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Hepatitis B virus (HBV) damages liver cells through abnormal immune responses. Mitochondrial metabolism is necessary for effector functions of white blood cells (WBCs). The aim was to investigate the altered counts and mitochondrial mass (MM) of WBCs by two novel indicators of mitochondrial mass, MM and percentage of low mitochondrial membrane potential, MMPlow%, due to chronic HBV infection. The counts of lymphocytes, neutrophils and monocytes in the HBV infection group were in decline, especially for lymphocyte (p = 0.034) and monocyte counts (p = 0.003). The degraded MM (p = 0.003) and MMPlow% (p = 0.002) of lymphocytes and MM (p = 0.005) of monocytes suggested mitochondrial dysfunction of WBCs. HBV DNA within WBCs showed an extensive effect on mitochondria metabolic potential of lymphocytes, neutrophils and monocytes indicated by MM; hepatitis B e antigen was associated with instant mitochondrial energy supply indicated by MMPlow% of neutrophils; hepatitis B surface antigen, antiviral therapy by nucleos(t)ide analogues and prolonged infection were also vital factors contributing to WBC alterations. Moreover, degraded neutrophils and monocytes could be used to monitor immune responses reflecting chronic liver fibrosis and inflammatory damage. In conclusion, MM combined with cell counts of WBCs could profoundly reflect WBC alterations for monitoring chronic HBV infection. Moreover, HBV DNA within WBCs may be a vital factor in injuring mitochondria metabolic potential. [ABSTRACT FROM AUTHOR]

We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11‐q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure‐free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti‐seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly. [ABSTRACT FROM AUTHOR]

Objective: Immune tolerance and evasion play a critical role in virus‐driven malignancies. However, the phenotype and clinical significance of programmed cell death 1 (PD‐1) and its ligands, PD‐L1 and PD‐L2, in aggressive acquired immunodeficiency syndrome (AIDS)‐related non‐Hodgkin lymphoma (AR‐NHL) remain poorly understood, particularly in the Epstein–Barr virus (EBV)‐positive subset. Methods: We used in situ hybridization with EBV‐encoded RNA (EBER) to assess the EBV status. We performed immunohistochemistry and flow cytometry analysis to evaluate components of the PD‐1/PD‐L1/L2 pathway in a multi‐institutional cohort of 58 patients with AR‐NHL and compared EBV‐positive and EBV‐negative cases. Results: The prevalence of EBV+ in AR‐NHL was 56.9% and was associated with a marked increase in the expression of PD‐1/PD‐L1/PD‐L2 in malignant cells. Patients with AR‐NHLs who tested positive for both EBER and PD‐1 exhibited lower survival rates compared to those negative for these markers (47.4% vs. 93.8%, p = 0.004). Similarly, patients positive for both EBER and PD‐L1 also demonstrated poorer survival (56.5% vs. 93.8%, p = 0.043). Importantly, PD‐1 tissue‐expression demonstrated independent prognostic significance for overall survival in multivariate analysis and was correlated to elevated levels of LDH (r = 0.313, p = 0.031), increased PD‐1+ Tregs (p = 0.006), and robust expression of EBER (r = 0.541, p < 0.001) and PD‐L1 (r = 0.354, p = 0.014) expression. Conclusions: These data emphasize the importance of PD‐1‐mediated immune evasion in the complex landscape of immune oncology in AR‐NHL co‐infected with EBV, and contribute to the diagnostic classification and possible definition of immunotherapeutic strategies for this unique subgroup. [ABSTRACT FROM AUTHOR]

ChinaMu is the largest sequence‐indexed Mutator (Mu) transposon insertional library in maize (Zea mays). In this study, we made significant improvements to the size and quality of the ChinaMu library. We developed a new Mu‐tag isolation method Mu‐Tn5‐seq (MuT‐seq). Compared to the previous method used by ChinaMu, MuT‐seq recovered 1/3 more germinal insertions, while requiring only about 1/14 of the sequencing volume and 1/5 of the experimental time. Using MuT‐seq, we identified 113,879 germinal insertions from 3,168 Mu‐active F1 families. We also assembled a high‐quality genome for the Mu‐active line Mu‐starter, which harbors the initial active MuDR element and was used as the pollen donor for the mutation population. Using the Mu‐starter genome, we recovered 33,662 (15.6%) additional germinal insertions in 3,244 (7.4%) genes in the Mu‐starter line. The Mu‐starter genome also improved the assignment of 117,689 (54.5%) germinal insertions. The newly upgraded ChinaMu dataset currently contains 215,889 high‐quality germinal insertions. These insertions cover 32,224 pan‐genes in the Mu‐starter and B73Ref5 genomes, including 23,006 (80.4%) core genes shared by the two genomes. As a test model, we investigated Mu insertions in the pentatricopeptide repeat (PPR) superfamily, discovering insertions for 92% (449/487) of PPR genes in ChinaMu, demonstrating the usefulness of ChinaMu as a functional genomics resource for maize. [ABSTRACT FROM AUTHOR]

The decline in female fertility as age advances is intricately linked to the diminished developmental potential of oocytes. Despite this challenge, the strategies available to enhance the quality of aged oocytes remain limited. Epigallocatechin‐3‐gallate (EGCG), characterised by its anti‐inflammatory, antioxidant and tissue protective properties, holds promise as a candidate for improving the quality of maternally aged oocytes. In this study, we explored the precise impact and underlying mechanisms of EGCG on aged oocytes. EGCG exhibited the capacity to enhance the quality of aged oocytes both in vitro and in vivo. Specifically, the application of EGCG in vitro resulted in noteworthy improvements, including an increased rate of first polar body extrusion, enhanced mitochondrial function, refined spindle morphology and a reduction in oxidative stress. These beneficial effects were further validated by the improved fertility observed among aged mice. In addition, our findings propose that EGCG might augment the expression of Arf6. This augmentation, in turn, contributes to the assembly of spindle‐associated F‐actin, which can contribute to mitigate the aneuploidy induced by the disruption of spindle F‐actin within aged oocytes. This work thus contributes not only to understanding the role of EGCG in bolstering oocyte health, but also underscores its potential as a therapeutic intervention to address fertility challenges associated with advanced age. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid carcinoma (ATC) is the most advanced and aggressive thyroid cancer, and poorly differentiated thyroid carcinoma (PDTC) lacks anaplastic histology but has lost architectural and cytologic differentiation. Only a few studies have focused on the genetic relationship between the two advanced carcinomas and coexisting differentiated thyroid carcinomas (DTCs). In the present study, we investigated clinicopathologic features and genetic profiles in 57 ATC and PDTC samples, among which 33 cases had concomitant DTC components or DTC history. We performed immunohistochemistry for BRAF V600E, p53, and PD‐L1 expression, Sanger sequencing for TERT promoter and RAS mutations, and fluorescence in situ hybridization for ALK and RET rearrangements. We found that ATCs and PDTCs shared similar gene alterations to their coexisting DTCs, and most DTCs were aggressive subtypes harboring frequent TERT promoter mutations. A significantly higher proportion of ATCs expressed p53 and PD‐L1, and a lower proportion expressed PAX‐8 and TTF‐1, than the coexisting DTCs. Our findings provide more reliable evidence that ATCs and PDTCs are derived from DTCs. [ABSTRACT FROM AUTHOR]

Venous leg ulcer (VLU) is the most severe manifestations of chronic venous disease, which has characterized by slow healing and high recurrence rates. This typically recalcitrant and recurring condition significantly impairs quality of life, prevention of VLU recurrence is essential for helping to reduce the huge burden of patients and health resources, the purpose of this scoping review is to analyse and determine the intervention measures for preventing recurrence of the current reported, to better inform healthcare professionals and patients. The PubMed, Embase, Web of Science, Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wan Fang Data and Chongqing VIP Information (CQVIP) were accessed up to June 17, 2023. This scoping review followed the five‐steps framework described by Arksey and O'Malley and the PRISMA extension was used to report the review. Eleven articles were included with a total of 1503 patients, and adopted the four effective measures: compression therapy, physical activity, health education, and self‐care. To conclude, the use of high pressure compression treatment for life, supplementary exercise therapy, and strengthen health education to promote self‐care are recommended strategies of VLU prevention and recurrence. In addition, the importance of multi‐disciplinary teams to participate in the care of VLU in crucial. [ABSTRACT FROM AUTHOR]

Development and regeneration in biological tissues are fundamentally affected by stem‐cell‐fate commitment. Bioelectricity is heterogeneous between different tissues and crucially regulates cell behaviors, including cell differentiation. However, the effects of heterogeneous bioelectricity on stem‐cell differentiation remain poorly understood. Herein, it is shown that providing stem cells with electrical stimulation matching the endogenous membrane potentials of cells derived from different tissues (osteogenic‐related: −55.05 ± 4.22 mV, neurogenic‐related: −84.8 ± 7.48 mV) can induce their osteogenic or neurogenic lineage commitment. Molecular dynamics simulations indicated that the osteogenic‐related surface potential favors the adsorption of fibronectin, while the neurogenic‐related surface potential enhances the adsorption of FGF‐2. These different protein adsorptions trigger either downstream Wnt or Erk signaling, which direct stem‐cell differentiation. Surface‐potential‐mediated lineage‐specification of stem cells using bioelectrical intensity has enormous potential application value in tissue regenerative therapy. [ABSTRACT FROM AUTHOR]

For bone defect repair, it is critical to utilize biomaterials with pro‐angiogenic properties to enhance osteogenesis. Hydroxyapatite (HA)‐based materials widely used in clinical applications have shown much potential for bone repair. However, their predominant calcium phosphate (CaP) composition and poor biodegradability limit their angiogenic potential and hence osteogenic efficiency of HA‐based materials. Here, a magnesium ion‐doped calcium silicate/HA composite microscaffold (Mg‐CS/HA) is fabricated to enhance angiogenesis and osteogenic efficiency for bone repair. Incorporation of CS improved the biodegradability of the Mg‐CS/HA microscaffold, which could simultaneously release Si and Mg bioactive ions during the early stage of implantation, synergistically enhancing angiogenesis and osteogenic efficiency. In co‐culture systems, the synergistic effects of Si and Mg ions promote the "osteogenesis‐angiogenesis coupling effect." In vivo, the Mg‐CS/HA microscaffold could significantly promote reconstruction of the vascular network and bone regeneration. This study thus provides a new strategy for coordinated release of bioactive ions to achieve synergistic effects on vascularized bone regeneration by HA‐based bone implant materials. [ABSTRACT FROM AUTHOR]

Background: Optimization of risk stratification is important for facilitating prognoses and therapeutic decisions regarding diffuse large B‐cell lymphoma (DLBCL). However, a simple and applicable prognostic tool is lacking for individuals with human immunodeficiency virus (HIV)‐related DLBCL in the era of combined antiretroviral therapy (cART). Methods: This retrospective multicenter observational study included 147 HIV‐related DLBCL patients with histologically confirmed DLBCL from 2013 to 2020. The total group was divided into training (n = 78) and validation (n = 69) cohorts to derive the best prognostic score. Clinicopathological and characteristic biomarkers correlated with clinical outcomes were analyzed. Results: Age, Ann Arbor stage, lactate dehydrogenase (LDH) ratio, bulky disease, and red blood cell distribution width (RDW) ratio retained robust independent correlations with overall survival (OS) in multivariate analysis. A new and practical prognostic model was generated and externally validated, classifying patients into three categories with significantly different survival rates. Moreover, the new index outperformed the International Prognostic Index (IPI) score (area under the curve values of 0.94 vs. 0.81 in the training cohort and 0.85 vs. 0.74 in the validation cohort, C‐indices of 0.80 vs. 0.70 in the training cohort and 0.74 vs. 0.70 in the validation cohort, and integrated discrimination improvement values of 0.203 in the training cohort and 0.175 in the validation cohort) and was better at defining intermediate‐ and high‐risk groups. The calibration curves performed satisfactorily for predicting 3‐year OS in the training and validation cohorts. Conclusions: We developed and validated a simple and feasible prognostic model for patients with HIV‐related DLBCL that had more discriminative and predictive accuracy than the IPI score for risk stratification and individualized treatment in the cART era. [ABSTRACT FROM AUTHOR]

Total fertilization failure (TFF), which refers to fertilization failure in all mature oocytes, accounting for 5%–10% of in vitro fertilization (IVF) cycles and 1%–3% of intracytoplasmic sperm injection (ICSI) cycles in human. In this study, we recruited three unrelated primary infertile men with repeated cycles of TFF and performed whole‐exome sequencing to identify the potential pathogenic variants. We identified homozygous or compound‐heterozygous variants of paternal‐effect genes ACTL7A and PLCZ1 that followed a Mendelian recessive inheritance pattern. Novel homozygous nonsense variant in ACTL7A [c.C146G: p.S49*] was identified in case 1, who came from a consanguineous family. Ultrastructural observation of ACTL7A‐mutated spermatozoa by transmission electron microscopy (TEM) indicated that apparent increased thickness of perinuclear matrix and the acrosome was detached from the nuclear envelop. Besides, two novel compound‐heterozygous variants in PLCZ1 were identified in case 2 [c.1174+3A>C:p.?; c.A1274G:p.N425S] and case 3 [c.136‐1G>C:p.?; c.G1358A:p.G453D]. Mutated spermatozoa from case 2 with reduced expression of PLCZ1 showed apparent acrosome detachment by TEM analysis. And ICSI with assisted oocyte activation (ICSI‐AOA) treatment can partly rescue the TFF. Taken together, our findings revealed that novel biallelic variants in the paternal‐effect genes ACTL7A and PLCZ1 were associated with human TFF, which expanding the spectrum of genetic causes and facilitating the genetic diagnosis of male infertility with TFF. [ABSTRACT FROM AUTHOR]

In this paper, two novel algorithms to find the Nash equilibrium solution of the non‐zero‐sum games for continuous‐time input‐affine nonlinear systems are presented. Based on integral reinforcement learning method, the integral‐exploration‐coupled Hamilton‐Jacobi (HJ) equations are derived, which does not contain any information of the system dynamics. Then, based on neural networks approximation, two different adaptive tuning law of weights are given to estimate the approximate solution of the coupled HJ equations. Both two algorithms can estimate the value function and the policy without knowing or identifying the system dynamics. The closed‐loop system stability and the convergence of weights are guaranteed based on Lyapunov analysis. Finally, the simulation results of a two‐player non‐zero‐sum game demonstrate the effectiveness of our algorithms. [ABSTRACT FROM AUTHOR]

Objectives: A classification system for endocervical adenocarcinoma (ECA) based on high‐risk human papillomavirus (HPV) status has been established; however, the immunohistochemical markers distinguishing HPV‐independent and HPV‐associated ECAs have not been fully described. Here, we aimed to characterize ECA immunopathological features. Methods: We evaluated the immunohistochemical profile of CLDN18, CDX2, PAX8, p16, p53, and CEA in 60 ECAs comprising 10 HPV‐independent ECAs and 50 HPV‐associated ECAs. Both the membranous and nuclear expression levels of CLDN18 were analyzed. Results: Membranous CLDN18 (CLDN18 [M]) was found to be expressed in the mucinous epithelium of all HPV‐independent ECAs, including eight gastric‐type ECAs (G‐ECAs), one endometrioid ECA, and one clear cell ECA, but no nuclear CLDN18 (CLDN18 [N]) expression was detected in HPV‐independent ECAs. Among HPV‐associated ECAs, CLDN18 (M) expression levels in intestinal‐type (I‐ECAs) and usual‐type ECAs (U‐ECAs) were significantly different from those in invasive stratified mucin‐producing (iSMILE) carcinomas (p = 0.036). Positive CLDN18 (M) staining was present in 55.6% (5/9) of intestinal‐type and 39.4% (13/33) of usual‐type ECAs and was not present in iSMILE ECAs. Silva pattern C cancers expressed higher levels of CLDN18 (M) than Silva pattern A and B cancers (p = 0.004), whereas the CLDN18 (N) expression levels in cancers showing Silva pattern A were significantly higher than those in cancers exhibiting Silva patterns B and C (p < 0.001). Conclusion: Membranous CLDN18 is expressed in ECAs and is particularly frequently expressed in HPV‐independent ECAs, and membranous CLDN18 expression has potential as a therapeutic target. Nuclear staining of CLDN18 is a new immunohistochemical marker for diagnosing Silva pattern A HPV‐associated ECAs and is associated with a good prognosis. Further studies should investigate the therapeutic and prognostic significance of membranous and nuclear CLDN18 expression and develop a related test that can be implemented in the clinical evaluation of ECAs. [ABSTRACT FROM AUTHOR]

Laser energy is commonly used in tissue ablation, wound suturing, and other precise manipulations during surgery. However, currently available laser scanners require further improvements in terms of miniaturization, driving voltage, and stability to steer the laser beam accurately within a constrained environment. Herein, the development of a liquid‐driven laser scanner installed on the end effector of a continuum endoscope to perform fast and reliable laser steering is proposed. The developed laser scanner is 7 mm in diameter and 7 mm in length, and it is actuated with a voltage lower than 15 V due to the liquid‐infused membrane. The miniature size and low driving voltage of the proposed laser scanner facilitate safe laser‐assisted surgery in confined spaces. A theoretical model is established to predict laser spot position quantitatively, and laser steering ability is also tested experimentally. The fiber‐delivered laser beam can be steered for 21.2° (±10.6°) with a standard deviation of 0.3° in 1000 cycles, demonstrating excellent stability. A laser steering speed of up to 27.3 mm s−1 and a reflection loss of less than 3.1% are achieved. [ABSTRACT FROM AUTHOR]

Knowledge of the transcription factor binding landscape (TFBL) is necessary to analyze gene regulatory networks for important agronomic traits. However, a low‐cost and high‐throughput in vivo chromatin profiling method is still lacking in plants. Here, we developed a transient and simplified cleavage under targets and tagmentation (tsCUT&Tag) that combines transient expression of transcription factor proteins in protoplasts with a simplified CUT&Tag without nucleus extraction. Our tsCUT&Tag method provided higher data quality and signal resolution with lower sequencing depth compared with traditional ChIP‐seq. Furthermore, we developed a strategy combining tsCUT&Tag with machine learning, which has great potential for profiling the TFBL across plant development. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to explore the association between the IRAK4 polymorphism rs4251545 and the severity of enterovirus 71 (EV71) infection in Chinese children. Methods: We analyzed the IRAK4 polymorphism rs4251545 in 617 EV71‐infected patients and 410 controls using the improved multiplex ligation detection reaction. IRAK4 mRNA expression was tested by qRT‐PCR. Serum concentrations of IL‐6 and NF‐κB were detected using ELISA. Results: The frequencies of the GA + AA genotype and A allele in the mild EV71 infection group and in the severe EV71 infection group were significantly higher than those in the normal control group. The frequency of the GA + AA genotype and A allele in severely infected EV71 patients was markedly higher than that in mildly infected EV71 patients. IRAK4 mRNA expression in mildly infected EV71 patients and severely infected patients was significantly higher than that in the control group. IRAK4 mRNA expression in GA + AA genotypes in both mild and severe EV71 infection groups was significantly higher than that in patients with the GG genotype. IL‐6 concentration and the ratio of IL‐6/NF‐κB in severe EV71 cases were significantly lower in patients with the GA + AA genotype than in those with the GG genotype. The ratio of IL‐6/NF‐κB was distinctly higher in severely infected EV71 patients than in mildly infected and control subjects. Conclusions: The IRAK4 polymorphism rs4251545 was associated with the susceptibility and severity of EV71 infection. The A allele is a susceptible factor in the development of severe EV71 infection in Chinese children. [ABSTRACT FROM AUTHOR]

Objective: Neuroendocrine cervical cancer (NECC) is a rare cervical cancer with high aggressivity that causes poor prognosis even in the early stage. Given other neuroendocrine carcinomas and other types of cervical cancer have been proved to have expression of programmed cell death protein 1 ligand 1(PD‐L1) and poly ADP‐ribose polymerase‐1(PARP1), we would measure and analyze these proteins in this invasive cancer. The purpose of this study is to investigate the application value of PD‐1/PD‐L1 and PARP1 inhibitors in NECC. Methods: The NECC cases in our center with formalin‐fixed paraffin‐embedded tissue blocks were collected, and immunohistochemical (IHC) staining of PD‐L1, PARP1, Mismatch repair proteins (MMRs), and P53 was performed. Chi‐square test was used to analyze associations between various protein expressions. We analyzed the efficacy of immunotherapy in a recent patient with secondary recurrence after two courses of chemotherapy. Results: After rigorous screening, 20 cases were finally included. Three cases did not undergo surgical treatment because of their advanced stage. Twelve (60%) developed distant metastases or relapsed within five years, and most of them within two years. The positive rate of PD‐L1 and PARP1 were 70% and 75% respectively. Among all the cases, microsatellite instability (MSI) was seen in six cases (30%) and abnormal p53 expression was in 15 patients (75%). PD‐L1 was associated with PARP1 expression in the MSI subgroup. The patient treated with chemotherapy + VEGF inhibitor (VEGFi) + programmed cell death protein 1(PD‐1) inhibitor had an excellent improvement in clinical symptoms, tumor markers, and mass size. Conclusion: The IHC results of PD‐L1, PARP1, and MMRs suggested that NECC was the target of immunotargeted therapy. Our case confirmed that immune checkpoint therapy was effective in patients with PD‐L1 positive and MMRs loss. Considering the clinical practicability, more cases should be collected, and effective biomarkers still need to be further searched. [ABSTRACT FROM AUTHOR]

Introduction: Frozen embryo transfer is associated with a higher rate of live birth and a lower risk for ovarian hyperstimulation syndrome in women with polycystic ovary syndrome (PCOS) compared with fresh embryo transfer. The aim of this study is to assess the optimal endometrial preparation protocol for women with PCOS undergoing frozen embryo transfer. Material and methods: We conducted a historical cohort analysis of 1720 women with PCOS who underwent the "freeze‐all" strategy between August 2014 and August 2017 because of their high risk for ovarian hyperstimulation syndrome. Three endometrial preparation protocols were used: natural cycle (NC; n = 191), which relies on the dominant follicle to secrete estrogen that then promotes endometrial growth; ovarian stimulation (OS; n = 96), which induces follicle growth using low doses of human menopausal gonadotropin; and hormone replacement (HRT; n = 1433), which uses exogenous estradiol to promote endometrial growth. The primary outcome was live birth. Results: For women who received a single embryo transfer, the live birth rates for the NC, OS, and HRT groups were 62.4%, 65.0%, and 52.2%, respectively. The live birth rate in the HRT group was significantly lower than that seen in the OS and NC groups (P =.009). The clinical pregnancy rates of the three groups were 72.3%, 73.8%, and 64.9%, respectively; this difference did not reach statistical significance (P =.071). Conclusions: The rate of live birth with the NC and OS regimens was higher than with the HRT protocol in women with PCOS who undergo single‐blastocyst frozen embryo transfer. [ABSTRACT FROM AUTHOR]

Variants of tubulin beta 8 class VIII (TUBB8) have been shown to be associated with female infertility characterized by oocyte or embryonic defects. To further investigate the mutational spectrum of TUBB8 and the prevalence of variants, we performed Sanger sequencing of TUBB8 on a total of 115 infertile females who had undergone repeated in vitro fertilization cycles with oocyte or embryonic defects and 200 healthy controls. A total of 31 variants which were absent from the controls were identified in 36 unrelated individuals, accounting for a large proportion of this cohort (31.3%). All of the variants including heterozygous/homozygous missense variants and a heterozygous frameshift insertion variant were at conserved sites and predicted to be deleterious. Besides, these variants had diverse phenotypic effects, including not only oocyte maturation arrest, fertilization failure, and early embryonic arrest, but also multi‐pronuclei (MPN) formation, which is a new phenotype associated with TUBB8 variants. Overall, this study reveals a large number of variants of the TUBB8 gene in infertile females with oocyte or embryonic defects. Our results not only broaden the mutational and phenotypic spectra of TUBB8 variants, but also further confirm the critical role of TUBB8 in oocyte maturation, fertilization, and early embryonic development. [ABSTRACT FROM AUTHOR]

SUMMARY: The root cell wall is the first and primary target of aluminum (Al) toxicity. Monocots such as rice (Oryza sativa) can accumulate appreciable levels of hydroxycinnamic acids (HCAs) to modify and cross‐link hemicellulose and/or lignin of the cell wall. Nevertheless, it is unclear whether this HCA‐mediated modification of the cell wall is important for Al accumulation and resistance. We previously isolated and characterized a rice ral1 (resistance to aluminum 1) mutant that shows enhanced Al resistance. In this study, we cloned RAL1 and found that it encodes the 4‐coumarate:coenzyme A ligase 4CL4, an enzyme putatively involved in lignin biosynthesis. Mutation of RAL1/4CL4 reduces lignin content and increases the accumulation of its substrates 4‐coumaric acid (PA) and ferulic acid (FA). We demonstrate that altered lignin accumulation is not required for the enhanced Al resistance in ral1/4cl4 mutants. We found that the increased accumulation of PA and FA can reduce Al binding to hemicellulose and consequently enhance Al resistance in ral1/4cl4 mutants. Al stress is able to trigger PA and FA accumulation, which is likely caused by the repression of the expression of RAL1/4CL4 and its homologous genes. Our results thus reveal that Al‐induced PA and FA accumulation is actively and positively involved in Al resistance in rice through the modification of the cell wall and thereby the reduced Al binding to the cell wall. Significance Statement: Monocots such as rice (Oryza sativa) can accumulate appreciable levels of 4‐coumaric acid (PA) and ferulic acid (FA) to modify the cell wall, but it is unclear whether PA and FA play a role in the resistance to aluminum (Al) stress. We demonstrate that Al stress can trigger the accumulation of PA and FA, which in turn modify hemicellulose to reduce Al binding to the cell wall and consequently increase Al resistance in rice. [ABSTRACT FROM AUTHOR]

Objective: Mononuclear cell infiltration and type I interferon (IFN) system activation play an important role in primary Sjögren's syndrome (SS). We undertook this study to investigate the mechanism of poly(ADP‐ribose) polymerase family member 9 (PARP‐9) on mononuclear cell infiltration triggered by type I IFN. Methods: A proteomic study was conducted in peripheral blood mononuclear cells from patients with primary SS (n = 30) and healthy controls (n = 30) to determine differentially expressed proteins (DEPs) (P < 0.05; fold change >1.20). Labial salivary glands (LSGs) were isolated for hematoxylin and eosin staining and immunohistochemical analysis. CD19+ B cells were purified by magnetic cell sorting for immunofluorescence staining, lentivirus–PARP‐9 transfection, and IFNα treatment experiments. PARP‐9 small interfering RNA (siRNA) and DTX3L siRNA were delivered into female NOD/LtJ female mice to determine their effect. Results: The overexpression of PARP‐9 and CXCL10 as well as their colocalization was confirmed in primary SS. PARP‐9 levels in LSGs rose with increased Chisholm scores in patients with primary SS. PARP‐9 and DTX3L were present in the infiltrating mononuclear cells from salivary glands in female NOD/LtJ mouse models. Additionally, Ingenuity Pathway Analysis networks of DEPs demonstrated that PARP‐9, STAT1, and IFN‐induced protein with tetratricopeptide repeats 1 (IFIT‐1) participated in the IFN‐related pathway. Furthermore, PARP‐9 could up‐regulate the expression of IFIT1 and CXCL10 in B cells. Moreover, PARP‐9 and CXCL10 could be induced by IFNα in B cells. Conclusion: This study is the first to implicate PARP‐9 as a regulator of infiltration of mononuclear cells in primary SS progression and to reveal that PARP‐9 increases CXCL10 expression through up‐regulating IFIT‐1, which is mediated by the phosphorylation of STAT1. PARP‐9 might therefore be a novel therapeutic target for primary SS. [ABSTRACT FROM AUTHOR]

Follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) play critical roles in female reproduction, while the underlying genetic basis is poorly understood. Genome‐wide association studies (GWASs) of FSH and LH levels were conducted in 2590 Chinese females including 1882 polycystic ovary syndrome (PCOS) cases and 708 controls. GWAS for FSH level identified multiple variants at FSHR showing genome‐wide significance with the top variant (rs2300441) located in the intron of FSHR. The A allele of rs2300441 led to a reduced level of FSH in the PCOS group (β = −.43, P = 6.70 × 10−14) as well as in the control group (β = −.35, P = 6.52 × 10−4). In the combined sample, this association was enhanced after adjusting for the PCOS status (before: β = −.38, P = 1.77 × 10−13; after: β = −.42, P = 3.33 × 10−16), suggesting the genetic effect is independent of the PCOS status. The rs2300441 explained sevenfold higher proportion of the FSH variance than the total variance explained by the two previously reported FSHR missense variants (rs2300441 R2 = 1.40% vs rs6166 R2 = 0.17%, rs6165 R2 = 0.03%). GWAS for LH did not identify any genome‐wide significant associations. In conclusion, we identified genome‐wide significant association between variants in FSHR and circulating FSH first, with the top associated variant rs2300441 might be a primary contributor at the population level. [ABSTRACT FROM AUTHOR]

Disk transparent ceramics with multilayer composite structure serves well as laser gain medium because of its excellent thermal and optical properties. For such a type of material, the preparation of corresponding outstanding slurry is the first yet most essential step, and it may determine the quality of both subsequent green tape and the sintered ceramics. In this work, the tape‐casting slurry with typically pseudoplastic behavior was carefully modulated in the mixture solvent of anhydrous ethanol and ethyl acetate, and its rheological property was systematically investigated using fine‐controlled rotary rheometer. The obtained result reveals 4wt.% fish oil to be the best dispersed agent. With the obtained slurry for tape‐casting followed by lamination and warm isostatic‐pressing, the multilayer ultrathin TCs was successfully fabricated via high‐temperature vacuum sintering technology. The obtained full‐dense microstructure with high optical quality may endow the studied ceramic with great potential for highly efficient solid‐state laser gain medium. [ABSTRACT FROM AUTHOR]

Summary: Maize exhibits marked growth and yield response to supplemental nitrogen (N). Here, we report the functional characterization of a maize NIN‐like protein ZmNLP5 as a central hub in a molecular network associated with N metabolism. Predominantly expressed and accumulated in roots and vascular tissues, ZmNLP5 was shown to rapidly respond to nitrate treatment. Under limited N supply, compared with that of wild‐type (WT) seedlings, the zmnlp5 mutant seedlings accumulated less nitrate and nitrite in the root tissues and ammonium in the shoot tissues. The zmnlp5 mutant plants accumulated less nitrogen than the WT plants in the ear leaves and seed kernels. Furthermore, the mutants carrying the transgenic ZmNLP5 cDNA fragment significantly increased the nitrate content in the root tissues compared with that of the zmnlp5 mutants. In the zmnlp5 mutant plants, loss of the ZmNLP5 function led to changes in expression for a significant number of genes involved in N signalling and metabolism. We further show that ZmNLP5 directly regulates the expression of nitrite reductase 1.1 (ZmNIR1.1) by binding to the nitrate‐responsive cis‐element at the 5′ UTR of the gene. Interestingly, a natural loss‐of‐function allele of ZmNLP5 in Mo17 conferred less N accumulation in the ear leaves and seed kernels resembling that of the zmnlp5 mutant plants. Our findings show that ZmNLP5 is involved in mediating the plant response to N in maize. Significance Statement: In this study, we report the functional characterization of ZmNLP5 for its role in modulating the N response, suggesting that ZmNLP5 is a potential candidate for improving N use efficiency in maize production. [ABSTRACT FROM AUTHOR]

Red carp and red crucian carp are ornamental fish with a red body color. Unlike in red crucian carp, no melanophores are observed in red carp embryos or larvae. To explore the roles of the mitfa gene in body color formation in red carp, we investigated the structural characteristics and physicochemical properties of the mitfa gene in 16 kinds of fish. The mitfa amino acid sequence similarity between red carp and red crucian carp was 95.6%, and this was 91.5% similar between carp and zebrafish. Compared with red crucian carp, red carp showed lower tyrp1 messenger ribonucleic acid (mRNA) expression but similar mitfa mRNA expression in the body pigment stage of the embryo. Moreover, mitfa+ cells as well as melanocytes could be observed in cultured embryo cells derived from red carp and red crucian carp. Our data show that the absence of melanophores in red carp is not the result of mitfa gene deletion or mutation, increasing our understanding of the molecular and genetic mechanisms of coloration in cyprinid fish. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods: We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results: The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions: Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood. [ABSTRACT FROM AUTHOR]

Objective To evaluate the influence of Scoliosis Research Society (SRS)- Schwab sagittal modifiers of pelvic incidence minus lumbar lordosis mismatch ( PI-LL) on clinical outcomes for adult degenerative scoliosis ( ADS) after long posterior instrumentation and fusion. Methods This was a single-institute, retrospective study. From 2012 to 2014, 44 patients with ADS who underwent posterior instrumentation and fusion treatment were reviewed. Radiological evaluations were investigated by standing whole spine (posteroanterior and lateral views) X-ray and all radiological measurements, including Cobb's angle, LL, PI, and the grading of vertebral rotation, were performed by two experienced surgeons who were blind to the operations. The patients were divided into three groups based on postoperative PI-LL and the classification of the SRS- Schwab: 0 grade PI-LL (<10°, n = 13); + grade PI-LL (10°-20°, n = 19); and ++ grade PI-LL (>20°, n = 12). The clinical outcomes were assessed according to Japanese Orthopaedic Association ( JOA) score, Oswestry Disability Index ( ODI), Visual Analog Scale ( VAS), Lumbar Stiffness Disability Index ( LSDI), and complications. Other characteristic data of patients were also collected, including intraoperative blood loss, operative time, length of hospital stay, complications, number of fusion levels, and number of decompressions. Results The mean operative time, blood loss, and hospital stay were 284.5 ± 30.2 min, 1040.5 ± 1207.6 mL, and 14.5 ± 1.9 day. At the last follow-up (2.6 ± 0.6 years), the radiological and functional parameters, except the grading of vertebral rotation, were all significantly improved in comparison with preoperative results ( P < 0.05), but it was obvious that an ideal PI-LL (≤10°) was not achieved in some patients. Significant differences were only observed among the three groups in the ODI and LSDI. Patients with + grade PI-LL seemed to have the best surgical outcome compared to those with 0 and ++ grade PI-LL, with the lowest ODI score (+ grade vs 0 grade, 17.3 ± 4.9 vs 26.0 ± 5.4; + grade vs ++ grade, 17.3 ± 4.9 vs 32.4 ± 7.3; P < 0.05) and lower LSDI (+ grade vs 0 grade, 1.6 ± 1.0 vs 3.5 ± 0.5, P < 0.05; + grade vs ++ grade, 1.6 ± 1.0 vs 0.6 ± 0.5, P > 0.05). A Pearson correlation analysis further demonstrated that LSDI was negatively associated with PI-LL. Furthermore, the incidence rate of postoperative complications was lower in patients with + grade PI-LL (1/19, 5.26%) than that in patients with 0 (2/13, 15.4%) and ++ grade PI-LL (3/12, 25%). Conclusion Our present study suggest that the ideal PI-LL may be between 10° and 20° in ADS patients after long posterior instrumentation and fusion. [ABSTRACT FROM AUTHOR]

Abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. HDAC6 is a transcriptional regulator of the histone deacetylase family, subfamily 2. Previous studies have shown that HDAC6 plays critical roles in transcription regulation, cell cycle progression and developmental events. However, its biological roles in the development of HCC remain largely unexplored. In the present study, we found that mRNA and protein levels of HDAC6 were up-regulated in HCC tissues and cell lines. The proinflammatory cytokines, which were up-regulated in the human HCC microenvironment, increased HDAC6 expression through a proximal NF-kappaB binding site on the HDAC6 gene promoter. Furthermore, overexpression of HDAC6 could promote cell proliferation in HCC cell lines. In contrast, HDAC6 knockdown using small interfering RNA inhibited cell proliferation. At the molecular level, we demonstrated that HDAC6 could interact with p53 and attenuate its transcriptional activity through promotion of its degradation. Therefore, our results suggest a previously unknown HDAC6-p53 molecular network controlling HCC development. [Copyright &y& Elsevier]

A number of genes involved in zygotic genome activation (ZGA) have been identified, but the RNA‐binding maternal factors that are directly related to ZGA in mice remain unclear. The present study shows that maternal deletion of Igf  2bp2 (also commonly known as Imp2) in mouse embryos causes early embryonic developmental arrest in vitro at the 2‐cell‐stage. Transcriptomics and proteomics analyses of 2‐cell‐stage embryos in mice reveal that deletion of IMP2 downregulates the expression of Ccar1 and Rps14, both of which are required for early embryonic developmental competence. IGF2, a target of IMP2, when added in culture media, increases the proportion of wild‐type embryos that develop successfully to the blastocyst stage: from 29% in untreated controls to 65% (50 × 10−9m IGF2). Furthermore, in an experiment related to embryo transfer, foster mothers receiving IGF2‐treated embryos deliver more pups per female than females who receive untreated control embryos. In clinically derived human oocytes, the addition of IGF2 to the culture media significantly enhances the proportion of embryos that develop successfully. Collectively, the findings demonstrate that IMP2 is essential for the regulation and activation of genes known to be involved in ZGA and reveal the potential embryonic development‐related utility of IGF2 for animal biotechnology and for assisted reproduction in humans. [ABSTRACT FROM AUTHOR]

The roles and regulatory mechanisms of transcriptome changes during aging are unclear. It has been proposed that the transcriptome suffers decay during aging owing to age‐associated down‐regulation of transcription factors. In this study, we characterized the role of a transcription factor DAF‐16, which is a highly conserved lifespan regulator, in the normal aging process of Caenorhabditis elegans. We found that DAF‐16 translocates into the nucleus in aged wild‐type worms and activates the expression of hundreds of genes in response to age‐associated cellular stress. Most of the age‐dependent DAF‐16 targets are different from the canonical DAF‐16 targets downstream of insulin signaling. This and other evidence suggest that activation of DAF‐16 during aging is distinct from activation of DAF‐16 due to reduced signaling from DAF‐2. Further analysis showed that it is due in part to a loss of proteostasis during aging. We also found that without daf‐16, dramatic gene expression changes occur as early as on adult day 2, indicating that DAF‐16 acts to stabilize the transcriptome during normal aging. Our results thus reveal that normal aging is not simply a process in which the gene expression program descends into chaos due to loss of regulatory activities; rather, there is active transcriptional regulation during aging. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented from Julia C. Radosa of the Department of Gynecology & Obstetrics at the University of Heidelberg discussing a case of acute compartment syndrome in obstetric care.

Preeclampsia (PE) is a pregnancy complication that is characterized by high blood pressure and is associated with high maternal and fetal morbidities. At a mechanistic level, PE is characterized by reduced invasion ability of trophoblasts. Collagen triple helix repeat containing-1 (CTHRC1) is a well-known tumor-promoting factor in several malignant tumors, but its role in trophoblasts remains unknown. In this study, we characterized the expression of CTHRC1 in placenta tissue samples from PE pregnancies and from normal pregnancies. We used the trophoblasts cell lines HTR-8/SVneo and JEG-3 to investigate the role of CTHRC1 in cell migration, invasion and proliferation. Western blot, PCR and TOP/FOP luciferase activity assays were used to investigate the molecular mechanisms underlying these cell behaviors. Placenta tissue samples obtained from pregnant women with PE expressed lower levels of CTHRC1 than those of placenta tissues from women with normal pregnancies. Down-regulation of CTHRC1 impaired cell proliferation, migration and invasion of trophoblasts, while CTHRC1 overexpression promoted nuclear translocation of β-catenin, a result that was further confirmed by TOP/FOP luciferase activity assay. Our findings suggest that CTHRC1 promotes migration and invasion of trophoblasts via reciprocal Wnt/β-catenin signaling pathway. Down-regulation of CTHRC1 may be a potential mechanism underpinning the development of preeclampsia., (© 2021. The International CCN Society.)