OGT and OGA: Sweet guardians of the genome.

The past 4 decades have witnessed tremendous efforts in deciphering the role of O-GlcNAcylation in a plethora of biological processes. Chemists and biologists have joined hand in hand in the sweet adventure to unravel this unique and universal yet uncharted post-translational modification, and the recent advent of cutting-edge chemical biology and mass spectrometry tools has greatly facilitated the process. Compared with O-GlcNAc, DNA damage response (DDR) is a relatively intensively studied area that could be traced to before the elucidation of the structure of DNA. Unexpectedly, yet somewhat expectedly, O-GlcNAc has been found to regulate various DDR pathways: homologous recombination, nonhomologous end joining, base excision repair, and translesion DNA synthesis. In this review, we first cover the recent structural studies of the O-GlcNAc transferase and O-GlcNAcase, the elegant duo that "writes" and "erases" O-GlcNAc modification. Then we delineate the intricate roles of O-GlcNAc transferase and O-GlcNAcase in DDR. We envision that this is only the beginning of our full appreciation of how O-GlcNAc regulates the blueprint of life-DNA.

Classification of PTEN missense VUS through exascale simulations.

Phosphatase and tensin homolog (PTEN), a tumor suppressor with dual phosphatase properties, is a key factor in PI3K/AKT signaling pathway. Pathogenic germline variation in PTEN can abrogate its ability to dephosphorylate, causing high cancer risk. Lack of functional evidence lets numerous PTEN variants be classified as variants of uncertain significance (VUS). Utilizing Molecular Dynamics (MD) simulations, we performed a thorough evaluation for 147 PTEN missense VUS, sorting them into 66 deleterious and 81 tolerated variants. Utilizing replica exchange molecular dynamic (REMD) simulations, we further assessed the variants situated in the catalytic core of PTEN's phosphatase domain and uncovered conformational alterations influencing the structural stability of the phosphatase domain. There was a high degree of agreement between our results and the variants classified by Variant Abundance by Massively Parallel Sequencing, saturation mutagenesis, multiplexed functional data and experimental assays. Our extensive analysis of PTEN missense VUS should benefit their clinical applications in PTEN-related cancer. SIGNIFICANCE STATEMENT: Classification of PTEN variants affecting its lipid phosphatase activity is important for understanding the roles of PTEN variation in the pathogenesis of hereditary and sporadic malignancies. Of the 3000 variants identified in PTEN, 1296 (43%) were assigned as VUS. Here, we applied MD and REMD simulations to investigate the effects of PTEN missense VUS on the structural integrity of the PTEN phosphatase domain consisting the WPD, P and TI active sites. We classified a total of 147 missense VUS into 66 deleterious and 81 tolerated variants by referring to the control group comprising 54 pathogenic and 12 benign variants. The classification was largely in concordance with these classified by experimental approaches.

Evolutionary origin of germline pathogenic variants in human DNA mismatch repair genes.

BACKGROUND: Mismatch repair (MMR) system is evolutionarily conserved for genome stability maintenance. Germline pathogenic variants (PVs) in MMR genes that lead to MMR functional deficiency are associated with high cancer risk. Knowing the evolutionary origin of germline PVs in human MMR genes will facilitate understanding the biological base of MMR deficiency in cancer. However, systematic knowledge is lacking to address the issue. In this study, we performed a comprehensive analysis to know the evolutionary origin of human MMR PVs. METHODS: We retrieved MMR gene variants from the ClinVar database. The genomes of 100 vertebrates were collected from the UCSC genome browser and ancient human sequencing data were obtained through comprehensive data mining. Cross-species conservation analysis was performed based on the phylogenetic relationship among 100 vertebrates. Rescaled ancient sequencing data were used to perform variant calling for archeological analysis. RESULTS: Using the phylogenetic approach, we traced the 3369 MMR PVs identified in modern humans in 99 non-human vertebrate genomes but found no evidence for cross-species conservation as the source for human MMR PVs. Using the archeological approach, we searched the human MMR PVs in over 5000 ancient human genomes dated from 45,045 to 100 years before present and identified a group of MMR PVs shared between modern and ancient humans mostly within 10,000 years with similar quantitative patterns. CONCLUSION: Our study reveals that MMR PVs in modern humans were arisen within the recent human evolutionary history.

Pathogenic variants in human DNA damage repair genes mostly arose in recent human history.

BACKGROUND: Genome stability is maintained by the DNA damage repair (DDR) system composed of multiple DNA repair pathways of hundreds of genes. Germline pathogenic variation (PV) in DDR genes damages function of the affected DDR genes, leading to genome instability and high risk of diseases, in particular, cancer. Knowing evolutionary origin of the PVs in human DDR genes is essential to understand the etiology of human diseases. However, answer to the issue remains largely elusive. In this study, we analyzed evolutionary origin for the PVs in human DDR genes. METHODS: We identified 169 DDR genes by referring to various databases and identified PVs in the DDR genes of modern humans from ClinVar database. We performed a phylogenetic analysis to analyze the conservation of human DDR PVs in 100 vertebrates through cross-species genomic data comparison using the phyloFit program of the PHAST package and visualized the results using the GraphPad Prism software and the ggplot module. We identified DDR PVs from over 5000 ancient humans developed a database to host the DDR PVs ( https://genemutation.fhs.um.edu.mo/dbDDR-AncientHumans ). Using the PV data, we performed a molecular archeological analysis to compare the DDR PVs between modern humans and ancient humans. We analyzed evolution selection of DDR genes across 20 vertebrates using the CodeML in PAML for phylogenetic analysis. RESULTS: Our phylogenic analysis ruled out cross-species conservation as the origin of human DDR PVs. Our archeological approach identified rich DDR PVs shared between modern and ancient humans, which were mostly dated within the last 5000 years. We also observed similar pattern of quantitative PV distribution between modern and ancient humans. We further detected a set of ATM, BRCA2 and CHEK2 PVs shared between human and Neanderthals. CONCLUSIONS: Our study reveals that human DDR PVs mostly arose in recent human history. We propose that human high cancer risk caused by DDR PVs can be a by-product of human evolution.

The association between chronotype profile and temporomandibular disorders among college students.

BACKGROUND: Temporomandibular joint disorders (TMDs) are common in young adults, and the link between chronotype profile and TMDs is unclear. OBJECTIVE: This study examined TMD prevalence and chronotype distribution and explored the relationship between chronotype and TMDs in young adults. MATERIALS AND METHODS: A total of 663 students from Sichuan University completed questionnaires. Chronotype profiles were assessed using the Morningness-Eveningness Questionnaire, and TMDs were screened using the Fonseca Memory Index. To validate the findings, 68 TMD patients and 136 controls were enrolled. RESULTS: The prevalence of TMDs was 69.7%, with significant differences among chronotype profiles. The intermediate profile was the most common chronotype. Eveningness profile was associated with higher TMDs prevalence and severity. Muscle pain and side movement difficulty scores were higher in eveningness and intermediate profiles. Female gender (OR 2.345; 95% CI 1.668-3.297) was a TMD risk factor, while morningness profile (OR 0.537; 95% CI 0.297-0.970) was protective. Validation with TMD patients and controls supported these findings, showing higher eveningness profile prevalence in the TMD groups. CONCLUSIONS: TMDs have a high prevalence in college students, chronotype profiles shown to be associated with TMDs. Morningness is the protection factor in TMDs and PT, eveningness is a risk factor for IT.

Comparison of the perinatal outcomes of expected high ovarian response patients and normal ovarian response patients undergoing frozen-thawed embryo transfer in natural/small amount of HMG induced ovulation cycles.

BACKGROUND: Due to the high risk of complications in fresh transfer cycles among expected high ovarian response patients, most choose frozen-thawed embryo transfer (FET). There are currently few researches on whether the FET outcomes of expected high ovarian response patients with regular menstrual cycles are similar to those of normal ovarian response. Therefore, our objective was to explore and compare pregnancy outcomes and maternal and neonatal outcomes of natural FET cycles between patients with expected high ovarian response and normal ovarian response with regular menstrual cycles based on the antral follicle count (AFC). METHODS: This retrospective cohort study included 5082 women undergoing natural or small amount of HMG induced ovulation FET cycles at the Reproductive Center of the Third Affiliated Hospital of Zhengzhou University from January 1, 2017, to March 31, 2021. The population was divided into expected high ovarian response group and normal ovarian response group based on the AFC, and the differences in patient characteristics, clinical outcomes and perinatal outcomes between the two groups were compared. RESULTS: Regarding clinical outcomes, compared with the normal ovarian response group, patients in the expected high ovarian response group had a higher clinical pregnancy rate (57.34% vs. 48.50%) and live birth rate (48.12% vs. 38.97%). There was no difference in the early miscarriage rate or twin pregnancy rate between the groups. Multivariate logistic regression analysis suggested that the clinical pregnancy rate (adjusted OR 1.190) and live birth rate (adjusted OR 1.171) of the expected high ovarian response group were higher than those of the normal ovarian response group. In terms of maternal and infant outcomes, the incidence of very preterm delivery in the normal ovarian response group was higher than that in the expected high ovarian response group (0.86% vs. 0.16%, adjusted OR 0.131), Other maternal and infant outcomes were not significantly different. After grouping by age (< 30 y, 30-34 y, 35-39 y), there was no difference in the incidence of very preterm delivery among the age subgroups. CONCLUSION: For patients with expected high ovarian response and regular menstrual cycles undergoing natural or small amount of HMG induced ovulation FET cycles, the clinical and perinatal outcomes are reassuring. For patients undergoing natural or small amount of HMG induced ovulation FET cycles, as age increases, perinatal care should be strengthened during pregnancy to reduce the incidence of very preterm delivery.

Do serum vitamin D levels affect assisted reproductive outcomes and perinatal outcomes in young non-PCOS patients? A retrospective study.

PURPOSE: This study aimed to determine the influence of serum vitamin D levels on assisted reproductive and perinatal outcomes in young non-polycystic ovary syndrome (PCOS) patients. METHODS: A total of 3397 non-PCOS women under 35 years who underwent their first IVF/ICSI cycle at the Reproductive Medicine Center of the Third Affiliated Hospital of Zhengzhou University, from 2018 to 2019, were included. The women were categorized into two groups based on their serum 25(OH)D concentrations: deficient group [25(OH)D < 50 nmol/L] and non-deficient group [25(OH)D ≥ 50 nmol/L]. Ovulation induction results, clinical pregnancy rate, cumulative live birth rate (CLBR), and perinatal outcomes of both groups were compared. RESULTS: A total of 1113 non-PCOS women had successful pregnancies in their first completed IVF cycle. Comparison of laboratory results between the two groups revealed a significantly higher number of oocytes retrieved in the vitamin D-non-deficient group (15.2 ± 6.8 vs. 14.5 ± 6.7, p = 0.015). After controlling for confounding factors, there was no significant difference in the CLBR between the vitamin D-deficient group and the non-deficient group (71.0%, 1,973/2,778 vs. 69.0%, 427/619, p = 0.314, unadjusted). The prevalence of gestational diabetes mellitus (GDM) was higher in the vitamin D-deficient group than in the vitamin D-non-deficient group in both fresh-cycle singleton live births (3.8% vs. 1.2%) and twin live births (2.3% vs. 1.5%). CONCLUSION: This study demonstrated that vitamin D-deficient group had a lower number of oocytes retrieved than the non-deficient group and a higher prevalence of GDM, suggesting that vitamin D deficiency impacts assisted pregnancies and perinatal outcomes in infertile non-PCOS women. However, further studies are required to confirm these findings.

Copper(I)-Catalyzed Asymmetric Allylation of Ketones with 2-Aza-1,4-Dienes.

Catalytic asymmetric allylation of ketones under proton-transfer conditions is a challenging issue due to the limited pronucleophiles and the electrophilic inertness of ketones. Herein, a copper(I)-catalyzed asymmetric allylation of ketones with 2-aza-1,4-dienes (N-allyl-1,1-diphenylmethanimines) is disclosed, which affords a series of functionalized homoallyl tertiary alcohols in high to excellent enantioselectivity. Interestingly, N-allyl-1,1-diphenylmethanimines work as synthetic equivalents of propanals. Upon the acidic workup, a formal asymmetric ß-addition of propanals to ketones is achieved. An investigation on KIE effect indicates that the deprotonation of N-allyl-1,1-diphenylmethanimines is the rate-determining step, which generates nucleophilic allyl copper(I) species. Finally, the synthetic utility of the present method is demonstrated by the asymmetric synthesis of (R)-boivinianin A and (R)-gossonorol.

Copper(I)-Catalyzed Asymmetric Conjugate Addition of 1,4-Dienes to ß-Substituted Alkenyl Azaarenes.

Chiral azaarene compounds are extremely important due to their prevalence in pharmaceutical ingredients. Herein, an array of chiral molecules bearing azaaryl groups is synthesized in moderate-to-excellent yields with moderate-to-excellent Z/E ratios, high dr, and excellent enantioselectivity by a copper(I)-catalyzed asymmetric conjugate addition of 1,4-dienes to (E)-ß-substituted alkenyl azaarenes. The reaction is carried out under mild proton-transfer conditions, which enjoys very high atom economy. Moreover, the reaction features a broad substrate scope on (E)-α,ß-unsaturated azaarenes as various azaarenes are well tolerated, such as benzothiazole, thiazole, N-methyl-benzimidazole, benzoxazole, quinoline, isoquinoline, pyrimidine, pyrazine, and triazine. Interestingly, the reaction with (Z)-α,ß-unsaturated azaarenes affords the same products in excellent results but with a reversed absolute configuration. DFT calculations indicate that the C-C bond-forming nucleophilic addition is a Z-/E- and enantio-selectivities-determining step and provides a rationale for the origin of selectivities. At last, the synthetic utilities of the product are showcased by several transformations, including olefin metathesis, [4 + 2] cyclization, [2 + 1] cyclization, and cleavage of the benzothiazole ring.

Ethnic-specificity, evolution origin and deleteriousness of Asian BRCA variation revealed by over 7500 BRCA variants derived from Asian population.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization. We identified 7587 BRCA variants from 685 592 Asian individuals in 40 Asia countries and regions, including 1762 clinically actionable pathogenic variants and 4915 functionally unknown variants (https://genemutation.fhs.um.edu.mo/Asian-BRCA/). We observed the highly ethnic-specific nature of Asian BRCA variants between Asian and non-Asian populations and within Asian populations, highlighting that the current European descendant population-based BRCA data is inadequate to reflect BRCA variation in the Asian population. We also provided archeological evidence for the evolutionary origin and arising time of Asian BRCA variation. We further provided structural-based evidence for the deleterious variants enriched within the functionally unknown Asian BRCA variants. The data from our study provide a current view of BRCA variation in the Asian population and a rich resource to guide clinical applications of BRCA-related cancer for the Asian population.

Therapeutic plasma exchange-free treatment for first-episode TTP: A systematic review.

OBJECTIVE: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA), and therapeutic plasma exchange (TPE) is currently the standard treatment. However, TPE sometimes cannot be implemented. The aim of this study was to systematically review patients with a first TTP episode who were treated without TPE. METHOD: The PubMed, Embase, Web of Science and Cochrane Library databases were searched by two investigators independently to collect case reports and clinical studies on TTP patients treated without TPE. After removing duplicate records and records that did not meet the inclusion criteria, the patients' data of eligible studies, including the basic characteristics, treatment regimens, and outcomes were extracted for further analysis. RESULTS: A total of 5338 potentially relevant original studies were identified, from which 21 studies, including 14 cases, 3 case series and 4 retrospective studies, met eligibility requirements and were included. Treatment regimens in the absence of TPE were found to vary based on individual information. Most patients recovered, with normal platelet counts and ADAMT13 activity at discharge. In the meta-analysis of retrospective studies, the TPE-free group had no higher mortality than the TPE-treated group. CONCLUSION: Our study shows that TPE-free treatment may not increase the mortality of TTP patients, which provides a new treatment concept for patients with first episodes of TTP. However, the current evidence is not high due to the lack of randomized controlled trials, so more well-designed prospective clinical trials are warranted to investigate the safety and efficacy of TPE-free treatment regimens in TTP patients.

Prevalence and spectrum of DNA mismatch repair gene variation in the general Chinese population.

BACKGROUND: Identifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation-caused cancer. In the current study, we addressed the issue by using the Chinese population as a model. METHODS: We performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population. RESULTS: We identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral. CONCLUSION: Our study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.

Analysis of cumulative live birth rate outcomes of three ovarian stimulation protocols in patients after laparoscopic cystectomy of ovarial endometrioma: a retrospective cohort study.

BACKGROUND: Previous studies have reported that after laparoscopic cystectomy of ovarial endometrioma, the ovarian response to gonadotropin (Gn) significantly decreased. However, for patients with diminished ovarian reserve (DOR) after ovarian surgery, how to choose the most appropriate controlled ovarian hyperstimulation protocol has not been concluded. Compared with the traditional agonist regimen, the gonadotropin (Gn)-releasing hormone (GnRH) antagonist, microstimulation, and progestin-primed ovarian stimulation (PPOS) protocols are simple to operate and have a shorter cycle, which are often used in patients with DOR. So the purpose of our study is to compare the assisted reproductive outcomes of these three controlled ovarian hyperstimulation protocols in patients with DOR following laparoscopic cystectomy of ovarial endometrioma. METHODS: In this retrospective cohort study, 89 patients with DOR who had undergone in vitro fertilisation/intracytoplasmic sperm injection at the Department of Reproductive Medicine at the Third Affiliated Hospital of Zhengzhou University from 1 to 2018 to 31 December 2020 were included. According to the controlled ovarian hyperstimulation protocols employed, the patients were divided into GnRH antagonist (38 patients), PPOS (27 patients), and microstimulation (24 patients) groups. The basic data and clinical outcomes of the three groups were compared. The main outcome measure was the cumulative live birth rate. RESULTS: No significant differences in the age of the female patients and their spouses and female patients' body mass index and basal endocrine levels (follicle-stimulating hormone and oestradiol) were noted among the three groups (P > 0.05). The GnRH antagonist group had higher antral follicle counts, greater endometrial thickness on the human chorionic Gn injection day, greater number of oocytes retrieved, and higher two pronuclear embryo counts than did the other two groups. However, the starting dosage of Gn was lower in the GnRH antagonist group than in the other two groups. The microstimulation group had a significantly higher oocyte output rate and high-quality embryo rate than did the other two groups (P < 0.05). No significant differences in the total dosage of Gn, cumulative pregnancy rate, cumulative live birth rate, viable embryo rate, and blastocyst formation rate were observed among the three groups (P > 0.05). CONCLUSION: In conclusion, for patients aged under 40 years who experienced DOR after laparoscopic cystectomy of ovarial endometrioma, GnRH antagonist protocol and PPOS protocol can obtain better ovulation induction outcomes and cumulative live birth rate than microstimulation protocol, and are more suitable ovulation induction protocols.

Evolution of the Electronic Structure of Ultrathin MnBi2Te4 Films.

Ultrathin films of intrinsic magnetic topological insulator MnBi2Te4 exhibit fascinating quantum properties such as the quantum anomalous Hall effect and the axion insulator state. In this work, we systematically investigate the evolution of the electronic structure of MnBi2Te4 thin films. With increasing film thickness, the electronic structure changes from an insulator type with a large energy gap to one with in-gap topological surface states, which is, however, still in drastic contrast to the bulk material. By surface doping of alkali-metal atoms, a Rashba split band gradually emerges and hybridizes with topological surface states, which not only reconciles the puzzling difference between the electronic structures of the bulk and thin-film MnBi2Te4 but also provides an interesting platform to establish Rashba ferromagnet that is attractive for (quantum) anomalous Hall effect. Our results provide important insights into the understanding and engineering of the intriguing quantum properties of MnBi2Te4 thin films.

Impact of different types of temporomandibular disorders on jaw functional limitation and psychological distress in orthodontic patients.

BACKGROUND: Some orthodontic patients are associated with temporomandibular joint disorders (TMDs), and the differences between jaw function and psychological states in orthodontic patients with different types of TMDs remain unknown. OBJECTIVE: This cross-sectional study aimed to investigate the prevalence of different types of TMDs in orthodontic patients and to evaluate the relationship between different types of TMDs and jaw functional limitation and psychological distress in orthodontic patients. METHODS: A questionnaire was sent to patients willing to participate in this survey, which included questions about the demographic characteristics of the participants, the five TMD symptoms (5Ts) of the Diagnostic Criteria for TMDs, the Jaw Functional Limitation Scale-8 (JFLS-8) and the Patient Health Questionnaire for Depression and Anxiety (PHQ-4). The subjects were divided into three groups: painful TMDs (PT), non-painful TMDs (NPT), and TMD-free according to whether they had TMDs and its subtypes. RESULTS: A total of 670 valid questionnaires were collected from 182 males and 488 females. The prevalence of TMDs was 35.4%, of which the prevalence of PT was 11.8% and the prevalence of NPT was 23.6%. The median JLFS-8 score of TMD patients was significantly higher than TMD-free, and PT patients were significantly higher than NPT (p = .026). After adjusting for confounding factors, the jaw function and psychological states of PT patients and NPT patients were worse than those of the TMD-free group. CONCLUSIONS: Among the orthodontic patients surveyed, more than one-third had TMDs and the prevalence of PT was lower than NPT. Having TMDs is associated with more severe jaw functional limitation, and PT patients were more serious than NPT patients. At the same time, the psychological states of TMDs patients were also worse.

Evolutionary Origin of Human PALB2 Germline Pathogenic Variants.

PALB2 (Partner and localizer of BRCA2) is crucial for repairing DNA double-stranded breaks (DSBs) through homologous recombination (HR). Germline pathogenic variation in PALB2 disrupts DNA damage repair and increases the risk of Fanconi Anemia, breast cancer, and ovarian cancer. Determination of the evolutionary origin of human PALB2 variants will promote a deeper understanding of the biological basis of PALB2 germline variation and its roles in human diseases. We tested the evolution origin for 1444 human PALB2 germline variants, including 484 pathogenic and 960 benign variants. We performed a phylogenic analysis by tracing the variants in 100 vertebrates. However, we found no evidence to show that cross-species conservation was the origin of PALB2 germline pathogenic variants, but it is indeed a rich source for PALB2 germline benign variants. We performed a paleoanthropological analysis by tracing the variants in over 5000 ancient humans. We identified 50 pathogenic in 71 ancient humans dated from 32,895 to 689 before the present, of which 90.1% were dated within the recent 10,000 years. PALB2 benign variants were also highly shared with ancient humans. Data from our study reveal that human PALB2 pathogenic variants mostly arose in recent human history.

Oxytocin inhibits hindpaw hyperalgesia induced by orofacial inflammation combined with stress.

Oxytocin (OT) is recognized as a critical neuropeptide in pain-related disorders. Chronic pain caused by the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) is common, but whether OT plays an analgesic role in the comorbidity of TMD and FMS is unknown. Female rats with masseter muscle inflammation combined with 3-day forced swim (FS) stress developed somatic hypersensitivity, which modeled the comorbidity of TMD and FMS. Using this model, the effects of spinal OT administration on mechanical allodynia and thermal hyperalgesia in hindpaws were examined. Furthermore, the protein levels of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn were analyzed by Western blot. The OT receptor antagonist atosiban and 5-HT2A receptor antagonist ritanserin were intrathecally injected prior to OT injection in the separate groups. Intrathecal injection of 0.125 µg and 0.5 µg OT attenuated the hindpaw hyperalgesia. The expression of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn significantly increased following intrathecal injection of 0.5 µg OT. Intrathecal administration of either the OT receptor antagonist atosiban or 5-HT2A receptor antagonist ritanserin blocked the analgesic effect of OT. These results suggest that OT may inhibit hindpaw hyperalgesia evoked by orofacial inflammation combined with stress through OT receptors and/or 5-HT2A receptors, thus providing a therapeutic prospect for drugs targeting the OT system and for patients with comorbidity of TMD and FMS.

A Fully Integrated, Ready-to-Use Distance-Based Chemosensor for Visual Quantification of Multiple Heavy Metal Ions.

Point-of-care devices offering quantitative results with simple steps would allow great useability for untrained end-users. Here, we report a ready-to-use chemosensor integrating automatic sample metering, on-chip reaction, gravitational-magnetic separation, and a distance-based readout for visual quantification of multiple heavy metal ions. Deoxyribozymes (DNAzymes), probe-modified magnetic microparticles (MMPs), and polystyrene microparticles (PMPs) are preloaded into a microfluidic chip and freeze-dried. After the water sample is collected with automatic volume metering, the particles are resuspended, and the MMPs and PMPs hybridize with DNAzyme at its two termini, forming the "MMPs-DNAzyme-PMPs" structure. When target metal ions are present, the DNAzymes are cleaved, yielding an increased number of free PMPs. All on-chip reactions are controlled by stopping the liquid flow at capillary valves and bursting it with hand-controlled tilting. Using the chip with a gravitational-magnetic separator, the free PMPs are separated from "MMPs-DNAzyme-PMPs" and accumulate into the trapping channel with a nozzle, forming a visual bar with growing distances proportional to the concentration of target metal ions. The achieved limit of detection (LOD) values for Cu2+ (103.1 nM), Pb2+ (69.5 nM), and Ag+ (793.6 nM) are below the maximum contamination levels. High selectivity of 100-fold, 200-fold, and 20-fold against interference is obtained. Moreover, by integrating three identical channels in parallel, simultaneous detection of the above-mentioned heavy metal ions in fresh and tap water samples is also achieved with high accuracy. Together, this fully integrated and easily operated platform embodies excellent potential for rapid, on-site sensing by unskilled users.

Is it necessary to monitor the serum luteinizing hormone (LH) concentration on the human chorionic gonadotropin (HCG) day among young women during the follicular-phase long protocol? A retrospective cohort study.

BACKGROUND: The normal physiological function of LH requires a certain concentration range, but because of pituitary desensitization, even on the day of HCG, endogenous levels of LH are low in the follicular-phase long protocol. Therefore, our study aimed to determine whether it is necessary to monitor serum LH concentrations on the day of HCG (LHHCG) and to determine whether there is an optimal LHHCG range to achieve the desired clinical outcome. METHODS: A retrospective cohort study included 4502 cycles of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) from January 1, 2016, to June 30, 2019, in a single department. The main outcome measures included retrieved eggs, available embryos, and live birth rate. RESULTS: The LHHCG was divided into five groups: Group A (LH ≤ 0.5), Group B (0.5 IU/L < LH ≤ 1.2 IU/L), Group C (1.2 IU/L < LH ≤ 2.0 IU/L), Group D (2.0 IU/L < LH ≤ 5.0 IU/L), Group E (LH > 5 IU/L). In terms of the numbers of retrieved eggs (15.22 ± 5.66 vs. 13.54 ± 5.23 vs. 12.90 ± 5.05 vs. 12.30 ± 4.88 vs. 9.6 ± 4.09), diploid fertilized oocytes (9.85 ± 4.70 vs. 8.69 ± 4.41 vs. 8.39 ± 4.33 vs. 7.78 ± 3.96 vs. 5.92 ± 2.78), embryos (7.90 ± 4.48 vs. 6.83 ± 4.03 vs. 6.44 ± 3.88 vs. 6.22 ± 3.62 vs. 4.40 ± 2.55), and high-quality embryos (4.32 ± 3.71 vs. 3.97 ± 3.42 vs. 3.76 ± 3.19 vs. 3.71 ± 3.04 vs. 2.52 ± 2.27), an increase in the LHHCG level showed a trend of a gradual decrease. However, there was no significant difference in clinical outcomes among the groups (66.67% vs. 64.33% vs. 63.21% vs. 64.48% vs. 63.33%). By adjusting for confounding factors, with an increase in LHHCG, the number of retrieved eggs decreased (OR: -0.351 95%CI - 0.453-[- 0.249]). CONCLUSION: In the follicular-phase long protocol among young women, monitoring LHHCG is recommended in the clinical guidelines to obtain the ideal number of eggs.

Core promoter mutation contributes to abnormal gene expression in bladder cancer.

BACKGROUND: Bladder cancer is one of the most mortal cancers. Bladder cancer has distinct gene expression signature, highlighting altered gene expression plays important roles in bladder cancer etiology. However, the mechanism for how the regulatory disorder causes the altered expression in bladder cancer remains elusive. Core promoter controls transcriptional initiation. We hypothesized that mutation in core promoter abnormality could cause abnormal transcriptional initiation thereby the altered gene expression in bladder cancer. METHODS: In this study, we performed a genome-wide characterization of core promoter mutation in 77 Spanish bladder cancer cases. RESULTS: We identified 69 recurrent somatic mutations in 61 core promoters of 62 genes and 28 recurrent germline mutations in 20 core promoters of 21 genes, including TERT, the only gene known with core promoter mutation in bladder cancer, and many oncogenes and tumor suppressors. From the RNA-seq data from bladder cancer, we observed  altered expression of the core promoter-mutated genes. We further validated the effects of core promoter mutation on gene expression by using luciferase reporter gene assay. We also identified potential drugs targeting the core promoter-mutated genes. CONCLUSIONS: Data from our study highlights that core promoter mutation contributes to bladder cancer development through altering gene expression.