Mitochondria-encoded peptide MOTS-c participates in plasma membrane repair by facilitating the translocation of TRIM72 to membrane.

Rationale: An impairment of plasma membrane repair has been implicated in various diseases such as muscular dystrophy and ischemia/reperfusion injury. MOTS-c, a short peptide encoded by mitochondria, has been shown to pass through the plasma membrane into the bloodstream. This study determined whether this biological behavior was involved in membrane repair and its underlying mechanism. Methods and Results: In human participants, the level of MOTS-c was positively correlated with the abundance of mitochondria, and the membrane repair molecule TRIM72. In contrast to high-intensity eccentric exercise, moderate-intensity exercise improved sarcolemma integrity and physical performance, accompanied by an increase of mitochondria beneath the damaged sarcolemma and secretion of MOTS-c. Furthermore, moderate-intensity exercise increased the interaction between MOTS-c and TRIM72, and MOTS-c facilitated the trafficking of TRIM72 to the sarcolemma. In vitro studies demonstrated that MOTS-c attenuated membrane damage induced by hypotonic solution, which could be blocked by siRNA-TRIM72, but not AMPK inhibitor. Co-immunoprecipitation study showed that MOTS-c interacted with TRIM72 C-terminus, but not N-terminus. The dynamic membrane repair assay revealed that MOTS-c boosted the trafficking of TRIM72 to the injured membrane. However, MOTS-c itself had negligible effects on membrane repair, which was recapitulated in TRIM72-/- mice. Unexpectedly, MOTS-c still increased the fusion of vesicles with the membrane in TRIM72-/- mice, and dot blot analysis revealed an interaction between MOTS-c and phosphatidylinositol (4,5) bisphosphate [PtdIns (4,5) P2]. Finally, MOTS-c blunted ischemia/reperfusion-induced membrane disruption, and preserved heart function. Conclusions: MOTS-c/TRIM72-mediated membrane integrity improvement participates in mitochondria-triggered membrane repair. An interaction between MOTS-c and plasma lipid contributes to the fusion of vesicles with membrane. Our data provide a novel therapeutic strategy for rescuing organ function by facilitating membrane repair with MOTS-c.

Hepatic Surf4 Deficiency Impairs Serum Amyloid A1 Secretion and Attenuates Liver Fibrosis in Mice.

Liver fibrosis is a severe global health problem. However, no effective antifibrotic drugs have been approved. Surf4 is primarily located in the endoplasmic reticulum (ER) and mediates the transport of secreted proteins from the ER to the Golgi apparatus. Knockout of hepatic Surf4 (Surf4 LKO) in mice impairs very-low-density lipoprotein secretion without causing overt liver damage. Here, we found that collagen levels are significantly reduced in the liver of Surf4 LKO mice compared with control Surf4 flox mice, as demonstrated by proteomics, Western blot, and quantitative reverse transcription polymerase chain reaction. Therefore, this study aims to investigate whether and how hepatic Surf4 affects liver fibrosis. We observed that CCl4-induced liver fibrosis is significantly lower in Surf4 LKO mice than in Surf4 flox mice. Mechanistically, hepatic Surf4 deficiency reduces serum amyloid A1 (SAA1) secretion and hepatic stellate cell (HSC) activation. Surf4 coimmunoprecipitates and colocalizes with SAA1. Lack of hepatic Surf4 significantly reduces SAA1 secretion from hepatocytes, and SAA1 activates cultured human HSCs (LX-2 cells). Conditioned medium (CM) from Surf4-deficient primary hepatocytes activates LX-2 cells to a much lesser extent than CM from Surf4 flox primary hepatocytes, and this reduced effect is restored by the addition of recombinant SAA1 to CM from Surf4-deficient hepatocytes. Knockdown of SAA1 in primary hepatocytes or TLR2 in LX-2 cells significantly reduces LX-2 activation induced by CM from Surf4 flox hepatocytes but not from Surf4 LKO hepatocytes. Furthermore, knockdown of SAA1 significantly ameliorates liver fibrosis in Surf4 flox mice but does not further reduce liver fibrosis in Surf4 LKO mice. We also observe substantial expression of Surf4 and SAA1 in human fibrotic livers. Therefore, hepatic Surf4 facilitates SAA1 secretion, activates HSCs, and aggravates liver fibrosis, suggesting that hepatic Surf4 and SAA1 may serve as treatment targets for liver fibrosis.

The spectrum of novel ABCB11 gene variations in children with progressive familial intrahepatic cholestasis type 2 in Pakistani cohorts.

Progressive familial intrahepatic cholestasis (PFIC) is a rare childhood manifested disease associated with impaired bile secretion with severe pruritus yellow stool, and sometimes hepatosplenomegaly. PFIC is caused by mutations in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, SLC51A, USP53, KIF12, ZFYVE19, and MYO5B genes depending on its type. ABCB11 mutations lead to PFIC2 that encodes the bile salt export pump (BSEP). Different mutations of ABCB11 have been reported in different population groups but no data available in Pakistani population being a consanguineous one. We sequenced coding exons of the ABCB11 gene along with its flanking regions in 66 unrelated Pakistani children along with parents with PFIC2 phenotype. We identified 20 variations of ABCB11: 12 in homozygous form, one compound heterozygous, and seven heterozygous. These variants include 11 missenses, two frameshifts, two nonsense mutations, and five splicing variants. Seven variants are novel candidate variants and are not detected in any of the 120 chromosomes from normal ethnically matched individuals. Insilico analysis revealed that four homozygous missense variations have high pathogenic scores. Minigene analysis of splicing variants showed exon skipping and the addition of exon. This data is a useful addition to the disease variants genomic database and would be used in the future to build a diagnostic algorithm.

Molecular detection, subtyping of Blastocystis sp. in migratory birds from nature reserves in northeastern China.

Migratory birds play an important role in the cross-regional transmission of zoonotic pathogens. Assessing the presence of zoonotic pathogens carried by migratory birds is critical for disease control. However, information about Blastocystis infection in the migratory birds is very limited. Thus, we conducted this study with the aim to explore the occurrence, prevalence and subtyping of Blastocystis in four breeds of migratory birds in northeastern China. From October 2022 to April 2023, a total of 427 fresh fecal samples were obtained from four breeds of migratory birds in five nature reserves in northeastern China, and screened for Blastocystis by PCR amplification. Twenty-one (4.92 %) of the studied samples were confirmed Blastocystis-positive, and two known zoonotic subtypes ST6 and ST7 were founded, with ST7 being the major subtype. Until now, we firstly reported the infection status and subtyping of Blastocystis in the migratory Greater White-Fronted Goose, White Stork, Oriental White Stork and Bean Goose in China. More importantly, these findings present further data on the genetic diversity and transmission routes of Blastocystis and further arouse public health concerns about this organism.

Melatonin Rescues Influenza A Virus-Induced Cellular Energy Exhaustion via OMA1-OPA1-S in Acute Exacerbation of COPD.

Although rapid progression and a poor prognosis in influenza A virus (IAV) infection-induced acute exacerbation of chronic obstructive pulmonary disease (AECOPD) are frequently associated with metabolic energy disorders, the underlying mechanisms and rescue strategies remain unknown. We herein demonstrated that the level of resting energy expenditure increased significantly in IAV-induced AECOPD patients and that cellular energy exhaustion emerged earlier and more significantly in IAV-infected primary COPD bronchial epithelial (pDHBE) cells. The differentially expressed genes were enriched in the oxidative phosphorylation (OXPHOS) pathway; additionally, we consistently uncovered much earlier ATP exhaustion, more severe mitochondrial structural destruction and dysfunction, and OXPHOS impairment in IAV-inoculated pDHBE cells, and these changes were rescued by melatonin. The level of OMA1-dependent cleavage of OPA1 in the mitochondrial inner membrane and the shift in energy metabolism from OXPHOS to glycolysis were significantly increased in IAV-infected pDHBE cells; however, these changes were rescued by OMA1-siRNA or melatonin further treatment. Collectively, our data revealed that melatonin rescued IAV-induced cellular energy exhaustion via OMA1-OPA1-S to improve the clinical prognosis in COPD. This treatment may serve as a potential therapeutic agent for patients in which AECOPD is induced by IAV.

Characterizing Chinese undergraduate students' empathizing-systemizing profiles: a person-centered approach.

While the empathizing-systemizing (E-S) theory provides a valuable framework for explaining gender differences in STEM majors, previous studies suffer from methodological issues (i.e., the arbitrary cut-off criteria and WEIRD sampling) as well as discrepancies in the behavioral correlates of E-S types. To address the gaps, this study utilized a 3-step latent profile analysis to identify naturally occurring E-S profiles in a Chinese sample and explored the predictors and distal outcomes of the identified profiles. The study recruited 785 (aged 18-25 years, 60% female) Chinese undergraduates. Results revealed five E-S profiles: Disengaged, Empathizers, Navigating systemizers, Technological systemizers, and Self-declared allrounders. Controlling for socioeconomic status, being male predicted a higher likelihood of membership into the Technological systemizers. Besides, membership to the Navigating systemizers and Technological systemizers was associated with better intuitive physics performance. However, no significant variation was observed for social sensitivity performance across E-S profiles. Overall, our results partially conformed to previous findings, highlighting the importance of cultural adaptation and methodological considerations when classifying students' cognitive types.

Gut microbiota-derived acetate attenuates lung injury induced by influenza infection via protecting airway tight junctions.

BACKGROUND: Gut microbiota (GM) have been implicated as important regulators of gastrointestinal symptom which is commonly occurred along with respiratory influenza A virus (IAV) infection, suggesting the involvement of the gut-to-lung axis in a host's response to IAV. IAV primarily destroys airway epithelium tight junctions (TJs) and consequently causes acute respiratory disease syndrome. It is known that GM and their metabolism produce an anti-influenza effect, but their role in IAV-induced airway epithelial integrity remains unknown. METHODS: A mouse model of IAV infection was established. GM were analyzed using 16S rRNA gene sequencing, and short-chain fatty acids (SCFAs) levels were measured. GM depletion and fecal microbiota transplantation (FMT) were conducted to validate the role of GM in IAV infection. A pair-feeding experiment was conducted to reveal whether IAV-induced GM dysbiosis is attributed to impaired food intake. Furthermore, human bronchial epithelial (HBE) cells were cocultured with IAV in the presence or absence of acetate. TJs function was analyzed by paracellular permeability and transepithelial electronic resistance (TEER). The mechanism of how acetate affects TJs integrity was evaluated in HBE cells transfected with G protein-coupled receptor 43 (GPR43) short hairpin RNA (shRNA). RESULTS: IAV-infected mice exhibited lower relative abundance of acetate-producing bacteria (Bacteroides, Bifidobacterium, and Akkermansia) and decreased acetate levels in gut and serum. These changes were partly caused by a decrease in food consumption (due to anorexia). GM depletion exacerbated and FMT restored IAV-induced lung inflammatory injury. IAV infection suppressed expressions of TJs (occludin, ZO-1) leading to disrupted airway epithelial barrier function as evidenced by decreased TEER and increased permeability. Acetate pretreatment activated GPR43, partially restored IAV-induced airway epithelial barrier function, and reduced inflammatory cytokines levels (TNF-α, IL-6, and IL-1ß). Such protective effects of acetate were absent in HBE cells transfected with GPR43 shRNA. Acetate and GPR43 improved TJs in an AMP-activated protein kinase (AMPK)-dependent manner. CONCLUSION: Collectively, our results demonstrated that GM protected airway TJs by modulating GPR43-AMPK signaling in IAV-induced lung injury. Therefore, improving GM dysbiosis may be a potential therapeutic target for patients with IAV infection.

Blood urea nitrogen to albumin ratio is a novel predictor of fatal outcome for patients with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is associated with a high death rate and lacks a targeted therapy plan. The ratio of blood urea nitrogen to albumin, known as BAR, is a valuable method for assessing the outlook of various infectious diseases. The objective of this research was to evaluate the effectiveness of BAR in forecasting the outcome of individuals with SFTS. Four hundred and thirty-seven patients with SFTS from two clinical centers were included in this study according to inclusion and exclusion criteria. Clinical characteristics and test parameters of SFTS patients were analyzed between survival and fatal groups. Least absolute shrinkage and selection operator (LASSO) regression and Cox regression suggested that BAR might serve as a standalone prognostic indicator for patients with SFTS in the initial phase (hazard ratio = 18.669, 95% confidence interval [CI]: 8.558-40.725, p < 0.001). And BAR had a better predictive effectiveness in clinical outcomes in patients with SFTS with an AUC of 0.832 (95% CI: 0.788-0.876, p < 0.001), a cutoff value of 0.19, a sensitivity of 0.812, and a specificity of 0.726 compared to C-reactive protein, procalcitonin, and platelet to lymphocyte ratio via receiver operating characteristic curve. KM (Kaplan Meier) curves demonstrated that high level of BAR was associated with poor survival condition in patients with SFTS. Furthermore, the high level of BAR was associated with long hospital stays and test paraments of kidney, liver, and coagulation function in survival patients. So, BAR could be used as a promising early warning biomarker of adverse outcomes in patients with SFTS.

Melatonin improves influenza virus infection-induced acute exacerbation of COPD by suppressing macrophage M1 polarization and apoptosis.

BACKGROUND: Influenza A viruses (IAV) are extremely common respiratory viruses for the acute exacerbation of chronic obstructive pulmonary disease (AECOPD), in which IAV infection may further evoke abnormal macrophage polarization, amplify cytokine storms. Melatonin exerts potential effects of anti-inflammation and anti-IAV infection, while its effects on IAV infection-induced AECOPD are poorly understood. METHODS: COPD mice models were established through cigarette smoke exposure for consecutive 24 weeks, evaluated by the detection of lung function. AECOPD mice models were established through the intratracheal atomization of influenza A/H3N2 stocks in COPD mice, and were injected intraperitoneally with melatonin (Mel). Then, The polarization of alveolar macrophages (AMs) was assayed by flow cytometry of bronchoalveolar lavage (BAL) cells. In vitro, the effects of melatonin on macrophage polarization were analyzed in IAV-infected Cigarette smoking extract (CSE)-stimulated Raw264.7 macrophages. Moreover, the roles of the melatonin receptors (MTs) in regulating macrophage polarization and apoptosis were determined using MTs antagonist luzindole. RESULTS: The present results demonstrated that IAV/H3N2 infection deteriorated lung function (reduced FEV20,50/FVC), exacerbated lung damages in COPD mice with higher dual polarization of AMs. Melatonin therapy improved airflow limitation and lung damages of AECOPD mice by decreasing IAV nucleoprotein (IAV-NP) protein levels and the M1 polarization of pulmonary macrophages. Furthermore, in CSE-stimulated Raw264.7 cells, IAV infection further promoted the dual polarization of macrophages accompanied with decreased MT1 expression. Melatonin decreased STAT1 phosphorylation, the levels of M1 markers and IAV-NP via MTs reflected by the addition of luzindole. Recombinant IL-1ß attenuated the inhibitory effects of melatonin on IAV infection and STAT1-driven M1 polarization, while its converting enzyme inhibitor VX765 potentiated the inhibitory effects of melatonin on them. Moreover, melatonin inhibited IAV infection-induced apoptosis by suppressing IL-1ß/STAT1 signaling via MTs. CONCLUSIONS: These findings suggested that melatonin inhibited IAV infection, improved lung function and lung damages of AECOPD via suppressing IL-1ß/STAT1-driven macrophage M1 polarization and apoptosis in a MTs-dependent manner. Melatonin may be considered as a potential therapeutic agent for influenza virus infection-induced AECOPD.

Robust Cooperative Control for Heterogeneous Uncertain Nonlinear High-Order Fully Actuated Multiagent Systems.

This research is intended to address a robust cooperative control problem of heterogeneous uncertain nonlinear high-order fully actuated multiagent systems (HUN-HOFAMASs). A nonlinear HOFA system model is used to describe the multiagent systems (MASs) with heterogeneous uncertain nonlinear dynamics, which is called the HUN-HOFAMASs. A predictive terminal sliding-mode control-based robust cooperative control scheme is presented to address this problem. In this scheme, heterogeneous nonlinear dynamics of original system are offset to establish a linear constant HOFA system with the help of full actuation feature. Then, a terminal sliding-mode variable for enhancing the system robustness is introduced to handle the uncertainties. Furthermore, a linear incremental prediction model is developed in a HOFA form by means of a Diophantine equation. According to this model, the multistep terminal sliding-mode predictions are yielded to optimize the robust cooperative control performance and compensate for the network-induced communication constraints in the feedback and forward channels. Based on a linear matrix inequality (LMI) method, a necessary and sufficient criterion is derived to discuss the simultaneous consensus and stability of closed-loop HUN-HOFAMASs. The simulation and comparison results of cooperative flying around of multiple spacecraft system are shown to illustrate the capability and advantage of the presented predictive terminal sliding-mode control for robust cooperative control.

Liquid lens based holographic camera for real 3D scene hologram acquisition using end-to-end physical model-driven network.

With the development of artificial intelligence, neural network provides unique opportunities for holography, such as high fidelity and dynamic calculation. How to obtain real 3D scene and generate high fidelity hologram in real time is an urgent problem. Here, we propose a liquid lens based holographic camera for real 3D scene hologram acquisition using an end-to-end physical model-driven network (EEPMD-Net). As the core component of the liquid camera, the first 10 mm large aperture electrowetting-based liquid lens is proposed by using specially fabricated solution. The design of the liquid camera ensures that the multi-layers of the real 3D scene can be obtained quickly and with great imaging performance. The EEPMD-Net takes the information of real 3D scene as the input, and uses two new structures of encoder and decoder networks to realize low-noise phase generation. By comparing the intensity information between the reconstructed image after depth fusion and the target scene, the composite loss function is constructed for phase optimization, and the high-fidelity training of hologram with true depth of the 3D scene is realized for the first time. The holographic camera achieves the high-fidelity and fast generation of the hologram of the real 3D scene, and the reconstructed experiment proves that the holographic image has the advantage of low noise. The proposed holographic camera is unique and can be used in 3D display, measurement, encryption and other fields.

Observer-based HOFA predictive cooperative control for networked multi-agent systems under time-variant communication constraints.

This research focuses on a cooperative control problem for networked multi-agent systems (NMASs) under time-variant communication constraints (containing time-variant communication delays and time-variant data losses) in the forward and feedback channels. From the perspective of high-order fully actuated (HOFA) system theory, a HOFA system model is adopted to describe the NMAS, which is called the networked HOFA multi-agent system (NHOFAMAS). Because of complicated working scenarios over the network, the states of NMASs are immeasurable and the communication constraints are always present, such that an observer-based HOFA predictive control (OB-HOFAPC) method is designed to implement the cooperative control when existing the immeasurable states and time-variant communication constraints. In this method, a HOFA observer is established to estimate the immeasurable states for constructing a consensus control protocol. Then, an incremental prediction model (IPM) in a HOFA form is developed via a Diophantine equation to take the place of a reduced-order prediction model. Through this IPM, multi-step output ahead predictions are derived to optimize the cooperative control performance and compensate for time-variant communication constraints in real-time. The depth discussion gives a sufficient and necessary criterion to analyze the simultaneous consensus and stability for closed-loop NHOFAMASs. The capability and advantage of OB-HOFAPC method are illustrated via numerical simulation and experimental verification on a cooperative flying-around task of three air-bearing spacecraft simulators.

Secure Predictive Coordinated Control of High-Order Fully Actuated Networked Multiagent Systems Under Random DoS Attacks.

This research addresses a coordinated control problem for high-order fully actuated networked multiagent systems (HOFANMASs) under random denial-of-service (DoS) attacks. A type of Bernoulli processes is exploited to denote the successful rate of launching random DoS attacks happened to the forward and feedback channels. When acting these attacks successfully, random data losses and disorders are caused in the forward and feedback channels. A high-order fully actuated (HOFA) secure predictive coordinated control scheme is provided to achieve the security coordination. In this scheme, a dynamic model of networked multiagent system is established with the help of a HOFA system model, which is called the HOFANMAS. Then, a prediction model in an incremental HOFA (IHOFA) form is developed by means of a Diophantine equation, which aims at constructing the multistep ahead output predictions for the optimization of coordinated control performance and the compensation of random data losses and disorders. Furthermore, a necessary and sufficient condition is proposed to analyze the consensus and stability of closed-loop HOFANMASs. The effectiveness and superiority of HOFA secure predictive control scheme can be demonstrated via simulated and experimental results of formation control for three air-bearing spacecraft (ABS) simulators.

A low-cost and portable fluorometer based on an optical pick-up unit for chlorophyll-a detection.

Chlorophyll-a (Chl-a) fluorescence detection is an important technique for monitoring water quality. In this work, we proposed an approach that employs the mass-produced low-cost optical pick-up unit (OPU) extracted from the high-definition digital versatile disc (HD-DVD) drive as the key optical component for our chlorophyll-a fluorometer. The built-in blue-violet 405 nm laser diode of the OPU acts as the excitation light to perform laser-induced fluorescence (LIF). The laser driver and a series of intrinsic lenses within the OPU, such as an objective lens with a numerical aperture (NA) of 0.65 and a collimating lens, help reduce the size, cost, and system complexity of the fluorometer. By integrating off-the-shelf electronic components, miniaturized optical setups, and 3D-printed assemblies, we have developed a low-cost, easy-to-make, standalone, and portable fluorometer. Finally, we validated the performance of the device for chlorophyll-a fluorescence detection under laboratory and on-site conditions, which demonstrated its great potential in water monitoring applications. The limit of detection (LOD) for chlorophyll-a is 0.35 µg/L, the size of the device is 151 × 100 × 80 mm3, and the total cost of the proposed fluorometer is as low as 137.5 USD. © 2023 Elsevier Science. All rights reserved.

Characterization of genes involved in micronutrients and toxic metals detoxification in Brassica napus by genome-wide cDNA library screening.

Stresses caused by deficiency/excess of mineral nutrients or of pollution of toxic metals have already become a primary factor in limiting crop production worldwide. Genes involved in minerals and toxic metals accumulation/tolerance could be potential candidates for improving crop plants with enhanced nutritional efficiency and environmental adaptability. In this study, we first generated a high-quality yeast expression cDNA library of Brassica napus (Westar), and 46 genes mediating excess micronutrients and toxic metals detoxification were screened using the yeast genetic complementation system, including 11, 5, 6, 14, 6, and 5 genes involved in cadmium (Cd), zinc (Zn), iron (Fe), manganese (Mn), boron (B), and copper (Cu) tolerance, respectively. Characterization of genes mediating excess ions stress resistance in this study is beneficial for us to further understand ions homeostasis in B. napus.

Clinical features, microbial spectrum, and antibiotic susceptibility patterns of spontaneous bacterial peritonitis in cirrhotic patients.

BACKGROUND AND AIMS: The microbial spectrum and antimicrobial resistance patterns change over time and vary across regions in patients with spontaneous bacterial peritonitis (SBP). There is an urgent need to clarify the factors associated with in-hospital mortality in these patients. METHODS: In this study, 377 patients with SBP and 794 patients with bacterascites were analyzed for the microbial spectrum, antimicrobial resistance profiles, and laboratory findings. RESULTS: The most common pathogens were Escherichia coli (96, 25.5%), Staphylococcus epidermidis (55, 14.6%), and Enterococcus faecium (42, 11.1%). Multidrug-resistant (MDR) bacteria comprised 49.7% of gram-positive bacteria (GPB) and 48.8% of gram-negative bacteria (GNB). The most sensitive antibiotics were amikacin (91.5%), meropenem (89.8%) and piperacillin/tazobactam (87.6%). Extensively drug-resistant (XDR) (OR=51.457, p < 0.001), neutrophil count (OR=1.088, p < 0.001), and the model for end-stage liver disease (MELD) score (OR=1.124, p < 0.001) were independent predictive factors of in-hospital mortality in patients with SBP. CONCLUSION: MDR represented nearly half of the bacteria isolated from patients with SBP, of which the high prevalence of extended-spectrum ß-lactamase-producing and Carbapenem-resistant bacteria is concerning. The presence of XDR, higher MELD score, and neutrophil count were independent predictive factors associated with higher in-hospital mortality in patients with SBP, indicating that intensive care should be provided to these patients.

Modulation of HIV-1 capsid multimerization by sennoside A and sennoside B via interaction with the NTD/CTD interface in capsid hexamer.

Small molecules that bind to the pocket targeted by a peptide, termed capsid assembly inhibitor (CAI), have shown antiviral effects with unique mechanisms of action. We report the discovery of two natural compounds, sennoside A (SA) and sennoside B (SB), derived from medicinal plants that bind to this pocket in the C-terminal domain of capsid (CA CTD). Both SA and SB were identified via a drug-screening campaign that utilized a time-resolved fluorescence resonance energy transfer assay. They inhibited the HIV-1 CA CTD/CAI interaction at sub-micromolar concentrations of 0.18 µM and 0.08 µM, respectively. Mutation of key residues (including Tyr 169, Leu 211, Asn 183, and Glu 187) in the CA CTD decreased their binding affinity to the CA monomer, from 1.35-fold to 4.17-fold. Furthermore, both compounds induced CA assembly in vitro and bound directly to the CA hexamer, suggesting that they interact with CA beyond the CA CTD. Molecular docking showed that both compounds were bound to the N-terminal domain (NTD)/CTD interface between adjacent protomers within the CA hexamer. SA established a hydrogen-bonding network with residues N57, V59, Q63, K70, and N74 of CA1-NTD and Q179 of CA2-CTD. SB formed hydrogen bonds with the N53, N70, and N74 residues of CA1-NTD, and the A177and Q179 residues of CA2-CTD. Both compounds, acting as glue, can bring αH4 in the NTD and αH9 in the CTD of the NTD/CTD interface close to each other. Collectively, our research indicates that SA and SB, which enhance CA assembly, could serve as novel chemical tools to identify agents that modulate HIV-1 CA assembly. These natural compounds may potentially lead to the development of new antiviral therapies with unique mechanisms of action.

Molecular characterization and effects of the TGIF1 gene on proliferation and steroidogenesis in yak (Bos grunniens) granulosa cells.

TG interaction factor 1 (TGIF1) plays a major role in transcriptional inhibition and suppression of TGF-ß signaling, but its functional roles in granulosa cells (GCs) have not been elucidated; in particular, there is no information about the yak (Bos grunniens) TGIF1 gene. Therefore, the objectives of this study were to clone yak TGIF1 and investigate TGIF1 functions in yak GCs. RT‒PCR results showed that the coding region of yak TGIF1 is 759 bp and encodes 252 amino acids. Its nucleotide sequence showed 85.24-99.74% similarity to mouse, human, pig, goat and cattle homologous genes. To explore the functional roles of TGIF1, we studied proliferation, apoptosis, cell cycle progression, steroidogenesis and the expression levels of related genes in yak GCs transfected with small interfering RNA specific to TGIF1. The results showed that TGIF1 knockdown promoted proliferation and cell cycle progression and inhibited apoptosis and estradiol (E2) and progesterone (P4) production in cultured yak GCs. Conversely, TGIF1 overexpression inhibited proliferation and cell cycle progression and stimulated apoptosis and E2 and P4 production. In addition, these functional changes in yak GCs were observed parallel to the expression changes in genes involved in the cell cycle (PCNA, CDK2, CCND1, CCNE1, CDK4 and P53), apoptosis (BCL2, BAX and CASPASE3), and steroidogenesis (CYP11A1, 3ß-HSD and StAR). In conclusion, TGIF1 was relatively conserved in the course of animal evolution. TGIF1 inhibited GC viability and stimulated apoptosis and the secretion of E2 and P4 by yak GCs. Our results will help to reveal the mechanism underlying yak follicular development and improve the reproductive efficiency of female yaks.

Impact factors of Blastocystis hominis infection in persons living with human immunodeficiency virus: a large-scale, multi-center observational study from China.

BACKGROUND: Blastocystis hominis (Bh) is zoonotic parasitic pathogen with a high prevalent globally, causing opportunistic infections and diarrhea disease. Human immunodeficiency virus (HIV) infection disrupts the immune system by depleting CD4+ T lymphocyte (CD4+ T) cell counts, thereby increasing Bh infection risk among persons living with HIV (PLWH). However, the precise association between Bh infection risk and HIV-related biological markers and treatment processes remains poorly understood. Hence, the purpose of the study was to explore the association between Bh infection risk and CD4+ T cell counts, HIV viral load (VL), and duration of interruption in antiviral therapy among PLWH. METHODS: A large-scale multi-center cross-sectional study was conducted in China from June 2020 to December 2022. The genetic presence of Bh in fecal samples was detected by real-time fluorescence quantitative polymerase chain reaction, the CD4+ T cell counts in venous blood was measured using flowcytometry, and the HIV VL in serum was quantified using fluorescence-based instruments. Restricted cubic spline (RCS) was applied to assess the non-linear association between Bh infection risk and CD4+ T cell counts, HIV VL, and duration of interruption in highly active antiretroviral therapy (HARRT). RESULTS: A total of 1245 PLWH were enrolled in the study, the average age of PLWH was 43 years [interquartile range (IQR): 33, 52], with 452 (36.3%) being female, 50.4% (n = 628) had no immunosuppression (CD4+ T cell counts > 500 cells/µl), and 78.1% (n = 972) achieved full virological suppression (HIV VL < 50 copies/ml). Approximately 10.5% (n = 131) of PLWH had interruption. The prevalence of Bh was found to be 4.9% [95% confidence interval (CI): 3.8-6.4%] among PLWH. Significant nonlinear associations were observed between the Bh infection risk and CD4+ T cell counts (Pfor nonlinearity < 0.001, L-shaped), HIV VL (Pfor nonlinearity < 0.001, inverted U-shaped), and duration of interruption in HARRT (Pfor nonlinearity < 0.001, inverted U-shaped). CONCLUSIONS: The study revealed that VL was a better predictor of Bh infection than CD4+ T cell counts. It is crucial to consider the simultaneous surveillance of HIV VL and CD4+ T cell counts in PLWH in the regions with high level of socioeconomic development. The integrated approach can offer more comprehensive and accurate understanding in the aspects of Bh infection and other opportunistic infections, the efficacy of therapeutic drugs, and the assessment of preventive and control strategies.

The mitophagy pathway and its implications in human diseases.

Mitochondria are dynamic organelles with multiple functions. They participate in necrotic cell death and programmed apoptotic, and are crucial for cell metabolism and survival. Mitophagy serves as a cytoprotective mechanism to remove superfluous or dysfunctional mitochondria and maintain mitochondrial fine-tuning numbers to balance intracellular homeostasis. Growing evidences show that mitophagy, as an acute tissue stress response, plays an important role in maintaining the health of the mitochondrial network. Since the timely removal of abnormal mitochondria is essential for cell survival, cells have evolved a variety of mitophagy pathways to ensure that mitophagy can be activated in time under various environments. A better understanding of the mechanism of mitophagy in various diseases is crucial for the treatment of diseases and therapeutic target design. In this review, we summarize the molecular mechanisms of mitophagy-mediated mitochondrial elimination, how mitophagy maintains mitochondrial homeostasis at the system levels and organ, and what alterations in mitophagy are related to the development of diseases, including neurological, cardiovascular, pulmonary, hepatic, renal disease, etc., in recent advances. Finally, we summarize the potential clinical applications and outline the conditions for mitophagy regulators to enter clinical trials. Research advances in signaling transduction of mitophagy will have an important role in developing new therapeutic strategies for precision medicine.