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Verma, M.

Publications and source records attributed to Verma, M..

At least 19 recordsLinked to original sources

Discovering Latent Scientific Concepts through Discrete Representation Learning

Scientific imaging is undergoing a fundamental transformation. Advances in multiplex immunofluorescence, computational pathology, and electron microscopy now enable observation of biological and physical systems at unprecedented spatial resolution. Rather than simply classifying known objects, these data offer the opportunity to discover previously unknown organizational principles. However, scientific image datasets are typically highly curated, information-rich, and limited in size, making reliable representation learning particularly challenging. We show that standard continuous self-supervised adaptation can become unstable in this regime, allowing teacher representations to drift and degrading downstream transfer. We introduce Kodiak, a discrete representation learning architecture that discovers latent scientific concepts through Sinkhorn-balanced codebook assignments. Instead of learning unconstrained continuous embeddings, Kodiak constructs a reusable vocabulary of discrete concepts that provides stable supervision for both masked-patch prediction and cross-view representation learning within a single-stage framework. Across five scientific imaging domains, including multiplex immunofluorescence for pancreatic cancer pathology and scanning electron microscopy, Kodiak consistently improves representation quality under both continued foundation-model adaptation and training from scratch. Beyond improved classification and transfer,the learned concepts are interpretable, reusable, and produce spatially coherent concept maps that support applications such as cell phenotyping, segmentation-free patch phenotyping, spatial niche discovery, tissue organization, and materials characterization. We view Kodiak as the representation-learning engine of our foundation model for spatial biology. More broadly, our results suggest that discrete representation learning provides a principled foundation for discovering reusable latent scientific concepts that can accelerate scientific interpretation across imaging domains.

cancer biology↗

Multi-cohort analysis of 37,739 oral microbiomes reveals ecologically influential health-associated microbial sub-communities across major oral subsites

The oral cavity contains multiple microbial sub-niches, but which taxa consistently play an ecologically important, health-associated role within each niche, and how conserved they are across populations, remains poorly understood, partly due to the lack of a standardised identification framework. We developed a multi-cohort framework integrating 37,739 oral microbiome profiles (16S rRNA and shotgun sequencing) from 142 cohorts (41 countries) ranking 542 taxa across four oral habitats, supragingival, subgingival, tongue-tonsil, and buccal-palate-mucosa, via a new Health-Associated-Core (HAC) score capturing consistent prevalence, ecological influence, and health-association. For saliva, with available longitudinal sampling, we extended this into a salivary-Health-Associated-Core-Keystone (sHACK) score additionally capturing stability-association, ranking 499 taxa. Using two complementary approaches for identifying ecological modules, high-sHACK salivary taxa concentrated within a single, connected sub-community of 28 members, consistently linked to prevalence, ecological influence, stability, and health. This sub-communitys abundance alone outperformed conventional dysbiosis indices in distinguishing healthy from diseased individuals and tracked stability in an independent cohort of 4,621 microbiomes. Comparable sub-communities emerged across three other subsites, with compositional differences mirroring physicochemical variation between sites. Machine learning linked taxa-specific-genome-encoded functions to their corresponding subsite-specific HAC/sHACK scores, offering a unified framework for prioritizing oral microbes diagnostically and therapeutically.

microbiology↗

The tortured past of young polymorphic sex chromosomes revealed through multiple de novo genome assemblies of the mountain pine beetle

Neo-sex chromosomes provide a powerful system for studying the early stages of sex chromosome evolution and the genomic mechanisms that may contribute to reproductive isolation. Using PacBio long-read HiFi sequencing, Hi-C scaffolding, and sex-specific transcriptomic data, we generated six chromosome-level assemblies (male and female from three populations) of the mountain pine beetle (Dendroctonus ponderosae), a species known to harbor three partially reproductively isolated neo-Y haplogroups. These assemblies reveal that the large neo-X and neo-Y chromosomes formed through sequential fusions of the ancestral X with three autosomes, with recombination cessation occurring at [~]8.6, [~]6.3, and [~]4.3 MYA for each event. Comparative analyses show that while neo-X chromosomes remain largely collinear across populations, neo-Ys exhibit dramatic structural divergence, with 900-1,200 inverted segments per haplogroup and only [~]65% of sequence able to be aligned to the neo-X. Repeat analyses demonstrate moderate TE accumulation on the neo-Y, particularly LTR elements, and gene mapping analyses reveal extensive degeneration: [~]62% of neo-Y genes exhibit gene loss, fragmentation, or disruptive mutations. All populations retain a single pseudoautosomal region (PAR), though PAR size and gene content vary due to neo-Y specific rearrangements. Across neo-Ys, 27 genes are uniquely missing in the Western haplogroup, including previously identified candidates implicated in hybrid male sterility. Broader comparisons among neo-Ys show widespread structural variation, population specific patterns of degeneration, and limited gene family expansions. Together, these results provide the first full characterization of neo-sex chromosome evolution in D. ponderosae, revealing rapid, lineage specific neo-Y degeneration and highlighting the potential for sex chromosome divergence to contribute to emerging reproductive incompatibilities within a single species.

genomics↗

Systematic identification and characterization of regulators of aryl hydrocarbon receptor signaling

The human aryl hydrocarbon receptor (AHR) integrates chemical signals derived from the environment, gut microbes, and endogenous sources to regulate processes ranging from intestinal barrier integrity to xenobiotic detoxification. Despite strong evidence that dysregulation of AHR signaling is a causal factor in metabolic and autoimmune disorders, we currently lack a comprehensive understanding of the factors that regulate AHR activity in human cells. Here, we use genome-scale CRISPR screening to systematically identify regulators of AHR signaling in hepatocytes. The resulting datasets recapitulate the core AHR signaling pathway and identify a large network of regulators. Many of these factors have roles beyond AHR signaling, reflecting that AHR signaling is deeply integrated into human cell biology. We further dissect this network to reveal novel modes of regulation of AHR expression, protein levels, and signaling. For example, we find that the E3 ubiquitin ligase UBR5 sustains AHR signaling by counteracting degradation of ligand-bound AHR. Finally, we identify components of the AHR regulatory network that are specific to cell types and ligands as potential nodes to manipulate AHR signaling in a targeted manner for therapeutic benefit. Overall, our results define the regulatory network that underpins AHR activation, with implications for our understanding of host-microbe interactions and integrative chemosensation and the etiology of metabolic and inflammatory disorders.

genomics↗

On-skin, micro-lens enabled camera module for speckle contrast optical spectroscopy/tomography

In this paper, we introduce a speckle contrast optical spectroscopy/tomography (SCOS/SCOT) configuration based on an integrated imaging approach exploiting 113 micro-objetives mounted on a commercial CMOS camera that operates without fiber coupling, suitable for direct skin contact measurements and simultaneous multiple source-detector separation acquisitions. This compact system was validated ex vivo on phantoms and in vivo by monitoring the blood flow on the forearm muscle of a healthy human subject. The measurements, performed at multiple source-detector separations and camera exposure times, demonstrate excellent agreement with the theory based on the correlation-diffusion model. In vivo data demonstrate the capability of tracking pulsatile blood flow with a high signal-to-noise ratio (>4 harmonics of the cardiac pulse frequency detected) and sensitivity to small changes in muscle blood flow. This micro-objective array-based design overcomes a key challenge towards wearable SCOS/SCOT devices.

bioengineering↗

Transcriptomic and physiological responses of soybean plants subjected to a combination of water deficit and heat stress under field conditions

Water deficit, heat stress, and a combination of water deficit and heat stress are highly disruptive to crop yield worldwide. Unfortunately, the frequency and intensity of these conditions is gradually increasing due to climate change. Previous studies of water deficit and heat stress combination were primarily conducted under controlled growth conditions, revealing that the combination of water deficit and heat stress resulted in the activation of unique stress responses and acclimation pathways. However, whether similar responses to stress combination occur in the field remained largely unknown. Here we report on a two-year field study in which the transcriptomic and physiological responses of vegetative and reproductive tissues of soybean (Glycine max) to water deficit, heat treatment and their combination were studied. Our findings reveal that the transcriptomic responses of soybeans grown in the field are different from those grown under controlled growth chamber conditions. These differences were especially noticeable in plants subjected to the heat or water deficit treatments, and less in plants subjected to the stress combination. In addition, we report that differential transpiration between leaves and pods, that was originally discovered in plants grown under controlled growth conditions, occurs in field grown soybeans in response to heat stress, as well as heat stress combined with water deficit. We hope that the transcriptomic datasets generated by our study will contribute to future studies of crop responses to different stresses in the field, as well as highlight the need for more omics studies of plants grown under field conditions.

plant biology↗

Mapping the dimerization specificity of bZIP transcription factors in bread wheat

Dimerization plays a pivotal role in target-binding interactions among various transcription factors (TFs), including bZIPs, bHLHs, MYBs, and zinc finger TFs. The bZIP family is defined by an -helix class of TFs containing a basic region that binds to the major groove of double-stranded DNA (dsDNA), followed by a leucine zipper motif that mediates dimerization through coiled-coil structures, forming homo- or heterodimers. In polyploid bread wheat (Triticum aestivum cv.), bZIPs and their homeologs interact through the dimerization motifs to form specific bZIP pairs with distinct regulatory functions. The dimerization pattern of bZIPs is critical for gene regulation, however, the mechanisms underlying their specificity remain poorly understood. Here, we focus on the dimerization specificity of coiled-coil - helical bZIP proteins in bread wheat, highlighting the leucine zipper region as a key dimerization motif. We identified 265 bZIPs containing the bZIP motif, following dimerization criteria established in humans, Drosophila, and Arabidopsis based on the presence of specific amino acids at the a, d, e, and g positions in heptads. Eight key bZIP TFs were cloned, expressed, and purified for the structural analysis. This study not only provides the dimerization trend exhibited by bZIPs during thermal stability analysis but also provides the reversibility pattern followed by the thermal denaturation exposure at 85{degrees}C. Our study also points towards that how amino acid substitutions and the length of the leucine zipper influence the formation of coiled-coil structures among bZIP homeologs of polyploid wheat. Overall, the study advances our understanding of the role of leucine zippers, in determining the specificity and stability of bZIP dimers, which in turn governs DNA binding and gene regulation in plants.

biochemistry↗

CD90 identifies distinct fractions of muscle stem cells with different modalities of activation and quiescence maintenance

Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here we show that CD90 diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subpopulations differing in the kinetics of activation, CD90+ve MuSCs exhibiting a faster exit quiescence and predominating the initial phases of regeneration compared to CD90-ve MuSCs. In the absence of injury, the CD90+ve fraction is primed toward activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. Our studies show that Collagen VI, which is preferentially expressed by CD90+ve MuSCs, binds to the Calcitonin receptor and plays a role in this context. Moreover, while the number of CD90+ve and CD90-ve subpopulations is similar in healthy muscles, the CD90-ve fraction predominates in the muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.

cell biology↗

Immune Infiltration and Survival Analysis in Lung Adenocarcinoma: Identifying Prognostic Cell Types

The tumor microenvironment (TME) plays a crucial role in the development and survival of neoplastic cells, with tumor-infiltrating leukocytes (TILs) constituting a significant component. This immune infiltrate exhibits a diverse composition of adaptive and innate immunological cell subtypes, with varying prognostic implications across different cancer types. Recent advancements in immunotherapy underscore the importance of evaluating TILs as potential biological identifiers, particularly in the context of novel treatment strategies. In lung adenocarcinoma, the most prevalent histological subtype of lung cancer, multiple immune cell types have been identified within the TME, influencing tumor classification, clinical outcomes, and patient survival. While prior research has demonstrated a correlation between tumor-infiltrating immune cells and the progression of lung adenocarcinoma, few studies have examined their prognostic implications comprehensively. Building upon our previous work, where we constructed a signature matrix (Verma, 2024b.) and evaluated the fractions of 14 immune cell types in TCGA-LUAD data and performed ESTIMATE analysis to assess immune infiltration, stromal infiltration, and tumor purity (Verma, 2024a.), in this study, we investigate the association between immune cell infiltration patterns and the overall survival and prognosis of TCGA-LUAD patients across different histological subtypes and stages. Our findings aim to elucidate the immune cell types positively or negatively impacting patient outcomes in lung adenocarcinoma and inform future therapeutic approaches.

bioinformatics↗

Impedance-based assay for pan-cancer early and rapid detection of cell-free DNA

Aberrant DNA methylation is a hallmark of cancer, and plasma cell-free DNA (cfDNA) containing these abnormal methylation patterns has emerged as a promising non-invasive biomarker for pan-cancer detection. However, intrinsic challenges remain that continue to limit its broad clinical application. Here we show a simple and rapid impedance biosensor called Asima Rev that can detect cancer cfDNA in under 5 min without the need for any molecular labelling, electrode modification, signal amplification, or target enrichment steps. Using 216 clinical samples (50 healthy) from 15 different cancer types (all stages) we show an overall sensitivity and specificity of 96.4% and 94.0%, respectively. Differences in methylation content between cancerous and healthy cfDNA lead to distinct solvation behaviour and electro-physicochemical property that remain consistent across cancer types regardless of the distribution patterns of methyl cytosine. Our test exploits this inherent difference.

biophysics↗

Assessing Immune Microenvironment in TCGA-LUAD via CIBERSORTx Using Single-Cell Derived Signature Matrix and ESTIMATE Algorithm

Lung cancer (LC) remains a significant global health concern, affecting millions worldwide each year. Tumor-infiltrating immune cells (TIICs) play a crucial role in Lung Cancer progression and prognosis, with various immune cell types infiltrating the tumor microenvironment. Traditional methods like immunohistochemistry and flow cytometry have limitations in accurately profiling TIIC subtypes. However, recent advancements in single-cell RNA sequencing and computational algorithms like CIBERSORTx offer a promising approach for characterizing TIICs in bulk tumor samples. In this study, we undertook the validation of the signature matrix comprising 14 distinct immune cell types and subtypes, which was originally derived from PBMC single-cell RNA-seq data, in our previous work (Verma, 2024). The positive controls included 8 bulk RNA-seq samples of whole blood and specific immune cell bulk RNA-seq samples, while the negative control comprised neuroblastoma cell lines lacking immune content. Subsequently, we applied this signature matrix to deconvolute TCGA-LUAD data (n = 598), and assessed tumor purity and immune-stromal content using the ESTIMATE algorithm. Our findings indicate that the signature matrix accurately reflected flow cytometry-derived fractions, supported by correlation analysis. Specifically, the second positive control and negative control accurately reflected immune and non-immune sample fractions, respectively, further validating the efficacy of our approach. This study also provide insights into the invasion of immunocytes in lung adenocarcinoma and highlight the potential of computational tools like CIBERSORTx and ESTIMATE in characterizing the immune microenvironment of LC.

bioinformatics↗

Unravelling Immune Cell Signatures: CIBERSORTx-assisted Construction of Signature Matrix from Single-Cell Data

The immune systems intricate orchestration is pivotal in combating infections and diseases, often leaving discernible signatures within circulating blood cells. Peripheral blood mononuclear cells (PBMCs), comprising diverse immune cell populations, serve as crucial indicators of immune system status and its responses to various conditions, including cancer. While traditional bulk metrics pose challenges in dissecting specific immune cell functionalities, advancements in single-cell technologies offer unprecedented insights into the dynamic activities of immune cell populations. In this study, we analyzed single-cell data from droplet sequencing to delineate immune cell types and subtypes within PBMCs. Employing the CIBERSORTx tool, we constructed a signature matrix to comprehensively represent significant cell populations within tissue. Through iterative optimization and minimization of the condition number based on marker genes, we aimed to enhance the robustness and stability of the gene signature matrices, enabling scalable investigation of novel or poorly understood phenotypic states in bulk tissue gene expression profiles. The resultant matrix consisted of 14 immune cell types represented by 275 gene having significant highest expression for their respective cell types and the least in other cells. This approach facilitates precise characterization of immune cell populations and their responses to diverse diseases, contributing to a deeper understanding of immunological processes and paving the way for targeted therapeutic interventions.

bioinformatics↗

Model-based prediction and ascription of deforestation risk within commodity sourcing domains: Improving traceability in the palm oil supply chain

Palm oil accounts for approximately 50% of global vegetable oil production, and trends in consumption have driven large-scale expansion of oil palm (Elaeis guineensis) plantations in Southeast Asia. This expansion has led to deforestation and other socio-environmental concerns that challenge consumer goods companies to meet no deforestation and sustainability commitments. In support of these commitments and supply chain traceability, we seek to improve on the current industry standard sourcing model for ascribing social and environmental risks to particular actors. Using passive geolocational traceability data (n = 3,355,437 cellular pings) and machine learning models, we evaluate the industry standard sourcing model, and we predict with high accuracy the undisclosed sourcing domains for 1,570 Indonesian and Malaysian palm oil mills on the Universal Mill List (as of November 2021). In combination with the World Wide Fund for Nature - Netherlands Forest Fore-sight, we use our predicted sourcing domains to provide an illustrative example of the proportional allocation of future deforestation, carbon loss, and biodiversity risk to relevant actors, permitting targeted outreach, contract negotiation, and mitigation of large-scale resource degradation. This example depends on a subset of model predictions in the absence of disclosed traceability data. The utilization of additional predictions or disclosed traceability data would influence and improve the results.

ecology↗

Anatomical Modeling and Optimization of Speckle Contrast Optical Tomography

Traditional methods for mapping cerebral blood flow (CBF), such as positron emission tomography and magnetic resonance imaging, offer only isolated snapshots of CBF due to scanner logistics. Speckle contrast optical tomography (SCOT) is a promising optical technique for mapping CBF. However, while SCOT has been established in mice, the method has not yet been demonstrated in humans - partly due to a lack of anatomical reconstruction methods and uncertainty over the optimal design parameters. Herein we develop SCOT reconstruction methods that leverage MRI-based anatomical head models and finite-element modeling of the SCOT forward problem (NIRFASTer). We then simulate SCOT for CBF perturbations to evaluate sensitivity of imaging performance to exposure time and SD-distances. We find image resolution comparable to intensity-based diffuse optical tomography at superficial cortical tissue depth ([~]1.5 cm). Localization errors can be reduced by including longer SD-measurements. With longer exposure times speckle contrast decreases, however, noise decreases faster, resulting in a net increase in SNR. Specifically, extending exposure time from 10s to 10ms increased SCOT SNR by 1000X. Overall, our modeling methods provide anatomically-based image reconstructions that can be used to evaluate a broad range of tissue conditions, measurement parameters, and noise sources and inform SCOT system design.

neuroscience↗

A comprehensive workflow and its validation for simulating diffuse speckle statistics for optical blood flow measurements

Diffuse optical methods including speckle contrast optical spectroscopy and tomography (SCOS and SCOT), use speckle contrast (k) to measure deep blood flow. In order to design practical systems, parameters such as signal-to-noise ratio (SNR) and the effects of limited sampling of statistical quantities, should be considered. To that end, we have developed a method for simulating speckle contrast signals including effects of detector noise. The method was validated experimentally, and the simulations were used to study the effects of physical and experimental parameters on the accuracy and precision of k. These results revealed that systematic detector effects resulted in decreased accuracy and precision of k in the regime of low detected signals. The method can provide guidelines for the design and usage of SCOS and/or SCOT instruments.

bioengineering↗

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and, reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from altered metabolism including increased fatty acid oxidation (FAO) and a striking induction of the stemness factor Lin28b in the resulting leukemia. Lin28b promotes a substantial increase in lipid content, upon which the survival of Rpl22-deficient leukemias depends. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC through regulation of FAO and promotes leukemogenesis through Lin28b promotion of lipid synthesis. HighlightsO_LIRPL22 insufficiency is observed in MDS/AML and is associated with reduced survival C_LIO_LIRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesis C_LIO_LIRpl22-deficiency does not impair global protein synthesis by HSC C_LIO_LIRpl22 controls leukemia survival through control of lipid synthesis C_LI eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through regulation of lipid metabolism.

cancer biology↗

Cellular Dynamics of Skeletal Muscle Regeneration

The function of many organs, including skeletal muscle, depends on its three-dimensional structure. Muscle regeneration therefore requires not only reestablishment of myofibers, but restoration of tissue architecture. Resident muscle stem cells (SCs) are essential for regeneration, but how SCs regenerate muscle architecture is largely unknown. We address this problem using genetic labeling of SCs and whole mount imaging to reconstruct in three dimensions muscle regeneration. Unexpectedly, we found that the residual basement membrane of necrotic myofibers is critical for promoting fusion and orienting regenerated myofibers and myofibers form via two distinct phases of fusion. Furthermore, the centralized myonuclei characteristic of regenerated myofibers are associated with myofibrillogenesis and permanently mark regenerated myofibers. Finally, we elucidate a new cellular mechanism for the formation of branched myofibers, a pathology characteristic of diseased muscle. We provide a new synthesis of the cellular events of regeneration and show these differ from those used during development.

cell biology↗

Multi-Mode Fiber-Based Speckle Contrast Optical Spectroscopy: Analysis of Speckle Statistics

Speckle contrast optical spectroscopy/tomography (SCOS/T) provides a real-time, non-invasive, and cost-efficient optical imaging approach to mapping of cerebral blood flow. By measuring many speckles (n>>10), SCOS/T has increased signal-to-noise ratio relative to diffuse correlation spectroscopy, which measures one or a few speckles. However, the current free-space SCOS/T designs are not ideal for large field-of-view imaging in humans because the curved head contour cannot be readily imaged with a single flat sensor and hair obstructs optical access. Herein we evaluate the feasibility of using cost-efficient multi-mode fiber (MMF) bundles for use in SCOS/T systems. One challenge with speckle contrast measurements is the potential for confounding noise sources (e.g., shot noise, readout noise) to contribute to the standard deviation measure and corrupt the speckle contrast measure that is central to the SCOS/T systems. However, for true speckle measurements, the histogram of pixel intensities from light interference follows a non-Gaussian distribution, specifically a gamma distribution with non-zero skew, whereas most noise sources have pixel intensity distributions that are Gaussian. By evaluating speckle data from static and dynamic targets imaged through MMF, we use histograms and statistical analysis of pixel histograms to evaluate whether the statistical properties of the speckles are retained. We show that flow-based speckle can be distinguished from static speckle and from sources of system noise through measures of skew in the pixel intensity histograms. Finally, we illustrate in humans that MMF bundles relay blood flow information. (C) 2022 Optica Publishing Group

bioengineering↗