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Abstract Post-transcriptional regulation mediated by RNA binding proteins is crucial for male germline development. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), an RNA binding protein, is specifically expressed in human and mouse male gonads and is involved in manifold biological processes and tumorigenesis. However, the function of IGF2BP1 in mammalian spermatogenesis remains poorly understood. Herein, we generated an Igf2bp1 conditional knockout mouse model using Nanos3-Cre. Germ cell deficiency of Igf2bp1 in mice caused spermatogenic defects in an age-dependent manner, resulting in decreased numbers of undifferentiated spermatogonia and increased germ cell apoptosis. Immunoprecipitation-mass spectrometry analysis revealed that ELAV-like RNA binding protein 1, a well-recognized mRNA stabilizer, interacted with IGF2BP1. Single cell RNA-sequencing showed distinct mRNA profiles in spermatogonia from conditional knockout versus wide type mice. Further research showed that IGF2BP1 plays a vital role in the modulation of spermatogenesis by regulating Lin28a mRNA, which is essential for clonal expansion of undifferentiated spermatogonia. Thus, our results highlight the crucial effects of IGF2BP1 on spermatogonia for the long-term maintenance of spermatogenesis.

As a typical Aurivillius-type compound, CaBi4Ti4O15 (CBT) is considered a strong competitor among high-temperature piezoelectric materials, but it is difficult to achieve both high piezoelectric activity and a high Curie temperature for CBT. In this work, the method of double-ion co-substituting at different crystalline sites was used to modify the electrical properties of CBT. The Gd/Mn co-doped CBT ceramics with the chemical formula of Ca1−xGdxBi4Ti4O15+0.2 wt% MnO2 (CBT–100xGM, x = 0–0.11) were prepared via the conventional sintering process. The phase and valence band structures, chemical compositions and microstructures, dielectric and ferroelectric properties, electrical conduction behaviors, and electroelastic and piezoelectric properties of the ceramics were characterized. The doping concentration effects of Gd3+ were analyzed according to the composition-dependent structures and properties of CBT–100xGM. The donor substitution of Gd3+ for Ca2+ at the A-site reduced the tolerance factor of the perovskite-like structure and decreased the concentration of intrinsic oxygen vacancies. While Mn3+ tended to substitute for Ti4+ at the B-site, the extrinsic oxygen vacancies are limited near the defect center of Ti(Mn) because of the formation of (VO⋅⋅‒MnTi')• as defect dipoles. The thermal depoling behavior of the CBT–100xGM ceramics between 300 and 700 °C was explained by the thermodynamic characteristics of the defect dipoles. The optimized composition with x = 0.08 (CBT–8GM) had a high TC ≈ 809 °C and a high piezoelectric coefficient (d33) ≈ 23 pC/N, as well as a piezoelectric voltage constant (g33) value of up to 21.5×10−3 (V·m)/N. Moreover, it can maintain a residual d33 ≈ 80% after being annealed at 700 °C. This good anti-thermal depoling ability endows this material with great application potential in high-temperature piezoelectric devices with operating temperatures exceeding 500 °C. The synergistic enhancement in the piezoelectric activity and Curie temperature of CBT can be attributed mainly to the donor-substituting effect of Gd3+ at the A-site, as well as the decreased elastic compliance contributed by MnO2 as the B-site dopant.

Abstract Considering the indispensable significance and utilities of meta-substituted pyridines in medicinal, chemical as well as materials science, a direct meta-selective C–H functionalization of pyridines is of paramount importance, but such reactions remain limited and highly challenging. In general, established methods for meta C–H functionalization of pyridines rely on the utilization of tailored electrophilic reagents to realize the intrinsic polarity match. Herein, we report a complementary electrochemical methodology; diverse nucleophilic sulfinates allow meta-sulfonylation of pyridines through a redox-neutral dearomatization-rearomatization strategy by a tandem dearomative cycloaddition/hydrogen-evolution electrooxidative C–H sulfonation of the resulting oxazino-pyridines/acid-promoted rearomatization sequence. Besides, several salient features, including exclusive regiocontrol, remarkable substrate/functional group compatibility, scale-up potential, and facile late-stage modification, have been demonstrated, which further contributes to the practicality and adaptability of this approach.

Abstract Exploring the promiscuity of native enzymes presents a promising strategy for expanding their synthetic applications, particularly for catalyzing challenging reactions in non-native contexts. In this study, we explore the promiscuous potential of old yellow enzymes (OYEs) to facilitate the Morita-Baylis-Hillman reaction (MBH reaction), leveraging substrate similarities between MBH reaction and reduction reaction. Using mass spectrometry and spectroscopic techniques, we confirm promiscuity of GkOYE in both MBH and reduction reactions. By blocking H- and H+ transfer pathways, we engineer GkOYE.8, which loses its reduction ability but enhances its MBH activity. The structural basis of MBH reaction catalyzed by GkOYE.8 is obtained through mutation studies and kinetic simulations. Furthermore, enantiocomplementary mutants GkOYE.11 and GkOYE.13 are obtained by directed evolution, exhibiting the ability to accept various aromatic aldehydes and alkenes as substrates. This study demonstrates the potential of leveraging substrate similarities to unlock enzyme functionalities, enabling the catalysis of new-to-nature reactions.

Summary: Background: Polycystic ovary syndrome (PCOS) represents a prevalent endocrine disorder affecting numerous females worldwide. Dysbiosis of gut microbiota has been linked to the occurrence of PCOS; however, research into the characteristics of gut microbiota in PCOS patients, especially those from different regions and with different testosterone level, remains limited. Additionally, it is still unclear whether gut microbiota helps to distinguish different PCOS subtypes. Methods: We searched four electronic databases (PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov) from Jan 1, 2010 to May 1, 2024. This combined analysis included studies providing the raw data of gut microbiota in PCOS patients. We reanalyzed the characteristics of gut microbiota in PCOS patients from different regions and with different testosterone level. Findings: Fourteen publications satisfying the inclusion criteria were included in the combined analysis. Based on data from 948 individuals, we found alpha-diversity was not significantly different between PCOS and healthy control (HC) groups. However, gut microbiota composition was distinct in PCOS patients compared with healthy individuals. Specifically, Fusobacterium, Ruminococcus_gnavus_group, and Escherichia-Shigella increased, while Dysosmobacter, Schaedlerella, Merdimonas, Clostridiisalibacter, Flintibacter et al. decreased in PCOS women. Regionally, Alistipes was enriched in primarily European patients, while Blautia and Roseburia were more abundant in Chinese patients. Subtype analysis revealed that the gut microbiota of PCOS patients with higher testosterone level (PCOS-HT) differed significantly from those with lower testosterone level (PCOS-LT). Prevotella, Blautia, Dialister, Ruminococcus_torques_group and UCG-002 were enhanced in PCOS-HT patients, while Alistipes, Dysosmobacter, Phocaeicola and Faecalibacterium were diminished. Importantly, a set of eight genera effectively differentiated PCOS-HT patients from PCOS-LT patients with an AUC of 0.95. Interpretation: This systematic anatomization of gut microbiota revealed the microbial characteristics of PCOS patients, particularly those with different testosterone level, thus laying the foundations for further research into pathogenesis of PCOS, and the development of effective diagnostic, treatment, and intervention strategies. Funding: This work was supported by the National Natural Science Foundation of China (No. 81973217, 82260304), the Hainan Province Clinical Medical Center (QWYH202175), and the Specific Research Fund of The Innovation Platform for Academicians of Hainan Province (YSPTZX202311).

Abstract In the context of the growing importance of heterocyclic compounds across various disciplines, numerous strategies for their construction have emerged. Exploiting the distinctive properties of cyclopropenes, this study introduces an innovative approach for the synthesis of benzo‐fused five‐membered oxa‐ and aza‐heterocycles through a formal [4+1] cyclization and subsequent acid‐catalyzed intramolecular O‐ to N‐ rearrangement. These transformations exhibit mild reaction conditions and a wide substrate scope. The applications in the late‐stage modification of complex molecules and in the synthesis of a potential PD‐L1 gene down‐regulator, make this method highly appealing in related fields. Combined experimental mechanistic studies and DFT calculations demonstrate Rh(III)‐mediated sequential C─H coupling/π‐allylation/dynamically favorable O‐attack route.

Abstract Static magnetic field (SMF) promoting bone tissue remodeling is a potential non-invasive therapy technique to accelerate orthodontic tooth movement (OTM). The periodontal ligament stem cells (PDLSCs), which are mechanosensitive cells, are essential for force-induced bone remodeling and OTM. However, whether and how the PDLSCs influence the process of inflammatory bone remodeling under mechanical force stimuli in the presence of SMFs remains unclear. In this study, we found that local SMF stimulation significantly enhanced the OTM distance and induced osteoclastogenesis on the compression side of a rat model of OTM. Further experiments with macrophages cultured with supernatants from force-loaded PDLSCs exposed to an SMF showed enhanced osteoclast formation. RNA-seq analysis showed that interleukin-6 (IL-6) was elevated in force-loaded PDLSCs exposed to SMFs. IL-6 expression was also elevated on the pressure side of a rat OTM model with an SMF. The OTM distance induced by an SMF was significantly decreased after injection of the IL-6 inhibitor tocilizumab. These results imply that SMF promotes osteoclastogenesis by inducing force-loaded PDLSCs to secrete the inflammatory cytokine IL-6, which accelerates OTM. This will help to reveal the mechanism of SMF accelerates tooth movement and should be evaluated for application in periodontitis patients.

Agricultural spatial division and suggestions for the optimization of the partition space were obtained by constructing a recognition system of the dominant agricultural space. The prerequisite was to master natural economic development in agriculture. It was vital to maintain national food security and promote healthy and sustainable agriculture. The suitability evaluation of agricultural production and the dominance evaluation of agricultural development were incorporated to recognize the dominant agricultural space in Cangzhou, Hebei, China in 2020. Besides, priority scenarios were set, e.g., economic development, low-carbon protection, and coordinated development of a low-carbon economy. The NSGA-II genetic algorithm model was used to optimize the quantitative structure of cultivated lands in the agricultural space of Cangzhou in three scenarios in 2030. The research results are as follows: (1) Cangzhou had the largest number of general suitable areas for agricultural production in 2020, accounting for 27.04%; suitable areas were the least, accounting for 10.99%. The proportion of current cultivated lands in unsuitable agricultural production areas still stood at 11.26%; (2) The dominance of agricultural development in 2020 in Cangzhou was mainly at Tier III, accounting for 33.60% with the general dominance of agricultural development; (3) The total area of the dominant agricultural space in Cangzhou was 238208.75 hm2, accounting for 16.72% of the national territorial area of Cangzhou. It included 35 villages and towns beyond ecological red lines, mainly distributed in the western part of Cangzhou; (4) The agricultural space of Cangzhou in 2030, optimized by the multi-objective NSGA-II genetic algorithm model, exhibited decreased cultivated lands across three scenarios. The total amount of cultivated lands was the largest under the priority scenario of economic development, and that was the smallest under the priority scenario of coordinated development of a low-carbon economy. Meanwhile, agricultural economic benefits and carbon emission density were reduced under three scenarios. The benefits and density were moderate under the coordinated development of low carbon and economy. The work provides a reference for further formulating and improving the policies of the agricultural space in various regions.

ABSTRACT While in hospite Symbiodiniaceae dinoflagellates are essential for coral health, ambient free-living counterparts are crucial for coral recruitment and resilience. Comparing free-living and in hospite Symbiodiniaceae communities can potentially provide insights into endosymbiont acquisition and recurrent recruitment in bleaching recovery. In this study, we studied coral-endosymbiotic and ambient free-living Symbiodiniaceae communities in the South China Sea. We collected samples from 183 coral and ambient plankton samples and conducted metabarcoding to investigate the diversity distribution, driving factors, and assembly mechanisms of the two groups of Symbiodiniaceae. Results revealed Cladocopium C1 and Durusdinium D1 as dominant genotypes. We detected a higher genotypic diversity in free-living than in hospite symbiodiniacean communities, but with shared dominant genotypes. This indicates a genetically diverse pool of Symbiodiniaceae available for recruitment by corals. Strikingly, we found that the cooler area had more Symbiodiniaceae thermosensitive genotypes, whereas the warmer area had more Symbiodiniaceae thermotolerant genotypes. Furthermore, in hospite and free-living Symbiodiniaceae communities were similarly affected by environmental factors, but shaped by different assembly mechanisms. The in hospite communities were controlled mainly by deterministic processes, whereas the ambient communities by stochastic processes. This study sheds light on the genetic diversity of source environmental Symbiodiniaceae and differential assembly mechanisms influencing Symbiodiniaceae inside and outside corals.IMPORTANCESymbiodiniaceae dinoflagellates play a pivotal role as key primary producers within coral reef ecosystems. Coral-endosymbiotic Symbiodiniaceae communities have been extensively studied, but relatively little work has been reported on the free-living Symbiodiniaceae community. Conducting a comparative analysis between sympatric coral-endosymbiotic and free-living Symbiodiniaceae communities can potentially enhance the understanding of how endosymbiont communities change in response to changing environments and the mechanisms driving these changes. Our findings shed light on the genetic diversity of source environmental Symbiodiniaceae and differential assembly mechanisms shaping free-living and in hospite Symbiodiniaceae communities, with implications in evaluating the adaptive and resilient capacity of corals in response to future climate change.

Polygala tenuifolia, commonly known as Yuanzhi (YZ) in Chinese, has been shown to possess anti-insomnia properties. However, the material basis and the mechanism underlying its sedative-hypnotic effects remain unclear. Herein, we investigated the active components and neurochemical mechanism of YZ extracts using liquid chromatography tandem mass spectrometry (LC-MS/MS)-based pharmacometabolomics and mass spectrometry imaging (MSI)-based spatial resolved metabolomics. According to the results, 17 prototypes out of 101 ingredients in the YZ extract were detected in both the plasma and brain, which might be the major components contributing to the sedative-hypnotic effects. Network pharmacology analysis revealed that these prototypes may exert their effects through neuroactive ligand-receptor interaction, serotonergic synapse, dopaminergic synapse, and dopaminergic synapse, among other pathways. LC-MS/MS-based targeted metabolomics and Western blot (WB) revealed that tryptophan-serotonin-melatonin (Trp-5-HT-Mel) and tyrosine-norepinephrine-adrenaline (Tyr-Ne-Ad) are the key regulated pathways. Dopa decarboxylase (DDC) upregulation and phenylethanolamine N-methyltransferase (PNMT) downregulation further confirmed these pathways. Furthermore, MSI-based spatially resolved metabolomics revealed notable alterations in 5-HT in the pineal gland (PG), and Ad in the brainstem, including the middle brain (MB), pons (PN), and hypothalamus (HY). In summary, this study illustrates the efficacy of an integrated multidimensional metabolomics approach in unraveling the sedative-hypnotic effects and neurochemical mechanisms of a Chinese herbal medicine, YZ.

Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development. In this study, we present an innovative, integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride (NC), a promising anti-tumor drug candidate. Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney, particularly within the inner cortex (IC) region, following single and repeated dose of NC. High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule. Employing spatial metabolomics based on AFADESI-MSI, we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure. These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters (organic cation transporters, multidrug and toxin extrusion, and organic cation transporter 2 (OCT2)), metabolic enzymes (protein arginine N-methyltransferase (PRMT) and nitric oxide synthase), mitochondria, oxidative stress, and inflammation in NC-induced nephrotoxicity. This study offers novel insights into NC-induced renal damage, representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and the non-self-replicating chemical phenotypes, generating a diverse chemical world. In analogy with the biological world, the DEL world can evolve by using a chemical central dogma, wherein DNA replicates using the PCR reactions to amplify the genetic codes, DNA sequencing transcripts the genetic information, and DNA-compatible synthesis translates into chemical phenotypes. Importantly, DNA-compatible synthesis is the key to expanding the DEL chemical space. Besides, the evolution-driven selection system pushes the chemicals to evolve under the selective pressure, i.e., desired selection strategies. In this perspective, we summarized recent advances in expanding DEL synthetic toolbox and panning strategies, which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

Abstract The use of titanium implants as fixed supports following fractures in patients with OP can often result in sterile loosening and poor osseointegration. Oxidative stress has been shown to play a particularly important role in this process. While TSA has been reported to facilitate in vivo osteogenesis, the underlying mechanisms remain to be clarified. It also remains unclear whether TSA can improve the osseointegration of titanium implants. This study investigated whether TSA could enhance the osseointegration of titanium rods by activating AKT/Nrf2 pathway signaling, thereby suppressing oxidative stress. MC3T3-E1 cells treated with CCCP to induce oxidative stress served as an in vitro model, while an OVX-induced OP rat model was employed for in vivo analysis of titanium rod implantation. In vitro, TSA treatment of CCCP-treated MC3T3-E1 cells resulted in the upregulation of osteogenic proteins together with increased AKT, total Nrf2, nuclear Nrf2, HO-1, and NQO1 expression, enhanced mitochondrial functionality, and decreased oxidative damage. Notably, the PI3K/AKT inhibitor LY294002 reversed these effects. In vivo, TSA effectively enhanced the microstructural characteristics of distal femur trabecular bone, increased BMSCs mineralization capacity, promoted bone formation, and improved the binding of titanium implants to the surrounding tissue. Finally, our results showed that TSA could reverse oxidative stress-induced cell damage while promoting bone healing and improving titanium rods' osseointegration through AKT/Nrf2 pathway activation.

Diabetic cardiomyopathy (DCM) is a metabolic disease and a leading cause of heart failure among people with diabetes. Mass spectrometry imaging (MSI) is a versatile technique capable of combining the molecular specificity of mass spectrometry (MS) with the spatial information of imaging. In this study, we used MSI to visualize metabolites in the rat heart with high spatial resolution and sensitivity. We optimized the air flow-assisted desorption electrospray ionization (AFADESI)-MSI platform to detect a wide range of metabolites, and then used matrix-assisted laser desorption ionization (MALDI)-MSI for increasing metabolic coverage and improving localization resolution. AFADESI-MSI detected 214 and 149 metabolites in positive and negative analyses of rat heart sections, respectively, while MALDI-MSI detected 61 metabolites in negative analysis. Our study revealed the heterogenous metabolic profile of the heart in a DCM model, with over 105 region-specific changes in the levels of a wide range of metabolite classes, including carbohydrates, amino acids, nucleotides, and their derivatives, fatty acids, glycerol phospholipids, carnitines, and metal ions. The repeated oral administration of ferulic acid during 20 weeks significantly improved most of the metabolic disorders in the DCM model. Our findings provide novel insights into the molecular mechanisms underlying DCM and the potential of ferulic acid as a therapeutic agent for treating this condition.

Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone function as peroxisome proliferator-activated receptor gamma (PPARγ) full agonists, which have been known as a class to be among the most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, side effects of TZDs such as fluid retention and weight gain are associated with their full agonistic activities toward PPARγ induced by the AF-2 helix-involved “locked” mechanism. Thereby, this study aimed to obtain novel PPARγ partial agonists without direct interaction with the AF-2 helix. Through performing virtual screening of the Targetmol L6000 Natural Product Library and utilizing molecular dynamics (MD) simulation, as well as molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis, four compounds including tubuloside b, podophyllotoxone, endomorphin 1 and paliperidone were identified as potential PPARγ partial agonists. An in vitro TR-FRET competitive binding assay showed podophyllotoxone displayed the optimal binding affinity toward PPARγ among the screened compounds, exhibiting IC50 and ki values of 27.43 µM and 9.86 µM, respectively. Further cell-based transcription assays were conducted and demonstrated podophyllotoxone’s weak agonistic activity against PPARγ compared to that of the PPARγ full agonist rosiglitazone. These results collectively demonstrated that podophyllotoxone could serve as a PPARγ partial agonist and might provide a novel candidate for the treatment of various diseases such as T2DM.

The cracking of link slabs in jointless bridges presents significant challenges due to the complexity of their stress conditions. This study focused on analyzing the transverse stresses in link slabs of jointless steel–concrete composite bridges. Utilizing linear elasticity theory and partial differential equations of plates, the deflection and stress distribution functions for the link slabs were determined. The validity of these analytical solutions was confirmed through comparisons with finite element models and load tests. Results from both the load tests and the finite element model indicate that the upper face of the girder end link slabs experiences maximum tensile stresses in both transverse and longitudinal directions. The stress values obtained from the analytical method align well with these results, showing that the total stress, when considering transverse stresses, reaches 107% of the longitudinal stresses alone. Furthermore, a 40% reduction in longitudinal girder spacing or a 50% increase in girder end length can lead to link slab stresses of 128% and 145% of the longitudinal stresses, respectively. This finding suggests that even loads lower than those designed based solely on longitudinal stresses can result in cracking. Therefore, it is recommended that transverse stresses be considered in the design of link slabs for jointless bridges. Relying solely on conventional longitudinal stress analyses may underestimate actual stress conditions and contribute to the formation of cracks.

BackgroundBoth alcohol consumption and HIV infection are associated with worse brain, cognitive, and clinical outcomes in older adults. However, the extent to which brain and cognitive dysfunction is reversible with reduction or cessation of drinking is unknown. ObjectiveThe 30-Day Challenge study was designed to determine whether reduction or cessation of drinking would be associated with improvements in cognition, reduction of systemic and brain inflammation, and improvement in HIV-related outcomes in adults with heavy drinking. MethodsThe study design was a mechanistic experimental trial, in which all participants received an alcohol reduction intervention followed by repeated assessments of behavioral and clinical outcomes. Persons were eligible if they were 45 years of age or older, had weekly alcohol consumption of 21 or more drinks (men) or 14 or more drinks (women), and were not at high risk of alcohol withdrawal. After a baseline assessment, participants received an intervention consisting of contingency management (money for nondrinking days) for at least 30 days followed by a brief motivational interview. After this, participants could either resume drinking or not. Study questionnaires, neurocognitive assessments, neuroimaging, and blood, urine, and stool samples were collected at baseline, 30 days, 90 days, and 1 year after enrollment. ResultsWe enrolled 57 persons with heavy drinking who initiated the contingency management protocol (mean age 56 years, SD 4.6 years; 63%, n=36 male, 77%, n=44 Black, and 58%, n=33 people with HIV) of whom 50 completed 30-day follow-up and 43 the 90-day follow-up. The planned study procedures were interrupted and modified due to the COVID-19 pandemic of 2020-2021. ConclusionsThis was the first study seeking to assess changes in brain (neuroimaging) and cognition after alcohol intervention in nontreatment-seeking people with HIV together with people without HIV as controls. Study design strengths, limitations, and lessons for future study design considerations are discussed. Planned analyses are in progress, after which deidentified study data will be available for sharing. Trial RegistrationClinicalTrials.gov NCT03353701; https://clinicaltrials.gov/study/NCT03353701 International Registered Report Identifier (IRRID)DERR1-10.2196/53684

Abstract Background Alzheimer’s disease is a prevalent disease with a heavy global burden. Proteomics is the systematic study of proteins and peptides to provide comprehensive descriptions. Aiming to obtain a more accurate and convenient clinical diagnosis, researchers are working for better biomarkers. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels. Methods We firstly enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples, and conducted an LC–MS/MS analysis. In parallel, clinical data were collected, and clinical examinations were performed. After statistical and bioinformatics analyses, significant risk factors and differential urinary proteins were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM. Results Fifty-seven AD patients, 43 MCI patients, and 62 CN subjects were enrolled. A total of 3366 proteins were identified, and 608 urine proteins were finally included in the analysis. There were 33 significantly differential proteins between the AD and CN groups and 15 significantly differential proteins between the MCI and CN groups. AD diagnostic panel included DDC, CTSC, EHD4, GSTA3, SLC44A4, GNS, GSTA1, ANXA4, PLD3, CTSH, HP, RPS3, CPVL, age, and APOE ε4 with an AUC of 0.9989 in the training test and 0.8824 in the test set while MCI diagnostic panel included TUBB, SUCLG2, PROCR, TCP1, ACE, FLOT2, EHD4, PROZ, C9, SERPINA3, age, and APOE ε4 with an AUC of 0.9985 in the training test and 0.8143 in the test set. Besides, diagnostic proteins were weakly correlated with cognitive functions. Conclusions In conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN.

Introduction: Post-traumatic stress disorder (PTSD) is a debilitating disorder experienced by a subgroup of individuals following a life-threatening trauma. Several US states have passed laws permitting the medical use of marijuana (MMJ) by individuals with PTSD, despite very little scientific indication on the appropriateness of marijuana as a therapy for PTSD. This prospective pilot study of adults with confirmed PTSD in Florida (FL) investigated whether PTSD symptoms, sleep quality, affect, and general physical and mental health/well-being improved post-initiation of MMJ treatment. Methods: Participants, N = 15, were recruited from two MMJ clinics in Gainesville and Jacksonville, FL. To be eligible, participants had to be 18 years of age or older, not currently on MMJ, and willing to abstain from recreational marijuana, if using any, until the State Medical Cannabis Card was obtained, screen positive for PTSD. Participants were assessed at baseline (pre-MMJ initiation) and 30 and 70 days post-MMJ initiation using the Pittsburgh Sleep Quality Index (PSQI), PTSD Checklist for DSM-5 (PCL-5), Positive and Negative Affect Schedule (PANAS), PROMIS Global Health V1.2, and semi-structured marijuana and other substance use assessment. Results: PTSD symptom severity as measured by total PCL-5 score improved significantly at 30- and 70-day follow-ups. Similarly, statistically significant reductions in nightmares were reported at 30- and 70-day follow-ups. Corresponding improvements in sleep were noticed with participants reporting increased duration of sleep hours, sleep quality, sleep efficiency, and total PSQI score. Likewise, negative affect and global mental health improved significantly at follow-up. According to the post hoc analyses, the most statistically significant changes occurred between baseline and 30-day follow-up. The exception to this pattern was nightmares, which did not show significant improvement until day 70. Conclusion: The findings of this study highlight the potential of MMJ in improving patient outcomes for those with PTSD, particularly concerning sleep disturbances, which often do not respond to currently available treatments.

Abstract Background The role of dendritic cells and the autophagy state of dendritic cells in the immune response of hepatitis B virus (HBV) infection was still controversial. In this study, we carefully examined the phenotype, function and autophagy pathway of dendritic cells in HBV infection. Methods Monocyte-derived dendritic cells from healthy blood donors and patients with chronic HBV infection were stimulated by lipopolysaccharide, supernatant of HepG2.2.15 cells or supernatant of HepG2 cells respectively. Phenotype of dendritic cells was examined by flow cytometry and cytokines secretion was detected by enzyme-linked immunosorbent assay. Autophagy related proteins were detected by western blot and immunofluorescence analysis. Results Our results showed that the expression of both major histocompatibility complex II molecules and co-stimulated molecules including cluster of differentiation antigen 80, cluster of differentiation antigen 86 in the monocyte-derived dendritic cells from patients with chronic HBV infection was significantly higher than that from healthy donors when cultured with supernatant of HepG2.2.15 cells. The amount of cytokines, including tumour necrosis factor-α, interleukin-10 and interleukin-12, secreted by monocyte-derived dendritic cells from patients with chronic HBV infection was also significantly higher than that from healthy donors when stimulate by HBV. Interestingly, the expression level of autophagy-related proteins including autophagy-related protein5 and associated protein 1 light chain in dendritic cells from patients with chronic HBV infection was significantly increased when compared with that from healthy donors when re-exposed to HBV. Conclusions Our results indicated that dendritic cells from patients with chronic HBV infection could intensively present antigen and express co-stimulatory molecules. The increased activation of dendritic cells might be related to the enhanced autophagy of dendritic cells in HBV infection.

Abstract Background MicroRNA-19b (miR-19b) has been reported to be downregulated in polycystic ovary syndrome (PCOS), while its upstream regulators are unclear. We speculated that miR-19b could potentially form a binding relationship with BBOX1 antisense RNA 1 (BBOX1-AS1), a long non-coding RNA recognized for its critical role in ovarian cancer. Subsequently, we investigated into their interaction in PCOS. Methods The expression of miR-19b and BBOX1-AS1 in follicular fluid from both control women (n = 80) and women with PCOS (n = 80) was detected by RT-qPCR. Correlations were analyzed with Pearson’ correlation coefficient. The binding of miR-19b to the wild-type (-wt) ad mutant (-mut) BBOX1-AS1 was determined by RNA-RNA pulldown assay. Their interactions were detected by overexpression assay. Bromodeoxyuridine (BrdU) assay was applied for proliferation analysis. Results BBOX1-AS1 was highly upregulated, while miR-19b was downregulated in PCOS. There was no close correlation across PCOS and the control samples. Consistently, they did not regulate the expression of each other in granulosa cells. However, BBOX1-AS1-wt, but not BBOX1-AS1-mut, could directly interact with miR-19b. BBOX1-AS1 suppressed the role of miR-19b in inhibiting granulosa cell proliferation. Conclusion BBOX1-AS1 is highly upregulated in PCOS, and it may serve as an endogenous competing RNA for miR-19b to suppress its role in inhibiting granulosa cell proliferation. Our study suggested the role of BBOX1-AS1 as a potential target to treat PCOS.

In order to study the effect of ultrasound-assisted salting on the flavor quality of microwave heating snakehead fillet, the parameters of ultrasonic and brining of snakehead fillet were first investigated, then the electronic nose, electronic tongue, volatile substances and free amino acid substance of microwave heated snakehead fillets were determined. The results showed that the optimum parameters of ultrasound-assisted brining were as follows: Salt content 4 g/mL, solid-to-liquid ratio 1:4 g/mL, constant temperature (24±1) ℃, ultrasonic frequency 40 kHz, ultrasonic power 200 W and ultrasonic time 60 min. In electronic nose and volatile flavor substances analysis, ultrasonic assisted salting treatment effectively inhibited the formation of organic sulfide and increased the contents of five volatile substances (alcohols, aldehydes, ketones, acids and esters) in microwave heated fillets. In electronic tongue and free amino acid substance content analysis, the response of ultrasonic assisted salting treatment to sour and bitter taste was the lowest, and the response to salty, umami and sweet taste was the highest. And the ultrasonic treatment increased the contents of 13 free amino acids of microwave heated snakehead fillet, suggesting the improvement of flavor and taste. Two-factor analysis of variance found that ultrasonic treatment had a more significant effect on flavor, and salting treatment had a more significant effect on taste. The results of this study provide theoretical support for the industrial production of prefabricated aquatic products.

High-performance Pb(Zr1−xTix)O3 (PZT) piezoceramics are urgently desired by the market in view of their expanded operating temperature range, reduced property temperature dependence, and enhanced sensitivity and acoustic power. In this work, we reported a kind of low-cost and high-performance 0.06BiYbO3–0.94Pb(Zr0.48Ti0.52)O3 ternary piezoceramics; the modifying effects of La2O3 on this perovskite system were investigated in terms of the structures, electrical properties, and thermal depolarization behaviors of ceramics. The field-dependent dielectric and conduction properties indicated that there are close correlations among oxygen vacancies (VO), conducting electrons, and intrinsic conduction process. The degradation in ferroelectric properties observed in those samples doped with more than 0.15 wt% of La2O3 indicated that the occupying mechanisms of La3+ changed from the donor substitution for Pb2+ to the isovalent substitution for Bi3+. The thermally depoling micromechanisms of ceramics were revealed from the thermodynamic processes of defect dipoles and intrinsic dipoles within ferroelectric domains. The sample doped with 0.15 wt% of La2O3 shows excellent electrical properties with TC = 387 ℃, d33 = 332 pC/N, TKε = 5.81×10−3 ℃−1, Pr = 20.66 μC/cm2, Td = 356 ℃. The significantly enhanced electrical properties and thermal depolarization temperature benefited from the donor substitution of La3+, decreasing the oxygen vacancy concentration in the lattice and possibly optimizing the ferroelectric domain structure of ceramics.

Abstract Background Elevated levels of oxidative stress as a consequence of estrogen deficiency serve as a key driver of the onset of osteoporosis (OP). In addition to increasing the risk of bone fractures, OP can reduce the bone volume proximal to titanium nails implanted to treat these osteoporotic fractures, thereby contributing to titanium nail loosening. Sodium butyrate (NaB) is a short-chain fatty acid produced by members of the gut microbiota that exhibits robust antioxidant and anti-inflammatory properties. Methods OP fracture model rats parameters including bone mineral density (BMD), new bone formation, and the number of bonelets around the implanted nail were analyzed via micro-CT scans, H&E staining, and Masson’s staining. The protective effects of NaB on such osseointegration and the underlying mechanisms were further studied in vitro using MC3T3-E1 cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) to induce oxidative stress. Techniques including Western immunoblotting, electron microscopy, flow cytometry, alkaline phosphatase (ALP) staining, and osteoblast mineralization assays were employed to probe behaviors such as reactive oxygen species production, mineralization activity, ALP activity, protein expression, and the ability of cells to attach to and survive on titanium plates. Results NaB treatment was found to enhance ALP activity, mineralization capacity, and Coll-I, BMP2, and OCN expression levels in CCCP-treated MC3T3-E1 cells, while also suppressing PKC and NF-κB expression and enhancing Nrf2 and HO-1 expression in these cells. NaB further suppressed intracellular ROS production and malondialdehyde levels within the cytosol while enhancing superoxide dismutase activity and lowering the apoptotic death rate. In line with these results, in vivo work revealed an increase in BMD in NaB-treated rats that was associated with enhanced bone formation surrounding titanium nails. Conclusion These findings indicate that NaB may represent a valuable compound that can be postoperatively administered to aid in treating OP fractures through the enhancement of titanium nail osseointegration.

ABSTRACTAs the main load bearing component, the steel strand has a significant impact on the safety of civil infrastructure. Real-time monitoring of steel strand stress distribution throughout the damage process is an important aspect of civil infrastructure health assessment. Hence, this study proposes an optical-electrical co-sensing (OECS) smart steel strand with the DOFS and CCFPI embedded in. It can simultaneously measure small strains in the initial damage phase with high accuracy and obtain information in the large deformation phase with relatively low precision. Several experiments were carried out to test its sensing performance. It shows both DOFS and CCFPI have good linearity, repeatability and hysteresis. In comparison to DOFS, CCFPI has a relatively lower accuracy and resolution, but a large enough measurement range to tolerate the large strain in the event of a steel strand failure. To verify the reliability of the proposed smart steel strand in real structures, the strand strain distribution in the full damage process of bonded prestressed beams under four-point bending loading was monitored using the smart steel strand as a prestressing tendon. The strain measured by the OECS steel strand is shown to reflect the deformation and stiffness variation of prestressed beams under different load.

Abstract Background Polycystic ovary syndrome (PCOS) is a reproductive hormonal abnormality and a metabolic disorder, which is frequently associated with insulin resistance (IR). We aim to investigate the potential therapeutic effects of Ubiquitin-protein ligase E3A (UBE3A) on IR in the PCOS rats via Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) activation. Methods The PCOS and IR rats model was established by dehydroepiandrosterone (DHEA) and high fat diet (HFD) treatment, and the fat rate, glucose tolerance and insulin tolerance were measured. The IR rats numbers were calculated. Besides, the mRNA levels of glucose transporter 4 (GLUT4) and UBE3A were detected by RT-qPCR. Furthermore, the relationship between was demonstrated by co-IP assay. The phosphorylation and ubiquitination of AMPK were analyzed by western blot. Results UBE3A was up-regulated in the PCOS rats. UBE3A knockdown significantly decreased the fat rate, glucose tolerance and insulin tolerance in the PCOS and IR rats. Additionally, the GLUT4 levels were significantly increased in PCOS + IR rats. Besides, after UBE3A knockdown, the IR rats were decreased, the p-IRS1 and p-AKT levels were significantly up-regulated. Furthermore, UBE3A knockdown enhanced phosphorylation of AMPK through decreasing the ubiquitination of AMPK. AMPK knockdown reversed the role of UBE3A knockdown in the PCOS + IR rats. Conclusions UBE3A knockdown inhibited the IR in PCOS rats through targeting AMPK. Our study indicated that UBE3A might become a potential biological target for the clinical treatment of PCOS.

ABSTRACTCarbon fiber reinforced polymer (CFRP) can be applied for bridge cables due to its excellent properties. As the important load-bearing structural component, real-time force monitoring of the CFRP cable is required. This paper presents a new smart CFRP cable that combines the self-sensing rods with embedded sensors and the anchorage system using extrusion technology. By embedding optical fiber (OF) and coaxial cable Fabry-Perot interferometer (CCFPI) into CFRP rods respectively, two types of self-sensing rods (CFRP-OF rod and CFRP-CCFPI rod) were fabricated. A new anchorage unit using an extrusion process was proposed as a basic component of smart CFRP cables. Anchorage units holding a CFRP-OF rod and a CFRP-CCFPI rod were tested to obtain their sensing and mechanical properties. Three anchorage units were assembled to form a smart CFRP cable with self-sensing functionality. A verification test was carried out to confirm the capability of monitoring the cable force. The test results demonstrate that the smart CFRP cable composed of multiple anchorage units has good potential in bridge engineering.

Potential field theory, as a theory that can also be applied to vehicle control, is an emerging risk quantification approach to accommodate the connected and self-driving vehicle environment. Vehicles have different risk impact effects on other road participants in each direction under the influence of road rules. This variability exhibited by vehicles in each direction is not considered in the previous potential field model. Therefore, this paper proposed a potential field model that takes the anisotropy of vehicle impact into account: (1) introducing equivalent distances to separate the potential field area in the different directions before and after the vehicle; (2) introducing co-virtual forces to characterize the effect of the side-by-side travel phenomenon on vehicle car-following travel; (3) introducing target forces and lane resistance, which regress the control of desired speed to control the acceptable risk of drivers. The Next Generation Simulation (NGSIM) dataset is used in this study to create the model's initial parameter values based on the artificial swarm algorithm. The simulation findings indicate that when the vehicle is given the capacity to perceive the surrounding traffic environment, the suggested the anisotropic safety potential field model (ASPFM) performs better in terms of driving safety.

Abstract Background Caries in young children has received more and more attention. The study of the oral microbiota may help to understand the polymicrobial etiology of dental caries. Objectives To investigate the diversity and structure of microbial communities in saliva samples from 5-year-old children with versus without dental caries. Methods A total of 36 saliva samples were collected from 18 children with high caries (HB group) and from 18 children without caries (NB group). Then, 16S rDNA was amplified from bacterial samples using polymerase chain reaction, and high-throughput sequencing was performed using Illumina Novaseq platforms. Results Sequences were clustered into operational taxonomic units (OTUs), which were distributed among 16 phyla, 26 classes, 56 orders, 93 families, 173 genera, and 218 species. Firmicutes, Bacteroides, Proteobacteria, Actinobacteria, Fusobacteria, Patescibacteria, Epsilonbacteraeota, Cyanobacteria, Acidobacteria and Spirochaetes were basically the same in different groups, but their relative abundances were different. The core microbiome was defined as the species from 218 shared microbial taxa. The alpha diversity test showed that there were no significant differences in microbial abundance and diversity between the high caries and no caries groups. The results from principal coordinate analysis (PCoA) and hierarchical clustering showed that the two groups had similar microorganisms. The biomarkers of different groups were defined by LEfSe analysis to identify potential caries-related and health-related bacteria. Co-occurrence network analysis of dominant genera showed that oral microbial communities in the no caries group were more complex and aggregated than those in the high caries group. Finally, the PICRUSt algorithm was used to predict the function of the microbial communities from saliva samples. The obtained results showed that mineral absorption was greater in the no caries group than in the high caries group. BugBase was used to determine phenotypes present in microbial community samples. The obtained results showed that Streptococcus was greater in the high caries group than in the no caries group. Conclusion Findings of this study provide a comprehensive understanding of the microbiological etiology of dental caries in 5-year-old children and are expected to provide new methods for its prevention and treatment.

Abstract An ideal DNA‐encoded library (DEL) selection requires the library to consist of diverse core skeletons and cover chemical space as much as possible. However, the lack of efficient on‐DNA synthetic approaches toward core skeletons has greatly restricted the diversity of DEL. To mitigate this issue, this work disclosed a “Mask & Release” strategy to streamline the challenging on‐DNA core skeleton synthesis. N‐phenoxyacetamide is used as a masked phenol and versatile directing group to mediate diversified DNA‐compatible C‐H functionalization, introducing the 1st‐dimensional diversity at a defined site, and simultaneously releasing the phenol functionality, which can facilitate the introduction of the 2nd diversity. This work not only provides a set of efficient syntheses toward DNA‐conjugated drug‐like core skeletons such as ortho‐alkenyl/sulfiliminyl/cyclopropyl phenol, benzofuran, dihydrobenzofuran but also provides a paradigm for on‐DNA core skeleton synthetic method development.

BackgroundAmong the advantaged population with clinical cure of chronic hepatitis B, chronic inactive hepatitis B virus carriers (IHCs) and nucleoside analog-experienced patients have similar serological manifestations. This study established non-interferon-treated groups as controls to compare the efficacy of pegylated interferon α-2b (Peg-IFNα-2b) in achieving clinical cure between IHCs and nucleoside analog (NA)-experienced patients.MethodA total of 270 patients were enrolled in this observational study. The IHC cohort comprised 55 patients who received Peg-IFNα-2b (Peg-IFN group), and the other 70 patients did not receive any antiviral treatment (untreated group). Patients treated with NAs were divided into two groups: one group (70 patients) receiving NA add-on Peg-IFNα-2b therapy regimen (NA add-on Peg-IFN group) and another group (75 patients) receiving continuous NA monotherapy (NA group). The primary endpoints were hepatitis B surface antigen (HBsAg) clearance and HBsAg seroconversion at 48 weeks and 72 weeks.ResultsAt 48 weeks, 65.5% (36/55) and 52.9% (37/70) patients achieved HBsAg clearance in the Peg-IFN group and NA add-on Peg-IFN group, respectively (p = 0.156). HBsAg seroconversion was achieved in 47.3% (26/55) of the Peg-IFN group and 34.3% (24/70) of the NA add-on Peg-IFN group (p = 0.141). At the follow-up of 72 weeks, 36 patients in the Peg-IFN group achieved HBsAg loss (65.5%, 36/55), and 33 patients in the NA add-on Peg-IFN group achieved HBsAg clearance (47.1%, 33/70), which were significantly higher than in the Peg-IFN group (p = 0.041). The HBsAg seroconversion rates in the Peg-IFN group and NA add-on Peg-IFN group at 72 weeks were 45.5% (25/55) and 32.9% (23/70), respectively (p = 0.151). No patient achieved HBsAg clearance or seroconversion in the NA group and untreated group. Furthermore, the receiver operating characteristic curve showed baseline HBsAg< 72 IU/mL, and the decline of HBsAg of more than 80% and 98% from baseline to 12 and 24 weeks provided good predictions for HBsAg clearance. Meanwhile, 77% of patients with baseline HBsAg< 100 IU/mL achieved a clinical cure at 48 weeks.ConclusionPeg-IFNα-2b results in a high rate of HBsAg clearance and seroconversion in both IHCs and NA-experienced patients, especially for those patients who have HBsAg below 100 IU/mL.

IntroductionAlzheimer’s disease is a prevalent disease with a heavy global burden and is suggested to be a metabolic disease in the brain in recent years. The metabolome is considered to be the most promising phenotype which reflects changes in genetic, transcript, and protein profiles as well as environmental effects. Aiming to obtain a comprehensive understanding and convenient diagnosis of MCI and AD from another perspective, researchers are working on AD metabolomics. Urine is more convenient which could reflect the change of disease at an earlier stage. Thus, we conducted a cross-sectional study to investigate novel diagnostic panels.MethodsWe first enrolled participants from China-Japan Friendship Hospital from April 2022 to November 2022, collected urine samples and conducted an LC–MS/MS analysis. In parallel, clinical data were collected and clinical examinations were performed. After statistical and bioinformatics analyzes, significant risk factors and differential urinary metabolites were determined. We attempt to investigate diagnostic panels based on machine learning including LASSO and SVM.ResultsFifty-seven AD patients, 43 MCI patients and 62 CN subjects were enrolled. A total of 2,140 metabolites were identified among which 125 significantly differed between the AD and CN groups, including 46 upregulated ones and 79 downregulated ones. In parallel, there were 93 significant differential metabolites between the MCI and CN groups, including 23 upregulated ones and 70 downregulated ones. AD diagnostic panel (30 metabolites+ age + APOE) achieved an AUC of 0.9575 in the test set while MCI diagnostic panel (45 metabolites+ age + APOE) achieved an AUC of 0.7333 in the test set. Atropine, S-Methyl-L-cysteine-S-oxide, D-Mannose 6-phosphate (M6P), Spiculisporic Acid, N-Acetyl-L-methionine, 13,14-dihydro-15-keto-tetranor Prostaglandin D2, Pyridoxal 5’-Phosphate (PLP) and 17(S)-HpDHA were considered valuable for both AD and MCI diagnosis and defined as hub metabolites. Besides, diagnostic metabolites were weakly correlated with cognitive functions.DiscussionIn conclusion, the procedure is convenient, non-invasive, and useful for diagnosis, which could assist physicians in differentiating AD and MCI from CN. Atropine, M6P and PLP were evidence-based hub metabolites in AD.

Abstract Background This study aimed to investigate the expression of serum miR-363-3p in patients with polycystic ovary syndrome (PCOS) and its predictive value for pregnancy after ovulation induction therapy. Methods The expression of serum miR-363-3p was detected by Reverse transcription quantitative polymerase chain reaction (RT-qPCR). PCOS patients were treated with ovulation induction therapy, and after the successful pregnancy was confirmed, they were followed up for 1 year in outpatient department to record the pregnancy outcomes of the patients. The Pearson correlation coefficient was used to evaluate the correlation between the expression level of miR-363-3p and biochemical indicators of PCOS patients. Logistic regression analysis was used to analyze the risk factors of pregnancy failure after ovulation induction therapy. Results The serum level of miR-363-3p in PCOS group was significantly lower than that in control group. Compared with the control group, both pregnant and non-pregnant groups had lower miR-363-3p levels, while the non-pregnant group had a greater reduction in miR-363-3p levels than the pregnant group. Low levels of miR-363-3p showed high accuracy in distinguishing pregnant and non-pregnant patients. Logistic regression analysis showed that high levels of luteinizing hormone, testosterone (T), prolactin (PRL) and low level of miR-363-3p were independent risk factors for pregnancy failure after ovulation induction in PCOS patients. Additionally, compared with pregnancy outcomes of healthy women, the incidence of premature delivery, macrosomia, and gestational diabetes in PCOS patients increased. Conclusions The expression of miR-363-3p in PCOS patients was reduced and correlated with abnormal hormone levels, suggesting that miR-363-3p may be involved in the occurrence and development of PCOS.

Abstract Background Stroke is a common cerebrovascular disease with great danger to public health. Educational inequality is a universal issue that influences populations’ stroke risk. This study aimed to investigate the causal relationship between education and stroke risk and the contributions of effects mediated by four modifiable factors. Materials and methods Public large-scale genome-wide association study (GWAS) summary data associated with educational attainment, hypertensive diseases, body mass index (BMI), smoking behavior, time spent on watching the television (TV), and stroke were obtained from European ancestry. The data were used to investigate the causal relationship among educational attainment, hypertensive disease, BMI, smoking, watching TV, and stroke risk. Inverse variance weighted (IVW) method was used as a primary algorithm for estimating causal direction and effect size in univariable and multivariable Mendelian randomization (MR) analyses. Results Higher educational attainment was a causal protective factor, while hypertensive diseases, higher BMI, smoking, and longer time spent on watching the TV were all causal risk factors for the risk of stroke. Hypertensive disease, BMI, smoking, and watching TV were all mediators for linking the causal relationship between educational attainment and stroke risk. Hypertensive disease, BMI, smoking, and watching TV explained 47.35%, 24.74%, 15.72%, and 2.29% of the variance in educational attainment’s effect on stroke risk, respectively. The explained proportion reached 69.32% after integrating the four factors. Conclusions These findings support the causal effect of educational attainment on the risk of stroke, with a substantial proportion mediated by modifiable risk factors. Interventions on these modifiable factors would lead to substantial reductions in stroke cases attributable to educational inequality.

Abstract Objective To explore the difference in the protective effects of intraperitoneal injection of exogenous melatonin of daytime or nighttime on bone loss in ovariectomized (OVX) rats. Methods After bilateral ovariectomy and sham surgery, 40 rats were randomly divided into four groups: sham operation group (Sham), ovariectomy (OVX), and daytime melatonin injection group (OVX + DMLT, 9:00, 30 mg/kg/d) and nighttime injection of melatonin (OVX + NMLT, 22:00, 30 mg/kg/d). After 12 weeks of treatment, the rats were sacrificed. The distal femur, blood and femoral marrow cavity contents were saved. The rest of the samples were tested by Micro-CT, histology, biomechanics and molecular biology. Blood was used for bone metabolism marker measurements. CCK-8, ROS, and Cell apoptosis are performed using MC3E3-T1 cells. Results Compared with treatment at night, the bone mass of the OVX rats was significantly increased after the daytime administration. All microscopic parameters of trabecular bone increased, only Tb.Sp decreased. Histologically, the bone microarchitecture of the OVX + DMLT was also more dense than the bone microarchitecture of the OVX + LMLT. In the biomechanical experiment, the femur samples of the day treatment group were able to withstand greater loads and deformation. In molecular biology experiments, bone formation-related molecules increased, while bone resorption-related molecules decreased. After treatment with melatonin administration at night, the expression of MT-1β was significantly decreased. In cell experiments, the MC3E3-T1 cells treated with low-dose MLT had higher cell viability and greater efficiency in inhibiting ROS production than the MC3E3-T1 cells treated with high-dose MLT, which in turn more effectively inhibited apoptosis. Conclusion Daytime administration of melatonin acquires better protective effects on bone loss than night in OVX rats.

Among the existing insulator defect detection methods, the automatic detection of inspection robots based on the instance segmentation algorithm is relatively more efficient, but the problem of the limited accuracy of the segmentation algorithm is still a bottleneck for increasing inspection efficiency. Therefore, we propose a single-stage insulator instance defect segmentation method based on both an attention mechanism and improved feature fusion network. YOLACT is selected as the basic instance segmentation model. Firstly, to improve the segmentation speed, MobileNetV2 embedded with an scSE attention mechanism is introduced as the backbone network. Secondly, a new feature map that combines semantic and positional information is obtained by improving the FPN module and fusing the feature maps of each layer, during which, an attention mechanism is introduced to further improve the quality of the feature map. Thirdly, in view of the problems that affect the insulator segmentation, a Restrained-IoU (RIoU) bounding box loss function which covers the area deviation, center deviation, and shape deviation is designed for object detection. Finally, for the validity evaluation of the proposed method, experiments are performed on the insulator defect data set. It is shown in the results that the improved algorithm achieves a mask accuracy improvement of 5.82% and a detection speed of 37.4 FPS, which better complete the instance segmentation of insulator defect images.

Casper, a type of transparent mutant-line zebrafish, was generated to overcome the opaque trunk of an adult zebrafish for tumor modeling to realize real-time visualization of transplanted cells in vivo. However, the molecular information at the metabolic level has not received much attention. Herein, a spatially resolved metabolomics method based on an airflow-assisted desorption electrospray ionization–mass spectrometry imaging (AFADESI-MSI) system for whole-body zebrafish was used to investigate small molecules and the distribution of adult casper (Mitfaw2/w2, roya9/a9) and the differences from wild-type zebrafish. Finally, the spatial distribution information of more than 1500 endogenous ions was obtained in positive and negative detection modes, and 186 metabolites belonging to a variety of structural categories were identified or annotated. Compared with wild-type samples, 85 variables, including 37 known metabolites, were screened out. In addition, the disordered metabolic pathways caused by the genetic mutation were excavated, involving downregulation of purine metabolism and arachidonic acid metabolism, upregulation of glycerophospholipid metabolism, and biosynthesis of unsaturated fatty acids. All these results were observed in the most intuitive way through MSI. This study revealed important metabolic characteristics of and perturbation in adult casper zebrafish, and provides indispensable fundamental knowledge for tumor research based on it.

In order to enhance the self-centering capacity of steel frame structures after earthquakes and reduce the tubes of traditional double-tube or triple-tube SC-BRB, an innovative single-tube self-centering buckling restrained brace (ST-SC-BRB) is proposed in this paper. Firstly, the structural configuration of the ST-SC-BRB component was described. Then, cyclic tests were conducted on one small-scaled BRB and one ST-SC-BRB with the same core steel plate. The test results indicate that the ST-SC-BRB specimen exhibits an excellent self-centering ability compared to the conventional BRB. However, their energy-dissipation capacities are still determined by the core steel plate. In addition, time–history analyses were conducted to evaluate the seismic performance of steel frame structures with BRBs and ST-SC-BRBs. The results suggest that the ST-SC-BRBs can effectively reduce the residual deformation of steel frame structures after earthquakes and contribute to the self-centering capacity of the steel frame structures. Finally, the influence of design parameters of ST-SC-BRB components on the seismic performance of steel frame structures was discussed. It is confirmed that the initial stiffness of the ST-SC-BRB component significantly influences the seismic response of the structure, while the self-centering ratio of the ST-SC-BRB component is a crucial factor in determining the residual deformations of the structure.

Abstract Postmenopausal osteoporosis (PMO) is often accompanied by neuroendocrine changes in the hypothalamus, which closely associates with the microbial diversity, community composition, and intestinal metabolites of gut microbiota (GM). With the emerging role of GM in bone metabolism, a potential neuroendocrine signal neuropeptide Y (NPY) mediated brain‐gut‐bone axis has come to light. Herein, it is reported that exogenous overexpression of NPY reduced bone formation, damaged bone microstructure, and up‐regulated the expressions of pyroptosis‐related proteins in subchondral cancellous bone in ovariectomized (OVX) rats, but Y1 receptor antagonist (Y1Ra) reversed these changes. In addition, it is found that exogenous overexpression of NPY aggravated colonic inflammation, impaired intestinal barrier integrity, enhanced intestinal permeability, and increased serum lipopolysaccharide (LPS) in OVX rats, and Y1Ra also reversed these changes. Most importantly, NPY and Y1Ra modulated the microbial diversity and changed the community composition of GM in OVX rats, and thereby affecting the metabolites of GM (e.g., LPS) entering the blood circulation. Moreover, fecal microbiota transplantation further testified the effect of NPY‐mediated GM changes on bone. In vitro, LPS induced pyroptosis, reduced viability, and inhibited differentiation of osteoblasts. The study demonstrated the existence of NPY‐mediated brain‐gut‐bone axis and it might be a novel emerging target to treat PMO.

Klinefelter syndrome (KS) is the most common genetic cause of human male infertility. However, the effect of the extra X chromosome on different testicular cell types remains poorly understood. Here, we profiled testicular single-cell transcriptomes from three KS patients and normal karyotype control individuals. Among the different somatic cells, Sertoli cells showed the greatest transcriptome changes in KS patients. Further analysis showed that X-inactive-specific transcript (XIST), a key factor that inactivates one X chromosome in female mammals, was widely expressed in each testicular somatic cell type but not in Sertoli cells. The loss of XIST in Sertoli cells leads to an increased level of X chromosome genes, and further disrupts their transcription pattern and cellular function. This phenomenon was not detected in other somatic cells such as Leydig cells and vascular endothelial cells. These results proposed a new mechanism to explain why testicular atrophy in KS patients is heterogeneous with loss of seminiferous tubules but interstitial hyperplasia. Our study provides a theoretical basis for subsequent research and related treatment of KS by identifying Sertoli cell-specific X chromosome inactivation failure.

With ever-increasing power-density requirements, technologies such as energy storage systems and electric-vehicles can benefit greatly from interfacing medium-voltage (MV)-AC grid like 13.8kV or 30kV using high-AC/low-DC voltage converter. Using modular high-AC/low-DC voltage converter can help increase power-density and efficiency, while reducing total conversion steps and providing flexibility. Full-bridge modular multilevel converters (FB-MMC) and solid-state transformers are existing solutions for such operations, but suffer from limitations of high semiconductor requirements, large submodule capacitors and/or many high-frequency transformers. Three new hybrid-MMC (HMMC) topologies are proposed in this paper as alternative solutions for such high-AC/low-DC voltage operations. Each of the three developed HMMCs utilizes a unique combination of low-frequency high-voltage switches and fast-switching low-voltage switch based submodules to generate multilevel-AC voltage. HMMCs are compared extensively to state-of-the-art FB-MMC and are shown to have semiconductor savings of over 27%, 38% lower submodule capacitor size, and 53% lower losses for 13.8-kV-AC/6-kV-DC operation. Due to these benefits like higher efficiency, significantly smaller submodule capacitance requirements, and fewer semiconductors, HMMCs can be an excellent option for high-AC/low-DC applications. Practical considerations like snubber and DC split-capacitor requirement are also elaborated for developing and commercializing HMMCs. Comparison results are verified using a 17.5 kW three-phase MV laboratory prototype.

Abstract Mage-D1 (MAGE family member D1) is involved in a variety of cell biological effects. Recent studies have shown that Mage-D1 is closely related to tooth development, but its specific regulatory mechanism is unclear. The purpose of this study was to investigate the expression pattern of Mage-D1 in rat dental germ development and its differential mineralization ability to ectomesenchymal stem cells (EMSCs), and to explore its potential mechanism. Results showed that the expression of Mage-D1 during rat dental germ development was temporally and spatially specific. Mage-D1 promotes the proliferation ability of EMSCs but inhibits their migration ability. Under induction by mineralized culture medium, Mage-D1 promotes osteogenesis and tooth-forming ability. Furthermore, the expression pattern of Mage-D1 at E19.5 d rat dental germ is similar to p75 neurotrophin receptor (p75NTR), distal-less homeobox 1 (Dlx1) and msh homeobox 1 (Msx1). In addition, Mage-D1 is binding to p75NTR, Dlx1, and Msx1 in vitro. These findings indicate that Mage-D1 is play an important regulatory role in normal mineralization of teeth. p75NTR, Dlx1, and Msx1 seem to be closely related to the underlying mechanism of Mage-D1 action.

This research was to obtain stable myofibrillar protein emulsion. Myofibrillar protein was extracted from frozen silver carp surimi, and the effects of heat treatment (85 ℃ for 10 min) and protein concentrations (5, 10, 15, 20 and 25 mg/mL) on the aggregation ratio, particle size, zeta-potential and microstructure of myofibrillar protein and structure, apparent viscosity and color of soybean oil-myofibrillar protein emulsion were investigated. The results showed that heat treatment led to the increase of particle size and decrease of apparent viscosity of myofibrillar protein, namely protein aggregation. While emulsion prepared with thermal treated myofibrillar protein displayed high L* and b* value and low hydrophobicity. With the increase of myofibrillar protein concentration, the apparent viscosity increased, and the zeta-potential fluctuate increased, no matter the myofibrillar protein solution subjected to heat treatment or not. The minimum particle size of un-heated and heated myofibrillar protein solution was obtained when the protein concentration was 10 and 25 mg/mL, respectively. Besides, the optical microscopy observed that the number of oil droplets involved in emulsification gradually increased, the particle size of oil droplets gradually decreased, the coalescence among oil droplets gradually reduced, when the concentration of myofibrillar protein increased. Therefore, when the protein concentration was in the range of 10~20 mg/mL and the oil ratio was 0.6, the emulsion prepared with thermal treated myofibrillar protein showed high stability and expressed as small and dispersed emulsion droplets and low apparent viscosity. This study is of great significance for the development of stable myofibrillar protein emulsion.

Abstract 6G is believed to go beyond communication and provide integrated sensing and computing capabilities for a vision of Connected Intelligence with everything connected, everything sensed, and everything intelligent. Integrated sensing and communication will play a vital role for the fusion of physical and cyber worlds. The exploration of higher frequency bands, larger bandwidth, and more advanced large antenna technologies is paving the way towards the goal. In particular, the study of THz opens the possibility to have high resolution sensing and imaging capability on a communication mobile device. In this paper, we take a step along this direction and justify such possibility by building a THz sensing prototype with millimeter level imaging resolution while considering the physical aperture constraint of typical mobile device.

Abstract Purpose To describe the cervical spine morphology and explore its relationship to global sagittal alignment parameters in the asymptomatic adolescent population. Methods A total of 111 adolescent subjects were included. Sagittal alignment parameters, including C7 Slope, C2-C7 Cobb, C2-7 plumb line (PL), C2-S1 Sagittal Vertical Axis (SVA), C7-S1 SVA, T5-12 Cobb, T10-L2 Cobb, L1-S1 Cobb, pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS), were obtained from lateral radiographs. Results Forty-four males and sixty-seven females with a mean age of 16.12 ± 2.40 years were included in this study. The mean values of C7 Slope, C2-7 Cobb and C2-7PL were 20.45 ± 8.88°, -7.72 ± 12.10°, and 13.53 ± 11.63 mm, respectively. C2-7 Cobb, C7 Slope showed significant differences between the male and female groups. Correlation analysis showed that C7 slope was significantly correlated with C2-7 Cobb (r = -0.544, P

Background Obesity is a chronic disease with a high prevalence rate and is an established risk factor for human health. Body mass index (BMI) is a common and primary indicator used in assessing obesity. This work aims to investigate the putative causal relationship among BMI, sex hormone-binding globulin (SHBG), bioavailable testosterone (BioT), and estradiol levels. Materials and Methods We conducted a bidirectional Mendelian randomization study, using single-nucleotide polymorphisms (SNPs) strongly associated with BMI, SHBG, BioT, and estradiol as instrumental variables. All SNPs were identified from the genome-wide association study (GWAS) summary data of large sample studies recruiting more than 150,000 European adult male individuals. The inverse-variance-weighted (IVW) approach was used as a primary algorithm for putative causal estimation. Results Genetically predicted elevated BMI was associated with decreased SHBG (IVW, β = −0.103, 95% confidence interval [CI] [−0.113 to −0.092], P = 1.50 × 10−77) and BioT levels (IVW, β = −0.139, 95% CI [−0.165 to −0.113], P = 9.54 × 10−26) and high estradiol levels (IVW, β = 0.014, 95% CI [0.009–0.019], P = 2.19 × 10−7). Increased SHBG levels were causally associated with low BMI (IVW, β = −0.051, 95% CI [−0.098 to −0.005], P = 0.030) and BioT (IVW, β = −0.126, 95% CI [−0.175 to −0.077], P = 5.97 × 10−7) and high estradiol levels (IVW, β = 0.046, 95% CI [0.035–0.056], P = 6.51 × 10−17). Conversely, no evidence of an effect of estradiol imbalance on SHBG levels (IVW, β = 1.035, 95% CI [−0.854 to 2.926], P = 0.283) and BMI (IVW, β = 0.091, 95% CI [−0.094 to 0.276], P = 0.336) was obtained. However, increased BioT levels were causally associated with lower SHBG levels (IVW, β = −0.044, 95% CI [−0.061 to −0.026], P = 8.76 × 10−7), not BMI (IVW, β = −0.006, 95% CI [−0.035 to 0.023], P = 0.679). Conclusions The findings support a network putative causal relationship among BMI, SHBG, BioT, and estradiol. SHBG, BioT, and estradiol may partly mediate the effect of obesity on male health. Reasonably modulating BioT and estradiol, especially SHBG, facilitated the attenuation of the harmful effects of obesity on male health.

ObjectiveThe aim of this study was to compare the differences in salivary metabolites between pregnant women with gestational diabetes mellitus (GDM), healthy pregnant women (HPW), and healthy non-pregnant women (HNPW), and analyze the possible associations between the identified metabolites and gingivitis.MethodThe study included women with GDM (n = 9, mean age 28.9 ± 3.6 years, mean gestational age 30.1 ± 3.2 weeks), HPW (n = 9, mean age 27.9 ± 3.0 years, mean gestational age 28.6 ± 4.7 weeks), and HNPW (n = 9, mean age 27.7 ± 2.1 years). Saliva samples were collected from all participants and were analyzed with LC-MS/MS-based untargeted metabolomic analysis. Metabolite extraction, qualitative and semi-quantitative analysis, and bioinformatics analysis were performed to identify the differential metabolites and metabolic pathways between groups. The identified differential metabolites were further analyzed in an attempt to explore their possible associations with periodontal health and provide evidence for the prevention and treatment of periodontal inflammation during pregnancy.ResultsIn positive ion mode, a total of 2,529 molecular features were detected in all samples, 166 differential metabolites were identified between the GDM and HPW groups (89 upregulated and 77 downregulated), 823 differential metabolites were identified between the GDM and HNPW groups (402 upregulated and 421 downregulated), and 647 differential metabolites were identified between the HPW and HNPW groups (351 upregulated and 296 downregulated). In negative ion mode, 983 metabolites were detected in all samples, 49 differential metabolites were identified between the GDM and HPW groups (29 upregulated and 20 downregulated), 341 differential metabolites were identified between the GDM and HNPW groups (167 upregulated and 174 downregulated), and 245 differential metabolites were identified between the HPW and HNPW groups (112 upregulated and 133 downregulated). A total of nine differential metabolites with high confidence levels were identified in both the positive and negative ion modes, namely, L-isoleucine, D-glucose 6-phosphate, docosahexaenoic acid, arachidonic acid, adenosine, adenosine-monophosphate, adenosine 5′-monophosphate, xanthine, and hypoxanthine. Among all pathways enriched by the upregulated differential metabolites, the largest number of pathways were enriched by four differential metabolites, adenosine, adenosine 5′-monophosphate, D-glucose 6-phosphate, and adenosine-monophosphate, and among all pathways enriched by the downregulated differential metabolites, the largest number of pathways were enriched by three differential metabolites, L-isoleucine, xanthine, and arachidonic acid.ConclusionUntargeted metabolomic analysis of saliva samples from pregnant women with GDM, HPW, and HNPW identified nine differential metabolites with high confidence. The results are similar to findings from previous metabolomics studies of serum and urine samples, which offer the possibility of using saliva for regular noninvasive testing in the population of pregnant women with and without GDM. Meanwhile, the associations between these identified differential metabolites and gingivitis need to be further validated by subsequent studies.

Abstract Background Aging is related with memory deterioration. However, some older adults demonstrate superior performance compared to age- and education-matched adults, who are referred to as superagers. To explore the neural mechanisms that mediate their unusually successful memory is important not only for the ameliorate the effects of aging in brain, but also for the prevention of neurodegenerative diseases, including Alzheimer’s disease. This case-control study is aimed to investigate the effects of volume and function of basal forebrain cholinergic neurons on the cognition of superagers. Methods The morphometric and resting-state functional MRI analysis, including 34 superagers and 48 typical older adults, were conducted. We compared the basal forebrain gray matter density and related resting-state functional connectivity (FC) in the two groups. To investigate the relationship of FC with cognition, we measure the correlation of significant altered FC and individual cognitive domain. Results No significant differences of gray matter density was observed between superagers and typical older adults. The superagers had stronger cortical FC of Ch1-3 with left putamen and insular cortex. The strength of FC positively correlated with global cognition, memory and executive function. Conclusions These findings demonstrated that the stronger FC of basal forebrain correlated with specific cognitive difference in global cognition and domains of memory and executive function in superagers.

Abstract Background Non-obstructive azoospermia (NOA) is the most severe disease in male infertility, but the genetic causes for majority of NOA remain unknown. Methods Two Chinese NOA-affected patients were recruited to identify the genetic causal factor of infertility. Whole-exome sequencing (WES) was conducted in the two patients with NOA. Sanger sequencing and CNV array were used to ascertain the WES results. Hematoxylin and eosin (H&E) staining and immunofluorescence (IF) were carried out to evaluate the stage of spermatogenesis arrested in the affected cases. Results Novel heterozygous deletion (LOH) within SYCE1 (seq[GRCh37] del(10)(10q26.3)chr10:g.135111754_135427143del) and heterozygous loss of function (LoF) variant in SYCE1 (NM_001143763: c.689_690 del:p.F230fs) were identified in one NOA-affected patient. While homozygous deletion within SYCE1 (seq[GRCh37] del(10)(10q26.3)chr10:g.135340247_135379115del) was detected in the other patient with meiotic arrest. H&E and IF staining demonstrated that the spermatogenesis was arrested at pachytene stage in the two patients with NOA, suggesting these two novel CNVs within SYCE1 could lead to meiotic defect and NOA. Conclusions We identified that two novel CNVs within SYCE1 are associated with meiotic arrest and male infertility. Thus, our study expands the knowledge of variants in SYCE1 and provides a new insight to understand the genetic etiologies of NOA.