Ecohydrological indicators and environmental flow assessment in the middle and lower reaches of the Huai River, China.

The vitality of river ecosystems is vital for the sustainable development of river basins, with the assessment of environmental flow (EF) playing a pivotal role in eco-informatics. This study delves into the middle and lower reaches (MLR) of the Huai River basin (HRB) in China, utilizing hydrological data spanning from 1950 to 2020. Its principal objective lies in the selection of ecohydrological indicators to refine the estimation of EF in the HRB. Employing principal component analysis (PCA), ecologically relevant hydrological indicators (ERHIs) were discerned and scrutinized for their hydrological characteristics. The analysis extended to evaluating hydrological shifts at different stations using ERHIs, determining suitable EF in the MLR, and delineating the trajectories of appropriate intra-annual flows in different hydrological years through HEC-RPT. Based on a variety of mutation test methods, the change point of runoff sequence was determined in 1991. The PCA analysis identified eight ERHIs, reflecting hydrological changes of 49.79 % and 56.26 % at Bengbu and Sanhezha, respectively, which indicate a moderate alteration. Based on ERHIs, the other stations in the HRB exhibited hydrological alterations ranging from 33 % to 47 %, notably highlighting substantial changes in maximal 30d flow and flow fall rate. The optimal flood pulse discharge in the middle reaches is 4150 m3/s, 3140 m3/s and 2150 m3/s in wet, dry and dry years, respectively. Downstream, flood pulse flow in wet, normal and dry years should exceed 4070 m3/s, 3110 m3/s and 1980 m3/s, respectively. The research contributes significantly to the management of rivers and the sustainable conservation of the ecological milieu.

Trps1 predicts poor prognosis in advanced high grade serous ovarian carcinoma.

TRPS1 is aberrantly expressed in a variety of tumors, including breast, prostate, and gastric cancers, and is strongly associated with tumorigenesis or prognosis. However, the role of TRPS1 in high grade serous ovarian carcinoma (HGSC) is unknown. We investigated the relationship between TRPS1 expression and clinicopathology in HGSC patients. The tumor-related regulatory mechanisms of TRPS1 was explored through in vivo and vitro experiments. The results showed that TRPS1 was highly expressed in HGSC compared to normal tissues. It was also linked to the cell proliferation index Ki67 and poor prognosis. In vivo experiments showed that knockdown of TRPS1 could inhibit tumor growth. In vitro experiments, knockdown of TRPS1 inhibited the proliferation of ovarian cancer cells. TRPS1 exerted its regulatory role as a transcription factor, binding to the PSAT1 promoter and promoting the expression of PSAT1 gene. Meanwhile, PSAT1 was positively correlated with CCND1 expression. These results suggest that TRPS1 affects HGSC proliferation and cell cycle by regulating PSAT1 and thus CCND1 expression.

A missing jigsaw within the hygiene hypothesis: Low-dose bisphenol A exposure attenuates lipopolysaccharide-induced asthma protection.

The rising occurrence of allergic asthma in early life across industrialized countries suggests that environmental factors play a crucial role in determining asthma susceptibility and severity. While prior exposure to microbial lipopolysaccharides (LPSs) has been found to offer protection against allergic asthma, infants residing in urban environments are increasingly exposed to environmental pollutants. Utilizing limulus lysate test screens and virtual screening models, we identified pollutants that can modulate LPS bioactivity. This investigation revealed that bisphenol A (BPA), a chemical commonly used in numerous household items and previously implicated in obesity and cancer, effectively neutralizes LPS. In-depth mechanistic analyses showed that BPA specifically binds to the lipid A component of LPS, leading to inactivation. This interaction eliminates the immunostimulatory activity of LPS, making mice more susceptible to house dust mite (HDM)-induced allergic asthma. BPA reactivates lung epithelial cells, consequently amplifying type 2 responses to HDMs in dendritic cells. This chemical interplay provides new insights into the pathophysiology of asthma in relation to human exposure. Understanding the intricate relationships between environmental chemicals and microbial antigens, as well as their impacts on innate immunity, is critical for the development of intervention strategies to address immune disorders resulting from urbanization.

Trps1 acts as a regulator of Sf-1 transcription and testosterone synthesis in mouse Leydig cells.

Infertility has attracted global concern, and disruption of testosterone is a common cause of male infertility. Exploring the critical factors in testosterone biosynthesis may provide new insights for disease research and clinical therapy. Research on trichorhinophalangeal syndrome-1 (Trps1) gene has recently been focus on cancers; it is yet unknown whether Trps1 produces a marked effect in the male reproductive system. In the current study, single-cell RNA sequencing analysis of trichorhinophalangeal syndrome-1 gene (Trps1) expression in mouse testes and cleavage under targets and tagmentation and RNA sequencing were utilized to investigate the functionality of Trps1 in mouse Leydig cells. Knockdown of Trps1 increased testosterone synthesis in vitro and vivo using adeno-associated viral delivery and conditional knockout models. The results showed that Trps1 was abundantly expressed in Leydig cells. The expression levels of both steroidogenic factor-1 (Sf-1) and steroidogenic enzymes (Cyp11a1, Hsd3b, Cyp17a1, and Hsd17b3) as well as testosterone secretion were increased after Trps1 deficiency in vivo and vitro. Furthermore, disruption of Trps1 reduced histone deacetylase 1/2 activity and increased histone H3 acetylation in the Sf-1 promoter, thereby promoting testosterone secretion. Interestingly, Sf-1 also regulated the transcription of Trps1 through activating transcription factor 2. These results indicate that Trps1 targets Sf-1 to affect steroidogenesis through histone acetylation and shed light on the critical role of Trps1 functioning in the mouse Leydig cells.

Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections.

BACKGROUND: Early studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear. METHODS: 142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air-liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses. RESULTS: In this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial-mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-ß signaling. CONCLUSIONS: Our findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.

Identification of Enolase 1 as a Potential Target for Magnaporthe oryzae: Integrated Proteomic and Molecular Dynamics Simulation.

Rice blast is an essential factor affecting rice yield and quality, which is caused by Magnaporthe oryzae (M. oryzae). Isobavachalcone (IBC) is a botanical fungicide derived from the seed extract of the Leguminosae plant Psoralea corylifolia L. and has shown an excellent rice blast control effect in field applications. To explore the potential targets of rice blast control, the analysis of the differentially expressed proteins (DEPs) between the liquid culture medium of mycelium treated by 10 mg/L of IBC for 2 h and the control group indicated that Enolase 1 (ENO1) was the most significantly down-regulated DEP with a fold change value of 0.305. In vitro experiments showed that after treating liquid culture mycelium with 10 mg/L of IBC for 0.5, 1, 2, 4, and 8 h, the enzymatic activity of ENO1 in the IBC experimental groups was 0.97, 0.75, 0.52, 0.44, and 0.39 times as much as in the control groups, respectively. To further explore the molecular interaction and binding mode between IBC and ENO1, the three-dimensional structure of ENO1 was established based on homology modeling. Molecular docking and molecular dynamics simulation showed that IBC had a pi-pi stacking effect with the residue TYR_365, a hydrogen bond interaction with the residue ARG_393, and hydrophobic interactions with non-polar residues ALA_361, LYS_362, and VAL_371 of ENO1. These findings indicated that ENO1 is a potential target of M. oryzae, which would pave the way for screening novel effective fungicides targeting ENO1.

Evaluating Bacterial Pathogenesis Using a Model of Human Airway Organoids Infected with Pseudomonas aeruginosa Biofilms.

Pseudomonas aeruginosa is one of the leading invasive agents of human pulmonary infection, especially in patients with compromised immunity. Prior studies have used various in vitro models to establish P. aeruginosa infection and to analyze transcriptomic profiles of either the host or pathogen, and yet how much those works are relevant to the genuine human airway still raises doubts. In this study, we cultured and differentiated human airway organoids (HAOs) that recapitulate, to a large extent, the histological and physiological features of the native human mucociliary epithelium. HAOs were then employed as a host model to monitor P. aeruginosa biofilm development. Through dual-species transcriptome sequencing (RNA-seq) analyses, we found that quorum sensing (QS) and several associated protein secretion systems were significantly upregulated in HAO-associated bacteria. Cocultures of HAOs and QS-defective mutants further validated the role of QS in the maintenance of a robust biofilm and disruption of host tissue. Simultaneously, the expression magnitude of multiple inflammation-associated signaling pathways was higher in the QS mutant-infected HAOs, suggesting that QS promotes immune evasion at the transcriptional level. Altogether, modeling infection of HAOs by P. aeruginosa captured several crucial facets in host responses and bacterial pathogenesis, with QS being the most dominant virulence pathway showing profound effects on both bacterial biofilm and host immune responses. Our results revealed that HAOs are an optimal model for studying the interaction between the airway epithelium and bacterial pathogens. IMPORTANCE Human airway organoids (HAOs) are an organotypic model of human airway mucociliary epithelium. The HAOs can closely resemble their origin organ in terms of epithelium architecture and physiological function. Accumulating studies have revealed the great values of the HAO cultures in host-pathogen interaction research. In this study, HAOs were used as a host model to grow Pseudomonas aeruginosa biofilm, which is one of the most common pathogens found in pulmonary infection cases. Dual transcriptome sequencing (RNA-seq) analyses showed that the cocultures have changed the gene expression pattern of both sides significantly and simultaneously. Bacterial quorum sensing (QS), the most upregulated pathway, contributed greatly to biofilm formation, disruption of barrier function, and subversion of host immune responses. Our study therefore provides a global insight into the transcriptomic responses of both P. aeruginosa and human airway epithelium.

Neisseria species as pathobionts in bronchiectasis.

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.

A nanomaterial targeting the spike protein captures SARS-CoV-2 variants and promotes viral elimination.

The global emergency caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic can only be solved with effective and widespread preventive and therapeutic strategies, and both are still insufficient. Here, we describe an ultrathin two-dimensional CuInP2S6 (CIPS) nanosheet as a new agent against SARS-CoV-2 infection. CIPS exhibits an extremely high and selective binding capacity (dissociation constant (KD) < 1 pM) for the receptor binding domain of the spike protein of wild-type SARS-CoV-2 and its variants of concern, including Delta and Omicron, inhibiting virus entry and infection in angiotensin converting enzyme 2 (ACE2)-bearing cells, human airway epithelial organoids and human ACE2-transgenic mice. On association with CIPS, the virus is quickly phagocytosed and eliminated by macrophages, suggesting that CIPS could be successfully used to capture and facilitate virus elimination by the host. Thus, we propose CIPS as a promising nanodrug for future safe and effective anti-SARS-CoV-2 therapy, and as a decontamination agent and surface-coating material to reduce SARS-CoV-2 infectivity.

A Retinol Derivative Inhibits SARS-CoV-2 Infection by Interrupting Spike-Mediated Cellular Entry.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the global pandemic and life-threatening coronavirus disease 2019 (COVID-19). Although vaccines and therapeutic antibodies are available, their efficacy is continuously undermined by rapidly emerging SARS-CoV-2 variants. Here, we found that all-trans retinoic acid (ATRA), a vitamin A (retinol) derivative, showed potent antiviral activity against all SARS-CoV-2 variants in both human cell lines and human organoids of the lower respiratory tract. Mechanistically, ATRA directly binds in a deep hydrophobic pocket of the receptor binding domain (RBD) located on the top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation. In summary, our results reveal the pharmacological biotargets and structural mechanism of ATRA and other retinoids in SARS-CoV-2 infection and suggest that ATRA and its derivatives could be potential hit compounds against a broad spectrum of coronaviruses. IMPORTANCE Retinoids, a group of compounds including vitamin A and its active metabolite all-trans retinoic acid (ATRA), regulate serial physiological activity in multiple organ systems, such as cell growth, differentiation, and apoptosis. The ATRA analogues reported to date include more than 4,000 natural and synthetic molecules that are structurally and/or functionally related to ATRA. Here, we found that ATRA showed potent antiviral activity against all SARS-CoV-2 variants by directly binding in a deep hydrophobic pocket of the receptor binding domain (RBD) located on top of the SARS-CoV-2 spike protein (S) trimer. The bound ATRA mediates strong interactions between the "down" RBDs and locks most of the S trimers in an RBD "all-down" and ACE2-inaccessible inhibitory conformation, suggesting the pharmacological feasibility of using ATRA or its derivatives as a remedy for and prevention of COVID-19 disease.

A glucose-like metabolite deficient in diabetes inhibits cellular entry of SARS-CoV-2.

The severity and mortality of COVID-19 are associated with pre-existing medical comorbidities such as diabetes mellitus. However, the underlying causes for increased susceptibility to viral infection in patients with diabetes is not fully understood. Here we identify several small-molecule metabolites from human blood with effective antiviral activity against SARS-CoV-2, one of which, 1,5-anhydro-D-glucitol (1,5-AG), is associated with diabetes mellitus. The serum 1,5-AG level is significantly lower in patients with diabetes. In vitro, the level of SARS-CoV-2 replication is higher in the presence of serum from patients with diabetes than from healthy individuals and this is counteracted by supplementation of 1,5-AG to the serum from patients. Diabetic (db/db) mice undergo SARS-CoV-2 infection accompanied by much higher viral loads and more severe respiratory tissue damage when compared to wild-type mice. Sustained supplementation of 1,5-AG in diabetic mice reduces SARS-CoV-2 loads and disease severity to similar levels in nondiabetic mice. Mechanistically, 1,5-AG directly binds the S2 subunit of the SARS-CoV-2 spike protein, thereby interrupting spike-mediated virus-host membrane fusion. Our results reveal a mechanism that contributes to COVID-19 pathogenesis in the diabetic population and suggest that 1,5-AG supplementation may be beneficial to diabetic patients against severe COVID-19.

Generation and Effect Testing of a SARS-CoV-2 RBD-Targeted Polyclonal Therapeutic Antibody Based on a 2-D Airway Organoid Screening System.

Coronavirus disease 2019 (COVID-19) is an acute respiratory infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The US FDA has approved several therapeutics and vaccines worldwide through the emergency use authorization in response to the rapid spread of COVID-19. Nevertheless, the efficacies of these treatments are being challenged by viral escape mutations. There is an urgent need to develop effective treatments protecting against SARS-CoV-2 infection and to establish a stable effect-screening model to test potential drugs. Polyclonal antibodies (pAbs) have an intrinsic advantage in such developments because they can target rapidly mutating viral strains as a result of the complexity of their binding epitopes. In this study, we generated anti-receptor-binding domain (anti-RBD) pAbs from rabbit serum and tested their safety and efficacy in response to SARS-CoV-2 infection both in vivo and ex vivo. Primary human bronchial epithelial two-dimensional (2-D) organoids were cultured and differentiated to a mature morphology and subsequently employed for SARS-CoV-2 infection and drug screening. The pAbs protected the airway organoids from viral infection and tissue damage. Potential side effects were tested in mouse models for both inhalation and vein injection. The pAbs displayed effective viral neutralization effects without significant side effects. Thus, the use of animal immune serum-derived pAbs might be a potential therapy for protection against SARS-CoV-2 infection, with the strategy developed to produce these pAbs providing new insight into the treatment of respiratory tract infections, especially for infections with viruses undergoing rapid mutation.

Harnessing Colloidal Self-Assembled Patterns (cSAPs) to Regulate Bacterial and Human Stem Cell Response at Biointerfaces In Vitro and In Vivo.

The generation of complex physicochemical signals on the surface of biomedical materials is still challenging despite the fact that a broad range of surface modification methods have been developed over the last few decades. Colloidal self-assembled patterns (cSAPs) are combinations of unique colloids differing in size and surface chemistry acting as building blocks that can be programmed to generate surface patterns with exquisite control of complexity. This study reports on producing a variety of pre-modified colloids for the fabrication of cSAPs as well as post-assembly modifications to yield complex surfaces. The surface of cSAPs presents hierarchical micro- and nanostructures, localized hydrophilic/hydrophobic characteristics, and tunable surface functionality imparted by the individual colloids. The selected cSAPs can control bacterial adhesion (S. aureus, P. aeruginosa, and E. coli) and affect the cell cycle of human bone marrow stem cells (hBMSCs). Moreover, in a mouse subcutaneous model, cSAPs with selective [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium (SBMA) modification can reduce the inflammatory response after being challenged with bacteria. This study reveals that functionalized cSAPs are versatile tools for controlling cellular responses at biointerfaces, which is instructive for biomaterials or biodevices.

Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation.

Under the concept of "united airway diseases," the airway is a single organ wherein upper and lower airway diseases are commonly comorbid. The upper and lower airways are lined with respiratory epithelium that plays a vital role in immune surveillance and modulation as the first line of defense to various infective pathogens, allergens, and physical insults. Recently, there is a common hypothesis emphasizing epithelium-derived cytokines, namely IL-25, IL-33, and TSLP, as key regulatory factors that link in immune-pathogenic mechanisms of allergic rhinitis (AR), chronic rhinosinusitis (CRS), and asthma, mainly involving in type 2 inflammatory responses and linking innate and adaptive immunities. Herein, we review studies that elucidated the role of epithelium-derived triple cytokines in both upper and lower airways with the purpose of expediting better clinical treatments and managements of AR, CRS, asthma, and other associated allergic diseases via applications of the modulators of these cytokines.

Dynamic projection of ecological risk in the Manas River basin based on terrain gradients.

With large-scale developments, the Manas River Basin (MRB) is in an extreme imbalance especially in land use, thus causing a series of ecological problems. A reliable dynamic ecological risk assessment is expected to provide useful information for the economic development. Through coupling spatial Cellular Automaton-Markov (CA-Markov) model and Landsat satellite images in 2000, 2008 and 2016, we forecasted the land use maps in 2024 and 2032. Based on the ecological risk model, we evaluated the ecological risk at landscape level from 2000 to 2032. More importantly, an improved evaluation of ecological risk was proposed based on terrain gradients and the correlation between terrain niche index (TNI) and future ecological risk was analyzed. The results showed that the artificial oases and urban are expanding, while the natural grassland is shrinking. Corresponding to the rapid development stage and stable consolidation stage, farmland will be followed by a slower increase (2016-2032) after a rapid increase (2000-2016), and water decreases first but then is projected to recover. As the overall spatial diversity increasing, the ecological risk in the whole basin is growing, especially in grassland. Compared with the stable critical state in artificial landscape, the future ecological risks in natural landscape tend to increase due to the cumulative effects of human activities. Also, we found that the great ecological risk mainly happens in "high altitude and complex terrain" or "low altitude and flat terrain" areas. The future ecological risk in medium terrain niche index (TNI) gradient will increase, while it will decrease in the lowest. Above all, the proposed framework can do well in forecasting ecological risk at landscape level, and can help simply infer the changes of ecological risk based on terrain.