CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.

CFAP58 is a testis-enriched gene that plays an important role in the sperm flagellogenesis of humans and mice. However, the effect of CFAP58 on bull semen quality and the underlying molecular mechanisms involved in spermatogenesis remain unknown. Here, we identified two single-nucleotide polymorphisms (rs110610797, A>G and rs133760846, G>T) and one indel (g.-1811_ g.-1810 ins147bp) in the promoter of CFAP58 that were significantly associated with semen quality of bulls, including sperm deformity rate and ejaculate volume. Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping. Cfap58 deficiency causes an increase in spermatozoa apoptosis. Further experiments confirmed that CFAP58 interacts with IFT88 and CCDC42. Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway. Collectively, our findings reveal that CFAP58 is required for spermatogenesis and provide genetic markers for evaluating semen quality in cattle.

CHTOP Promotes Microglia-Mediated Inflammation by Regulating Cell Metabolism and Inflammatory Gene Expression.

During the initiation of the inflammatory response of microglia, the expression of many inflammation- and cell metabolism-related genes alters. However, how the transcription of inflammation- and metabolism-related genes are coordinately regulated during inflammation initiation is poorly understood. In this study, we found that LPS stimulation induced the expression of the chromatin target of PRMT1 (protein arginine methyltransferase 1) (CHTOP) in microglia. Knocking down CHTOP in microglia decreased proinflammatory cytokine expression. In addition, CHTOP knockdown altered cell metabolism, as both the upregulated genes were enriched in cell metabolism-related pathways and the metabolites profile was greatly altered based on untargeted metabolomics analysis. Mechanistically, CHTOP could directly bind the regulatory elements of inflammation and cell metabolism-related genes to regulate their transcription. In addition, knocking down CHTOP increased neuronal viability in vitro and alleviated microglia-mediated neuroinflammation in a systemic LPS treatment mouse model. Collectively, these data revealed CHTOP as a novel regulator to promote microglia-mediated neuroinflammation by coordinately regulating the transcription of inflammation and cell metabolism-related genes.

Identification of a conserved G-quadruplex within the E165R of African swine fever virus (ASFV) as a potential antiviral target.

Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.

Structure and mechanogating of the mammalian tactile channel PIEZO2.

PIEZO2 is a mechanosensitive cation channel that has a key role in sensing touch, tactile pain, breathing and blood pressure. Here we describe the cryo-electron microscopy structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 transmembrane helices (38 per protomer). Transmembrane helices 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades. The three blades are collectively curved into a nano-dome of 28-nm diameter and 10-nm depth, with an extracellular cap-like structure embedded in the centre and a 9-nm-long intracellular beam connecting to the central pore. TM38 and the C-terminal domain are surrounded by the anchor domain and TM37, and enclose the central pore with both transmembrane and cytoplasmic constriction sites. Structural comparison between PIEZO2 and its homologue PIEZO1 reveals that the transmembrane constriction site might act as a transmembrane gate that is controlled by the cap domain. Together, our studies provide insights into the structure and mechanogating mechanism of Piezo channels.

Unifying the order and disorder dynamics in photoexcited VO2.

Photoinduced phase transition (PIPT) is always treated as a coherent process, but ultrafast disordering in PIPT is observed in recent experiments. Utilizing the real-time time-dependent density functional theory method, here we track the motion of individual vanadium (V) ions during PIPT in VO2 and uncover that their coherent or disordered dynamics can be manipulated by tuning the laser fluence. We find that the photoexcited holes generate a force on each V-V dimer to drive their collective coherent motion, in competing with the thermal-induced vibrations. If the laser fluence is so weak that the photoexcited hole density is too low to drive the phase transition alone, the PIPT is a disordered process due to the interference of thermal phonons. We also reveal that the photoexcited holes populated by the V-V dimerized bonding states will become saturated if the laser fluence is too strong, limiting the timescale of photoinduced phase transition.

Spin-Mechanical Coupling in 2D Antiferromagnet CrSBr.

Spin-mechanical coupling is vital in diverse fields including spintronics, sensing, and quantum transduction. Two-dimensional (2D) magnetic materials provide a unique platform for investigating spin-mechanical coupling, attributed to their mechanical flexibility and novel spin orderings. However, studying their spin-mechanical coupling presents challenges in probing mechanical deformation and thermodynamic property changes at the nanoscale. Here we use nano-optoelectromechanical interferometry to mechanically detect the phase transition and magnetostriction effect in multilayer CrSBr, an air-stable antiferromagnet with large magnon-exciton coupling. The transitions among antiferromagnetism, spin-canted ferromagnetism, and paramagnetism are visualized. Nontrivial magnetostriction coefficient 2.3 × 10-5 and magnetoelastic coupling strength on the order of 106 J/m3 have been found. Moreover, we demonstrate the substantial tunability of the magnetoelastic constant by nearly 50% via gate-induced strain. Our findings demonstrate the strong spin-mechanical coupling in CrSBr and pave the way for developing sensitive magnetic sensing and efficient quantum transduction at the atomically thin limit.

NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.

BACKGROUND: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1ß (interleukin-1ß) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1ß production to induce adaptive hypertrophy in the stressed heart. METHODS: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1ß antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1ß and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. RESULTS: Genetic disruption of NLRP3 resulted in significant loss of IL-1ß production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1ß production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1ß-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic ß-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1ß production, and adaptive cardiac hypertrophy during pressure overload. CONCLUSIONS: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.

Low Concentration of Lipoprotein(a) is an Independent Predictor of Incident Type 2 Diabetes.

The aim of the study was to assess the association between lipoprotein(a) [Lp(a)] concentration and incident type 2 diabetes. A meta-analysis of qualified studies on the relationship of low levels of Lp(a) concentration with incident type 2 diabetes was conducted. PubMed and Cochrane libraries were searched for randomized controlled trials containing data on events. Seven randomized trials with 227178 subjects were included in this analysis. We found an inverse association of the levels of Lp(a) concentration with risk of type 2 diabetes with approximately 37% lower relative risk in the group with the highest concentration compared with group with the lowest concentration. The current available evidence from prospective studies suggests that there is an inverse association between the levels of Lp(a) concentration and risk of type 2 diabetes, with a higher risk of type 2 diabetes at low levels of Lp(a) concentration. Therefore, we believe that the low levels of Lp(a) concentration is an independent predictor of incident type 2 diabetes.

Self-Catalyzed, Visible-Light-Induced Selective C3-H Aroylation of Quinoxalin-2(1H)-ones with Arylaldehydes by Air as an Oxidant.

A self-catalyzed, visible-light-induced, directly selective C3-H aroylation of quinoxalin-2(1H)-ones via energy transfer and hydrogen atom transfer (HAT) catalysis has been developed. The method is highly atom-economical, eco-friendly, and easy to handle. Notably, the reaction proceeded efficiently with ambient air as the sole oxidant at room temperature.

Author Correction: Structure and mechanogating mechanism of the Piezo1 channel.

In Extended Data Fig. 9a of this Article, the bottom micrographs of mPiezo1-ΔL3-4-IRES-GFP and mPiezo1-ΔL7-8-IRES-GFP (labelled 'permeabilized') are inadvertently the same images. The corrected figure panels are shown in the accompanying Amendment.

Structure and mechanogating mechanism of the Piezo1 channel.

The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure. The last transmembrane helix encloses a hydrophobic pore, followed by three intracellular fenestration sites and side portals that contain pore-property-determining residues. The central region forms a 90 Å-long intracellular beam-like structure, which undergoes a lever-like motion to connect THUs to the pore via the interfaces of the C-terminal domain, the anchor-resembling domain and the outer helix. Deleting extracellular loops in the distal THUs or mutating single residues in the beam impairs the mechanical activation of Piezo1. Overall, Piezo1 possesses a unique 38-transmembrane-helix topology and designated mechanotransduction components, which enable a lever-like mechanogating mechanism.

Benzophenone-4 inhibition in marine diatoms: Physiological and molecular perspectives.

Benzophenone-4 (BP-4), a widely utilized organic ultraviolet (UV) filter, is recognized as a pseudo-persistent contaminant in aquatic environments. To elucidate the effects and mechanisms of BP-4 on marine diatoms, an investigation was conducted on the growth rate, photosynthetic pigment content, photosynthetic parameters, antioxidant enzyme activity, malondialdehyde (MDA) levels, cellular structure, and transcriptome profile of the model species, Phaeodactylum tricornutum. The results showed a pronounced inhibition of algal growth upon exposure to BP-4, with a 144 h-EC50 value of 201 mg·L-1. In addition, BP-4 exposure resulted in a significant reduction in biomass, disruption of cell membrane integrity, and increased MDA accumulation, with levels escalating 3.57-fold at 125 mg·L-1 of BP-4. In the BP-4-treated samples, 1556 differentially expressed genes (DEGs) were identified, of which 985 were upregulated and 571 were downregulated. Gene ontology and KEGG pathway enrichment analysis revealed that the carbon fixation and carbon metabolism processes in P. tricornatum were disrupted in response to BP-4 exposure, along with excessive reactive oxygen species (ROS) production. The upregulation of genes associated with photosynthetic pigment (chlorophyll and carotenoids) synthesis, phospholipid synthesis, ribosome biogenesis, and translation-related pathways may be regarded as a component of P. tricornatum's tolerance mechanism towards BP-4. These results provide preliminary insights into the toxicity and tolerance mechanisms of BP-4 on P. tricornatum. They will contribute to a better understanding of the ecotoxicological impacts of BP-4 on the marine ecosystem and provide valuable information for elimination of BP-4 in aquatic environment by bioremediation.

Light-Boosting Highly Sensitive and Ultrafast Piezoelectric Sensor Based on Composite Membrane of Copper Phthalocyanine and Graphene Oxide.

Self-powered wearable pressure sensors based on flexible electronics have emerged as a new trend due to the increasing demand for intelligent and portable devices. Improvements in pressure-sensing performance, including in the output voltage, sensitivity and response time, can greatly expand their related applications; however, this remains challenging. Here, we report on a highly sensitive piezoelectric sensor with novel light-boosting pressure-sensing performance, based on a composite membrane of copper phthalocyanine (CuPC) and graphene oxide (GO) (CuPC@GO). Under light illumination, the CuPC@GO piezoelectric sensor demonstrates a remarkable increase in output voltage (381.17 mV, 50 kPa) and sensitivity (116.80 mV/kPa, <5 kPa), which are approximately twice and three times of that the sensor without light illumination, respectively. Furthermore, light exposure significantly improves the response speed of the sensor with a response time of 38.04 µs and recovery time of 58.48 µs, while maintaining excellent mechanical stability even after 2000 cycles. Density functional theory calculations reveal that increased electron transfer from graphene to CuPC can occur when the CuPC is in the excited state, which indicates that the light illumination promotes the electron excitation of CuPC, and thus brings about the high polarization of the sensor. Importantly, these sensors exhibit universal spatial non-contact adjustability, highlighting their versatility and applicability in various settings.

Empagliflozin Prevent High-Glucose Stimulation Inducing Apoptosis and Mitochondria Fragmentation in H9C2 Cells through the Calcium-Dependent Activation Extracellular Signal-Regulated Kinase 1/2 Pathway.

A previous study showed that high-glucose (HG) conditions induce mitochondria fragmentation through the calcium-mediated activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) in H9C2 cells. This study tested whether empagliflozin could prevent HG-induced mitochondria fragmentation through this pathway. We found that exposing H9C2 cells to an HG concentration decreased cell viability and increased cell apoptosis and caspase-3. Empagliflozin could reverse the apoptosis effect of HG stimulation on H9C2 cells. In addition, the HG condition caused mitochondria fragmentation, which was reduced by empagliflozin. The expression of mitochondria fission protein was upregulated, and fusion proteins were downregulated under HG stimulation. The expression of fission proteins was decreased under empagliflozin treatment. Increased calcium accumulation was observed under the HG condition, which was decreased by empagliflozin. The increased expression of ERK 1/2 under HG stimulation was also reversed by empagliflozin. Our study shows that empagliflozin could reverse the HG condition, causing a calcium-dependent activation of the ERK 1/2 pathway, which caused mitochondria fragmentation in H9C2 cells.

Influence of GPRC5A-Regulated ABCB1 Expression on Lung Adenocarcinoma Proliferation.

Objective Aberrant expression of ATP binding cassette subfamily B member 1 (ABCB1) plays a key role in several cancers. However, influence of G protein coupled receptor family C group 5 type A (GPRC5A)-regulated ABCB1 expression on lung adenocarcinoma proliferation remains unclear. Therefore, this study investigated the effect of GPRC5A regulated ABCB1 expression on the proliferation of lung adenocarcinoma. Methods ABCB1 expressions in lung adenocarcinoma cell lines, human lung adenocarcinoma tissues, and tracheal epithelial cells and lung tissues of GPRC5A knockout mice and wild-type mice were analyzed with RT-PCR, Western blot, or immunohistochemical analysis. Cell counting kit-8 assay was performed to analyze the sensitivity of tracheal epithelial cells from GPRC5A knockout mice to chemotherapeutic agents. Subcutaneous tumor formation assay was performed to confirm whether down-regulation of ABCB1 could inhibit the proliferation of lung adenocarcinoma in vivo. To verify the potential regulatory relationship between GPRC5A and ABCB1, immunofluorescence and immunoprecipitation assays were performed. Results ABCB1 expression was up-regulated in lung adenocarcinoma cell lines and human lung adenocarcinoma tissues. ABCB1 expression in the tracheal epithelial cells and lung tissues of GPRC5Adeficient mice was higher than that in the wild type mice. Tracheal epithelial cells of GPRC5A knockout mice were much more sensitive to tariquidar and doxorubicin than those of GPRC5A wild type mice. Accordingly, 28 days after injection of the transplanted cells, the volume and weight of lung tumor in ABCB1knockout cell-transplanted GPRC5A-/-C57BL/6 mice were significantly smaller than those in wild type cell-transplanted mice (P= 0.0043, P= 0.0060). Furthermore, immunofluorescence and immunoprecipitation assays showed that GPRC5A regulated ABCB1 expression by direct binding.Conclusion GPRC5A reduces lung adenocarcinoma proliferation via inhibiting ABCB1 expression. The pathway by which GPRC5A regulates ABCB1 expression needs to be investigated.

Current research hotspots and frontier trends on carbon budget of coastal wetlands: A bibliometric analysis.

Coastal wetlands are the main distribution of blue carbon in coastal zones and well known for their high carbon sequestration capacity. Investigating the variation of carbon budget is crucial for understanding the functionality of coastal wetlands and effectively addressing climate change. In this study, a bibliometric analysis of 4,509 articles was conducted to reveal research progress, hot issues, and emerging trends in the coastal wetland carbon budget field. The number of publications and citations in this field increased exponentially from 1991 to 2022. The leading subject category was Environmental Sciences with 1,844 articles (40.9%). At present, studies have been focused on blue carbon, the effects of climate change and man-made disturbances on carbon cycle, and the restoration of coastal wetlands. Based on the hotspots and trends in this field, the future researches should include (1) exploring the functional mechanisms of various factors affecting carbon cycle and establishing a methodological system for the estimation of blue carbon in coastal wetlands; (2) researching restoration techniques of coastal wetland and constructing wetland restoration evaluation index system; and (3) formulating enforceable carbon trading policy and strengthening international cooperation.

MRAs may have lost their cornerstone position for heart failure treatment in the age of SGLT-2 inhibitors: A meta-analysis of randomized controlled trials.

Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for heart failure therapy. Several clinical studies have demonstrated its role in heart failure therapy. However, due to the recommendation of sodium-glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of SGLT-2 inhibitors and MRAs on various clinical endpoints of heart failure. The incidence of cardiovascular-related death or heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death, heart failure hospitalization, renal outcomes, and hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52), heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to SGLT-2 inhibitors, combined therapy increased the risk of moderate-severe hyperkalemia (blood potassium > 6.0 mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to SGLT-2 inhibitors to treat heart failure is not essential.

Origin of Immediate Damping of Coherent Oscillations in Photoinduced Charge-Density-Wave Transition.

In stark contrast to the conventional charge density wave (CDW) materials, the one-dimensional CDW on the In/Si(111) surface exhibits immediate damping of the CDW oscillation during the photoinduced phase transition. Here, we successfully reproduce the experimental observation of the photoinduced CDW transition on the In/Si(111) surface by performing real-time time-dependent density functional theory (rt-TDDFT) simulations. We show that photoexcitation promotes valence electrons from the Si substrate to the empty surface bands composed primarily of the covalent p-p bonding states of the long In-In bonds. Such photoexcitation generates interatomic forces to shorten the long In-In bonds and thus drives the structural transition. After the structural transition, these surface bands undergo a switch among different In-In bonds, causing a rotation of the interatomic forces by about π/6 and thus quickly damping the oscillations in feature CDW modes. These findings provide a deeper understanding of photoinduced phase transitions.

ACSL4 promotes microglia-mediated neuroinflammation by regulating lipid metabolism and VGLL4 expression.

Acyl-CoA synthetase long-chain family member 4 (ACSL4) is an important isozyme in polyunsaturated fatty acid (PUFA) metabolism. The role of ACSL4 in the lipopolysaccharide (LPS)-induced inflammation of microglia, and the effects of ACSL4-mediated inflammation on the progression of Parkinson's disease (PD) are unknown. In this study, we found that ACSL4 expression was increased after LPS stimulation. Knocking down ACSL4 in microglia decreased proinflammatory cytokine production. Mechanistically, ACSL4 reduced vestigial-like family member 4(VGLL4) expression to promote NF-κB signal transduction; and ACSL4 regulated lipid composition after LPS stimulation. In addition, knocking down ACSL4 alleviated neuroinflammation in a systemic LPS model and acute l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) model. These data revealed ACSL4 to be a novel regulator that promotes microglia-mediated neuroinflammation by regulating VGLL4 expression and lipid metabolism.

Hydrogen-Bond-Connected 2D Zn-LMOF with Fluorescent Sensing for Inorganic Pollutants and Nitro Aromatic Explosives in the Aqueous Phase.

Herein, a novel luminescent Zn-LMOF, JLU-MOF109 ([Zn(PBBA)(H2O)]·3DMF·2H2O, PBBA = 4,4'-(2,6-pyrazinediyl)bis[benzoic acid], DMF = N,N-dimethylformamide), was successfully synthesized under solvothermal conditions. Zinc ions are connected by PBBA ligands to form two-dimensional (2D) layers, and the layers are further propped up through hydrogen-bonding interactions. JLU-MOF109 exhibits good sensitivity to inorganic pollutants, Fe3+ and Cr2O72-, as well as nitro aromatic explosives, 2,4,6-trinitrophenol and 2,4-dinitrophenol. JLU-MOF109 exhibits high Ksv (at 104 M-1 level) and low limit of detection values (∼10-6 mol/L) for the abovementioned hazardous pollutants, which is better than a majority of previously reported MOF-based fluorescent sensors. With good stability in the aqueous phase, JLU-MOF109 can serve as a promising chemical sensor for pollutant detection in wastewater.