Atmospheric pressure plasma preconditioning reduces oxygen and glucose deprivation induced human neuronal SH-SY5Y cells apoptosis by activating protective autophagy and ROS/AMPK/mTOR pathway.

Reactive oxygen species (ROS)/reactive nitrogen species (RNS) exert a "double edged" effect on the occurrence and development of ischemic stroke. We previously indicate that atmospheric pressure plasma (APP) shows a neuroprotective effect in vitro based on the ROS/RNS generations. However, the mechanism is still unknown. In this work, SH-SY5Y cells were treated with oxygen and glucose deprivation (OGD) injuries for stimulating the ischemic stroke pathological injury process. A helium APP was used for SH-SY5Y cell treatment for evaluating the neuroprotective impacts of APP preconditioning against OGD injuries with the optimized parameters. During the preconditioning, APP significantly raised the extracellular and intracellular ROS/RNS production. As a result, APP preconditioning increased SH-SY5Y cell autophagy by elevating LC3-II/LC3-I ratio and autophagosome formation. Meanwhile, APP preconditioning reduced cell apoptosis caused by OGD with the increased APP treatment time, which was abolished by pretreatment with autophagy inhibitor 3-methyladenine (3-MA). The ROS scavenger N-acetyl-L-cysteine (NAC) alone or combined with NO scavenger carboxy-PTIO abolished the APP preconditioning induced SH-SY5Y autophagy and the cytoprotection, whereas the NO scavenger alone did not. In addition, we observed the elevated phosphorylation of AMP-activated protein kinase (AMPK) and decreased phosphorylation of mammalian target of rapamycin (mTOR) in APP treated SH-SY5Y cells. This effect was attenuated by AMPK inhibitor Compound C (CC), the ROS scavenger NAC and autophagy inhibitor 3-MA. Furthermore, the cytoprotective effect of APP was preliminarily confirmed in the rats of middle cerebral artery occlusion (MCAO) model. Results showed that APP inhalation by rats during MCAO process could improve neurological functions, reduce cell apoptosis in brain tissues and decrease cerebral infarct volume. Our data suggested that ROS produced by APP preconditioning played a vital role in the neuroprotective effect of SH-SY5Y cells against OGD injuries by activating autophagy and ROS/AMPK/mTOR pathway.

Targeting LSD1 in cancer: Molecular elucidation and recent advances.

Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer.

Childhood intra- and extra-familial maltreatment and later-life trajectories of depressive symptoms: evidence from China.

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 (ß = 1.628, p < 0.001), and intrafamilial physical abuse (ß = 0.746, p < 0.001) and emotional neglect (ß = 0.880, p < 0.001) were associated with higher later-life depressive symptoms levels in the whole sample. Peer bullying differences in depressive symptoms widened with age for both men and women. Physical abuse differences in depressive symptoms remained stable over the life course among men but increased among women. Emotional neglect differences in depressive symptoms decreased with age among men, while it increased first and then decreased among women. CONCLUSIONS: Findings in this study suggest that childhood maltreatment is not only associated with later-life poorer mental health but contributes to increasing inequalities in mental health as people age, especially among peer-bullying victims and women.

Efficacy and safety of rituximab induction therapy and effect of rituximab maintenance for IgG4-related disease: a systematic review and meta-analysis.

BACKGROUND: Previous studies have reported that rituximab (RTX) therapy might be beneficial in reducing relapse rates in patients with IgG4-related disease (IgG4-RD). Therefore, we aimed to systematically assess the efficacy and safety of RTX induction treatment and the effect of RTX maintenance in patients with IgG4-RD. METHODS: The protocol was registered in the PROSPERO (CRD42023427352). PubMed, Embase, the Cochrane database, Scopus, and the Web of Science were interrogated to identify studies that evaluated the impact of RTX on prognosis in IgG4-RD. We explored the impact of various subgroups of factors on relapse outcomes and focused on the possible role of maintenance therapy in reducing relapse rates. The pooled incidence of adverse events of RTX therapy and the influencing factors have also been evaluated. RESULTS: Eighteen studies comprising 374 patients (mean age 56.0 ± 8.7 years; male 73.7 %) with a mean follow-up duration of 23.4 ± 16.3 months were included. The pooled estimate of the response rate, complete remission rate, overall relapse rate, adverse event rate, and serious adverse event rate of RTX induction therapy were 97.3 % (95 % CI, 94.7 %-99.1 %), 55.8 % (95 % CI, 39.6 %-71.3 %), 16.9 % (95 % CI, 8.7 %-27.1 %), 31.6 % (95 % CI, 16.7 %-48.9 %) and 3.9 % (95 % CI, 0.8 %-8.9 %), respectively. In subgroup analysis, the pooled relapse rate was significantly lower in studies with maintenance than without maintenance (2.8% vs 21.5 %, p < 0.01). Pooled Kaplan-Meier relapse curves also demonstrated that RTX maintenance therapy provided a better prognosis. CONCLUSIONS: RTX induction therapy appears to have satisfactory efficacy in the induction of remission in IgG4-RD. In addition, prophylactic RTX maintenance therapy after induction may be beneficial in preventing relapse of IgG4-RD.

Structural basis of the recognition of adeno-associated virus by the neurological system-related receptor carbonic anhydrase IV.

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.

Prognostic model for predicting the survival benefit of adjuvant chemotherapy for elderly patients with stage II colon cancer: a population-based study.

OBJECTIVES: Adjuvant chemotherapy benefits in elderly patients with stage II colon cancer (CC) remain controversial. We aimed to construct a nomogram to estimate the chemotherapy survival benefits in elderly patients. METHODS: The training and testing cohort were patients with stage II CC older than 70 years from the Surveillance, Epidemiology, and End Results (SEER) database, while the external validation cohort included patients from the National Cancer Center (NCC). Cox proportional hazard models were used to determine the covariates associated with overall survival (OS). Using the risk factors identified by Cox proportional hazards regression, a nomogram was developed to predict OS. Nomogram precision was assessed using receiver operating characteristic and calibration curves. RESULTS: The present study recruited 42 097 and 504 patients from the SEER database and NCC, respectively. The OS of patients who underwent surgery plus adjuvant chemotherapy was considerably longer than patients who underwent surgery alone. The nomogram included variables related to OS, including age, year of diagnosis, sex, AJCC T stage, tumor location, tumor size, harvested lymph nodes, and chemotherapy. According to the nomogram score, the elderly patients were separated into high- and low-risk groups, with high-risk group nomogram scores being greater than the median value, and vice versa. Patients in the high-risk group witnessed worse prognosis and were more likely to benefit from postoperative chemotherapy. CONCLUSION: This nomogram can be regarded as a useful clinical tool for assessing the potential adjuvant chemotherapy benefits and for predicting survival in elderly patients with stage II CC.

Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data.

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.

Optimization of secukinumab dose regimens in patients with moderate-to-severe plaque psoriasis via exposure-response modeling.

BACKGROUND: Further dose optimization is required for patients with moderate-to-severe plaque psoriasis who do not benefit from the approved secukinumab dose regimen. This study aimed to develop an exposure-response model for secukinumab to recommend dose regimens for patients of different body weights. METHODS: We searched the PubMed and Cochrane Library databases for randomized controlled trials using PASI 75 and PASI 90 response rates as primary outcomes. A model-based meta-analysis was developed to quantitatively analyze the distribution of six secukinumab dose regimens in patients weighing 50-120 kg. RESULTS: Sixteen trials involving 6,197 subjects were included in the analysis. The established model accurately described the time-course characteristics of PASI 75 and PASI 90 response rates over 52 weeks. Simulations indicated that maintenance doses could be reduced to 150 mg every 4 weeks and to 150 mg every 3 weeks for patients weighing 50 and 60 kg, respectively. In contrast, maintenance doses of 300 mg every 3 weeks should be selected for patients weighing 120 kg. Patients weighing 70-110 kg remained on approved maintenance doses of 300 mg every 4 weeks. CONCLUSIONS: Based on patient body weights, the exposure-response model recommends efficacious and economical dose regimens for patients with moderate-to-severe plaque psoriasis.

Provenance variation of root C, N, P, and K stoichiometric characteristics under different diameter classes of Larix gmelinii.

For exploring the difference of root stoichiometric characteristics among diameter classes and provenances, we examined the contents and stoichiometric ratios of carbon (C), nitrogen (N), phosphorus (P), and potassium (K) in three diameter classes of roots (0-1, 1-2 and 2-5 mm, respectively) of 39-year-old Larix gmelinii grown in a common garden. The results showed that root element contents and their stoichiometric ratios had significant difference among three diameter classes of roots. C content, C:N, C:P, C:K were the lowest, and N, P, K contents, N:P, and N:K were the highest in 0-1 mm diameter class roots. Compared with the 1-2 and 2-5 mm diameter class roots, 0-1 mm diameter class roots had different seasonal dynamics, which might be caused by the fact that 0-1 mm diameter class roots are absorptive roots and the other diameter class roots are transport roots. There was no provenance difference in C content among all diameter class roots, while significant provenance differences were found in N, K contents, C:N, and C:K in 0-1 mm diameter class roots, and great provenance differences for in P content, C:P, N:P, and N:K in 0-1 and 1-2 mm diameter class roots. N content, K content, C:P, N:P, and N:K in 0-1 mm diameter class roots had positive correlation with the aridity index of seed-source sites, while the P content, C:N and C:K had negative correlations. The stoichiometric characteristics were related with the diameter (or function) of roots, and had significant provenance differences in 0-1 mm (absorptive root) and 1-2 mm diameter class roots, which might be attributed to their genotypic adaptation to the environment of seed-source sites.

Survey-based investigation into the current use of paediatric medicines and administration devices in China.

The accurate, rapid and convenient administration of medicines to children is not possible without the use of appropriate administration devices. However, due to the unique nature of this patient population, inappropriate paediatric medication administration has been widely observed worldwide. According to previous surveys carried out in other countries including the UK and Japan, there has been a wide variation in the handling of paediatric devices among children. To date, little is known about the current situation in China where the variety of available paediatric administration devices is more limited than in Europe and the UK. The aim of this study was therefore to conduct a China-wide survey to gain a better understanding of the perspectives of children and their caregivers on paediatric medicines and devices. This study was conducted throughout China with 215 children as well as 749 caregivers of paediatric year groups from 1 to less than 18 years old. The majority of participants (83%) took oral dosage forms where granules, syrup and tablets were ranked as the Top 3 commonly used oral dosage forms. The most commonly used devices, i.e., measuring cups (47.3%) and household spoons (41.1%) were both well accepted by the vast majority of children. More instruction and demonstration by the healthcare professionals were provided to inhalation devices users with the nebuliser and facemask being the most commonly used. In particular, the role of pharmacists in China is expected to be better defined, which may in turn help with the education provided to paediatric users in operating medical devices. The data collected varied considerably with the age of children but not statistically significantly with the region in which the survey was conducted.

Parental marriage and the non-cognitive abilities of infants and toddlers: Survey findings from China Family Panel Studies.

Early childhood is a critical period for developing children's abilities. Non-cognitive abilities are comparable to or even stronger than cognitive abilities in predicting many socioeconomic outcomes. Usually, most scholars take personality as the core indicator of non-cognitive abilities. While temperament is also an important component of children's non-cognitive abilities, it was often ignored in previous studies. Based on the panel data from the 2018 and 2020 China Family Panel Studies (CFPS), this study investigates the effects of parental marital satisfaction on the non-cognitive development of children aged one to three; meanwhile, the heterogeneous effects and mechanisms were also examined. The results show that young children exhibit more negative emotions when their parents reported dissatisfaction with their marriages. Parental depression was an important mechanism of parental marital satisfaction affecting children's non-cognitive development, while the frequency of parent-child interaction was not. The effects of marital dissatisfaction on non-cognitive abilities were heterogeneous across child age and gender, as well as parental genders and education levels. The findings shed some light on the early interventions and offer important reference values for public policies aimed at improving family welfare and children's non-cognitive development.

An H2 O-Initiated Crosslinking Strategy for Ultrafine-Nanoclusters-Reinforced High-Toughness Polymer-In-Plasticizer Solid Electrolyte.

Incorporating plasticizers is an effective way to facilitate conduction of ions in solid polymer electrolytes (SPEs). However, this conductivity enhancement often comes at the cost of reduced mechanical properties, which can make the electrolyte membrane more difficult to process and increase safety hazards. Here, a novel crosslinking strategy, wherein metal-alkoxy-terminated polymers can be crosslinked by precisely controlling the content of H2 O as an initiator, is proposed. As a proof-of-concept, trimethylaluminum (TMA)-functionalized poly(ethylene oxide) (PEO) is used to demonstrate that ultrafine Al-O nanoclusters can serve as nodes to crosslink PEO chains with a wide range of molecular weights from 10 000 to 8 000 000 g mol-1 . The crosslinked polymer network can incorporate a high concentration of plasticizers, with a total weight percentage over 75%, while still maintaining excellent stretchability (4640%) and toughness (3.87 × 104  kJ m-3 ). The resulting electrolyte demonstrates high ionic conductivity (1.41 mS cm-1 ), low interfacial resistance toward Li metal (48.1 Ω cm2 ), and a wide electrochemical window (>4.8 V vs Li+ /Li) at 30 °C. Furthermore, the LiFePO4 /Li battery shows stable cycle performance with a capacity retention of 98.6% (146.3 mAh g-1 ) over 1000 cycles at 1C (1C = 170 mAh g-1 ) at 30 °C.

Difference in Efficacy and Safety of Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy Containing 4-1BB and CD28 Co-Stimulatory Domains for B-Cell Acute Lymphoblastic Leukemia.

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.

Somatic and germline aberrations in homologous recombination repair genes in Chinese prostate cancer patients.

Simple summary: Somatic 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. Background: Homologous 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. Methods: We 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. Results: TP53, 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 <60 years old, PSA at diagnosis, and Gleason scores at biopsy were clinical factors associated with positive germline aberrations in BRCA2/ATM. Conclusions: Our results showed a distinct genomic profile in homologous recombination repair genes for patients with prostate cancer across all clinical states from north China. Clinicians may consider to expand the prostate cancer patients receiving genetic tests to include more individuals due to the weak guiding role by the clinical factors currently available.

Visualization of porosity and pore size gradients in electrospun scaffolds using laser metrology.

We applied a recently developed method, laser metrology, to characterize the influence of collector rotation on porosity gradients of electrospun polycaprolactone (PCL) widely investigated for use in tissue engineering. The prior- and post-sintering dimensions of PCL scaffolds were compared to derive quantitative, spatially-resolved porosity 'maps' from net shrinkage. Deposited on a rotating mandrel (200 RPM), the central region of deposition reaches the highest porosity, ~92%, surrounded by approximately symmetrical decreases to ~89% at the edges. At 1100 RPM, a uniform porosity of ~88-89% is observed. At 2000 RPM, the lowest porosity, ~87%, is found in the middle of the deposition, rebounding to ~89% at the edges. Using a statistical model of random fiber network, we demonstrated that these relatively small changes in porosity values produce disproportionately large variations in pore size. The model predicts an exponential dependence of pore size on porosity when the scaffold is highly porous (e.g., >80%) and, accordingly, the observed porosity variation is associated with dramatic changes in pore size and ability to accommodate cell infiltration. Within the thickest regions most likely to 'bottleneck' cell infiltration, pore size decreases from ~37 to 23 µm (38%) when rotational speeds increased from 200 to 2000 RPM. This trend is corroborated by electron microscopy. While faster rotational speeds ultimately overcome axial alignment induced by cylindrical electric fields associated with the collector geometry, it does so at the cost of eliminating larger pores favoring cell infiltration. This puts the bio-mechanical advantages associated with collector rotation-induced alignment at odds with biological goals. A more significant decrease in pore size from ~54 to ~19 µm (65%), well below the minimum associated with cellular infiltration, is observed from enhanced collector biases. Finally, similar predictions show that sacrificial fiber approaches are inefficient in achieving cell-permissive pore sizes.

Parental burnout and resilience intervention among Chinese parents during the COVID-19 pandemic.

Introduction: Parental burnout is a mental state that combines long-term stress and depression with an overwhelming feeling of parental pressure. Methods: In 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. Results: The 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. Discussion: These 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.

Bi-potential hPSC-derived Müllerian duct-like cells for full-thickness and functional endometrium regeneration.

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.

Scale bar of aging trajectories for screening personal rejuvenation treatments.

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.

A Deep Learning System to Predict the Histopathological Results From Urine Cytopathological Images.

Background: Although 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. Methods: We 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. Results: We 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%). Conclusions: The 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.

Free or fixed state of nHAP differentially regulates hBMSC morphology and osteogenesis through the valve role of ITGA7.

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.