Biology subjects

Pal, B.

Publications and source records attributed to Pal, B..

23 records · Page 2Linked to original sources

bioRxiv2020

The KCNQ4-mediated M-current regulates the circadian rhythm in mesopontine cholinergic neurons

The M-current is a voltage gated potassium current inhibited by muscarinic activation and affected by several other G-protein coupled receptors. Its channels are formed by KCNQ subunits, from which KCNQ4 is restricted to certain brainstem structures. We sought evidence for the function of the M-current in the pedunculopontine nucleus (PPN) and the contribution of KCNQ4 subunits to the M-current and aimed to find its functional significance in the PPN. We found that cholinergic inputs of the PPN can effectively inhibit M-current. This current is capable of synchronizing neighboring neurons and inhibition of the M-current decreases neuronal synchronization. We showed that only a subpopulation of cholinergic neurons has KCNQ4-dependent M-current. The KCNQ4 subunit expression potentially regulates the presence of other KCNQ subunits. Deletion of KCNQ4 leads to alterations in adaptation of activity to light-darkness cycles, thus representing the potential role of KCNQ4 in regulation of sleep-wakefulness cycles. The presence of this protein restricted to certain brainstem nuclei raises the possibility that it might be a potential target for selective therapeutic interventions affecting the reticular activating system.

neuroscience↗

bioRxiv2020

Modulation of motor behavior by the mesencephalic locomotor region

The mesencephalic locomotor region (MLR) serves as an interface between higher-order motor systems and lower motor neurons. The excitatory module of the MLR is composed of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), and their activation has been proposed to elicit different modalities of movement, but how the differences in connectivity and physiological properties explain their contributions to motor activity is not known. Here we report that CnF glutamatergic neurons are electrophysiologically homogeneous and have short-range axonal projections, whereas PPN glutamatergic neurons are heterogeneous and maintain long-range connections, most notably with the basal ganglia. Optogenetic activation of CnF neurons produced fast-onset, involuntary motor activity mediated by short-lasting muscle activation. In contrast, activation of PPN neurons produced long-lasting increases in muscle tone that reduced motor activity and disrupted gait. Our results thus reveal a differential contribution to motor behavior by the structures that compose the MLR.

neuroscience↗

bioRxiv2020

Coronavirus activates a stem cell-mediated defense mechanism that accelerates the activation of dormant tuberculosis: implications for the COVID-19 pandemic

We postulate that similar to bacteria, adult stem cells may also exhibit an innate defense mechanism to protect their niche. Here, we provide preliminary data on stem cell based innate defense against a mouse model of coronavirus, murine hepatitis virus-1 (MHV-1) infection. In a mouse model of mesenchymal stem cell (MSC) mediated Mycobacterium tuberculosis (Mtb) dormancy, MHV-1 infection in the lung exhibited 20 fold lower viral loads than the healthy control mice, suggesting the potential enhancement of an anti-MHV-1 defense by Mtb. This defense mechanism involves the in vivo expansion and reprogramming of CD271+MSCs in the lung to an enhanced stemness phenotype. The reprogrammed MSCs facilitate the activation of stemness genes, intracellular Mtb replication, and extracellular release of Mtb. The conditioned media of the reprogrammed MSCs exhibit direct anti-viral activity in an in vitro model of MHV-1 induced toxicity to type II alveolar epithelial cells. Thus, our data suggest that reprogrammed MSCs exert a unique innate defense against MHV-1 by activating dormant Mtb. The molecular details of this anti-viral defense mechanism against coronavirus could be further studied to develop a vaccine against COVID-19.

microbiology↗

bioRxiv2020

ID4 represses myoepithelial differentiation of mammary stem cells through its interaction with HEB

Differentiation of stem cells embedded within the mammary epithelium is orchestrated by lineage-specifying transcription factors. Unlike the well-defined luminal hierarchy, dissection of the basal lineage has been hindered by a lack of specific markers. Inhibitor of Differentiation 4 (ID4) is a basally-restricted helix-loop-helix (HLH) transcription factor essential for mammary development. Here we show that ID4 is highly expressed in basal stem cells and decreases during myoepithelial differentiation. By integrating transcriptomic, proteomic, and ChIP-sequencing data, we reveal that ID4 is required to suppress myoepithelial gene expression and cell fate. We identify the bHLH protein HEB as a direct binding partner of ID4, and describe a previously-unknown role for this regulator in mammary development. HEB binds to E-boxes in regulatory elements of developmental genes, negatively regulated by ID4, involved in extracellular matrix synthesis and cytoskeletal contraction. Together our findings support a model whereby ID4 binds to HEB and blocks it from promoting myoepithelial specialisation. These new insights expand our current understanding into control of myoepithelial differentiation and mammary gland morphogenesis.

developmental biology↗

bioRxiv2020

Dissection of prostate tumour, stroma and immune transcription reveals a key contribution by the microenvironment to disease progression

Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. In this study, the experimental enrichment of selected cell-types and the development of a Bayesian inference model for continuous differential transcript abundance permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

cancer biology↗