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Multi-resistant Staphylococcus aureus (S. aureus) infection is a significant global health concern owing to its high mortality and morbidity rates. Coagulase (Coa), a key enzyme that activates prothrombin to initiate host coagulation, has emerged as a promising target for anti-infective therapeutic approaches. This study identified sinigrin as a potent Coa inhibitor that significantly inhibited S. aureus-induced coagulation at concentration as low as 32 mg/L. Additionally, at a higher concentration of 128 mg/L, sinigrin disrupted the self-protection mechanism of S. aureus. Thermal shift and fluorescence-quenching assays confirmed the direct binding of sinigrin to the Coa protein. Molecular docking analysis predicted specific binding sites for sinigrin in the Coa molecule, and point mutation experiments highlighted the importance of Arg-187 and Asp-222 as critical binding sites for both Coa and sinigrin. In vivo studies demonstrated that the combination of sinigrin with oxacillin exhibited greater antibacterial efficacy than oxacillin alone in the treatment of S. aureus-induced pneumonia in mice. Furthermore, sinigrin was shown to reduce bacterial counts and inflammatory cytokine levels in the lung tissues of S. aureus-infected mice. In summary, sinigrin was shown to directly target Coa, resulting in the attenuation of S. aureus virulence, which suggests the potential of sinigrin as an adjuvant for future antimicrobial therapies.

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HYPOTHESIS: Perfluorocarbon is commonly used as a coolant, chemical reaction carrier solvent, medical anti-hypoxic agents and blood substitutes. The realization of non-contact complex manipulation of perfluorocarbon liquids is urgently needed in human life and industrial production. However, most liquid-repellent interfaces are ineffective for the transport of ultra-low surface tension perfluorocarbon liquids, and struggle to maintain good durability due to unstable air or oil cushions in the surface. Therefore, preparing surfaces for stable non-contact complex manipulation of ultra-low surface tension droplets remains a challenge. EXPERIMENTS: In this paper, a novel solution, a photothermal responsive droplet manipulation surface based on polydimethylsiloxane brushes, has been reported. On this surface, droplets with different surface tensions (as low as 10 mN/m) can be efficiently manipulated through induced near-infrared light. Notably, this surface maintains its effectiveness after exposure to extreme anthropogenic conditions. FINDINGS: The interface effect between perfluorocarbon droplets and polydimethylsiloxane brushes by near-infrared light-induced was investigated in detail. In addition, ultra-low surface tension droplets demonstrate the ability to transport solid particles. The conductive droplets exhibit sophisticated manipulation realizing the controlled switching of smart circuits. This research opens up new possibilities for advancing the capabilities and adaptability of ultralow surface tension droplets in a range of applications.

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BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

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OBJECTIVE: To summarize the clinical features and genetic mutation characteristics of Chinese children with KCNQ2-related epilepsy. METHODS: A cohort of children with genetically caused epilepsy was evaluated at Linyi People's Hospital from January 2017 to December 2023. After next-generation sequencing and pathogenicity analysis, we summarized the medical records and genetic testing data of the children who had KCNQ2 gene mutations. RESULTS: We identified 23 KCNQ2 gene mutations. 73.9% (n = 17) of the mutation sites were located in S5-S6 segments and the C-terminal region. In addition to the common phenotypes, 2 new phenotypes were identified: infantile convulsion with paroxysmal choreoathetosis (ICCA) and febrile seizure plus (FS+). Of all the cases with abnormal video-electro-encephalography, three cases with self-limited familial infantile epilepsy (SeLNE) exhibited a small number of multifocal discharges. Of the patients who have taken a particular antiepileptic drug, the statistics on the number of patients who have responded to the drug are as follows: oxcarbazepine (8/9, 88.9%), levetiracetam (5/7, 71.4%), phenobarbital (9/16, 56.3%), and topiramate (2/5, 40.0%). However, the efficacy of phenobarbital varied widely in treating SeLNE and KCNQ2-DEE. At the final follow-up, 1 case with SeLNE had a transient developmental regression and 7 cases with KCNQ2-DEE had mild to severe developmental backwardness. SIGNIFICANCE: Although clinically rare, we report 10 new KCNQ2 mutations and two new phenotypes: ICCA and FS+. This further expands genetic and phenotypic spectrum of KCNQ2-related epilepsy. The gene mutation sites are mostly located in S5-S6 segments and the C-terminal region, and the former is usually associated with KCNQ2-DEE. Sodium channel blockers (including oxcarbazepine and topiramate) and levetiracetam should be prioritized over phenobarbital for KCNQ2-DEE. Some cases with KCNQ2-related epilepsy may have transient developmental regression during periods of frequent seizures. Early treatment and early seizure control may be beneficial for willing outcomes in children with KCNQ2-DEE. PLAIN LANGUAGE SUMMARY: This article reports 23 cases of children with KCNQ2-related epilepsy, including 10 new mutation sites and 2 new phenotypes. It further expands the genetic and phenotypic spectrum of KCNQ2-related epilepsy. In addition, the article summarizes the gene mutation characteristics and clinical manifestations of children with KCNQ2-related epilepsy, with the expectation of providing a certain theoretical basis for the diagnosis and treatment of such patients.

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BACKGROUND AND OBJECTIVE: Spinal muscular atrophy (SMA) is one of the most common monogenic neuromuscular diseases, and the pathogenesis mechanisms, especially the brain network topological properties, remain unknown. This study aimed to use individual-level morphological brain network analysis to explore the brain neural network mechanisms in SMA. METHODS: Individual-level gray matter (GM) networks were constructed by estimating the interregional similarity of GM volume distribution using both Kullback-Leibler divergence-based similarity (KLDs) and Jesen-Shannon divergence-based similarity (JSDs) measurements based on Automated Anatomical Labeling 116 and Hammersmith 83 atlases for 38 individuals with SMA types 2 and 3 and 38 age- and sex-matched healthy controls (HCs). The topological properties were analyzed by the graph theory approach and compared between groups by a nonparametric permutation test. Additionally, correlation analysis was used to assess the associations between altered topological metrics and clinical characteristics. RESULTS: Compared with HCs, although global network topology remained preserved in individuals with SMA, brain regions with altered nodal properties mainly involved the right olfactory gyrus, right insula, bilateral parahippocampal gyrus, right amygdala, right thalamus, left superior temporal gyrus, left cerebellar lobule IV-V, bilateral cerebellar lobule VI, right cerebellar lobule VII, and vermis VII and IX. Further correlation analysis showed that the nodal degree of the right cerebellar lobule VII was positively correlated with the disease duration, and the right amygdala was negatively correlated with the Hammersmith Functional Motor Scale Expanded (HFMSE) scores. CONCLUSIONS: Our findings demonstrated that topological reorganization may prioritize global properties over nodal properties, and disrupted topological properties in the cortical-limbic-cerebellum circuit in SMA may help to further understand the network pathogenesis underlying SMA.

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OBJECTIVE: To explore the clinical features and genetic etiology of a child with SPONASTRIME dysplasia (SD). METHODS: A 9-month-old female who had presented at the Linyi People's Hospital in August 2022 for short stature was selected as the study subject. Clinical data of the child were collected, and whole exome sequencing (WES) was carried out. Sanger sequencing was used for validating the candidate variants. RESULTS: The child has manifested short stature, mid-face hypoplasia, joint laxity, internal knee rotation, irregularities in the metaphysis of long bones, and flat and concave lumbar vertebrae. WES revealed that she has harbored compound heterozygous variants of the TONSL gene, namely c.3088G>T (p.Glu1030*) and c.3053G>A (p.Arg1018His), which were inherited from her phenotypically normal parents. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3088G>T variant was classified as likely pathogenic (PVS1+PM2_Supporting), whilst the c.3053G>A was classified as a variant of uncertain significance (PM2_Supporting+PM3+PP3). CONCLUSION: The c.3088G>T and c.3053G>A compound heterozygous variants of the TONSL gene probably underlay the pathogenesis in this patient. Above finding has facilitated the clinical diagnosis and genetic counseling for her family.

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BACKGROUND: Pathogenic variants of the IRF2BPL gene have been reported to cause neurodevelopmental disorders; however, studies focused on IRF2BPL in zebrafish are limited. RESULTS: We reported three probands diagnosed with developmental delay and epilepsy and investigated the role of IRF2BPL in neurodevelopmental disorders in zebrafish. The clinical and genetic characteristics of three patients with neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures (NEDAMSS) were collected. Three de novo variants (NM_024496.4: c.1171 C > T, p.Arg391Cys; c.1157 C > T, p.Thr386Met; and c.273_307del, p.Ala92Thrfs*29) were detected and classified as pathogenic or likely pathogenic according to ACMG guidelines. Zebrafish crispants with disruption of the ortholog gene irf2bpl demonstrated a reduced body length and spontaneous ictal-like and interictal-like discharges in an electrophysiology study. After their spasms were controlled, they gain some development improvements. CONCLUSION: We contribute two new pathogenic variants for IRF2BPL related developmental epileptic disorder which provided evidences for genetic counseling. In zebrafish model, we for the first time confirm that disruption of irf2bpl could introduce spontaneous electrographic seizures which mimics key phenotypes in human patients. Our follow-up results suggest that timely cessation of spasmodic seizures can improve the patient's neurodevelopment.

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OBJECTIVE: To explore the clinical manifestations and pathogenic variant in a family with epilepsy, developmental delay and brain deformity. METHODS: Clinical data of the child and his family members who had visited the Department of Pediatrics, Linyi People's Hospital on July 2, 2022 were collected. The child, his sister and parents were subjected to high-throughput sequencing, and the result was verified by Sanger sequencing. RESULTS: The child was a 6-year-old boy with developmentally delay and had epileptic seizures with fever sensitivity for four years. Cranial imaging showed brain dysplasia, while the video electroencephalogram showed abnormal discharge. High-throughput sequencing showed the child has harbored a heterozygous c.5G>T (p.Arg2Leu) variant of TUBB2A gene, which was unreported previously. His sister also carried the variant and had similar clinical manifestations, whilst his parents were of the wild-type and had normal clinical phenotypes. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PM2_Supporting+PM5+PP1+PP2+PP3). CONCLUSION: The heterozygous c.5G>T (p.Arg2Leu) variant of the TUBB2A gene, in the form of gonadal mosaicism, probably underlay the disorders in this family.

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OBJECTIVE: To explore the clinical and genetic characteristics of five children with epilepsies due to variants of SCN8A gene. METHODS: Clinical data of five children (four males and one female) admitted to Linyi People's Hospital due to hereditary epilepsies between August 2015 and August 2022 were collected. Whole exome sequencing was carried out for these children, and candidate variants were verified by Sanger sequencing. RESULTS: All of the five children were found to harbor variants of the SCN8A gene. Case 1, who had benign familial infantile epilepsy, inherited a known pathogenic c.4840A>G variant from his father with similar symptoms. Cases 2 to 4 had presented with intermediate epilepsy. Among these, case 2 has harbored a de novo c.3967G>A variant which was rated as pathogenic (PS1+PS2+PM1+PM2_Supporting+PP3) based on the guidelines from the American College of Medical Genetics and Genomics. Cases 3 and 4 were found to respectively harbor a de novo c.415A>T and a c.4697C>T variant, which were both rated as likely pathogenic (PS2+PM1+PM2_Supporting+PP3). Case 5, who had early-onset infantile epileptic encephalopathy transformed into Lennox Gastaut-like syndrome, has harbored a de novo c.5615G>A variant, which was known to be pathogenic. The children had their age of onset ranging from 2 to 14 months, and all had focal seizures and generalized tonic clonic seizures. Four children (cases 1, 2, 3 and 5) had cluster seizures, four (cases 1 to 4) had become seizure-free after single or dual treatment and showed normal growth and development, whilst case 5 was drug-resistant and showed severe developmental retardation. CONCLUSION: The five children had new features such as cluster seizures, occasional benign seizures in adulthood, and intermediate epilepsy which are prone to relapse after discontinuation of medication, which may be attributed to the pathogenic variants of the SCN8A gene.

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BACKGROUND: Nuclear pleomorphism and tumor microenvironment (TME) play a critical role in cancer development and progression. Identifying most predictive nuclei and TME features of basal cell carcinoma (BCC) may provide insights into which characteristics pathologists can use to distinguish and stratify this entity. OBJECTIVES: To develop an automated workflow based on nuclei and TME features from basaloid cell tumor regions to differentiate BCC from trichoepithelioma (TE) and stratify BCC into high-risk (HR) and low-risk (LR) subtypes, and to identify the nuclear and TME characteristics profile of different basaloid cell tumors. METHODS: The deep learning systems were trained on 161 H&E -stained sections which contained 51 sections of HR-BCC, 50 sections of LR-BCC and 60 sections of TE from one institution (D1), and externally and independently validated on D2 (46 sections) and D3 (76 sections), from 2015 to 2022. 60%, 20% and 20% of D1 data were randomly splitted for training, validation and testing, respectively. The framework comprised four stages: tumor regions identification by multi-head self-attention (MSA) U-Net, nuclei segmentation by HoVer-Net, quantitative feature by handcrafted extraction, and differentiation and risk stratification classifier construction. Pixel accuracy, precision, recall, dice score, intersection over union (IoU) and area under the curve (AUC) were used to evaluate the performance of tumor segmentation model and classifiers. RESULTS: MSA-U-Net model detected tumor regions with 0.910 precision, 0.869 recall, 0.889 dice score and 0.800 IoU. The differentiation classifier achieved 0.977 ± 0.0159, 0.955 ± 0.0181, 0.885 ± 0.0237 AUC in D1, D2 and D3, respectively. The most discriminative features between BCC and TE contained Homogeneity, Elongation, T-T_meanEdgeLength, T-T_Nsubgraph, S-T_HarmonicCentrality, S-S_Degrees. The risk stratification model can well predict HR-BCC and LR-BCC with 0.920 ± 0.0579, 0.839 ± 0.0176, 0.825 ± 0.0153 AUC in D1, D2 and D3, respectively. The most discriminative features between HR-BCC and LR-BCC comprised IntensityMin, Solidity, T-T_minEdgeLength, T-T_Coreness, T-T_Degrees, T-T_Betweenness, S-T_Degrees. CONCLUSIONS: This framework hold potential for future use as a second opinion helping inform diagnosis of BCC, and identify nuclei and TME features related with malignancy and tumor risk stratification.

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Methane-dependent nitrate and nitrite removal in anoxic environments is thought to rely on syntrophy between ANME-2d archaea and bacteria in the genus 'Candidatus Methylomirabilis'. Here we enriched and purified a single Methylomirabilis from paddy soil fed with nitrate and methane, which is capable of coupling methane oxidation to nitrate reduction via nitrite to dinitrogen independently. Isotope labelling showed that this bacterium we name 'Ca. Methylomirabilis sinica' stoichiometrically performed methane-dependent complete nitrate reduction to dinitrogen gas. Multi-omics analyses collectively demonstrated that 'M. sinica' actively expressed a well-established pathway for this process, especially including nitrate reductase Nap. Furthermore, 'M. sinica' exhibited a higher nitrate affinity than most denitrifiers, implying its competitive fitness under oligotrophic nitrogen-limited conditions. Our findings revise the paradigm of methane-dependent denitrification performed by two organisms, and the widespread presence of 'M. sinica' in public databases suggests that the coupling of methane oxidation and complete denitrification in single cells substantially contributes to global methane and nitrogen budgets.

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OBJECTIVES: To investigate the effectiveness and safety of combination of 655 nm low level laser helmet device with topical 2 % minoxidil solution at FPHL in Chinese population. MATERIALS AND METHODS: Randomized, parallel, controlled, single-blind clinical trial was conducted. FPHL subjects were randomly allocated into 2 % minoxidil group and combination group. The 2 % minoxidil group received 1 ml topical 2 % minoxidil solution twice daily for 24 weeks. The combination group received 1 ml topical 2 % minoxidil solution twice daily together with 20 min 655 nm low-level laser helmet once every other day for 24 weeks. Hair parameters in two scalp areas including midscalp and vertex were evaluated at baseline, 12th week and 24th week. RESULTS: In midscalp area, the combination group showed a lower increase in intermediate hair percentage than 2 % minoxidil group, which was statistically significant. Besides, the combination group had statistically significant increase than 2 % minoxidil group in mean hair diameter. Reported relative adverse events included slightly hair loss (27.8 %), desquamation (19.0 %), pruritus (15.2 %), seborrhea (2.5 %) and hypertrichosis (2.5 %). CONCLUSION: In our trial, LLLT was demonstrated as a useful supplementary treatment for FPHL and the combination with 2 % minoxidil accomplished better improvement in intermediate hair enlargement and hair diameter of midscalp for FPHL.

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The pollution of dissolved and particulate polycyclic aromatic hydrocarbons (PAHs) in coastal waters has been increasing in recent decades. However, limited research has been conducted on the characteristics of dissolved and particulate PAHs in seawater and their associated risk assessment. Here, we focused on the bioavailability and environmental risk of PAHs in four typical bays of Shandong Province, China, and used scallop Chlamys farreri and clam Mactra veneriformis as sentinel species. The results revealed that dissolved PAHs tended to bioaccumulate in scallop C. farreri, and their ecological risk exhibited a significant correlation with the health risk of bioaccumulated PAHs and the bioeffect of screened biomarkers in scallop. Conversely, particulate PAHs demonstrated a higher bioaccumulation potential in the clam M. veneriformis, showing a stronger correlation between their ecological risk, health risk, and bioeffect in clams. This study provides the first elucidation of the connection between the ecological risk, health risk, and bioeffect of PAHs. Furthermore, based on the better correlation of health risk and bioeffect caused by PAHs with total PAHs in seawater, we propose that the clam M. veneriformis is a more suitable sentinel species for assessing environmental risk in typical bays of Shandong Province.

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Industrialization and urbanization have led to increasing levels of PAH pollution in highly urbanized estuaries and their adjacent coastal areas globally. This study focused on the adjacent coastal area of the Yellow River Estuary (YRE) and collected surface seawater, surface sediment, and clams Ruditapes philippinarum and Mactra veneriformis at four sites (S1 to S4) in May, August, and October 2021 to analyze the source-specific ecological and health risks and bioeffects. The findings revealed that the main sources of PAHs were traffic emission (25.2% to 28.5%), petroleum sources (23.3% to 29.5%), coal combustion (24.7% to 27.5%), and biomass combustion (19.8% to 20.7%). Further, the PMF-RQ and PMF-ILCR analyses indicated that traffic emission was the primary contributor to ecological risks in seawater and health risks in both clam species, while coal combustion was the major contributor in sediment. Taken together, it is recommended to implement control strategies for PAH pollution following the priority order: traffic > coal > petroleum > biomass, to reduce the content and risk of PAHs in the YRE.

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PURPOSE: Seizure threshold 2 protein homolog gene (SZT2, MIM: 615463) related diseases are extremely rare autosomal recessive disorders with a wide spectrum of clinical phenotypes ranging from mild intellectual impairment to severe developmental epileptic encephalopathy (DEE). Most SZT2 related diseases are accompanied by craniofacial malformation and corpus callosum malformation. This study attempts to analyze and summarize the clinical phenotype and genetic characteristics of SZT2 related diseases, providing a basis for early diagnosis, treatment, and prognosis. METHOD: We analyzed the clinical characteristics of a Chinese child with pathogenic variants of SZT2. We also performed whole-exome sequencing (WES) on the patient. In addition, we conducted a literature review of previously reported patients with pathogenic mutations in the SZT2 gene. RESULT: The proband was a boy aged 1 year and 9 months with severe global developmental delay, transient drug-controlled focal epilepsy, cluster epilepsy, autism spectrum disorder, craniofacial deformity, hypotonia, focal EEG discharge, corpus callosum malformation, and persistent cavum septum pellucidum. WES revealed that the patient carried the SZT2 gene c.7584dupA and c.6302A>C complex heterozygous variants; the former being Likely Pathogenic (LP) and the latter Uncertain Significance (VUS) according to ACMG classification guidelines. According to our literature review, 43 cases of SZT2 related diseases have been reported so far; these include 15 cases with homozygous variations and 28 cases with complex heterozygous variations. A total of 57 types of variation were found, including 47 genetic variants, 2 de novo variants, and 8 unknown genetic modes. In addition, 2 high-frequency variants were found (c.5949_5951delTGT and c.6553C>T). The main clinical manifestations of the 40 patients were global developmental delay (GDD) of varying degrees (38/40, 95.00 %), seizures (36/40, 90.00 %), cranial deformity (27/40, 67.50 %), facial deformity (22/40, 55.00 %), hypotonia (22/40, 55.00 %), abnormal interseizure EEG discharge (26/40, 65.00 %), slow background activity (20/40, 50.00 %), corpus callosum deformity (18/40, 45.00 %). There was also one case of sudden unexpected death in epilepsy (SUDEP) and 3 cases of death from infection. In addition, three fetuses with the same variant had hydrocephalus and encephalocele. CONCLUSION: The compound heterozygous mutation of c.7584dupA and c.6302A>C in the SZT2 gene is the genetic etiology of this patient, expanding the mutation spectrum of SZT2 related diseases. Early genetic testing is the best choice for clear diagnosis, treatment, and prognosis.

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BACKGROUND: Lonely hair sign is considered as a clue to the diagnosis of frontal fibrosing alopecia (FFA). OBJECTIVE: To report an undescribed variant of alopecia areata (AA) with which the patient developed single hairs and other features similar to FFA and to determine the underlying mechanism. METHODS: We conducted a prospective observational study in patients who presented with receding hairline and single hairs, evaluating the clinical, trichoscopic, and histological features and their correlation. Immunochemistry studies were performed to describe the microenvironment. RESULTS: Eighteen patients were enrolled in the study. Despite the similarity to FFA clinically, these patients showed different histopathology which revealed a normal number of pilosebaceous units, one anagen hair in one or more pilosebaceous units, and others in telogen stage, consistent with single hairs under the naked eye or under trichoscopy. The severity of the hair loss assessed by SALT was no more than 50, but the response to conventional therapy was poor. CONCLUSIONS: This study reports a unique variant of AA. The pathological basis is an increase in the telogen hair follicles, with one anagen hair in one or more pilosebaceous units. Minimal inflammation consisting of CD3+ T lymphocytes and mast cells was demonstrated in the microenvironment.

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OBJECTIVE: To summarize echocardiographic characteristics of the anatomy and hemodynamic and clinical outcomes in fetuses with isolated pulmonary stenosis (PS) or pulmonary atresia with intact ventricular septum (PA/IVS). METHODS: This was a single-center retrospective study of fetuses with isolated PS or PA/IVS. Echocardiographic variables and clinical outcomes after delivery were evaluated and compared. RESULTS: Between 2016 and 2021, 115 livebirths with isolated PS or PA/IVS were included. Proportion of fetuses with mild, moderate and critical PS and PA/IVS was 41.7 %, 18.3 %, 26.1 % and 13.9 %. Fetuses with more severe PS had worse anatomic and hemodynamic profiles. Specifically, the cardiothoracic ratio, pulmonary valve (PV) velocity, degree and velocity of tricuspid regurgitation increased as PS severity increased; and the pulmonary artery/aorta ratio, right ventricle/left ventricle long-axis (TV/MV) ratio, tricuspid valve/mitral valve annulus (TV/MV) ratio, and tricuspid valve inflow duration/cardiac cycle ratio decreased as PS severity increased (P <0.001 for all). PV velocity ≥2 m/s predicted PV pressure ≥40 mm Hg after delivery, with an AUC of 0.81; TV/MV ratio combined with RV/LV ratio predicted clinical outcomes, with an AUC of 0.88. Live births with more severe PS had higher mortality rate (mild 0 vs. moderate 0 vs. critical 11 % vs. PA-IVS 36 %) and lower rate of developing bi-ventricles (mild 100 % vs. moderate 95 % vs. critical 89 % vs. PA-IVS 36 %). CONCLUSION: Findings of this study help better understand the anatomy and hemodynamic and clinical outcomes in fetuses with isolated PS or PA/IVS, which could have implications for prenatal counseling and prediction of fetal outcome.

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Smart adhesives with switchable adhesion have attracted considerable attention for their potential applications in sensors, soft grippers, and robots. In particular, surfaces with controlled adhesion to both solids and liquids have received more attention, because of their wider range of applications. However, surfaces that exhibit controllable adhesion to both solids and liquids often cannot provide sufficient adhesion strength for strong solid adhesion. To overcome this limitation, this study developed a triple-bioinspired shape memory smart adhesive, drawing inspiration from the adhesion structures found in octopus suckers, lotus leaves, and creepers. Our adhesive design incorporates microcavities formed by a shape memory polymer (SMP), which can transition between rubbery and glassy states in response to temperature changes. By leveraging the shape memory effect and the rubber-glass (R-G) phase transition of the SMP, the adhesion of the surface to smooth solids, rough solids, and water droplets could be switched by adjusting the temperature and applied force. Notably, the adhesives designed herein exhibited high adhesion strength (up to 420 kPa) on solids, facilitated by the shape interlocking effect and the negative pressure generated within the microcavities. Furthermore, the programmable transport of solids and liquids can be achieved by utilizing this switchable adhesion. This approach expands the possibilities for designing smart adhesives and holds potential for various applications in different fields.

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The constantly increasing amount of road vehicles causes massive exhaust emissions of pollutants, including polycyclic aromatic hydrocarbons (PAHs), necessitating a global responsibility to implement the policy of the ban on the sale of new petrol and diesel cars. Here, we assessed the policy control efficiency on marine pollution of PAHs in China through scenario modeling and prediction models, based on pollution monitoring, risk assessment, and source apportionment of PAHs in typical bays of Shandong Province. The results showed that in 2021, the pollution risk levels were relatively low (HI: 0.008-0.068, M-ERM-Q: 0.001-0.016, IBR: 1.23-2.69, ILCR: 8.11 ×10-6-1.99 ×10-5), and PAHs were mainly derived from traffic emissions (24.9%-35.2%), coal combustion (25.2%-32.9%), petroleum (17.2%-28.9%), and biomass combustion (17.6%-22.8%). In 2050, the predicted decrease of pollution risk values after the implementation of the policy was significant (12%-26%), and the gap between 2021 and 2050 was also significantly huge (18%-85%) without considering possible substitution of conventional energy. Collectively, this study built systematic approaches for assessing prospective marine pollution of PAHs. However, due to the particularity of Shandong Province, i.e., its national predominance of conventional energy consumption, the policy may be more effective when it comes to other coastal areas worldwide, calling for a larger scale research.

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Antimicrobial resistance (AMR) is a global health threat. The dramatic increase of Methicillin-resistant Staphylococcus aureus (MRSA) infections emphasizes the need to find new anti-infective agents with a novel mode of action. The Caseinolytic protease (ClpP) is a central virulence factor in stress survival, virulence, and antibiotic resistance of MRSA. Here, we found ayanin, a flavonoid isolated from Callicarpa nudiflora, was an inhibitor of MRSA ClpP with an IC50 of 19.63 µM. Using quantitative real-time PCR, ayanin reduced the virulence of Staphylococcus aureus (S. aureus) by down-regulating the level of some important virulence factors, including agrA, RNAⅢ, hla, pvl, psmα and spa. The results of cellular thermal shift assay and thermal shift assay revealed a binding between ayanin and ClpP. Molecular docking showed that ASP-168, ASN-173 and ARG-171 were the potential binding sites for ClpP binding to ayanin. ClpP mutagenesis study further indicated that ARG-171 and ASN-173 were the main active sites of ClpP. The affinity constant (KD) value of ayanin with ClpP was 3.15 × 10-5 M measured by surface plasmon resonance. In addition, ayanin exhibited a significant therapeutic effect on pneumonia infection induced by S. aureus in mice in vivo, especially in combination with vancomycin. This is the first report of ayanin with in vivo and in vitro efficacy against S. aureus infection. In conclusion, ayanin is a promising therapeutic agent to combat MRSA infections by targeting ClpP.

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