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Tyagi, A.

Publications and source records attributed to Tyagi, A..

At least 19 recordsLinked to original sources

Spatial transcriptomics identifies the Pseudomonas aeruginosa major outer membrane protein OprF as a critical factor in blinding corneal infections

Pseudomonas aeruginosa is a globally recognized pathogen causing pulmonary, skin, and severe corneal infections (keratitis), with the potential to induce irreversible blindness if untreated. Spatial transcriptomic analysis of P. aeruginosa infected corneas identified elevated expression of the outer membrane proteins OprF and OprL and PA1414, which encodes the small RNA SicX in the corneal stroma compared with corneal epithelium. Comparative spatial transcriptomics analysis of corneas infected with an oprF transposon (TN) mutant showed reduced expression of the type III effector protein ExoT, which was absent in an oprF deficient mutant ({Delta}oprF) and in contrast to PA14, did not inhibit reactive oxygen species (ROS) production by neutrophils. Corneal infection with the {Delta}oprF mutant resulted in reduced corneal virulence and lower CFU compared to the parental PA14 strain. Collectively, our findings demonstrate a coordinated virulence program connecting OprF functionality with the release of ExoT and its ability to block ROS production and survive in infected corneas.

microbiology↗

Characterization of six environmental coli-phages isolated in Astana, Kazakhstan, during the School of Molecular and Theoretical Biology

Bacteriophage (phage) collections are essential resources for studying virus-host interactions in bacterial species. Here, we report six Escherichia coli-infecting phages that expand the Lund Collection of Bacteriophages. These phages were isolated in 2025 within the framework of the School of Molecular and Theoretical Biology for high-school students, from samples collected in Lake Taldykol, Astana, Kazakhstan, using E. coli strains MG1655{Delta}RM and EV36 as hosts. The isolated phages comprise Taldykol (LuPh6), a member of the genus Kagunavirus; Aidakhar (LuPh7) of the genus Phapecoctavirus; Samruk (LuPh8) of the genus Tequintavirus; the T-odd-like phage Baiterek (LuPh9) of the genus Vequintavirus; and two T-even-like phages Tulpar (LuPh10) and Shurale (LuPh11) that belong to the Tequatrovirus genus. This expanded phage collection enhances the toolkit for investigating phage-host interactions and their molecular mechanisms and highlights the use of phage isolation as a component of high school research education. ImportancePhage collections are a key resource for studying phage biology, phage-bacteria interactions and bacterial immune systems. Here, we extend the Lund Phage Collection through the isolation and characterisation of six E. coli-infecting phages, including three novel species (LuPh6, LuPh8 and LuPh11) as well as a member of the genus Phapecoctavirus that not represented in widely used collections such as BASEL (LuPh7). This study expands the resources available for probing phage-host interactions and demonstrates an example of integrating phage research into education of high school students.

microbiology↗

Resource abundance and dietary specialization predict elevational migration in a hyperdiverse montane bird community

Migration is a well-described behavioural strategy that allows species to track variation in resources and climatic conditions by moving in response to seasonality. A common form is elevational migration, an annual short-distance movement undertaken by many mountain bird species globally. While studies show that the timing of migration may relate to food availability, the mechanisms determining which species migrate remain unclear. Our study investigated if the degree of dietary specialization explains why some high-elevation bird species in seasonal environments migrate downslope for the winter while others remain resident at high altitudes despite the apparent scarcity of their preferred food resources. We mist-netted birds along a 2300-m elevational gradient in the Eastern Himalaya and collected blood and faecal samples from 261 individual birds belonging to 18 species of high-elevation residents (ten) and elevational migrants (eight) in their breeding and wintering ranges. Using stable isotope ratios of carbon and nitrogen in whole blood and faecal DNA metabarcoding, we compared their seasonal trophic levels and dietary niches. Nitrogen isotope ratios showed that residents had a substantially lower trophic position in the winter compared to summer (-0.35 [-0.52, -0.17]), whereas migrants had a slightly higher trophic position in the winter (0.15 [-0.02, 0.32]). This trophic shift in residents was likely due to a decrease in insectivory and an increase in frugivory in the winter. The frequency of key insect orders (Lepidoptera, Hemiptera, and Coleoptera) declined by 20-35% in their winter diets alongside an increase in fruit, particularly from the family Polygonaceae (0.33 [0.18, 0.46]). Additionally, compared with residents, migrants showed greater overlap in their dietary niches between summer and winter (98% vs 80%). Because arthropod abundances in the Himalayas peak at high elevations in the summer and decline in the winter, we suggest that elevational migrants are likely dietary specialists that track resources, while high-elevation residents are dietary generalists that supplement their winter diet with fruit and nectar because of the scarcity of arthropods. These findings indicate that a species dietary specialization is linked to its migratory behaviour, providing a potential mechanistic explanation for how different species solve the challenge of seasonal resource limitation.

ecology↗

Virtual Population to Re-assess AAA Risk Using Neck Geometry and Shape Compactness Alongside Maximum Diameter

We present an automated, constraint-aware framework to generate demographically stratified virtual populations of AAAs and quantifies, at cohort scale, how neck geometry, shape compactness, and maximum diameter jointly modulate AAA haemodynamics. Using 258 CTA-derived cases, we generated 182 validated AAA geometries and ran 364 simulations, extracting 10 geometric descriptors and correlated with six haemodynamic biomarkers. The automated framework blends statistically grounded sampling, anatomical plausibility and regional morphing to provide a scalable route for reproducible computational fluid dynamics (CFD) to uncover geometry-biomarker relations at cohort scale. Proximal neck diameter and sphericity were the dominant determinants of wall shear magnitude. Neck diameter increased mean wall shear stress (WSS) (r {approx} 0.49) while reducing peak WSS0.95 (r {approx} -0.31) and low-time-averaged wall shear stress (TAWSS) area (r {approx} -0.27), whereas sphericity, a largely under-explored AAA shape descriptor, was the strongest inverse correlate of mean WSS (r {approx} -0.57). Maximum diameter minimally affected peak shear (r {approx} +0.06) but was associated with reduced mean WSS (r {approx} -0.41). Convexity, another such descriptor, was the dominant correlate of oscillatory shear, increasing OSI (r {approx} +0.46) while modestly lowering mean WSS (r {approx} -0.28). The framework reveals neck calibre and shape compactness, not maximum diameter alone, as dominant modulators of AAA haemodynamics.

bioengineering↗

LDLR variant classification through activity-normalized prime editing screening

BackgroundInherited variants in the LDL receptor (LDLR) gene are the most common cause of familial hypercholesterolemia (FH), significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt intervention with lipid-lowering therapies; however, the majority of LDLR variants observed in the population have uncertain or absent clinical classifications, limiting the potential to improve clinical management. MethodsWe developed an innovative, activity-normalized prime editing screening pipeline to measure the impact of 5,184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Through pairing a genotypic outcome reporter with every prime editing guide RNA (pegRNA), we adjust phenotypic measurements to account for variable editing efficiency, extending activity normalization to prime editing for the first time at this scale. Further, we use a statistical estimation approach that leverages measurements for all missense variants at a given position to denoise the resulting scores. ResultsWe show that prime editing-mediated reporter editing correlates with endogenous variant installation frequency, allowing activity normalization to improve imputation of LDLR variant effect. Our optimized prime editing assay identifies a broad, continuous spectrum of variant functional effects. We achieve robust separation of pathogenic vs. benign ClinVar variants and concordance between experimentally derived functional scores and LDL-C levels measured in UK Biobank participants. Further, when calibrating the strength of evidence provided by this functional screening data to align with the ACMG/AMP variant interpretation guidelines, and integrating additional sources of evidence, a majority of currently unclassified rare LDLR variants meet evidence thresholds for reclassification. We use the broad coverage of this screen to gain insight into how apolipoproteins bind to LDLR. In particular, we identify and characterize rare LDLR variants that enhance LDL-C uptake through increased interaction with apolipoprotein B. Finally, we compare prime editing-based functional scores with those derived from recent base editing and cDNA-based LDLR variant screens, showing that these approaches all show robust correlation with clinically observed LDL-C levels and computational scores, while prime editing identifies candidate splice-altering coding variants that are not modeled by cDNA screening. ConclusionsAltogether, our approach demonstrates the power of prime editing to significantly improve understanding of how variants in LDLR impact function and contribute to FH.

genetics↗

Characterization of five environmental phages infecting Escherichia coli K-12 isolated during a phage biology training course

Phage collections are essential tools for discovering and dissecting bacterial anti-phage defense systems. Here, we report the isolation and characterization of five environmental Escherichia coli-infecting phages, obtained during the 2023 Fundamentals of Basic and Applied Phage Biology course at Lund University. The phages were isolated using a motile E. coli K-12 BW25113 strain, whose motility is conferred by an IS5 insertion upstream of the flhDC operon, the master regulator of flagellar synthesis. The isolated Escherichia phages include Lubas (LuPh1) and Lucat (LuPh2) of the genus Tequatrovirus; Lupin (LuPh3) and Lucris (LuPh4) of the genus Tequintavirus; and Kompetensportalen (LuPh5) of the genus Chivirus. Transmission electron microscopy confirmed myovirus and siphovirus morphologies consistent with these genera. As expected for phages in the flagellotropic Chivirus genus, LuPh5 failed to infect a poorly motile BW25113 strain lacking the IS5 element upstream of flhDC. By testing a panel of eight previously described anti-phage defense systems, we found that LuPh1 and LuPh2 are inhibited by the toxin-antitoxin-chaperone CmdTAC system; LuPh5 is inhibited by both the restriction-modification system EcoRI and the abortive infection reverse transcriptase AbiK; and all five phages are sensitive to the hybrid artificial CmdTA-HigC system. Collectively, our findings expand the toolkit for probing phage-host interactions and underscore the pedagogical value of incorporating phage isolation into practical training for emerging researchers.

microbiology↗

Therapy resistance in AML is mediated by cytoplasmic sequestration of the transcriptional repressor IRF2BP2

While the development of venetoclax with azacitidine (ven/aza) has improved AML therapy, drug resistance remains a major challenge. Notably, primary ven/aza-resistant AML are frequently reliant on MCL1, however, the underlying mechanisms remain unclear. Co-immunoprecipitation of MCL1 from ven/aza-resistant AML samples coupled with mass spectrometry analysis identified the transcriptional repressor Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) as an MCL1 binding partner. This interaction results in cytoplasmic IRF2BP2 localization and loss of transcriptional repression within ven/aza-resistant leukemic stem cells (LSC). Consequently, ven/aza-resistant LSC have increased IRF2BP2 target gene expression, including acyl-CoA synthetase long-chain family member 1 (ACSL1), an essential rate-limiting enzyme for fatty acid oxidation (FAO). Inhibition of ACSL1 functionally impaired ven/aza-resistant LSC through a depletion of long-chain acyl-carnitine metabolites and FAO. Collectively, these data provide evidence for a previously undescribed mechanism by which MCL1 mediates IRF2BP2 cytoplasmic sequestration and consequent de-repression of ACSL1, thereby promoting ven/aza-resistance in AML.

cancer biology↗

Genomic insights into six clinical isolates of Stenotrophomonas maltophilia from Northern India

Stenotrophomonas maltophilia is a gram-negative opportunistic pathogen that causes respiratory, urinary and bloodstream infections. Due to rising prevalence of difficult to treat S. maltophilia infections, it is considered as one of the important pathogens in many regions, including India. Despite its importance in public health, very few studies provide detailed characterization of the genomes of clinical isolates of S. maltophilia. In this study, we sequence six isolates of S. maltophilia from a tertiary healthcare centre in the Northern India. Along with the culture sensitivity, we report the genomic underpinnings of resistance and virulence in these isolates. In three out of six isolates, we identify a rare beta-lactamase gene kbl-1 that can confer resistance to variety of beta-lactam antibiotics. Though truncated in two isolates, an intact copy of kbl-1 is present in the third isolate. This intact copy of kbl-1 is flanked by insertion elements that are commonly found in several pathogenic species indicating high potential for horizontal gene transfer. To the best of our knowledge, this is a first report of kbl-1 in S. maltophilia from India. ImportanceAntimicrobial resistance (AMR) is one of the biggest global public health challenges. Tackling AMR gets complicated as diverse pathogenic species are involved and resistance is manifested against several different kinds of antibiotics. Genomic surveillance of the resistant pathogens is a key to fight this global threat and needs to extend to important emerging pathogens as well. Here we report genomic sequences and associated characteristics of six Stenotrophomonas maltophilia isolates from Northern India. Along with several resistance and virulence genes we also discover a rare beta-lactamase, blaKBL-1, gene with a high potential of transfer to other species. blaKBL-1 beta-lactamase confers resistance to several beta-lactam antibiotics like ampicillin, amoxicillin, penicillin G, piperacillin, ceftazidime and cefozopran. This is the first report of the presences of this beta-lactamase from India.

microbiology↗

One Health assessment of poultry and cattle farms as reservoirs for ESBL-producing Escherichia coli

BACKGROUNDUnregulated use of antibiotics in animal food production leads to the emergence of multidrug resistant bacteria, notably extended-spectrum beta-lactamases producing Escherichia coli (ESBL E. coli). ESBLs severely limit treatment options and pose a significant threat to public health. Investigating the potential role of livestock and poultry farms in harboring ESBL E. coli is crucial, given the prevalence of ESBL E. coli in humans, animals, and the environment, following the One Health framework. OBJECTIVESThe aim of this study was to assess and compare the potential contribution of cattle and poultry farms along with their respective human handlers to the emergence and spread of ESBL E. coli following One Health approach. METHODSTwenty cattle and twenty poultry farms were surveyed in Ludhiana, India to determine antibiotic usage, prevalent diseases in the farms. Animal faeces/poultry droppings, handler hand swabs, and stool samples were examined for the presence of ESBL E. coli. The isolates were examined for their susceptibility to 16 antibiotics and for the presence of selected antimicrobial resistance genes, including ESBL genes. Generalized linear mixed models were applied to investigate variations in the prevalence of ESBL E. coli associated with farm animal species, farm practices, and farm biosecurity measures. RESULTSOur findings revealed a higher prevalence of ESBL E. coli in poultry farms (53.75%) than in cattle farms (40.72%) and overall lower prevalence (12%) in human handlers. Of the total isolates, 86.52% were multidrug resistant, and 93.91% showed a high multiple antibiotic resistance (MAR) index (>0.2). Isolates from poultry farms exhibited a higher level of resistance with 97% of isolates exhibiting multidrug resistance, 100% isolates with MAR index of more than 0.2, and 90.70% carrying the blaCTXM gene. CONCLUSIONOur findings highlight cattle and poultry farms as potential reservoirs for multidrug-resistant and ESBL E. coli, contributing to the rising environmental burden of antibiotic resistance genes. This emphasizes the urgency of limiting antibiotic use in animal farming, especially in poultry production, to address the escalating problem of antibiotic resistance and protect both animal and human health.

microbiology↗

Unbounding fish: Assessing vulnerability to overexploitation for transboundary fish populations

SummeryGlobally coastal fisheries are managed according to political jurisdictions of nations and their provinces. This practice often results in multiple states/provinces managing a single genetically distinct fish population autonomously and without coordination. In multi-species, decentralized and data poor fisheries such management lead to poor assessment and eventually overharvest of fish. To assess overexploitation risk for such interjurisdictional populations, we propose a risk indicator IRIIS which incorporates 1) species-specific vulnerability 2) distribution of genetically-distinct populations with respect to jurisdictional boundaries and 3) differences in management practices across jurisdictions. As a case study we evaluated overexploitation risk for individual populations of nine commonly caught fish species spanning across multiple jurisdictions along Indias west coast. Our results indicate that interjurisdictional differences in management alters innate biological susceptibility. IRIIS is also sensitive to population-level differences and policy changes. Our analyses emphasize the need for population-level assessments and interjurisdictional cooperation to achieve sustainable fisheries. Science and society statementCoastal fisheries worldwide are managed through politically defined maritime jurisdictions, while fish populations are structured by biological processes such as dispersal, ocean currents, and natural barriers. This fundamental mismatch between biological population boundaries and jurisdictional management boundaries often results in the same population being exploited under multiple, uncoordinated governance regimes. In the context of the global overfishing crisis, such governance fragmentation can lead to inaccurate stock assessments and heightened risk of local population collapse. This challenge is particularly acute in developing and tropical countries, where fisheries are multispecies, data-limited, and increasingly decentralized to support community-based governance. While decentralization promotes social justice, it can inadvertently intensify the misalignment between biological and administrative boundaries, complicating sustainable management. In this manuscript, we introduce a robust framework -- the Integrative Risk Indicator for Interjurisdictional Stocks (IRIIS) -- which has a high applicability for multispecies, data-poor, and decentralized fisheries. Building on, and extending beyond, species-level Productivity Susceptibility Analysis (PSA), IRIIS integrates population genomics to delineate biologically meaningful population boundaries and combines these with fisheries policies and regulations across jurisdictions to quantify management-associated risks of overexploitation at the population level. We apply IRIIS to case studies of nine commercially important fish species harvested along the west coast of India. Our results demonstrate that the framework can (i) distinguish differential vulnerability among populations of the same species, (ii) explicitly capture management disparities across jurisdictions exploiting shared populations, and (iii) detect sensitivity to temporal changes in fisheries policies. By linking genomics, governance, and risk assessment, IRIIS provides a practical framework for identifying interjurisdictional management gaps and actionable entry points for policy coordination. This approach is particularly relevant for the Global South, where reconciling social equity objectives with ecological sustainability is both essential and challenging.

ecology↗

On the road to losing connectivity: Fecal samples provide genome-wide insights into anthropogenic impacts on two large herbivore species in central India

Humans have impacted most of the planet, and the ensuing fragmentation results in small, isolated habitat patches posing a risk of genetic diversity loss, inbreeding and genetic load. Understanding how natural and anthropogenic landscape features affect gene flow among habitat patches is critical for maintaining connectivity. Genome-wide data is required to comprehend the impacts of recent fragmentation, which can be challenging when only non-invasive samples are available. Here, we build upon advancements in conservation genomics to address connectivity of two large herbivores, gaur (Bos gaurus) and sambar (Rusa unicolor) in central India. Given their habitat associations, we expected these species to respond similarly to habitat fragmentation. We used fecal-DNA and methylation-based host-DNA enrichment with modified ddRAD protocol to generate genome-wide single nucleotide polymorphism (SNP) data for 124 Gaur and 99 Sambar individuals. Our findings reveal that gaur populations in central India are fragmented, displaying high genetic differentiation, with drift significantly affecting small populations like Umred-Karhandala Wildlife Sanctuary. Although Sambar shows low genetic structure, another small population, Bor Tiger Reserve is genetically differentiated. Our results suggest that although landcover change and roads restrict animal movement, the extent of this impact varies across the two species. We show that different species, respond differently to landscape features, even with similar habitat associations. We highlight small and isolated populations requiring urgent conservation intervention. Such multi-species approaches enhance our understanding of cross-species connectivity patterns. We suggest shifting from single-species to multi-species holistic conservation approach in rapidly developing landscapes to better manage co-occurring endangered species.

genomics↗

Transcriptome analysis reveals temporally regulated genetic networks during Drosophila border cell collective migration

BackgroundCollective cell migration underlies many essential processes, including sculpting organs during embryogenesis, wound healing in the adult, and metastasis of cancer cells. At mid-oogenesis, Drosophila border cells undergo collective migration. Border cells round up into a small group, detach from the epithelium, and migrate - at first rapidly through the surrounding tissue, then slower, with the cluster rotating several times before stopping at the oocyte. While specific genes that promote cell signaling, polarization of the cluster, formation of protrusions, and cell-cell adhesion are known to regulate border cell migration, there may be additional genes that promote these distinct dynamic phases of border cell migration. Therefore, we sought to identify genes whose expression patterns changed during border cell migration. ResultsWe performed RNA-sequencing on border cells isolated at pre-, mid-, and late-migration stages. We report that 1,729 transcripts, in nine co-expression gene clusters, are temporally and differentially expressed across the three migration stages. Gene ontology analyses and constructed protein-protein interaction networks identified genes expected to function in collective migration, such as regulators of the cytoskeleton, adhesion, and tissue morphogenesis, but also a notable enrichment of genes involved in immune signaling, ribosome biogenesis, and stress responses. Finally, we validated the in vivo expression and function of a subset of identified genes in border cells. ConclusionsOverall, our results identified differentially and temporally expressed genetic networks that may facilitate the efficient development and migration of border cells. The genes identified here represent a wealth of new candidates to investigate the molecular nature of dynamic collective cell migrations in developing tissues.

developmental biology↗

Mutations in S2 subunit of SARS-CoV-2 Omicron spike strongly influence its conformation, fusogenicity and neutralization sensitivity

SARS-CoV-2 has remarkable ability to respond to and evolve against the selection pressure by host immunity exemplified by emergence of Omicron lineage. Here, we characterized the functional significance of mutations in Omicron spike. By systematic transfer of mutations in WT spike we assessed neutralization sensitivity, fusogenicity, and TMPRSS2-dependence for entry. The data revealed that the mutations in both S1 and S2 complement to make Omicron highly resistant. Strikingly, the mutations in Omicron S2 modulated the neutralization sensitivity to NTD- and RBD-antibodies, but not to S2 specific neutralizing antibodies, suggesting that the mutations in S2 were primarily acquired to gain resistance to S1-antibodies. Although all six mutations in S2 appeared to act in concert, D796Y showed greatest impact on neutralization sensitivity and rendered WT virus >100-fold resistant to S309, COVA2-17, and 4A8. S2 mutations greatly reduced the antigenicity for NAbs due to reduced exposure of epitopes. In terms of the entry pathway, S1 or S2 mutations only partially altered the entry phenotype of WT and required both sets of mutations for complete switch to endosomal route and loss of syncytia formation. In particular, N856K and L981F in Omicron reduced fusion capacity and explain why subsequent Omicron variants lost them to regain fusogenicity.

microbiology↗

Transcriptional Responses of Cancer Cells to Heat Shock-Inducing Stimuli Involve Amplification of Robust HSF1 Binding

Responses of cells to signals are increasingly discovered to involve the binding of sequence-specific transcription factors outside of known target genes. We wanted to determine to what extent the genome-wide binding and function of a transcription factor are shaped by the cell type versus the stimulus. To do so, we induced the Heat Shock Response pathway in two distant cell lines with two different stimuli and related the binding of its master regulator HSF1 to nascent RNA and chromatin accessibility. We show that HSF1 binding patterns robustly retain their identity under different magnitudes of activation so that common HSF1 binding is globally associated with stimulus-specific transcription outcomes. HSF1-induced increase in DNA accessibility was modest in scale but occurred predominantly at remote genomic sites. Apart from regulating transcription at existing elements including promoters and enhancers, responses to heat shock may directly engage inactive chromatin.

genomics↗

Transcription Factor Gene Pea3 Regulates Erectile Function in Mice

BackgroundMale mice with homozygous loss of function mutations of the ETS transcription factor gene Pea3 (Pea3 null) are infertile due to their inability to deposit semen plugs, however the specific deficits in male sexual behaviors that drive this phenotype are unknown. AimTo investigate the regulatory role of the Pea3 gene in organizing gross sexual behaviors and erectile functioning during active copulation. MethodsThe copulatory behavior of male mice (Pea3 null and control) with hormonally primed ovariectomized females was monitored via high-speed and high-resolution digital videography to assess for differences in female-directed social behaviors, gross sexual behaviors (mounting, thrusting), and erectile and ejaculatory function. OutcomesPea3 null male mice have dramatically reduced erectile function during sexual intercourse, however other aspects of male sexual behaviors are largely intact. ResultsPea3 null male mice exhibit greatly reduced erectile function, with 44% of males displaying no visible erections during mounting behaviors, and none achieving sustained erections. As such, Pea3 null males are incapable of intromission, and semen plug deposition, despite displaying largely normal female-directed social behaviors, mounting behaviors, and ejaculatory grasping behavior. Additionally, the coordination of the timing of thrusting trains is impaired in Pea3 null males. Clinical ImplicationsThe identification of the transcription factor Pea3 in regulating erectile function in mice may provide a useful target for understanding the genetics of male sexual dysfunction in human patients. Strengths and LimitationsHigh-speed and high-resolution videography allows for a detailed analysis of male sexual behaviors and erectile functioning in Pea3 null and control mice. How disruption of the Pea3 gene translates to erectile dysfunction is still unknown. ConclusionThe transcription factor gene Pea3 regulates the ability to achieve and maintain erections in male mice.

animal behavior and cognition↗

High fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

Approximately 70% of Alzheimers disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women. HighlightsO_LICreated a mouse model of mixed dementia (MxD) with both AD + VCID pathology. C_LIO_LIHF diet caused greater metabolic impairment in AD and MxD females, compared to males. C_LIO_LIAD and MxD females showed a wider array of cognitive deficits, compared to males. C_LIO_LIAstrogliosis and A{beta} pathology were more severe in AD/MxD females, compared to males. C_LIO_LIMetabolic impairment was more consistently associated with reductions in cognitive function in females. C_LIO_LIMore severe glucose intolerance was associated with worse microgliosis in females only. C_LI

neuroscience↗

Genomic Surveillance of COVID-19 Variants with Language Models and Machine Learning

The global efforts to control COVID-19 are threatened by the rapid emergence of novel SARS-CoV-2 variants that may display undesirable characteristics such as immune escape, increased transmissibility or pathogenicity. Early prediction for emergence of new strains with these features is critical for pandemic preparedness. We present Strainflow, a supervised and causally predictive model using unsupervised latent space features of SARS-CoV-2 genome sequences. Strainflow was trained and validated on 0.9 million sequences for the period December, 2019 to June, 2021 and the frozen model was prospectively validated from July, 2021 to December, 2021. Strainflow captured the rise in cases two months ahead of the Delta and Omicron surges in most countries including the prediction of a surge in India as early as beginning of November, 2021. Entropy analysis of Strainflow unsupervised embeddings clearly reveals the explore-exploit cycles in genomic feature-space, thus adding interpretability to the deep learning based model. We also conducted codon-level analysis of our model for interpretability and biological validity of our unsupervised features. Strainflow application is openly available as an interactive web-application for prospective genomic surveillance of COVID-19 across the globe.

bioinformatics↗

Deep learning-based pan-cancer classification model reveals cancer-specific gene expression signatures

The identification of cancer-specific biomarkers and therapeutic targets is one of the primary goals of cancer genomics. Thousands of cancer genomes, exomes, and transcriptomes have been sequenced to date. In this study, we conducted a pan-cancer analysis of transcriptome datasets from 37 cancer types provided by The Cancer Genome Atlas (TCGA) in an effort to identify cancer-specific gene expression signatures. We employed deep neural networks to train a model on the transcriptome profile datasets for all cancer types. The model was validated, and its predictive accuracy was determined using an independent dataset, achieving > 97% prediction accuracy across cancer types. This strongly suggests that there are distinct gene expression signatures associated with various cancer types. We interpreted the model using SHapley Additive exPlanations (SHAP) to identify specific gene signatures that significantly contributed to the classification of cancer types. In addition to known biomarkers, we identified several novel biomarkers in different cancer types. These cancer-specific gene signatures are valuable candidates for future studies of their potential utility as cancer biomarkers and putative therapeutic targets.

bioinformatics↗