Biology subjects

Tiwari, P.

Publications and source records attributed to Tiwari, P..

24 records · Page 2Linked to original sources

bioRxiv2020

Postnatal fluoxetine treatment alters perineuronal net formation and maintenance in the hippocampus

Elevation of serotonin via postnatal fluoxetine (PNFlx) treatment during critical temporal windows is hypothesized to perturb the development of limbic circuits thus establishing a substratum for persistent disruption of mood-related behavior. We examined the impact of PNFlx treatment on the formation and maintenance of perineuronal nets (PNNs), extracellular matrix (ECM) structures that deposit primarily around inhibitory interneurons, and mark the closure of critical period plasticity. PNFlx treatment evoked a significant decline in PNN number, with a robust reduction in PNNs deposited around parvalbumin (PV) interneurons, within the CA1 and CA3 hippocampal subfields at postnatal day 21 in Sprague-Dawley rat pups. While the reduction in CA1 subfield PNN number was still observed in adulthood, we observed no change in colocalization of PV-positive interneurons with PNNs in the hippocampi of adult PNFlx animals. PNFlx treatment did not alter hippocampal parvalbumin, calretinin, or reelin-positive neuron numbers in PNFlx animals at P21 or in adulthood. We did observe a small, but significant increase in somatostatin (SST)-positive interneurons in the DG subfield of PNFlx-treated animals in adulthood. This was accompanied by altered GABA-A receptor subunit composition, increased dendritic complexity of apical dendrites of CA1 pyramidal neurons, and enhanced neuronal activation revealed by increased c-Fos-positive cell numbers within hippocampi of PNFlx-treated animals in adulthood. These results indicate that PNFlx treatment alters the developmental trajectory of PNNs within the hippocampus, raising the possibility of a disruption of critical period plasticity and the establishment of an altered excitation-inhibition balance within this key limbic brain region. Significance StatementClinical and preclinical studies indicate that developmental exposure to fluoxetine programs persistent dysregulation of mood-related behaviors. This is hypothesized to involve the disruption of the normal development of key brain regions, such as the hippocampus that regulate mood behaviors. We show that postnatal exposure to fluoxetine alters hippocampal perineuronal nets (PNNs), extracellular matrix structures that regulate plasticity and mark the closure of critical periods. The decline in PNNs is noted in early postnatal life, and persists into adulthood in specific hippocampal subfields. Adult animals with a history of postnatal fluoxetine exposure exhibit altered numbers of somatostatin interneurons, GABA receptor subunit expression and neuronal activation within the hippocampus. This indicates that postnatal fluoxetine disrupts the normal developmental trajectory of the hippocampus.

neuroscience↗

bioRxiv2020

Limited inhibition of multiple nodes in a driver network blocks metastasis

Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stress-regulated MAP kinase network activity, reducing the output to metastatic transcription factor BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment.

cancer biology↗

bioRxiv2020

Chronic chemogenetic activation of forebrain excitatory neurons in postnatal life evokes long-lasting changes in mood-related behavior

Early adversity is a key risk factor for the development of adult psychopathology, including anxiety, depression and schizophrenia. Rodent models of early adversity program persistent behavioral, molecular, metabolic, and neurophysiological changes. Perturbed signaling via forebrain Gq-coupled neurotransmitter receptors is a common feature across multiple models of early adversity. We addressed whether enhanced Gq-mediated signaling in forebrain excitatory neurons during postnatal life can evoke long-lasting mood-related behavioral changes. Excitatory hM3Dq DREADD-mediated chemogenetic activation of CamKII-positive forebrain excitatory neurons during postnatal life (P2-14) increased anxiety- and despair-like behavior, and evoked sensorimotor gating deficits in adulthood. In contrast, chronic chemogenetic hM3Dq DREADD activation of forebrain excitatory neurons in the juvenile or adult window did not evoke any mood-related behavioral alterations, highlighting the criticality of the postnatal temporal window. The enhanced anxiety-, despair- and schizophrenia-like behavioral changes evoked by chronic chemogenetic activation of forebrain excitatory neurons in postnatal life, was accompanied by an increased cortical and hippocampal metabolic rate of glutamatergic and GABAergic neurons in adulthood. Furthermore, animals with a history of postnatal hM3Dq activation exhibited a decline in the expression of activity-dependent and plasticity-associated markers within the hippocampus, along with perturbed hippocampal excitatory and inhibitory currents in adulthood. These results indicate that Gq signaling mediated activation of forebrain excitatory neurons during the critical postnatal window is sufficient to program altered mood-related behavior, as well as metabolic and neurophysiological changes in forebrain glutamate and GABA systems, recapitulating specific aspects of the consequences of early adversity.

neuroscience↗

bioRxiv2019

Development of a Prediction Model for Incident Atrial Fibrillation using Machine Learning Applied to Harmonized Electronic Health Record Data

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, whose early detection could lead to significant improvements in outcomes through appropriate prescription of anticoagulation. Although a variety of methods exist for screening for AF, there is general agreement that a targeted approach would be preferred. Implicit within this approach is the need for an efficient method for identification of patients at risk. In this investigation, we examined the strengths and weaknesses of an approach based on application of machine-learning algorithms to electronic health record (EHR) data that has been harmonized to the Observational Medical Outcomes Partnership (OMOP) common data model. We examined data from a total of 2.3M individuals, of whom 1.16% developed incident AF over designated 6-month time intervals. We examined and compared several approaches for data reduction, sample balancing (re-sampling) and predictive modeling using cross-validation for hyperparameter selection, and out-of-sample testing for validation. Although no approach provided outstanding classification accuracy, we found that the optimal approach for prediction of 6-month incident AF used a random forest classifier, raw features (no data reduction), and synthetic minority oversampling technique (SMOTE) resampling (F1 statistic 0.12, AUC 0.65). This model performed better than a predictive model based only on known AF risk factors, and highlighted the importance of using resampling methods to optimize ML approaches to imbalanced data as exists in EHRs. Further studies using EHR data in other medical systems are needed to validate the clinical applicability of these findings.

epidemiology↗

bioRxiv2018

Synthetic mRNA expressed Cas13a mitigates RNA virus infections

The emergence of the CRISPR-Cas system as a technology has transformed our ability to modify nucleic acids. Prokaryotes evolved one member of this family, CRISPR-Cas effector, Cas13a, as an RNA-guided ribonuclease that protects them from invading bacteriophages. Here, we demonstrate that Cas13a can be programmed to target eukaryotic viral pathogens, influenza virus A (IVA) and human respiratory syncytial virus (hRSV) in human cells. We designed synthetic mRNA coding for Cas13a, which when guided by CRISPR RNAs (crRNA) to target influenza virus or hRSV RNA, significantly mitigates these infections both prophylactically, therapeutically, and over time. These data demonstrate a possible new class of synthetic mRNA-powered anti-viral interventions.\n\nOne Sentence SummarycrRNA guided Cas13a halts RNA virus infections

molecular biology↗

bioRxiv2018

Metabolically activated macrophages in mammary adipose tissue link obesity to triple-negative breast cancer

Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Macrophages, which accumulate in adipose tissue and are activated during obesity, are an attractive mechanistic link. Here, we show that, during obesity, murine and human mammary adipose tissue macrophages adopt a pro-inflammatory, metabolically- activated (MMe) macrophage phenotype that promotes TNBC stem-like markers and functions, including increased tumorsphere growth in vitro and tumor-initiating potential in vivo. We demonstrate that MMe macrophages release cytokines in an NADPH oxidase 2 (NOX2)-dependent manner that signal through glycoprotein 130 (GP130) on TNBC cells to promote their stem-like properties. Accordingly, deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates the ability of obesity to drive TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue during obesity as a mechanism for promoting TNBC stemness and tumorigenesis.\n\nHIGHLIGHTS Obesity promotes TNBC tumor formation and stemness.\nMammary adipose tissue macrophages are metabolically activated (MMe) in obese mice and humans.\nMMe macrophages in mammary adipose tissue contribute to obesity-induced stemness.\nMMe macrophages promote TNBC stemness through GP130 signaling.

cancer biology↗