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Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting.

GDF15 has potent anti-obesity effects, but its receptor was previously unknown. GFRAL has now been identified as the receptor for GDF15, and it mediates the effects of GDF15 via central actions in the hindbrain. Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant member of the transforming growth factor-β (TGF-β) superfamily and has been implicated in various biological functions, including cancer cachexia, renal and heart failure, atherosclerosis and metabolism 1 . A connection between GDF15 and body-weight regulation was initially suggested on the basis of an observation that increasing GDF15 levels in serum correlated with weight loss in individuals with advanced prostate cancer 2 . In animal models, overexpression of GDF15 leads to a lean phenotype, hypophagia and other improvements in metabolic parameters 3 , suggesting that recombinant GDF15 protein could potentially be used in the treatment of obesity and type 2 diabetes. However, the signaling and mechanism of action of GDF15 are poorly understood owing to the absence of a clearly identified cognate receptor. Here we report that GDNF-family receptor α-like (GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions of GDF15 with respect to body weight and food intake in vivo in mice. Gfral −/− mice were refractory to the effects of recombinant human GDF15 on body-weight, food-intake and glucose parameters. Blocking the interaction between GDF15 and GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and monkey, in accordance with previous reports implicating this region of the brain in the metabolic actions of GDF15 (refs. 4 , 5 , 6 ). Together, our data demonstrate that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.

In quantitative PCR research, appropriate reference genes are key to determining accurate mRNA expression levels. In order to screen the reference genes suitable for detecting gene expression in tissues of the reproductive axis, a total of 420 (males and females = 1:5) 3-year-old Magang geese were selected and subjected to light treatment. The hypothalamus, pituitary and testicular tissues were subsequently collected at different stages. Ten genes including HPRT1 , GAPDH , ACTB , LDHA , SDHA , B2M , TUBB4 , TFRC , RPS2 and RPL4 were selected as candidate reference genes. The expression of these genes in goose reproductive axis tissues was detected by real-time fluorescent quantitative PCR. The ΔCT, geNorm, NormFinder and BestKeeper algorithms were applied to sort gene expression according to stability. The results showed that ACTB and TUBB4 were the most suitable reference genes for the hypothalamic tissue of Magang goose in the three breeding stages; HPRT1 and RPL4 for pituitary tissue; and HPRT1 and LDHA for testicular tissue. For all three reproductive axis tissues, ACTB was the most suitable reference gene, whereas the least stable reference gene was GAPDH . Altogether, these results can provide references for tissue expression studies in geese under light treatment.

The global infectious disease COVID-19 is caused by SARS-CoV-2, a new member of the Coronaviridae family. Though presented as a novel disease that primarily affects the respiratory system, multi-organ involvement has been well-noticed and documented since the beginning of the pandemic. When performed properly with adequate safety measures, autopsy provides the most valuable information to decipher the pathogenesis of this novel disease, therefore providing a basis for clinical management. In addition to reviewing the macroscopic changes in organs and tissues involved in COVID-19, the relevant microscopic alterations and possible pathogenesis are also discussed.

Since the outbreak of a large-scale epidemic can trigger fear and uncertainty, disease and death, and cause a great disruption to daily life while having a significant negative impact on the national and world economies, effective planning and research to deal with the spread of epidemics are of great importance. Since the outbreak of COVID-19 in 2019, applied mathematical-statistical models have been widely used in the control and research of world epidemics. In their response to the COVID-19 pandemic, countries and the World Health Organization (WHO) have used a variety of statistical tools and mathematical models to respond to and combat pandemic diseases. The continuing threat posed by infectious diseases has led to renewed research efforts around the world. This paper analyzed 13 relevant articles from 2010 to 2022, summarized and analyzed the main contributions of statistical and mathematical models in epidemic prevention and control, and put forward suggestions for future research directions, to increase the significance of data-based statistics for the study of infectious diseases, emphasizes the role and advantages of statistical and mathematical models in the control of infectious diseases, and advocates expanding the use of mathematical modelling of epidemics and encouraging increased cross-border collaboration in epidemiology among other related disciplines. This will bring a lot of benefits to future epidemiological research.

Aim: To explore large-scale patterns and the drivers of carbon:nitrogen:phosphorus (C:N:P) stoichiometry in heterotrophic microbes. Location: A 3500-km grassland transect on the Tibetan Plateau. Methods: We investigated large-scale C:N:P stoichiometry patterns in the soil microbial biomass and their relationships with abiotic factors and soil microbial community structures by obtaining soil samples from 173 sites across the Tibetan alpine grasslands. Results: C:N:P ratios in the soil microbial biomass varied widely among grassland types, with higher microbial C:N, C:P and N:P ratios in the alpine steppe than the alpine meadow. The soil microbial C:N:P ratio (81:6:1) in the alpine steppe was significantly wider than the global average (42:6:1). Combined stepwise regression and generalized additive models revealed that variations in the microbial C:N ratio were primarily related to abiotic variables, with the microbial C:N ratio exhibiting a decreasing trend along the precipitation gradient. In contrast, variations in microbial C:P and N:P ratios were primarily associated with shifts in the community structure of soil microbes. The microbial C:P and N:P ratios were both negatively associated with all components of the soil microbial communities. However, the fungi to bacteria ratio only regulated the microbial C:P ratio. Main conclusions: These results demonstrate that microbial C:N:P stoichiometry exhibits significant flexibility across various ecosystem types. This flexibility is partly induced by shifts in microbial community structure and variations in environmental conditions.

Disturbed homeostasis of gut microbiota has been suggested to be closely associated with 5-fluorouracil (5-Fu) induced mucositis. However, current knowledge of the overall profiles of 5-Fu-disturbed gut microbiota is limited, and so far there is no direct convincing evidence proving the causality between 5-Fu-disturbed microbiota and colonic mucositis. In mice, in agreement with previous reports, 5-Fu resulted in severe colonic mucositis indicated by weight loss, diarrhea, bloody stool, shortened colon, and infiltration of inflammatory cells. It significantly changed the profiles of inflammatory cytokines/chemokines in serum and colon. Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and VE-Cadherin were increased. While tight junction protein occludin was reduced, however, zonula occludens-1 (ZO-1) and junctional adhesion molecule-A (JAM-A) were increased in colonic tissues of 5-Fu treated mice. Meanwhile, inflammation related signaling pathways including NF-κB and mitogen activated protein kinase (MAPKs) in the colon were activated. Further study disclosed that 5-Fu diminished bacterial community richness and diversity, leading to the relative lower abundance of Firmicutes and decreased Firmicutes/Bacteroidetes (F/B) ratio in feces and cecum contents. 5-Fu also reduced the proportion of Proteobacteria, Tenericutes, Cyanobacteria, and Candidate division TM7, but increased that of Verrucomicrobia and Actinobacteria in feces and/or cecum contents. The fecal transplant from healthy mice prevented body weight loss and colon shortening of 5-Fu treated mice. In addition, the fecal transplant from 5-Fu treated mice reduced body weight and colon length of vancomycin-pretreated mice. Taken together, our study demonstrated that gut microbiota was actively involved in the pathological process of 5-Fu induced intestinal mucositis, suggesting potential attenuation of 5-Fu induced intestinal mucositis by manipulating gut microbiota homeostasis.

Patches of ionization are common in the polar ionosphere, where their motion and associated density gradients give variable disturbances to high-frequency (HF) radio communications, over-the-horizon radar location errors, and disruption and errors to satellite navigation and communication. Their formation and evolution are poorly understood, particularly under disturbed space weather conditions. We report direct observations of the full evolution of patches during a geomagnetic storm, including formation, polar cap entry, transpolar evolution, polar cap exit, and sunward return flow. Our observations show that modulation of nightside reconnection in the substorm cycle of the magnetosphere helps form the gaps between patches where steady convection would give a \"tongue\" of ionization (TOI).

Cancer stem cells (CSCs) are believed as the initiators of the occurrence, development and recurrence of malignant tumors. Targeting this unique cell population would provide a less toxic approach than regular chemotherapeutic agents that kill bulk rapid proliferating tumor cells and also normal cells which divide rapidly. To date, major research effort has been aimed at identifying and eradicating CSC population. The metabolism heterogeneity of mitochondria in CSCs shows a big promise for cancer research. Of them, mitochondrial membrane potential (Δψm), reflecting the functional status of the mitochondrion is proved to be highly related to cancer malignancy. Reactive oxygen species, mainly produced from mitochondria, are also increased in many types of cancer cells. However, their statuses in CSCs remain poorly understood. Here we shall review the mitochondrial membrane potential and reactive oxygen species of CSCs and propose the novel potential targets for cancer therapy.

The long-term trends in maternal and child health (MCH) in China and the national-level factors that may be associated with these changes have been poorly explored. This study aimed to assess trends in MCH indicators nationally and separately in urban and rural areas and the impact of public policies over a 30‒year period. An ecological study was conducted using data on neonatal mortality rate (NMR), infant mortality rate (IMR), under-five mortality rate (U5MR), and maternal mortality ratio (MMR) nationally and separately in urban and rural areas in China from 1991 to 2020. Joinpoint regression models were used to estimate the annual percentage changes (APC), average annual percentage changes (AAPC) with 95% confidence intervals (CIs), and mortality differences between urban and rural areas. From 1991 to 2020, maternal and child mortalities in China gradually declined (national AAPC [95% CI]: NMRs − 7.7% [− 8.6%, − 6.8%], IMRs − 7.5% [− 8.4%, − 6.6%], U5MRs − 7.5% [− 8.5%, − 6.5%], MMRs − 5.0% [− 5.7%, − 4.4%]). However, the rate of decline nationally in child mortality slowed after 2005, and in maternal mortality after 2013. For all indicators, the decline in mortality was greater in rural areas than in urban areas. The AAPCs in rate differences between rural and urban areas were − 8.5% for NMRs, − 8.6% for IMRs, − 7.7% for U5MRs, and − 9.6% for MMRs. The AAPCs in rate ratios (rural vs. urban) were − 1.2 for NMRs, − 2.1 for IMRs, − 1.7 for U5MRs, and − 1.9 for MMRs. After 2010, urban‒rural disparity in MMR did not diminish and in NMR, IMR, and U5MR, it gradually narrowed but persisted. MCH indicators have declined at the national level as well as separately in urban and rural areas but may have reached a plateau. Urban‒rural disparities in MCH indicators have narrowed but still exist. Regular analyses of temporal trends in MCH are necessary to assess the effectiveness of measures for timely adjustments.