Population-specific putative causal variants shape quantitative traits.

Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10-15 and odds ratio = 4.5, 95% confidence interval = 3.1-6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3' untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.

R150S mutation in the human oxytocin receptor: gain-of-function effects and implication in autism spectrum disorder.

This study investigates the rs547238576 (R150S) missense variant in the oxytocin receptor (OXTR) gene, previously observed through screening of rare variants in Japanese individuals with autism spectrum disorders (ASD). Contrary to the anticipated loss-of-function, R150S exhibits gain-of-function effects, enhancing oxytocin (OXT) sensitivity, ligand-binding affinity, and OXT-induced Ca2+ mobilization in vitro. This suggests R150S may alter OXT signaling, potentially contributing to the excitatory/inhibitory imbalance seen in ASD and other psychiatric disorders. Our findings underscore the significance of genetic variations in OXTR on functional activity and highlight the necessity for population-specific genetic study and in vitro analysis to elucidate genetic susceptibilities to neuropsychiatric conditions.

Initial Experience of Metabolic Imaging With Hyperpolarized [1-13C]pyruvate MRI in Kidney Transplant Patients.

BACKGROUND: Kidney transplant is the treatment of choice for patients with end-stage renal disease. Early detection of allograft injury is important to delay or prevent irreversible damage. PURPOSE: To investigate the feasibility of hyperpolarized (HP) [1-13C]pyruvate MRI for assessing kidney allograft metabolism. STUDY TYPE: Prospective. SUBJECTS: Six participants (mean age, 45.2 ± 12.4 years, two females) scheduled for kidney allograft biopsy and five patients (mean age, 59.6 ± 10.4 years, two females) with renal cell carcinoma (RCC). FIELD STRENGTH/SEQUENCE: Three Tesla, T2-weighted fast spin echo, multi-echo gradient echo, single shot diffusion-weighted echo-planar imaging, and time-resolved HP 13C metabolite-selective imaging. ASSESSMENT: Five of the six kidney allograft participants underwent biopsy after MRI. Estimated glomerular filtration rate (eGFR) and urine protein-to-creatine ratio (uPCR) were collected within 4 weeks of MRI. Kidney metabolism was quantified from HP [1-13C]pyruvate MRI using the lactate-to-pyruvate ratio in allograft kidneys and non-tumor bearing kidneys from RCC patients. STATISTICAL TESTS: Descriptive statistics (mean ± SD). RESULTS: Biopsy was performed a mean of 9 days (range 5-19 days) after HP [1-13C]pyruvate MRI. Three biopsies were normal, one showed low-grade fibrosis and one showed moderate microvascular inflammation. All had stable functioning allografts with eGFR >60 mL/min/1.73 m2 and normal uPCR. One participant who did not undergo biopsy had reduced eGFR of 49 mL/min/1.73 m2 and elevated uPCR. The mean lactate-to-pyruvate ratio was 0.373 in participants with normal findings (N = 3) and 0.552 in participants with abnormal findings (N = 2). The lactate-to-pyruvate ratio was highest (0.847) in the participant with reduced eGFR and elevated uPRC. Native non-tumor bearing kidneys had a mean lactate-to-pyruvate ratio of 0.309. DATA CONCLUSION: Stable allografts with normal findings at biopsy showed lactate-to-pyruvate ratios similar to native non-tumor bearing kidneys, whereas allografts with abnormal findings showed higher lactate-to-pyruvate ratios. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Genome-wide association studies for pelvic organ prolapse in the Japanese population.

Pelvic organ prolapse (POP) affects approximately 40% of elderly women, characterized by the descent of the pelvic organs into the vaginal cavity. Here we present the results of a genome-wide association study (GWAS) for susceptibility to POP comprising 771 cases and 76,625 controls in the Japanese population. We identified a significant association of WT1 locus with POP in the Japanese population; rs10742277; odds ratio (OR) = 1.48, 95% confidence interval (CI), 1.29-1.68, P = 6.72 × 10-9. Subsequent cross-ancestry GWAS meta-analysis combining the Japanese data and previously reported European data, including 28,857 cases and 622,916 controls, identified FGFR2 locus as a novel susceptibility locus to POP (rs7072877; OR = 1.06, 95% CI, 1.04-1.08, P = 4.11 × 10-8). We also observed consistent directions of the effects for 21 out of 24 European GWAS derived loci (binomial test P = 2.8 × 10-4), indicating that most of susceptibility loci for POP are shared across the Japanese and European populations.

Chemosensory anhedonia facilitates depressive symptoms and cognitive impairment in late-life depression.

AIM: Chemosensory anhedonia refers to the lack of hedonic ability to experience pleasure through the senses of smell and taste, which reduces the pleasure and comfort of food, and increases the risk of nutritional and immune deficiencies. However, there is no direct scientific evidence regarding chemosensory anhedonia in patients with late-life depression (LLD). The aim of this study was to investigate chemosensory anhedonia in patients with LLD, and its potential association with depressive symptoms and cognitive function. METHODS: A total of 114 patients with LLD and 92 normal controls were included in this study. They experienced clinical assessment, Chemosensory Pleasure Scale assessment, 17-item Hamilton Depression Rating Scale assessment and cognitive assessments, which contain the Verbal Fluency Test. The associations between chemosensory pleasure and depressive symptoms or cognitive function in patients with LLD were explored using partial correlation analysis and mediation analysis. RESULTS: The Chemosensory Pleasure Scale scores were lower in the LLD group than in the normal control group, and were negatively correlated with the total scores and factors' scores (retardation, cognitive bias and anxiety/somatization) of the 17-item Hamilton Depression Rating Scale, and positively correlated with the Verbal Fluency Test scores. The scores for the Food and Imagination dimensions of the Chemosensory Pleasure Scale showed partial mediating effects on the differences in Cognitive bias (a factor of the 17-item Hamilton Depression Rating Scale) between patients with LLD and normal controls. CONCLUSIONS: Patients with LLD showed significant chemosensory anhedonia, and both depressive symptoms and cognitive impairment were associated with the severity of chemosensory anhedonia. Enhancing chemosensory pleasure in patients with LLD could potentially ameliorate their depressive symptoms. Geriatr Gerontol Int 2024; 24: 1022-1029.

Initial Experience of Metabolic Imaging with Hyperpolarized [1-13C]pyruvate MRI in Kidney Transplant Patients.

BACKGROUND: Kidney transplant is the treatment of choice for patients with end-stage renal disease. Early detection of allograft injury is important to delay or prevent irreversible damage. PURPOSE: To investigate the feasibility of hyperpolarized (HP) [1-13C]pyruvate MRI for assessing kidney allograft metabolism. STUDY TYPE: Prospective. SUBJECTS: 6 participants (mean age, 45.2 ± 12.4 years, 2 females) scheduled for kidney allograft biopsy and 5 patients (mean age, 59.6 ± 10.4 years, 2 females) with renal cell carcinoma (RCC). FIELD STRENGTH/SEQUENCE: 3 Tesla, T2-weighted fast spin echo, multi-echo gradient echo, single shot diffusion-weighted echo-planar imaging, and time-resolved HP 13C metabolite-selective imaging. ASSESSMENT: Five of the six kidney allograft participants underwent biopsy after MRI. Estimated glomerular filtration rate (eGFR) and urine protein-to-creatine ratio (uPCR) were collected within 4 weeks of MRI. Kidney metabolism was quantified from HP [1-13C]pyruvate MRI using the lactate-to-pyruvate ratio in allograft kidneys and non-tumor bearing kidneys from RCC patients. STATISTICAL TESTS: Descriptive statistics (mean ± standard deviation). RESULTS: Biopsy was performed a mean of 9 days (range 5-19 days) after HP [1-13C]pyruvate MRI. Three biopsies were normal, one showed low-grade fibrosis and one showed moderate microvascular inflammation. All had stable functioning allografts with eGFR > 60 mL/min/1.73 m2 and normal uPCR. One participant who did not undergo biopsy had reduced eGFR of 49 mL/min/1.73 m2 and elevated uPCR. The mean lactate-to-pyruvate ratio was 0.373 in participants with normal findings (n = 3) and 0.552 in participants with abnormal findings (n = 2). The lactate-to-pyruvate ratio was highest (0.847) in the participant with reduced eGFR and elevated uPRC. Native non-tumor bearing kidneys had a mean lactate-to-pyruvate ratio of 0.309. DATA CONCLUSION: Stable allografts with normal findings at biopsy showed lactate-to-pyruvate ratios similar to native non-tumor bearing kidneys, whereas allografts with abnormal findings showed higher lactate-to-pyruvate ratios.

Baicalin methyl ester prevents the LPS - induced mice intestinal barrier damage in vivo and in vitro via P65/TNF-α/MLCK/ZO-1 signal pathway.

The effect of baicalin methyl ester (BME) on the regulation of mice intestinal barrier in the inflammatory response was studied in vivo and in vitro. Thirty six C57/BL mice were randomly divided into six groups (n = 6): control group; LPS group (LPS 3.5 mg/kg given intraperitoneal [ip] on day 7 of the study only), PBS group, and three BME groups (low: 50 mg/kg; medium: 100 mg/kg; high: 200 mg/kg) orally dosed with BME for 7d and LPS ip on day 7. All mice were sacrificed on day 8, and jejunum tissue collected for histopathology (H&E and PAS staining), protein expression of pro-inflammatory factors (TNF-α, IL-6, IL-8, IFN-γ) by ELISA, and intestinal tight junction proteins (ZO-1, occludin, claudin-1 and claudin-4) by Western Blot. Compared with the control group, LPS significantly increased the serum cytokines DAO (p < 0.01) and DLA (p < 0.01), upregulated the expression of pro-inflammatory factors, MLCK proteins (p <0.05) and increased the MLCK/ZO-1ratio (p <0.001). LPS also decreased the expression of claudin-4 (p < 0.01) in the jejunum and induced an inflammatory response damaging the jejunal mucosal barrier. Pretreatment with BME (100-200 mg/kg) significantly decreased the cytokines DAO (p < 0.05) and DLA (p < 0.01) in the serum, pro-inflammatory factors in the jejunum, significantly down-regulated the expression of MLCK (p <0.05) and the ratio of MLCK/ZO-1(p <0.001) but upregulated the expressions of ZO-1(p < 0.01), occludin (p < 0.05), claudin-1(p < 0.05) and claudin-4 (p < 0.05), and thereby restored the intestinal tissue structure, suggestive of alleviation of LPS-induced intestinal inflammation by BME. In vitro, MODE-K cells (derived from mice intestinal epithelium) were exposed to BME at 0 (control group-No LPS), 10, 20 and 40 µM BME for 24 h prior to LPS addition at 50 µg/mL for 2 h. LPS significantly increased the expression of pro-inflammatory factors, MLCK (p < 0.01) and the ratio of MLCK/ZO-1(p <0.001), decreased the expressions of ZO-1 (p < 0.05), occludin (p < 0.01), claudin-1 (p < 0.01) and claudin-4 (p < 0.01) in MODE-K cells compared with the control group. Compared with the LPS group, BME (10 - 40 µM) significantly decreased the expression of pro-inflammatory factors, MLCK (p < 0.05) and the ratio of MLCK/ZO-1(p <0.01) but increased the expressions of ZO-1(p < 0.01), occludin (p < 0.05) and claudin-4(p < 0.01) indicating an up-regulation of the expression of tight junction proteins by BME. On addition of extrinsic TNF-α plus LPS, the TNF- α level increased (p < 0.001) in MODE-K cells and the protein expression of MLCK (p < 0.01) was markedly up-regulated. Molecular docking predicted BME interacted with P65 by forming hydrogen bonds. IP-WB further confirmed that BME was directly bound to P65 protein in MODE-K cells. In conclusion, BME was able to restore the intestinal barrier through the P65 / TNF-α / MLCK / ZO-1 signaling pathway.

Increased somatic mosaicism in autosomal and X chromosomes for suicide death.

Mosaic chromosomal alterations (mCAs) are classified as mosaic deletions (loss), copy-neutral loss of heterozygosity (CN-LOH), and duplications (gain), attracting special attention as biological aging-related acquired genetic alterations. While these mCAs have been linked with aging and various diseases, no study has investigated their association with suicide risk which is associated with abnormal biological aging. Here, we examined the association between suicide deaths and mCAs, including mosaic loss of the X (mLOX) and Y chromosomes, by leveraging blood-derived single nucleotide polymorphism-array data. The first (410 suicide decedents and 88,870 controls) and the second (363 suicide decedents and 88,870 controls) cohorts were analyzed and integrated using meta-analyses (773 suicide decedents and 177,740 controls). Total mCAs in autosomal chromosomes were significantly increased in suicide (p = 1.28 × 10-6, odds ratio [OR] = 1.78), mostly driven by loss (p = 4.05 × 10-9, OR = 2.70) and gain (p = 1.08 × 10-3, OR = 2.23). mLOX were significantly increased in female suicide (p = 2.66 × 10-21, OR = 4.00). The directions of effects of all mCAs in autosomal and sex chromosomes on suicide were the same in the first and second sets. Subgroup analyses suggest that our findings were mostly driven by suicide itself, and not confounded by comorbid psychiatric disorders or physical diseases, smoking status, sample location, or postmortem sample status. In conclusion, we provide the first evidence for aberrant mCAs in somatic autosomal and X chromosomes in suicide, which may contribute to an improved understanding of the genomic pathophysiology underlying suicide.

RILP Induces Cholesterol Accumulation in Lysosomes by Inhibiting Endoplasmic Reticulum-Endolysosome Interactions.

Endoplasmic reticulum (ER)-endolysosome interactions regulate cholesterol exchange between the ER and the endolysosome. ER-endolysosome membrane contact sites mediate the ER-endolysosome interaction. VAP-ORP1L (vesicle-associated membrane protein-associated protein- OSBP-related protein 1L) interaction forms the major contact site between the ER and the lysosome, which is regulated by Rab7. RILP (Rab7-interacting lysosomal protein) is the downstream effector of Rab7, but its role in the organelle interaction between the ER and the lysosome is not clear. In this study, we found RILP interacts with ORP1L to competitively inhibit the formation of the VAP-ORP1L contact site. Immunofluorescence microscopy revealed that RILP induces late endosome/lysosome clustering, which reduces the contact of endolysosomes with the ER, interfering with the ER-endolysosome interaction. Further examination demonstrated that over-expression of RILP results in the accumulation of cholesterol in the clustered endolysosomes, which triggers cellular autophagy depending on RILP. Our results suggest that RILP interferes with the ER-endolysosome interaction to inhibit cholesterol flow from the endolysosome to the ER, which feedbacks to trigger autophagy.

Siraitia grosvenorii Extract Protects Lipopolysaccharide-Induced Intestinal Inflammation in Mice via Promoting M2 Macrophage Polarization.

Siraitia grosvenorii has anti-inflammatory, antioxidant, and immune-regulating effects, while macrophages play an important role in reducing inflammation. However, it is still unclear whether Siraitia grosvenorii extract (SGE) is effective in reducing inflammation by regulating macrophages. This study investigated the regulatory effect of SGE on macrophage polarization in a lipopolysaccharide (LPS)-induced intestinal inflammation model after establishing the model in vitro and in vivo. The results from the in vivo model showed that, compared with the LPS group, SGE significantly improved ileal morphology, restored the ileal mucosal barrier, and reduced intestinal and systemic inflammation by increasing CD206 and reducing iNOS proteins. In the in vitro model, compared with the LPS group, SGE significantly reduced the expression of iNOS protein and cytokines (TNF-α, IL-1ß, and IFN-γ) while significantly increasing the protein expression of CD206 in RAW264.7 cells. In conclusion, SGE can alleviate intestinal inflammation, protect the mucus barrier, and block the systemic immunosuppressive response by increasing M2 macrophages.

LncRNA MALAT-1 modulates EGFR-TKI resistance in lung adenocarcinoma cells by downregulating miR-125.

Molecular targeted therapy resistance remains a major challenge in treating lung adenocarcinoma (LUAD). The resistance of Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs, epidermal growth factor receptor-tyrosine kinase inhibitor) plays a dominant role in molecular targeted therapy. Our previous research demonstrated the role of MALAT-1 (Metastasis-associated lung adenocarcinoma transcript 1) in the formation of Erlotinib-resistant LUAD cells. This study aims to uncover the mechanism of MALAT-1 overexpression in Erlotinib-resistant LUAD cells. The RT2 LncRNA PCR array system was used to explore MALAT-1 regulation in Erlotinib-resistant LUAD cells through patient serum analysis. Dual luciferase reporter experiments confirmed the binding between MALAT-1 and miR-125, leading to regulation of miR-125 expression. Functional assays were performed to elucidate the impact of MALAT1 on modulating drug resistance, growth, and Epithelial-mesenchymal transition (EMT, Epithelial-mesenchymal transition) in both parental and Erlotinib-resistant LUAD cells. The investigation unveiled the mechanism underlying the competing endogenous RNA (ceRNA, competing endogenouse RNA) pathway. MALAT1 exerted its regulatory effect on miR-125 as a competing endogenous RNA (ceRNA). Moreover, MALAT1 played a role in modulating the sensitivity of LUAD cells to Erlotinib. Rab25 was identified as the direct target of miR-125 and mediated the functional effects of MALAT1 in Erlotinib-resistant LUAD cells. In conclusion, our study reveals overexpress MALAT-1 cause the drug resistance of EGFR-TKIs in non-small cell lung cancer (NSCLC) through the MALAT-1/miR-125/Rab25 axis. These findings present a potential novel therapeutic target and perspective for the treatment of LUAD.

Harmine promotes megakaryocyte differentiation and thrombopoiesis by activating the Rac1/Cdc42/JNK pathway through a potential target of 5-HTR2A.

Harmine (HM), a ß-carboline alkaloid extracted from plants, is a crucial component of traditional Chinese medicine (TCM) known for its diverse pharmacological activities. Thrombocytopenia, a common and challenging hematological disorder, often coexists with serious illnesses. Previous research has shown a correlation between HM and thrombocytopenia, but the mechanism needs further elucidation. The aim of this study was to clarify the mechanisms underlying the effects of HM on thrombocytopenia and to develop new therapeutic strategies. Flow cytometry, Giemsa staining, and Phalloidin staining were used to assess HM's impact on Meg-01 and HEL cell differentiation and maturation in vitro. A radiation-induced thrombocytopenic mouse model was employed to evaluate HM's effect on platelet production in vivo. Network pharmacology, molecular docking, and protein blotting were utilized to investigate HM's targets and mechanisms. The results demonstrated that HM dose-dependently promoted Meg-01 and HEL cell differentiation and maturation in vitro and restored platelet levels in irradiated mice in vivo. Subsequently, HM was found to be involved in the biological process of platelet production by upregulating the expressions of Rac1, Cdc42, JNK, and 5-HTR2A. Furthermore, the targeting of HM to 5-HTR2A and its correlation with downstream Rac1/Cdc42/JNK were also confirmed. In conclusion, HM regulates megakaryocyte differentiation and thrombopoiesis through the 5-HTR2A and Rac1/Cdc42/JNK pathways, providing a potential treatment strategy for thrombocytopenia.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

Network pharmacology analysis of the regulatory effects and mechanisms of ALAE on sow reproduction in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Reproductive ability of sows is a primary element influencing the development of pig farming. Herbal extracts of Angelica sinensis (Oliv.) Diels, Astragalus mongholicus Bunge, Eucommia ulmoides Oliv., and Polypodium glycyrrhiza D.C.Eaton showed effects on improvement of reproduction in sows. AIMS OF THE STUDY: To investigate the mechanism of the treatment effects by a compound of these four Chinese herbs in a 1:1:1:1 ratio (ALAE) on endometriosis, endometritis, uterine adhesion, intrauterine growth retardation, pre-eclampsia, and its enhancement of reproductive efficiency in sows. MATERIALS AND METHODS: Active components of ALAE were identified by using ultra-performance liquid chromatography-mass spectrometry analysis and network pharmacology. Then we used the results to construct a visualization network. Key targets and pathways of ALAE involved in sow reproduction improvement were validated in sow animals and porcine endometrial epithelial cells (PEECs). RESULTS: A total of 62 active compounds were found in ALAE (41 in Polypodium glycyrrhiza D.C.Eaton, 5 in Astragalus mongholicus Bunge, 11 in Eucommia ulmoides Oliv., 5 in Angelica sinensis (Oliv.) Diels) with 563 disease-related targets (e.g. caspase-3, EGFR, IL-6) involved in EGFR tyrosine kinase inhibitor resistance, PI3K-AKT, and other signaling pathways. Molecular docking results indicated GC41 (glabridin), GC18 (medicarpin), EGFR and CCND1 are possible key components and target proteins related to reproductive improvement in sows. In PEECs, EGFR expression decreased at the mRNA and protein levels by three doses (160, 320, and 640 µg/mL) of ALAE. The phosphorylation of downstream pathway PI3K-AKT1 was enhanced. The expression of inflammatory factors (IL-6, IL-1ß), ESR1 and caspase-3 decreased through multiple pathways. Additionally, the expression levels of an anti-inflammatory factor (IL-10), angiogenesis-related factors (MMP9, PIGF, PPARγ, IgG), and placental junction-related factors (CTNNB1, occludin, and claudin1) increased. Furthermore, the total born number of piglets, the number of live and healthy litters were significantly increased. The number of stillbirths decreased by ALAE treatment in sow animals. CONCLUSIONS: Dministration of ALAE significantly increased the total number of piglets born, the numbers of live and healthy litters and decreased the number of stillbirths through improving placental structure, attenuating inflammatory response, modulating placental angiogenesis and growth factor receptors in sows. The improvement of reproductive ability may be related to activation of the EGFR-PI3K-AKT1 pathway in PEECs. Moreover, ALAE maybe involved in modulation of estrogen receptors, apoptotic factors, and cell cycle proteins.

A 3.2 kW Single Stage Narrow Linewidth Fiber Amplifier Emitting at 1050 nm.

In this paper, we have demonstrated a narrow linewidth high power fiber laser emitting at a short wavelength of ~1050 nm. The fiber laser is based on a structure of master oscillator power amplification (MOPA) with an optimized fiber Bragg-grating-based laser cavity as the seed. Both stimulated Brillouin scattering (SBS) and stimulated Raman scattering (SRS) effects have been effectively suppressed by using a long passive fiber between the seed and the amplifier. Based on the fiber amplifier, we have ultimately boosted the narrow linewidth laser from ~40 W to 3.2 kW with a slope efficiency of 85.1% and a 3-dB linewidth of ~0.1 nm. The SRS suppression ratio of the laser is ~29.7 dB at maximum power. Due to our fiber mode control strategies, the beam quality always stays near-diffraction-limited while amplifying, and the measured M2 factor is ~1.4 at the maximum power. Further increase in output power is limited by the SBS effect.

Prevalence of anemia of varying severity, geographic variations, and association with metabolic factors among women of reproductive age in China: a nationwide, population-based study.

To investigate the epidemiological characteristics of anemia of varying severity among women of reproductive age, we conducted a nationwide, cross-sectional study between January 1, 2019 and December 31, 2019, including 4 184 547 nonpregnant women aged 18-49 years from all 31 provinces in the mainland of China. Anemia was defined as having hemoglobin concentration < 120.0 g/L and categorized as mild, moderate, and severe. Multivariate logistic models with cluster effect were used to explore the association of anemia and metabolic risk factors. The standardized prevalence of anemia and moderate and worse anemia among women of reproductive age in China was 15.8% (95% CI 15.1%-16.6%) and 6.6% (6.3%-7.0%), respectively. The prevalence of anemia and the proportion of moderate and worse anemia significantly increased with age. We also observed great geographic variations in the prevalence of anemia, with a high likelihood in south, central, and northwest China. Moderate and/or severe anemia was positively associated with overweight and obesity, diabetes, and impaired kidney function. In conclusion, anemia remains a significant challenge for women of reproductive age in China. Geographic variations and metabolic risk factors should be considered in the comprehensive and targeting strategy for anemia reduction.

Protocol for producing hyperpolarized 13C-bicarbonate for clinical MRI of extracellular pH in aggressive tumors.

Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) 13C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule 13C-glycerol carbonate (13C-GLC), the post-dissolution reaction, and converting HP 13C-GLC to an injectable HP 13C-bicarbonate solution. We then detail procedures for MRI data acquisition to generate tumor pH maps for assessing tumor aggressiveness. For complete details on the use and execution of this protocol, please refer to Mu et al.1.

Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

RNF213 Variants, Vasospastic Angina, and Risk of Fatal Myocardial Infarction.

Importance: Vasospastic angina (VSA) is vasospasm of the coronary artery and is particularly prevalent in East Asian populations. However, the specific genetic architecture for VSA at genome-wide levels is not fully understood. Objective: To identify genetic factors associated with VSA. Design, Setting, and Participants: This was a case-control genome-wide association study of VSA. Data from Biobank Japan (BBJ; enrolled patients from 2002-2008 and 2013-2018) were used, and controls without coronary artery disease (CAD) were enrolled. Patients from the BBJ were genotyped using arrays or a set of arrays. Patients recruited between 2002 and 2005 were classified within the first dataset, and those recruited between 2006 and 2008 were classified within the second dataset. To replicate the genome-wide association study in the first and second datasets, VSA cases and control samples from the latest patients in the BBJ recruited between 2013 and 2018 were analyzed in a third dataset. Exposures: Single-nucleotide variants associated with VSA. Main Outcomes and Measures: Cases with VSA and controls without CAD. Results: A total of 5720 cases (mean [SD] age, 67 [10] years; 3672 male [64.2%]) and 153 864 controls (mean [SD] age, 62 [15] years; 77 362 male [50.3%]) in 3 datasets were included in this study. The variants at the RNF213 locus showed the strongest association with VSA across the 3 datasets (odds ratio [OR], 2.34; 95% CI, 1.99-2.74; P = 4.4 × 10-25). Additionally, rs112735431, an Asian-specific rare deleterious variant (p.Arg4810Lys) experimentally shown to be associated with reduced angiogenesis and a well-known causal risk for Moyamoya disease was the most promising candidate for a causal variant explaining the association. The effect size of rs112735431 on VSA was distinct from that of other CADs. Furthermore, homozygous carriers of rs112735431 showed an association with VSA characterized by a large effect estimate (OR, 18.34; 95% CI, 5.15-65.22; P = 7.0 × 10-6), deviating from the additive model (OR, 4.35; 95% CI, 1.18-16.05; P = .03). Stratified analyses revealed that rs112735431 exhibited a stronger association in males (χ21 = 7.24; P = .007) and a younger age group (OR, 3.06; 95% CI, 2.24-4.19), corresponding to the epidemiologic features of VSA. In the registry, carriers without CAD of the risk allele rs112735431 had a strikingly high mortality rate due to acute myocardial infarction during the follow-up period (hazard ratio, 2.71; 95% CI, 1.57-4.65; P = 3.3 × 10-4). As previously reported, a possible overlap between VSA and Moyamoya disease was not found. Conclusions and Relevance: Results of this study suggest that vascular cell dysfunction mediated by variants in the RNF213 locus may promote coronary vasospasm, and the presence of the risk allele could serve as a predictive factor for the prognosis.