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Objectives: Observational studies suggested that obesity may promote the development of allergic rhinitis. The aim of this study was to explore the association of obesity, lipids and adipokines with this allergic disease at the genetic level using Mendelian randomization strategies. Methods: Summary data for three obesity indicators (such as body mass index), eight lipid indicators (such as triglycerides) and six adipokines (such as interleukin-6 and adipocyte fatty acid-binding protein) were collected, and suitable instrumental variables were extracted from these summary data according to the three main assumptions of Mendelian randomization. Three Mendelian randomization methods (such as inverse variance weighted) were used to detect the casual effect of the above indicators on allergic rhinitis risk. Sensitivity analyses were performed to assess heterogeneity and horizontal pleiotropy. Results: After Bonferroni correction, the inverse variance weighted reported that elevated levels of interleukin-6 and adipocyte fatty acid-binding protein were nominally associated with the decreased risk of allergic rhinitis (OR = 0.870, 95% CI 0.765–0.990, p = 0.035; OR = 0.732, 95% CI 0.551–0.973, p = 0.032). The other Mendelian randomization methods supported these results. Obesity, lipids and other adipokines were not related to this allergic disease. Sensitivity analyses found no heterogeneity and horizontal pleiotropy in the study. Conclusion: The study provided some interesting, but not sufficient, evidence to suggest that interleukin-6 and adipocyte fatty acid-binding protein might play a protective role in the development of allergic rhinitis at the genetic level. These findings should be validated by more research. Level of evidence: This was a Mendelian randomized study with a level of evidence second only to clinical randomized trials, and higher than cohort and case-control studies.

The dramatic changes in global climate on human health have been extremely severe. The immune disorder caused by low temperature and high humidity (LTHH) have become a severe public health issue. Clinically, Jingfang granule (JF) has the effect of dispelling cold and eliminating dampness, and is widely used in the treatment of cold caused by wind and cold, autoimmune diseases, and COVID-19 with cold-dampness stagnating in the lung pattern. Our study aims to elucidate the effect of JF on LTHH-induced immune disorders in mice as well as the underlying mechanisms. In this study, JF increased the spleen index, improved fecal character, repaired the intestinal barrier and alleviated intestinal inflammatory responses. Most importantly, JF ameliorated immune disorder in LTHH mice, which was manifested primarily by the significant increase in gdT, CD8+ Tcm, and CD8+ Tem cells, as well as the decrease in TH1, TH17, CD4+ Tem1, CD4+ Tem2, immature NK, mature NK cells, and M1-like macrophages. Interestingly, the JF treatment not only regulated the gut microbiota by decreasing the abundance of harmful bacteria, as well as up-regulating the abundance of beneficial bacteria, but also ameliorated the metabolic disorders by reversing the levels of fecal metabolites to normality. The results of the correlation analysis demonstrated a significant association among gut microbiota, fecal metabolites and immune cells. In addition, JF inhibited the TLR4/NF-κB/NLRP3 pathway in LTHH mice. In conclusion, our results suggested that JF alleviated inflammation and immune disorders in LTHH mice by restoring gut microbiota and fecal metabolism.

Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which effectively improve the symptoms of constipation. However, the mechanism has not been fully evaluated. The purpose of this study was to evaluate the effect of SHTB on the symptoms and intestinal barrier of mice with constipation. Our data showed that SHTB effectively improved the constipation induced by diphenoxylate, which was confirmed by shorter first defecation time, higher internal propulsion rate and fecal water content. Additionally, SHTB improved the intestinal barrier function, which was manifested by inhibiting the leakage of Evans blue in intestinal tissues and increasing the expression of occludin and ZO-1. SHTB inhibited NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway, reduced the number of proinflammatory cell subsets and increased the number of immunosuppressive cell subsets to relieve inflammation. The photochemically induced reaction coupling system combined with cellular thermal shift assay and central carbon metabolomics technology confirmed that SHTB activated AMPKα through targeted binding to Prkaa1 to regulate Glycolysis/Gluconeogenesis and Pentose Phosphate Pathway, and finally inhibited intestinal inflammation. Finally, no obvious toxicity related to SHTB was found in a repeated drug administration toxicity test for consecutive 13 weeks. Collectively, we reported SHTB as a TCM targeting Prkaa1 for anti-inflammation to improve intestinal barrier in mice with constipation. These findings broaden our knowledge of Prkaa1 as a druggable target protein for inflammation inhibition, and open a new avenue to novel therapy strategy for constipation injury.

Purpose: The role of serum thymidine kinase 1 (STK1) in predicting the prognosis of T4-stage lung squamous cell carcinoma (LUSC) with immunotherapy is the focus of our work. Methods: A total of 180 LUSC patients were enrolled. In this study, according to the T stage, the patients were divided into two groups: the T1-T2 stage and the T3-T4 stage. Receiver operating characteristic (ROC) curves were used to determine the best cutoff value for predicting overall survival (OS) outcomes. The next step is to use this cutoff value to introduce univariate and multivariate Cox regression models to screen the prognostic factors in different T stages of LUSC. The association of STK1 with other clinicopathological factors was also determined. Finally, to further explore the link between STK1 and the staging of LUSC patients, we have further divided the staging into T1-3 and T4 stages. We identified factors influencing the prognosis of patients who received immunotherapy in T4 stage LUSC. Results: First, we determined that the optimal cutoff for STK1 for predicting OS outcome was 1.165 pmol/L. Correlation analysis revealed that STK1 was over-expressed in LUSC patients at the T3-4 stage. Univariate and multivariate analysis showed that immunotherapy was an independent prognostic factor in patients with T4 stage LUSC. In the group of patients who received immunotherapy or not, the STK1 expression level was found to be an independent prognostic factor in T4 LUSC patients receiving PD-1/PD-L1 inhibitor treatment; patients with high levels of STK1 had an increased risk of death (95%CI = 1.028–2.04). Conclusion: STK1 is associated with a higher T stage and may be an effective prognostic marker for advanced LUSC immunotherapy patients.

Chimeric antigen receptor (CAR) T-cell therapy is emerging as an effective cancer treatment, such as for hematological malignancies, however its effectiveness as an approach to treat solid tumors, such as in colorectal cancer (CRC), remains to be better developed. One area of intense development has been in the identification and characterization of novel cancer-related ligand receptors for CAR design and evaluation. It is known that the CD6 receptors CD166 and CD318 are highly expressed in CRC, and several CAR-Ts have also been explored in preclinical and clinical studies for the treatment of CRC, with promising safety and efficacy findings. Here, we constructed a CAR based on the extracellular domain of CD6 and demonstrate its cytotoxic effect in target positive human CRC cell lines. Unexpectedly, we found that CD6-CAR-T cells targeted CD166 instead of CD318. Furthermore, CD6-CAR-T cells show robust cytotoxicity to CD166-positive cell lines in a dose-dependent manner with cytokine IFN-γ significantly released. Particularly, CD6-CAR-T cells show potent cytotoxicity targeting CRC cancer stem cells (CSCs), highlighting that CD6-CAR-T is a promising approach for the therapy of CRC.

Mastitis is the most common malignant disease in women, which seriously threatens women's physical and mental health. Jingfang Granules (JF) is a Chinese medicine compound, derived from the classic famous prescription-''Jingfang Baidu Powder''. JF has been widely used to relieve symptoms such as fever, headache, and cough caused by a cold. Our previous studies have shown that JF contains various active ingredients (β-sitosterol, isorhamnetin, hesperetin), which has the effect on antibacterial, anti-inflammatory and anti-apoptotic. Previous studies conveyed that JF had the potential to treat metabolic abnormalities and inflammation, which promoted us to investigate its therapeutic effects on LPS-induced mastitis and the underlying mechanisms. The pathologic changes suggested that the mammary gland edema and inflammatory factor infiltration were alleviated by JF in LPS-induced mastitis model. Furthermore, The ELISA assays suggested that the activity of Myeloperoxidase (MPO) and the expression of pro-inflammatory factors such as IL-1β, IL-6 and TNF-α were reduced by JF. The protein levels of TLR4, P-NF-κB, NLRP3, ASC, Caspase-1, IL-1β, P-P38, P-ERK1/2, and P-AKT were detected by western blotting. And then we found that JF alleviated mastitis inflammation by regulating NF-κB, NLRP3, PI3K/AKT, MAPK signaling pathways. In addition, we found that JF improved the integrity of the blood-milk barrier by increasing the expression of ZO-1, Claudin-3 and Occludin. Interestingly, JF could also significantly inhibit LPS-induced apoptosis. In summary, we successfully established a model of LPS-induced mastitis in mice and confirmed that JF could inhibit inflammation, improve the integrity of the blood-milk barrier and inhibit apoptosis, which also indicates the potential applicability of JF for the prevention and treatment of mastitis.

Abstract: We have previously shown that immunomodulatory drug (IMiD) compounds induce a shift into immature myeloid precursors with a maturational arrest and subsequent neutropenia. The mechanism of action is unknown. Here we found that IMiD compounds cause selective ubiquitination and degradation of the transcription factor IKZF1 in CD34+ cells by the Cereblon (CRBN) E3 ubiquitin ligase. Loss of IKZF1 is associated with a decrease of the IKZF1-dependent transcription factor PU.1, critical for the development and maturation of neutrophils. Using a thalidomide analog bead pull-down assay, we showed that IMiD compounds directly bind CRBN in CD34+ cells. Knockdown of CRBN in CD34+ cells resulted in resistance to POM-induced IKZF1 downregulation and reversed the POM-induced lineage shift in colony-formation assays, suggesting that the POM-induced degradation of IKZF1 in CD34+ cells requires CRBN. Chromatin immunoprecipitation assays revealed that IKZF1 binds to the promoter region of PU.1, suggesting that PU.1 is a direct downstream target of IKZF1 in CD34+ cells. POM failed to induce IKZF1 degradation in IKZF1-Q146H-OE CD34+ cells, indicating that CRBN binding to IKZF1 and subsequent IKZF1 ubiquitination is critical in this process. Using the NOD/SCID/γ-c KO mouse model, we confirmed the induction of myeloid progenitor cells by IMiD compounds at the expense of common lymphoid progenitors. These results demonstrate a novel mechanism of action of IMiD compounds in hematopoietic progenitor cells, leading to selective degradation of transcription factors critical for myeloid maturation, and explain the occurrence of neutropenia associated with treatment by IMiD compounds.

1. Forest ecosystem is a basic component of terrestrial ecosystem that mitigates the impact of climate change through absorbing significant amount of carbon dioxide. Forest is crucial in maintaining ecological equilibrium, reducing greenhouse gas emission, and preserving biodiversity. Thus, standardised and precise methodologies for measuring forest carbon sequestration and assessing its potential are of paramount importance in evaluating the impacts of climate change.2. We presented the “forestat”, an approach for assessing forest carbon sequestration and its potential based on annual growth of biomass, considering site class and forest age conditions, wrapped in an R package, which is applicable to all forest types. By using a comprehensive system of forest stand models, “forestat” contributes to a refined comprehension of relationships between forest biomass and carbon sequestration and offers an evaluation of the carbon sequestration potential in forest ecosystem, unifying the methods of carbon measurement and its potential estimation in both natural and plantation forests.3. Based on the two applications, this study (a) introduces and demonstrates the methods in R package “forestat”; (b) uses the 6th, 7th, 8th, and 9th National Forest Inventory data to investigate carbon sequestration and potential productivity of degraded forests in China; and (c) conducts suitability analysis for tree species in the Yellow River Basin.4. “forestat” provides a unified, efficient, and standardized analytical tool for forest carbon sequestration and its potential. This study also highlights the primary forest functionalities.

Global warming has been leading to frequent climate extremes, and a single variable of climate extremes is no longer sufficient to fully assess the impact of climate extremes on ecosystems, requiring a synergistic multivariate inquiry. We obtain the compound warm-dry index (CWD) and the compound cold-dry index (CCD), based on a Copula theory with a binary distribution of a standardized precipitation index (SPI) and a standardized temperature index (STI). Changes in the spatial and temporal patterns of the compound extreme climate indices (CECIs) and the direct and lag responses of ecological indicators (EIs) to the CECIs in Southwestern China (SWC) are analyzed using these two indices. We find that CECIs rise continually during 1980–2019 (p 3000 m). Spring CCD promotes the growth of vegetation at low elevation (

Study region: The Natural Forest Protection Project area in China (NFPP). Study focus: Applying the Pattern-Process-Mechanism theory, we analyzed the spatiotemporal differentiation pattern and change trend of evapotranspiration (ET) in NFPP from 2000 to 2018. We employed methods such as geographical detectors and path analysis to identify the dominant factors and response mechanisms of ET changes in NFPP, specifically those resulting from vegetation recovery and climate change. New hydrological insights for the region: Our study reveals that ET in NFPP exhibits a fluctuating increasing trend, rising from 299.155 mm/yr in 2000–336.805 mm/yr in 2018, with an annual average of 316.486 mm/yr and a change rate of 2.092 mm/yr. The proportion of areas with decreasing ET trend in NFPP (50.944%) is approximately equal to that of areas with increasing ET trend (49.056%). Vegetation restoration (18.959%), water conditions (18.460%), and thermal conditions (56.526%) are the predominant factors that influence the changes and distribution of ET in NFPP. However, the trend of ET and its dominant factors vary by region. We emphasize that, given the circumstances of climate change and the continued increase in ET, future vegetation recovery strategies must consider water usage, as this has critical practical implications for the sustained maintenance of regional ecological engineering outcomes.

Knowledge of habitats and food distribution patterns of Hainan gibbon (Nomascus hainanus) is essential for developing an effective conservation management for the threatened species. Despite having been rediscovered nearly a decade ago, very little is known about its food resources or habitats. In this study, we assessed differences in the food plant diversity as well as identifying the dominant species of food plants between the high- and low-altitude habitats of Hainan gibbons. We particularly focused on large trees (DBH ≥ 10 cm) because they are recognized to provide abundant fruit resources and good environments to gibbons. Results showed that food plants richness, and large food plants richness with abundance at high-altitude habitat were significantly higher than low-altitude ones.The species similarity between the two habitats was low, exhibiting rich berry food plants in the primary mountain rainforest and rich nut-type food plants in the secondary lowland rainforest, respectively. The findings suggest that the high-altitude forests are the current optimal habitat for gibbons which should be strictly protected for the survival of Hainan gibbons. The low diversity of large trees in the low-altitude secondary forests highlights the importance of large food plants for the development of secondary lowland rainforest as potential habitats for Hainan gibbons.

Water resources are a basic need for social sustainable development and human existence. As an important national strategy for water resources security, spatial and temporal patterns and driving mechanisms of water yield ecosystem services on the Qingzang Plateau (QP) are critical for water resources management, optimal water allocation and the improvement of ecological water protection efficiency. However, only a few relevant studies are currently available. In this study, we simulated the water yield (WY) of the QP over 34 years, from 1982 to 2015, using the InVEST model and analyzed the spatiotemporal dynamic relationships between WY and climate change as well as between WY and vegetation change, using geographically weighted regression (GWR) models. The results showed that: 1) from 1982 to 2015, the WY of the QP increased at an average rate of 3.8 mm/yr; 2) WY presented a reduced spatial pattern from southeast to northwest; and 3) the WY driving factors have individual and spatial differences. In terms of the area percentage in promoting WY when analyzing each driving factor, precipitation (99.8%) and air pressure (53.3%) played the major roles in promoting WY, while temperature (71.9%), wind speed (57.2%), net primary productivity (87.2%), radiation (68.3%) and lake (87.7%) played negative roles. The areas where WY are dominated by temperature are the largest (41.1%), and followed by areas dominated by pressure (19.7%) and precipitation (18.5%). The results of this study provide scientific support for formulating regional water resources policy, social and economic development planning and other macro decisions for the QP.

Summary: Splenic Ly6Chigh monocytes are innate immune cells involved in the regulation of central nervous system-related diseases. Recent studies have reported the shaping of peripheral immune responses by the gut microbiome via mostly unexplored pathways. In this study, we report that a 4-day antibiotic treatment eliminates certain families of the Bacteroidetes, Firmicutes, Tenericutes, and Actinobacteria phyla in the gut and reduces the levels of multiple pattern recognition receptor (PRR) ligands in the serum. Reduction of PRR ligands was associated with reduced numbers and perturbed function of splenic Ly6Chigh monocytes, which acquired an immature phenotype producing decreased levels of inflammatory cytokines and exhibiting increased phagocytic and anti-microbial abilities. Addition of PRR ligands in antibiotic-treated mice restored the number and functions of splenic Ly6Chigh monocytes. Our data identify circulating PRR ligands as critical regulators of the splenic Ly6Chigh monocyte behavior and suggest possible intervention pathways to manipulate this crucial immune cell subset.

Random forests (RF) is a powerful species distribution model (SDM) algorithm. This ensemble model by default can produce categorical and numerical species distribution maps based on its classification tree (CT) and regression tree (RT) algorithms, respectively. The CT algorithm can also produce numerical predictions (class probability). Here, we present a detailed procedure involving the use of the CT and RT algorithms using the RF method with presence-only data to model the distribution of species. CT and RT are used to generate numerical prediction maps, and then numerical predictions are converted to binary predictions through objective threshold-setting methods. We also applied simple methods to deal with collinearity of predictor variables and spatial autocorrelation of species occurrence data. A geographically stratified sampling method was employed for generating pseudo-absences. The detailed procedural framework is meant to be a generic method to be applied to virtually any SDM prediction question using presence-only data. • How to use RF as a standard method for generic species distributions with presence-only data • How to choose RF (CT or RT) methods for the distribution modeling of species • A general and detailed procedure for any SDM prediction question. Method name: Random forests models species distribution, Keywords: Binary prediction, Numerical prediction, Threshold, Machine learning, Species traits, Climate change, Forestation

Tibetan sacred mountains, the unique landforms influenced by the Buddhist religion in many Himalayan regions, are suggested to have great potential for preserving animal diversity. Yet, a bias might lie in evaluating the effectiveness of such areas, given the local culture of respect for, and protection of, wildlife, resulting in many animals that are relatively tame and, thus, easier to be detected visually compared with other regions. Here, we provide the first assessment of this issue, using Galliformes as a representative taxon on a typical Tibetan sacred mountain in western China. We estimated diversity of Galliformes relying on direct sightings versus an indirect technique of counting feathers, which avoids detectability issues associated with habitat and tameness of species. The data from direct sightings showed a higher relative abundance on the sacred mountain compared with its surrounding matrix, whereas the indirect technique of counting feathers suggested no considerable gains in species richness and abundance on the sacred mountain. Given the bias, we suggest that the biodiversity effects of Tibetan sacred mountains should be revisited. For management practices, we suggest that care will be needed to link Tibetan sacred mountains with conservation efforts. Keywords: Abundance, Conservation, Detectability, Human habituation, Richness, Sacred site

Objectives: This study aimed to compare clinical courses and outcomes between pregnant and reproductive-aged non-pregnant women with COVID-19, and to assess the vertical transmission potential of COVID-19 in pregnancy., Methods: Medical records of pregnant and reproductive-aged non-pregnant women hospitalized with COVID-19 from January 15 to March 15, 2020 were retrospectively reviewed. The severity of disease, virus clearance time, and length of hospital stay were measured as the primary objective, while the vertical transmission potential of COVID-19 was also assessed., Results: Eighty-two patients (28 pregnant women, 54 reproductive-aged non-pregnant women) with laboratory-confirmed COVID-19 were enrolled in this study. Univariate regression indicated no association between pregnancy and severity of disease (OR 0.73, 95% CI 0.08-5.15; p=0.76), virus clearance time (HR 1.16, 95% CI 0.65-2.01; p=0.62), and length of hospital stay (HR 1.10, 95% CI 0.66-1.84; p=0.71). Of the pregnant women, 22 delivered 23 live births, either by cesarean section (17, 60.7%) or vaginal delivery (5, 17.9%), and no neonate was infected with SARS-CoV-2., Conclusions: Pregnant women have comparable clinical courses and outcomes with reproductive-aged non-pregnant women when infected with SARS-CoV-2. No evidence supported vertical transmission of COVID-19 in the late stage of pregnancy, including vaginal delivery., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)