Biology subjects

Rajendran, A.

Publications and source records attributed to Rajendran, A..

16 recordsLinked to original sources

bioRxiv2026

Transcriptomic analysis reveals differential regulation of synaptic components in pediatric and adult brain tumors

Neuronal-cancer cell interactions are a key component of brain tumor pathophysiology, yet many fundamental questions remain unanswered, with even more remaining unasked. Here, we present a comprehensive brain tumor reference map generated from bulk RNA-seq data of ~4,300 adult and pediatric brain tumors, including various glioma subtypes, medulloblastomas, ependymomas, and meningiomas, alongside ~1,400 healthy brain samples. By analyzing synaptic processes and synaptic gene expression across tumor types, we reveal the complexity of neuron-tumor crosstalk and its potential impact on patient survival. Our findings identify key synaptic signaling pathways and dysregulated patterns in brain tumors, including HNRNPH2 upregulation, a key factor in RNA processing and metabolism, in gliomas and medulloblastomas. Additionally, we highlight the role of cholinergic signaling, particularly CHRNA9, as a driver of glioma progression, which is also upregulated in WNT and Group 4 medulloblastomas, ependymomas, and meningiomas. Furthermore, P2 purinergic signaling emerges as a key player in glioma progression. These insights lay the groundwork for future studies exploring whether targeting these pathways could reprogram the tumor microenvironment toward an anti-tumor state, ultimately leading to novel therapeutic strategies and improved patient outcomes.

cancer biology↗

bioRxiv2026

SARS-CoV-2 S1 spike protein induces a temporal systemic immune response and promotes long-term anxiety-like behaviors

The SARS-CoV-2 S1 protein is associated with immune cell activation and persistent neurological symptoms, yet the underlying mechanisms remain unclear, posing a major challenge in elucidating Long COVID pathophysiology. To investigate how circulating S1 contributes to long-term neurological alterations, we intravenously injected hACE2 mice with varying doses of S1 (5, 10, and 20 {micro}g) and observed temporally dysregulated systemic inflammatory responses accompanied by sub-acute CD4+ T cell infiltration into central limbic regions. This immune response induced mild sustained increases in cFos+ cells in the amygdala and mild neuroinflammation in the hippocampal CA1 region, resulting in both acute and long-term anxiety-like behaviors, while working memory remained unaffected. Together, these findings suggest that systemic S1 protein induces a sustained proinflammatory response that promotes lasting neurological alterations through immune-to-brain signaling pathways. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/733010v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@10982caorg.highwire.dtl.DTLVardef@169a275org.highwire.dtl.DTLVardef@28e66aorg.highwire.dtl.DTLVardef@12f6c85_HPS_FORMAT_FIGEXP M_FIG C_FIG

Molecular Biology↗

bioRxiv2026

Pre-existing chromatin accessibility primes δ-cells for injury-induced endocrine plasticity

Adult zebrafish rapidly recover glucose homeostasis after {beta}-cell loss, but the cellular basis and regulatory mechanisms that enable this response remain unclear. Here we combine single-cell transcriptomics, single-cell chromatin accessibility profiling, paired multiome analysis and functional perturbation to define early pancreatic recovery after {beta}-cell ablation. We show that, during the first month after injury, insulin production is restored predominantly by sst1.1+ {delta}1-cells rather than by rapid reconstitution of canonical {beta}-cells. Following ablation, {delta}1-cells adopt a bihormonal hybrid state and induce metabolic, secretory and {beta}-cell-associated gene programs. Systematic comparison of chromatin accessibility across endocrine cell types reveals that these {delta}1-cells are uniquely close to {beta}-cells and exhibit open chromatin at {beta}-cell enhancers in the steady state. Moreover, hybrid-cell formation occurs without major chromatin remodeling, with {beta}-cell associated loci being already accessible in {delta}1-cells before {beta}-cell injury. A comparable permissive state is present in medaka but not in human {delta}-cells, suggesting that restricted insulin accessibility may represent a barrier to endocrine plasticity in the human pancreas. In zebrafish, {delta}1-cells also show evidence of metabolic remodeling after {beta}-cell loss, including rapid accumulation of neutral lipids. Gene regulatory network analysis and perturbation identify meis1a/b as required regulators of {delta}1 hybrid-cell formation after {beta}-cell loss in zebrafish, whereas meis1a/b are not upregulated following {beta}-cell ablation in medaka. Together, our results define pre-existing chromatin accessibility, metabolic remodeling and instructive transcriptional regulation as key features of early functional recovery after {beta}-cell loss in the adult zebrafish pancreas.

developmental biology↗

bioRxiv2026

Aging macaques bridge the translational gap in perivascular space biology

The prevalence of MR-visible perivascular spaces (PVS) is age-dependent in rhesus macaques. Automated quantification in 94 male and female animals ranging 5-28 years of age demonstrated a robust association between age and PVS burden, with an anatomical distribution paralleling that of humans. Preliminary ex vivo validation confirmed that the MRI-detected tubular structures correspond to perivascular spaces. These findings establish the rhesus macaque as a tractable model for understanding the role of perivascular dysfunction in age-related brain vulnerability.

neuroscience↗

bioRxiv2025

Elucidating Neurodevelopmental Trajectories in Cancer with Topic Modeling: Revealing Persistent External Granule Layer Lineages in Medulloblastoma

Single-cell transcriptomics transformed our understanding of cellular heterogeneity, yet cross-dataset comparison remains fundamentally limited by batch effects, technology differences, and inconsistent annotation frameworks. These challenges have impeded efforts to connect developmental programs with disease states which creates a critical gap for understanding pediatric cancers with suspected developmental origins. Here, we demonstrate that topic modeling, an unsupervised natural language processing technique, overcomes these barriers by learning transferable transcriptional genetic signatures that generalize across datasets, technologies, and biological contexts without requiring data integration. Applying this framework to over one million fetal cerebellar nuclei, we identify seven distinct topics that capture the developmental spectrum of rhombic lip progenitors through external granule layer (EGL) differentiation, including transitional states missed by conventional clustering. These topics transfer successfully across sequencing technologies (SPLiT-seq to sci-RNA-seq3), developmental timepoints, species (human to mouse), and from single-cell to bulk RNA sequencing of 876 medulloblastoma tumors. We reveal that Sonic hedgehog (SHH) medulloblastoma subtypes retain these topics, corresponding to distinct stages of EGL development. Our findings highlight that developmental timing at tumor initiation fundamentally shapes tumor biology, with immediate implications for subtype-specific therapeutic strategies in pediatric brain cancer. Our workflow establishes topic modeling as a scalable solution for mining expanding genomic atlases with broad applications across different datasets, technologies, and biological contexts.

bioinformatics↗

bioRxiv2025

Deciphering the transcriptomic landscape of pyrazinamide resistance in Mycobacterium tuberculosis

Pyrazinamide resistance in Mycobacterium tuberculosis poses a major challenge to tuberculosis management and is primarily linked to pncA mutations, while the broader transcriptional adaptations underlying this resistance remain unclear. In this study, we performed a comparative analysis of the transcriptomic response of a mutant clinical strain and the drug-susceptible laboratory strain H37Rv under PZA exposure and non-exposure conditions. The clinical strain used for this analysis carried a 10-nucleotide deletion mutation in pncA (positions 118-127) that abolished PZA activation, identified in our previous study. The critical drug concentrations were established at 200 {micro}g/mL for the clinical strain (CST) and 12.5 {micro}g/mL for the H37Rv strain (RvT), with the untreated H37Rv strain (UTRv) used as a reference. RNA-sequence profiles from treated and untreated conditions were analyzed to identify differentially expressed genes, followed by functional enrichment, KEGG pathway mapping, and protein-protein interaction network analysis. Analysis revealed 3,413 differentially expressed genes (padj [≤] 0.05), including 1,428 upregulated and 1,360 downregulated genes. Functional enrichment was predominantly detected in CST vs. RvT followed by CST vs. UTRv, whereas no significant enrichment emerged in RvT vs. UTRv, underscoring the mutations dominant influence on the pyrazinamide response. The ribosomal machinery genes rplC, rplD, and rpsH were significantly enriched and strongly upregulated in the mutant strain under treatment but only mildly regulated in the laboratory strain. We observed that several anti-TB drug targets (katG, ethA, atpE, panD) were downregulated, and a few efflux pumps (Rv1258, Rv3008, Rv3756c) were upregulated, reflecting cross-resistance mechanisms. Network analysis identified 19 clusters, and prominent modules comprised polyketide synthases, PDIM synthesis genes, fatty acid {beta}-oxidation enzymes and ESX secretion system. These interconnected modules highlight the metabolic and structural strategies that support persistence under drug pressure. Collectively, our findings link mutation-driven and PZA-induced transcriptomic alterations to adaptive pathways and provide insights into the mechanisms underlying tolerance and potential therapeutic opportunities. Author summaryPyrazinamide is a vital anti-tuberculosis drug, which helps to shorten the treatment duration and while resistance is common, it is not completely understood. Our previous work identified a clinical strain of Mycobacterium tuberculosis that was resistant to pyrazinamide due to a mutation in target gene responsible for drug activity. In this study, we compared the gene expression pattern of this resistant strain with a standard laboratory strain under drug exposure. The resistant strain exhibited distinct gene expression patterns, specifically, the activated genes associated with cell damage repair, lipid biosynthesis for the cell envelope, and ATP maintenance for energy production while it repressed genes that promote dormancy and virulence. Our findings suggest that the resistant strain is actively and metabolically adapts to the drug stress, rather than simply becoming dormant. We also found notable gene alterations in the other anti-tuberculosis drug targets, indicating possible cross resistance with pyrazinamide. Collectively, our findings provide insights into how genetic mutations alter the gene expression of resistant strains that adapt to survive drug exposure.

microbiology↗

bioRxiv2025

Cell wall integrity and elicitor peptide signaling modulate antimicrobial defense in Arabidopsis via jasmonic acid

Plant cell walls constitute dynamic barriers that are essential for defense against pathogens. The receptor kinase THESEUS1 (THE1) monitors cell wall integrity (CWI) and contributes to pathogen resistance in Arabidopsis, but the underlying mechanisms remain unclear. Here we show that THE1-dependent CWI signaling induces accumulation of the antimicrobial metabolite camalexin upon cell wall damage (CWD) caused by cellulose biosynthesis inhibition or fungal infection. CWD alters THE1 plasma membrane nanodomain organization and involves calcium signaling components that modulate camalexin production. Induction of camalexin requires jasmonic acid (JA)-dependent expression of the transcription factors MYB47 and MYB95. In line with its antagonistic function on CWI signaling, the plant elicitor peptide Pep3 suppresses camalexin biosynthesis downstream of THE1 by inhibiting JA-dependent pathways. Our findings reveal a regulatory network where CWI and Pep3 signaling modulate antimicrobial defense via JA-mediated camalexin production. This network requires independent CWD-induced pathways, providing insights into how plants balance defense activation and suppression in response to cell wall stress.

plant biology↗

bioRxiv2025

Preclinical efficacy of combinatorial B7-H3 CAR T cells and ONC206 against diffuse intrinsic pontine glioma

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor affecting over 300 children annually in the United States. Chimeric antigen receptor (CAR) T cells are a targeted immune effector cell therapy with substantial clinical benefit against hematologic cancers. Against CNS tumors, CAR T cells targeting B7-H3, a protein highly expressed on DIPG, have rapidly advanced from preclinical studies to clinical trials. BrainChild-03 (NCT04185038), a phase 1 trial of repeatedly delivered intracerebroventricular (ICV) B7-H3-targeting CAR T cells (B7-H3 CAR T cells), demonstrated tolerability and potential efficacy for children and young adults with DIPG. However, clinical benefits were not uniformly seen, and multi-agent treatment strategies may be required against such an aggressive disease. Here, we combined B7-H3 CAR T cells with ONC206, an imipridone molecule also under clinical investigation. MethodsWe tested B7-H3 CAR T cells combined with ONC206 across multiple DIPG cell cultures and orthotopic xenograft mouse models. ResultsB7-H3 CAR T cell monotherapy induced robust cytotoxicity while ONC206 treatment resulted in significant mitochondrial dysfunction against DMG/DIPG cells. The combination of low effector-to-target ratios of B7-H3 CAR T cells and IC50 concentrations of ONC206 led to significantly enhanced cytotoxicity in vitro (p<0.003) and increased IL-2, IL-29, VEGF-A, and Granzyme B levels. In vivo combinatorial studies of ONC206 and a single ICV dose of B7-H3 CAR T cells significantly extended survival in multiple DIPG xenograft mouse models (p<0.05). ConclusionsB7-H3 CAR T cells combined with ONC206 is a feasible and efficacious multi-agent approach against multiple DIPG models. Importance of the studyDiffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor. While B7-H3 CAR T cells have shown tolerability and potential benefit in early trials, combinatorial regimens may be required for consistent cures against this aggressive disease. This study demonstrates that a preclinical therapeutic regimen of B7-H3 CAR T cells with ONC206, a second-generation imipridone, increases anti-tumor efficacy in vitro and in orthotopic DIPG mouse models. To our knowledge, this is the first study to evaluate ONC206 in combination with CAR T cells. Our findings provide a preclinical roadmap for evaluating small molecules with CAR T cells to interrogate both their combined benefit and the effect of small molecules on T cells themselves. This work offers a biologically-informed, clinically translatable strategy integrating small molecule therapeutics with CAR T cell therapy and support the development of multi-agent immunotherapy trials for children with DIPG and other high-grade brain and spinal cord tumors. Key PointsO_LIB7-H3 CAR T cells are cytotoxic against preclinical DMG models. C_LIO_LIONC206 causes metabolic apoptosis in preclinical DMG models. C_LIO_LIB7-H3 CAR T cells and ONC206 have combinatorial efficacy against DMG. C_LI

cancer biology↗

bioRxiv2025

Mind the Gap: An Embedding Guide to Safely Travel in Sequence Space

We present a hybrid approach combining a protein language model (pLM) with Monte Carlo (MC) sampling for generating enzyme mutants free of mutations deleterious for structural preservation. Given the amino acid sequence of the original enzyme and a set of residues for which the local environment should be conserved, i.e., the catalytic site, our approach generates mutants that differ vastly in the overall sequence while retaining the geometry of the conserved region, thereby representing promising candidates for further experimental screening. Unlike end-to-end deep learning approaches, whose results are harder to interpret and control, the use of a well-established, classic technique such as MC sampling allows us to easily interpret the generative process as the sampling of an energy landscape determined by the pLM. In turn, such an interpretation enables us to steer this generative process and control its outcome by making use of robust statistical mechanics concepts, e.g., temperature, thereby explicitly guaranteeing certain properties of the generated mutants. Given the increasing relevance of generative algorithms in the design and search for novel, optimised enzymes, we believe that our results constitute an important step for the future development of this class of techniques. To facilitate experimental verification, we finally provide hundreds of sequences for 13 different enzymes involved in catalytic processes ranging from carbon dioxide conversion to DNA replication.

synthetic biology↗

bioRxiv2025

Females versus males exhibit greater brain activation in sensorimotor regions during motor imagery after stroke

Motor imagery (MI; the mental rehearsal of movement) activates sensorimotor regions, providing the basis for its effectiveness as an intervention for motor recovery after stroke. Yet, the impact of biological sex on MI-related brain activation after stroke is unexplored. Here, we investigated sex-related differences in MI-related brain activation after stroke and explored associations between questionnaire-based MI ability and MI-related brain activation. Thirty-four individuals with chronic stroke performed MI of a complex, upper-limb movement using their paretic arm/hand. Brain activation was captured using functional magnetic resonance imaging (fMRI). Individual differences in MI ability were also assessed prior to the scan using an established MI questionnaire. MI-related brain activation was observed across sensorimotor regions. Yet, group-level contrasts revealed greater activation in sensorimotor regions for females vs. males, while greater activation in the cerebellar and parietal regions was noted in males vs. females. Females also recruited greater ipsilesional regions vs. males. Questionnaire-based MI ability was associated with brain activation localized to occipital regions. Our findings suggest that females and males may respond differently to MI-based tasks. Further, we did not find a relationship between questionnaire-based data and activity in sensorimotor regions. This finding suggests that multiple measures of MI may be needed to assess its impact. Overall, this work informs the use of MI after stroke.

neuroscience↗

bioRxiv2024

CTPS1 inhibition synergizes with replication stress signaling inhibition in MYC-amplified Group 3 medulloblastoma

MYC-driven medulloblastomas (MBs) represent the most aggressive and deadly subgroup of MB, the most common malignant pediatric brain tumor. Direct targeting of MYC itself remains an unmet clinical need, therefore focusing on vulnerabilities driven by MYC may be a viable option for novel therapeutic interventions. Using whole-genome CRISPR screening, we identified the de novo pyrimidine synthesis enzyme CTP synthase (CTPS1) as a strong dependency in MYC-driven MB. CTPS1 is the final and rate-limiting step in the de novo pyrimidine synthesis pathway. Targeted inhibition of CTPS1 leads to decreased tumor cell proliferation and markedly reduces MYC expression in G3 MB models. Mechanistically, we demonstrate that single agent CTPS1 inhibition activates the replication stress signaling pathway mediated by ATM-CHK2 and ATR-CHK1. Blockade of CHK1 kinase activity increases sensitivity to CTPS1 inhibition and significantly impedes heterotopic MB tumor growth. CTPS1 enzymatic activity requires the amino acid glutamine, therefore we inhibited CTPS1 using the glutamine antagonists, JHU083 and JHU395. These compounds are prodrugs of 6-diazo-5-oxo-L-norleucine (DON) which were developed to exhibit better tumor targeting and enhanced blood-brain barrier penetrability. Combining JHU083 and CHK1 inhibition demonstrates potent synergy against patient-derived MB xenografts in vivo. Our findings strongly suggest that combining de novo pyrimidine synthesis and ATR-CHK1 inhibitors is a promising treatment for MYC-driven MBs. Key PointsO_LICTPS1 is a unique vulnerability in MYC-driven medulloblastoma C_LIO_LICTPS1 inhibition activates the ATR-CHK1 replication stress response pathway for cell survival C_LIO_LIBlockade of CTPS1 enzymatic activity synergizes with CHK1 inhibition in vitro and in vivo C_LI Importance of the StudyMYC hyperactivation in tumors drives multiple anabolic processes which contribute to tumor proliferation and aggressiveness in patients. We show that targeting de novo pyrimidine synthesis (via CTPS1) limits tumor growth and targets MYC itself through a feedback mechanism. CTPS1 inhibition potently combines with CHK1 blockade and enhances disease control in both heterotopic and orthotopic models of medulloblastoma (MB). Our results support the clinical evaluation of combined CTPS1 and CHK1 inhibition in patients with MYC-driven MB.

cancer biology↗

bioRxiv2024

Association of Macular Pigment Density with Plasma Macular Carotenoids levels, And lipids in Indian patients with early Age-Related Macular Degeneration

PurposeThe objective of the present study was to investigate the relationship of macular pigment optical density (MPOD) with plasma carotenoids [(L) and (Z)] and serum lipids in South Indian young healthy volunteers and patients with early AMD. MethodsTwo hundred and fourteen (N= 214) study participants (Healthy control group (N) = 178; Early AMD group (N) = 36) were enrolled after getting their written informed consent. The MPOD of the study participants was assessed using MPS II (Electron Technology, UK) after completing their routine ocular examination. Serum lipids were measured by the standard technique. Plasma levels of L, Z, lycopene and beta-carotene were estimated by HPLC with PDA detector. Statistical analysis usedCorrelations among variables in serum, plasma and the MPOD were established using Spearmans rho correlation coefficient. ResultsThe overall mean MPOD in healthy control group and early AMD group was found to be 0.47 {+/-} 0.16 (N= 178; 317 eyes) and 0.35 {+/-} 0.22 (N=36; 38 eyes) at 1{degrees} eccentricity respectively and was found to be significantly low as compared to healthy control group (p<0.001). A strong positive association was found between plasma L, Z and L+Z and MPOD. Serum HDL showed a strong negative association with MPOD and other lipids showed very weak association. MPOD was unaffected by BMI. ConclusionsMPOD is positively associated with plasma L,Z and L+Z, adding further evidence that additional intake of L/Z may be beneficial in delaying the risk of AMD in our population

pharmacology and toxicology↗

bioRxiv2023

Short N-terminal disordered regions and the proline-rich domain are major regulators of phase transitions for full-length UBQLN1, UBQLN2 and UBQLN4

Highly homologous ubiquitin-binding shuttle proteins UBQLN1, UBQLN2 and UBQLN4 differ in both their specific protein quality control functions and their propensities to localize to stress-induced condensates, cellular aggregates and aggresomes. We previously showed that UBQLN2 phase separates in vitro, and that the phase separation propensities of UBQLN2 deletion constructs correlate with their ability to form condensates in cells. Here, we demonstrated that full-length UBQLN1, UBQLN2 and UBQLN4 exhibit distinct phase behaviors in vitro. Strikingly, UBQLN4 phase separates at a much lower saturation concentration than UBQLN1. However, neither UBQLN1 nor UBQLN4 phase separates with a strong temperature dependence, unlike UBQLN2. We determined that the temperature-dependent phase behavior of UBQLN2 stems from its unique proline-rich (Pxx) region, which is absent in the other UBQLNs. We found that the short N-terminal disordered regions of UBQLN1, UBQLN2 and UBQLN4 inhibit UBQLN phase separation via electrostatics interactions. Charge variants of the N-terminal regions exhibit altered phase behaviors. Consistent with the sensitivity of UBQLN phase separation to the composition of the N-terminal regions, epitope tags placed on the N-termini of the UBQLNs tune phase separation. Overall, our in vitro results have important implications for studies of UBQLNs in cells, including the identification of phase separation as a potential mechanism to distinguish the cellular roles of UBQLNs, and the need to apply caution when using epitope tags to prevent experimental artifacts. Highlights1) Full-length UBQLN1, UBQLN2 and UBQLN4 all exhibit LCST phase transitions but to different degrees. 2) The N-terminal region (N-terminal to the UBL) substantially regulates UBQLN phase separation. 3) Removal of the disease-associated proline-rich (Pxx) region in UBQLN2 removes the strong temperature dependence of UBQLN2 phase separation.

biophysics↗

bioRxiv2023

Fabrication and Characterization of Ceramic-Polymer composite 3D scaffolds and Demonstration of Osteoinductive propensity with gingival Mesenchymal Stem Cells

Bone tissue engineering involves the usage of metals, polymers, and ceramics as the base constituents in the fabrication of various biomaterial 3D scaffolds. Of late, the composite materials facilitating enhanced osteogenic differentiation/regeneration have been endorsed as the ideally suited bone grafts for addressing critical-sized bone defects. Here, we report the successful fabrication of 3D composite scaffolds with collagen type I (Col-I) in conjunction with three different crystalline phases of calcium-phosphate (CP) nanomaterials [hydroxyapatite (HAp), beta-tricalcium phosphate ({beta}TCP), biphasic hydroxyapatite ({beta}TCP-HAp or BCP)], obtained by altering the pH as the major variable. The fabricated 3D scaffolds consisting of [~]70 wt % CP nanomaterials and [~] 30 Wt % of Col-I did mimic the ECM of bone tissue. The different Ca/P ratio and the orientation of CP nanomaterials in CP/Col-I composite scaffolds altered the microstructure, surface area, porosity, and mechanical strength of the scaffolds and also influenced the bioactivity, biocompatibility, and osteogenic differentiation of gingival-derived mesenchymal stem cells (gMSCs). The microstructure of CP/Col-I 3D scaffolds assessed by Micro-CT analysis revealed randomly oriented interconnected pores with pore sizes ranging from 80-250, 125-380, and 100-450{micro}m respectively for {beta}TCP/Col-I, BCP/Col-I, and HAp/Col-I scaffolds. Among these, the BCP/Col-I achieved the highest surface area ([~] 42.6 m2/g) and porosity ([~]85%), demonstrated improved bioactivity and biocompatibility, and promoted osteogenic differentiation of gMSCs. Interestingly, the Ca2+ ions (3 mM) released from scaffolds could also facilitate the osteocyte differentiation of gMSCs sans osteoinduction. Collectively, our study has demonstrated the ECM mimicking biphasic CP/Col-I 3D scaffold as an ideally suited tissue-engineered bone graft.

bioengineering↗

bioRxiv2018

Emergence of a Dengue virus serotype 2 causing the largest ever dengue epidemic in Sri Lanka

BackgroundSri Lanka experienced the largest ever dengue outbreak in year 2017, which coincided with the shift of the predominant circulating dengue virus (DENV) 1 to DENV2 after 9 years. As it was felt that more patients appeared to develop complications and severe dengue, we compared clinical features of patients with acute dengue, with the previous circulating serotype (DENV1) and also sequenced the new virus, to determine the lineage of the virus.\n\nMethodology/Principal findingsWe studied the clinical and laboratory features of 172 adult patients with acute DENV1 (n=79) and DENV2 (n=93) infection. 65 (82.3%) of those with DENV1 and 86 (92.4%) of those with DENV2 were experiencing a secondary infection. The risk of developing dengue haemorrhagic fever (DHF) was significantly higher (=0.005, odds ratio=2.5) in those infected with DENV2 (54.8%) when compared to DENV1(32.9%), even though similar proportions of patients had a secondary dengue infection. Patients with DENV2 infection developed leakage significantly earlier (p<0.0001, median= 3, days) when compared to those with a DENV1 infection (median 5 days) and were more likely to develop significant bleeding and to require blood transfusions. Furthermore, patients with DENV2 were more likely to have significantly lower platelet counts during day 3, 4 and 5 since onset of illness.\n\nWhole genome sequencing showed that these DENV-2 isolates belonged to a cosmopolitan strain and was genetically more distant than the DENV-2 strains that circulated from 1981 to 2004 in Sri Lanka.\n\nConclusions/significanceSince this DENV2 strain appears to cause more severe forms of clinical disease, it would be important to determine variations in the virus genome or other factors that could have contributed to severe disease.\n\nAuthor summarySri Lanka experienced the largest ever dengue outbreak in year 2017, which coincided with the shift of the predominant circulating dengue virus (DENV) 1 to DENV2 after 9 years. We studied the clinical and laboratory features of 172 adult patients with acute DENV1 (n=79) and DENV2 (n=93) infection. The risk of developing dengue haemorrhagic fever was significantly higher (=0.005, odds ratio=2.5) in those infected with DENV2 (54.8%) when compared to DENV1(32.9%), even though similar proportions of patients had a secondary dengue infection. Patients with DENV2 infection developed leakage significantly earlier (p<0.0001, median= 3, days) when compared to those with a DENV1 infection (median 5 days) and were more likely to develop significant bleeding. Whole genome sequencing showed that these DENV-2 isolates belonged to cosmopolitan strain and was genetically more distant to the DENV-2 strains that circulated from 1981 to 2004 in Sri Lanka.

epidemiology↗

bioRxiv2018

Binding Affinity Regression Models from Repeats Mutation in Polyglutamine Disease

Diagnosing and curing neurodegenarative disorder such as spinocerebellar ataxia is complicated when there is differences in formation of protein sequences and structures. Affinity prediction plays vital role to identify drugs for various genetic disorders. Spinocerebellar ataxia occurs but mainly it occurs due to polyglutamine repeats. This research work aims in predicting the affinity of spinocerebellar ataxia from the protein complexes by extracting the well-defined descriptors. Regression models are built to predict the affinity through machine learning techniques coded in python using the Scikit-Learn framework. Energy complexes and protein sequence descriptors are defined and extracted from the complex and sequences. Results show that the SVR is found to predict the affinity with high accuracy of 98% for spinocerebellar ataxia. This paper also deliberates the results of statistical learning carried out with the same set of complexes with various regression techniques.

systems biology↗