The paradox of bone mineral density and fracture risk in type 2 diabetes.

Fracture risk in type 2 diabetes (T2D) patients is paradoxically increased despite no decrease in areal bone mineraldensity (BMD). This phenomenon, known as the "diabetic bone paradox", has been attributed to various factorsincluding alterations in bone microarchitecture and composition, hyperinsulinemia and hyperglycemia, advancedglycation end products (AGEs), and comorbidities associated with T2D. Zhao et al. recently investigated therelationship between T2D and fracture risk using both genetic and phenotypic datasets. Their findings suggest thatgenetically predicted T2D is associated with higher BMD and lower fracture risk, indicating that the bone paradox isnot observed when confounding factors are controlled using Mendelian randomization (MR) analysis. However, inprospective phenotypic analysis, T2D remained associated with higher BMD and higher fracture risk, even afteradjusting for confounding factors. Stratified analysis revealed that the bone paradox may disappear when T2Drelatedrisk factors are eliminated. The study also highlighted the role of obesity in the relationship between T2Dand fracture risk, with BMI mediating a significant portion of the protective effect. Overall, managing T2D-relatedrisk factors may be crucial in preventing fracture risk in T2D patients.

Deciphering the complex relationship between type 2 diabetes and fracture risk with both genetic and observational evidence.

The 'diabetic bone paradox' suggested that type 2 diabetes (T2D) patients would have higher areal bone mineral density (BMD) but higher fracture risk than individuals without T2D. In this study, we found that the genetically predicted T2D was associated with higher BMD and lower risk of fracture in both weighted genetic risk score (wGRS) and two-sample Mendelian randomization (MR) analyses. We also identified ten genomic loci shared between T2D and fracture, with the top signal at SNP rs4580892 in the intron of gene RSPO3. And the higher expression in adipose subcutaneous and higher protein level in plasma of RSPO3 were associated with increased risk of T2D, but decreased risk of fracture. In the prospective study, T2D was observed to be associated with higher risk of fracture, but BMI mediated 30.2% of the protective effect. However, when stratified by the T2D-related risk factors for fracture, we observed that the effect of T2D on the risk of fracture decreased when the number of T2D-related risk factors decreased, and the association became non-significant if the T2D patients carried none of the risk factors. In conclusion, the genetically determined T2D might not be associated with higher risk of fracture. And the shared genetic architecture between T2D and fracture suggested a top signal around RSPO3 gene. The observed effect size of T2D on fracture risk decreased if the T2D-related risk factors could be eliminated. Therefore, it is important to manage the complications of T2D to prevent the risk of fracture.

Human genetics of face recognition: discovery of MCTP2 mutations in humans with face blindness (congenital prosopagnosia).

Face recognition is important for both visual and social cognition. While prosopagnosia or face blindness has been known for seven decades and face-specific neurons for half a century, the molecular genetic mechanism is not clear. Here we report results after 17 years of research with classic genetics and modern genomics. From a large family with 18 congenital prosopagnosia (CP) members with obvious difficulties in face recognition in daily life, we uncovered a fully cosegregating private mutation in the MCTP2 gene which encodes a calcium binding transmembrane protein expressed in the brain. After screening through cohorts of 6589, we found more CPs and their families, allowing detection of more CP associated mutations in MCTP2. Face recognition differences were detected between 14 carriers with the frameshift mutation S80fs in MCTP2 and 19 noncarrying volunteers. Six families including one with 10 members showed the S80fs-CP correlation. Functional magnetic resonance imaging found association of impaired recognition of individual faces by MCTP2 mutant CPs with reduced repetition suppression to repeated facial identities in the right fusiform face area. Our results have revealed genetic predisposition of MCTP2 mutations in CP, 76 years after the initial report of prosopagnosia and 47 years after the report of the first CP. This is the first time a gene required for a higher form of visual social cognition was found in humans.

Searching across-cohort relatives in 54,092 GWAS samples via encrypted genotype regression.

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier.

Ambient PM2.5 Exposure and Bone Homeostasis: Analysis of UK Biobank Data and Experimental Studies in Mice and in Vitro.

BACKGROUND: Previous evidence has identified exposure to fine ambient particulate matter (PM2.5) as a leading risk factor for adverse health outcomes. However, to date, only a few studies have examined the potential association between long-term exposure to PM2.5 and bone homeostasis. OBJECTIVE: We sought to examine the relationship between long-term PM2.5 exposure and bone health and explore its potential mechanism. METHODS: This research included both observational and experimental studies. First, based on human data from UK Biobank, linear regression was used to explore the associations between long-term exposure to PM2.5 (i.e., annual average PM2.5 concentration for 2010) and bone mineral density [BMD; i.e., heel BMD (n=37,440) and femur neck and lumbar spine BMD (n=29,766)], which were measured during 2014-2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient PM2.5 or filtered air for 6 months via a whole-body exposure system. Micro-computed tomography analyses were applied to measure BMD and bone microstructures. Biomarkers for bone turnover and inflammation were examined with histological staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. We also performed tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay to determine the effect of PM2.5 exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot. RESULTS: We observed that long-term exposure to PM2.5 was significantly associated with lower BMD at different anatomical sites, according to the analysis of UK Biobank data. In experimental study, mice exposed long-term to PM2.5 exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha (TNF-α) expression, and shorter femur length than control mice, but they demonstrated no significant differences in femur structure or BMD. In vitro, cells stimulated with conditional medium of PM2.5-stimulated macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the TNF-α/Traf6/c-Fos pathway, which could be partially rescued by TNF-α inhibition. DISCUSSION: Our prospective observational evidence suggested that long-term exposure to PM2.5 is associated with lower BMD and further experimental results demonstrated exposure to PM2.5 could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646.

Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss.

Sulfation is a widespread modification of biomolecules that has been incompletely explored to date. Through cross-phenotype meta-analysis of bone mineral density in up to 426,824 genotyped human participants along with phenotypic characterization of multiple mutant mouse lines, we identified a causative role for sulfate transporter solute carrier family 26 member A2 (SLC26A2) deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited peculiar pericellular matrix (PCM) production characterized by undersulfation coupled with decreased stiffness. These altered chemophysical properties of the PCM disrupted the formation of focal adhesions in osteoblasts. Bulk RNA sequencing and functional assays revealed that the mechanoreciprocal inhibition of focal adhesion kinase (FAK) and Yes1-associated transcriptional regulator (YAP)/WW domain containing transcription regulator 1 (TAZ) signaling impinged osteoblast maturation upon SLC26A2 deficiency. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running ameliorated SLC26A2-deficient osteoporosis by promoting YAP/TAZ activity. Analysis of mouse single-cell RNA sequencing data suggested coordination among sulfate metabolism, focal adhesion, and YAP/TAZ activity during osteoblast-to-osteocyte transition. In addition to the SLC26A2-deficient setting, altered FAK and YAP/TAZ signaling was also observed in bone cells of ovariectomized mice and patients with osteoporosis, and pharmacological enforcing of YAP/TAZ activity ameliorated bone loss in ovariectomized mice. Collectively, these data unveil a role for sulfation in the developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.

Research on Improving Humanistic Quality of Medical Students in Obstetrics and Gynecology Based on Blend-learning / 中国医学伦理学

Under the new situation of rapid development of medical science and technology, how to effectively cultivate medical students’ humanistic spirit and comprehensively improve medical quality is an important responsibility of medical college teachers. Blend-learning can guide students to immersive learning in multiple dimensions and forms. Obstetrics and Gynecology is one of the main compulsory courses for clinical medical students, which is faced more sensitive and vulnerable female patients, and required higher humanistic quality training for medical students. Through the construction of the blend-learning platform, medical humanities can be better integrated into the content and teaching design of medical education, and students can be more appropriately imperceptibly trained in medical humanities in obstetrics and gynecology teaching, so as to enhance medical students’ medical humanities quality in the process of obstetrics and gynecology diagnosis and treatment, and improve doctor-patient relationship.

Both indirect maternal and direct fetal genetic effects reflect the observational relationship between higher birth weight and lower adult bone mass.

BACKGROUND: Birth weight is considered not only to undermine future growth, but also to induce lifelong diseases; the aim of this study is to explore the relationship between birth weight and adult bone mass. METHODS: We performed multivariable regression analyses to assess the association of birth weight with bone parameters measured by dual-energy X-ray absorptiometry (DXA) and by quantitative ultrasound (QUS), independently. We also implemented a systemic Mendelian randomization (MR) analysis to explore the causal association between them with both fetal-specific and maternal-specific instrumental variables. RESULTS: In the observational analyses, we found that higher birth weight could increase the adult bone area (lumbar spine, ß-coefficient= 0.17, P < 2.00 × 10-16; lateral spine, ß-coefficient = 0.02, P = 0.04), decrease bone mineral content-adjusted bone area (BMCadjArea) (lumbar spine, ß-coefficient= - 0.01, P = 2.27 × 10-14; lateral spine, ß-coefficient = - 0.05, P = 0.001), and decrease adult bone mineral density (BMD) (lumbar spine, ß-coefficient = - 0.04, P = 0.007; lateral spine; ß-coefficient = - 0.03, P = 0.02; heel, ß-coefficient = - 0.06, P < 2.00 × 10-16), and we observed that the effect of birth weight on bone size was larger than that on BMC. In MR analyses, the higher fetal-specific genetically determined birth weight was identified to be associated with higher bone area (lumbar spine; ß-coefficient = 0.15, P = 1.26 × 10-6, total hip, ß-coefficient = 0.15, P = 0.005; intertrochanteric area, ß-coefficient = 0.13, P = 0.0009; trochanter area, ß-coefficient = 0.11, P = 0.03) but lower BMD (lumbar spine, ß-coefficient = - 0.10, P = 0.01; lateral spine, ß-coefficient = - 0.12, P = 0.0003, and heel ß-coefficient = - 0.11, P = 3.33 × 10-13). In addition, we found that the higher maternal-specific genetically determined offspring birth weight was associated with lower offspring adult heel BMD (ß-coefficient = - 0.001, P = 0.04). CONCLUSIONS: The observational analyses suggested that higher birth weight was associated with the increased adult bone area but decreased BMD. By leveraging the genetic instrumental variables with maternal- and fetal-specific effects on birth weight, the observed relationship could be reflected by both the direct fetal and indirect maternal genetic effects.

Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession.

PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 is considered as a "pseudokinase", contributing to different kinds of cancer. However, the detailed roles of TRIB2 in regulating cancer metabolism by PKM2 remain unclear. This study demonstrated that TRIB2, not a "pseudokinase", has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. The elevated pSer37-PKM2 would subsequently promote the PKM2 dimers to enter into nucleus and increase the expression of LDHA, GLUT1, and PTBP1. The aerobic glycolysis is then elevated to promote cancer cell proliferation and migration in TRIB2- or PKM2-overexpressed cultures. The glucose uptake and lactate production increased, but the ATP content decreased in TRIB2- or PKM2-treated cultures. Experiments of TRIB2-/- mice further supported that TRIB2 could regulate aerobic glycolysis by PKM2. Thus, these results reveal the new kinase activity of TRIB2 and its mechanism in cancer metabolism may be related to regulating PKM2 to promote lung cancer cell proliferation in vitro and in vivo, suggesting promising therapeutic targets for cancer therapy by controlling cancer metabolism.

General and abdominal obesity operate differently as influencing factors of fracture risk in old adults.

To infer the causality between obesity and fracture and the difference between general and abdominal obesity, a prospective study was performed in 456,921 participants, and 10,142 participants developed an incident fracture with follow-up period of 7.96 years. A U-shape relationship was observed between BMI and fracture, with the lowest risk of fracture in overweight participants. The obesity individuals had higher fracture risk when BMD was adjusted, and the protective effect of moderate-high BMI on fracture was mostly mediated by bone mineral density (BMD). However, for abdominal obesity, the higher WCadjBMI (linear) and HCadjBMI (J-shape) were found to be related to higher fracture risk, and less than 30% of the effect was mediated by BMD. By leveraging genetic instrumental variables, it provided additional evidences to support the aforementioned findings. In conclusion, keeping moderate-high BMI might be of benefit to old people in terms of fracture risk, whereas abdominal adiposity might increase risk of fracture.

Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project.

We initiate the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing (WGS) individuals and 5,841 high-density genotyping individuals, and identify 81.5 million SNPs and INDELs, of which 38.5% are absent in dbSNP Build 151. We provide a population-specific reference panel and an online imputation server ( https://wbbc.westlake.edu.cn/ ) which could yield substantial improvement of imputation performance in Chinese population, especially for low-frequency and rare variants. By analyzing the singleton density of the WGS data, we find selection signatures in SNX29, DNAH1 and WDR1 genes, and the derived alleles of the alcohol metabolism genes (ADH1A and ADH1B) emerge around 7,000 years ago and tend to be more common from 4,000 years ago in East Asia. Genetic evidence supports the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains, which separate the Han Chinese into subgroups, and we reveal that North Han was more homogeneous than South Han.

Morroniside ameliorates inflammatory skeletal muscle atrophy via inhibiting canonical and non-canonical NF-κB and regulating protein synthesis/degradation.

No drug options exist for skeletal muscle atrophy in clinical, which poses a huge socio-economic burden, making development on drug interventions a general wellbeing need. Patients with a variety of pathologic conditions associated with skeletal muscle atrophy have systemically elevated inflammatory factors. Morroniside, derived from medicinal herb Cornus officinalis, possesses anti-inflammatory effect. However, whether and how morroniside combat muscle atrophy remain unknown. Here, we identified crucial genetic associations between TNFα/NF-κB pathway and grip strength based on population using 377,807 European participants from the United Kingdom Biobank dataset. Denervation increased TNFα in atrophying skeletal muscles, which inhibited myotube formation in vitro. Notably, morroniside treatment rescued TNFα-induced myotube atrophy in vitro and impeded skeletal muscle atrophy in vivo, resulting in increased body/muscles weights, No. of satellite cells, size of type IIA, IIX and IIB myofibers, and percentage of type IIA myofibers in denervated mice. Mechanistically, in vitro and/or in vivo studies demonstrated that morroniside could not only inhibit canonical and non-canonical NF-κB, inflammatory mediators (IL6, IL-1b, CRP, NIRP3, PTGS2, TNFα), but also down-regulate protein degradation signals (Follistatin, Myostatin, ALK4/5/7, Smad7/3), ubiquitin-proteasome molecules (FoxO3, Atrogin-1, MuRF1), autophagy-lysosomal molecules (Bnip3, LC3A, and LC3B), while promoting protein synthesis signals (IGF-1/IGF-1R/IRS-1/PI3K/Akt, and BMP14/BMPR2/ALK2/3/Smad5/9). Moreover, morroniside had no obvious liver and kidney toxicity. This human genetic, cells and mice pathological evidence indicates that morroniside is an efficacious and safe inflammatory muscle atrophy treatment and suggests its translational potential on muscle wasting.

Observational and genetic evidence highlight the association of human sleep behaviors with the incidence of fracture.

We combined conventional evidence from longitudinal data in UK Biobank and genetic evidence from Mendelian randomization (MR) approach to infer the causality between sleep behaviors and fracture risk. We found that participants with insomnia showed 6.4% higher risk of fracture (hazard ratio [HR] = 1.064, 95% CI = 1.038-1.090, P = 7.84 × 10-7), falls and bone mineral density (BMD) mediated 24.6% and 10.6% of the intermediary effect; the MR analyses provided the consistent evidence. A U-shape relationship was observed between sleep duration and fracture risk (P < 0.001) with the lowest risk at sleeping 7-8 h per day. The excessive daytime sleepiness and "evening" chronotype were associated with fracture risk in observational study, but the association between chronotype and fracture did not show in MR analyses. We further generated a sleep risk score (SRS) with potential risk factors (i.e., insomnia, sleep duration, chronotype, and daytime sleepiness). We found that the risk of fracture increased with an increasing SRS (HR = 1.087, 95% CI = 1.065-1.111, P = 1.27 × 10-14). Moreover, 17.4% of the fracture cases would be removed if all participants exhibited a healthy sleep pattern. In conclusion, insomnia had a causal effect on fracture, falls had a larger intermediary effect than BMD in this association. Individuals with fracture risk could benefit from the intervention on unhealthy sleep pattern.

Integrative analysis of genomic and epigenomic data reveal underlying superenhancer-mediated microRNA regulatory network for human bone mineral density.

Bone mineral density (BMD) is a highly heritable complex trait and is a key indicator for diagnosis and treatment for osteoporosis. In the last decade, numerous susceptibility loci for BMD and fracture have been identified by genome-wide association studies (GWAS); however, fine mapping of these loci is challengeable. Here, we proposed a new long-range fine-mapping approach that combined superenhancers (SEs) and microRNAs (miRNAs) data, which were two important factors in control of cell identity and specific differentiation, with the GWAS summary datasets in cell-type-restricted way. Genome-wide SE-based analysis found that the BMD-related variants were significantly enriched in the osteoblast SE regions, indicative of potential long-range effects of such SNPs. With the SNP-mapped SEs (mSEs), 13 accessible long-range mSE-interacted miRNAs (mSE-miRNAs) were identified by integrating osteoblast Hi-C and ATAC-seq data, including three known bone-related miRNAs (miR-132-3p, miR-212-3p and miR-125b-5p). The putative targets of the two newly identified mSE-miRNAs (miR-548aj-3p and miR-190a-3p) were found largely enriched in osteogenic-related pathway and processes, suggesting that these mSE-miRNAs could be functional in the regulation of osteoblast differentiation. Furthermore, we identified 54 genes with the long-range 'mSE-miRNA' approach, and 24 of them were previously reported to be related to skeletal development. Besides, enrichment analysis found that these genes were specifically enriched in the post-transcriptional regulation and bone formation processes. This study provided a new insight into the approach of fine-mapping of GWAS loci. A tool was provided for the genome-wide SE-based analysis and the detection of long-range osteoblast-restricted mSE-miRNAs (https://github.com/Zheng-Lab-Westlake/Osteo-Fine-Mapp-SNP2SE2miRNA).

Cohort profile: the Westlake BioBank for Chinese (WBBC) pilot project.

PURPOSE: The Westlake BioBank for Chinese (WBBC) pilot cohort is a population-based prospective study with its major purpose to better understand the effect of genetic and environmental factors on growth and development from adolescents to adults. PARTICIPANTS: A total of 14 726 participants (4751 males and 9975 females) aged 14-25 years were recruited and the baseline survey was carried out from 2017 to 2019. The pilot cohort contains rich range of information regarding of demographics and anthropometric measurements, lifestyle and sleep patterns, clinical and health outcomes. Visit the WBBC website for more information (https://wbbc.westlake.edu.cn/index.html). FINDINGS TO DATE: The mean age of the study samples were 18.6 years for males and 18.5 years for females, respectively. The mean height and weight were 172.9 cm and 65.81 kg for males, and 160.1 cm and 52.85 kg for females. Results indicated that the prevalence of underweight in female was much higher than male, but the prevalence of overweight and obesity in female was lower than male. The mean serum 25(OH)D level in the 14 726 young participants was 22.4±5.3 ng/mL, and male had a higher level of serum 25(OH)D than female, overall, 33.5% of the participants had vitamin D deficiency and even more participants suffered from vitamin D insufficiency (58.2%). The proportion of deficiency in females was much higher than that in males (41.8 vs 16.4%). The issue of underweight and vitamin D deficiency in young people should be paid attention, especially in females. These results reflected the fact that thinness and paler skin are preferred in modern aesthetics of Chinese culture. FUTURE PLANS: WBBC pilot is designed as a prospective cohort study and provides a unique and rich data set analysing health trajectories from adolescents to young adults. WBBC will continue to collect samples with old age.

Reproductive outcomes of intracytoplasmic sperm injection using testicular sperm and ejaculated sperm in patients with AZFc microdeletions: a systematic review and meta-analysis.

Studies have explored the assisted reproductive technology (ART) outcomes of Y-chromosome azoospermia factor c (AZFc) microdeletions, but the effect of sperm source on intracytoplasmic sperm injection (ICSI) remains unknown. To determine the ART results of ICSI using testicular sperm and ejaculated sperm from males with AZFc microdeletions, we searched Embase, Web of Science, and PubMed to conduct a systematic review and meta-analysis. The first meta-analysis results for 106 cycles in five studies showed no significant differences in the live birth rate between the testicular sperm group and the ejaculated sperm group (risk ratio: 0.97, 95% confidence interval [CI]: 0.73-1.28, P = 0.82). The second meta-analysis of 106 cycles in five studies showed no difference in the abortion rate between the testicular sperm group and ejaculated sperm group (risk ratio: 1.06, 95% CI: 0.54-2.06, P = 0.87). The third meta-analysis of 386 cycles in seven studies showed no significant difference in clinical pregnancy rates between the testicular sperm group and the ejaculated sperm group (risk ratio: 1.24, 95% CI: 0.66-2.34, P = 0.50). Inevitable heterogeneity weakened our results. However, our results indicated that testicular sperm and ejaculated sperm yield similar ART outcomes, representing a meaningful result for clinical treatment. More properly designed studies are needed to further confirm our conclusions.