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Abstract Background Both late-life depression and childhood maltreatment have become major global public health issues, given their prevalence and social-economic and health consequences. However, previous studies have solely focused on the relationship of childhood maltreatment to average levels of depressive symptoms. The current study addresses this gap of knowledge by simultaneously examining the impacts of childhood intra- and extra-familial maltreatment on age trajectories of depressive symptoms in later life in the Chinese context. Methods Hierarchical linear models were applied to data from the China Health and Retirement Longitudinal Study (2011–2018, N = 12,669 individuals aged 45 to 80, comprising N = 43,348 person-years). Depressive symptoms were measured by the CES-D-10 scale. Childhood intra-familial maltreatments were measured by physical abuse and emotional neglect, while extra-familial maltreatment was measured by peer bullying. All analyses were conducted separately by gender in Stata 16. Results Childhood extrafamilial peer bullying (β = 1.628, p

Abstract Background Amyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development. Methods We conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points. Results In total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months. Conclusions The established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.

Carbonic anhydrase IV (Car4) is a newly identified receptor that allows adeno-associated virus (AAV) 9P31 to cross the blood-brain barrier and achieve efficient infection in the central nervous system (CNS) in mouse models. However, the molecular mechanism by which engineered AAV capsids with 7-mer insertion in the variable region (VR) VIII recognize these novel cellular receptors is unknown. Here we report the cryo-EM structures of AAV9P31 and its complex with Mus musculus Car4 at atomic resolution by utilizing the block-based reconstruction (BBR) method. The structures demonstrated that Car4 binds to the protrusions at 3-fold axes of the capsid. The inserted 7-mer extends into a hydrophobic region near the catalytic center of Car4 to form stable interactions. Mutagenesis studies also identified the key residues in Car4 responsible for the AAV9P31 interaction. These findings provide new insights into the novel receptor recognition mechanism of AAV generated by directed evolution and highlight the application of the BBR method to studying the virus-receptor molecular mechanism.

Nano-hydroxyapatite (nHAP) has been widely used in bone repair as an osteo-inductive and naturally-occurring material. However, the optimal applied form of nHAP and the underlying mechanisms involved remain unclear. Herein, to investigate into these, a range of corresponding models were designed, including three applied forms of nHAP (Free, Coating and 3D) that belong to two states (Free or fixed). The results indicate that when fixed nHAP was applied in the 3D form, optimal osteogenesis was induced in human bone marrow stem cells (hBMSCs) with increased bone volume via integrin α7 (ITGA7)-mediated upregulation of the PI3K-AKT signaling pathway, while contrary results were observed with free nHAP. Ectopic osteogenesis experiments in mice subcutaneous transplantation model further confirmed the different tendencies of ITGA7 expression and osteogenesis of hBMSCs in free and fixed states of nHAP. Our results revealed that the two states of nHAP play a different regulatory role in cell morphology and osteogenesis through the valve role of ITGA7, providing cues for better application of nanoparticles and a potential new molecular target in bone tissue engineering.

We study 10 spectroscopically confirmed Ly α emitters (LAEs) at z ≈ 3.1 in the Ultra Deep Survey field, covered by the James Webb Space Telescope/NIRCam in the Public Release Imaging for Extragalactic Research program. All LAEs are detected in all NIRCam bands from F090W to F444W, corresponding to rest frame wavelengths of 2200 Å to 1.2 μ m. Based on morphological analysis of the F200W images, three out of the 10 targets are resolved into pair-like systems with separations of

Abstract Stem cell-based tissue regeneration strategies are promising treatments for severe endometrial injuries. However, there are few appropriate seed cells for regenerating a full-thickness endometrium, which mainly consists of epithelia and stroma. Müllerian ducts in female embryonic development develop into endometrial epithelia and stroma. Hence, we first generated human pluripotent stem cells (hPSC)-derived Müllerian duct-like cells (MDLCs) using a defined and effective protocol. The MDLCs are bi-potent, can gradually differentiate into endometrial epithelial and stromal cells, and reconstitute full-thickness endometrium in vitro and in vivo. Furthermore, MDLCs showed the in situ repair capabilities of reconstructing endometrial structure and recovering pregnancy function in full-thickness endometrial injury rats, and their differentiation fate was revealed by single-cell RNA sequencing (scRNA-seq). Our study provides a strategy for hPSC differentiation into endometrial lineages and an alternative seed cell for injured endometrial regeneration.

Simple summarySomatic and germline aberrations in homologous recombinant repair (HHR) genes are associated with increased incidence and poor prognosis for prostate cancer. Through next-generation sequencing of prostate cancer patients across all clinical states from north China, here the authors identified a somatic mutational rate of 3% and a germline mutational rate of 3.9% for HRR genes using 200 tumor tissues and 714 blood specimens. Thus, mutational rates in HRR genes were lower compared with previous studies.BackgroundHomologous recombination repair deficiency is associated with higher risk and poorer prognosis for prostate cancer. However, the landscapes of somatic and germline mutations in these genes remain poorly defined in Chinese patients, especially for those with localized disease and those from north part of China. In this study, we explore the genomic profiles of these patients.MethodsWe performed next-generation sequencing with 200 tumor tissues and 714 blood samples from prostate cancer patients at Peking University First Hospital, using a 32 gene panel including 19 homologous recombination repair genes.ResultsTP53, PTEN, KRAS were the most common somatic aberrations; BRCA2, NBN, ATM were the most common germline aberrations. In terms of HRR genes, 3% (6/200) patients harbored somatic aberrations, and 3.8% (28/714) patients harbored germline aberrations. 98.0% (196/200) somatic-tested and 72.7% (519/714) germline tested patients underwent prostatectomy, of which 28.6% and 42.0% had Gleason scores ≥8 respectively. Gleason scores at either biopsy or prostatectomy were predictive for somatic aberrations in general and in TP53; while age of onset

IntroductionParental burnout is a mental state that combines long-term stress and depression with an overwhelming feeling of parental pressure.MethodsIn Study 1, we conducted a web-based survey of 390 Chinese parents (75.1% mothers) with children aged 1–18 years old (Mean age = 9.05 years, SD = 5.098) to examine the parental burnout during the COVID-19 global pandemic and to identify associated factors during the national lockdown. In Study 2, eight weeks of resilience intervention was administered to 20 parents to compare parental resilience and parental burnout before and after the intervention.ResultsThe correlational study showed that greater parental burnout occurred in parents with the lower educational levels and in parents of school-age children. The risk factors of parental burnout included household burden and children’s interference with work; while protective factors included living materials, family atmosphere, and parent–child meeting frequency. The intervention study showed the effectiveness of meditation intervention in resilience and parental burnout, suggesting that meditation training can effectively increase parental resilience and reduce parental burnout.DiscussionThese findings demonstrate the risk and protective factors associated with parental burnout during the COVID-19 lockdown and highlight the positive role of meditation in mitigating parental burnout.

Although aging is an increasingly severe healthy, economic, and social global problem, it is far from well-modeling aging due to the aging process’s complexity. To promote the aging modeling, here we did the quantitative measurement based on aging blood transcriptome. Specifically, the aging blood transcriptome landscape was constructed through ensemble modeling in a cohort of 505 people, and 1138 age-related genes were identified. To assess the aging rate in the linear dimension of aging, we constructed a simplified linear aging clock, which distinguished fast-aging and slow-aging populations and showed the differences in the composition of immune cells. Meanwhile, the non-linear dimension of aging revealed the transcriptome fluctuations with a crest around the age of 40 and showed that this crest came earlier and was more vigorous in the fast-aging population. Moreover, the aging clock was applied to evaluate the rejuvenation effect of molecules in vitro, such as Nicotinamide Mononucleotide (NMN) and Metformin. In sum, this study developed a de novo aging clock to evaluate age-dependent precise medicine by revealing its fluctuation nature based on comprehensively mining the aging blood transcriptome, promoting the development of personal aging monitoring and anti-aging therapies.

This study quantified the differences in the efficacy and safety of different stimulation domains of anti-CD19 chimeric antigen receptor (CAR) T therapy for B-cell acute lymphoblastic leukemia (B-ALL). Clinical trials related to anti-CD19 CAR T-cell therapy for B-ALL were searched in public databases from database inception to 13 November 2021. The differences in overall survival (OS) and progression-free survival (PFS) of B-ALL patients treated with anti-CAR T-cell therapy containing 4-1BB and CD28 co-stimulatory domains were compared by establishing a parametric survival function. The overall remission rate (ORR), the proportion of people with minimal residual disease (MRD)-negative complete remission (CR), the incidence of cytokine release syndrome (CRS), and the neurotoxicity across different co-stimulatory domains was assessed using a random-effects model. The correlation between the ORR, MRD-negative CR, PFS, and OS was tested. The results showed that the median OS of anti-CAR T-cell treatment containing 4-1BB and CD28 co-stimulatory domains was 15.0 months (95% CI: 11.0–20.0) and 8.5 months (95% CI: 5.0–14.0), and the median PFS was 7.0 months (95% CI: 4.0–11.5) and 3.0 months (95% CI: 1.5–7.0), respectively. Anti-CD19 CAR T-cells in the 4-1BB co-stimulatory domain showed superior benefits in patients who achieved ORR. The incidence of neurotoxicity was significantly higher in the CD28 co-stimulatory domain of anti-CD19 CAR T-cells than in the 4-1BB co-stimulatory domain. In addition, the ORR and MRD-negative CR were strongly correlated with OS and PFS, and PFS and OS were strongly correlated. The 4-1BB co-stimulatory domain suggested a better benefit–risk ratio than the CD28 co-stimulatory domain in B-ALL.

BackgroundAlthough deep learning systems (DLSs) have been developed to diagnose urine cytology, more evidence is required to prove if such systems can predict histopathology results as well.MethodsWe retrospectively retrieved urine cytology slides and matched histological results. High-power field panel images were annotated by a certified urological pathologist. A deep learning system was designed with a ResNet101 Faster R-CNN (faster region-based convolutional neural network). It was firstly built to spot cancer cells. Then, it was directly used to predict the likelihood of the presence of tissue malignancy.ResultsWe retrieved 441 positive cases and 395 negative cases. The development involved 387 positive cases, accounting for 2,668 labeled cells, to train the DLS to spot cancer cells. The DLS was then used to predict corresponding histopathology results. In an internal test set of 85 cases, the area under the curve (AUC) was 0.90 (95%CI 0.84–0.96), and the kappa score was 0.68 (95%CI 0.52–0.84), indicating substantial agreement. The F1 score was 0.56, sensitivity was 71% (95%CI 52%–85%), and specificity was 94% (95%CI 84%–98%). In an extra test set of 333 cases, the DLS achieved 0.25 false-positive cells per image. The AUC was 0.93 (95%CI 0.90–0.95), and the kappa score was 0.58 (95%CI 0.46–0.70) indicating moderate agreement. The F1 score was 0.66, sensitivity was 67% (95%CI 54%–78%), and specificity was 92% (95%CI 88%–95%).ConclusionsThe deep learning system could predict if there was malignancy using cytocentrifuged urine cytology images. The process was explainable since the prediction of malignancy was directly based on the abnormal cells selected by the model and can be verified by examining those candidate abnormal cells in each image. Thus, this DLS was not just a tool for pathologists in cytology diagnosis. It simultaneously provided novel histopathologic insights for urologists.

After more than three decades of implementation, China’s one-child policy has generated a large number of only children. Although extensive research has documented the developmental outcomes of being an only child, research on the parent–child relational quality of the only child is somewhat limited. Using China Education Panel Survey (2014), this study examined whether the only child status was associated with parent–child relationships among Chinese junior high school students. It further explored whether children’s gender moderated the association between the only child status and parent–child relationships. Two-level ordered logit models suggested that only children were more likely to report a close relationship with their mothers and fathers compared to children from multiple-child families (including two-child families). Taking birth order into consideration, we found that, only children were more likely to have close parent–child relationships than firstborns, whereas no significant differences were found between only children and lastborns. Interaction analyses further suggested that the only child advantages were gender-specific: the positive effects of the only child status were stronger for daughters than for sons, that is, daughters benefited more from being only children. Our findings highlight the importance of considering children’s gender and birth order in exploring the only child effects in the Chinese context. Additional analyses about sibling-gender composition indicated female children were more likely to be disadvantaged with the presence of younger brothers, whereas male children benefited more from having older sisters. This reveals that the son preference culture is still deep-rooted in the Chinese multiple-child families.

The endometrial layer comprises luminal and glandular epithelia that both develop from the same simple layer of fetal uterine epithelium. Mechanisms of uterine epithelial progenitor self-renewal and differentiation are unclear. This study aims to systematically analyze the molecular and cellular mechanisms of uterine epithelial development by single-cell analysis. An integrated set of single-cell transcriptomic data of uterine epithelial progenitors and their differentiated progenies is provided. Additionally the unique molecular signatures of these cells, characterized by sequential upregulation of specific epigenetic and metabolic activities, and activation of unique signaling pathways and transcription factors, were also investigated. Finally a unique subpopulation of early progenitor, as well as differentiated luminal and glandular lineages, were identified. A complex cellular hierarchy of uterine epithelial development was thus delineated. Our study therefore systematically decoded molecular markers and a cellular program of uterine epithelial development that sheds light on uterine developmental biology.

Background: Diabetes mellitus is a growing global health issue nearly across the world. Diabetic patients who are prone to develop diabetes-related complications often exhibit progressive neuropathy (painless and sensory loss). It is usual for small wounds to progress to ulceration, which especially worsens with peripheral arterial disease and in the presence of anaerobic bacteria, culminating into gangrene. In our study, vaccarin (VAC), the main active monomer extracted from Chinese herb vaccariae semen, is proven to have a role in promoting diabetic chronic wound healing through a cytoprotective role under high glucose conditions. Materials and methods: We constructed a pressure ulcer on both VAC-treated and control mice based on a type 1 diabetes (T1DM) model. The wound healing index was evaluated by an experimental wound assessment tool (EWAT). We also determined the effect of VAC on the proliferation and cell migration of human microvascular endothelial cells (HMEC-1) by a cell counting kit (CCK-8), a scratch and transwell assay. Results: The results demonstrated that VAC could promote the proliferation and migration of high glucose-stimulated HMEC-1 cells, which depend on the activation of FOXP2/AGGF1. Activation of the angiogenic factor with G patch and FHA domains 1 (AGGF1) caused enhanced phosphorylation of serine/threonine kinase (Akt) and extracellular regulated protein kinases (Erk1/2). By silencing the expression of forkhead box p2 (FOXP2) protein by siRNA, both mRNA and protein expression of AGGF1 were downregulated, leading to a decreased proliferation and migration of HMEC-1 cells. In addition, a diabetic chronic wound model in vivo unveiled that VAC had a positive effect on chronic wound healing, which involved the activation of the above-mentioned pathways. Conclusions: In summary, our study found that VAC promoted chronic wound healing in T1DM mice by activating the FOXP2/AGGF1 pathway, indicating that VAC may be a promising candidate for the treatment of the chronic wounds of diabetic patients.

This study describes the chemical constituents of Albiziae Cortex and their ability to ameliorate steatosis and promote proliferation and anti-oxidation in vitro. Together, five known lignan glycosides, (7S,8R)-erythro-syringylglycerol-β−O-4′-sinapyl ether 9-O-β-D-glucopyranoside (1), (+)-lyoniresinol-9′-O-gluco-side (2), (−)-lyoniresinol-9′-O-glucoside (3), picraquassioside C (4), and icariside E5 (5), were isolated from the Albiziae Cortex. Their structures were elucidated by extensive NMR and high-resolution mass spectrometry analysis and compared with reported data. Oil Red O staining results revealed that compounds 1, 2, and 3 attenuated lipid accumulation and lipid metabolic disorders in FFAs (oleate/palmitate, 2:1 ratio, 0.3 mM)-exposed HepG2 cells. The Cell Counting Kit 8 (CCK-8) assay results revealed that compounds 1 and 5 can significantly promote human umbilical vein endothelial cell (HUVEC) proliferation; meanwhile, these compounds did not exhibit significant cytotoxicity against HUVECs. In addition, 2′,7′-dichlorofluorescein diacetate (DCFH-DA) staining results revealed that high glucose (HG)-induced reactive oxygen species (ROS) production was abolished by compounds 1, 2, and 3. This is the first report of the isolation of lignan skeletons from the genus Albizzia julibrissin with the ability to ameliorate steatosis and promote proliferation and anti-oxidation activities.

Cardiovascular complications are a major leading cause of mortality in patients suffering from type 2 diabetes mellitus (T2DM). Vascular endothelial dysfunction is a core pathophysiological event in the early stage of T2DM and eventually leads to cardiovascular disease. Vaccarin (VAC), an active flavonoid glycoside extracted from vaccariae semen, exhibits extensive biological activities including vascular endothelial cell protection effects. However, little is known about whether VAC is involved in endothelial dysfunction regulation under high glucose (HG) or hyperglycemia conditions. Here, in an in vivo study, we found that VAC attenuated increased blood glucose, increased glucose and insulin tolerance, relieved the disorder of lipid metabolism and oxidative stress, and improved endothelium-dependent vasorelaxation in STZ/HFD-induced T2DM mice. Furthermore, in cultured human microvascular endothelial cell-1 (HMEC-1) cells, we showed that pretreatment with VAC dose-dependently increased nitric oxide (NO) generation and the phosphorylation of eNOS under HG conditions. Mechanistically, VAC-treated HMEC-1 cells exhibited higher AMPK phosphorylation, which was attenuated by HG stimulation. Moreover, HG-triggered miRNA-34a upregulation was inhibited by VAC pretreatment, which is in accordance with pretreatment with AMPK inhibitor compound C (CC). In addition, both reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine (NAC) and VAC abolished HG-evoked dephosphorylation of AMPK and eNOS, increased miRNA-34a expression, and decreased NO production. These results suggest that VAC impedes HG-induced endothelial dysfunction via inhibition of the ROS/AMPK/miRNA-34a/eNOS signaling cascade.

As a new type of micro-electro-mechanical systems (MEMS) inertial sensor, the Quartz Vibrating Beam Accelerometer (QVBA) is widely used in intelligent sweeping robots, small aircraft, navigation systems, etc. For these applications, correcting and compensating the attitude angle with the result of acceleration plays an important role to improve the measurement accuracy. The synchronization error between the measurement of the accelerometer and gyroscope attitude angle has an adverse impact on the accuracy of the attitude angle. In this paper, a synchronous acquisition scheme of the accelerometer and gyroscope attitude angle in a strapdown inertial navigation system (SINS) is proposed. At the same time, to improve the sampling accuracy and the conversion speed of QVBA, an improved equal-precision frequency measuring method is also implemented in this paper. The hardware float point unit (FPU) is used to accelerate the calculation of the frequency measurement value. The long-term cumulative error of the frequency measurement value is less than 10 − 4 . The calculation process time from sampling to attitude angle compensation calculation is reduced by 40.8%. This work has played a very good role in improving the measurement accuracy and speed of the SINS.

Transcriptional/translational feedback loops drive daily cycles of expression in clock genes and clock-controlled genes, which ultimately underlie many of the overt circadian rhythms manifested by organisms. Moreover, phosphorylation of clock proteins plays crucial roles in the temporal regulation of clock protein activity, stability and subcellular localization. dCLOCK (dCLK), the master transcription factor driving cyclical gene expression and the rate-limiting component in the Drosophila circadian clock, undergoes daily changes in phosphorylation. However, the physiological role of dCLK phosphorylation is not clear. Using a Drosophila tissue culture system, we identified multiple phosphorylation sites on dCLK. Expression of a mutated version of dCLK where all the mapped phospho-sites were switched to alanine (dCLK-15A) rescues the arrythmicity of Clk(out) flies, yet with an approximately 1.5 hr shorter period. The dCLK-15A protein attains substantially higher levels in flies compared to the control situation, and also appears to have enhanced transcriptional activity, consistent with the observed higher peak values and amplitudes in the mRNA rhythms of several core clock genes. Surprisingly, the clock-controlled daily activity rhythm in dCLK-15A expressing flies does not synchronize properly to daily temperature cycles, although there is no defect in aligning to light/dark cycles. Our findings suggest a novel role for clock protein phosphorylation in governing the relative strengths of entraining modalities by adjusting the dynamics of circadian gene expression.