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Mitochondria constantly fuse and divide for mitochondrial inheritance and functions. Here, we identified a distinct type of naturally occurring fission, tail-autotomy fission, wherein a tail-like thin tubule protrudes from the mitochondrial body and disconnects, resembling autotomy. Next, utilizing an optogenetic mitochondria-specific mechanostimulator, we revealed that mechanical tensile force drives tail-autotomy fission. This force-induced fission involves DRP1/MFF and endoplasmic reticulum tubule wrapping. It redistributes mitochondrial DNA, producing mitochondrial fragments with or without mitochondrial DNA for different fates. Moreover, tensile force can decouple outer and inner mitochondrial membranes, pulling out matrix-excluded tubule segments. Subsequent tail-autotomy fission separates the matrix-excluded tubule segments into matrix-excluded mitochondrial-derived vesicles (MDVs) which recruit Parkin and LC3B, indicating the unique role of tail-autotomy fission in segregating only outer membrane components for mitophagy. Sustained force promotes fission and MDV biogenesis more effectively than transient one. Our results uncover a mechanistically and functionally distinct type of fission and unveil the role of tensile forces in modulating fission and MDV biogenesis for quality control, underscoring the heterogeneity of fission and mechanoregulation of mitochondrial dynamics. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a lethal metabolic syndrome featuring muscle wasting with preferential loss of fast-twitching muscle mass through an undefined mechanism. Here, we show that cancer induces muscle wasting by selectively degrading myosin heavy chain (MHC) subtypes IIb and IIx through E3 ligase UBR2-mediated ubiquitylation. Induction of MHC loss and atrophy in C2C12 myotubes and mouse tibialis anterior (TA) by murine cancer cells required UBR2 up-regulation by cancer. Genetic gain or loss of UBR2 function inversely altered MHC level and muscle mass in TA of tumor-free mice. UBR2 selectively interacted with and ubiquitylated MHC-IIb and MHC-IIx through its substrate recognition and catalytic domain, respectively, in C2C12 myotubes. Elevation of UBR2 in muscle of tumor-bearing or free mice caused loss of MHC-IIb and MHC-IIx but not MHC-I and MHC-IIa or other myofibrillar proteins, including a-actin, troponin, tropomyosin, and tropomodulin. Muscle-specific knockout of UBR2 spared KPC tumor-bearing mice from losing MHC-IIb and MHC-IIx, fasttwitching muscle mass, cross-sectional area, and contractile force. The rectus abdominis (RA) muscle of patients with cachexia-prone cancers displayed a selective reduction of MHC-IIx in correlation with higher UBR2 levels. These data suggest that UBR2 is a regulator of MHC-IIb/IIx essential for cancer-induced muscle wasting, and that therapeutic interventions can be designed by blocking UBR2 up-regulation by cancer. [ABSTRACT FROM AUTHOR]

Since its outbreak in December 2019, the novel coronavirus 2019 (COVID-19) has spread to 191 countries and caused millions of deaths. Many countries have experienced multiple epidemic waves and faced containment pressures from both domestic and international transmission. In this study, we conduct a multiscale geographic analysis of the spread of COVID-19 in a policy-influenced dynamic network to quantify COVID-19 importation risk under different policy scenarios using evidence from China. Our spatial dynamic panel data (SDPD) model explicitly distinguishes the effects of travel flows from the effects of transmissibility within cities, across cities, and across national borders. We find that within-city transmission was the dominant transmission mechanism in China at the beginning of the outbreak and that all domestic transmission mechanisms were muted or significantly weakened before importation posed a threat. We identify effective containment policies by matching the change points of domestic and importation transmissibility parameters to the timing of various interventions. Our simulations suggest that importation risk is limited when domestic transmission is under control, but that cumulative cases would have been almost 13 times higher if domestic transmissibility had resurged to its precontainment level after importation and 32 times higher if domestic transmissibility had remained at its precontainment level since the outbreak. Our findings provide practical insights into infectious disease containment and call for collaborative and coordinated global suppression efforts. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic is a global threat presenting health, economic, and social challenges that continue to escalate. Metapopulation epidemic modeling studies in the susceptible–exposed– infectious–removed (SEIR) style have played important roles in informing public health policy making to mitigate the spread of COVID-19. These models typically rely on a key assumption on the homogeneity of the population. This assumption certainly cannot be expected to hold true in real situations; various geographic, socioeconomic, and cultural environments affect the behaviors that drive the spread of COVID-19 in different communities. What’s more, variation of intracounty environments creates spatial heterogeneity of transmission in different regions. To address this issue, we develop a human mobility flow-augmented stochastic SEIR-style epidemic modeling framework with the ability to distinguish different regions and their corresponding behaviors. This modeling framework is then combined with data assimilation and machine learning techniques to reconstruct the historical growth trajectories of COVID-19 confirmed cases in two counties in Wisconsin. The associations between the spread of COVID-19 and business foot traffic, race and ethnicity, and age structure are then investigated. The results reveal that, in a college town (Dane County), the most important heterogeneity is age structure, while, in a large city area (Milwaukee County), racial and ethnic heterogeneity becomes more apparent. Scenario studies further indicate a strong response of the spread rate to various reopening policies, which suggests that policy makers may need to take these heterogeneities into account very carefully when designing policies for mitigating the ongoing spread of COVID-19 and reopening. [ABSTRACT FROM AUTHOR]

Notch controls skeletogenesis, but its role in the remodeling of adult bone remains conflicting. In mature mice, the skeleton can become osteopenic or osteosclerotic depending on the time point at which Notch is activated or inactivated. Using adult EGFP reporter mice, we find that Notch expression is localized to osteocytes embedded within bone matrix. Conditional activation of Notch signaling in osteocytes triggers profound bone formation, mainly due to increased mineralization, which rescues both age-associated and ovariectomy-induced bone loss and promotes bone healing following osteotomy. In parallel, mice rendered haploinsufficient in γ-secretase presenilin-1 (Psen1), which inhibits downstream Notch activation, display almost-absent terminal osteoblast differentiation. Consistent with this finding, pharmacologic or genetic disruption of Notch or its ligand Jagged1 inhibits mineralization. We suggest that stimulation of Notch signaling in osteocytes initiates a profound, therapeutically relevant, anabolic response. [ABSTRACT FROM AUTHOR]

Tailed DNA bacteriophages assemble empty procapsids that are subsequently filled with the viral genome by means of a DNA packaging machine situated at a special fivefold vertex. The packaging machine consists of a "small terminase" and a "large terminase" component. One of the functions of the small terminase is to initiate packaging of the viral genome, whereas the large terminase is responsible for the ATP-powered translocation of DNA. The small terminase subunit has three domains, an N-terminal DNA-binding domain, a central oligomerization domain, and a C-terminal domain for interacting with the large terminase. Here we report structures of the central domain in two different oligomerization states for a small terminase from the T4 family of phages. In addition, we report biochemical studies that establish the function for each of the small terminase domains. On the basis of the structural and biochemical information, we propose a model for DNA packaging initiation. [ABSTRACT FROM AUTHOR]

Cytokine-activated receptors undergo extracellular domain dimerization, which is necessary to activate intracellular signaling path- ways. Here, we report that in prolactin (PRL)-treated cells, PRL receptor (PRLR) undergoes cytoplasmic loop dimerization that is acetylation-dependent. PRLR-recruited CREB-binding protein (CBP) acetylates multiple lysine sites randomly distributed along the cytoplasmic loop of PRLR. Two PRLR monomers appear to interact with each other at multiple parts from the membrane-proximal region to the membrane-distal region, relying on the coordination among multiple lysine sites neutralized via acetylation. Cytoplasmic loop-dimerized PRLR activates STAT5. which is also acetylated by CBP and undergoes acetylation-dependent dimerization. PRLR dimerization and subsequent signaling are enhanced by treating the cells with deacetylase sirtuin (SIRT) inhibitor nicotinamide or histone deacetylase (HDAC) inhibitor trichostatin A but inhibited by expressing exogenous deacetylase SIRT2 or HDAC6. Our results suggest that acetylation and deacetylation provide the rheostat- like regulation for the cytokine receptor PRLR in its cytoplasmic loop dimerization and subsequent STAT5 activation. [ABSTRACT FROM AUTHOR]