Discovery of a Novel and Potent LCK Inhibitor for Leukemia Treatment via Deep Learning and Molecular Docking.

The lymphocyte-specific protein tyrosine kinase (LCK) plays a crucial role in both T-cell development and activation. Dysregulation of LCK signaling has been demonstrated to drive the oncogenesis of T-cell acute lymphoblastic leukemia (T-ALL), thus providing a therapeutic target for leukemia treatment. In this study, we introduced a sophisticated virtual screening strategy combined with biological evaluations to discover potent LCK inhibitors. Our initial approach involved utilizing the PLANET algorithm to assess and contrast various scoring methodologies suitable for LCK inhibitor screening. After effectively evaluating PLANET, we progressed to devise a virtual screening workflow that synergistically combines the strengths of PLANET with the capabilities of Schrödinger's suite. This integrative strategy led to the efficient identification of four potential LCK inhibitors. Among them, compound 1232030-35-1 stood out as the most promising candidate with an IC50 of 0.43 nM. Further in vitro bioassays revealed that 1232030-35-1 exhibited robust antiproliferative effects on T-ALL cells, which was attributed to its ability to suppress the phosphorylations of key molecules in the LCK signaling pathway. More importantly, 1232030-35-1 treatment demonstrated profound in vivo antileukemia efficacy in a human T-ALL xenograft model. In addition, complementary molecular dynamics simulations provided deeper insight into the binding kinetics between 1232030-35-1 and LCK, highlighting the formation of a hydrogen bond with Met319. Collectively, our study established a robust and effective screening strategy that integrates AI-driven and conventional methodologies for the identification of LCK inhibitors, positioning 1232030-35-1 as a highly promising and novel drug-like candidate for potential applications in treating T-ALL.

Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy-based virtual screening and machine learning evaluation.

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Nomogram for Predicting Early Mortality after Umbilical Cord Blood Transplantation in Children with Inborn Errors of Immunity.

PURPOSE: Pediatric patients with inborn errors of immunity (IEI) undergoing umbilical cord blood transplantation (UCBT) are at risk of early mortality. Our aim was to develop and validate a prediction model for early mortality after UCBT in pediatric IEI patients based on pretransplant factors. METHODS: Data from 230 pediatric IEI patients who received their first UCBT between 2014 and 2021 at a single center were analyzed retrospectively. Data from 2014-2019 and 2020-2021 were used as training and validation sets, respectively. The primary outcome of interest was early mortality. Machine learning algorithms were used to identify risk factors associated with early mortality and to build predictive models. The model with the best performance was visualized using a nomogram. Discriminative ability was measured using the area under the curve (AUC) and decision curve analysis. RESULTS: Fifty days was determined as the cutoff for distinguishing early mortality in pediatric IEI patients undergoing UCBT. Of the 230 patients, 43 (18.7%) suffered early mortality. Multivariate logistic regression with pretransplant albumin, CD4 (absolute count), elevated C-reactive protein, and medical history of sepsis showed good discriminant AUC values of 0.7385 (95% CI, 0.5824-0.8945) and 0.827 (95% CI, 0.7409-0.9132) in predicting early mortality in the validation and training sets, respectively. The sensitivity and specificity were 0.5385 and 0.8154 for validation and 0.7667 and 0.7705 for training, respectively. The final model yielded net benefits across a reasonable range of risk thresholds. CONCLUSION: The developed nomogram can predict early mortality in pediatric IEI patients undergoing UCBT.

Synergistic co-regulation and competition by a SOX9-GLI-FOXA phasic transcriptional network coordinate chondrocyte differentiation transitions.

The growth plate mediates bone growth where SOX9 and GLI factors control chondrocyte proliferation, differentiation and entry into hypertrophy. FOXA factors regulate hypertrophic chondrocyte maturation. How these factors integrate into a Gene Regulatory Network (GRN) controlling these differentiation transitions is incompletely understood. We adopted a genome-wide whole tissue approach to establish a Growth Plate Differential Gene Expression Library (GP-DGEL) for fractionated proliferating, pre-hypertrophic, early and late hypertrophic chondrocytes, as an overarching resource for discovery of pathways and disease candidates. De novo motif discovery revealed the enrichment of SOX9 and GLI binding sites in the genes preferentially expressed in proliferating and prehypertrophic chondrocytes, suggesting the potential cooperation between SOX9 and GLI proteins. We integrated the analyses of the transcriptome, SOX9, GLI1 and GLI3 ChIP-seq datasets, with functional validation by transactivation assays and mouse mutants. We identified new SOX9 targets and showed SOX9-GLI directly and cooperatively regulate many genes such as Trps1, Sox9, Sox5, Sox6, Col2a1, Ptch1, Gli1 and Gli2. Further, FOXA2 competes with SOX9 for the transactivation of target genes. The data support a model of SOX9-GLI-FOXA phasic GRN in chondrocyte development. Together, SOX9-GLI auto-regulate and cooperate to activate and repress genes in proliferating chondrocytes. Upon hypertrophy, FOXA competes with SOX9, and control toward terminal differentiation passes to FOXA, RUNX, AP1 and MEF2 factors.

Machine Learning Approaches-Driven for Mortality Prediction for Patients Undergoing Craniotomy in ICU.

OBJECTIVES: We aimed to predict the mortality of patients with craniotomy in ICU by using predictive models to extract the high-risk factors leading to the death of patients from a retrospective a study. METHODS: Five machine-learning (ML) algorithms were applied for training on mortality predictive models with the data from a surgical intensive care unit (ICU) database of the Fujian Provincial Hospital in China. The accuracy, precision, recall, f1 score and the area under the receiver operator characteristic curve (AUC) were used to evaluate the performance of different models, and the calibration of the model was evaluated by brier score. RESULTS: We demonstrated that eXtreme Gradient Boosting (XGBoost) was more suitable for the task, demonstrating a AUC of 0.84. We analyzed the feature importance with the Local Interpretable Model-agnostic Explanations (LIME) analysis and further identified the high-risk factors of mortality in ICU through this study. CONCLUSIONS: This study established the mortality predictive model of patients who had undergone craniotomy in ICU. Identification of the factors that had great influence on mortality has the potential to provide auxiliary decision support for clinical medical staff on their practices.

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy.

An analysis of Sox9 binding profiles in developing chondrocytes identified marked enrichment of an AP-1-like motif. Here, we have explored the functional interplay between Sox9 and AP-1 in mammalian chondrocyte development. Among AP-1 family members, Jun and Fosl2 were highly expressed within prehypertrophic and early hypertrophic chondrocytes. Chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) showed a striking overlap in Jun- and Sox9-bound regions throughout the chondrocyte genome, reflecting direct binding of each factor to the same enhancers and a potential for protein-protein interactions within AP-1- and Sox9-containing complexes. In vitro reporter analysis indicated that direct co-binding of Sox9 and AP-1 at target motifs promoted gene activity. By contrast, where only one factor can engage its DNA target, the presence of the other factor suppresses target activation consistent with protein-protein interactions attenuating transcription. Analysis of prehypertrophic chondrocyte removal of Sox9 confirmed the requirement of Sox9 for hypertrophic chondrocyte development, and in vitro and ex vivo analyses showed that AP-1 promotes chondrocyte hypertrophy. Sox9 and Jun co-bound and co-activated a Col10a1 enhancer in Sox9 and AP-1 motif-dependent manners consistent with their combined action promoting hypertrophic gene expression. Together, the data support a model in which AP-1 family members contribute to Sox9 action in the transition of chondrocytes to the hypertrophic program.

Roles of brca2 (fancd1) in oocyte nuclear architecture, gametogenesis, gonad tumors, and genome stability in zebrafish.

Mild mutations in BRCA2 (FANCD1) cause Fanconi anemia (FA) when homozygous, while severe mutations cause common cancers including breast, ovarian, and prostate cancers when heterozygous. Here we report a zebrafish brca2 insertional mutant that shares phenotypes with human patients and identifies a novel brca2 function in oogenesis. Experiments showed that mutant embryos and mutant cells in culture experienced genome instability, as do cells in FA patients. In wild-type zebrafish, meiotic cells expressed brca2; and, unexpectedly, transcripts in oocytes localized asymmetrically to the animal pole. In juvenile brca2 mutants, oocytes failed to progress through meiosis, leading to female-to-male sex reversal. Adult mutants became sterile males due to the meiotic arrest of spermatocytes, which then died by apoptosis, followed by neoplastic proliferation of gonad somatic cells that was similar to neoplasia observed in ageing dead end (dnd)-knockdown males, which lack germ cells. The construction of animals doubly mutant for brca2 and the apoptotic gene tp53 (p53) rescued brca2-dependent sex reversal. Double mutants developed oocytes and became sterile females that produced only aberrant embryos and showed elevated risk for invasive ovarian tumors. Oocytes in double-mutant females showed normal localization of brca2 and pou5f1 transcripts to the animal pole and vasa transcripts to the vegetal pole, but had a polarized rather than symmetrical nucleus with the distribution of nucleoli and chromosomes to opposite nuclear poles; this result revealed a novel role for Brca2 in establishing or maintaining oocyte nuclear architecture. Mutating tp53 did not rescue the infertility phenotype in brca2 mutant males, suggesting that brca2 plays an essential role in zebrafish spermatogenesis. Overall, this work verified zebrafish as a model for the role of Brca2 in human disease and uncovered a novel function of Brca2 in vertebrate oocyte nuclear architecture.

Selenium substitution for dielectric constant improvement and hole-transfer acceleration in non-fullerene organic solar cells.

Dielectric constant of non-fullerene acceptors plays a critical role in organic solar cells in terms of exciton dissociation and charge recombination. Current acceptors feature a dielectric constant of 3-4, correlating to relatively high recombination loss. We demonstrate that selenium substitution on acceptor central core can effectively modify molecule dielectric constant. The corresponding blend film presents faster hole-transfer of ~5 ps compared to the sulfur-based derivative (~10 ps). However, the blends with Se-acceptor also show faster charge recombination after 100 ps upon optical pumping, which is explained by the relatively disordered stacking of the Se-acceptor. Encouragingly, dispersing the Se-acceptor in an optimized organic solar cell system can interrupt the disordered aggregation while still retain high dielectric constant. With the improved dielectric constant and optimized fibril morphology, the ternary device exhibits an obvious reduction of non-radiative recombination to 0.221 eV and high efficiency of 19.0%. This work unveils heteroatom-substitution induced dielectric constant improvement, and the associated exciton dynamics and morphology manipulation, which finally contributes to better material/device design and improved device performance.

Tri-system integration in metal-oxide nanocomposites via in-situ solution-processed method for ultrathin flexible transparent electrodes.

For stable operation of ultrathin flexible transparent electrodes (uFTEs), it is critical to implement effective risk management during concurrent multi-loading operation of electrical bias and mechanical folding cycles in high-humidity environments. Despite extensive efforts in preparing solution-processed uFTEs with cost-effective and high-throughput means, achieving in-situ nano-adhesion in heterogeneous metal-oxide nanocomposites remains challenging. In this work, we observed by serendipity liquid-like behaviour of transparent metal-oxide-semiconductor zinc oxide nanoparticles (ZnONPs) onto silver nanowires (AgNWs) developed by in-situ solution processed method (iSPM). This enabled us to address the long-standing issue of vulnerability in the nanocomposite caused by the interface of dissimilar materials between AgNWs and ZnONPs, resulting in a remarkably improved multi-loading operation. Importantly, substrate-integrated uFTEs constituted of the metal-oxide nanocomposite electrode semi-embedded in the polymer matrix of greatly thin <0.5 µm thickness is successfully demonstrated with the smooth surface topography, promoted by the tri-system integration including (i) AgNW-AgNW, (ii) ZnONP-ZnONP, and (iii) AgNW-ZnONP systems. Our finding unveils the complex interfacial dynamics associated with the heterogeneous interface system between AgNWs and ZnONPs and holds great promise in understanding the in-situ nano-adhesion process and increasing the design flexibility of next generation solution-processed uFTEs.

Discovery of potent small molecule ubiquitin-specific protease 10 inhibitors with anti-hepatocellular carcinoma activity through regulating YAP expression.

High expression of ubiquitin-specific protease 10 (USP10) promote the proliferation of hepatocellular carcinoma (HCC), thus the development of USP10 inhibitors holds promise as a novel therapeutic approach for HCC treatment. However, the development of selective USP10 inhibitor is still limited. In this study, we developed a novel USP10 inhibitor for investigating the feasibility of targeting USP10 for the treatment of HCC. Due to high USP10 inhibition potency and prominent selectivity, compound D1 bearing quinolin-4(1H)-one scaffold was identified as a lead compound. Subsequent research revealed that D1 significantly inhibits cell proliferation and clone formation in HCC cells. Mechanistic insights indicated that D1 targets the ubiquitin pathway, facilitating the degradation of YAP (Yes-associated protein), thereby triggering the downregulation of p53 and its downstream protein p21. Ultimately, this cascade leads to S-phase arrest in HCC cells, followed by cell apoptosis. Collectively, our findings highlight D1 as a promising starting point for USP10-positive HCC treatment, underscoring its potential as a vital tool for unraveling the functional intricacies of USP10.

Durability of Hepatitis B surface antigen seroclearance in patients experienced nucleoside analogs or interferon monotherapy: A real-world data from Electronic Health Record.

Little is known about the difference in durability of HBsAg seroclearance induced by nucleoside analogs (NAs) or by interferon (IFN). A real-world, retrospective cohort study was conducted. Patients were assigned into two groups: NAs monotherapy-induced HBsAg seroclearance subjects and IFN monotherapy induced-HBsAg seroclearance subjects. A total of 198 subjects, comprised by 168 NAs monotherapy-induced and 30 IFN monotherapy-induced, who achieved HBsAg seroclearance were included in this study. The one-year probabilities of confirmed HBsAg seroclearance were significantly different in patients with NAs monotherapy and IFN monotherapy (0.960 (with 95% CI 0.922-0.999) vs. 0.691 (with 95% CI 0.523-0.913), log-rank-P = 4.04e-4). 73.3% (11 of 15) HBsAg recurrence occurred within one year after HBsAg seroclearance. The one-year probabilities of confirmed HBsAg seroclearance were higher in IFN monotherapy patients with anti-HBs than in IFN monotherapy patients without anti-HBs (0.839 (with 95% CI 0.657-1.000) vs. 0.489 (with 95% CI 0.251-0.953), log-rank test, P = 0.024). Our study thus provided novel insights into the durability of HBsAg seroclearance induced by NAs or IFN monotherapy. In particular, the HBsAg seroreversion rate was relatively high in IFN monotherapy subjects. The presence of anti-HBs was significantly correlated with a longer durability of functional cure induced by IFN treatment. And one-year follow-up in HBsAg seroclearance achieved individuals is proper for averting HBsAg seroreversion and other liver disease.

The Role of "Hierarchical and Classified Prevention and Control Measures (HCPC)" Strategy for SARS-CoV-2 Delta Variant in Guangzhou: A Modeling Study.

BACKGROUND: The Delta variant of SARS-COV-2 has replaced previously circulating strains around the world in 2021. Sporadic outbreaks of the Delta variant in China have posed a concern about how to properly respond to the battle against evolving COVID-19. Here, we analyzed the "hierarchical and classified prevention and control (HCPC)" measures strategy deployed during the recent Guangzhou outbreak. METHODS: A modified susceptible-exposed-pre-symptomatic-infectious-recovered (SEPIR) model was developed and applied to study a range of different scenarios to evaluate the effectiveness of policy deployment. We simulated severe different scenarios to understand policy implementation and timing of implementation. Two outcomes were measured: magnitude of transmission and duration of transmission. The outcomes of scenario evaluations were presented relative to the reality case (i.e., 368 cases in 34 days) with 95% confidence interval (CI). RESULTS: Based on our simulation, the outbreak would become out of control with 7 million estimated infections under the assumption of the absence of any interventions than the 153 reported cases in reality in Guangzhou. The simulation on delayed implementation of interventions showed that the total case numbers would also increase by 166.67%-813.07% if the interventions were delayed by 3 days or 7 days. CONCLUSIONS: It may be concluded that timely and more precise interventions including mass testing and graded community management are effective measures for Delta variant containment in China.

miR-196 regulates axial patterning and pectoral appendage initiation.

Vertebrate Hox clusters contain protein-coding genes that regulate body axis development and microRNA (miRNA) genes whose functions are not yet well understood. We overexpressed the Hox cluster microRNA miR-196 in zebrafish embryos and found four specific, viable phenotypes: failure of pectoral fin bud initiation, deletion of the 6th pharyngeal arch, homeotic aberration and loss of rostral vertebrae, and reduced number of ribs and somites. Reciprocally, miR-196 knockdown evoked an extra pharyngeal arch, extra ribs, and extra somites, confirming endogenous roles of miR-196. miR-196 injection altered expression of hox genes and the signaling of retinoic acid through the retinoic acid receptor gene rarab. Knocking down rarab mimicked the pectoral fin phenotype of miR-196 overexpression, and reporter constructs tested in tissue culture and in embryos showed that the rarab 3'UTR is a miR-196 target for pectoral fin bud initiation. These results show that a Hox cluster microRNA modulates development of axial patterning similar to nearby protein-coding Hox genes, and acts on appendicular patterning at least in part by modulating retinoic acid signaling.

1-Chloronaphthalene-Induced Donor/Acceptor Vertical Distribution and Carrier Dynamics Changes in Nonfullerene Organic Solar Cells and the Governed Mechanism.

Electron donors and acceptors in organic solar cells (OSCs) shall strike a favorable vertical phase separation that acceptors and donors have sufficient contact and gradient accumulation near the cathodes and anodes, respectively. Random mixing of donors/acceptors at surface will result in charge accumulation and severe recombination for low carrier-mobility organic materials. However, it is challenging to tune the vertical distribution in bulk-heterojunction films as they are usually made from a well-mixed donor/acceptor solution. Here, for the first time, it presents with solid evidence that the commonly used 1-chloronaphthalene (CN) additive can tune the donor/acceptor vertical distribution and establish the mechanism. Different from the previous understanding that ascribed the efficiency enhancement brought by CN to the improved molecular stacking/crystallization, it is revealed that the induced vertical distribution is the dominant factor leading to the significantly increased performance. Importantly, the vertical distribution tunability is effective in various hot nonfullerene OSC systems and creates more channels for the collection of dissociated carriers at corresponding organic/electrode interfaces, which contributes the high efficiency of 18.29%. This study of the material vertical distribution and its correlation with molecular stacking offers methods for additives selection and provides insights for the understanding and construction of high-performance OSCs.

Runx2 regulates chromatin accessibility to direct the osteoblast program at neonatal stages.

The transcriptional regulator Runx2 (runt-related transcription factor 2) has essential but distinct roles in osteoblasts and chondrocytes in skeletal development. However, Runx2-mediated regulatory mechanisms underlying the distinctive programming of osteoblasts and chondrocytes are not well understood. Here, we perform an integrative analysis to investigate Runx2-DNA binding and chromatin accessibility ex vivo using neonatal osteoblasts and chondrocytes. We find that Runx2 engages with cell-type-distinct chromatin-accessible regions, potentially interacting with different combinations of transcriptional regulators, forming cell-type-specific hotspots, and potentiating chromatin accessibility. Genetic analysis and direct cellular reprogramming studies suggest that Runx2 is essential for establishment of chromatin accessibility in osteoblasts. Functional enhancer studies identify an Sp7 distal enhancer driven by Runx2-dependent binding and osteoblast-specific chromatin accessibility, contributing to normal osteoblast differentiation. Our findings provide a framework for understanding the regulatory landscape encompassing Runx2-mediated and cell-type-distinct enhancer networks that underlie the specification of osteoblasts.

Suppressing Nickel Oxide/Perovskite Interface Redox Reaction and Defects for Highly Performed and Stable Inverted Perovskite Solar Cells.

The inorganic hole transport layer of nickel oxide (NiOx ) has shown highly efficient, low-cost, and scalable in perovskite photovoltaics. However, redox reactions at the interface between NiOx and perovskites limit their commercialization. In this study, ABABr (4-(2-Aminoethyl) benzoic acid bromide) between the NiOx and different perovskite layers to address the issues has been introduced. How the ABABr interacts with NiOx and perovskites is experimentally and theoretically investigated. These results show that the ABABr molecule chemically reacts with the NiOx via electrostatic attraction on one side, whereas on the other side, it forms a strong hydrogen bond via the NH3 + group with perovskites layers, thus directly diminishing the redox reaction between the NiOx and perovskites layers and passivating the layer surfaces. Additionally, the ABABr interface modification leads to significant improvements in perovskite film morphology, crystallization, and band alignment. The perovskites solar cells (PSCs) based on an ABABr interface modification show power conversion efficiency (PCE) improvement by over 13% and maintain over 90% of its PCE after continuous operation at maximum power point for over 500 h. The work not only contributes to the development of novel interlayers for stable PSCs but also to the understanding of how to prevent interface redox reactions.

UDP xylose synthase 1 is required for morphogenesis and histogenesis of the craniofacial skeleton.

UDP-xylose synthase (Uxs1) is strongly conserved from bacteria to humans, but because no mutation has been studied in any animal, we do not understand its roles in development. Furthermore, no crystal structure has been published. Uxs1 synthesizes UDP-xylose, which initiates glycosaminoglycan attachment to a protein core during proteoglycan formation. Crystal structure and biochemical analyses revealed that an R233H substitution mutation in zebrafish uxs1 alters an arginine buried in the dimer interface, thereby destabilizing and, as enzyme assays show, inactivating the enzyme. Homozygous uxs1 mutants lack Alcian blue-positive, proteoglycan-rich extracellular matrix in cartilages of the neurocranium, pharyngeal arches, and pectoral girdle. Transcripts for uxs1 localize to skeletal domains at hatching. GFP-labeled neural crest cells revealed defective organization and morphogenesis of chondrocytes, perichondrium, and bone in uxs1 mutants. Proteoglycans were dramatically reduced and defectively localized in uxs1 mutants. Although col2a1a transcripts over-accumulated in uxs1 mutants, diminished quantities of Col2a1 protein suggested a role for proteoglycans in collagen secretion or localization. Expression of col10a1, indian hedgehog, and patched was disrupted in mutants, reflecting improper chondrocyte/perichondrium signaling. Up-regulation of sox9a, sox9b, and runx2b in mutants suggested a molecular mechanism consistent with a role for proteoglycans in regulating skeletal cell fate. Together, our data reveal time-dependent changes to gene expression in uxs1 mutants that support a signaling role for proteoglycans during at least two distinct phases of skeletal development. These investigations are the first to examine the effect of mutation on the structure and function of Uxs1 protein in any vertebrate embryos, and reveal that Uxs1 activity is essential for the production and organization of skeletal extracellular matrix, with consequent effects on cartilage, perichondral, and bone morphogenesis.

Wetland Changes and Their Relation to Climate Change in the Pumqu Basin, Tibetan Plateau.

Wetland ecosystems play one of the most crucial roles in the world. Wetlands have the functions of ecological water storage, water supply, and climate regulation, which plays an indispensable role in global environmental security. The Pumqu River Basin (PRB) is located in an area with extremely vulnerable ecological environment, where climate change is obvious. Understanding wetland distribution, changes and causes in the PRB are of great importance to the rational management and protection of wetlands. Using the Landsat series satellite images, wetlands of this area in 2000, 2010, and 2018 were extracted. The results showed that (1) there were obvious regional differences in wetland types and their distribution patterns in the basin. Wetlands were mainly distributed in areas with slopes less than 12° and at elevations between 4000 m and 5500 m. (2) During the past 20 years, the wetland area in the basin decreased, and the changing trend of wetlands was different. Palustrine wetlands decreased tremendously, riverine and lacustrine wetlands first decreased and then increased, while floodplain wetlands first increased and then decreased. Palustrine wetlands were reclaimed to cultivated land, but the proportion of reclamation is small. (3) Climate dominated wetland changes in the PRB. The changes in riverine and lacustrine wetlands were mainly affected by the warm-season average temperature, the change in palustrine wetlands was mainly related to the annual precipitation and the warm-season average temperature, and the change in floodplain wetlands was related to the warm-season precipitation. To achieve sustainable development, the government plays a guiding role and actively formulates and implements wetland protection policies, such as restricting or prohibiting grazing on wetlands, which play an important role in wetland protection and restoration.

Coronavirus disease 2019 outbreak in Beijing's Xinfadi Market, China: a modeling study to inform future resurgence response.

BACKGROUND: A local coronavirus disease 2019 (COVID-19) case confirmed on June 11, 2020 triggered an outbreak in Beijing, China after 56 consecutive days without a newly confirmed case. Non-pharmaceutical interventions (NPIs) were used to contain the source in Xinfadi (XFD) market. To rapidly control the outbreak, both traditional and newly introduced NPIs including large-scale management of high-risk populations and expanded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR-based screening in the general population were conducted in Beijing. We aimed to assess the effectiveness of the response to the COVID-19 outbreak in Beijing's XFD market and inform future response efforts of resurgence across regions. METHODS: A modified susceptible-exposed-infectious-recovered (SEIR) model was developed and applied to evaluate a range of different scenarios from the public health perspective. Two outcomes were measured: magnitude of transmission (i.e., number of cases in the outbreak) and endpoint of transmission (i.e., date of containment). The outcomes of scenario evaluations were presented relative to the reality case (i.e., 368 cases in 34 days) with 95% Confidence Interval (CI). RESULTS: Our results indicated that a 3 to 14 day delay in the identification of XFD as the infection source and initiation of NPIs would have caused a 3 to 28-fold increase in total case number (31-77 day delay in containment). A failure to implement the quarantine scheme employed in the XFD outbreak for defined key population would have caused a fivefold greater number of cases (73 day delay in containment). Similarly, failure to implement the quarantine plan executed in the XFD outbreak for close contacts would have caused twofold greater transmission (44 day delay in containment). Finally, failure to implement expanded nucleic acid screening in the general population would have yielded 1.6-fold greater transmission and a 32 day delay to containment. CONCLUSIONS: This study informs new evidence that in form the selection of NPI to use as countermeasures in response to a COVID-19 outbreak and optimal timing of their implementation. The evidence provided by this study should inform responses to future outbreaks of COVID-19 and future infectious disease outbreak preparedness efforts in China and elsewhere.

Zebrafish sp7:EGFP: a transgenic for studying otic vesicle formation, skeletogenesis, and bone regeneration.

We report the expression pattern and construction of a transgenic zebrafish line for a transcription factor involved in otic vesicle formation and skeletogenesis. The zinc finger transcription factor sp7 (formerly called osterix) is reported as a marker of osteoblasts. Using bacterial artificial chromosome (BAC)-mediated transgenesis, we generated a zebrafish transgenic line for studying skeletal development, Tg(sp7:EGFP)b1212. Using a zebrafish BAC, EGFP was introduced downstream of the regulatory regions of sp7 and injected into one cell-stage embryos. In this transgenic line, GFP expression reproduces endogenous sp7 gene expression in the otic placode and vesicle, and in forming skeletal structures. GFP-positive cells were also detected in adult fish, and were found associated with regenerating fin rays post-amputation. This line provides an essential tool for the further study of zebrafish otic vesicle formation and the development and regeneration of the skeleton.