Infrared: a declarative tree decomposition-powered framework for bioinformatics.

MOTIVATION: Many bioinformatics problems can be approached as optimization or controlled sampling tasks, and solved exactly and efficiently using Dynamic Programming (DP). However, such exact methods are typically tailored towards specific settings, complex to develop, and hard to implement and adapt to problem variations. METHODS: We introduce the Infrared framework to overcome such hindrances for a large class of problems. Its underlying paradigm is tailored toward problems that can be declaratively formalized as sparse feature networks, a generalization of constraint networks. Classic Boolean constraints specify a search space, consisting of putative solutions whose evaluation is performed through a combination of features. Problems are then solved using generic cluster tree elimination algorithms over a tree decomposition of the feature network. Their overall complexities are linear on the number of variables, and only exponential in the treewidth of the feature network. For sparse feature networks, associated with low to moderate treewidths, these algorithms allow to find optimal solutions, or generate controlled samples, with practical empirical efficiency. RESULTS: Implementing these methods, the Infrared software allows Python programmers to rapidly develop exact optimization and sampling applications based on a tree decomposition-based efficient processing. Instead of directly coding specialized algorithms, problems are declaratively modeled as sets of variables over finite domains, whose dependencies are captured by constraints and functions. Such models are then automatically solved by generic DP algorithms. To illustrate the applicability of Infrared in bioinformatics and guide new users, we model and discuss variants of bioinformatics applications. We provide reimplementations and extensions of methods for RNA design, RNA sequence-structure alignment, parsimony-driven inference of ancestral traits in phylogenetic trees/networks, and design of coding sequences. Moreover, we demonstrate multidimensional Boltzmann sampling. These applications of the framework-together with our novel results-underline the practical relevance of Infrared. Remarkably, the achieved complexities are typically equivalent to the ones of specialized algorithms and implementations. AVAILABILITY: Infrared is available at https://amibio.gitlabpages.inria.fr/Infrared with extensive documentation, including various usage examples and API reference; it can be installed using Conda or from source.

Regional homogeneity alterations in patients with functional constipation and their associations with gene expression profiles.

Functional constipation, a highly prevalent functional gastrointestinal disorder, often accompanies by mental and psychological disorders. Previous neuroimaging studies have demonstrated brain functional and structural alterations in patients with functional constipation. However, little is known about whether and how regional homogeneity is altered in these patients. Moreover, the potential genetic mechanisms associated with these alterations remain largely unknown. The study included 73 patients with functional constipation and 68 healthy controls, and regional homogeneity comparison was conducted to identify the abnormal spontaneous brain activities in patients with functional constipation. Using Allen Human Brain Atlas, we further investigated gene expression profiles associated with regional homogeneity alterations in functional constipation patients with partial least squares regression analysis applied. Compared with healthy controls, functional constipation patients demonstrated significantly decreased regional homogeneity in both bilateral caudate nucleus, putamen, anterior insula, thalamus and right middle cingulate cortex, supplementary motor area, and increased regional homogeneity in the bilateral orbitofrontal cortex. Genes related to synaptic signaling, central nervous system development, fatty acid metabolism, and immunity were spatially correlated with abnormal regional homogeneity patterns. Our findings showed significant regional homogeneity alterations in functional constipation patients, and the changes may be caused by complex polygenetic and poly-pathway mechanisms, which provides a new perspective on functional constipation's pathophysiology.

An extracellular humanized IFNAR immunocompetent mouse model for analyses of human interferon alpha and subtypes.

Type I interferons (IFN-Is) have key roles in immune defense and treatments for various diseases, including chronic hepatitis B virus (HBV) infection. All IFN-Is signal through a shared IFN-I heterodimeric receptor complex comprising IFN-α receptor 1 (IFNAR1) and IFNAR2 subunits, but differences in antiviral and immunomodulatory responses among IFN-I subtypes remain largely unknown. Because the IFN-IFNAR interactions are species-specific, mice exhibit weak responses to human IFN-I. To more fully characterize the actions of human IFN-α and its subtypes in vivo, a gene targeting strategy was employed to generate gene knock-in mice with extracellular-humanized IFNAR1/2 (IFNAR-hEC) in the C57BL/6N strain. IFNAR-hEC mice actively responded to human IFN-I, and endogenous mouse IFN-I signalling remained active in heterozygous mice (IfnarhEC/+). Analyses of IFNAR-hEC mice and isolated cells showed that human IFN-α2 and α14 subtypes exerted differential effect on the activation of JAK-STAT signalling and immune responses. Compared with IFN-α2, IFN-α14 induced greater activation of STAT1/2 and IFN-stimulated genes, synergistically elicited IFN-α and -γ signalling, and induced higher numbers of antigen-specific CD8+ T cells. Moreover, IFNAR-hEC mice with HBV replication displayed long-term viral suppression upon treatment with the clinically-used PEGylated hIFN-α2. These results indicate that IFNAR-hEC mice may be useful for elucidating antiviral and immunomodulatory functions of human IFN-Is and for conducting preclinical studies. A better understanding of the distinct activities of IFN-α subtypes can provide insights concerning the development of improved IFN-based therapy.

Genome-Wide Extrachromosomal Circular DNA Profiling of Paired Hepatocellular Carcinoma and Adjacent Liver Tissues.

Hepatocellular carcinoma (HCC) develops through multiple mechanisms. While recent studies have shown the presence of extrachromosomal circular DNA (eccDNA) in most cancer types, the eccDNA expression pattern and its association with HCC remain obscure. We aimed to investigate this problem. The genome-wide eccDNA profiles of eight paired HCC and adjacent non-tumor tissue samples were comprehensively elucidated based on Circle-seq, and they were further cross-analyzed with the RNA sequencing data to determine the association between eccDNA expression and transcriptome dysregulation. A total of 60,423 unique eccDNA types were identified. Most of the detected eccDNAs were smaller than 1 kb, with a length up to 182,363 bp and a mean sizes of 674 bp (non-tumor) and 813 bp (tumor), showing a greater association with gene-rich rather than with gene-poor regions. Although there was no statistical difference in length and chromosome distribution, the eccDNA patterns between HCC and adjacent non-tumor tissues showed significant differences at both the chromosomal and single gene levels. Five of the eight HCC tissues showed significantly higher amounts of chromosome 22-derived eccDNA expression compared to the non-tumor tissue. Furthermore, two genes, SLC16A3 and BAIAP2L2, with a higher transcription level in tumor tissues, were related to eccDNAs exclusively detected in three HCC samples and were negatively associated with survival rates in HCC cohorts from public databases. These results indicate the existence and massive heterogeneity of eccDNAs in HCC and adjacent liver tissues, and suggest their potential association with dysregulated gene expression.

Noninvasive external therapy of traditional Chinese medicine for preventing postpartum urinary retention in women with vaginal delivery: A network meta-analysis.

BACKGROUND: To compare the effect of different noninvasive external therapies of traditional Chinese medicine (TCM) on the prevention of postpartum urinary retention (PUR) using a network meta-analysis (NMA). METHODS: A search of the China National Knowledge Infrastructure, WanFangDate, VIP, China Biomedical Literature Database, PubMed, The Cochrane Library, Embase, and Web of Science databases were reviewed for related randomized controlled trials dated between database inception and December 31, 2022, on the prevention of PUR by noninvasive TCM. Two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies; then, a NMA was performed using Revman5.3 software, State13.1 software, and frequency methodology. RESULTS: In total, 16 studies involving 3637 cases of parturients and 9 types of noninvasive TCM external treatments were incorporated into the NMA. The NMA results show that based on routine nursing, in terms of reducing the incidence of urinary retention, acupoint compressing combined with auricular acupressure is ranked first, followed by acupoint hot compress, acupoint massage combined with auricular acupressure, Yin-Yang therapy, acupoint massage, auricular acupressure, acupoint compressing, and routine nursing. In terms of urination time, acupoint compressing combined with auricular acupressure ranked first, followed by acupoint massage combined with auricular acupressure, acupoint electrical stimulation, acupoint compressing, TCM heating therapy, acupoint massage, auricular acupressure, and routine nursing. In terms of reducing residual urine volume after the first urination, acupoint compressing combined with auricular acupressure was ranked first, followed by auricular acupressure, acupoint compressing, acupoint massage, TCM heating therapy, and routine nursing. CONCLUSION: Current evidence shows that acupoint compressing combined with auricular acupressure may be the best noninvasive TCM treatment for preventing PUR based on routine nursing; however, further high-quality clinical randomized controlled trials are needed for validation and support.

Mono-valent salt corrections for RNA secondary structures in the ViennaRNA package.

BACKGROUND: RNA features a highly negatively charged phosphate backbone that attracts a cloud of counter-ions that reduce the electrostatic repulsion in a concentration dependent manner. Ion concentrations thus have a large influence on folding and stability of RNA structures. Despite their well-documented effects, salt effects are not handled consistently by currently available secondary structure prediction algorithms. Combining Debye-Hückel potentials for line charges and Manning's counter-ion condensation theory, Einert et al. (Biophys J 100: 2745-2753, 2011) modeled the energetic contributions of monovalent cations on loops and helices. RESULTS: The model of Einert et al. is adapted to match the structure of the dynamic programming recursion of RNA secondary structure prediction algorithms. An empirical term describing the salt dependence of the duplex initiation energy is added to improve co-folding predictions for two or more RNA strands. The slightly modified model is implemented in the ViennaRNA package in such way that only the energy parameters but not the algorithmic structure is affected. A comparison with data from the literature show that predicted free energies and melting temperatures are in reasonable agreement with experiments. CONCLUSION: The new feature in the ViennaRNA package makes it possible to study effects of salt concentrations on RNA folding in a systematic manner. Strictly speaking, the model pertains only to mono-valent cations, and thus covers the most important parameter, i.e., the NaCl concentration. It remains a question for future research to what extent unspecific effects of bi- and tri-valent cations can be approximated in a similar manner. AVAILABILITY: Corrections for the concentration of monovalent cations are available in the ViennaRNA package starting from version 2.6.0.

Extreme precipitation stable isotopic compositions reveal unexpected summer monsoon incursions in the Qilian Mountains.

Isotope composition and moisture sources of precipitation are important for understanding water cycles and reconstructing paleoclimate. Based on 15-years' precipitation stable Isotope composition (δ18O and δ2H) from four stations of the Qilian Mountains, we found unique δ18O and δ2H features associated with the incursion of the summer monsoon over the Qilian Mountains, northwestern China. In 12 of the 15 years, similar seasonal variations of δ18O and δ2H confirmed a dominant source of moisture from Westerly circulation, and higher intercepts of the local meteoric water line (LMWL) indicated strong recycling of continental moisture. However, in August 2016 and 2018, extremely low slopes and intercepts of the LMWL, and more negative δ18O and δ2H revealed substantial contributions of the Asian summer monsoon to precipitation of the Qilian Mountains, with extremely heavy precipitation in August 2016. The column moisture flux, land-sea thermal contrast, correlations of precipitation δ18O with East Asian Summer Monsoon Index and Westerlies Index, HYSPLIT modeling results and precipitation δ18O along backward trajectories confirmed incursions of the summer monsoon in August 2016 and 2018. Our redefining of the boundary of the summer monsoon region confirmed the summer monsoon incursion zone can extend to the west of longitude 96°E and north of latitude 40°N in strong monsoon years, corresponding to boundaries of monsoon incursions in the mid-Holocene. Temperature correlated with precipitation δ18O at monthly and shorter time scales, but not for whole seasons or at yearly scale, revealing that summer monsoon incursions are therefore more likely than changing temperature to explain the multi-year cycles in the Qilian Mountains ice archives. Continent-scale shifts in atmospheric circulation strongly influence water resources in the Qilian mountains, and may change in frequency as climate warms. This study therefore has important implications for understanding water resources in the Qilian mountains in the past and into the future.

[Arsenic speciation and valence].

As arsenic widely exists in nature and has been used in the pharmaceutical preparations, the traditional Chinese medicine(TCM) with arsenic include realgar(As_2S_2 or As_4S_4), orpiment(As_2S_3), and white arsenic(As_2O_3). Among the above representative medicine, the TCM compound formulas with realgar are utilized extensively. Just in Chinese Pharmacopoeia(2020 edition), there are 37 Chinese patent medicines including realgar. The traditional element analysis focuses on the detection of the total amount of elements, which neglects the study on the speciation and valence of elements. The activity, toxicity, bioavailability, and metabolic pathways of arsenic in vivo are closely related to the existence of its form, and different forms of arsenic have different effects on organisms. Therefore, the study on the speciation and valence of arsenic is of great importance for arsenic-containing TCMs and their compound formulas. This paper reviewed four aspects of the speciation and valence of arsenic, including property, absorption and metabolism, toxicity, and analytical assay.

[Varieties systematization and standards status analysis of fermented Chinese medicine].

Fermented Chinese medicine has long been used. Amid the advance for preservation of experience, the connotation of fermented Chinese medicine has been enriched and improved. However, fermented Chinese medicine prescriptions generally contain a lot of medicinals. The fermentation process is complicated and the conventional fermentation conditions fail to be strictly controlled. In addition, the judgment of the fermentation end point is highly subjective. As a result, quality of fermented Chinese medicine is of great difference among regions and unstable. At the moment, the quality standards of fermented Chinese medicine are generally outdated and different among regions, with simple quality control methods and lacking objective safe fermentation-specific evaluation indictors. It is difficult to comprehensively evaluate and control the quality of fermented medicine. These problems have aroused concern in the industry and also affected the clinical application of fermented Chinese medicine. This article summarized and analyzed the application, quality standards, and the modernization of fermentation technology and quality control methods of fermented Chinese medicine and proposed suggestions for improving the quality standards of the medicine, with a view to improving the overall quality of it.

The role of nature reserves in conservation effectiveness of ecosystem services in China.

Establishing nature reserves (NRs) is a common method to avoid biodiversity loss and degradation of ecosystem services (ESs). The evaluation of ESs in NRs and the exploration of associated influencing factors are the basis for improving ESs and management. However, the ES effectiveness of NRs over time remains questionable, namely due to the heterogeneity of landscape characteristics inside and outside of NRs. This study (i) quantifies the role of 75 NRs in China in maintaining ESs (i.e., net primary production (NPP), soil conservation, sandstorm prevention and water yield) from 2000 to 2020, (ii) reveals the trade-offs/synergies, and (iii) identifies the main influencing factors of the ES effectiveness of NRs. The results show that more than 80% of NRs had positive ES effectiveness, which was greater in older NRs. For different ESs, effectiveness over time increases for NPP (E_NPP), soil conservation (E_SC) and sandstorm prevention (E_SP) but declines for water yield (E_WY). There is a clear synergistic relationship between E_NPP and E_SC. Moreover, the effectiveness of ESs is closely correlated with elevation, precipitation, and perimeter area ratio. Our findings can provide important information to support site selection and management of reserves to improve the delivery of critical ecosystem services.

An action plan for the agri-food sector at the time of the climate and biodiversity crises.

Agriculture is responsible for about one third of global greenhouse gas emissions and it is the primary driver of habitat destruction. A paradigm shift embracing changes in lifestyles, agricultural practices, and policies is required to realize a sustainable transition in the agri-food sector.

Notable conservation gaps for biodiversity, ecosystem services and climate change adaptation on the Tibetan Plateau, China.

Incorporating biodiversity, ecosystem services (ESs) and climate change adaptation into the conservation targets of protected areas (PAs) is being acknowledged. Targeting conservation actions requires a thorough understanding of the relationship between PAs and these important regions. However, few studies have identified conservation gaps while simultaneously considering these three aspects. Here, we assessed the representativeness of the PAs network for biodiversity, ESs and climate refugia (as a proxy for climate change adaptation ability) on the Tibetan Plateau (TP). Our analysis showed that these priority conservation regions were primarily located in the south and southeast of the TP, while they were impacted by intense human pressure. Most ESs and all types of species richness showed a significant positive correlation. Additionally, a positive correlation between multiple climate refugia and different types of species richness was detected. Representativeness analysis revealed notable conservation gaps for these three aspects in existing PAs, highlighting the urgency of adjusting their distribution and improving their representativeness. By integrating these conservation targets, priority regions for future conservation were further delineated. Taken together, our findings contribute to improving the efficiency of PAs and optimizing conservation planning.

SLC5A3 is important for cervical cancer cell growth.

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis. Furthermore, SLC5A3 knockdown or KO downregulated myo-inositol levels, induced oxidative injury, and decreased Akt-mTOR activation in cervical cancer cells. In contrast, supplementation of myo-inositol or n-acetyl-L-cysteine or transduction of a constitutively active Akt1 construct mitigated SLC5A3 KO-induced cytotoxicity in cervical cancer cells. Lentiviral SLC5A3 overexpression construct transduction upregulated the cellular myo-inositol level and promoted Akt-mTOR activation, enhancing cervical cancer cell proliferation and migration. The binding of TonEBP to the SLC5A3 promoter was upregulated in cervical cancer. In vivo studies showed that intratumoral injection of SLC5A3 shRNA-expressing virus arrested cervical cancer xenograft growth in mice. SLC5A3 KO also inhibited pCCa-1 cervical cancer xenograft growth. The SLC5A3-depleted xenograft tissues exhibited myo-inositol downregulation, Akt-mTOR inactivation, and oxidative injury. Transduction of sh-TonEBP AAV construct downregulated SLC5A3 expression and inhibited pCCa-1 cervical cancer xenograft growth. Together, overexpressed SLC5A3 promotes growth of cervical cancer cells, representing as a novel therapeutic oncotarget for the devastating disease.

Upgrading protected areas can improve or reverse the decline in conservation effectiveness: Evidence from the Tibetan Plateau, China.

Protected areas (PAs) are considered essential for maintaining biodiversity. Several governments would like to strengthen the management levels of their PAs (as shorthand for a hierarchy in PA administrative governance) to consolidate their conservation effectiveness. This upgrade (e.g., from provincial- to national-level PAs) means stricter protection and increased funds for PA management. However, confirming whether such an upgrade can produce the expected positive outcomes is key given limited conservation funds. Here, we used the Propensity Score Matching (PSM) method to quantify the impacts of upgrading PAs (i.e., from provincial to national) on vegetation growth on the Tibetan Plateau (TP). We found that the impacts of PA's upgrading can be divided into two impact types: 1) curbed or reversed declines in conservation effectiveness and 2) rapidly increased conservation effectiveness before the upgrade. These results indicate that the PA's upgrading process (including the pre-upgrade operations) can improve PA effectiveness. Nevertheless, the gains did not always occur after the official upgrade. This study demonstrated that in comparison to other PAs, those with more resources or stronger management policies were more effective.

Evaluation of left ventricular blood flow kinetic energy in patients with hypertension by four-dimensional flow cardiovascular magnetic resonance imaging: a preliminary study.

OBJECTIVES: To evaluate the intra-cavity left ventricular (LV) blood flow kinetic energy (KE) parameters using four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) in patients with hypertension (HTN). METHODS: Forty-two HTN patients and twenty age-/gender-matched healthy controls who underwent CMR including cines, pre-/post-T1 mapping, and whole-heart 4D flow imaging were retrospectively evaluated. HTN patients were further divided into two subgroups: with preserved ejection fraction (HTN-pEF) and with reduced ejection fraction (HTN-rEF). KE parameters were indexed to LV end-diastolic volume (EDV) to obtain averaged LV, minimal, systolic, diastolic, peak E-wave, peak A-wave, E-wave, and A-wave KEiEDV, as well as the proportion of in-plane LV KE (%), the time difference (TD). These parameters were compared between the HTN group and healthy controls, also between two subgroups. The correlation of LV blood flow KE parameters with LV function and extracellular volume fraction (ECV) were analyzed in the HTN group using multivariate regression analysis. RESULTS: Peak E-wave KEiEDV in the HTN group was significantly lower (p = 0.01), while in-plane KE and TD were significantly higher (all p < 0.01) than those in healthy controls. Compared to the HTN-pEF subgroup, the proportion of in-plane KE and TD was significantly increased in the HTN-rEF subgroup (all p < 0.01). Only the proportion of in-plane KE demonstrated an independent correlation with ECV (ß* = 0.59, p < 0.01). CONCLUSIONS: The decreased peak E-wave KEiEDV and the increased proportion of in-plane KE, TD reflected the alterations of LV blood flow in HTN patients, and the proportion of in-plane KE was independently associated with ECV. KEY POINTS: • 4D flow CMR demonstrated that the peak E-wave KEiEDV was decreased, while the in-plane KE and time difference (TD) were increased in hypertensive (HTN) patients. • The proportion of in-plane KE and TD was further increased in HTN patients with reduced ejection fraction than in HTN patients with preserved ejection fraction, and the proportion of in-plane KE was independently associated with extracellular volume fraction in HTN patients. • 4D flow CMR intra-cavity blood flow KE parameters might reveal the LV hemodynamic status in preclinical HTN patients.

Unintended consequences of combating desertification in China.

Since the early 2000s, China has carried out extensive "grain-for-green" and grazing exclusion practices to combat desertification in the desertification-prone region (DPR). However, the environmental and socioeconomic impacts of these practices remain unclear. We quantify and compare the changes in fractional vegetation cover (FVC) with economic and population data in the DPR before and after the implementation of these environmental programmes. Here we show that climatic change and CO2 fertilization are relatively strong drivers of vegetation rehabilitation from 2001-2020 in the DPR, and the declines in the direct incomes of farmers and herders caused by ecological practices exceed the subsidies provided by governments. To minimize economic hardship, enhance food security, and improve the returns on policy investments in the DPR, China needs to adapt its environmental programmes to address the potential impacts of future climate change and create positive synergies to combat desertification and improve the economy in this region.

mDIXON-Quant technique diagnostic accuracy for assessing bone mineral density in male adult population.

BACKGROUND: To investigate the diagnostic efficacy of mDIXON-Quant technique for prediction of bone loss in male adults. METHODS: One hundred thirty-eight male adults were divided into normal, osteopenia, and osteoporosis groups based on DXA and QCT for the lumbar spine. Differences in mDIXON-Quant parameters [fat fraction (FF) and T2* value] among three groups, as well as the correlation of mDIXON-Quant parameters and bone mineral density (BMD) were analyzed. The areas under the curves (AUCs) for mDIXON-Quant parameters for prediction of low bone mass were calculated. RESULTS: According to DXA standard, FF and T2* value were significantly increased in osteoporosis group compared with normal group (P = 0.012 and P < 0.001). According to QCT standard, FF was significantly increased in osteopenia and osteoporosis groups compared with normal group (both P < 0.001). T2* values were significantly different among three groups (all P < 0.05). After correction for age and body mass index, FF was negatively correlated with areal BMD and volumetric BMD (r = -0.205 and -0.604, respectively; both P < 0.05), and so was T2* value (r = -0.324 and -0.444, respectively; both P < 0.05). The AUCs for predicting low bone mass according to DXA and QCT standards were 0.642 and 0.898 for FF, 0.648 and 0.740 for T2* value, and 0.677 and 0.920 for both combined, respectively. CONCLUSIONS: FF combined with T2* value has a better diagnostic efficacy than FF or T2* value alone in prediction of low bone mass in male adults, which is expected to be a promising MRI method for the screening of bone quality. TRIAL REGISTRATION: ChiCTR1900024511 (Registered 13-07-2019).

Computationally guided discovery of novel non-steroidal AR-GR dual antagonists demonstrating potency against antiandrogen resistance.

As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.

Divergent effects of moderate grazing duration on carbon sequestration between temperate and alpine grasslands in China.

Moderate grazing has been widely proven to improve ecosystem functioning and have profound effects on the carbon cycling and storage in grassland ecosystems, which highly depend on grazing duration and grassland type. However, the effects of moderate grazing durations on carbon sequestration with different grassland types over broad geographic scales across China remain underexplored in the context of striving for carbon neutrality. Here, we explored the probably different responses of carbon sequestration to moderate grazing duration for temperate and alpine grasslands based on 129 published literatures regarding the China's grasslands. The results showed the soil organic carbon stocks were significantly increased during short-term (<5 years) grazing duration, while significantly decreased during medium- (5-10 years) and long-term (≥ 10 years) grazing durations in temperate grasslands. However, the soil organic carbon stocks were significantly decreased during short-term grazing duration, while showed no significant changes during medium- and long-term grazing durations in alpine grasslands. The changes in soil organic stock were significantly positively correlated with the changes in belowground biomass, root:shoot, and microbial biomass carbon (P < 0.05). These findings suggest that the temperate grasslands change from carbon sink to carbon source with moderate grazing duration increasing, while the alpine grasslands present an opposite change pattern from carbon source to carbon sink, regulated by grazing-altered carbon input and microbial activities. Our study might have significant implications for future sustainable management practices for carbon sequestration of China's grasslands.