Biology subjects

Mandal, A.

Publications and source records attributed to Mandal, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Bicarbonate-free pH neutralization resensitizes ovarian cancer to chemotherapy and is tracked by 3T CEST MRI

Ovarian tumors that initially respond to platinum-taxane chemotherapy often relapse as chemoresistant disease. The acidic tumor microenvironment is a well-known but under-exploited driver of this resistance, and neutralization strategies such as oral bicarbonate have not translated. Here we show that inhibiting specific tumor pH regulators at noncytotoxic doses relieves acidosis and restores frontline chemotherapy, monitored noninvasively at clinical 3T. In OVCAR3 and SKOV-3 ovarian cancer cells, MCT1 and MCT4 were overexpressed under acidosis, and the MCT4 inhibitor acriflavine reduced extracellular acidification at concentrations well below its cytotoxic IC50, without bicarbonate buffering. Acidosis blunted the efficacy of both paclitaxel and carboplatin, raising their IC50 values, which acriflavine reversed. In SKOV-3 tumors, acidoCEST MRI with iopromide noninvasively measured baseline tumor acidosis and its normalization following acriflavine treatment. These results establish tumor acidosis as an imageable, druggable determinant of chemoresistance and a bicarbonate-free therapeutic target.

bioengineering↗

bioRxiv2026

Stepwise Proteinase K Digestion Improves Genomic DNA Yield and Purity from Goat Semen: A Comparative Pilot Study of Five Extraction Protocols

Background: Genomic DNA of high quality is a prerequisite for molecular genetic analyses. However, DNA extraction from goat semen is frequently challenged by highly compacted sperm chromatin and the presence of enzymatic inhibitors within the seminal plasma. Objectives: This pilot study aimed to identify a reliable and cost-effective method for isolating high-quality genomic DNA from caprine semen. Methods: Five extraction protocols were evaluated: an unmodified blood protocol (Protocol B), two modifications of a sperm protocol (Modified Protocols 1 and 2), and a stool protocol (Protocol BS) using a commercial spin-column kit (Kit A), alongside a second commercial silica membrane kit (Kit B). Three technical replicates per protocol were processed from a single frozen semen straw of a Black Bengal buck (with one replicate evaluated for Protocol B). Extracted DNA was evaluated based on concentration, purity (absorbance ratios A260/A280 and A260/A230), cost per sample, and PCR amplification success of the mitochondrial hypervariable region 1 (HVR1). Results: Modified Protocol 2 utilizing 100 uL of semen and two sequential 1.5-hour proteinase K incubations at 55 degrees C yielded the highest normalized DNA concentration (mean +/- SD: 55.9 +/- 30.4 ng/uL semen), optimal purity ratios (A260/A280 = 1.78; A260/A230 = 2.06), and the lowest cost per nanogram of DNA (INR 0.073 +/- 0.037). All extracts from this protocol were successfully amplified via PCR. While the Kruskal-Wallis test for normalized yield did not reach statistical significance (p = 0.075), rendering yield differences exploratory, Modified Protocol 2 demonstrated the strongest overall performance. Conclusions: Modified Protocol 2 offers a promising, cost-efficient workflow for caprine sperm DNA isolation. Given that this pilot study sampled a single animal, these findings must be validated using biological replicates from multiple bucks prior to widespread implementation.

molecular biology↗

bioRxiv2026

LIF-LIFR/gp130 Survival Signaling and Connexin 47 Dysregulation upon Murine-β-Coronavirus Infection: Discovery of a Novel ERK2 Phosphorylation Site at Cx47 C-Terminal Domain

Oligodendrocyte (OLG) injury and loss are increasingly recognized as major determinants of demyelination and remyelination failure in multiple sclerosis (MS), alongside conventional immune-mediated processes. However, the mechanism underlying OLG injury and remyelination failure remains incompletely understood. Astrocyte-oligodendrocyte interactions mediated by Connexin (Cx)-43-Cx47 gap junction (GJ) communication and leukemia inhibitory factor (LIF)-LIFR/gp130 signaling are critical for oligodendroglial survival, homeostasis, and myelination. Despite their established role, how these pathways are altered during neuroinflammatory diseases remains unclear. To address this, we integrated a murine {beta}-coronavirus (RSA59)-induced in vivo model with enriched primary oligodendrocyte precursor cell (OPC) and mature OLG cultures to investigate the effect of RSA59 infection on OLGs, Cx47-mediated GJ communication, and LIF-LIFR/gp130 Signaling. We observed that RSA59 directly targets oligodendroglial lineage cells, including OPCs and mature OLGs, and induces apoptosis in mature OLGs. Despite increased OPC abundance, RSA59 infection reduces the expression of mature and myelinating markers CNPase and MBP, raising the possibility of impaired oligodendrocyte maturation and myelination. RSA59 infection also differentially regulates Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling, crucial for OLG survival and homeostasis. Furthermore, our studies demonstrate that extracellular signal-regulated kinase (ERK), a downstream effector of LIF signaling, phosphorylates the Cx47 C-terminal domain (Cx47CT) at Serine-372 residue, identifying a previously unreported mechanism. Collectively, these findings reveal that RSA59 infection disrupts interconnected oligodendroglial communication and survival pathways, providing mechanistic insights into virus-induced chronic demyelination pathology. The study further identifies Cx47-mediated GJ communication and LIF-LIFR/gp130 signaling as crucial therapeutic targets, and highlights ERK-dependent Cx47CT phosphorylation as a potential regulatory mechanism.

neuroscience↗

bioRxiv2026

Testing for gene-environment (GxE) interaction using p-value aggregation identifies many GxE loci

Genome-wide gene-environment (GxE) interaction studies have seen limited success in detecting reliable GxE signals. A standard genome-wide GxE scan assumes a single genetic mode of inheritance, such as an additive model. It can lead to reduced statistical power when the true genetic model is non-additive, such as a recessive model. We propose a robust GxE testing approach that uses Cauchy p-value aggregation. It combines the p-values from GxE tests based on the additive, dominant, and recessive genetic models. Using extensive simulation studies, we demonstrate that the p-value combination strategy offers a robust and powerful approach to identifying GxE interactions regardless of the underlying genetic model. The method is substantially more powerful than the additive model when the true genetic model is recessive. It is also more powerful than the general two-degree-of-freedom genotypic test for GxE interaction. We apply our approach to analyze GxE interactions in the UK Biobank data across several combinations of phenotypes and environmental factors. For glycated hemoglobin (HbA1c) level, treating cumulative smoking exposure as the lifestyle factor, our approach identified 82 independent GxE loci while controlling FDR at 5%. The GxE test based on the additive genetic model detected 24 loci. For type 2 diabetes with sleep duration as a lifestyle factor, the proposed approach detected 563 independent GxE loci at 5% FDR, substantially exceeding the number of discoveries by the other approaches.

genomics↗

bioRxiv2026

Mettl3-catalyzed m6A methylation determines CD8+ T cell differentiation fate in tumor

The heterogeneity in patient responses to immune checkpoint blockade (ICB) is dictated by the relative abundance of exhausted CD8 T cell (Tex) subsets with distinct therapeutic responsiveness. Progenitor exhausted (pTex) cells remain sensitive to ICB, whereas terminally exhausted (tTex) cells are refractory; however, the molecular cues that bias differentiation toward these divergent fates remain poorly defined. Here, we identify the RNA methyltransferase Mettl3 as a central regulator of Tex fate. Across murine tumor models, human T cells, and adoptive transfer systems, Mettl3 expression is selectively enriched in tTex cells and inversely correlated with TCF1 pTex populations. Mechanistically, Mettl3 drives terminal exhaustion by stabilizing DNMT3B transcripts via mA modification, enforcing CpG methylation and chromatin compaction at memory-associated loci. Inhibition of the Mettl3-Dnmt3b axis reprograms chromatin accessibility toward memory-like states, thereby preserving progenitor potential and effector function. Consequently, T cells lacking Mettl3-Dnmt3b activity persist longer, mount robust recall responses, and achieve superior tumor control with enhanced responsiveness to PD-1 blockade. These findings establish the Mettl3-mA-Dnmt3b axis as a molecular rheostat of CD8 T cell fate, coupling epitranscriptomic regulation to epigenetic remodeling, and reveal a tractable pathway to improve the durability of cancer immunotherapy.

immunology↗

bioRxiv2025

Long-Read epigenetic clocks identify improved brain aging predictions

Epigenetic clocks are widely used to estimate biological aging, yet most are built from array-based data from peripheral tissues of predominantly European-ancestry individuals, limiting their generalizability. Here, we present aging clocks on DNA methylation from Oxford Nanopore long-read sequencing (LRS), leveraging over 28 million CpG sites from prefrontal cortex samples across individuals of African and European ancestry. These models were developed using GenoML, an automated machine learning platform for multi-omics data that leverages a diverse catalog of existing model architectures. Our long-read-informed clocks were developed using promoter-based and whole-genome window-based features, yielding models for each individual cohort as well as a combined-cohort clock. Each of these models demonstrated favorable performance compared to existing methylation clocks and was externally validated in a cohort of Colombian individuals. We further performed enrichment analyses and nominated both shared and cohort-specific pathways, cell types, and transcription factor binding motifs which may be implicated in aging and were not fully explained by cell type proportions or postmortem interval. Altogether, our findings highlight the power of long-read methylation data for constructing accurate, ancestry-aware aging clocks and emphasize the importance of inclusive training datasets.

bioinformatics↗

bioRxiv2025

Haplotype-Resolved DNA Methylation at the APOE Locus identifies Allele-Specific Epigenetic Signatures Relevant to Alzheimer's Disease Risk

The APOE gene encodes a key lipid transport protein and plays a central role in Alzheimers disease (AD) pathogenesis. Three common APOE alleles, {varepsilon}2 (rs7412(C>T), {varepsilon}3 (reference), and {varepsilon}4 (rs429358(T>C)), arise from two coding variants in exon 4 and confer distinct AD risk profiles, with {varepsilon}4 increasing risk and {varepsilon}2 providing protection. The {varepsilon}3-linked APOE variant rs769455[T] has also been associated with elevated AD risk in individuals of African ancestry carrying both rs769455[T] and {varepsilon}4 alleles. These single nucleotide variants (SNVs) reside in a cytosine-phosphate-guanine (CpG) island, which is a region with a higher frequency of CpG sites compared to the rest of the genome. CpG sites are subject to 5-methylcytosine (5mC) methylation by DNA methyltransferases which add a methyl group to the fifth carbon on the cytosine residue of a CpG site. The presence of SNVs can disrupt this process, making these regions prime targets for differential methylation; however, allele-specific methylation patterns in APOE remain poorly resolved due to technical limitations of conventional bisulfite and methylation array based methods, including degraded DNA quality, sparse CpG coverage, and lack of haplotype phasing. Here, we leverage high-accuracy long-read sequencing data to generate haplotype-resolved methylation profiles of the APOE locus in 332 postmortem brain samples from two ancestrally different cohorts. This includes 201 individuals of European ancestry from the North American Brain Expression Consortium (NABEC), comprising 402 haplotypes (48 {varepsilon}2 and 58 {varepsilon}4 alleles), and 131 individuals of African and African admixed ancestry from the Human Brain Core Collection (HBCC), comprising 262 haplotypes (25 {varepsilon}2, 64 {varepsilon}4, and 7 rs769455 alleles). A linear regression analysis identified 18 novel differentially methylated CpG sites (DMCs) associated with APOE {varepsilon}2, {varepsilon}4, and rs769455 within a gene cluster spanning TOMM40, APOE, APOC1, and APOC4-APOC2. This represents the most comprehensive haplotype-resolved methylation study of APOE in human brain tissue to date. Our results uncover distinct allele-specific methylation signatures and demonstrate the power of long-read sequencing for resolving epigenetic variation relevant to AD risk.

genomics↗

bioRxiv2024

Long-read sequencing of hundreds of diverse brains provides insight into the impact of structural variation on gene expression and DNA methylation

Structural variants (SVs) drive gene expression in the human brain and are causative of many neurological conditions. However, most existing genetic studies have been based on short-read sequencing methods, which capture fewer than half of the SVs present in any one individual. Long-read sequencing (LRS) enhances our ability to detect disease-associated and functionally relevant structural variants; however, its application in large-scale genomic studies has been limited by challenges in sample preparation and high costs. Here, we leverage a new scalable wet-lab protocol and computational pipeline for whole-genome Oxford Nanopore Technologies sequencing and apply it to neurologically normal control samples from the North American Brain Expression Consortium (NABEC) (European ancestry) and Human Brain Collection Core (HBCC) (African or African admixed ancestry) cohorts. Through this work, we present a publicly available long-read resource from 351 human brain samples (median N50: 27 Kbp and at an average depth of ~40x genome coverage). We discover approximately 234,905 SVs and produce locally phased assemblies that cover 95% of all protein-coding genes in GRCh38. To resolve cis-regulatory effects, we develop ASM-LR, a method for allele-specific methylation analysis from long-read data, revealing both strong and subtle regulatory effects, including numerous novel methylation QTLs masked in unphased models. Our results highlight the power of haplotype-resolved methylation to uncover regulatory mechanisms and establish a foundational resource for exploring how genetic variation shapes gene expression and epigenetic architecture across diverse ancestries.

genomics↗

bioRxiv2024

Enteropathogenic E. coli effector Map regulates the depletion of the tight junction proteins occludin and claudin-4 via cathepsin B and Rab13-mediated mechanisms

Infections by Enteropathogenic E. coli (EPEC) cause acute diarrheal disease in infants accounting for severe morbidity and mortality. One of the underlying causes of the disease is the break-down of the intestinal barrier maintained by the tight junctions (TJs). EPEC uses a type 3 secretion system to translocate more than twenty effectors into infected cells which disrupt several functions of the host cells. The effectors EspF, Map, EspG1/G2 and NleA have been reported to disrupt the TJs and cause the leakage of charged ions and uncharged molecules through the barrier. We have reported earlier that EspF and Map cause the depletion of TJ proteins claudin-1, claudin-4 and occludin through both transcriptional and post-transcriptional mechanisms. Here, we show that the EPEC effector Map modulates the lysosomal protease, cathepsin B to deplete claudins and occludin. Expression of mutant Map proteins that lacked the mitochondrial targeting sequence (MTS) completely restored the total levels of occludin and its localization at the TJs and partially restored claudin-4 levels and its junctional localization. We also identified a novel interaction of Map with the GTPase Rab13. As Rab13 has been reported to mediate the recycling of occludin to the plasma membrane, its interaction with Map has important implications for the loss of TJ integrity in EPEC pathogenesis. Occludin regulates the passage of water and uncharged solutes through TJs and Map may block its recycling to compromise the TJs thus causing excessive leakage through the barrier.

cell biology↗

bioRxiv2023

Tracking the misallocation and reallocation of spatial attention towards auditory stimuli

Completely ignoring a salient distractor presented concurrently with a target is difficult and sometimes attention is involuntarily attracted to the distractors location (attentional capture). Employing the N2ac component as a marker of attention allocation towards sounds, in this study we investigate the spatio-temporal dynamics of auditory attention across two experiments. Human participants (male and female) performed an auditory search task, where the target was accompanied by a distractor in 2/3rd of the trials. For a distractor more salient than target (Exp. 1), we observe not only a distractor N2ac (indicating attentional capture), but the full chain of attentional dynamics implied by the notion of attentional capture, namely: (a) the distractor captures attention before the target is attended, (b) allocation of attention to the target is delayed by distractor presence, and (c) the target is attended after the distractor. Conversely, for a distractor less salient than the target (Exp. 2), although behavioral interference was present, no attentional capture was observed. Together, these findings reveal two types of spatial-attentional dynamics in the auditory modality (distraction with and without attentional capture). Significance StatementOftentimes, we find it hard to ignore the location of a salient sound that distracts us from our current tasks. Although, a common everyday experience, little is known about how spatial distraction unfolds at the neural level in the auditory modality. Using electrophysiological markers of attention allocations, we report comprehensive evidence of spatial attentional capture by a salient auditory distractor, indicating that attention is first misallocated to the distractor and only afterwards reallocated towards the target. Similar patterns were observed earlier only in vision and their discovery in the auditory modality indicates towards the existence of domain-general spatial attentional dynamics consistent across sensory modalities. Finally, we demonstrate that only a distractor more salient than the target reliably captures attention.

neuroscience↗

bioRxiv2023

Microglial NF-κB Signaling Deficiency Protects Against Metabolic Disruptions Caused by Volatile Organic Compound via Modulating the Hypothalamic Transcriptome

Prolonged exposure to benzene, a prevalent volatile organic compound (VOC), at concentrations found in smoke, triggers hyperglycemia, and inflammation in mice. Corroborating this with existing epidemiological data, we show a strong correlation between environmental benzene exposure and metabolic impairments in humans. To uncover the underlying mechanisms, we employed a controlled exposure system and continuous glucose monitoring (CGM), revealing rapid blood glucose surges and disturbances in energy homeostasis in mice. These effects were attributed to alterations in the hypothalamic transcriptome, specifically impacting insulin and immune response genes, leading to hypothalamic insulin resistance and neuroinflammation. Moreover, benzene exposure activated microglial transcription characterized by heightened expression of IKK{beta}/NF-{kappa}B-related genes. Remarkably, selective removal of IKK{beta} in immune cells or adult microglia in mice alleviated benzene-induced hypothalamic gliosis, and protected against hyperglycemia. In summary, our study uncovers a crucial pathophysiological mechanism, establishing a clear link between airborne toxicant exposure and the onset of metabolic diseases.

neuroscience↗

bioRxiv2023

Mutational order and epistasis determine the consequences of FBXW7 mutations during colorectal cancer evolution

Somatic driver mutations, in genes such as FBXW7, have been discovered in phenotypically normal colonic tissue, however their role in cancer initiation remains elusive. Using normal and gene-edited patient-derived human colon organoids as models of early tumour evolution we observed that FBXW7-/- mutations exerted an epistatic effect on subsequent transcription depending on the mutational background of the cell. Specifically, the timing of acquiring an FBXW7-/- mutation respective to an APC mutation, led to profound phenotypic and transcriptomic differences. When FBXW7 was mutated before APC, a near-normal cell state was maintained alongside repression of the APC transcriptional response. However, when APC was mutated before FBXW7, cells acquired classical cancer-stem cell features. Single-cell RNA sequencing revealed that mutation of FBXW7 in normal tissue subtly switched cells from adult to a foetal/regenerative stem cell state. Further analysis using transposase-accessible chromatin sequencing identified this cellular plasticity was driven by changes in chromatin accessibility of transcriptional start site regions associated with TEAD, SNAI1 and AP-1 motifs, which in turn activate the foetal-like state. Taken together, we demonstrate a critical role of FBXW7 mutations in preventing colorectal cancer initiation and provide exemplar evidence for the importance of epistasis and mutational order in cancer biology.

cancer biology↗

bioRxiv2022

Metastatic infiltration of nervous tissue and periosteal nerve sprouting in multiple myeloma induced bone pain

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin-gene related protein (CGRP+) and growth associated protein 43 (GAP43+) fibres occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone and found alterations in pathways associated with cell cycle, immune response and neuronal signalling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP. Significance statementMultiple myeloma is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population.

neuroscience↗

bioRxiv2022

Genomic Sequencing from Sputum for Tuberculosis Disease Diagnosis, Lineage Determination and Drug Susceptibility Prediction

BackgroundUniversal access to drug susceptibility testing for newly diagnosed tuberculosis patients is recommended. Access to culture-based diagnostics remains limited and targeted molecular assays are vulnerable to emerging resistance conferring mutations. Improved sample preparation protocols for direct-from-sputum sequencing of Mycobacterium tuberculosis would accelerate access to comprehensive drug susceptibility testing and molecular typing. MethodsWe assessed a thermo-protection buffer-based direct-from-sample M. tuberculosis whole-genome sequencing protocol. We prospectively processed and analyzed 60 acid-fast bacilli smear-positive sputum samples from tuberculosis patients in India and Madagascar. A diversity of semi-quantitative smear positivity level samples were included. Sequencing was performed using Illumina and MinION (monoplex and multiplex) technologies. We measured the impact of bacterial inoculum and sequencing platforms on M. tuberculosis genomic mean read depth, drug susceptibility prediction performance and typing accuracy. ResultsM. tuberculosis was identified from 88% (Illumina), 89% (MinION-monoplex) and 83% (MinION-multiplex) of samples for which sufficient DNA could be extracted. The fraction of M. tuberculosis reads from MinION sequencing was lower than from Illumina, but monoplexing grade 3+ sputum samples on MinION produced higher read depth than Illumina (p<0.05) and MinION multiplex (p<0.01). No significant difference in overall sensitivity and specificity of drug susceptibility predictions was seen across these sequencing modalities or within each sequencing technology when stratified by smear grade. Lineage typing agreement percentages between direct and culture-based sequencing were 85% (MinION-monoplex), 88% (Illumina) and 100% (MinION-multiplex) ConclusionsM. tuberculosis direct-from-sample whole-genome sequencing remains challenging. Improved and affordable sample treatment protocols are needed prior to clinical deployment.

microbiology↗

bioRxiv2022

Computer-aided diagnosis of reflectance confocal images to differentiate between lentigo maligna (LM) and atypical intraepidermal melanocytic proliferation (AIMP)

Lentigo maligna (LM), a form of melanoma in situ that predominantly affects sun-exposed areas such as the face, has an ill-defined clinical border and has a high rate of recurrence. Atypical Intraepidermal Melanocytic Proliferation (AIMP) is a term used to describe the melanocytic proliferation of an uncertain malignant potential. Clinically and histologically, AIMP can be difficult to distinguish from LM, and indeed AIMP may in some cases progress to LM. Reflectance Confocal Microscopy (RCM) is often used to investigate these lesions non-invasively, however, RCM is often not readily available nor is the associated expertise for RCM image interpretation. Here, we demonstrate machine learning architectures that can correctly classify lesions between LM and AIMP on stacks of RCM images. Overall, our methods showcase the potential for computer-aided diagnosis in dermatology, which in conjunction with the remote acquisition, can expand the range of diagnostic tools in the community.

bioinformatics↗

bioRxiv2021

ProDCoNN-server: a web server for protein sequence prediction and design from a three-dimensional structure

We present ProDCoNN-server, a web server for protein sequence design and prediction from a given protein structure. The server is based on a previously developed deep learning model for protein design, ProDCoNN, which achieved state-of-the-art performance when tested on large numbers of test proteins and benchmark datasets. The prediction is very fast compared with other protein sequence prediction servers - it takes only a few minutes for a query protein on average. Two models could be selected for different purposes: BBO for full sequence prediction, extendable for multiple sequence generation, and BBS for single position prediction with the type of other residues known. ProDCoNN-server outputs the predicted sequence and the probability matrix for each amino acid at each predicted residue. The probability matrix can also be visualized as a sequence logos figure (BBO) or probability distribution plot (BBS). The server is available at: https://prodconn.stat.fsu.edu/.

bioinformatics↗

bioRxiv2021

Protein loop modeling and refinement using deep learning models

Loops in proteins play essential roles in protein functions and interactions. The structural characterization of loops is challenging because of their conformational flexibility and relatively poor conservation in multiple sequence alignments. Many experimental and computational approaches have been carried out during the last few decades for loop modeling. Although the latest AlphaFold2 achieved remarkable performance in protein structure predictions, the accuracy of loop regions for many proteins still needs to be improved for downstream applications such as protein function prediction and structure based drug design. In this paper, we proposed two novel deep learning architectures for loop modeling: one uses a combined convolutional neural network (CNN)-recursive neural network (RNN) structure (DeepMUSICS) and the other is based on refinement of histograms using a 2D CNN architecture (DeepHisto). In each of the methods, two types of models, conformation sampling model and energy scoring model, were trained and applied in the loop folding process. Both methods achieved promising results and worth further investigations. Since multiple sequence alignments (MSA) were not used in our architecture, the energy scoring models have less bias from MSA. We believe the methods may serve as good complements for refining AlphaFold2 predicted structures.

bioinformatics↗

bioRxiv2021

Structural Disconnection of the Posterior Medial Frontal Cortex Reduces Speech Error Monitoring

Optimal performance in any task relies on the ability to detect and repair errors. The anterior cingulate cortex and the broader posterior medial frontal cortex (pMFC) are active during error processing. However, it is unclear whether damage to the pMFC impairs error monitoring. We hypothesized that successful error monitoring critically relies on connections between the pMFC and broader cortical networks involved in executive functions and the task being monitored. We tested this hypothesis in the context of speech error monitoring in people with post-stroke aphasia. Diffusion weighted images were collected in 51 adults with chronic left-hemisphere stroke and 37 age-matched control participants. Whole-brain connectomes were derived using constrained spherical deconvolution and anatomically-constrained probabilistic tractography. Support vector regressions identified white matter connections in which lost integrity in stroke survivors related to reduced error detection during confrontation naming. Lesioned connections to the bilateral pMFC were related to reduce error monitoring, including many connections to regions associated with speech production and executive function. We conclude that connections to the pMFC support error monitoring. Error monitoring in speech production is supported by the structural connectivity between the pMFC and regions involved in speech production and executive function. Interactions between pMFC and other taskrelevant processors may similarly be critical for error monitoring in other task contexts.

neuroscience↗