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Depression, anxiety, stress symptoms among overweight and obesity in medical students, with mediating effects of academic burnout and internet addiction
Cyclic peptide inhibitors function as molecular glues to stabilize Gq/11 heterotrimers
Heterotrimeric Gα:Gβγ G proteins function as molecular switches downstream of G protein–coupled receptors (GPCRs). They alternate between a heterotrimeric GDP-bound OFF-state and a GTP-bound ON-state in which Gα GTP is separated from the Gβγ dimer. Consequently, pharmacological tools to securely prevent the OFF-ON transition are of utmost importance to investigate their molecular switch function, specific contribution to GPCR signal transduction, and potential as drug targets. FR900359 (FR) and YM-254890 (YM), two natural cyclic peptides and highly specific inhibitors of Gq/11 heterotrimers, are exactly such tools. To date, their efficient and long-lasting inhibition of Gq/11 signaling has been attributed solely to a wedge-like binding to Gα, thereby preventing separation of the GTPase and α-helical domains and thus GDP release. Here, we use X-ray crystallography, biochemical and signaling assays, and BRET-based biosensors to show that FR and YM also function as stabilizers of the Gα:Gβγ subunit interface. Our high-resolution structures reveal a network of residues in Gα and two highly conserved amino acids in Gβ that are targeted by FR and YM to glue the Gβγ complex to the inactive Gα GDP subunit. Unlike all previously developed nucleotide-state specific inhibitors that sequester Gα in its OFF-state but compete with Gβγ, FR and YM actively promote the inhibitory occlusion of Gα GDP by Gβγ. In doing so, they securely lock the entire heterotrimer, not just Gα, in its inactive state. Our results identify FR and YM as molecular glues for Gα and Gβγ that combine simultaneous binding to both subunits with inhibition of G protein signaling.
Poultry manure improves soil properties and grain mineral composition, maize productivity and economic profitability
Where do comets come from?
Interferon-induced activation of dendritic cells and monocytes by yellow fever vaccination correlates with early antibody responses
Yellow fever vaccination provides long-lasting protection and is a unique model for studying the immune response to an acute RNA virus infection in humans. To elucidate the early innate immune events preceding the rapid generation of protective immunity, we performed transcriptome analysis of human blood dendritic cell (DC) and monocyte subpopulations before and 3, 7, 14, and 28 d after vaccination. We detected temporary upregulation of IFN-stimulated genes (ISG) in all DC and monocyte subsets on days 3 and 7 after vaccination as well as cell type–specific responses and response kinetics. Single-cell RNA sequencing revealed rapid appearance of activated DC and monocyte clusters dominated by ISGs, inflammatory chemokines, and genes involved in antigen processing and presentation. This was confirmed by flow cytometric analysis in a large cohort of vaccinees. We identified SIGLEC1/CD169 upregulation as a sensitive indicator of the transient IFN-induced activation state elicited in DCs and monocytes by YF17D vaccination correlating with early protective IgM antibody responses.
Therapeutic effect of exogenous tumor necrosis factor-stimulating protein 6 intervention on lung injury in newborn rats by intrauterine infection
Abstract To investigate the therapeutic effect of exogenous tumor necrosis factor-stimulating protein 6(TSG-6) on lung injury in newborn rats induced by intrauterine infection, and to analyze its underlying mechanism. Twelve pregnant rats were randomly divided into a blank control group, a negative control group, a model group, and a TSG-6 treatment group. The blank control group was not modeled. The negative control group was injected with normal saline (NS) intraperitoneally on gestation day (E)14, and the remaining two groups were intraperitoneally injected with lipopolysaccharide at 0.6 mg/kg × body weight(kg) on E14 to establish the intrauterine infection model. The negative control and model groups were injected with NS via the tail vein on E16, and the TSG-6 treatment group was injected with TSG-6 at 0.25 mg/kg × body weight(kg) via the tail vein on E16. After delivery, the placentas of pregnant rats and the right lungs of newborn rats on postnatal day (P) 3, 7, and 14 were stained with hematoxylin-eosin to observe the inflammatory infiltration of placentas, the pathology of the lungs, and the radical alveolar count (RAC) was performed. The left lung tissues of newborn rats were collected on P3, P7d, and P14. Using Enzyme-linked immunosorbent assay (ELISA) kits to measure the levels of TSG-6, tumor necrosis factor-α(TNF-α), vascular endothelial growth factor (VEGF), and Interleukin-6 (IL-6) in lung tissues of newborn rats. Compared with the model group, the growth of the control group and the TSG-6 treatment group was better, the bronchial epithelial structure of the control and TSG-6 treatment group was intact, and the epithelial cells were normal and closely arranged. The levels of RAC, VEGF, and TSG-6 in the TSG-6 treatment group were significantly increased, and the levels of IL-6 and TNF-α were significantly decreased at the early stage of life compared with the model group; the differences were statistically significant (P < 0.05). TSG-6 intervention can reduce the inflammatory response of pregnant rats with intrauterine infection and significantly improve the pathological degree of lung injury in newborn rats caused by intrauterine infection. Its mechanism may be related to promoting the increase of TSG-6 and VEGF levels, regulating the balance of inflammatory factors and promoting tissue repair.
We need better ways to re-evaluate conservation policies when they’re founded on flawed research
Nutritional and cooking quality superiority of black rice genotype BPT 2841 with enhanced lysine content
Daily briefing: Five secrets of super-healthy seniors
Improved synapsis dynamics accompany meiotic stability in <i>Arabidopsis arenosa</i> autotetraploids
During meiosis, the correct pairing, synapsis, and recombination of homologous chromosome pairs is critical for fertility of sexual eukaryotes. These processes are challenged in polyploids, which possess additional copies of each chromosome. Polyploidy thus provides a unique context to study how evolution can modify meiotic programs in response to challenges. We previously observed that in newly formed (neo-)polyploids of Arabidopsis arenosa , synapsis defects precede chromosomes associating in aberrant multivalent and univalent configurations. Here, we study synapsis dynamics in genotypes with varying levels of meiotic stability to ask whether efficient synaptic progression is a key component of evolving stable tetraploid meiosis. We develop a method to quantify synapsis dynamics using the progression of foci of the pro-crossover factor HEI10 as a reference. HEI10 initially appears at many small foci before accumulating only at crossover sites. In diploids, this transition begins while significant asynapsis is still present, though it quickly declines as HEI10 accumulates at fewer foci. In neo-tetraploids, suboptimal elongation of synaptic initiation sites and stalled synapsis, perhaps due to defective pairing, occurs before the onset of HEI10 accumulation. In established tetraploids, HEI10 accumulation begins only when synapsis is near complete, suggesting enhanced HEI10/synapsis codynamics (even compared to diploids). Hybrids generated by crossing neo- and established tetraploids exhibit intermediate phenotypes. We find the extent of asynapsis correlates positively with crossover numbers, and the frequency of multivalents and univalents, which can disturb chromosome segregation. Our work supports the hypothesis that improving the efficiency of synapsis is important for evolving polyploid meiotic stability.
Correction: Integrating artificial neural networks, multi-objective metaheuristic optimization, and multi-criteria decision-making for improving MXene-based ionanofluids applicable in PV/T solar systems
What an angry exchange with a reviewer taught me about arrogance and humility
Intercellular contractile force attenuates chemosensitivity through Notch-MVP-mediated nuclear drug export
Resistance to chemotherapeutics is one major challenge to clinical effectiveness of cancer treatment and is primarily interpreted by various biochemical mechanisms. This study establishes an inverse correlation between tumor cell contractility and chemosensitivity. In both clinical biopsies and cancer cell lines, high/low actomyosin-mediated contractile force attenuates/enhances the vulnerability to chemotherapy, which depends on intercellular force propagation. Cell–cell interaction force activates the mechanosensitive Notch signaling that upregulates the downstream effector major vault protein, which facilitates the export of chemotherapy drugs from nuclei, leading to the reduction of chemosensitivity. Cellular contractility promotes the tolerance of tumor xenografts to chemotherapy and sustains tumor growth in vivo, which can be reversed by the inhibition of contractile force, Notch signaling, or major vault protein. Further, the actomyosin-Notch signaling is associated with drug resistance and cancer recurrence of patients. These findings unveil a regulatory role of intercellular force in chemosensitivity, which could be harnessed as a promising target for cancer mechanotherapeutics.
Sleep-disordered breathing profiles in patients with cardiovascular diseases: Kurume SDB-CVD study
Healthy sleep durations appear to vary across cultures
Past research finds that sleep duration is reliably linked with health yet sleep durations differ substantially between countries. We investigated whether countries with shorter sleep durations have worse health. Study 1 analyzed national sleep durations from 14 past investigations ( k = 353) and found that they were not associated with national health. Study 2 collected sleep duration and health data from people from 20 different countries ( N = 4,933). Average sleep durations varied substantially between countries (range = 1.57 h). A quadratic relation between sleep duration and health was found in all countries, although the turning points varied between countries. Individuals whose sleep duration was closer to their country’s perceived ideal reported better health. The results suggest that the amount of sleep associated with optimal health varies across countries.
Development and internal validation of a prediction model for rheumatoid arthritis: a case-control study
Monsoon hysteresis reveals atmospheric memory
Within Earth’s climate system, the ocean, cryosphere, and vegetation exhibit hysteresis behavior such that their state depends on their past and not merely on their current boundary conditions. The atmosphere’s fast mixing time scales were thought to inhibit the necessary memory effect for such multistability. Here, we show that moisture accumulation within the atmospheric column generates hysteresis in monsoon circulation independent of oceanic heat storage and yields two stable atmospheric states for the same solar insolation. The dynamics of monsoon rainfall is thus that of a seasonal transition between two stable states. The resulting hysteresis is shown in observational data and reproduced in a general circulation model where it increases with decreasing oceanic memory and exhibits the two distinct states that persist for more than 60 y. They are stabilized by moisture accumulation within the atmospheric column that carries information across time scales much longer than those typical for mixing. The possibility of abrupt shifts between these two states has implications for the future evolution of global monsoon rainfall that is crucial for the agricultural productivity currently feeding more than two billion people.
Ginsenoside CK and retinol on UVA-induced photoaging exert the synergistic effect through antioxidant and antiapoptotic mechanisms
Abstract Retinol and retinoids can effectively intervene skin aging process, but usually induce skin intolerance. In this study, we aimed to determine the synergistic anti-aging effects of retinol and two retinol derivatives-hydroxypinacolone retinoate (HPR) and retinol palmitate (VAPA) combined with ginsenoside CK in terms of preventing and treating the UVA radiation-induced skin aging. We found that the combination formulation of retinol and ginsenoside CK alleviated the inhibition of photoaging proliferation of HaCaT cells caused by UVA, and reduced the proportion of senescence. Additionally, the combination of retinol, HPR, VAPA with ginsenoside CK significantly down-regulated the expression of P53 and P21, up-regulated P63 in UVA irradiated cells, and had potential anti-apoptotic activity. Ginsenoside CK intervention also inhibited the degradation of collagen and elastin by reducing the expression of matrix metalloproteinases, and significantly alleviated oxidative stress. Further transcriptomic and molecular docking studies suggested that ginsenoside CK may play an anti-photoaging role by binding to the active pocket of AKR1C1 and AKR1C2 proteins. Zebrafish experiment showed that retinol combined with ginsenoside CK had the effect of reducing skin toxicity. In conclusion, our results show that retinol, HPR and VAPA combined with ginsenoside CK have good anti-aging and irritation-reducing effects in vitro and in vivo.
Mechanism and application of thiol–disulfide redox biosensors with a fluorescence-lifetime readout
Genetically encoded biosensors with changes in fluorescence lifetime (as opposed to fluorescence intensity) can quantify small molecules in complex contexts, even in vivo. However, lifetime-readout sensors are poorly understood at a molecular level, complicating their development. Although there are many sensors that have fluorescence-intensity changes, there are currently only a few with fluorescence-lifetime changes. Here, we optimized two biosensors for thiol–disulfide redox (RoTq-Off and RoTq-On) with opposite changes in fluorescence lifetime in response to oxidation. Using biophysical approaches, we showed that the high-lifetime states of these sensors lock the chromophore more firmly in place than their low-lifetime states do. Two-photon fluorescence lifetime imaging of RoTq-On fused to a glutaredoxin (Grx1) enabled robust, straightforward monitoring of cytosolic glutathione redox state in acute mouse brain slices. The motional mechanism described here is probably common and may inform the design of other lifetime-readout sensors; the Grx1-RoTq-On fusion sensor will be useful for studying glutathione redox in physiology.