GRIM19 deficiency aggravates metabolic disorder and ovarian dysfunction in PCOS.

CONTEXT: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Retinoid-interferon-induced mortality 19 (GRIM19) is a functional component of mitochondrial complex I that plays a role in cellular energy metabolism. However, the role of GRIM19 in the pathogenesis of PCOS is still unclear. OBJECTIVE: To investigate the role of GRIM19 in the pathogenesis of PCOS. DESIGN: We first measured the expression of GRIM19 in human granulosa cells (hGCs) from patients with and without PCOS (n = 16 per group), and then established a PCOS mouse model with WT and Grim19+/- mice for in vivo experiments. Glucose uptake-related genes RAC1 and GLUT4 and energy metabolism levels in KGN cells were examined in vitro by knocking down GRIM19 in the cell lines. Additionally, ovulation-related genes such as p-ERK1/2, HAS2, and PTX3 were also studied to determine their expression levels. RESULTS: GRIM19 expression was reduced in hGCs of PCOS patients, which was negatively correlated with BMI and serum testosterone level. Grim19+/- mice with PCOS exhibited a markedly anovulatory phenotype and disturbed glycolipid metabolism. In vitro experiments, GRIM19 deficiency inhibited the RAC1/GLUT4 pathway, reducing insulin-stimulated glucose uptake in KGN cells. Moreover, GRIM19 deficiency induced mitochondrial dysfunction, defective glucose metabolism, and apoptosis. In addition, GRIM19 deficiency suppressed the expression of ovulation-related genes in KGN cells, which was regulated by dihydrotestosterone mediated androgen receptor. CONCLUSIONS: GRIM19 deficiency may mediate ovulation and glucose metabolism disorders in PCOS patients. Our results suggest that GRIM19 may be a new target for diagnosis and treatment.

TP63 gain-of-function mutations cause premature ovarian insufficiency by inducing oocyte apoptosis.

The transcription factor p63 guards genome integrity in the female germline, and its mutations have been reported in patients with premature ovarian insufficiency (POI). However, the precise contribution of the TP63 gene to the pathogenesis of POI needs to be further determined. Here, in 1,030 Chinese patients with POI, we identified 6 heterozygous mutations of the TP63 gene that impaired the C-terminal transactivation-inhibitory domain (TID) of the TAp63α protein and resulted in tetramer formation and constitutive activation of the mutant proteins. The mutant proteins induced cell apoptosis by increasing the expression of apoptosis-inducing factors in vitro. We next introduced a premature stop codon and selectively deleted the TID of TAp63α in mice and observed rapid depletion of the p63+/ΔTID mouse oocytes through apoptosis after birth. Finally, to further verify the pathogenicity of the mutation p.R647C in the TID that was present in 3 patients, we generated p63+/R647C mice and also found accelerated oocyte loss, but to a lesser degree than in the p63+/ΔTID mice. Together, these findings show that TID-related variants causing constitutive activation of TAp63α lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for extending female fertility.

The effect of hyperbaric oxygen therapy on the clinical outcomes of necrotizing soft tissue infections: a systematic review and meta-analysis.

BACKGROUND: To determine the efficacy of hyperbaric oxygen therapy (HBO) in the treatment of necrotizing soft tissue infections (NSTI), we conducted a meta-analysis of the available evidence. METHODS: Data sources were PubMed, Embase, Web of Science, Cochrane Library, and reference lists. The study included observational trials that compared HBO with non-HBO, or standard care. The primary outcome was the mortality rate. Secondary outcomes were the number of debridement, amputation rate and complication rate. Relative risks or standardized mean differences with 95% confidence intervals were calculated for dichotomous and continuous outcomes, respectively. RESULTS: A total of retrospective cohort and case-control studies were included, including 49,152 patients, 1448 who received HBO and 47,704 in control. The mortality rate in the HBO group was significantly lower than that in the non-HBO group [RR = 0.522, 95% CI (0.403, 0.677), p < 0.05]. However, the number of debridements performed in the HBO group was higher than in the non-HBO group [SMD = 0.611, 95% CI (0.012, 1.211), p < 0.05]. There was no significant difference in amputation rates between the two groups [RR = 0.836, 95% CI (0.619, 1.129), p > 0.05]. In terms of complications, the incidence of MODS was lower in the HBO group than in the non-HBO group [RR = 0.205, 95% CI (0.164, 0.256), p < 0.05]. There was no significant difference in the incidence of other complications, such as sepsis, shock, myocardial infarction, pulmonary embolism, and pneumonia, between the two groups (p > 0.05). CONCLUSION: The current evidence suggests that the use of HBO in the treatment of NSTI can significantly reduce the mortality rates and the incidence rates of complications. However, due to the retrospective nature of the studies, the evidence is weak, and further research is needed to establish its efficacy. It is also important to note that HBO is not available in all hospitals, and its use should be carefully considered based on the patient's individual circumstances. Additionally, it is still worthwhile to stress the significance of promptly evaluating surgical risks to prevent missing the optimal treatment time.

DNA repair protein FANCD2 has both ubiquitination-dependent and ubiquitination-independent functions during germ cell development.

When DNA interstrand crosslink lesions occur, a core complex of Fanconi anemia proteins promotes the ubiquitination of FANCD2 and FANCI, which recruit downstream factors to repair the lesion. However, FANCD2 maintains genome stability not only through its ubiquitination-dependent but also its ubiquitination-independent functions in various DNA damage response pathways. Increasing evidence suggests that FANCD2 is essential for fertility, but its ubiquitination-dependent and ubiquitination-independent roles during germ cell development are not well characterized. In this study, we analyzed germ cell development in Fancd2 KO and ubiquitination-deficient mutant (Fancd2K559R/K559R) mice. We showed that in the embryonic stage, both the ubiquitination-dependent and ubiquitination-independent functions of FANCD2 were required for the expansion of primordial germ cells and establishment of the reproductive reserve by reducing transcription-replication conflicts and thus maintaining genome stability in primordial germ cells. Furthermore, we found that during meiosis in spermatogenesis, FANCD2 promoted chromosome synapsis and regulated crossover formation independently of its ubiquitination, but that both ubiquitinated and nonubiquitinated FANCD2 functioned in programmed double strand break repair. Finally, we revealed that on meiotic XY chromosomes, H3K4me2 accumulation required ubiquitination-independent functionality of FANCD2, while the regulation of H3K9me2 and H3K9me3 depended on FANCD2 ubiquitination. Taken together, our findings suggest that FANCD2 has distinct functions that are both dependent on and independent of its ubiquitination during germ cell development.

Pulse compression of a single-frequency Q-switched fiber laser based on the cascaded four-wave mixing effect.

A pulse compressing technology of single-frequency Q-switched laser based on the cascaded four-wave mixing (CFWM) effect is demonstrated theoretically and experimentally, for the first time to the best of our knowledge. A theoretical model of the pulse compression is established through deconstructing the pulse duration evolution in the high-order Stokes and anti-Stokes lights of CFWM. A pulse compression ratio of (2|m|+1)1/2 is quantificationally obtained with m corresponding to the order number of the CFWM light. Utilizing dual-wavelength (DW) single-frequency Q-switched laser injected into a highly nonlinear fiber (HNLF), the pulse compression and the spectral broadening phenomenon are observed simultaneously. As the order number of the CFWM light increases from 0-order to 3-order, the pulse duration has reduced from 115 ns to 47 ns with a compression ratio of 2.45, which is essentially consistent with the theoretical analysis. The pulse compressing technique by CFWM is conducive to promoting the performance development of the single-frequency Q-switched laser, which can improve the system precision in the Lidar, trace gas detection, and high-precision ranging. Furthermore, this technology based on time-frequency transformation dynamics may be generally applicable to other single-frequency pulsed fiber lasers.

[Electroacupuncture combined with acupoint catgut embedding for postoperative pain after fistulotomy].

OBJECTIVE: To evaluate the effect of electroacupuncture(EA) combined with acupoint catgut embedding the-rapy for postoperative pain after fistulotomy. METHODS: A total of 138 patients were randomly assigned into EA, acupoint catgut embedding and combination groups, with 46 patients in each group. The interventions were performed 30 min before surgery in all the three groups. The acupoints were Changqiang(GV1) and Chengshan(BL57). The visual analogue scale (VAS) score and limb activity score of the three groups at 6, 12, 24, 48 and 72 h after surgery, as well as maximum VAS score within 24 h(T24max VAS) of 1-3 d and total amounts of oral analgesic within 72 h after surgery were observed and recorded. RESULTS: The VAS score and limb activity score from the 6, 12 and 24 h after surgery, and T24max VAS score on the 1st day of the EA group were lower than those of the acupoint embedding group (P<0.05). While the VAS pain score and limb activity score at the 48 h and 72 h after surgery, and T24max VAS score at the 2nd to 3rd day, and total dose of oral analgesic within 72 h in the acupoint embedding group were lower than those of the EA group (P<0.05). The combination group was superior to the EA and acupoint embedding groups in terms of VAS score and limb activity score at different postoperative time, T24max VAS score at 1-3 d after surgery, and the total amounts of analgesic used within 72 h (P<0.05). CONCLUSION: EA combined with acupoint catgut embedding is more effective than simple EA or acupoint catgut embedding for postoperative pain after fistulotomy, with significant curative effect and no adverse reactions.

Meiotic Recombination Defects and Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is the depletion of ovarian function before 40 years of age due to insufficient oocyte formation or accelerated follicle atresia. Approximately 1-5% of women below 40 years old are affected by POI. The etiology of POI is heterogeneous, including genetic disorders, autoimmune diseases, infection, iatrogenic factors, and environmental toxins. Genetic factors account for 20-25% of patients. However, more than half of the patients were idiopathic. With the widespread application of next-generation sequencing (NGS), the genetic spectrum of POI has been expanded, especially the latest identification in meiosis and DNA repair-related genes. During meiotic prophase I, the key processes include DNA double-strand break (DSB) formation and subsequent homologous recombination (HR), which are essential for chromosome segregation at the first meiotic division and genome diversity of oocytes. Many animal models with defective meiotic recombination present with meiotic arrest, DSB accumulation, and oocyte apoptosis, which are similar to human POI phenotype. In the article, based on different stages of meiotic recombination, including DSB formation, DSB end processing, single-strand invasion, intermediate processing, recombination, and resolution and essential proteins involved in synaptonemal complex (SC), cohesion complex, and fanconi anemia (FA) pathway, we reviewed the individual gene mutations identified in POI patients and the potential candidate genes for POI pathogenesis, which will shed new light on the genetic architecture of POI and facilitate risk prediction, ovarian protection, and early intervention for POI women.

Perovskite neural trees.

Trees are used by animals, humans and machines to classify information and make decisions. Natural tree structures displayed by synapses of the brain involves potentiation and depression capable of branching and is essential for survival and learning. Demonstration of such features in synthetic matter is challenging due to the need to host a complex energy landscape capable of learning, memory and electrical interrogation. We report experimental realization of tree-like conductance states at room temperature in strongly correlated perovskite nickelates by modulating proton distribution under high speed electric pulses. This demonstration represents physical realization of ultrametric trees, a concept from number theory applied to the study of spin glasses in physics that inspired early neural network theory dating almost forty years ago. We apply the tree-like memory features in spiking neural networks to demonstrate high fidelity object recognition, and in future can open new directions for neuromorphic computing and artificial intelligence.

[A case of Antley-Bixler syndrome caused by novel POR mutations].

OBJECTIVE: To explore the genetic basis for a child affected with multiple malformations. METHODS: Genomic DNA was extracted from peripheral blood samples from the child and her parents. Tro whole exome sequencing and bioinformatics analysis were carried out. Suspicted mutations were verified by PCR and Sanger sequencing. RESULTS: The patient, a 2-year-old girl, presented with multiple malformations including dysmorphism, skeletal malformations and ambigulous genitalia. Through genetic testing, she was diagnosed with Antley-Bixler syndrome caused by compound heterozygous mutations of the POR gene (c.919G>T and c.1615G>A), which were derived from her mother and father, respectively. CONCLUSION: The compound heterozygous mutations of the POR gene probably underlie the Antley-Bixler syndrome in this patient.

Novel variants in the KERA gene cause autosomal recessive cornea plana in a Chinese family: A case report.

Autosomal recessive cornea plana is a very rare hereditary ocular disease, characterized by a flattened corneal curvature, marked hyperopia due to low refractive power and frequently consequent accommodative esotropia. Other features include various cornea anterior segment abnormalities, without systemic problems. The purpose of the present study was to investigate the clinical and molecular alterations in a Chinese family with cornea plana. Full ophthalmic examinations of the patients were performed, including slit­lamp examination, fundus examination and ocular ultrasound. Whole­exome sequencing data were screened for pathological variants in the proband, which were confirmed by Sanger sequencing. One novel missense mutation, c.242A>G (p.N81S) and another novel 7 base­pair deletion mutation, c.772­779del (p.G258Cfs*30), were detected in the keratocan (KERA) gene; two affected siblings inherited these variations in a compound heterozygous state, which were derived from the clinically unaffected heterozygous father (c.772_779del) and mother (c.242A>G), respectively. Neither mutation was observed in unrelated healthy controls (n=200). Multiple computer software predictions supported the pathogenicity of the two variants. Furthermore, protein modeling prediction was performed to better understand the molecular basis of cornea plana, particularly the importance of the leucine­rich repeat domain. This study presents the 14th pathogenic KERA mutations identified worldwide and the first in East Asia so far, to the best of our knowledge. These findings guided prenatal diagnosis for the family in question and expand on the variant spectrum of KERA, therefore facilitating genetic counseling.

Y-shaped ZnO Nanobelts Driven from Twinned Dislocations.

Y-shaped ZnO nanobelts are fabricated by a simple thermal evaporation method. Transmission Electron Microscopy (TEM) investigation shows that these ZnO nanobelts are crystals with twinned planes {11-21}. Convergent Beam Electron Diffraction studies show that the two sides of twinned nanobelts are O-terminated towards the twinned boundary and Zn-terminated outwards. The two branches of twinned ZnO nanobelts grow along [11-26] from the trunk and then turn to the polarization direction [0001]. The featured Y-shape morphology and TEM characterizations indicate that the growth of these novel nanostructures is driven by an unusual twinned dislocation growth mechanism.

Three Dimensional Sculpturing of Vertical Nanowire Arrays by Conventional Photolithography.

Ordered nanoarchitectures have attracted an intense research interest recently because of their promising device applications. They are always fabricated by self-assembling building blocks such as nanowires, nanodots. This kind of bottom up approaches is limited in poor control over height, lateral resolution, aspect ratio, and patterning. Here, we break these limits and realize 3D sculpturing of vertical ZnO nanowire arrays (NAs) based on the conventional photolithography approach. These are achieved by immersing nanowire NAs in thick photoresist (PR) layers, which enable the cutting and patterning of ZnO NAs as well as the tailoring of NAs. Our strategy of 3D sculpturing of NAs promisingly paves the way for designing novel NAs-based nanoarchitectures.

Hierarchical ZnO nanostructures with blooming flowers driven by screw dislocations.

Hierarchical ZnO nanostructures with a large yield were fabricated by a simple thermal evaporation method. For the first time, novel ZnO flowers were observed blooming at certain sites of a variety of spines, identified as Zn-terminated polar (0001) planes or tips. The spines for as-synthesized hierarchical structures can be nanowires, nanobelts, nanodendrites, nanobrushes, etc. This growth phenomenon determines the key role of polar sites in the fabrication of hierarchical structures. The spiral feature of ZnO flowers indicates an unusual screw dislocation driven growth mechanism, which is attributed to a high concentration of Zn vapor.