Potential Channels Research Articles

The intergenerational effects of requiring unemployment benefit recipients to engage in non-search activities

We use a quasi-experimental design and national administrative data to analyze the intergenerational effects of introducing non-search activity requirements for long-term unemployment benefit recipients aged 18–34. The young-adult children of these recipients were in early adolescence when the requirements were introduced. Using a regression discontinuity approach, we find that young adults, particularly men, whose fathers were subject to the requirements have a lower incidence of unemployment benefit receipt compared to those whose fathers were not. More detailed investigation suggests completion of the mandated activities, role modeling, changes in attitudes, improved health, and greater support and stability as potential channels.

Design, In silico Screening, Synthesis, Characterisation and DFT-based Electronic Properties of Dihydropyridine-based Molecule as L-type Calcium Channel Blocker.

People of all nationalities and social classes are now affected by the growing issue of hypertension. Over time, there has been a consistent rise in the fatality rate. A range of therapeutic compounds, on the other hand, are often used to handle hypertension. The objectives of this study are first to design potential antihypertensive drugs based on the DHP scaffold, secondly, to analyse drug-likeness properties of the ligands and investigate their molecular mechanisms of binding to the model protein Cav1.2 and finally to synthesise the best ligand. Due to the lack of 3D structures for human Cav1.2, the protein structure was modelled using a homology modelling approach. A protein-ligand complex's strength and binding interaction were investigated using molecular docking and molecular dynamics techniques. DFT-based electronic properties of the ligand were calculated using the M06-2X/ def2- TZVP level of theory. The SwissADME website was used to study the ADMET properties. In this study, a series of DHP compounds (19 compounds) were properly designed to act as calcium channel blockers. Among these compounds, compound 16 showed excellent binding scores (-11.6 kcal/mol). This compound was synthesised with good yield and characterised. To assess the structural features of the synthesised molecule quantum chemical calculations were performed. Based on molecular docking, molecular dynamics simulations, and drug-likeness properties of compound 16 can be used as a potential calcium channel blocker.

Generation of two isogenic human iPSC lines (ZIPi013-B-1, ZIPi013-B-2) carrying a CRISPR/Cas9-mediated deletion of TRPM4

Two isogenic hiPSC lines, ZIPi013-B-1 and ZIPi013-B-2, were generated by CRISPR/Cas9-mediated indels in the TRPM4 gene of the previously published ZIPi013-B. TRPM4 belongs to the evolutionarily conserved family of transient receptor potential (TRP) channels. It is expressed ubiquitously and its activity is regulated by intracellular calcium binding, changes in membrane potential, phosphoinositide lipids in the plasma membrane and the local concentration of cytoplasmic ATP and ADP. TRPM4 has been implicated in various diseases, including neurological and immune system disorders, cardiac diseases and cancer. Both new cell lines offer the opportunity to model human diseases and test therapeutic modalities addressing these

Porcine transient receptor potential channel 1 promotes adipogenesis and lipid deposition

Adipose tissue, an important organ involved in energy metabolism and endocrine, is closely related to animal meat quality and human health. Transient receptor potential channel 1 (TRPC1), an ion transporter, is adipocytes’ major Ca2+ entry channel. However, its function in fat deposition is poorly understood, particularly in pigs, which are both an ideal model for human obesity research and a primary meat source for human diets. In the present investigation, our findings demonstrate a prominent expression of TRPC1 within the adipose tissue of pigs with a strong fat deposition ability. Functional analysis showed that TRPC1 promotes primary preadipocyte proliferation and adipogenic differentiation. In vivo, transgenic mice expressing porcine TRPC1 (Tg-pTRPC1) exhibited aggravated high-fat diet-induced obesity, hepatic steatosis, and insulin resistance. Moreover, TRPC1 may facilitate adipogenesis via activating PI3K/AKT and β-catenin signaling pathways. Our research underscores the pivotal role of porcine TRPC1 as a positive regulator in adipogenesis and lipid accumulation processes, providing a potential target for improving animal meat quality and treating obesity-related diseases in humans.

Emerging roles of mechanosensitive ion channels in ventilator induced lung injury: a systematic review

BackgroundThe pathogenetic mechanisms of ventilator-induced lung injury (VILI) still need to be elucidated. The mechanical forces during mechanical ventilation are continually sensed and transmitted by mechanosensitive ion channels (MSICs) in pulmonary endothelial, epithelial, and immune cells. In recent years, MSICs have been shown to be involved in VILI.MethodsA systematic search across PubMed, the Cochrane Library, Web of Science, and ScienceDirect was performed from inception to March 2024, and the review was conducted in accordance with PRISMA guidelines. The potential eligible studies were evaluated by two authors independently. Study characteristics, quality assessment, and potential mechanisms were analyzed.ResultsWe included 23 eligible studies, most of which were performed with murine animals in vivo. At the in vitro level, 52% and 48% of the experiments were conducted with human or animal cells, respectively. No clinical studies were found. The most reported MSICs include Piezo channels, transient receptor potential channels, potassium channels, and stretch-activated sodium channels. Piezo1 has been the most concerned channel in the recent five years. This study found that signal pathways, such as RhoA/ROCK1, could be enhanced by cyclic stretch-activated MSICs, which contribute to VILI through dysregulated inflammation and immune responses mediated by ion transport. The review indicates the emerging role of MSICs in the pathogenesis of VILI, especially as a signal-transmitting link between mechanical stretch and pathogenesis such as inflammation, disruption of cell junctions, and edema formation.ConclusionsMechanical stretch stimulates MSICs to increase transcellular ion exchange and subsequently generates VILI through inflammation and other pathogeneses mediated by MSICs signal-transmitting pathways. These findings make it possible to identify potential therapeutic targets for the prevention of lung injury through further exploration and more studies.Systematic review registrationhttps://inplasy.com/inplasy-2024-10-0115/, identifier INPLASY2024100115.

Chronic Hypobaric Hypoxia Stimulates Differential Expression of Cognitive Proteins in Hippocampal Tissue.

Objective: We aimed to determine changes in cognitive function resulting from chronic hypobaric hypoxia through proteomic analysis of hippocampal tissue. We screened cognition-related proteins to provide ideas and directions that could help prevent and treat hypoxia-associated cognitive impairment. Methods: We analyzed hippocampal tissues from mice exposed to high altitudes and control mice using 4 D label-free quantitative proteomics. The data were analyzed by protein quantitative analysis, functional annotation, differential protein screening, clustering analyses, and functional classification and enrichment. Differential protein expression was investigated using targeted quantitative omics based on parallel response monitoring. Results: We identified and quantified 20 target proteins in 12 samples, of which 18 were significant validated proteins that were or might be related to cognitive functions. Signaling pathways that were significantly enriched in differentially expressed proteins were pyrimidine metabolism, 5'-Adenosine Triphosphate-activated protein kinase signaling, phospholipase D signaling, purine metabolism, inflammatory mediator regulation of transient receptor potential channels, hedgehog signaling pathways, dilated cardiomyopathy, platelet activation, insulin resistance, mRNA surveillance pathways, drug metabolism-other enzymes, and drug metabolism-cytochrome P450. Conclusion: Chronic hypoxia alters protein expression in murine hippocampal tissues. Eighteen differentially expressed cognition-related proteins might be related to cognitive impairment in mice exposed to chronic high-altitude hypoxia.

The unintended consequences of targeted poverty alleviation: Evidence from China

This study examines the effect of corporate targeted poverty alleviation (TPA) activities endorsed by Chinese governments on audit outcomes. We find that firms engaging in TPA activities are less likely to receive modified audit opinions (MAOs) relative to those without TPA activities and more TPA investments induce less MAO issuance, documenting an unintentional beneficial consequence of TPA. These findings are robust to a battery of sensitivity tests, including addressing endogeneity issues and ruling out the alternative explanation. Our cross-sectional results show that the negative relation between TPA and MAOs is more significant for firms audited by non-industry specialists and short-tenure auditors, non-state-owned enterprises (non-SOEs), and labor-intensive firms. We perform the mediation analyses and identify three potential channels- improved operating performance, enhanced information disclosure quality, and elevated reputation- through which TPA engagements influence the likelihood of receiving MAOs. Moreover, we find industrial development TPA has a more pronounced effect on audit outcomes due to its positive impact on firms’ business operations. Overall, our research documents an unintended consequence of firms’ TPA initiatives in mitigating audit risk. As a vital facet of policy-oriented CSR, TPA engagements exhibit unique characteristics compared to other CSR perspectives. Given its economic relevance and political features, our study contributes to this stream of research and offers implications for TPA initiatives.

The Roles of Transient Receptor Potential (TRP) Channels Underlying Aberrant Calcium Signaling in Blood-Retinal Barrier Dysfunction.

The inner blood-retinal barrier (iBRB) protects the retinal vasculature from the peripheral circulation. Endothelial cells (ECs) are the core component of the iBRB; their close apposition and linkage via tight junctions limit the passage of fluids, proteins, and cells from the bloodstream to the parenchyma. Dysfunction of the iBRB is a hallmark of many retinal disorders. Vascular endothelial growth factor (VEGF) has been identified as the primary driver leading to a dysfunctional iBRB, thereby becoming the main target for therapy. However, a complete understanding of the molecular mechanisms underlying iBRB dysfunction is elusive and alternative therapeutic targets remain unexplored. Calcium (Ca2+) is a universal intracellular messenger whose homeostasis and dynamics are dysregulated in many pathological disorders. Among the extensive components of the cellular Ca2+-signaling toolkit, cation-selective transient receptor potential (TRP) channels are broadly involved in cell physiology and disease and, therefore, are widely studied as possible targets for therapy. Albeit that TRP channels have been discovered in the photoreceptors of Drosophila and have been studied in the neuroretina, their presence and function in the iBRB have only recently emerged. Within this article, we discuss the structure and functions of the iBRB with a particular focus on Ca2+ signaling in retinal ECs and highlight the potential of TRP channels as new targets for retinal diseases.

Transient Receptor Potential Channels in Vascular Mechanotransduction.

Transmural pressure and shear stress are mechanical forces that profoundly affect the smooth muscle cells (SMCs) comprising the vascular wall and the endothelial cells (ECs) lining the lumen. Pressure and flow are detected by mechanosensors in these cells and translated into appropriate responses to regulate blood pressure and flow. This review focuses on the role of the transient receptor potential (TRP) superfamily of cation channels in this process. We discuss how specific members of the TRP superfamily (TRPC6, TRPM4, TRPV1, TRPV4, and TRPP1) regulate the resting membrane and intracellular Ca2+ levels in SMCs and ECs to promote changes in vascular tone in response to intraluminal pressure and shear stress. Although TRP channels participate in vascular mechanotransduction, little evidence supports their intrinsic mechanosensitivity. Therefore, we also examine the evidence exploring the force-sensitive signal transduction pathways acting upstream of vascular TRP channels. Understanding the interplay between mechanosensors, force-induced signaling cascades, and TRP channels holds promise for the development of targeted therapies for diseases caused by vascular dysfunction.

Bank Financial Distress and Stock Price Crashes: A Quasi‐Experimental Approach

ABSTRACTUsing 118,292 US bank‐month observations, we examine the effects of short‐term changes in bank's financial distress on stock price crash risk. There is a significant positive association between short‐term changes in distress on stock price crash risk. The results remain consistent across alternative measures of distress and crash risk. We confirm robustness by employing additional tests for reverse causality and propensity score matching. We find opacity, proxied by discretionary loan‐loss provisions to be a potential channel through which increase in distress affects future crash risk. Our study underscores the critical association between increasing financial distress, loan‐loss reporting, and crash risk.

Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components.

Brown and beige adipocytes utilize a variety of substrates for cold-induced thermogenesis, contributing to the clearance of metabolites in circulation and, consequently, metabolic health. Food-derived compounds that exhibit agonistic activity at temperature-sensitive transient receptor potential channels may serve as cold mimics to elicit thermogenesis and substrate utilization in brown adipose tissue (BAT). In addition to fatty acids and glucose, branched-chain amino acids (BCAAs), which are essential amino acids obtained from foods, are actively catabolized in BAT through mitochondrial BCAA carrier (MBC). The relative contribution of BCAAs to fueling the tricarboxylic acid cycle as a substrate (i.e., anaplerosis) is estimated to be relatively small, yet BCAA catabolism in BAT exerts a critical role in systemic insulin sensitivity. The nature of this apparent tension remained unclear until the recent discovery that active BCAA catabolism in BAT through MBC is critical for the synthesis of metabolites such as glutathione, which is delivered to the liver to improve hepatic insulin sensitivity through redox homeostasis. Novel mechanistic insights into the control of BAT function and systemic metabolism reveal the therapeutic potential of food-derived compounds for improving metabolic flexibility and insulin sensitivity.

Information and communication technology and female employment in India

We revisit the issue of declining female labour force participation in India by investigating the role of information and communication technology (ICT) adoption. Given that ICT has been rapidly penetrating in India in the past few decades, we explore the impact of ICT ownership and use on female labour market behaviour. We use a nationally representative survey, the India Human Development Survey and estimate instrumental variable regression models and find that ICT adoption increases the likelihood of female employment. Our results show that the positive impact of ICT adoption is limited to individuals who are salaried or are self-employed. Further, we find that ICT adoption increases (decreases) the likelihood of entry into (exit from) the labour market. We contrast our analysis by comparing it with male employment and find evidence of differential impact of ICT adoption. Finally, we find that the effect is limited to women with relatively higher levels of education and those belonging to relatively higher income households. We investigate the potential channels that could drive our results and find that women who adopt ICT have more flexible work options where they spend lesser time to travel to work, have a higher autonomy in work related decisions and a higher willingness to enter the workforce. Thus, ICT adoption by reducing information asymmetries in the labour market could increase female labour market participation.

Abstract PR010: TRPV1+ sensory innervation as a novel driver of ovarian cancer progression

Abstract Introduction: A primary challenge currently faced in ovarian cancer (OVCA) treatment is that patient prognoses remain poor despite current therapeutic interventions. Overall survival for OVCA patients with advanced disease is <30%, and most patients recur within 5 years. As such, there is a critical need for new therapies that can overcome OVCA chemoresistance and produce meaningful increases in patient survival. Recent efforts that have targeted the tumor microenvironment (TME), such as immune checkpoint inhibitors, have been successful in some cancers but have limited therapeutic benefit when used to treat OVCA. Thus, new TME targeting therapies must be developed to effectively treat OVCA patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains a gap in knowledge. Here we show that Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer progression. Methods: We performed IHC staining to determine the extent of TRPV1+ nerve infiltration in OVCA vs normal reproductive tissue in patients. We examined the ability of OVCA cells to promote tumor innervation using a neurite outgrowth assay. We utilized both syngeneic and patient derived xenograft (PDX) mouse models of ovarian cancer metastasis, where mouse or human OVCA cells were injected intraperitoneally, to explore the functional role of TRPV1+ sensory nerves in OVCA. TRPV1+ sensory nerves were ablated genetically using TRPV1 driven expression of diphtheria toxin alpha (DTA) or chemically using resiniferatoxin. TRPV1+ sensory nerves were activated pharmacologically using capsaicin. Results: Analysis of patient samples showed that TRPV1+ sensory innervation is much higher in ovarian tumors vs benign reproductive tissue. We found that conditioned media from OVCA cells was able to promote neurite outgrowth of dissociated mouse sensory neurons. Ablation of TRPV1+ sensory nerve fibers in vivo caused reduced tumor burden and prolonged survival in our syngeneic and PDX OVCA mouse models. Stimulation of TRPV1+ sensory nerves with capsaicin accelerated OVCA growth and decreased survival in tumor bearing mice. Conclusions: Our results establish TRPV1+ sensory innervation as a novel driver of OVCA growth/metastasis and a potential therapeutic target for OVCA treatment. Significance to tumor microenvironment field: Our data add to a growing body of evidence that sensory nerves are pro-tumorigenic in multiple cancer types and could be therapeutically targeted for cancer treatment. Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Jamie Moon, Dave S.B. Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. TRPV1+ sensory innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR010.

HERGBoost: A gradient boosting model for quantitative IC50 prediction of hERG channel blockers

The human ether-a-go-go-related gene (hERG) potassium channel is pivotal in drug discovery due to its susceptibility to blockage by drug candidate molecules, which can cause severe cardiotoxic effects. Consequently, identifying and excluding potential hERG channel blockers at the earliest stages of drug development is crucial. Most traditional machine learning models predict a molecule's cardiotoxicity or non-cardiotoxicity typically at 10 μM, which doesn't account for compounds with low IC50 values that are non-toxic at therapeutic levels due to their high effectiveness at lower concentrations. To address the need for more precise, quantitative predictions, we developed hERGBoost, a cutting-edge machine learning model employing a gradient-boosting algorithm. This model demonstrates superior accuracy in predicting the IC50 of drug candidates. Trained on a specially curated dataset for this study, hERGBoost not only exhibited excellent performance in external validation, achieving an R2 score of 0.394 and a low root mean square error of 0.616 but also significantly outstripped previous models in both qualitative and quantitative assessments. Representing a notable leap forward in the prediction of hERG channel blockers, the hERGBoost model and its datasets are freely available to the drug discovery community on our web server at. http://ssbio.cau.ac.kr/software/hergboost This resource promises to be invaluable in advancing safer pharmaceutical development.

Are there “Ratatouille” restaurants? On anticorrelation of food quality and hygiene

We study the empirical relationship between restaurants’ hygiene standards and their food quality scores, as evaluated by professional reviewers. By using data from the UK high-end restaurants, we show that this relationship is negative, observed across several econometric specifications and food quality measurements. We report that 3% of Michelin-starred restaurants have poor hygiene, while the same is true for 2.5% of high-end guidebook-listed restaurants in our dataset. We highlight two possibilities for this observed negative association: a strategic hypothesis (capturing restaurants’ choices trading off hygiene for quality), and a selection hypothesis (reflecting restaurants’ differential survival rates under competition). Our results indicate that the latter has more support. Our findings also illuminate potential channels through which the anticorrelation between hygiene and food quality could be mitigated and can be informative for hygiene inspectors in order to prioritize restaurants in their inspection schedule based on observable characteristics.

The co-expression of the depolarizing and hyperpolarizing mechanosensitive ion channels in mammalian retinal neurons.

The elevation of the intraocular and extraocular pressures is associated with various visual conditions, including glaucoma and traumatic retinal injury. The retina expresses mechanosensitive channels (MSCs), but the role of MSCs in retinal physiology and pathologies has been unclear. Using immunocytochemistry, confocal microscopy, and patch-clamp recording techniques, we studied the co-expression of K+-permeable (K-MSCs) TRAAK and big potassium channel BK with the epithelial sodium channel ENaC and transient receptor potential channel vanilloid TPRV4 and TRPV2 favorably permeable to Ca2+ than Na+ (together named N-MSCs), and TRPV4 activity in the mouse retina. TRAAK immunoreactivity (IR) was mainly located in Müller cells. Photoreceptor outer segments (OSs) expressed BK and ENaCα intensively and TRAAK, TRPV2, and TRPV4 weakly. Somas and axons of retinal ganglion cells (RGCs) retrograde-identified clearly expressed ENaCα, TRPV4, and TRPV2 but lacked TRAAK and BK. Rod bipolar cells (RBCs) showed TRPV4-IR in somas and BK-IR in axonal globules. Horizontal cells were BK-negative, and some cone BCs lacked TRPV4-IR. TRPV4 agonist depolarized RGCs, enhanced spontaneous spikes and excitatory postsynaptic currents, reduced the visual signal reliability (VSR = 1-noise/signal) by ~50%, and resulted in ATP crisis, which could inactivate voltage-gated sodium channels in RGCs. Individual neurons co-express hyperpolarizing K-MSCs with depolarizing N-MSCs to counterbalance the pressure-induced excitation, and the level of K-MSCs relative to N-MSCs (RK/N ratio) is balanced in the outer retina but low in RGCs, bringing out novel determinants for the pressure vulnerability of retinal neurons and new targets for clinical interventions.

Fintech development, corporate tax avoidance and firm value

We examine the relationship between fintech development and tax avoidance, as well as investigate whether this relationship has an impact on firm value. Using the data from Chinese A-listed firms, we provide evidence that fintech development increases tax avoidance, which facilitates firm value. Moreover, we find that fintech raises after-tax income and future cash flow by facilitating firms to avoid tax. Fintech development is negatively associated with tax risk and positively related to the effectiveness of firms in capitalizing on tax preferences. We further determine that the positive effects of fintech are more pronounced among firms with low internal information quality, weak internal control, and more geographically dispersed operations. Digital transformation, cash flow uncertainty, and regional economic development are the important potential channels through which fintech development influences tax avoidance. Our results are robust to alternative measures and endogeneity issues.

The influence of urban new energy development orientation on new energy technology innovation in firms

Unlike existing energy policies that adopt a macro-level perspective, this paper examines the impact of China's new energy demonstration cities (NEDC) policy on micro-agents. Using longitudinal data covering Chinese publicly listed firms in new energy industries, the empirical results show that the NEDC policy significantly increases firm's new energy patents in pilot cities compared to those in non-pilot cities. We examine the potential channels via industrial upgrading effect, relative scale effect, direct incentive effect, and factor aggregation effect. In addition, we find that the NEDC policy performs better in areas with more governmental new energy attention and higher infrastructure levels, and state-owned businesses are more proactive.

The effect of state-owned equity participation on tax burdens of non-state-owned enterprises: evidence from China

ABSTRACT This paper examines the effect of state-owned equity participation on the tax burdens of non-state-owned enterprises. Using Chinese-listed non-SOEs from 2009 to 2022 as the sample, we find that the participation of state-owned equity in non-SOEs significantly reduces tax burdens. This effect is more pronounced in firms with local state-owned shareholders, higher involvement of state-owned equity participation, and directors appointed by state-owned shareholders. Increasing tax incentives and weaker tax enforcement are two potential channels. Our study provides empirical evidence for understanding how the participation of state-owned equity in non-SOEs shapes corporate tax burdens through the political resource effect.

Transient receptor potential channel 6 knockout ameliorates hepatic fibrosis by inhibiting the activation and proliferation of hepatic stellate cells.

Hepatic fibrosis is a common outcome of chronic liver injury and can eventually lead to cirrhosis, which is a major public health concern. Hepatic stellate cells (HSCs) are the major producers of extracellular matrix (ECM) and regulate the synthesis and decomposition of ECM, but the specific mechanism of them remains unclear. Transient receptor potential channel 6 (TRPC6), a non-selective cation channel, plays an important role in organic fibrosis. However, the role of TRPC6 in liver fibrosis is rarely studied. Here, we investigated the function of TRPC6 in the activation of the human hepatic stellate cell line LX-2 in vitro and bile duct ligation (BDL)-induced hepatic fibrosis in vivo by western blot, Ca2+ imaging, and immunohistochemistry. We first found that TRPC6 was upregulated in fibrotic liver tissues and TRPC6 knockout inhibited BDL-induced hepatic fibrosis. Transforming growth factor-β1 (TGF-β1) treatment increased TRPC6 expression and thapsigargin (Tg)-mediated SOCE in LX-2 cells, which was decreased by the TRPC6 specific inhibitor SAR7334. Blockage of TRPC6 by SAR7334 or TRPC6-shRNA transfection attenuated TGF-β1-induced LX-2 cell activation and proliferation via the PI3K/AKT/p70S6K signaling pathway. These observations suggested that TRPC6 contribute to LX-2 cell activation and hepatic fibrosis, and downregulation of TRPC6 may become a therapeutic strategy for the treatment of hepatic fibrosis in the future.