Biology subjects

Mani, R.

Publications and source records attributed to Mani, R..

6 recordsLinked to original sources

bioRxiv2026

Genomic Characterization and Therapeutic Potential of the Lytic Bacteriophage Curly against Klebsiella pneumoniae in Human Innate Immune Cells and a Murine Pneumonia Model

Klebsiella pneumoniae is an important cause of severe respiratory and systemic infections, and the increasing prevalence of multidrug-resistant strains has created an urgent need for alternative antibacterial strategies. In this study, nine K. pneumoniae-infecting bacteriophages isolated from diverse environmental sources were characterized genomically and functionally. Genome analyses revealed substantial genomic and proteomic diversity among the isolates. Functional screening against the clinical K. pneumoniae isolate JJD85 identified Curly as the most active phage, producing the highest plaque-forming titer and rapid suppression of bacterial growth in liquid culture. Curly was predicted to have a virulent lifestyle and encoded structural, genome-packaging, and DNA replication-associated proteins. In primary human monocyte-derived macrophage cultures, Curly markedly reduced bacterial burden in both cell-associated and cell-free fractions, while treatment of primary human neutrophil cultures produced an approximately 10^6-fold reduction in total recoverable bacterial burden. Transmission electron microscopy demonstrated phage-like particles within bacterial profiles located in both extracellular and macrophage-associated intracellular compartments. In a C57BL/6J murine pneumonia model, intranasal Curly treatment reduced pulmonary bacterial burden in a dose-associated manner, with approximately 10-fold and 100-fold reductions at the low and high doses, respectively. Curly treatment also attenuated infection-associated lung inflammation and preserved pulmonary architecture. These findings identify Curly as a promising bacteriophage candidate against K. pneumoniae and support further evaluation of its host range, resistance profile, and therapeutic potential.

microbiology↗

bioRxiv2026

Leptospirosis in Southern Sea Otters from Central California: Detection of Fatal Infections and Pathologic Findings

Leptospira interrogans serovar Pomona infections cause periodic outbreaks among California sea lions (CSL; Zalophus californianus) and sporadic deaths in phocids; however, frequency of infection and associated health impacts are uncharacterized among sympatric threatened southern sea otters (SSO; Enhydra lutris nereis), which are important sentinels of coastal health. Given the broad impacts of L. interrogans on other marine mammals, our objective was to screen selected SSO for infection, determine whether leptospirosis contributes to SSO mortality, and describe leptospiral-associated lesions. A retrospective review (2005-2025) yielded 19 candidates that underwent case review, including Leptospira immunohistochemistry (IHC), serology, and polymerase chain reaction (PCR), with a special focus on renal and hepatic lesions. Kidney was PCR-positive for 74% (14/19) of suspected cases and for eight of these, DNA sequence-based serogroup typing detected L. interrogans serogroup Pomona. Seven of the 14 PCR-positive leptospirosis cases were classed as fatal based on positive renal IHC and moderate to severe tubulointerstitial nephritis. All fatal cases had anti-L. interrogans serovar Pomona antibody titers [≥]1:25,600. All remaining (n=7) PCR-positive cases were considered nonfatal leptospirosis cases due to minimal and/or unrelated renal lesions, and negative IHC. Nonfatal Leptospira-infected cases ranged from seronegative to low positive (1:400) for serovar Pomona. Antibody titers for Leptospira PCR-negative cases were negative. For fatal cases, gross renal changes were often inapparent or characterized by miliary white cortical foci. Renal histologic lesions included tubulointerstitial nephritis, acute tubular necrosis and suppurative tubulitis with intratubular bacteria in fatal cases, and positive IHC staining for leptospiral antigen in lesions. Gross hepatic changes were also inapparent in fatal cases and histologic lesions were rare, characterized in one animal by hepatocellular disassociation and in two sea otters by limited leptospiral antigen detection by IHC. Most Leptospira-infected sea otters (71%, 10/14) stranded during higher rainfall months in California, suggesting possible land-to-sea transmission from terrestrial hosts. Given these findings, and because L. interrogans serovar Pomona infections have been confirmed in sympatric CSLs and terrestrial mammals from adjacent watersheds, focused investigation of potential marine and terrestrial disease transmission dynamics could provide new information to reduce mortalities of SSO.

pathology↗

bioRxiv2025

Integrating Genomics into Multimodal EHR Foundation Models

AO_SCPLOWBSTRACTC_SCPLOWThis paper introduces an innovative Electronic Health Record (EHR) foundation model that integrates Polygenic Risk Scores (PRS) as a foundational data modality, moving beyond traditional EHR-only approaches to build more holistic health profiles. Leveraging the extensive and diverse data from the All of Us (AoU) Research Program, this multimodal framework aims to learn complex relationships between clinical data and genetic predispositions. The methodology extends advancements in generative AI to the EHR foundation model space, enhancing predictive capabilities and interpretability. Evaluation on AoU data demonstrates the models predictive value for the onset of various conditions, particularly Type 2 Diabetes (T2D), and illustrates the interplay between PRS and EHR data. The work also explores transfer learning for custom classification tasks, showcasing the architectures versatility and efficiency. This approach is pivotal for unlocking new insights into disease prediction, proactive health management, risk stratification, and personalized treatment strategies, laying the groundwork for more personalized, equitable, and actionable real-world evidence generation in healthcare.

bioinformatics↗

bioRxiv2019

Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform specific start-loss mutations of essential genes can cause genetic diseases

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early onset, therapy resistant seizures and developmental delay. Here we report on 12 individuals from 10 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly and visual disturbance. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A>G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in brain cell types, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modelled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE. Importantly, it also shows that isoform specific start-loss mutations causing expression loss of a tissue relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.

genetics↗

bioRxiv2019

Injectable nanoclay gels for angiogenesis

The retention and sustained activity of therapeutic proteins at delivery sites are goals of regenerative medicine. Vascular endothelial growth factor (VEGF) has significant potential in promoting the growth and regeneration of blood vessels but is intrinsically labile. This is exacerbated by the inflammatory microenvironments at sites requiring regeneration. For VEGF to be efficacious it may require a carrier that stabilises it, protects it from degradation and retains it at a site of interest. In this study we tested the hypothesis that injectable nanoclay gels composed of Laponite XLG can stabilise VEGF and retain it in active form for therapeutic delivery. To achieve this, VEGF was incorporated in Laponite gels and its activity tested at a range of concentrations using in vivo cell culture tubulogenesis assays and in vivo angiogenesis assays. We found that VEGF-Laponite gels enhanced tubulogenesis in a dose-dependent manner in vivo. When administered subcutaneously in vivo Laponite was retained at an injection site for up to a period of three weeks and promoted a 4-fold increase in blood vessel formation compared with alginate or vehicle controls as confirmed by CD31 staining. Notably, in contrast to alginate, Laponite gels did not release VEGF, indicating a strong interaction between the growth factor and the nanoclay, and suggesting that Laponite enhancement of VEGF efficacy is due to its retention at an implantation site over a prolonged period. Our approach provides a robust method for delivery of bioactive recombinant VEGF without the necessity for complex hydrogel or protein engineering.

bioengineering↗

bioRxiv2018

Reading eye movements in traumatic brain injury

BackgroundThe aim of our study was to measure the reading eye movements in subjects with traumatic brain injury using ReadAlyzer. ReadAlyzer is an objective eye movement recording device that tracks the eye movements while reading.\n\nMethodsReading eye movements were measured using ReadAlyzer in 30 subjects with traumatic brain injury (mild, moderate and severe) who had binocular vision and reading related symptoms and 60 asymptomatic controls.\n\nResultsThere was a significant decrease in reading eye movement parameters in subjects with traumatic brain injury compared to controls. Reading eye movement parameters were represented in median (IQR). Subjects with traumatic brain injury presented with an increased number of fixations/100 words: 137 (106-159) and regressions/100 words: 24 (12-36), and reduced reading rate 154 (128-173) words per minute. They also had a lesser grade level equivalent: 4.0 (3.0-7.0) and reduced comprehension: 70 (60-80) percentage (Mann-Whitney U test, p<0.05). Reading eye movement parameters were significantly affected in mild and moderate-severe traumatic brain injury subjects compared to controls (Kruskal-Wallis test, p<0.05).\n\nConclusionReading eye movement performance using ReadAlyzer was found to be decreased in traumatic brain injury. Reading assessment may serve as a clinical measure to understand the oculomotor system due to traumatic brain injury.

neuroscience↗