Prevalence and correlations of schistosomiasis mansoni and schistosomiasis haematobium among humans and intermediate snail hosts: a systematic review and meta-analysis.

BACKGROUND: The control of schistosomiasis is particularly difficult in sub-Saharan Africa, which currently harbours 95% of this disease. The target population for preventive chemotherapy (PC) is expanded to all age group at risk of infection, thus increasing the demands of praziquantel (PZQ) tablets according to the new released guideline by World Health Organization. Due to the gap between available PZQ for PC and requirements, alternative approaches to assess endemicity of schistosomiasis in a community, are urgently needed for more quick and precise methods. We aimed to find out to which degree the infection status of snails can be used to guide chemotherapy against schistosomiasis. METHODS: We searched literature published from January 1991 to December 2022, that reported on the prevalence rates of Schistosoma mansoni, S. haematobium in the intermediate snails Biomphalaria spp. and Bulinus spp., respectively, and in humans. A random effect model for meta-analyses was used to calculate the pooled prevalence estimate (PPE), with heterogeneity assessed using I-squared statistic (I2), with correlation and regression analysis for the exploration of the relationship between human S. mansoni and S. haematobium infections and that in their specific intermediate hosts. RESULTS: Forty-seven publications comprising 59 field investigations were included. The pooled PPE of schistosomiasis, schistosomiasis mansoni and schistosomiasis haematobium in humans were 27.5% [95% confidence interval (CI): 24.0-31.1%], 25.6% (95% CI: 19.9-31.3%), and 28.8% (95% CI: 23.4-34.3%), respectively. The snails showed an overall infection rate of 8.6% (95% CI: 7.7-9.4%), with 12.1% (95% CI: 9.9-14.2%) in the Biomphalaria spp. snails and 6.9% (95% CI: 5.7-8.1%) in the Bulinus spp. snails. The correlation coefficient was 0.3 (95% CI: 0.01-0.5%, P < 0.05) indicating that the two variables, i.e. all intermediate host snails on the one hand and the human host on the other, were positively correlated. CONCLUSIONS: The prevalence rate of S. mansoni and S. haematobium is still high in endemic areas. Given the significant, positive correlation between the prevalence of schistosomes in humans and the intermediate snail hosts, more attention should be paid to programme integration of snail surveillance in future.

Preclinical characterization of [18F]D2-LW223: an improved metabolically stable PET tracer for imaging the translocator protein 18 kDa (TSPO) in neuroinflammatory rodent models and non-human primates.

Positron emission tomography (PET) targeting translocator protein 18 kDa (TSPO) can be used for the noninvasive detection of neuroinflammation. Improved in vivo stability of a TSPO tracer is beneficial for minimizing the potential confounding effects of radiometabolites. Deuteration represents an important strategy for improving the pharmacokinetics and stability of existing drug molecules in the plasma. This study developed a novel tracer via the deuteration of [18F]LW223 and evaluated its in vivo stability and specific binding in neuroinflammatory rodent models and nonhuman primate (NHP) brains. Compared with LW223, D2-LW223 exhibited improved binding affinity to TSPO. Compared with [18F]LW223, [18F]D2-LW223 has superior physicochemical properties and favorable brain kinetics, with enhanced metabolic stability and reduced defluorination. Preclinical investigations in rodent models of LPS-induced neuroinflammation and cerebral ischemia revealed specific [18F]D2-LW223 binding to TSPO in regions affected by neuroinflammation. Two-tissue compartment model analyses provided excellent model fits and allowed the quantitative mapping of TSPO across the NHP brain. These results indicate that [18F]D2-LW223 holds significant promise for the precise quantification of TSPO expression in neuroinflammatory pathologies of the brain.

Association and causal impact of TERT genetic variants on peripheral blood leukocyte telomere length and cerebral small vessel disease risk in a Chinese Han population: a mendelian randomization analysis.

BACKGROUND: Previous observational studies have highlighted potential relationships between the telomerase reverse transcriptase (TERT) gene, short leukocyte telomere length (LTL), and cerebrovascular disease. However, it remains to be established as to whether TERT gene variants are associated with an elevated risk of cerebral small vessel disease (CSVD), and whether there is a causal relationship between LTL and CSVD. METHODS: Five TERT single nucleotide polymorphisms (SNPs) were analyzed in 307 CSVD patients and 320 healthy controls in whom LTL values were quantified. Allele models and four genetic models were used to explore the relationship between these SNP genotypes and CSVD risk. A Mendelian randomization analysis of CSVD risk was then performed using LTL-related SNPs and the polygenic risk score (PRS) constructed from these SNPs as genetic instrumental variables to predict the causal relationship between LTL and CSVD risk. RESULTS: Model association analyses identified two SNPs that were significantly associated with CSVD risk. LTL was significantly correlated with age (P < 0.001), and the MR analysis revealed an association between short LTL and an elevated risk of CSVD. PRS-based genetic prediction of short LTLs was also significantly related to an elevated CSVD risk. CONCLUSION: Multiple genetic models and MR results indicate that TERT gene SNPs may be related to an elevated risk of CSVD, and that shorter LTL may be causally linked to such CSVD risk.

Photocatalytic deuterocarboxylation of alkynes with oxalate.

Herein, a catalytic photoredox-neutral strategy for alkyne deuterocarboxylation with tetrabutylammonium oxalate as the carbonyl source and D2O as the deuteration agent was described. For the first time, the oxalic salt acted as both the reductant and carbonyl source through single electron transfer and subsequential homolysis of the C-C bond. The strongly reductive CO2 radical anion species in situ generated from oxalate played significant roles in realizing the global deuterocarboxylation of terminal and internal alkynes to access various tetra- and tri-deuterated aryl propionic acids with high yields and deuteration ratios.

Analysis of the current status and associated risk factors of cognitive function in Tibetan hypertensive patients at various altitudes.

OBJECTIVE: This study aims to explore the current cognitive status and identify risk factors associated with cognitive function in Tibetan hypertensive patients living at various altitudes. METHODS: The Simple Mental Status Scale (MMSE) was used to evaluate the cognitive function of 611 Tibetan hypertensive patients at various altitudes in Gannan Tibetan Autonomous Prefecture. Afterward, we conducted an analysis to identify the factors influencing their cognitive function. RESULTS: The study found that the prevalence of cognitive dysfunction was 22.3%, with a higher incidence at high altitude (group D 29.0%) compared to low altitude (group A 16.0%). The study conducted a binary logistic regression analysis to identify the risk factors for cognitive dysfunction. The analysis revealed that altitude, age, body mass index, marital status, education, income level, and blood pressure control level were all significant risk factors. After controlling for age, body mass index, marital status, educational level, income level, and blood pressure control level, the risk of developing cognitive dysfunction was 2.773 times higher (p < .05) for individuals in group C at high altitude and 2.381 times higher (p < .05) for individuals in group D at high altitude compared to those in group A at low altitude. CONCLUSIONS: Altitude plays a role in the development of cognitive dysfunction in hypertensive patients. Tibetan hypertensive patients living at high altitudes may be at a higher risk of cognitive dysfunction compared to those living at lower altitudes. Therefore, interventions should be targeted to prevent or mitigate potential cognitive impairment.

Assessment of the influence of levees along Yangtze River on Oncomelania hupensis, the intermediate host of Schistosoma japonicum.

BACKGROUND: Oncomelania hupensis is the exclusive intermediate host of Schistosoma japonicum in China. Snail control is an essential component of schistosomiasis elimination programme. With 70 years of continuous efforts, the range of O. hupensis had reduced significantly, but slowed down in last decades. A large number of levees against flooding were constructed along Yangtze River and its affiliated lakes in the middle and lower reaches, which influenced the hydrology and ecology in the alluvial plains. The purpose of this study was to assess the impact of levees on the distribution of O. hupensis in the middle and lower reaches of the Yangtze River. METHODS: The snail habitats were digitalised by hand-held GPS system. The years for discovery and elimination of snail habitats were extracted from historical records. The accumulated snail-infested range for each habitat was calculated on the basis of annual reports. The current distribution of O. hupensis was determined by systematic and environmental sampling. The geographical distribution of levees was obtained from satellite imagery. To assess the impact of levees, the data pertaining to O. hupensis were divided into two parts: inside and outside the Yangtze River. Joinpoint regression was utilised to divide the study time span and further characterise the regression in each period. The 5-year-period moving averages of eliminated area infested by snails were calculated for the habitats inside and outside Yangtze River. The moving routes of corresponding geographical median centres were simulated in ArcGIS. Hotspot analysis was used to determine the areas with statistical significance clustering of O. hupensis density. RESULTS: Three periods were identified according to Joinpoint regression both inside and outside Yangtze River. The area infested by O. hupensis increased in the first two periods. It decreased rapidly outside Yangtze River year over year after 1970, while that inside the Yangtze River did not change significantly. Furthermore, the latter was significantly higher than the former. It was observed that the present density of O. hupensis inside Yangtze River was lower than outside the Yangtze River. The median centre for eliminated ranges inside Yangtze River wavered between the east (lower reach) and the west (middle reach). In contrast, the median centre for eliminated ranges continuously moved from the east to the west. CONCLUSIONS: Our findings indicated that the levees had a considerable negative impact on the distribution of O. hupensis outside Yangtze River. Some hotspots observed in the irrigation areas need a sluice system at the inlet of branch for snail control. The major distribution of O. hupensis located in Hubei might be caused by severe waterlogging. The intensive surveillance should be implemented there. The biggest two freshwater lakes, the major endemic regions historically, were identified as cold spots. The long-term impact of Three Gorges Dam on the distribution of O. hupensis in the lakes should be monitored and evaluated.

Formate and CO2 Enable Reductive Carboxylation of Imines: Synthesis of Unnatural α-Amino Acids.

Herein, a photocatalytic umpolung strategy for reductive carboxylation of imines for the synthesis of α-amino acids was disclosed. Carbon dioxide radical anion (CO2•-) generated from formate is the key single electron reductant in the reactions. An unprecedentedly broad substrate scope of imines with excellent reaction yields was obtained with carbon dioxide (CO2) and formate salt as carbon sources.

Development and validation of bioanalytical assays for the quantification of 9MW2821, a nectin-4-targeting antibody-drug conjugate.

We designed and developed 9MW2821, an anti-Nectin-4 antibody-drug conjugate (ADC) with an enzymatically cleavable valine-citrulline linker and monomethyl auristatin E (MMAE) as the payload. Four bioanalytical assays for total antibodies, conjugated antibodies, conjugated payload, and free payload were then developed and validated for the comprehensive evaluation of the multiple drug forms of 9MW2821. Specific sandwich enzyme-linked immunosorbent assays were used to quantify total antibodies and conjugated antibody, showing good drug-to-antibody ratio (DAR) tolerance. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine free MMAE, and conjugated MMAE was quantified using a combination of ligand-binding assay (LBA) and LC-MS/MS. Based on these four assays, we studied the serum stability and monkey pharmacokinetic profiles of 9MW2821, and the in vivo DAR of 9MW2821 was calculated and dynamically monitored. In conclusion, we developed and validated series of bioanalytical assays to quantify multiple forms of 9MW2821, a new ADC, and used the assays to evaluate the serum stability and monkey pharmacokinetic characteristics. The results indicate good linker stability and suggest that the developed assays can be further used in clinical settings.

Structural modification and biomechanical analysis of lumbar disc prosthesis: A finite element study.

BACKGROUND: Most ball-in-socket artificial lumbar disc implanted in the spine result in increased hypermobility of the operative level and overloading of the facet joint. METHODS: A finite element model was established and validated for the lumbar spine (L1-L5). The structure of the Mobidisc prosthesis was modified, resulting in the development of two new intervertebral disc prostheses, Movcore and Mcopro. The prostheses were implanted into the L3/L4 level to simulate total disc replacement, and the biomechanical properties of the lumbar spine model were analyzed after the operation. FINDINGS: Following the implantation of the prostheses, the mobility of operative level, peak stress of lumbar spine models, and peak stress of facet joint increased. The performance of mobility was found to be more similar between Movcore and Mobidisc. The mobility and facet joint peak stress of the Mcopro model decreased progressively with an increase in the Young's modulus of the artificial annulus during flexion, extension, and lateral bending. Among all the models, the Mcopro50 model had the mobility closest to the intact model. It showed a 3% decrease in flexion, equal range of motion in extension, a 9% increase in left lateral bending, a 7% increase in right lateral bending, and a 3% decrease in axial rotation. INTERPRETATION: The feasibility of the new intervertebral disc prostheses, Movcore and Mcopro, has been established. The Mcopro prosthesis, which features an artificial annular structure, offers significant advantages in terms of reduced mobility of the operative level and peak stress of facet joint.

Preparation and epitope analysis of monoclonal antibodies against African swine fever virus DP96R protein.

BACKGROUND: Many proteins of African swine fever virus (ASFV, such as p72, p54, p30, CD2v, K205R) have been successfully expressed and characterized. However, there are few reports on the DP96R protein of ASFV, which is the virulence protein of ASFV and plays an important role in the process of host infection and invasion of ASFV. RESULTS: Firstly, the prokaryotic expression vector of DP96R gene was constructed, the prokaryotic system was used to induce the expression of DP96R protein, and monoclonal antibody was prepared by immunizing mice. Four monoclonal cells of DP96R protein were obtained by three ELISA screening and two sub-cloning; the titer of ascites antibody was up to 1:500,000, and the monoclonal antibody could specifically recognize DP96R protein. Finally, the subtypes of the four strains of monoclonal antibodies were identified and the minimum epitopes recognized by them were determined. CONCLUSION: Monoclonal antibody against ASFV DP96R protein was successfully prepared and identified, which lays a foundation for further exploration of the structure and function of DP96R protein and ASFV diagnostic technology.

Multifunctional double-network hydrogel with antibacterial and anti-inflammatory synergistic effects contributes to wound healing of bacterial infection.

Wound infection not only hinders the time sequence of tissue repair, but also may lead to serious complications. Multifunctional wound dressings with biocompatibility, excellent mechanical properties and antibacterial properties can promote wound healing during skin infection and reduce the use of antibiotics. In this study, a multifunctional dual-network antibacterial hydrogel was constructed based on the electrostatic interaction of two polyelectrolytes, hydroxypropyl trimethyl ammonium chloride chitosan (HACC) and sodium alginate (SA). Attributing to the suitable physical crosslinking between HACC and SA, the hydrogel not only has good biocompatibility, mechanical property, but also has broad-spectrum antibacterial properties. In vivo results showed that the hydrogel could regulate M2 polarization, promote early vascular regeneration, and create a good microenvironment for wound healing. Therefore, this hydrogel is an effective multifunctional wound dressing. Consequently, we propose a novel hydrogel with combined elements to expedite the intricate repair of wound infection.

Synthesis of Tetrasubstituted Alkenes by Rhodium-Catalyzed Regioselective Cyano Transfer.

We describe herein a novel, general, and robust approach to structurally diversified alkenyl nitriles through a Rh-catalyzed cyano transfer reaction between alkynyl-malononitrile derivatives and aryl/alkenyl boronic acids. This reaction exhibits high chemo- and regioselectivity and a broad substrate scope. The tetrasubstituted alkenyl dinitriles (34 examples, average 58% yield) are obtained through substrate tuning and ligand control.

Isotemporal substitution effect of 24-hour movement behavior on the mental health of Chinese preschool children.

The 24-h movement behavior of preschoolers comprises a spectrum of activities, including moderate-to-vigorous intensity physical activity (MVPA), light-intensity physical activity (LPA), screen-based sedentary behavior (SCSB), non-screen-based sedentary behavior (NSCSB), and sleep. While previous research has shed light on the link between movement behaviors and children's mental health, the specific impacts on the unique demographic of Chinese preschoolers remain underexplored. This study significantly contributes to the literature by exploring how 24-h movement behavior affects the mental health of preschoolers in a Chinese context. The study involved205 Chinese preschool children (117 boys and 88 girls) between the ages of 3 and 6 years wore accelerometers to measure their LPA, MVPA, and sedentary behavior (SB), while their parents reported the time spent on sleep and SCSB. The parents also completed the Strength and Difficulties Questionnaire to assess their children's mental health. The study used compositional regression and isotemporal substitution models to examine the relationship between the various components of 24-h movement behavior and mental health. The results showed that greater NCSSB compared to MVPA, LPA, sleep, and SCSB was associated with good prosocial behavior and lower scores on externalizing problems. This highlights the potential of NSCSB as a beneficial component in the daily routine of preschoolers for fostering mental well-being. Replacing 15 min of sleep and SCSB with 15 min of NSCSB was associated with a decrease of 0.24 and 0.15 units, respectively, in externalizing problems. Reallocating 15 min of sleep to NSCSB was linked to an increase of 0.11 units in prosocial behavior. There were no significant substitution effects between LPA and MVPA time with any other movement behavior on prosocial behavior and externalizing problems. Given the positive associations observed, further longitudinal studies are necessary to explore the link between 24-h movement behavior and mental health in preschool children.

Benzothiazole derivatives as histone deacetylase inhibitors for the treatment of autosomal dominant polycystic kidney disease.

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC50 < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC50 = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC inhibitor for the treatment of ADPKD.

Examining the relationship between meeting 24-hour movement behaviour guidelines and mental health in Chinese preschool children.

Background: Limited research has explored the relationship between adhering to 24-h Movement Behaviour guidelines and mental health in Chinese preschool children. The objectives of this study encompassed two primary goals: (1) to investigate the adherence of preschool children in China to the 24-h Movement Behaviour guidelines; and (2) to analyze the relationship between fulfilling various combinations of these guidelines and mental health, identifying the most advantageous combination. Methods: Utilizing a convenience sampling approach, this study included 205 preschool children (117 boys and 88 girls, average age 4.8 ± 0.51 years) from five kindergartens in Hengyang, Hunan Province. The physical activity (PA) and sedentary behaviour of preschool children were objectively assessed using waist-worn accelerometers, while sleep duration and screen time were reported by the children's parents. To evaluate mental health, the parent version of the internationally validated Strength and Difficulties Questionnaire (SDQ) was employed, which measures externalizing problems, internalizing problems, and prosocial behaviour. Employing Mplus 8.0 for Structural Equation Modeling analysis, while controlling for demographic variables, the study explored the connection between preschool children's mental health and their adherence to the 24-h Movement Behaviour guidelines. Results: Worryingly, merely 14.6% of preschoolers met the recommended guidelines for all three aspects (PA, sleep duration, and screen time). Positive correlations were identified between meeting PA guidelines and displaying prosocial behaviour (ß = 0.184; p < 0.05), while screen time adherence exhibited a negative correlation with externalizing problems (ß = -0.207; p < 0.05). Similarly, there was a negative association between sleep duration adherence and externalizing problems (ß = -0.191; p < 0.05). Meeting all three recommended guidelines was notably linked to enhanced prosocial behaviour (ß = 0.464; p < 0.05), while following the screen time and sleep duration guidelines was negatively associated with externalizing problems (ß = -0.246; p < 0.05). Conclusion: This study underscores the limited adherence of Chinese preschoolers to the comprehensive 24-h Movement Behaviour guidelines. Noteworthy findings include the positive influence of PA on prosocial behaviour, alongside the significant roles that sleep duration and screen time play in mitigating externalizing problems within this age group. Alignment with the 24-h Movement Behaviour guidelines is associated with more favorable mental health indicators in preschoolers.

Asymmetric Tandem Michael Addition/Interrupted Nef Reactions of Nitromethane with Oxindole-Derived Alkenes: Enantioselective Synthesis of Spiro-polycyclic Oxindoles.

Chiral spiro-polycyclic oxindoles are valuable heterocyclic ring systems that are widely distributed in natural alkaloids and biologically active compounds. Herein, we reported an asymmetric tandem Michael addition/interrupted Nef reaction of nitromethane with oxindole-derived alkenes catalyzed by a chiral 2-aminobenzimidazole bifunctional organocatalyst. A series of novel enantiomerically enriched spiro-polycyclic oxindole derivatives bearing an oxime group were synthesized in moderate to excellent isolated yields (up to 99%) with an excellent level of enantioselectivities (up to 99% ee). Furthermore, the antiproliferation activity of the resulting oxindoles derivatives were evaluated, and compound 2d demonstrated promising anticancer properties against HCT116 (IC50 = 14.08 µM) and HT29 (IC50 = 15.46 µM) cell lines.

Correlation-Induced Symmetry-Broken States in Large-Angle Twisted Bilayer Graphene on MoS2.

Strongly correlated states commonly emerge in twisted bilayer graphene (TBG) with "magic-angle" (1.1°), where the electron-electron (e-e) interaction U becomes prominent relative to the small bandwidth W of the nearly flat band. However, the stringent requirement of this magic angle makes the sample preparation and the further application facing great challenges. Here, using scanning tunneling microscopy (STM) and spectroscopy (STS), we demonstrate that the correlation-induced symmetry-broken states can also be achieved in a 3.45° TBG, via engineering this nonmagic-angle TBG into regimes of U/W > 1. We enhance the e-e interaction through controlling the microscopic dielectric environment by using a MoS2 substrate. Simultaneously, the width of the low-energy van Hove singularity (VHS) peak is reduced by enhancing the interlayer coupling via STM tip modulation. When partially filled, the VHS peak exhibits a giant splitting into two states flanked by the Fermi level and shows a symmetry-broken LDOS distribution with a stripy charge order, which confirms the existence of strong correlation effect in our 3.45° TBG. Our result demonstrates the feasibility of the study and application of the correlation physics in TBGs with a wider range of twist angle.

Asymmetric synthesis of P-stereogenic phosphindane oxides via kinetic resolution and their biological activity.

The importance of P-stereogenic heterocycles has been widely recognized with their extensive use as privileged chiral ligands and bioactive compounds. The catalytic asymmetric synthesis of P-stereogenic phosphindane derivatives, however, remains a challenging task. Herein, we report a catalytic kinetic resolution of phosphindole oxides via rhodium-catalyzed diastereo- and enantioselective conjugate addition to access enantiopure P-stereogenic phosphindane and phosphindole derivatives. This kinetic resolution method features high efficiency (s factor up to >1057), excellent stereoselectivities (all >20:1 dr, up to >99% ee), and a broad substrate scope. The obtained chiral phosphindane oxides exhibit promising therapeutic efficacy in autosomal dominant polycystic kidney disease (ADPKD), and compound 3az is found to significantly inhibit renal cyst growth both in vitro and in vivo, thus ushering in a promising scaffold for ADPKD drug discovery. This study will not only advance efforts towards the asymmetric synthesis of challenging P-stereogenic heterocycles, but also surely inspire further development of P-stereogenic entities for bioactive small-molecule discovery.

Twist-Angle Tuning of Electronic Structure in Two-Dimensional Dirac Nodal Line Semimetal Au2Ge on Au(111).

Topological semimetals have emerged as quantum materials including Dirac, Weyl, and nodal line semimetals, and so on. Dirac nodal line (DNL) semimetals possess topologically nontrivial bands crossing along a line or a loop and are considered precursor states for other types of semimetals. Here, we combine scanning tunneling microscopy/spectroscopy (STM/S) measurements and density functional theory (DFT) calculations to investigate a twist angle tuning of electronic structure in two-dimensional DNL semimetal Au2Ge. Theoretical calculations show that two bands of Au2Ge touch each other in Γ-M and Γ-K paths, forming a DNL. A significant transition of electronic structure occurs by tuning the twist angle from 30° to 24° between monolayer Au2Ge and Au(111), as confirmed by STS measurements and DFT calculations. The disappearing of DNL state is a direct consequence of symmetry breaking.