Biology subjects

Sood, S.

Publications and source records attributed to Sood, S..

14 recordsLinked to original sources

bioRxiv2026

Leukemic Stem Cell Subtypes Drive Distinct Niche Remodeling in Acute Myeloid Leukemia

Leukemic stem cells (LSCs) sustain acute myeloid leukemia (AML) and are implicated in therapy resistance and relapse. Yet, it remains unknown how LSCs remodel the bone marrow niche. AML is known to alter stromal and vascular microenvironments, but these effects are difficult to separate from bulk leukemic burden and immune inflammation. Here, we use isogenic human AML xenografts with distinct LSC characteristics but comparable engraftment to define LSC-associated niche remodeling in vivo. Single-cell profiling revealed that LSC-high AML shifts the mesenchymal niche toward fibro-inflammatory states, expanding Fmod+ fibroblasts and Cd34+ perivascular fibroblast-like cells while suppressing osteolineage differentiation. The leukemic compartment remained heterogeneous, with a specific MEP-like LSC population expressing niche-remodeling ligands including TGFB1, IL1B, and ANGPT1. LSC-high AML activated a TGF{beta}-responsive, CREB3L1-controlled fibroblast trajectory, and perturbing TGF{beta} signaling or CREB3L1 activation reduced stromal support for AML cells. These findings identify a specific LSC subtype as a source of niche-remodeling cues that shape specialized leukemia-supportive niches.

molecular biology↗

bioRxiv2026

Tracking vaginal microbiome transitions in bacterial vaginosis for cues of antibiotic resilience

BackgroundBacterial vaginosis (BV) is a common and difficult-to-treat vaginal disorder, with significant implications for reproductive health, particularly in low and middle-income countries. Clinical cure based on symptom resolution or Nugent scores often do not correspond to restoration of healthy vaginal microbiome. Factors underlying treatment failure remain poorly defined, warranting the need for understanding post-treatment microbiome dynamics to improve long-term outcomes. ObjectivesTo delineate longitudinal vaginal bacteriome dynamics, integrating microbial composition, transition patterns, and clinical symptoms in a closely followed cohort of women with BV based on treatment outcome. MethodsVaginal swabs from reproductive-age women (18-45 years) were collected and classified as BV-positive ([≥]7) or healthy ([≤]3) using Nugent scoring. BV cases were treated using single-dose secnidazole and followed for three months. Sociodemographic, clinical, and behavioral data were statistically analyzed across groups. Vaginal microbiome composition was assessed using 16S rRNA sequencing, evaluating taxonomic profiles, alpha and beta diversity, differential abundance, and co-occurrence networks. ResultsAntibiotic treatment reduced overall microbial diversity and shifted community composition toward healthy controls, though relapse samples retained higher diversity of BV-associated taxa such as Sneathia, Dialister, and Gardnerella, while no-relapse and control groups showed higher Lactobacillus abundance. Corynebacterium amycolatum appeared protective, while Mycoplasma and Fusobacterium played symptom-specific roles. Microbial network analysis showed denser and more persistent associations in baseline and relapse groups, with Sneathia remaining a central node. ConclusionShort-term symptom resolution in BV does not correspond to full microbial recovery; necessary for long-term remission. Functional traits of resilient taxa like Sneathia, Fannyhessea and Dialister may confer resilience and enable recolonization, undermining long term treatment efficacy.

microbiology↗

bioRxiv2025

Normative high-frequency oscillation phase-amplitude coupling and effective connectivity under sevoflurane

Resective surgery for pediatric drug-resistant focal epilepsy often requires extraoperative intracranial electroencephalography recording to accurately localize the epileptogenic zone. This procedure entails multiple neurosurgeries, intracranial electrode implantation and explantation, and days of invasive inpatient evaluation. There is a need for methods to reduce diagnostic burden and introduce objective epilepsy biomarkers. Our preliminary studies aimed to address these issues by using sevoflurane anesthesia to rapidly and reversibly activate intraoperative phase-amplitude coupling between delta and high-frequency activities, as well as high-frequency activity-based effective connectivity. Phase-amplitude coupling can serve as a proxy for spike-and-wave discharges, and effective connectivity describes the spatiotemporal dynamics of neural information flow among regions. Notably, sevoflurane activated these interictal electrocorticography biomarkers most robustly in areas whose resection led to seizure freedom. However, they were also increased in normative brain regions that did not require removal for seizure control. Before using these electrocorticography biomarkers prospectively to guide resection, we should understand their endogenous distribution and propagation pathways, at different anesthetic stages. In the current study, we highlighted the normative distribution of delta and high-frequency activity phase-amplitude coupling and effective connectivity under sevoflurane. Normative data was derived from nineteen patients, whose ages ranged from four to eighteen years and included eleven males. All achieved seizure control following focal resection. Electrocorticography was recorded at an isoflurane baseline, during stepwise increases in sevoflurane concentration, and also during extraoperative slow-wave sleep without anesthesia. Normative electrode sites were then mapped onto a standard cortical surface for anatomical visualization. Dynamic tractography traced white matter pathways that connected sites with significantly augmented biomarkers. Finally, we analyzed all sites --regardless of normal or abnormal status -- to determine whether sevoflurane-enhanced biomarker values could intraoperatively localize the epileptogenic sites. We found that normative electrocorticography biomarkers increased as a function of sevoflurane concentration, especially in bilateral frontal and parietal lobe regions (Bonferroni-corrected p-values <0.05). Callosal fibers directly connected homotopic Rolandic regions exhibiting elevated phase-amplitude coupling. The superior longitudinal fasciculus linked frontal and parietal association cortices showing augmented effective connectivity. Higher biomarker values, particularly at three to four volume percent sevoflurane, characterized epileptogenicity and seizure-onset zone status (Bonferroni-corrected p-values <0.05). Supplementary analysis showed that epileptogenic sites exhibited less augmentation in delta-based effective connectivity. This study helps clarify the normative distribution of, and plausible propagation pathways supporting, sevoflurane enhanced electrocorticographic biomarkers. Future work should confirm that sevoflurane-activated electrocorticography biomarkers can predict postoperative seizure outcomes in larger cohorts, to establish their clinical utility.

neuroscience↗

bioRxiv2025

Modulation of cellular ageing regulates Integrated Stress Response signalling to control blood cell homeostasis

Organismal ageing is associated with a decline in cellular and molecular functions. One of the hallmarks of ageing is stem cell exhaustion which occurs due to dynamic changes in the stem cell - niche microenvironment. Ageing affects stem cell potency impacting self-renewal and differentiation trajectories. Blood cell homeostasis in the hematopoietic system is tightly regulated by a fine balance between stemness and differentiation. Here, we employ the Drosophila hematopoietic organ, the larval lymph gland (LG) to investigate the impact of modulating cellular ageing on organ homeostasis. LG consists of a Posterior Signalling Center (PSC) that acts as a stem cell niche and maintains the prohemocytes housed in the Medullary Zone (MZ). Cortical Zone (CZ) consists of differentiated hemocytes namely plasmatocytes, crystal cells and lamellocytes. Intricate signalling networks active in the PSC and MZ orchestrate and regulate homeostasis. In this study, we characterize the effect of genetic perturbation of the molecular circuitry of ageing locally and systemically to investigate its effect on LG blood cell homeostasis. Genetic modulation of cellular ageing displays traditional hallmarks of ageing validating our model in the LG. Our results indicate that induction of accelerated ageing both locally and systemically leads to a reduction in stem cell niche size, DNA damage accumulation and increased progenitor differentiation whereas decelerated ageing shows an opposite trend. We show that the Integrated Stress Response (ISR) pathway is activated upon inducing accelerated ageing in the LG hemocytes possibly to recoup back to homeostatic conditions. Furthermore, LGs of ISR pathway mutants or upon perturbation of ISR pathway components in prohemocytes show increased blood cell differentiation indicating disruption of homeostasis. Genetic epistasis analysis shows that ectopic over-expression of ISR pathway genes in an accelerated ageing scenario over and above the existing levels can rescue the defects in blood cell homeostasis. Overall, our study explores how modulation of cellular aging locally or systemically can impact tissue homeostasis. Our research paves way to understand the cellular mechanisms underlying an aged versus young stem cell-niche microenvironment and how its abrogation may lead to onset of disease.

developmental biology↗

bioRxiv2024

Loss of Bicra/Gltscr1 leads to a defect in fetal liver macrophages responsible for erythrocyte maturation in mice.

Key pointsBicra/Gltscr1 homozygous knockout mice are perinatal lethal with aberrant liver resident macrophage gene expression and function. Dysfunctional macrophages result in accumulation of immature nucleated red blood cells in peripheral blood and liver of the knockout mice. GLTSCR1, a protein encoded by the Bicra gene, is a defining subunit of the SWI/SNF (also called mammalian BAF) chromatin remodeling subcomplex called GBAF/ncBAF. To determine the role of GLTSCR1 during mouse development, we generated a Bicra germline knockout mouse using CRISPR/Cas9. Mice with homozygous loss of Bicra were born at Mendelian ratios but were small, pale and died within 24 hours after birth. Histology indicated blood-related defects including defective erythroblastic islands and irregularly sized red blood cells. Gene expression profiling of fetal livers pinpointed a defect in liver resident macrophages involved in the last stage of erythrocyte maturation, resulting in accumulation of nucleated erythrocytes in Bicra-/- pups. Together, these results demonstrate that Bicra is critical for fetal liver macrophage function during development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/618940v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@150ac36org.highwire.dtl.DTLVardef@15a4758org.highwire.dtl.DTLVardef@2176aorg.highwire.dtl.DTLVardef@14f5d49_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual AbstractC_FLOATNO C_FIG

developmental biology↗

bioRxiv2023

Strong immunogenicity & protection in mice with PlaCCine: A COVID-19 DNA vaccine formulated with a functional polymer

DNA- based vaccines have demonstrated the potential as a safe and effective modality. PlaCCine, a DNA-based vaccine approach described subsequently relies on a synthetic DNA delivery system and is independent of virus or device. The synthetic functionalized polymer combined with DNA demonstrated stability over 12 months at 4C and for one month at 25C. Transfection efficiency compared to naked DNA increased by 5-15-fold in murine skeletal muscle. Studies of DNA vaccines expressing spike proteins from variants D614G (pVAC15), Delta (pVAC16), or a D614G + Delta combination (pVAC17) were conducted. Mice immunized intramuscular injection (IM) with pVAC15, pVAC16 or pVAC17 formulated with functionalized polymer and adjuvant resulted in induction of spike-specific humoral and cellular responses. Antibody responses were observed after one immunization. And endpoint IgG titers increased to greater than 1x 105 two weeks after the second injection. Neutralizing antibodies as determined by a pseudovirus competition assay were observed following vaccination with pVAC15, pVAC16 or pVAC17. Spike specific T cell immune responses were also observed following vaccination and flow cytometry analysis demonstrated the cellular immune responses included both CD4 and CD8 spike specific T cells. The immune responses in vaccinated mice were maintained for up to 14 months after vaccination. In an immunization and challenge study of K18 hACE2 transgenic mice pVAC15, pVAC16 and pVAC17 induced immune responses lead to decreased lung viral loads by greater than 90% along with improved clinical score. These findings suggest that PlaCCine DNA vaccines are effective and stable and further development against emerging SARS-CoV-2 variants is warranted.

immunology↗

bioRxiv2023

Single-cell time series analysis reveals the dynamics of in vivo HSPC responses to inflammation

Hematopoietic stem and progenitor cells (HSPCs) are known to respond to acute inflammation; however, little is understood about the dynamics and heterogeneity of these stress responses in HSPCs. Here, we performed single-cell sequencing of HSPCs during the sensing, response and recovery phases of the inflammatory response of HSPCs to treatment with the pro-inflammatory cytokine IFN to investigate the HSPCs dynamic changes during acute inflammation. For the analysis of the resulting datasets, we developed a computational pipeline for single-cell time series. Using a semi-supervised response-pseudotime inference approach, we discover a variety of different gene responses of the HSPCs to the treatment. Interestingly, we were able to associate reduced myeloid differentiation programs in HSPCs with reduced myeloid progenitor and differentiated cells following IFN treatment. Altogether, single-cell time series analysis have allowed us to unbiasedly study the heterogeneous and dynamic impact of IFN on the HSPCs.

cell biology↗

bioRxiv2022

Dynamic cortical and tractography atlases of proactive and reactive alpha and high-gamma activities

Alpha waves - posterior-dominant rhythms at 8-12 Hz reactive to eye opening and closure - are among the most fundamental EEG findings in clinical practice and research since Hans Berger first documented them in the early 20th century. Yet, the exact network dynamics of alpha waves in regard to eye movements remains unknown. High-gamma activity at 70-110 Hz is also reactive to eye movements and a summary measure of local cortical activation supporting sensorimotor or cognitive function. We aimed to build the first-ever brain atlases directly visualizing the network dynamics of eye movement-related alpha and high-gamma modulations, at cortical and white matter levels. We studied 28 patients (age: 5-20 years) who underwent intracranial EEG and electrooculography recordings. We measured alpha and high-gamma modulations at 2,170 electrode sites outside the seizure onset zone, interictal spike-generating areas, and MRI-visible structural lesions. Dynamic tractography animated white matter streamlines modulated significantly and simultaneously beyond chance, on a millisecond scale. Before eye closure onset, significant alpha augmentation occurred at the occipital and frontal cortices. After eye closure onset, alpha-based functional connectivity was strengthened, while high gamma-based connectivity was weakened extensively in both intrahemispheric and interhemispheric pathways involving the central visual areas. The inferior fronto-occipital fasciculus supported the strengthened alpha coaugmentation-based functional connectivity between occipital and frontal lobe regions, whereas the posterior corpus callosum supported the interhemispheric functional connectivity between the occipital lobes. After eye opening offset, significant high gamma augmentation and alpha attenuation occurred at occipital, fusiform, and inferior parietal cortices. High gamma coaugmentation-based functional connectivity was strengthened, whereas alpha-based connectivity was weakened in the posterior interhemispheric and intrahemispheric white matter pathways involving central and peripheral visual areas. Proactive and reactive alpha waves involve extensive, distinct white matter networks that include the frontal lobe cortices, along with low- and high-order visual areas. High-gamma co-attenuation coupled to alpha co-augmentation in shared brain circuitry after eye closure supports the notion of an idling role for alpha waves during eye closure. These dynamic tractography atlases may improve understanding of the significance of EEG alpha waves in assessing the functional integrity of brain networks in clinical practice; they also may help elucidate the effects of eye movements on task-related brain network measures observed in cognitive neuroscience research.

neuroscience↗

bioRxiv2022

Non-rapid eye movement sleep determines resilience to social stress

Resilience, the ability to overcome stressful conditions, is found in most mammals and varies significantly among individuals. A lack of resilience can lead to the development of neuropsychiatric and sleep disorders, often within the same individual. Despite extensive research into the brain mechanisms causing maladaptive behavioral-responses to stress, it is not clear why some individuals exhibit resilience. To examine if sleep has a determinative role in maladaptive behavioral-response to social stress, we investigated individual variations in resilience using a social-defeat model for male mice. Our results reveal a direct, causal relationship between sleep amount and resilience--demonstrating that sleep increases after social-defeat stress only occur in resilient mice. Further, we found that within the prefrontal cortex, a regulator of maladaptive responses to stress, pre-existing differences in sleep regulation predict resilience. Overall, these results demonstrate that increased NREM sleep, mediated cortically, is an active response to social-defeat stress that is both necessary and sufficient for promoting resilience. They also show that differences in resilience are strongly correlated with inter-individual variability in sleep regulation.

neuroscience↗

bioRxiv2022

PBRM1 BD2 and BD4 associate with RNA to facilitate chromatin association

PBRM1 is a subunit of the PBAF chromatin remodeling complex, which is mutated in 40-50% of clear cell renal cell carcinoma patients. It is thought to largely function as a chromatin binding subunit of the PBAF complex, but the molecular mechanism underlying this activity is not fully known. PBRM1 contains six tandem bromodomains which are known to cooperate in binding of nucleosomes acetylated at histone H3 lysine 14 (H3K14ac). Here we demonstrate that the second and fourth bromodomains from PBRM1 also bind nucleic acids, selectively associating with double stranded RNA elements. Disruption of the RNA binding pocket is found to compromise PBRM1 chromatin binding and inhibit PBRM1-mediated cellular growth effects.

biochemistry↗

bioRxiv2021

Spontaneous modulations of high frequency cortical activity

ObjectiveWe clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state. MethodsWe studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hz preceding saccade onset would predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation. ResultsThe whole-brain level dynamic atlas demonstrated transient high-gamma suppression in the striatal region before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%. ConclusionsWe successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortex per se may prepare actively in advance for massive image motion expected during upcoming prolonged saccades. SignificanceMeasuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic. Highlights- The whole-brain level dynamic atlas animated spontaneous high gamma modulations associated with saccadic eye movements. - Preceding high gamma activity in the striatal cortex predicted the direction and duration of the upcoming saccades. - Saccade-related high-gamma modulations localized the stimulation-defined visual cortex with an accuracy of 95%.

neuroscience↗

bioRxiv2021

Naming-related spectral responses predict neuropsychological outcome after epilepsy surgery

This prospective study determined the utility of intracranially-recorded spectral responses during naming tasks in predicting neuropsychological performance following epilepsy surgery. We recruited 65 patients with drug-resistant focal epilepsy who underwent preoperative neuropsychological assessment and intracranial EEG (iEEG) recording. The Clinical Evaluation of Language Fundamentals (CELF) evaluated the baseline and postoperative language function. During extraoperative iEEG recording, we assigned patients to undergo auditory and picture naming tasks. Time-frequency analysis determined the spatiotemporal characteristics of naming-related amplitude modulations, including high gamma augmentation (HGA) at 70-110 Hz. We surgically removed the presumed epileptogenic zone based on the extent of iEEG and MRI abnormalities while maximally preserving the eloquent areas defined by electrical stimulation mapping (ESM). The multivariate regression model incorporating auditory naming-related HGA predicted the postoperative changes in Core Language Score (CLS) on CELF with r2 of 0.37 (p = 0.015) and in Expressive Language Index (ELI) with r2 of 0.32 (p = 0.047). Independently of the effects of epilepsy and neuroimaging profiles, higher HGA at the resected language-dominant hemispheric area predicted a more severe postoperative decline in CLS (p = 0.004) and ELI (p = 0.012). Conversely, the model incorporating picture naming-related HGA predicted the change in Receptive Language Index (RLI) with r2 of 0.50 (p < 0.001). Higher HGA independently predicted a more severe postoperative decline in RLI (p = 0.03). Ancillary regression analysis indicated that naming-related low gamma augmentation as well as alpha/beta attenuation likewise independently predicted a more severe CLS decline. The machine learning-based prediction model, referred to as the boosted tree ensemble model, suggested that naming-related HGA, among all spectral responses utilized as predictors, most strongly contributed to the improved prediction of patients showing a >5-point CLS decline (reflecting the lower 25 percentile among patients). We generated the model-based atlas visualizing sites, which, if resected, would lead to such a CLS decline. The auditory naming-based model predicted patients who developed the CLS decline with an accuracy of 0.80. The model indicated that virtual resection of an ESM-defined language site would have increased the relative risk of the CLS decline by 5.28 (95%CI: 3.47 to 8.02). Especially, that of an ESM-defined receptive language site would have maximized it to 15.90 (95%CI: 9.59-26.33). In summary, naming-related spectral responses predict objectively-measured neuropsychological outcome after epilepsy surgery. We have provided our prediction model as an open-source material, which will indicate the postoperative language function of future patients and facilitate external validation at tertiary epilepsy centers.

neuroscience↗

bioRxiv2020

Four-dimensional tractography animates neural propagations via distinct interhemispheric pathways

ObjectiveTo visualize and validate the dynamics of interhemispheric neural propagations induced by single-pulse electrical stimulation (SPES). MethodsThis methodological study included three patients with drug-resistant focal epilepsy who underwent measurement of cortico-cortical spectral responses (CCSRs) during bilateral stereo-electroencephalography recording. We delivered SPES to 83 electrode pairs and analyzed CCSRs recorded at 268 nonepileptic electrode sites. Diffusion-weighted imaging (DWI) tractography localized the interhemispheric white matter pathways as streamlines directly connecting two electrode sites. We localized and visualized the putative SPES-related fiber activation, at each 1-ms time window, based on the propagation velocity defined as the DWI-based streamline length divided by the early CCSR peak latency. ResultsThe resulting movie, herein referred to as four-dimensional tractography, delineated the spatiotemporal dynamics of fiber activation via the corpus callosum and anterior commissure. Longer streamline length was associated with delayed peak latency and smaller amplitude of CCSRs. The cortical regions adjacent to each fiber activation site indeed exhibited CCSRs at the same time window. ConclusionsOur four-dimensional tractography successfully animated neural propagations via distinct interhemispheric pathways. SignificanceOur novel animation method has the potential to help investigators in addressing the mechanistic significance of the interhemispheric network dynamics supporting physiological function.

neuroscience↗

bioRxiv2018

Genome-wide association study of multiple yield components in a diversity panel of polyploid sugarcane (Saccharum spp.)

Sugarcane (Saccharum spp.) is an important economic crop, contributes up to 80% of sugar and approximately 60% bio-fuel globally. To meet the increased demand for sugar and bio-fuel supplies, it is critical to breed sugarcane cultivars with robust performance in yield components. Therefore, dissection of causal DNA sequence variants is of great importance by providing genetic resources and fundamental information for crop improvement. In this study, we evaluated and analyzed nine yield components in a sugarcane diversity panel consisting of 308 accessions primarily selected from the \"world collection of sugarcane and related grasses\". By genotyping the diversity panel using target enrichment sequencing, we identified a large number of sequence variants. Genome-wide association study between the markers and traits were conducted with dosages and gene actions taken into consideration. In total, 217 non-redundant markers and 225 candidate genes were identified to be significantly associated with the yield components, which can serve as a comprehensive genetic resource database for future gene identification, characterization, and selection for sugarcane improvement. We further investigated runs of homozygosity (ROH) in the sugarcane diversity panel. We characterized 282 ROHs, and found that the occurrence of ROH in the genome were non-random and probably under selection. ROHs were associated with total weight and dry weight, and high ROHs resulted in decrease of the two traits. This study approved that genomic inbreeding has led to negative impacts on sugarcane yield.

genomics↗