Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19, so understanding its biology and infection mechanisms is critical to facing this major medical ...challenge. SARS-CoV-2 is known to use its spike glycoprotein to interact with the cell surface as a first step in the infection process. As for other coronaviruses, it is likely that SARS-CoV-2 next undergoes endocytosis, but whether or not this is required for infectivity and the precise endocytic mechanism used are unknown. Using purified spike glycoprotein and lentivirus pseudotyped with spike glycoprotein, a common model of SARS-CoV-2 infectivity, we now demonstrate that after engagement with the plasma membrane, SARS-CoV-2 undergoes rapid, clathrin-mediated endocytosis. This suggests that transfer of viral RNA to the cell cytosol occurs from the lumen of the endosomal system. Importantly, we further demonstrate that knockdown of clathrin heavy chain, which blocks clathrin-mediated endocytosis, reduces viral infectivity. These discoveries reveal that SARS-CoV-2 uses clathrin-mediated endocytosis to gain access into cells and suggests that this process is a key aspect of virus infectivity.
Religious traditions with their universal intent on human salvation or well-being have de-territorialized themselves or migrated from the place of their origin along trade routes in the company of ...merchants, invaders, and colonizers ...
The current synodal process (2021–2024) engaging the worldwide Catholic Church at the micro, meso and macro levels involves bringing Christians from across cultures, ethnic communities, linguistic ...groups and nationalities to interact and shape their journey as people of God. Without wanting to reproduce the intense debate that is in progress, we limit ourselves to examining the crucial issue—to a great extent ignored—of the intercultural lived ecclesiology associated with the inter gentes synodal praxis of communion, participation and mission. Although the synodal journey appears to be promising, the endogenous and exogenous ecclesial and societal differences implied in the inter gentes discernment can render it a complex transformative endeavor, entailing reciprocal enrichment and mutual critique. Taking up ideas that emerged in the various episcopal conferences in Asia in dialogue with some key themes in one of the European, namely, the German Episcopal Conference, we trace the intercultural challenges and prospects of communio, partecipatio et missio inter gentes, with a view to transforming the Church’s way of being and functioning.
There is no gainsaying that in a globalized world, economic and technological development greatly determine human wellbeing. In the Indian context, the dialectics between socialist and capitalist ...economy, while giving way to the latter since 1991, has progressively led to the enlargement of the middle class, yet widened the gap between the rich and the poor. Such a situation points to the importance of socioeconomic rights for guaranteeing human flourishing. The question that we pose is whether religions can play a significant role in favoring these human rights, given their own specific vision of human life and of its socioeconomic facets, such as work, wealth, leisure, health, and education. In other words, can personal and contextual religious attitudes and religious socialization contribute to socioeconomic wellbeing? The empirical research undertaken in the pluralistic and democratic context of Tamil Nadu, India, seeks to verify among 1215 Christian, Muslim, and Hindu students, the impact of religion on their attitude towards socioeconomic rights. The emerging results reveal that some aspects of religious attitudes and socialization have a significant impact on students’ agreement with socioeconomic rights, particularly in the case of Christians and Muslims. We conclude with a discussion on the salient findings and their implications.
Cognitive tasks are essential for the modern applications of electronics, and rely on the capability to perform inference. The Von Neumann bottleneck is an important issue for such tasks, and ...emerging memory devices offer an opportunity to overcome this issue by fusing computing and memory, in nonvolatile instant on/off systems. A vision for accomplishing this is to use brain-inspired architectures, which excel at inference and do not differentiate between computing and memory. In this work, we use a neuroscience-inspired model of learning, spike-timing-dependent plasticity, to develop a bioinspired approach for programming memory devices, which naturally gives rise to an inference engine. The method is then adapted to different memory devices, including multivalued memories (cumulative memristive device, phase-change memory) and stochastic binary memories (conductive bridge memory, spin transfer torque magnetic tunnel junction). By means of system-level simulations, we investigate several applications, including image recognition and pattern detection within video and auditory data. We compare the results of the different devices. Stochastic binary devices require the use of redundancy, the extent of which depends tremendously on the considered task. A theoretical analysis allows us to understand how the various devices differ, and ties the inference engine to the machine learning algorithm of expectation-maximization. Monte Carlo simulations demonstrate an exceptional robustness of the inference engine with respect to device variations and other issues. A theoretical analysis explains the roots of this robustness. These results highlight a possible new bioinspired paradigm for programming emerging memory devices, allowing the natural learning of a complex inference engine. The physics of the memory devices plays an active role. The results open the way for a reinvention of the role of memory, when solving inference tasks.
Lysosomes help maintain cellular proteostasis, and defects in lysosomal positioning and function can cause disease, including neurodegenerative disorders. The spatiotemporal distribution of lysosomes ...is regulated by small GTPases including Rabs, which are activated by guanine nucleotide exchange factors (GEFs). DENN domain proteins are the largest family of Rab GEFs. Using a cell-based assay, we screened DENND6A, a member of the DENN domain protein family against all known Rabs and identified it as a potential GEF for 20 Rabs, including Rab34. Here, we demonstrate that DENND6A activates Rab34, which recruits a RILP/dynein complex to lysosomes, promoting lysosome retrograde transport. Further, we identify DENND6A as an effector of Arl8b, a major regulatory GTPase on lysosomes. We demonstrate that Arl8b recruits DENND6A to peripheral lysosomes to activate Rab34 and initiate retrograde transport, regulating nutrient-dependent lysosomal juxtanuclear repositioning. Loss of DENND6A impairs autophagic flux. Our findings support a model whereby Arl8b/DENND6A/Rab34-dependent lysosomal retrograde trafficking controls autophagy.
Human phospholipid scramblase 1 (hPLSCR1), a type II integral class membrane protein, is known to mediate bidirectional scrambling of phospholipids in a Ca2+-dependent manner. hPLSCR2, a homolog of ...hPLSCR1 that lacks N-terminal proline-rich domain (PRD), did not show scramblase activity. We attribute this absence of scramblase activity of hPLSCR2 to the lack of N-terminal PRD. Hence to investigate the above hypothesis, we added the PRD of hPLSCR1 to hPLSCR2 (PRD-hPLSCR2) and checked whether scramblase activity was restored. Functional assays showed that the addition of PRD to hPLSCR2 restored scrambling activity, and deletion of PRD in hPLSCR1 (ΔPRD-hPLSCR1) resulted in a lack of activity. These results suggest that PRD is crucial for the function of the protein. The effects of the PRD deletion in hPLSCR1 and the addition of PRD to hPLSCR2 were characterized using various spectroscopic techniques. Our results clearly showed that hPLSCR1 and PRD-hPLSCR2 showed Ca2+-dependent aggregation and scrambling activity, whereas hPLSCR2 and ΔPRD-hPLSCR1 did not show aggregation and activity. Thus we conclude that scramblases exhibit Ca2+-dependent scrambling activity by aggregation of protein. Our results provide a possible mechanism for phospholipid scrambling mediated by PLSCRs and the importance of PRD in its function and cellular localization.
The role of PRD in scrambling of phospholipids by hPLSCR1 is not known.
The addition of PRD of hPLSCR1 to hPLSCR2 restored its PL scrambling activity, which in turn leads to aggregation of the protein.
PRD is crucial for PL scrambling activity and could probably mediate its function by metal ion-dependent oligomerization.
The results provide an insight in understanding the mechanism of scramblases.
Cytokinesis relies on membrane trafficking pathways regulated by Rabs and guanine nucleotide exchange factors (GEFs). During cytokinesis, the intercellular cytokinetic bridge (ICB) connecting ...daughter cells undergoes abscission, which requires actin depolymerization. Rab35 recruits MICAL1 to oxidize and depolymerize actin filaments. We show that DENND2B, a protein linked to cancer and congenital disorders, functions as a Rab35 GEF, recruiting and activating Rab35 at the ICB. DENND2B’s N-terminal region also interacts with an active form of Rab35, suggesting that DENND2B is both a Rab35 GEF and effector. Knockdown of DENND2B delays abscission, leading to multinucleated cells and filamentous actin (F-actin) accumulation at the ICB, impairing recruitment of ESCRT-III at the abscission site. Additionally, F-actin accumulation triggers the formation of a chromatin bridge, activating the NoCut/abscission checkpoint, and DENND2B knockdown activates Aurora B kinase, a hallmark of checkpoint activation. Thus, our study identifies DENND2B as a crucial player in cytokinetic abscission.
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•DENND2B is required for successful cytokinesis•DENND2B functions as both a Rab35 GEF and effector•Loss of DENND2B impairs recruitment of ESCRT-III to the cytokinetic bridge•DENND2B negatively regulates the abscission checkpoint machinery
Kumar et al. show that DENND2B activates Rab35 to regulate cytokinetic abscission, an important step in cell division. This process involves Rab35-dependent recruitment of proteins that depolymerize actin filaments. Absence of DENND2B disrupts actin depolymerization, which blocks the recruitment of downstream machinery required for cleavage of the cytokinetic bridge.
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