Biology subjects

Chawla, A.

Publications and source records attributed to Chawla, A..

27 records · Page 2Linked to original sources

bioRxiv2022

Computer Study of Metric Perturbations Impinging onCoupled Axon Tracts

Metric perturbations are deviations from a homogeneous spacetime background. In this paper, the authors extend an earlier investigation by using high precision computer simulations and show that there is definite impact of metric perturbations, that is, gravitational radiation, on the time-coded information conducted by a tract of neural axons as found in the human central nervous system. O_QD"... the personal self equals the omnipresent, all-comprehending eternal self ... the quintessence of deepest insight into the happenings of the world." - E. Schrodinger, What is Life? C_QD

neuroscience↗

bioRxiv2022

On the Geometry of Interacting Axon Tracts in Relation to Their Functional Properties

It is well known that demyelination associated with multiple sclerosis alters coupling between axons in a diseased nerve tract due to exposure of ion channels. In this work we ask the question whether the presence of electric fields as a coupling mechanism between nerve axons, has any impact on the expected conduction properties of the nerve under focal demyelination. Using an approximate geometry for a bundle of three axons, we allow electric fields generated at a node of Ranvier to influence other nodes of Ranvier on different axons. In order to introduce focal demyelination, we allow a new type of structure, intermediate between a node and an internodal segment. We find that the nerves conduction profiles are different with and without field-based coupling. This is important because it opens up the possibility for an experimental investigation to study whether field-based coupling predominates over current-based coupling. Fields and currents may also be measured using different methods and so there are implications for bio-instrumentation. From a systems perspective, the study is based on a novel equation which allows electric fields to act as sources of current at axons nodes of Ranvier, thereby generating new behaviors from the set of coupled partial differential equations that model the electrodynamics of the nerve. In addition to our simulation study of focal demyelination, we present a justification for a certain geometric W-matrix used in our phenomenological 2019 model. We also provide the first simulations of a tract of tortuous axons, showing the impact of tract tortuosity on conduction velocity. The tortuous model is analyzed geometrically to illustrate the mechanism of synchronization. Finally, this same model is shown to be castable as a learning machine - a formulation that has neuroscience implications.

neuroscience↗

bioRxiv2022

Trade-Offs Between Hepatic Host Defense and Metabolic Programs Underlie Sex-Biased Diseases

Current concepts in evolutionary medicine propose that trade-offs and mismatches with a shifting environment increase disease risk. While biological sex also impacts disease prevalence, contributions of environmental pressures to sex-biased diseases remain unexplored. Here, we show that sex-dependent hepatic programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor BCL6, which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 comes at a cost following dietary excess, resulting in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male fitness during infection, thus establishing a sex-dependent tradeoff between host defense and metabolic systems. We suggest that these tradeoffs, coupled with current environmental pressures, drive metabolic disease in males.

physiology↗

bioRxiv2021

Transcriptomes and metabolism define mouse and human MAIT cell heterogeneity

Mucosal-associated invariant T (MAIT) cells are a subpopulation of T lymphocytes that respond to microbial metabolites. We performed single-cell RNA sequencing and metabolic analyses of MAIT cell subsets in thymus and peripheral tissues from mice and humans to define the heterogeneity and developmental pathway of these innate-like lymphocytes. We show that the predominant mouse subset, which produces IL-17 (MAIT17), and the subset that produces IFN{gamma} (MAIT1), have greatly different transcriptomes and metabolic states in the thymus and periphery. A splenic MAIT subset has a transcriptome similar to circulating lymphocytes, and in mice these also are found in recent thymic emigrants, suggesting partially mature cells emigrate from the thymus. Human MAIT cells are predominantly MAIT1 cells, but have a different metabolism from their mouse counterparts with increased fatty acid uptake and storage. Although mouse and human subsets are similar in thymus, in the periphery they diverge, likely reflecting environmental influences.

immunology↗

bioRxiv2021

Auditory Brainstem Responses in the C57BL/6J Fragile X Syndrome Knockout Mouse Model

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X Syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brainstem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure hearing range, monaural and binaural auditory responses in hemizygous males, homozygous females and heterozygous females compared to wildtype mice. Consistent with previous work we showed no difference in morphological parameters across genotypes or sexes. Male FXS mice had increased threshold for high frequency hearing at 64 kHz compared to wildtype males, while females had no difference in hearing range between genotypes. In contrast, female homozygous FXS mice had decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Lastly, FXS males had increased latency of the binaural interaction component (BIC) at 0 ITD compared to wildtype males. These findings further clarify auditory brainstem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

neuroscience↗

bioRxiv2021

Cell culture-based production of defective interfering influenza A virus particles in perfusion mode using an alternating tangential flow filtration system

Respiratory diseases including influenza A virus (IAV) infections represent a major threat to human health. While the development of a vaccine requires a lot of time, a fast countermeasure could be the use of defective interfering particles (DIPs) for antiviral therapy. IAV DIPs are usually characterized by a large internal deletion in one viral RNA segment. Consequentially, DIPs can only propagate in presence of infectious standard viruses (STVs), compensating the missing gene function. Here, they interfere with and suppress the STV replication and might act "universally" against many IAV subtypes. We recently reported a production system for purely clonal DIPs utilizing genetically modified cells. In the present study, we established an automated perfusion process for production of a DIP, called DI244, using an alternating tangential flow filtration (ATF) system for cell retention. Viable cell concentrations and DIP titers more than 10-times higher than for a previously reported batch cultivation were observed. Further, we investigated a novel tubular cell retention device for its potential for continuous virus harvesting into the permeate. Very comparable performances to typically used hollow fiber membranes were found during the cell growth phase. During the virus replication phase the tubular membrane, in contrast to the hollow fiber membrane, allowed 100% of the produced virus particles to pass through. To our knowledge, this is the first time a continuous virus harvest was shown for a membrane-based perfusion process. Overall, the process established offers interesting possibilities for advanced process integration strategies for next-generation virus particle and virus vector manufacturing. Key pointsO_LIAn automated perfusion process for production of IAV DIPs was established C_LIO_LIDIP titers of 7.40E+9 plaque forming units per mL were reached C_LIO_LIA novel tubular cell retention device enabled continuous virus harvesting C_LI

bioengineering↗

bioRxiv2020

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

systems biology↗

bioRxiv2018

Arterial carboxyhaemoglobin levels in children admitted to PICU: a retrospective observational study

While carbon monoxide (CO) is considered toxic, low levels of endogenously produced CO are protective against cellular injury induced by oxidative stress. Carboxyhaemoglobin (COHb) levels have been associated with outcomes in critically ill adults. We aimed to describe the distribution of carboxyhaemoglobin in critically ill children and the relationship of these levels with clinical outcomes. This retrospective observational study was conducted at a large tertiary paediatric intensive care unit (PICU). We included all children admitted to the PICU over a two-year period who underwent arterial blood gas analysis. We measured the following: Population and age-related differences in COHb distribution; (ii) Change in COHb over the first week of admission using a multi-level linear regression analysis; (ii) Uni- and multivariable relationships between COHb and length of ventilation and PICU survival. Arterial COHb levels were available for 559/2029 admissions. The median COHb level was 1.20% (IQR 1.00-1.60%). Younger children had significantly higher COHb levels (p-value <2 x 10-16). Maximum Carboxyhaemoglobin was associated with survival 1.67 (95% CI 1.01-2.57, p-value=0.02) and length of ventilation (odds ratio 5.20, 95% CI 3.07-7.30, p-value 1.8 x 10-6) following multi-variable analysis. First measured and minimum COHb values were weakly associated with length of ventilation, but not survival. In conclusion, children have increased COHb levels in critical illness, which are greater in younger children. Higher COHb levels are associated with longer length of ventilation and death in PICU. This is likely to reflect increased oxidative stress.

physiology↗

bioRxiv2018

Copy number variants in clinical WGS: deployment and interpretation for rare and undiagnosed disease

PurposeCurrent diagnostic testing for genetic disorders involves serial use of specialized assays spanning multiple technologies. In principle, whole genome sequencing (WGS) has the potential to detect all genomic mutation types on a single platform and workflow. Here we sought to evaluate copy number variant (CNV) calling as part of a clinically accredited WGS test.\n\nMethodsUsing a depth-based copy number caller we performed analytical validation of CNV calling on a reference panel of 17 samples, compared the sensitivity of WGS-based variants to those from a clinical microarray, and set a bound on precision using orthogonal technologies. We developed a protocol for family-based analysis, annotation, filtering, visualization of WGS based CNV calls, and deployed this across a clinical cohort of 79 rare and undiagnosed cases.\n\nResultsWe found that CNV calls from WGS are at least as sensitive as those from microarrays, while only creating a modest increase in the number of variants interpreted (~10 CNVs per case). We identified clinically significant CNVs in 15% of the first 79 cases analyzed. This pipeline also enabled identification of cases of uniparental disomy (UPD) and a 50% mosaic trisomy 14. Directed analysis of some CNVs enabled break-point level resolution of genomic rearrangements and phasing of de-novo CNVs.\n\nConclusionRobust identification of CNVs by WGS is possible within a clinical testing environment, and further developments will bring improvements in resolution of smaller and more complex CNVs.

genomics↗