motor system pathologies, and cognitive impairment. This is the first study to report behavior abnormalities and memory deficiencies in a zebrafish vps16(-/-) mutant line. Finally, we conclude that the deficits observed in vps16(-/-) zebrafish mutants do not mimic pathologies associated with dystonia, but more align to abnormalities associated with MPS and gLE.

Exploring the paradox of Muslim advantage in undernutrition among under-5 children in India: a decomposition analysis.

BACKGROUND: While there is a substantial body of research on inequalities in child nutrition along the axes of gender and socioeconomic gradient, the socio-religious differences in health and nutrition outcomes remain grossly understudied. The handful of studies on the socio-religious differential in child health outcomes has found a Muslim advantage in chances of survival and nutritional status over Hindus despite their comparatively lower socioeconomic status, which undeniably warrants investigating the pathways through which this paradoxical Muslim advantage manifests. METHODS: Using data from the National Family Health Survey, 2015-16, we quantify the inter-group differentials in child undernutrition (stunting, wasting, and underweight) between Muslims and caste-disaggregated Hindus. We further decompose the gap to delineate its major contributory factors by employing Fairlie's decomposition method. RESULTS: The analysis revealed that, compared to the Hindus as an aggregated group, Muslims have a higher rate of stunting and lower rates of wasting and being underweight. However, the differences get altered when we disaggregate the Hindus into high and low castes. Muslims have a lower prevalence of all three measures of undernutrition than the low-caste Hindus and a higher prevalence of stunting and underweight than the high-caste Hindus, consistent with their levels of socioeconomic status. However, the prevalence of wasting among Muslim children is lower than among high-caste Hindus. This nutritional advantage is paradoxical because Muslims' relatively poorer socioeconomic status compared to high-caste Hindus should have disadvantaged them. In the decomposition analysis, the Muslim advantage over the low-caste Hindus could only be partially attributed to the former's better economic status and access to sanitation. Moreover, the poor performance of Muslim children compared to the high-caste Hindus in stunting and underweight could mainly be explained by the religious differentials in birth order, mother's education, and wealth index. However, Muslim children's comparatively better performance in wasting than the high-caste Hindus remained a puzzle. CONCLUSION: The Muslim advantage over high-caste Hindus in wasting and low-caste Hindus in all the indicators of undernutrition may have been rendered by certain 'unobserved' behavioural and cultural differences. However, further exploration is needed to make a definitive claim in this respect.

Suppression of classical nuclear import pathway by importazole and ivermectin inhibits rotavirus replication.

BACKGROUND: Rotavirus is the foremost cause of acute gastroenteritis among infants in resource-poor countries, causing severe morbidity and mortality. The currently available rotavirus vaccines are effective in reducing severity of the disease but not the infection rates, thus antivirals as an adjunct therapy are needed to reduce the morbidity in children. Viruses rely on host cellular machinery for nearly every step of the replication cycle. Therefore, targeting host factors that are indispensable for virus replication could be a promising strategy. OBJECTIVES: To assess the therapeutic potential of ivermectin and importazole against rotaviruses. METHODS: Antirotaviral activity of importazole and ivermectin was measured against various rotavirus strains (RV-SA11, RV-Wa, RV-A5-13, RV-EW) in vitro and in vivo by quantifying viral protein expression by western blot, analysing viroplasm formation by confocal microscopy, and measuring virus yield by plaque assay. RESULTS: Importin-ß1 and Ran were found to be induced during rotavirus infection. Knocking down importin-ß1 severely impaired rotavirus replication, suggesting a critical role for importin-ß1 in the rotavirus life cycle. In vitro studies revealed that treatment of ivermectin and importazole resulted in reduced synthesis of viral proteins, diminished production of infectious virus particles, and decrease in viroplasm-positive cells. Mechanistic study proved that both drugs perform antirotavirus activity by inhibiting the function of importin-ß1. In vivo investigations in mice also confirmed the antirotavirus potential of importazole and ivermectin at non-toxic doses. Treatments of rotavirus-infected mice with either drug resulted in diminished shedding of viral particles in the stool sample, reduced expression of viral protein in the small intestine and restoration of damaged intestinal villi comapared to untreated infected mice. CONCLUSIONS: The study highlights the potential of importazole and ivermectin as antirotavirus therapeutics.

Genomic insights into variation in thermotolerance between hybridizing swordtail fishes.

Understanding how organisms adapt to changing environments is a core focus of research in evolutionary biology. One common mechanism is adaptive introgression, which has received increasing attention as a potential route to rapid adaptation in populations struggling in the face of ecological change, particularly global climate change. However, hybridization can also result in deleterious genetic interactions that may limit the benefits of adaptive introgression. Here, we used a combination of genome-wide quantitative trait locus mapping and differential gene expression analyses between the swordtail fish species Xiphophorus malinche and X. birchmanni to study the consequences of hybridization on thermotolerance. While these two species are adapted to different thermal environments, we document a complicated architecture of thermotolerance in hybrids. We identify a region of the genome that contributes to reduced thermotolerance in individuals heterozygous for X. malinche and X. birchmanni ancestry, as well as widespread misexpression in hybrids of genes that respond to thermal stress in the parental species, particularly in the circadian clock pathway. We also show that a previously mapped hybrid incompatibility between X. malinche and X. birchmanni contributes to reduced thermotolerance in hybrids. Together, our results highlight the challenges of understanding the impact of hybridization on complex ecological traits and its potential impact on adaptive introgression.

Understanding the anomaly of cis-trans isomerism in Pro-His sequence.

The anomalous absence of cisPro stabilizing CαHαXaa···πAro interactions at Xaa-Pro-Aro exclusively when Aro is His, is understood by NMR structural analyses of model peptides, as due to i â†’ i backbone-side chain C6 H-bond that forms uniquely when Aro is His, which significantly decreases its χ1-g- population essential for CαHαXaa···πAro formation.

Decomposing the rural-urban gap in the prevalence of undiagnosed, untreated and under-treated hypertension among older adults in India.

BACKGROUND: Although awareness and treatment rates of hypertension have significantly improved in recent years, the prevalence of undiagnosed and untreated hypertension remains a major public health concern for Indian policymakers. While the urban-rural variation in the prevalence, diagnosis, control, and treatment of hypertension is reasonably well-documented, the explanation behind such variation remains poorly understood given the dearth of studies conducted on exploring the determinants of the rural-urban gap in the prevalence of undiagnosed, untreated, and uncontrolled hypertension in India. In view of this research gap, our paper aims to decompose the inter-group differences between rural and urban areas in undiagnosed, untreated, and undertreated hypertension among older adults in India into the major contributing factors. METHODS: Nationally representative data collected in the Longitudinal Ageing Study of India, Wave-1 (2017-18), was utilized for this study. Maximum-likelihood binary logistic-regression models were employed to capture the crude and adjusted associations between the place of residence and prevalence of undiagnosed, untreated, and undertreated hypertension. Fairlie's decomposition technique was used to decompose the inter-group differences between rural and urban residents in the prevalence of undiagnosed, untreated, and undertreated hypertension among the older population in India, into the major contributing factors, in order to explore the pathways through which these differences manifest. RESULTS: The overall prevalence rates of undiagnosed, untreated, and undertreated hypertension among older adults were 42.3%, 6%, and 18.7%, respectively. However, the prevalence of undiagnosed and untreated hypertension was higher in rural areas, by 12.4 and 1.7 percentage-points, respectively, while undertreated hypertension was more prevalent in the urban areas (by 7.2 percentage-points). The decomposition analysis explained roughly 41% and 34% of the urban advantage over rural areas in the case of undiagnosed and untreated hypertension, while it explained 51% of the urban disadvantage in respect of undertreated hypertension. The rural-urban differentials in education and comorbidities accounted for the majority of the explained rural disadvantage in the prevalence of undiagnosed hypertension, explaining 13.51% and 13.27% of the gap, respectively. The regional factor was found to be the major driver behind urban advantage in the prevalence of untreated hypertension, contributing 37.47% to the overall gap. In the case of undertreated hypertension, education, comorbidities, and tobacco consumption were the major contributors to the urban-rural inequality, which accounted for 12.3%, 10.6%, and 9.8% of the gap, respectively. CONCLUSION: Socio-economic and lifestyle factors seemed to contribute significantly to the urban-rural gap in undiagnosed, untreated and undertreated hypertension in India among older adults. There is an urgent need of creating awareness programmes for the early identification of hypertensive cases and regular treatment, particularly in under-serviced rural India. Interventions should be made targeting specific population groups to tackle inequality in healthcare utilization.

Analysing the role of sleep quality, functional limitation and depressive symptoms in determining life satisfaction among the older Population in India: a moderated mediation approach.

BACKGROUND: Life satisfaction (LS), a useful construct in the study of psycho-social well-being, is an important indicator of healthy aging. With a view to investigate whether the improved longevity in India is accompanied by commensurate levels of well-being and contentment among the older adults , this study aimed to examine (1) the association between LS and sleep quality among older Indian adults aged 60 years and above (2) the mediating role of depression that accounts for the association and (3) the moderating role of functional limitation in this mediation. METHODS: Cross-sectional data from the Longitudinal Ageing Study in India (LASI), Wave-1 (2017-18) was used. Pearson's correlation coefficients were calculated to investigate the pair-wise relationship between sleep quality, depressive symptoms, functional limitation, and LS. Structural Equation Model was employed to analyse the moderated-mediated association between sleep quality and the level of LS. RESULTS: Sleep quality had a direct effect (ß=-0.12) as well as an indirect effect (ß=-0.024) via depressive symptoms on LS, accounting for 83.6 and 16.4 per cent of the total effects, respectively. Also, the interaction term between poor seep quality and functional limitation was positive (ß = 0.03, p < 0.001) in determining depressive symptoms, suggesting that higher level of functional limitation aggravated the indirect effect of poor sleep quality on LS. CONCLUSION: The findings of the study suggested that ensuring both the physical as well as the mental well-being of the population during the life course may confer in later life the desired level of life satisfaction.

A regression-based three-phase approach to assess outdoor thermal comfort in informal micro-entrepreneurial settings in tropical Mumbai.

Urban heat poses a public health risk to the residents of megacities in developing countries because the population spends a significant amount of time outdoors to work and socialize with limited cooling resources. Understanding the drivers of outdoor comfort and heat stress in informal work settings is important to design climate-sensitive outdoor spaces and reduce heat vulnerability. We present outdoor thermal comfort perceptions (OTCPs) of people engaged in outdoor micro entrepreneurial activities in Mumbai using seasonal surveys and biometeorological observations. We propose a three-phase approach to analyze the relative importance of climatic and non-climatic variables for OTCPs. The first phase evaluates the seasonal and intra-neighborhood variation of thermal sensation votes (TSV) with respect to physiological equivalent temperature (PET) and air temperature. Second, we include physiological parameters to evaluate the seasonal and intra-neighborhood variation of overall sensation votes (OSV). Third, we consider aggregated survey responses and include behavioral and perceptual variables to determine their relative significance. We employ three linear modeling techniques to assess model performance in explaining the variability of OTCP using OSV as dependent variable. Results reveal that microclimatic parameters alone are unable to explain the variability of OTCP. Our results yield a neutral PET value (PETneutral) of 23.75 °C for Mumbai in the winter. PETneutral was higher for activities at the clothing market compared to other micro entrepreneurial activities. Acclimatization significantly improved comfort in the summer, while evaporative cooling was beneficial in the winter. Further, an ANCOVA and ordinal logistic regressions demonstrate the importance of behavioral attributes (presence in the location, expectation, beverage intake) in explaining the variance in OTCP. Our study also reveals that wind speed and humidity play an important role in shaping overall comfort in the Mumbai neighborhoods.

Targeting the Achilles' Heel of Multidrug-Resistant Staphylococcus aureus by the Endocannabinoid Anandamide.

Antibiotic-resistant Staphylococcus aureus is a major health issue that requires new therapeutic approaches. Accumulating data suggest that it is possible to sensitize these bacteria to antibiotics by combining them with inhibitors targeting efflux pumps, the low-affinity penicillin-binding protein PBP2a, cell wall teichoic acid, or the cell division protein FtsZ. We have previously shown that the endocannabinoid Anandamide (N-arachidonoylethanolamine; AEA) could sensitize drug-resistant S. aureus to a variety of antibiotics, among others, through growth arrest and inhibition of drug efflux. Here, we looked at biochemical alterations caused by AEA. We observed that AEA increased the intracellular drug concentration of a fluorescent penicillin and augmented its binding to membrane proteins with concomitant altered membrane distribution of these proteins. AEA also prevented the secretion of exopolysaccharides (EPS) and reduced the cell wall teichoic acid content, both processes known to require transporter proteins. Notably, AEA was found to inhibit membrane ATPase activity that is necessary for transmembrane transport. AEA did not affect the membrane GTPase activity, and the GTPase cell division protein FtsZ formed the Z-ring of the divisome normally in the presence of AEA. Rather, AEA caused a reduction in murein hydrolase activities involved in daughter cell separation. Altogether, this study shows that AEA affects several biochemical processes that culminate in the sensitization of the drug-resistant bacteria to antibiotics.

Species and population specific gene expression in blood transcriptomes of marine turtles.

BACKGROUND: Transcriptomic data has demonstrated utility to advance the study of physiological diversity and organisms' responses to environmental stressors. However, a lack of genomic resources and challenges associated with collecting high-quality RNA can limit its application for many wild populations. Minimally invasive blood sampling combined with de novo transcriptomic approaches has great potential to alleviate these barriers. Here, we advance these goals for marine turtles by generating high quality de novo blood transcriptome assemblies to characterize functional diversity and compare global transcriptional profiles between tissues, species, and foraging aggregations. RESULTS: We generated high quality blood transcriptome assemblies for hawksbill (Eretmochelys imbricata), loggerhead (Caretta caretta), green (Chelonia mydas), and leatherback (Dermochelys coriacea) turtles. The functional diversity in assembled blood transcriptomes was comparable to those from more traditionally sampled tissues. A total of 31.3% of orthogroups identified were present in all four species, representing a core set of conserved genes expressed in blood and shared across marine turtle species. We observed strong species-specific expression of these genes, as well as distinct transcriptomic profiles between green turtle foraging aggregations that inhabit areas of greater or lesser anthropogenic disturbance. CONCLUSIONS: Obtaining global gene expression data through non-lethal, minimally invasive sampling can greatly expand the applications of RNA-sequencing in protected long-lived species such as marine turtles. The distinct differences in gene expression signatures between species and foraging aggregations provide insight into the functional genomics underlying the diversity in this ancient vertebrate lineage. The transcriptomic resources generated here can be used in further studies examining the evolutionary ecology and anthropogenic impacts on marine turtles.

Determinants of rural-urban differential in healthcare utilization among the elderly population in India.

BACKGROUND: Population aging poses a demographic burden on a country such as India with inadequate social security systems and very low public investment in health sector. This challenge of accelerated demographic transition is coupled by the rural-urban disparity in access to healthcare services among the elderly people in India. An important objective of India's National Health Policy (2017) is to "progressively achieve universal health coverage" which is posited upon mitigating the sub-national disparity that necessitates identifying the drivers of the disparity for targeted policy intervention. This study, therefore, makes an attempt towards the exploration of the prominent contributory factors behind the rural-urban gap in utilisation of healthcare among the older population in India. METHODS: The analysis has been done by using the unit level data of Social Consumption: Health (Schedule number 25.0) of the 75th round of the National sample Survey conducted during July 2017-June 2018. Two binary logistic models have been proposed to capture the crude and the adjusted association between health seeking behaviour and place of residence (rural/ urban). To compute the group differences (between rural and urban) in the rate of healthcare utilization among the elderly population in India and to decompose these differences into the major contributing factors, Fairlie's decomposition method has been employed. RESULTS: The logistic regression models established a strong association between place of residence and likelihood of healthcare utilisation among the Indian elderly people. The results of the Fairlie's decomposition analysis revealed considerable rural-urban inequality disfavouring the rural residents and health care utilisation was found to be 7 percentage points higher among the older population residing in urban India than their rural counterparts. Level of education and economic status, both of which are indicators of a person's Socio-Economic Status, were the two major determinants of the existing rural-urban differential in healthcare utilisation, together explaining 41% of the existing rural-urban differential. CONCLUSION: Public health care provisions need to be strengthened both in terms of quality and outreach by way of greater public investments in the health sector and by building advanced health infrastructure in the rural areas. Implementation of poverty alleviation programmes and ensuring social-security of the elderly are also indispensable in bringing about equity in healthcare utilisation.

Helix-Coil Transition at a Glycine Following a Nascent α-Helix: A Synergetic Guidance Mechanism for Helix Growth.

A detailed understanding of forces guiding the rapid folding of a polypeptide from an apparently random coil state to an ordered α-helical structure following the rate-limiting preorganization of the initial three residue backbones into helical conformation is imperative to comprehending and regulating protein folding and for the rational design of biological mimetics. However, several details of this process are still unknown. First, although the helix-coil transition was proposed to originate at the residue level (J. Chem. Phys. 1959, 31, 526-535; J. Chem. Phys. 1961, 34, 1963-1974), all helix-folding studies have only established it between time-averaged bulk states of a long-lived helix and several transiently populated random coils, along the whole helix model sequence. Second, the predominant thermodynamic forces driving either this two-state transition or the faster helix growth following helix nucleation are still unclear. Third, the conformational space of the random coil state is not well-defined unlike its corresponding α-helix. Here we investigate the restrictions placed on the conformational space of a Gly residue backbone, as a result of it immediately succeeding a nascent α-helical turn. Analyses of the temperature-dependent 1D-, 2D-NMR, FT-IR, and CD spectra and GROMACS MD simulation trajectory of a Gly residue backbone following a model α-helical turn, which is artificially rigidified by a covalent hydrogen bond surrogate, reveal that: (i) the α-helical turn guides the ϕ torsion of the Gly exclusively into either a predominantly populated entropically favored α-helical (α-ϕ) state or a scarcely populated random coil (RC-ϕ) state; (ii) the α-ϕ state of Gly in turn favors the stability of the preceding α-helical turn, while the RC-ϕ state disrupts it, revealing an entropy-driven synergetic guidance for helix growth in the residue following helix nucleation. The applicability of a current synergetic guidance mechanism to explain rapid helix growth in folded and unfolded states of proteins and helical peptides is discussed.

A Virtual Drug Discovery Screening Illuminates Campesterol as a Potent Estrogen Receptor Alpha Inhibitor in Breast Cancer.

Breast cancer remains a global health challenge, and innovative strategies are required to target estrogen receptor α (ERα), a key player in its development. This study investigates the potential of campesterol, a natural phytosterol, as an ERα inhibitor for breast cancer. Our approach integrates in silico, in vitro, and ex vivo experiments to assess the therapeutic potential of campesterol. In silico analyses highlight campesterol as a promising ERα ligand with favorable binding affinities and dynamic properties. Structural analysis reveals conformational changes in ERα upon campesterol binding. In vitro studies confirm the selective growth inhibition of campesterol against ERα-positive breast cancer cells. This study extends to ER+ breast cancer patient-derived organoids (PDOs), showing the effectiveness of campesterol in ERα-positive breast cancer PDOs. Importantly, it emphasizes the receptor-specific nature of campesterol, providing insights into its context-dependent action. In conclusion, campesterol displays potential as an ERα inhibitor, offering new avenues for ER+ breast cancer treatment.

Rotavirus-induced lncRNA SLC7A11-AS1 promotes ferroptosis by targeting cystine/glutamate antiporter xCT (SLC7A11) to facilitate virus infection.

Rotavirus (RV) is the primary etiological agent of virus-associated gastroenteritis in infants, causing 200,000 childhood death annually. Despite the availability of vaccines, rotaviral diarrhea continues to be a severe issue in underdeveloped nations in Asia and Africa. The situation demands continual studies on host-rotavirus interactions to understand disease pathogenesis and develop effective antiviral therapeutics. Long non-coding RNAs (lncRNAs), which are a subset of non-coding RNAs of more than 200 nucleotides in length, are reported to play a regulatory function in numerous viral infections. Virus infection often alters the host transcriptome including lncRNA that are differentially expressed either to play an antiviral role or to be advantageous towards virus propagation. In the current study, qPCR array-based expression profiling of host lncRNAs was performed in rotavirus-infected HT-29 cells that identified the lncRNA SLC7A11-AS1 to be upregulated during RV infection. Knockdown of SLC7A11-AS1 conspicuously reduced RV titers implying its pro-viral significance. RV-induced SLC7A11-AS1 downregulates the gene SLC7A11/xCT that encodes the light chain subunit of the system XC- cystine-glutamate exchange transporter, leading to decrease in intracellular glutathione level and increase in lipid peroxidation, which are signature features of ferroptotic pathway. Ectopic expression of xCT also abrogated RV infection by reversing the virus optimized levels of intracellular GSH and lipid ROS levels. Cumulatively, the study reveals that RV infection triggers ferroptotic cell death via SLC7A11-AS1/xCT axis to facilitate its own propagation.

Patterns of recombination in snakes reveal a tug-of-war between PRDM9 and promoter-like features.

In some mammals, notably humans, recombination occurs almost exclusively where the protein PRDM9 binds, whereas in vertebrates lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To determine whether PRDM9 directs recombination in nonmammalian vertebrates, we focused on an exemplar species with a single, intact PRDM9 ortholog, the corn snake (Pantherophis guttatus). Analyzing historical recombination rates along the genome and crossovers in pedigrees, we found evidence that PRDM9 specifies the location of recombination events, but we also detected a separable effect of promoter-like features. These findings reveal that the uses of PRDM9 and promoter-like features need not be mutually exclusive and instead reflect a tug-of-war that is more even in some species than others.