A BSL-2 compliant mouse model of SARS-CoV-2 infection for efficient and convenient antiviral evaluation.

Animal models of authentic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require operation in biosafety level 3 (BSL-3) containment. In the present study, we established a mouse model employing a single-cycle infectious virus replicon particle (VRP) system of SARS-CoV-2 that can be safely handled in BSL-2 laboratories. The VRP [ΔS-VRP(G)-Luc] contains a SARS-CoV-2 genome in which the spike gene was replaced by a firefly luciferase (Fluc) reporter gene (Rep-Luci), and incorporates the vesicular stomatitis virus glycoprotein on the surface. Intranasal inoculation of ΔS-VRP(G)-Luc can successfully transduce the Rep-Luci genome into mouse lungs, initiating self-replication of Rep-Luci and, accordingly, inducing acute lung injury mimicking the authentic SARS-CoV-2 pathology. In addition, the reporter Fluc expression can be monitored using a bioluminescence imaging approach, allowing a rapid and convenient determination of viral replication in ΔS-VRP(G)-Luc-infected mouse lungs. Upon treatment with an approved anti-SARS-CoV-2 drug, VV116, the viral replication in infected mouse lungs was significantly reduced, suggesting that the animal model is feasible for antiviral evaluation. In summary, we have developed a BSL-2-compliant mouse model of SARS-CoV-2 infection, providing an advanced approach to study aspects of the viral pathogenesis, viral-host interactions, as well as the efficacy of antiviral therapeutics in the future.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly contagious and pathogenic in humans; thus, research on authentic SARS-CoV-2 has been restricted to biosafety level 3 (BSL-3) laboratories. However, due to the scarcity of BSL-3 facilities and trained personnel, the participation of a broad scientific community in SARS-CoV-2 research had been greatly limited, hindering the advancement of our understanding on the basic virology as well as the urgently necessitated drug development. Previously, our colleagues Jin et al. had generated a SARS-CoV-2 replicon by replacing the essential spike gene in the viral genome with a Fluc reporter (Rep-Luci), which can be safely operated under BSL-2 conditions. By incorporating the Rep-Luci into viral replicon particles carrying vesicular stomatitis virus glycoprotein on their surface, and via intranasal inoculation, we successfully transduced the Rep-Luci into mouse lungs, developing a mouse model mimicking SARS-CoV-2 infection. Our model can serve as a useful platform for SARS-CoV-2 pathological studies and antiviral evaluation under BSL2 containment.

Synergistic Modulation of Mass Transfer and Parasitic Reactions of Zn Metal Anode via Bioinspired Artificial Protection Layer.

Rechargeable aqueous zinc-ion batteries are regarded as promising energy storage devices due to their attractive economic benefits and extraordinary electrochemical performance. However, the sluggish Zn2+ mass transfer behavior and water-induced parasitic reactions that occurred on the anode-electrode interface inevitably restrain their applications. Herein, inspired by the selective permeability and superior stability of plasma membrane, a thin UiO-66 metal-organic framework layer with smart aperture size is ex-situ decorated onto the Zn anode. Experimental characterizations in conjunction with theoretical calculations demonstrate that this bio-inspired layer promotes the de-solvation process of hydrated Zn2+ and reduces the effective contact between the anode and H2 O molecules, thereby boosting Zn2+ deposition kinetics and restraining interfacial parasitic reactions. Hence, the Zn||Zn cells could sustain a long lifespan of 1680 h and the Zn||Cu cells yielded a stable coulombic efficiency of over 99.3% throughout 600 cycles under the assistance of the bio-inspired layer. Moreover, pairing with δ-MnO2 cathode, the full cells also demonstrate prominent cycling stability and rate performance. From the bio-inspired design philosophy, this work provides a novel insight into the development of aqueous batteries.

CircUGGT2 downregulation by METTL14-dependent m6A modification suppresses gastric cancer progression and cisplatin resistance through interaction with miR-186-3p/MAP3K9 axis.

Chemoresistance is a major therapeutic challenge in advanced gastric cancer (GC). N6-methyladenosine (m6A) RNA modification has been shown to play fundamental roles in cancer progression. However, the underlying mechanisms by which m6A modification of circRNAs contributes to GC and chemoresistance remain unknown. We found that hsa_circ_0030632 (circUGGT2) was a predominant m6A target of METTL14, and METTL14 knockdown (KD) reduced circUGGT2 m6A levels but increased its mRNA levels. The expression of circUGGT2 was markedly increased in cisplatin (DDP)-resistant GC cells. CircUGGT2 KD impaired cell growth, metastasis and DDP-resistance in vitro and in vivo, but circUGGT2 overexpression prompted these effects. Furthermore, circUGGT2 was validated to sponge miR-186-3p and upregulate MAP3K9 and could abolish METTL14-caused miR-186-3p upregulation and MAP3K9 downregulation in GC cells. circUGGT2 negatively correlated with miR-186-3p expression and harbored a poor prognosis in patients with GC. Our findings unveil that METTL14-dependent m6A modification of circUGGT2 inhibits GC progression and DDP resistance by regulating miR-186-3p/MAP3K9 axis.

Oxymatrine alleviates NSAID-associated small bowel mucosal injury by regulating MIP-1/CCR1 signalling and gut microbiota.

Oxymatrine (OMT) as a quinazine alkaloid extracted from matrine has been shown to exhibit anti-inflammatory and anti-tumour effects. However, the protective mechanism of OMT on NSAID-associated small bowel mucosal injury remains unreported. We found that OMT could improve the clinical symptoms and pathological inflammation scoring, reduce the secretion of proinflammatory cytokines IL-1ß, IL-6 and TNF-α and cell apoptosis, promote cell proliferation and protect intestinal mucosal barrier as compared with the Diclofenac Sodium (DS) group. Further RNA-seq and KEGG analysis uncovered that the differentially expressed genes between DS and control groups were mainly enriched in immune regulation, of which MIP-1γ and its receptor CCR1 expression were validated to be repressed by OMTH. MAPK/NF-κB as the MIP-1 upstream signalling was also inactivated by OMT treatment. In this study, OMT regulated gut microbiota. Venn diagrams visualized and identified 1163 shared OTUs between DS group and OMTH group. The results showed that the α diversity index in the DS group was lower than that in the OMTH group, indicating that the complexity of the flora was reduced in the intestinal inflammatory state. ß diversity mainly includes Principal Component Analysis (PCA) and Principal Co-ordinates Analysis (PCoA). The differences between groups can be observed through PCA. The more similar the composition of the flora, the closer the samples are. We found that the difference was smaller in the DS group than in the OMTH group. The results of PcoA showed that the sample similarity between OMTH groups was the highest. Moreover, gut microbiota analysis unveiled that the abundances of Ruminococcus 1, Oscillibacter and Prevotellaceae at the genus level as well as Lactobacillus SP-L-Yj at the species level were increased in OMTH group as compared with the DS group but the abundance of Allobaculum, Ruminococceos-UCG-005, Ruminococceos-NK4A214 and Clostridium associated with DS-induced small bowel mucosal injury could be decreased by OMTH. MIP-1α and CCR1 were upregulated in human small bowel injury samples as compared with the normal ileal mucosa tissues. In conclusion, our findings demonstrated that OMT could alleviate NSAID-associated small bowel mucosal injury by inhibiting MIP-1γ/CCR1 signalling and regulating gut microbiota.

Intracavity frequency doubling acousto-optic Q-switched high repetition rate high-energy Nd:YLF laser.

The ongoing advancement of Ti:sapphire femtosecond laser technology has drawn increasing attention to high repetition rate, high-energy green lasers as ideal pump sources for Ti:sapphire regenerative amplifiers. This study employed a neodymium-doped yttrium lithium fluoride (Nd:YLF) as the gain medium, supplemented with side-pumped laser diodes, acousto-optic Q-switching, and intracavity frequency doubling technologies. The results demonstrated a repetition rate ranging from 1-10 kHz, a pulse width of less than 100 ns, and a single pulse energy exceeding 50 mJ at 527 nm green light output. Furthermore, an operating stability (RMS) of ≤0.15% was maintained for 14 h at a repetition rate of 1 kHz and an output power of 40 W.

Relationship Between Serum MMP-2, Siglec-1, Th1/Th2 Cell Ratio, and Disease Activity in Rheumatoid Arthritis.

Objective: To investigate the association of serum MMP-2, Siglec-1, and Th1/Th2 cell ratio with disease activity in rheumatoid arthritis (RA). Methods: Between August and November 2020, Peking University People's Hospital recruited 40 patients with RA and 40 healthy individuals. Various methods such as ELISA, flow cytometry, and RT-PCR were used to assess the levels of sCR1, MMP-2, MMP-9, and Siglec-1 in the participants. Correlation analysis was conducted between Siglec-1 expression and DAS28 and hs-CRP. T lymphocyte subsets; cytokines IFN-γ and IL-4, were assessed using flow cytometry and ELISA in both patient groups. Results: Rheumatoid arthritis was linked to lower levels of serum sCR1 and higher levels of MMP-2 and MMP-9 compared to healthy individuals (P < .05). The percentage of Siglec-1-positive cells in PBMCs was significantly higher in patients with RA than in the healthy group (P < .05), with monocytes being the predominant cells expressing Siglec-1. Patients with RA exhibited a significantly higher expression of Siglec-1 mRNA compared to those in a healthy condition (P < .05), and the expression of Siglec-1 in these patients was positively correlated with DAS28 and hs-CRP (P < .05). Study patients demonstrated a notably lower level of peripheral blood CD8+ cells and a higher CD4+/CD8+ ratio when compared to healthy individuals (P < .05). There was no statistically significant difference in CD3+CD4+ levels between the 2 groups (P > .05). Rheumatoid arthritis was associated with a higher level of peripheral blood IFN-γ and a lower IL-4 level than healthy individuals (P < .05). Conclusion: There was a strong link between sCRl, MMP-2, and MMP-9 and the progression of rheumatoid arthritis. These markers can effectively monitor disease activity in patients with rheumatoid arthritis. Siglec-1 is highly expressed in peripheral blood and can be used to track disease activity and inflammation in these patients. Regulating Th1/Th2-mediated homeostasis may help alleviate symptoms in individuals with rheumatoid arthritis.

Effect of Exercise Rehabilitation Combined with Alfacalcidol Administration on Patellofemoral Traumatic Dysfunction.

Objective: To investigate the efficacy and clinical value of alfacalcidol combined with exercise rehabilitation in therapy of the postoperative dysfunction of patients with patella fractures. Methods: In this study, 100 patients who underwent patella fracture surgery at Peking University People's Hospital between April 2018 and December 2019 were randomly selected and divided into a control group (n=50) and an experimental group (n=50) by lottery. The control group received exercise therapy, while the experimental group received alfacalcidol based on exercise rehabilitation. The functional assessment measure (FAM) score, visual analog scale (VAS) score, therapy efficiency, adverse effects, callus volume, and callus density were compared between the two groups. Results: The FAM score and therapy efficiency in the experimental group were significantly higher than in the control group [P < .001, RR: 95%CI (10.28, 5.12 to 15.52)], but the VAS score was lower [P < .001 RR: 95% CI (22.83, 1.99 to 3.31)]. Patients in the experimental group had fewer adverse effects [P < .001, RR: 95% CI (14.62, 6.49 to 32.92)] than those in the control group but significantly larger callus volume and density [both P < .001, RR: 95% CI (26.03, 3.21 to 4.07): (17.92, 2.83 to 3.34)]. Conclusion: Alfacalcidol combined with exercise rehabilitation therapy could significantly improve motor function, callus volume, and callus density in patients with patella fracture, resulting in a high applicable value in managing postoperative functional impairment of patellar fractures.

Titanium-Oxygen Clusters Brazing Li with Li6.5La3Zr1.5Ta0.5O12 for High-Performance All-Solid-State Li Batteries.

Garnet-based solid-state electrolytes are considered crucial candidates for solid-state Li batteries due to their high Li+ conductivity and nonflammability; however, poor interfacial contact with the Li anode and growth of Li dendrites limit their application. Herein, a high-activity titanium-oxygen cluster is used as a brazing filler to braze the Li6.5La3Zr1.5Ta0.5O12 (LLZTO) with an Li anode into the whole unit. The brazing layer leads to a significantly lower interfacial impedance of 8.32 Ω cm2. Furthermore, the brazing layer is an isotropic amorphous ion-electron hybrid conductive layer, which significantly promotes Li+ transport and regulates the distribution of the electric field, therefore inhibiting the growth of Li dendrites. The cell exhibits an ultrahigh critical current density of 2.3 mA cm-2 and stable cycling of over 4000 h at 0.5 mA cm-2 (25 °C).

Engineering Lattice Oxygen Regeneration of NiFe Layered Double Hydroxide Enhances Oxygen Evolution Catalysis Durability.

The lattice oxygen mechanism (LOM) endows NiFe layered double hydroxide (NiFe-LDH) with superior oxygen evolution reaction (OER) activity, yet the frequent evolution and sluggish regeneration of lattice oxygen intensify the dissolution of active species. Herein, we overcome this challenge by constructing the NiFe hydroxide/Ni4Mo alloy (NiFe-LDH/Ni4Mo) heterojunction electrocatalyst, featuring the Ni4Mo alloy as the oxygen pump to provide oxygenous intermediates and electrons for NiFe-LDH. The released lattice oxygen can be timely offset by the oxygenous species during the LOM process, balancing the regeneration of lattice oxygen and assuring the enhancement of the durability. In consequence, the durability of NiFe-LDH is significantly enhanced after the modification of Ni4Mo with an impressively durability for over 60 h, much longer than that of NiFe-LDH counterpart with only 10 h. In-situ spectra and first-principle simulations reveal that the adsorption of OH- is significantly strengthened owing to the introduction of Ni4Mo, ensuring the rapid regeneration of lattice oxygen. Moreover, NiFe-LDH/Ni4Mo-based anion exchange membrane water electrolyzer (AEMWE) presents an impressive durability for over 150 h at 100 mA cm-2. The oxygen pump strategy opens opportunities to balance the evolution and regeneration of lattice oxygen, enhancing the durability of efficient OER catalysts.

Unmasking the biological function and regulatory mechanism of NOC2L: a novel inhibitor of histone acetyltransferase.

NOC2 like nucleolar associated transcriptional repressor (NOC2L) was recently identified as a novel inhibitor of histone acetyltransferase (INHAT). NOC2L is found to have two INHAT function domains and regulates histone acetylation in a histone deacetylases (HDAC) independent manner, which is distinct from other INHATs. In this review, we summarize the biological function of NOC2L in histone acetylation regulation, P53-mediated transcription, ribosome RNA processing, certain development events and carcinogenesis. We propose that NOC2L may be explored as a potential biomarker and a therapeutic target in clinical practice.

Interaction of Phytohormones and External Environmental Factors in the Regulation of the Bud Dormancy in Woody Plants.

Bud dormancy and release are essential phenomena that greatly assist in adapting to adverse growing conditions and promoting the holistic growth and development of perennial plants. The dormancy and release process of buds in temperate perennial trees involves complex interactions between physiological and biochemical processes influenced by various environmental factors, representing a meticulously orchestrated life cycle. In this review, we summarize the role of phytohormones and their crosstalk in the establishment and release of bud dormancy. External environmental factors, such as light and temperature, play a crucial role in regulating bud germination. We also highlight the mechanisms of how light and temperature are involved in the regulation of bud dormancy by modulating phytohormones. Moreover, the role of nutrient factors, including sugar, in regulating bud dormancy is also discussed. This review provides a foundation for enhancing our understanding of plant growth and development patterns, fostering agricultural production, and exploring plant adaptive responses to adversity.

Financial reform and haze pollution: A quasi-natural experiment of the financial reform pilot zones in China.

Financial reform becomes a new tool for environmental governance because it can indirectly affect the environment by promoting economic and financial agglomeration and technological innovation. Despite China's aggressive financial reform pilot (FRP) policy since 2012, little is known about whether and how such policy affects haze pollution (HP). We exploit geographic and temporal variations in China's FRP policy and compile a dataset covering 284 cities over the period from 2003 to 2019. Employing a difference-in-differences (DID) approach, we document that China's FRP policy has a negative causal effect on HP in the pilot cities. The estimates obtained from an instrumental variable constructed by religious temples also support the haze-abatement effect of such policy. This effect is largely driven by advances in technological innovation and increases in economic agglomeration, while financial agglomeration is proven to have little effect. Finally, our estimate is particularly pronounced in cities with high levels of economic development, financial development and technological innovation, and that in large-sized and non-mineral resourced cities. Overall, our findings shed light on the importance of financial reform in environmental governance in a developing country.

The outgoing audit of natural resources assets and enterprise productivity: New evidence from difference-in-differences-in-differences in China.

Despite increasing evidence documenting the role of the outgoing audit of natural resources (OANRA) in environmental governance and enterprise innovation, little is known about its impact on enterprises' total factor productivity (TFP). To address this question, we treat the OANRA policy launched in 2014 in China as a quasi-natural experiment. We adopt a difference-in-differences-in-differences (DDD) method that exploits three-dimensional variations: city (i.e., OANRA cities versus non-OANRA cities), industry (i.e., more polluting industries versus less polluting ones), and year (i.e., before and after the OANRA policy). Employing a dataset of Chinese industrial listed companies from 2012 to 2019, we reveal that after the OANRA implementation, enterprises' TFP in more polluting industries of OANRA cities decreases by 4.0%. Our mechanism analysis shows that the OANRA restrains the TFP by reducing the financing scale of enterprises and increasing environmental investment of governments. Further, the heterogeneity analysis finds the inhibitory effect of the OANRA is more prominent in large-scale and state-owned enterprises, as well as enterprises located in eastern, low fiscal pressure, and high pollutant emission cities. Our findings provide support for the neoclassical economics hypothesis that the OANRA increases enterprises' compliance costs and decreases their productivity.

SCFusion: Infrared and Visible Fusion Based on Salient Compensation.

The aim of infrared and visible image fusion is to integrate the complementary information of the two modalities for high-quality fused images. However, many deep learning fusion algorithms have not considered the characteristics of infrared images in low-light scenes, leading to the problems of weak texture details, low contrast of infrared targets and poor visual perception in the existing methods. Therefore, in this paper, we propose a salient compensation-based fusion method that makes sufficient use of the characteristics of infrared and visible images to generate high-quality fused images under low-light conditions. First, we design a multi-scale edge gradient module (MEGB) in the texture mainstream to adequately extract the texture information of the dual input of infrared and visible images; on the other hand, the salient tributary is pre-trained by salient loss to obtain the saliency map based on the salient dense residual module (SRDB) to extract salient features, which is supplemented in the process of overall network training. We propose the spatial bias module (SBM) to fuse global information with local information. Finally, extensive comparison experiments with existing methods show that our method has significant advantages in describing target features and global scenes, the effectiveness of the proposed module is demonstrated by ablation experiments. In addition, we also verify the facilitation of this paper's method for high-level vision on a semantic segmentation task.

[Analysis of diet structure of Kashin-beck disease area in Chamdo-Lhorong of Tibet in 2021].

OBJECTIVE: To investigate and compare the dietary structure between healthy people and patients in KBD area of Chamdo-Lhorong of Tibet. METHODS: A case-control study design was used, retrospectively select patients who had completed screening and registered in the national Kashin-Beck Disease surveillance system in 2021 in Luolong County, Qamdo, Tibet as the source population of the case group, and randomly selected people who had not been screened for Kashin-Beck disease in the same county as the control group. The self-made diet questionnaire was used to record the types of food consumption, frequency of food intake, basic information of the respondents, family size and other basic information in the past year by one-on-one interview. RESULTS: The staple food with the highest response among the patients(97.33%) was rice(rice/rice noodle), and the highest response among the healthy people(90%) was non-wheat products, non-fried pasta(bread/steamed bun/noodles/dumplings), except instant noodles.78.7% of patients chose not to eat local wheat(Tibetan noodles), and the number of non-patients who chose to eat non-local wheat(Tibetan noodles) 3-4 times a week was significantly higher than that of patients. The meat and meat products with the highest response in both patients(93.33%) and healthy people(90%) was yak meat(local). The control group also chose to consume beef(non-local/lamb/mutton/other non-processed meat), poultry and livestock offal, fish(all seawater and freshwater fish), shrimp and crabs or other seafood, and their consumption rate and intake frequency were significantly higher than those of the case group. The consumption rate and frequency of tomato, onion and garlic(garlic shoots/leek/onion/onion) and fresh eggs(egg/duck egg/quail egg/goose egg) in control group were significantly higher than those in case group. There was no significant difference in consumption rate and frequency of fruits, milk and dairy products between the two groups. CONCLUSION: In addition to the local highland barley(zanba), most people also chose to purchase rice and flour, which changed the situation of single staple food in the past. However, compared with the healthy population in the disease area, the consumption rate and intake frequency of fish, shrimp and crabs, poultry and livestock viscera, eggs(fresh eggs) and vegetables(tomatoes, scallions, ginger and garlic) in KBD patients were significantly lower, the selection of meat varieties is single, mainly local yak meat, and the overall dietary structure still presents the risk of single type and unbalanced diet.

Peptide Self-Assemblies from Unusual α-Sheet Conformations Based on Alternation of d/l Amino Acids.

Peptide self-assembly is a hierarchical process during which secondary structures formed in the initial stages play a critical role in determining the subsequent assembling processes and final structural ordering. Unusual secondary structures hold promise as a source to develop novel supramolecular architectures with unique properties. In this work, we report the design of a new peptide self-assembly strategy based on unusual α-sheet secondary structures. In light of the strong propensity of leucine toward forming helical conformations and its high hydrophobicity, we design two short amphiphilic peptides Ac-LDLLDLK-NH2 and Ac-DLLDLLDK-NH2 with alternating l- and d-form amino acids. Microscopic imaging, neutron scattering, and spectroscopic measurements indicate that the two heterochiral peptides form highly ordered wide nanotubes and helical ribbons with monolayer thickness, in sharp contrast to twisted nanofibrils formed by the homochiral peptide Ac-LLLLK-NH2. Molecular dynamics simulations from monomers to trimers reveal that the two heteropeptides fold into α-sheets instead of ß-sheets, which readily pack into tubular architectures in oligomer simulations. Simulated circular dichroism spectra based on α-sheet oligomers validate the proposed α-sheet secondary structures. These results form an important basis for the rational design of higher-order peptide assemblies with novel properties based on unusual α-sheet secondary structures.

METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

BACKGROUND: N6-methyladenosine (m6A) RNA methylation and circular RNAs (circRNAs) have been shown to act vital roles in multiple malignancies including gastric cancer (GC). However, there is little knowledge about how m6A modification of circRNAs contributes to GC progression. METHODS: The association of METTL14 expression with the clinicopathological characteristics and prognosis in patients with GC was assessed by Western blot, Immunohistochemistry and public datasets. In vitro and vivo function experiments were conducted to investigate the role of METTL14 in GC. Furthermore, m6A-circRNA epitranscriptomic microarray was utilized to identify METTL14-mediated m6A modification of circRNAs, which were validated by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in GC cells. The sponge of circORC5 with miR-30c-2-3p was confirmed by luciferase gene report and RNA immunoprecipitation assays. The expression, localization and prognosis of circORC5 in GC were evaluated by fluorescence in situ hybridization. The effects of METTL14 and (or) circORC5 on miR-30c-2-3p-mediated AKT1S1 and EIF4B were estimated by RT-qPCR and Western blot analyses. RESULTS: We found that METTL14 was downregulated in GC tissue samples and its low expression acted as a prognostic factor of poor survival in patients with GC. Ectopic expression of METTL14 markedly repressed growth and invasion of GC cells in vitro and in vivo, whereas knockdown of METTL14 harbored the opposite effects. Mechanically, m6A-circRNA epitranscriptomic microarray and Me-RIP identified circORC5 as the downstream target of METTL14. Silencing of METTL14 reduced the m6A level of circORC5, but increased circORC5 expression. Moreover, circORC5 could sponge miR-30c-2-3p, and reverse METTL14-caused upregulation of miR-30c-2-3p and downregulation of AKT1S1 and EIF4B. In addition, circORC5 possessed a negative correlation with miR-30c-2-3p and indicated a poor survival in GC. CONCLUSION: Our findings demonstrate that METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis.

Influencing factors for the decline of limb muscle strength and the association with all-cause mortality: evidence from a nationwide population-based cohort study.

BACKGROUND: The decline of muscle strength, a typical characteristic of sarcopenia, greatly affects aging-related health outcomes; however, prospective data on influencing factors and mortality in the Chinese population are relatively sparse. AIMS: We investigated the influencing factors for the declined limb muscle strength and the association with all-cause mortality among the elderly Chinese individuals aged ≥ 65 years in a large long-term prospective cohort study. METHODS: We used data from the China Health and Retirement Longitudinal Study (CHARLS). Logistic regression analyses were performed to investigate the influencing factors of declined limb muscle strength. Cox proportional hazard models were used to analyze the impact on all-cause mortality, whose performance was evaluated by train-test cross-validation. RESULTS: The prevalences of declined upper and lower limb strength, which were defined by low hand grip strength (HS) and gait speed (GS), respectively, were 34.4% and 59.7%. The declined HS was significantly associated with older age (p < 0.001), female (p < 0.001), lower educational level (p < 0.001), lower BMI (p < 0.001), and combined with chronic diseases (p = 0.001). Moreover, the declined limb muscle strength was correlated with all-cause mortality (HR: 1.13, 95% CI 1.03-1.21 for HS; HR: 1.09, 95% CI 1.04-1.15 for GS), according to a multi-adjusted model with moderate predictive ability (C-index: 0.714, AUC of 7 year follow-up: 0.716). CONCLUSIONS: The decline of limb muscle strength was prevalent among elderly Chinese individuals and had a strong impact on all-cause mortality. Identification of key populations and tailored interventions on their influencing factors should be implemented in further research.

Constipation induced gut microbiota dysbiosis exacerbates experimental autoimmune encephalomyelitis in C57BL/6 mice.

BACKGROUND: Constipation is a common gastrointestinal dysfunction which has a potential impact on people's immune state and their quality of life. Here we investigated the effects of constipation on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). METHODS: Constipation was induced by loperamide in female C57BL/6 mice. The alternations of gut microbiota, permeability of intestinal barrier and blood-brain barrier, and histopathology of colon were assessed after constipation induction. EAE was induced in the constipation mice. Fecal microbiota transplantation (FMT) was performed from constipation mice into microbiota-depleted mice. Clinical scores, histopathology of inflammation and demyelination, Treg/Th17 and Treg17/Teff17 imbalance both in the peripheral lymphatic organs and central nervous system, cytokines include TGF-ß, GM-CSF, IL-10, IL-17A, IL-17F, IL-21, IL-22, and IL-23 in serum were assessed in different groups. RESULTS: Compared with the vehicle group, the constipation mice showed gut microbiota dysbiosis, colon inflammation and injury, and increased permeability of intestinal barrier and blood-brain barrier. We found that the clinical and pathological scores of the constipation EAE mice were severer than that of the EAE mice. Compared with the EAE mice, the constipation EAE mice showed reduced percentage of Treg and Treg17 cells, increased percentage of Th17 and Teff17 cells, and decreased ratio of Treg/Th17 and Treg17/Teff17 in the spleen, inguinal lymph nodes, brain, and spinal cord. Moreover, the serum levels of TGF-ß, IL-10, and IL-21 were decreased while the GM-CSF, IL-17A, IL-17F, IL-22, and IL-23 were increased in the constipation EAE mice. In addition, these pathological processes could be transferred via their gut microbiota. CONCLUSIONS: Our results verified that constipation induced gut microbiota dysbiosis exacerbated EAE via aggravating Treg/Th17 and Treg17/Teff17 imbalance and cytokines disturbance in C57BL/6 mice.

Punicalagin is a neuraminidase inhibitor of influenza viruses.

Influenza A virus (IAV) causes great morbidity and mortality worldwide every year. However, there are only a limited number of drugs clinically available against IAV infection. Further, emergence of drug-resistant strains can render those drugs ineffective. Thus there is an unmet medical need to develop new anti-influenza agents. In this study, we show that punicalagin from plants possesses strong anti-influenza activity with a low micromolar IC50 value in tissue culture. Using a battery of bioassays such as single-cycle replication assay, neuraminidase (NA) inhibition assay, and virus yield reduction assay, we demonstrate that the primary mechanism of action (MOA) of punicalagin is the NA-mediated viral release. Moreover, punicalagin can inhibit replication of different strains of influenza A and B viruses, including oseltamivir-resistant virus (NA/H274Y), indicating that punicalagin is a broad spectrum antiviral against both IAV and IBV. Further, although punicalagin targets NA like oseltamivir, it has a different MOA. These results suggest that punicalagin is an influenza NA inhibitor that may be further developed as a novel antiviral against influenza viruses.