The combination of apatinib and antigen-specific DC-induced T cells exert antitumor effects by potently improving the immune microenvironment of osteosarcoma.

Objective: Osteosarcoma (OS) is the most common primary bone sarcoma with a high propensity for local invasion and metastasis. Although the antitumor effect of apatinib has been well confirmed in advanced OS, the synergistic effect of apatinib and immunotherapies has not yet been elucidated. Methods: In this study, we established tumour-bearing mice and observed tumour size with low and high doses of apatinib treatments. The expression of 17 cytokines, including vascular endothelial growth factor (VEGF), was detected by protein microarray analysis. Moreover, we designed apatinib and antigen-specific dendritic cell (DC)-T combination treatment for tumour-bearing mice. Tumour growth was detected by statistical analysis of tumour size and microvessel density (MVD) counting, the protein expression of VEGF by western blotting, the cytokines interleukin 6 (IL-6), IL-17 and interferon-gamma (IFN-γ) by enzyme-linked immunosorbent assay (ELISA), and the numbers of myeloid-derived suppressor cells (MDSCs) and tumour-infiltration macrophages (TAMs) by flow cytometry. Results: The results showed that apatinib efficiently suppressed tumour growth, and high-dose apatinib achieved a stronger effect. The same was true for DC-T immunotherapy. However, their combination treatment revealed a better oncolytic effect. Meanwhile, apatinib or DC-T treatment inhibited the expression of VEGF and the proangiogenic mediators IL-6 and IL-17 but increased IFN-γ production. Combination therapy further reduced/increased these effects. In addition, the combination treatment reduced MDSC but enhanced TAM-M1 ratios in the OS microenvironment. These findings indicated that apatinib and antigen-specific DC-T combination therapy was more efficient in oncolysis by regulating pro-/anti-angiogenic inducers and improving the immune state in the OS microenvironment. Conclusion: This study proved that it was feasible to employ immunotherapy with therapeutic agents in OS treatment, which may provide a new approach in addition to the combination of surgery with chemotherapy in tumour treatment.

A novel variant (p.A524P) in Spastin is responsible for a Chinese family with hereditary spastic paraplegia.

BACKGROUND: Hereditary spastic paraplegia (HSP) represents a group of monogenic neurodegenerative disorders characterized by high clinical and genetic heterogeneity. HSP is characterized by slowly progressing hypertonia of both lower extremities, spastic gait, and myasthenia. The most prevalent autosomal dominant form of HSP, known as spastic paraplegia 4 (SPG4), is attributed to variants in the spastin (SPAST) gene. METHODS AND RESULTS: Here, a Chinese family presenting with spasticity in both legs and a shuffling gait participated in our investigation. Whole exome sequencing of the proband was utilized to identify the genetic lesion in the family. Through data filtering, Sanger sequencing validation, and co-separation analysis, a novel variant (NM_014946.3: c.1669G > C:p.A557P) of SPAST was identified as the genetic lesion of this family. Furthermore, bioinformatic analysis revealed that this variant was deleterious and located in a highly evolutionarily conserved site. CONCLUSION: Our study confirmed the diagnosis of SPG4 in this family, contributing to genetic counseling for families affected by SPG4. Additionally, our study broadened the spectrum of SPAST variants and highlighted the importance of ATPases associated with various cellular activity domains of SPAST.

How to safeguard the continuous renal replacement therapy circuit: a narrative review.

The high prevalence of acute kidney injury (AKI) in ICU patients emphasizes the need to understand factors influencing continuous renal replacement therapy (CRRT) circuit lifespan for optimal outcomes. This review examines key pharmacological interventions-citrate (especially in regional citrate anticoagulation), unfractionated heparin (UFH), low molecular weight heparin (LMWH), and nafamostat mesylate (NM)-and their effects on filter longevity. Citrate shows efficacy with lower bleeding risks, while UFH remains cost-effective, particularly in COVID-19 cases. LMWH is effective but associated with higher bleeding risks. NM is promising for high-bleeding risk scenarios. The review advocates for non-tunneled, non-cuffed temporary catheters, especially bedside-inserted ones, and discusses the advantages of surface-modified dual-lumen catheters. Material composition, such as polysulfone membranes, impacts filter lifespan. The choice of treatment modality, such as Continuous Veno-Venous Hemodialysis (CVVHD) or Continuous Veno-Venous Hemofiltration with Dialysis (CVVHDF), along with the management of effluent volume, blood flow rates, and downtime, are critical in prolonging filter longevity in CRRT. Patient-specific conditions, particularly the type of underlying disease, and the implementation of early mobilization strategies during CRRT are identified as influential factors that can extend the lifespan of CRRT filters. In conclusion, this review offers insights into factors influencing CRRT circuit longevity, supporting evidence-based practices and suggesting further multicenter studies to guide ICU clinical decisions.

A Modified Mason-Allen Suture Enhancement Technique (Sunglasses Loop) for Single-Row Repair of Medium-to-Large Rotator Cuffs.

We propose a single-row repair method for medium-to-large rotator cuff rotator cuff tears using a modified Mason-Allen suture enhancement technique (sunglasses loop), which uses high-tensile modified Mason-Allen sutures to close the medial rotator cuff tissues to form a sunglasses loop, resets the rotator cuff tissues via traction with the high-tensile suture, repairs the rotator cuff in a single row with triple-loaded suture anchor (anchor with 3 high-strength sutures), and finally employs an outer row of staples to secure the suture to the lateral aspect of the greater tuberosity, preventing the tendon from pulling out. This method uses a special sunglasses-shaped suture loop, which produces an increase in holding power and a reduction in tension relative to other single-row repair techniques and reduces the rate of rotator cuff retear.

Coordinated Multi-Scenario Optimization Strategy for Park Photovoltaic Storage Based on Master-Slave Game.

Optimizing the operation of photovoltaic (PV) storage systems is crucial for meeting the load demands of parks while minimizing curtailment and enhancing economic efficiency. This paper proposes a multi-scenario collaborative optimization strategy for PV storage systems based on a master-slave game model. Three types of energy storage system (ESS) application scenarios are designed to comprehensively stabilize PV fluctuations, compensate for load transfers, and participate in the frequency regulation (FR) market, thereby optimizing the overall operational strategy of PV storage systems in parks. The upper-level objective is to maximize the park operators' profit, while the lower-level objective is to minimize the user's power supply costs. Case studies demonstrate that this strategy can significantly increase the economic benefits for park operators by 25.8%, reduce user electricity expenditures by 5.27%, and lower curtailment through a load response mechanism, thereby promoting the development and construction of PV storage parks.

Clinicopathological characteristics and oncologic outcomes of patients with gestational trophoblastic neoplasia manifesting as isolated pulmonary lesions.

OBJECTIVE: To elucidate the clinicopathological characteristics and oncological outcomes of a special group of patients with gestational trophoblastic neoplasia (GTN) initially presenting with isolated lung lesions, elevated human chorionic gonadotropin (hCG) levels, and unobserved pelvic lesions. METHODS: Overall, 2358 patients with GTN treated at our hospital between 2000 and 2023 were retrospectively reviewed, and 40 patients were evaluated. The demographic characteristics, clinicopathological features, treatment data, and follow-up information of each patient were collected. The primary outcome was progression free survival. Kaplan-Meier analysis and univariate and multivariate Cox proportional hazard analyses were used to identify the risk factors. RESULTS: Among the 40 patients, 95.0 % had solitary lung lesions, with a median size of 1.9 cm. Moreover, 72.5 % of patients were pathologically confirmed as epithelioid trophoblastic tumors (ETT). During a median follow-up period of 53.5 months (range, 2-143), 11 patients experienced recurrence, including all patients who received chemotherapy alone as the initial treatment, and no death was observed. Relapse treatment involved lung segmentectomy and lobectomy combined with chemotherapy and immunotherapy. Univariate and multivariate Cox analyses identified comparing with surgery±chemotherapy, chemotherapy alone as the initial treatment (hazard ratio [HR] =7.738, 95 % confidence interval [CI] 1.698-35.269, P = 0.008) as independent risk factor for recurrence. CONCLUSIONS: In patients with a history of pregnancy exhibiting isolated pulmonary lesions, elevated hCG levels (mostly <1000 mIU/mL), and unobserved pelvic lesions, ETT should be considered first. Surgical resection of lung lesion is crucial for optimal management. When chemotherapy is considered, multidrug regimen is recommended.

[Incidence of comorbid ED with LUTS and its risk factors in patients with BPH].

OBJECTIVE: To investigate the incidence of comorbid ED with lower urinary tract symptoms (LUTS) and its risk factors in BPH patients. METHODS: Based on inclusion and exclusion criteria, we selected BPH patients visiting the outpatient department of the Second Xiangya Hospital of Central South University from January 2020 to January 2023. We collected the general and clinical data from the patients, including age, height, body weight, abdominal circumference, hip circumference, blood pressure, blood routine, liver function, kidney function, blood lipids and fasting blood glucose, obtained their IPSS, quality of life (QOL) scores, and IIEF-5 scores by questionnaire investigation, and performed data processing and analysis with the SPSS 22.0 software. RESULTS: The incidence rate of comorbid ED with LUTS in the BPH patients rose with the increase of age, 36.46% in the 45－49-year group, 43.72% in the 50－54-year group, 53.66% in the 55－59-year group, 69.23% in the 60－64-year group, and 78.74% in the 65－70-year group. The lipid accumulation product (LAP), visceral adiposity index (VAI), triglycerides and glucose (TyG), hepatic steatosis index (HSI), body mass index (BMI), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) were correlated positively with IPSS scores and negatively with IIEF-5 scores, while LDL-C and total cholesterol (TC) negatively with IPSS scores and positively with IIEF-5 scores. CONCLUSION: The incidence of comorbid ED with LUTS in BPH patients increases with age. The risk factors for this comorbidity include hypertension, dyslipidemia, diabetes, BMI, and lifestyle, and the risk of the condition can be effectively assessed by LAP, VAI, TYG, HSI, BMI, WHtR, WHR, TG and HDL-C.

Enhancing H2-driven CO2 biomethanation performance in bidirectional flow tidal bioreactor by reducing liquid film resistance and heterogeneity.

This study presents a bidirectional flow tidal bioreactor designed to enhance H2-driven CO2 biomethanation. The bioreactor alternated biofilms between immersion in nutrient solution and exposure to H2/CO2, creating alternating dry and wet states. This tidal operation minimized liquid film thickness during dry periods and ensured uniform nutrient distribution during wet periods. Bidirectional H2/CO2 supply was used to reduce biofilm thickness heterogeneity across the reactor height. CO2 biomethanation remained stable with an empty bed residence time of 9.7 min, achieving a methane (CH4) formation rate of 26.8 Nm3 CH4/(m3·d). The product gas contained 95.0 ± 2.5 % CH4, with a H2/CO2 conversion efficiency of 90.8 %. Tidal operation mitigated the buildup of dissolved and suspended organics, such as organic acids and detached biofilms. Dominant bacteria in biofilms included fermentative species like Petrimonas and H2-utilizing homoacetogens like Sporomusa. Enriched hydrogenotrophic methanogens, particularly Methanobacterium, were observed. Overall, this study highlights the bioreactor's effectiveness in improving CO2 biomethanation.

Gender differences in risk factors for suicide attempts among young, first-episode and drug-naive major depressive disorder patients with anxiety symptoms.

Background: Suicide attempts and anxiety are common commodities in patients with major depressive disorder (MDD), and suicide attempts are often associated with anxiety symptoms. Studies have found gender differences in several aspects of MDD; however, gender differences in suicide attempts in young first-episode and drug-naive (FEDN) MDD patients with anxiety remain unknown. This study aimed to investigate potential gender differences in the prevalence of suicide attempts and associated risk factors among young FEDN MDD patients with anxiety in a Chinese Han population. Methods: A cross-sectional study was conducted on 1289 young patients with FEDN MDD. Demographics, clinical characteristics, and biochemical parameters of patients were collected. Results: Suicide attempters accounted for 23.80% and 26.12% of male and female FEDN MDD patients with anxiety, respectively, with no significant gender differences. Binary logistic regression analyses showed that anxiety, clinical global impression severity, and thyroid peroxidase antibody significantly predicted suicide attempts in both male and female FEDN MDD patients with anxiety, while body mass index significantly predicted suicide attempts only in males, and psychotic symptoms predicted suicide attempts only in females. Conclusion: The present study represents the first large-scale investigation of gender differences in the prevalence of suicide attempts and related risk factors among young FEND MDD patients with anxiety in the Chinese Han population. The results indicate that risk factors associated with suicide attempts vary by gender among young FEND MDD patients with anxiety, although a comparable rate of suicide attempts was observed in both female and male patients.

Case report: Roxadustat overdose in an anemia patient of chronic kidney disease: insight beyond insignificant consequence.

A 71-year-old man with a 20-year history of grade 3 hypertension experienced kidney dysfunction 2 years earlier. His serum creatinine (SCr) at the time was 140 µmol/L [with estimated glomerular filtration rate (eGFR) of 43.9 ml/min per 1.73m2], for which he received irbesartan since. At initial presentation, the spot urine dipstick protein was 1+, with an albumin-to-creatinine ratio of 230 mg/g (0-30) and normal urine sediments. The SCr was 176 µmol/L (eGFR = 32.8 ml/min per 1.73m2). The hemoglobulin (Hb) level decreased from 102 to 96 g/L despite oral ferrous succinate 100 mg twice daily starting 2 months ago. Roxadustat (ROXA) 50 mg (body weight, 70 kg) three times weekly was then prescribed. Unfortunately, the patient mistakenly took the drug at 50 mg three times a day (i.e., 1,050 mg instead of the intended 150 mg per week), which was 3.5 times the recommended starting dose for non-dialysis-dependent chronic kidney disease (CKD) patients (100 mg three times weekly for body weight >60 kg) and two times the highest drug manual-recommended weekly dose (2.5 mg/kg three times weekly) approved in the country. When the attending nephrologist discovered the misuse 1 month later, the patient reported no apparent discomfort, and his home blood pressure was in the range 110-130/60-80 mmHg. Repeat blood tests showed that the Hb increased from 96 to 163 g/L and the SCr from 199 to 201 µmol/L in a month. The serum alanine transaminase (ALT) remained within the normal range (from 12 U/L at baseline to 20 U/L), while the serum total and indirect bilirubin levels were slightly elevated. ROXA was withheld immediately. In 30 days, the serum bilirubin returned to baseline, but the Hb decreased from 163 to 140 g/L, and then to 108 g/L after 3 months. On the other hand, the SCr increased from 179 to 203 µmol/L. At 9 months after the initial dosing, when the SCr increased to 256 µmol/L and the Hb decreased to 94 g/L again, ROXA 50 mg three times weekly was reinitiated uneventfully. Herein, by introducing a case who erroneously consumed twice the highest recommended dose of ROXA for a month, but had apparently no obvious discomfort or unfavorable consequence, we attempt to provide a brief overview of the mechanism of action, characteristics, drug metabolism, and side effect profile associated with this agent.

Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (Mpro).

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 and its variants, has further highlighted the urgent need for the development of effective therapeutic agents. Currently, the highly conserved and broad-spectrum nature of main proteases (Mpro) renders them of great importance in the field of inhibitor study. In this study, we categorize inhibitors targeting Mpro into three major groups: mimetic, nonmimetic, and natural inhibitors. We then present the research progress of these inhibitors in detail, including their mechanism of action, antiviral activity, pharmacokinetic properties, animal experiments, and clinical studies. This review aims to provide valuable insights and potential avenues for the development of more effective antiviral drugs against SARS-CoV-2.

Association between angiotensin-converting enzyme gene insertion/deletion polymorphism and cognition impairment in patients with schizophrenia.

RATIONALE: Several lines of evidence indicate that an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) gene may be involved in the pathogenesis of schizophrenia and cognitive impairment. However, the relationship between ACE I/D polymorphism and cognitive impairment in patients with schizophrenia remains unclear. OBJECTIVES: The aim of this study was to examine whether ACE gene I/D polymorphism contributed to cognitive impairment in Chinese patients with schizophrenia, and whether the association between clinical symptoms and cognitive impairment depended on different ACE genotypes. METHODS: The ACE I/D polymorphism was genotyped in 928 schizophrenia patients and 325 healthy controls using a case-control design. The severity of psychopathological symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive functioning was assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: There were significant differences in genotype and allele frequencies of the ACE I/D polymorphism between patients and healthy controls (both P < 0.01). After controlling for demographic characteristics, patients who are homozygous carriers of D and I performed worse on the RBANS attention index than heterozygous carriers (P = 0.009). In addition, attention index score was negatively correlated with PANSS negative symptom score in patients of all genotypes (all P < 0.05), and positively correlated with positive symptom score only in the I/I genotype (P = 0.005). CONCLUSIONS: These findings suggest that ACE I/D gene variants play a role in susceptibility to schizophrenia, specific cognitive impairment and the association between clinical symptoms and cognitive impairment in schizophrenia patients.

An activity-regulated transcriptional program directly drives synaptogenesis.

Although the molecular composition and architecture of synapses have been widely explored, much less is known about what genetic programs directly activate synaptic gene expression and how they are modulated. Here, using Caenorhabditis elegans dopaminergic neurons, we reveal that EGL-43/MECOM and FOS-1/FOS control an activity-dependent synaptogenesis program. Loss of either factor severely reduces presynaptic protein expression. Both factors bind directly to promoters of synaptic genes and act together with CUT homeobox transcription factors to activate transcription. egl-43 and fos-1 mutually promote each other's expression, and increasing the binding affinity of FOS-1 to the egl-43 locus results in increased presynaptic protein expression and synaptic function. EGL-43 regulates the expression of multiple transcription factors, including activity-regulated factors and developmental factors that define multiple aspects of dopaminergic identity. Together, we describe a robust genetic program underlying activity-regulated synapse formation during development.

"On-the-Fly" Nonadiabatic Dynamics Simulation on the Ultrafast Photoisomerization of a Molecular Photoswitch Iminothioindoxyl: An RMS-CASPT2 Investigation.

Iminothioindoxyl (ITI) is a new class of photoswitch that exhibits many excellent properties including well-separated absorption bands in the visible region for both conformers, ultrafast Z to E photoisomerization as well as the millisecond reisomerization at room temperature for the E isomer, and switchable ability in both solids and various solvents. However, the underlying ultrafast photoisomerization mechanism at the atomic level remains unclear. In this work, we have employed a combination of high-level RMS-CASPT2-based static electronic structure calculations and nonadiabatic dynamics simulations to investigate the ultrafast photoisomerization dynamics of ITI. Based on the minimum-energy structures, minimum-energy conical intersections, linear interpolation internal coordinate paths, and nonadiabatic dynamics simulations, the overall photoisomerization scenario of ITI upon excitation is established. Upon excitation around 416 nm, the molecule will be excited to the S2 state considering its close energy to the experimentally measured absorption maximum and larger oscillator strength, from which ultrafast decay of S2 to S1 state can take place efficiently with a time constant of 62 fs. However, the photoisomerization is not likely to complete in the S2 state since the dihedral associated with the Z to E isomerization changes little during the relaxation. Upon relaxing to the S1 state, the molecule will decay to the S0 state ultrafast with a time constant of 232 fs. In contrast, the decay of the S1 state is important for the isomerization considering that the dihedral related to the isomerization of the hopping structures is close to 90°. Therefore, the S1/S0 intersection region should be important for the isomerization of ITI. Arriving at the S0 state, the molecule can either go back to the original Z reactant or isomerize to the E products. At the end of the 500 fs simulation time, the E configuration accounts for nearly 37% of the final structures. Moreover, the photoisomerization mechanism is different from the isomerization mechanism in the ground state; i.e., instead of the inversion mechanism in the ground state, the photoisomerization prefers the rotation mechanism. Our results not only agree well with previous experimental studies but also provide some novel insights that could be helpful for future improvements in the performance of the ITI photoswitches.

Abatacept versus tumor necrosis factor inhibitors on mortality and medical utilizations in the treatment of rheumatoid arthritis associated interstitial lung disease: a large-scale real-world retrospective cohort study.

Rheumatoid arthritis is a chronic inflammatory disease, and interstitial lung disease is one of the important extra-articular manifestations. There is limited evidence comparing abatacept (ABA) and tumor necrosis factor inhibitors (TNFi) regarding the risk of mortality among patients with rheumatoid arthritis associated interstitial lung disease (RA-ILD). The aim of this study is to investigate the risk of mortality in patients with RA-ILD treated with ABA compared to TNFi. This retrospective cohort study utilized TriNetX electronic health record database. We enrolled patients who were diagnosed with RA-ILD and had received a new prescription for either ABA or TNFi. Patients were categorized into two cohorts based on their initial prescription. The primary outcome was all-cause mortality, and secondary outcomes were healthcare utilizations, including hospitalization, critical care services, and mechanical ventilation. Subgroup analyses were performed on age, presence of anti-citrullinated peptide antibodies (ACPA), and cardiovascular risk. Among 34,388 RA-ILD patients, 895 were selected for each group (ABA and TNFi) following propensity score matching. The ABA group exhibited a higher all-cause mortality risk. (HR 1.296, 95% CI 1.006-1.671). Subgroup analysis showed a heightened risk of receiving mechanical ventilation in ABA-treated patients aged 18-64 years old (HR 1.853, 95% CI 1.002-3.426), and those with cardiovascular risk factors (HR 2.015, 95% CI 1.118-3.630). Another subgroup analysis indicated a higher risk of mortality among ABA-treated patients with positive-ACPA. (HR 4.138 95% CI 1.343-12.75). This real-world data research demonstrated a higher risk of all-cause mortality in RA-ILD patients treated with ABA compared to TNFi, particularly those aged 18-64 years, lacking cardiovascular risk factors, and positive-ACPA. ABA was associated with an increased risk of mechanical ventilation in patients aged 18-64 years and those with cardiovascular risk factors.

Roles of Nonadiabatic Processes, Reaction Mechanism, and Selectivity in Cu-Catalyzed [2 + 2] Photocycloaddition of Norbornene and Acetone to Oxetane.

Oxetane has been extensively studied for its applications in medicinal chemistry and as a reactive intermediate in synthesis. Experiments report a Cu-catalyzed [2 + 2] photocycloaddition of acetone and norbornene to oxetane, which is proposed to deviate from the conventional Paternò-Büchi reaction. However, its mechanism at the atomic level is not clear. In this study, we used a combination of multistate complete active space second-order perturbation theory (MS-CASPT2) and density functional theory to systematically investigate the reaction mechanism and elucidate the factors contributing to the diastereomeric selectivity. Initially, the formation of the TpCu(Norb) complex is achieved by strong interaction between tris(pyrazolyl)borate Cu(I) (TpCu) and norbornene in the ground state (S0). Upon photoexcitation, TpCu(Norb) eventually decays to the T1 state, in which TpCu(Norb) attacks acetone to initiate subsequent reactions and produces final endo- or exo-oxetane products. All these reactions initially involve the C-C bond formation in the T1 state thereto leading to a ring-opening intermediate. This intermediate then undergoes a nonradiative transition to the S0 state, producing a five-membered ring intermediate, from which the C-O bond is formed, leading to the experimentally dominant exo-product. In contrast, the endo-oxetane formation requires a rearrangement process after the C-C bond is formed because of the large steric effects. As a consequence, the different reaction pathways generating exo- and endo-products exhibit large differences in the free-energy barriers, which results in a diastereomeric selectivity observed experimentally. Additionally, the nonradiative transition is found to play an important role in facilitating these reaction steps. The present computational study provides valuable mechanistic insights into Cu-catalyzed photocycloaddition reactions.

Spatiotemporal evolution and interaction of water constraints and their socio-ecological drivers in the Taihu Lake Basin.

To effectively manage water constraints (WCs) within a basin, it is crucial to first scientifically delineate their spatial distribution and thoroughly understand the interactions between WCs. Investigating the complex driving mechanisms at multiple scales is also essential. In this study, a basin WC evaluation framework is constructed using a conflict risk assessment model. The spatiotemporal variations of four types of WCs across three spatial scales in the Taihu Lake Basin (TLB) are thoroughly investigated. Furthermore, the study quantifies the trade-offs, synergy effects, and bundle patterns of these water constraints. The study employs the Optimal Parameters-based Geographic Detector (OPGD) and multivariate linear regression to identify the key socio-ecological drivers of WCs. Our findings indicate that between 2010 and 2020, water resource constraint (WREC), water environment constraint (WENC), water safety constraint (WSAC), water ecology constraint (WECC), and the comprehensive WC (CWC) displayed varying degrees of heterogeneity. Particularly, the mean values of WSAC, WECC, and CWC witnessed an increase over the decade. Additionally, all WCs exhibited a strong positive spatial autocorrelation. Synergistic interactions among WCs were predominantly observed in pairs such as WREC-WSAC, WREC-WECC, and WSAC-WECC, while a weaker trade-off effect was noted in the WENC-WECC pair. At multiple scales, we identified eight types of WC bundles capable of undergoing mutual transformations, especially at the basin scale. The primary drivers of WCs varied across different stages and scales, with most factors collectively exerting a more significant impact than individually. Notably, factors like secondary and tertiary industry GDP (X2), population density (X3), precipitation (X6), and elevation (X7) were identified as core drivers influencing the evolution of WCs in the TLB. Integrating these spatiotemporal characteristics and driving mechanisms of WC interactions into basin planning and management can significantly support the alleviation of multidimensional water constraints in territorial spaces.

Accelerating denoising diffusion probabilistic model via truncated inverse processes for medical image segmentation.

Medical image segmentation demands precise accuracy and the capability to assess segmentation uncertainty for informed clinical decision-making. Denoising Diffusion Probability Models (DDPMs), with their advancements in image generation, can treat segmentation as a conditional generation task, providing accurate segmentation and uncertainty estimation. However, current DDPMs used in medical image segmentation suffer from low inference efficiency and prediction errors caused by excessive noise at the end of the forward process. To address this issue, we propose an accelerated denoising diffusion probabilistic model via truncated inverse processes (ADDPM) that is specifically designed for medical image segmentation. The inverse process of ADDPM starts from a non-Gaussian distribution and terminates early once a prediction with relatively low noise is obtained after multiple iterations of denoising. We employ a separate powerful segmentation network to obtain pre-segmentation and construct the non-Gaussian distribution of the segmentation based on the forward diffusion rule. By further adopting a separate denoising network, the final segmentation can be obtained with just one denoising step from the predictions with low noise. ADDPM greatly reduces the number of denoising steps to approximately one-tenth of that in vanilla DDPMs. Our experiments on four segmentation tasks demonstrate that ADDPM outperforms both vanilla DDPMs and existing representative accelerating DDPMs methods. Moreover, ADDPM can be easily integrated with existing advanced segmentation models to improve segmentation performance and provide uncertainty estimation. Implementation code: https://github.com/Guoxt/ADDPM.

A retrospective survey on the effectiveness of vaccines administered to individuals in China with regard to inactivated COVID-19 vaccines, Ad5-nCoV and/or aerosolized Ad5-nCoV.

We administered a questionnaire to participants who received different vaccination regimens to evaluate the effectiveness of Ad5-vectored COVID-19 vaccines. The results showed that administration of intramuscular Ad5-nCoV provided 21.32% more protection against SARS-CoV-2 infection than that of the inactivated COVID-19 vaccine in people who had received only one type of COVID-19 vaccine. Furthermore, aerosolized Ad5-nCoV exhibited good protection, whether it was administered as a homologous booster to people vaccinated with the intramuscular Ad5-nCoV or as a heterologous booster to people vaccinated with inactivated COVID-19 vaccines. Our research indicates that Ad5-nCoV is an effective booster. This finding supports the future selection of COVID-19 immunization strategies.

Attenuation of renal fibrosis in mice due to lack of bombesin receptor-activated protein homologue.

Bombesin receptor-activated protein (BRAP), encoded by the C6orf89 gene in humans, is expressed in various cells with undefined functions. BC004004, the mouse homologue of C6orf89, has been shown to play a role in bleomycin-induced pulmonary fibrosis through the use of a BC004004 gene knockout mouse (BC004004-/-). In this study, we investigated the potential involvement of BRAP in renal fibrosis using two mouse models: unilateral ureteral obstruction (UUO) and type 2 diabetes mellitus induced by combination of a high-fat diet (HFD) and streptozocin (STZ). BRAP or its homologue was expressed in tubular epithelial cells (TECs) in the kidneys of patients with chronic kidney disease (CKD) and in BC004004+/+ mice. Compared to control mice, BC004004-/- mice exhibited attenuated renal injury and renal fibrosis after UUO or after HFD/STZ treatment. Immunohistochemistry and immunoblot analyses of the kidneys of BC004004+/+ mice after UUO surgery showed a more significant decrease in E-cadherin expression and a more significant increase in both α smooth muscle actin (α-SMA) and vimentin expression compared to BC004004-/- mice. Additionally, stimulation with transforming growth factor-ß1 (TGF-ß1) led to a more significant decrease in E-cadherin expression and a more significant increase in α-SMA and vimentin expression in isolated TECs from BC004004+/+ than in those from BC004004-/- mice. These results suggest that an enhanced epithelial-mesenchymal transition (EMT) process occurred in TECs in BC004004+/+ mice during renal injury, which might contribute to renal fibrosis. The loss of the BRAP homologue in BC004004-/- mice suppressed EMT activation in kidneys and contributed to the suppression of fibrosis during renal injury.