China Postdoctoral Science Foundation Research Articles

Effects of triaxial deformation on the fission barrier in the Z = 118 − 120 nuclei* *Supported by the National Natural Science Foundation of China (Grant Nos. 12205076 and 12047504), the China Postdoctoral Science Foundation (Grant No. 2020M670012), and the Launching Fund of Henan University of Technology (Grant No. 2021BS047).

By using potential energy surface (PES) calculations in the three-dimensional space (β 2, γ, β 4) within the framework of the macroscopic-microscopic model, the fission trajectory and fission barrier for Z = 118(Og), 119, 120 nuclei has been systematically investigated. The calculated PES includes macroscopic liquid-drop energy, microscopic shell correction and pairing correction. Taking the 294Og176 nucleus as an example, we discuss the next closed shell after Z = 82 and N = 126 with the calculated Woods–Saxon single-particle levels. Then, the results of PES in 294Og is illustrated from the (X, Y) scale to the (β 2, γ) scale. The γ degree of freedom reveals the shape evolution clearly during the fission process. The structure near the minimum and saddle point of the PES in the Z = 118, 119, 120 nuclei is demonstrated simultaneously. Based on the potential energy curves, general trends of the evolution of the fission barrier heights and widths are also studied. The triaxial deformation in these superheavy mass regions plays a vital role in the first fission barrier, showing a significant reduction in both triaxial paths. In addition, the model-dependent fission barriers of proton-rich nuclei 295Og, 296119, and 297120 are analyzed briefly. Our studies could be valuable for synthesizing the superheavy new elements in the forthcoming HIAF and other facilities.

Neutralization of EG.5, EG.5.1, BA.2.86, and JN.1 by antisera from dimeric receptor-binding domain subunit vaccines and 41 human monoclonal antibodies

The recently circulating Omicron variants BA.2.86 and JN.1 were identified with more than 30 amino acid changes on the spike protein compared to BA.2 or XBB.1.5. This study aimed to comprehensively assess the immune escape potential of BA.2.86, JN.1, EG.5, and EG.5.1. We collected human and murine sera to evaluate serological neutralization activities. The participants received three doses of coronavirus disease 2019 (COVID-19) vaccines or a booster dose of the ZF2022-A vaccine (Delta-BA.5 receptor-binding domain [RBD]-heterodimer immunogen) or experienced a breakthrough infection (BTI). The ZF2202-A vaccine is under clinical trial study (ClinicalTrials.gov: NCT05850507). BALB/c mice were vaccinated with a panel of severe acute respiratory syndrome coronavirus 2 RBD-dimer proteins. The antibody evasion properties of these variants were analyzed with 41 representative human monoclonal antibodies targeting the eight RBD epitopes. We found that BA.2.86 had less neutralization evasion than EG.5 and EG.5.1 in humans. The ZF2202-A booster induced significantly higher neutralizing titers than BTI. Furthermore, BA.2.86 and JN.1 exhibited stronger antibody evasion than EG.5 and EG.5.1 on RBD-4 and RBD-5 epitopes. Compared to BA.2.86, JN.1 further lost the ability to bind to several RBD-1 monoclonal antibodies and displayed further immune escape. Our data showed that the currently dominating sub-variant, JN.1, showed increased immune evasion compared to BA.2.86 and EG.5.1, which is highly concerning. This study provides a timely risk assessment of the interested sub-variants and the basis for updating COVID-19 vaccines. This work was funded by the National Key R&D Program of China, the National Natural Science Foundation of China, the Beijing Life Science Academy, the Bill& Melinda Gates Foundation, and the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation (CPSF).

Production of charmonium pentaquarks from b-baryon and B-meson decays: SU(3) analysis* *W. H. H and J. X. is supported in part by the National Natural Science Foundation of China (12105247), the China Postdoctoral Science Foundation (2021M702957). Y.X is supported in part by the National Natural Science Foundation of China (12005294)

Here, we study the production of charmonium pentaquarks from bottom baryon and B-meson decays under the flavor symmetry. Decay amplitudes for various processes are parameterized in terms of irreducible nonperturbative amplitudes. Numerous relations between decay widths are deduced. Moreover, the strong decays of pentaquarks are considered. Our results can be tested in future measurements at LHCb, Belle II, and CEPC. Once decay branching fractions are measured, this study will be useful for the exploration of new decay channels and pentaquark states.

Development of ethnicity-adjusted global alignment and proportion score to predict the risk of mechanical complications following corrective surgery for adult spinal deformity

BACKGROUND CONTEXTSurgery for degenerative scoliosis (DS) is a complex procedure with high complication and revision rates. Based on the concept that pelvic incidence (PI) is a constant parameter, the global alignment and proportional (GAP) score was developed from sagittal alignment data collected in the Caucasian populations to predict mechanical complications. However, the PI varies among different ethnic groups, and the GAP score may not apply to Chinese populations. Thus, this study aims to assess the predictability of the GAP score for mechanical complications in the Chinese populations and develop an ethnicity-adjusted GAP score. PURPOSETo test the predictability of the original GAP score in the Chinese population and develop a Chinese ethnicity-tailored GAP scoring system. STUDY DESIGN/SETTINGSRetrospective cohort study. PATIENT SAMPLEA total of 560 asymptomatic healthy volunteers were enrolled to develop Chinese ethnicity-tailored GAP (C-GAP) score and a total of 114 DS patients were enrolled to test the predictability of original GAP score and C-GAP score. OUTCOME MEASURESDemographic information, sagittal spinopelvic parameters of healthy volunteers and DS patients were collected. Mechanical complications were recorded at a minimum of 2-year follow-up after corrective surgery for DS patients. METHODSA total of 560 asymptomatic healthy volunteers with a mean age of 61.9±14.1 years were enrolled to develop ethnicity-adjusted GAP score. Besides, 114 surgically trated DS patients (M/F=10/104) with a mean age of 60.7±7.1 years were retrospectively reviewed. Demographic data and radiological parameters of both groups, including PI, lumbar lordosis (LL), sacral slope (SS), the sagittal vertical axis (SVA), and global tilt (GT) were collected. Ideal LL, SS, and GT were obtained by calculating their correlation with PI of healthy volunteers using linear regression analysis. Relative pelvic version (RPV), relative lumbar lordosis (RLL), lordosis distribution index (LDI), and relative spinopelvic alignment (RSA) were obtained using the ideal parameters, and the Chinese population adjusted GAP score (C-GAP) was developed based on these values. The predictability of original and C-GAP for mechanical failure was evaluated using clinical and radiological data of DS patients by evaluating the area under the curve (AUC) using receiver operating characteristic curve. This study was supported the National Natural Science Foundation of China (NSFC) (No. 82272545), ($ 8,000–10,000) and the Jiangsu Provincial Key Medical Center, and the China Postdoctoral Science Foundation (2021M701677), Level B ($ 5,000–7,000). RESULTSIdeal SS=0.53×PI+9 (p=.002), ideal LL=0.48×PI+22 (p=.023) and ideal GT=0.46 × PI-9 (p=.011). were obtained by correlation analysis using sagittal parameters from those healthy volunteers, and RPV, RLL, RSA, and LDI were calculated accordingly. Then, the ethnicity-adjusted C-GAP score was developed by summing up the numeric value of calculated RPV, RLL, RSA, and LDI. The AUC was classified as ‘‘no or low discriminatory power’’ for the original GAP score in predicting mechanical complications (AUC=0.592, p=.078). Similarly, the original GAP score did not correlate with mechanical complications in DS patients. According to the C-GAP score, the sagittal parameters were proportional in 25 (21.9%) cases, moderately disproportional in 68 (59.6%), and severely disproportional in 21% (18.5%) cases. The incidence of mechanical complications was statistically different among proportioned and moderately disproportional and severely disproportional portions of the C-GAP score (p=.03). The predictability of the C-GAP score is high with an AUC=0.773 (p<.001). In addition, there is a linear correlation between mechanical complication rate and C-GAP score (χ=0.102, p=.02). CONCLUSIONThe Ethnicity-adjusted C-GAP score system developed in the current study provided a more accurate and reliable for predicting the risk of mechanical complications after corrective surgery for adult spinal deformity.

Bi-allelic variants in DNAH3 cause male infertility with asthenoteratozoospermia in humans and mice.

Are there other pathogenic genes for asthenoteratozoospermia (AT)? DNAH3 is a novel candidate gene for AT in humans and mice. AT is a major cause of male infertility. Several genes underlying AT have been reported; however, the genetic aetiology remains unknown in a majority of affected men. A total of 432 patients with AT were recruited in this study. DNAH3 mutations were identified by whole-exome sequencing (WES). Dnah3 knockout mice were generated using the genome editing tool. The morphology and motility of sperm from Dnah3 knockout mice were investigated. The entire study was conducted over 3 years. WES was performed on 432 infertile patients with AT. In addition, two lines of Dnah3 knockout mice were generated. Haematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunostaining, and computer-aided sperm analysis (CASA) were performed to investigate the morphology and motility of the spermatozoa. ICSI was used to overcome the infertility of one patient and of the Dnah3 knockout mice. DNAH3 biallelic variants were identified in three patients from three unrelated families. H&E staining revealed various morphological abnormalities in the flagella of sperm from the patients, and TEM and immunostaining further showed the loss of the central pair of microtubules, a dislocated mitochondrial sheath and fibrous sheath, as well as a partial absence of the inner dynein arms. In addition, the two Dnah3 knockout mouse lines demonstrated AT. One patient and the Dnah3 knockout mice showed good treatment outcomes after ICSI. N/A. This is a preliminary report suggesting that defects in DNAH3 can lead to asthenoteratozoospermia in humans and mice. The pathogenic mechanism needs to be further examined in a future study. Our findings show that DNAH3 is a novel candidate gene for AT in humans and mice and provide crucial insights into the biological underpinnings of this disorder. The findings may also be beneficial for counselling affected individuals. This work was supported by grants from National Natural Science Foundation of China (82201773, 82101961, 82171608, 32322017, 82071697, and 81971447), National Key Research and Development Program of China (2022YFC2702604), Scientific Research Foundation of the Health Committee of Hunan Province (B202301039323, B202301039518), Hunan Provincial Natural Science Foundation (2023JJ30716), the Medical Innovation Project of Fujian Province (2020-CXB-051), the Science and Technology Project of Fujian Province (2023D017), China Postdoctoral Science Foundation (2022M711119), and Guilin technology project for people's benefit (20180106-4-7). The authors declare no competing interests.

Battery Venting Caused By Fast Charging

Lithium-ion batteries (LIBs) experience high risks of failure during unreasonable fast charging. Various degradation mechanisms inside the LIBs such as lithium (Li) plating, solid electrolyte interphase growth and electrolyte dry-out can undermine the electrochemical performance and induce massive gas generation alongside the operation. As a typical failure behaviour, venting occurs when the internal pressure of battery cell exceeds the safety threshold, releasing the gaseous products as well as depressurizing the cell. Recent studies1–3 of thermal runaway (TR) tests after fast charging have found that accumulated plated Li can react with electrolyte at elevated external temperatures, decreasing both self-heating and onset temperatures of TR. Yet, how fast-charging degradation will affect battery venting behaviours remains unclear.To answer this question, in this study, a series of fast charging experiments under controlled cooling as well as adiabatic TR tests were conducted with 51 Ah LiNi0.6Mn0.2Co0.2O2/graphite prismatic LIBs. The results showed that the prismatic battery underwent severe Li plating with over 30% capacity fade after 10 cycles of 4C charging. In the adiabatic TR tests, the aged batteries after 4C charging exhibited lower self-heating temperature and venting temperature as compared to the fresh batteries, by 51 ℃ and 34.4 ℃ respectively. This can be explained by the additional gas generation from the reaction between plated Li and electrolyte in the fast-charged batteries. Gas analyses of 120 ℃ hot-box tests for the degraded anodes with the electrolyte showed that the vented gas at the early venting stage primarily consisted of carbon dioxide, carbon monoxide and ethylene. The same charging protocols were then conducted in a natural convection thermal chamber with poor heat dissipation, where the temperature rise was much higher than those under forced convection as expected. Excessive cycling operations with off-limit charge rates (5C and 5.6C) were observed to directly cause battery swelling and venting without TR, and the temperature decreasing rates during rest after each charging process tend to slow down and even remain stable during a certain period of time. This indicates that the exothermic reaction between plated Li and electrolyte can be directly triggered by fast charging if heat removal is not effective enough. The findings provide useful insights into battery venting induced by fast charging, which can shed light on battery safety evaluation for fast charging techniques.Acknowledgements:This work is supported by the Faraday Institution BESAFE project (FIRG038), the Imperial College President’s PhD Scholarship Scheme (funded by EPSRC), the National Natural Science Foundation of China (Grant No. 52207241), China National Postdoctoral Program for Innovative Talents (grant no. BX20220171), China Postdoctoral Science Foundation (grant no. 2022M711760), and Shuimu Tsinghua Scholar Program (grant no. 2021SM130).

Prioritizing de novo potential non-canonical splicing variants in neurodevelopmental disorders

Genomic variants outside of the canonical splicing site (±2) may generate abnormal mRNA splicing, which are defined as non-canonical splicing variants (NCSVs). However, the clinical interpretation of NCSVs in neurodevelopmental disorders (NDDs) is largely unknown. We investigated the contribution of NCSVs to NDDs from 345,787 de novo variants (DNVs) in 47,574 patients with NDDs. We performed functional enrichment and protein-protein interaction analysis to assess the association between genes carrying prioritised NCSVs and NDDs. Minigene was used to validate the impact of NCSVs on mRNA splicing. We observed significantly more NCSVs (p=0.02, odds ratio [OR]=2.05) among patients with NDD than in controls. Both canonical splicing variants (CSVs) and NCSVs contributed to an equal proportion of patients with NDD (0.76% vs. 0.82%). The candidate genes carrying NCSVs were associated with glutamatergic synapse and chromatin remodelling. Minigene successfully validated 59 of 79 (74.68%) NCSVs that led to abnormal splicing in 40 candidate genes, and 9 of the genes (ARID1B, KAT6B, TCF4, SMARCA2, SHANK3, PDHA1, WDR45, SCN2A, SYNGAP1) harboured recurrent NCSVs with the same variant present in more than two unrelated patients with NDD. Moreover, 36 of 59 (61.02%) NCSVs are novel clinically relevant variants, including 34 unreported and 2 clinically conflicting interpretations or of uncertain significance NCSVs in the ClinVar database. This study highlights the common pathology and clinical importance of NCSVs in unsolved patients with NDD. The present study was funded by grants from the National Natural Science Foundation of China, China Postdoctoral Science Foundation, the Hunan Youth Science and Technology Innovation Talent Project, the Provincial Natural Science Foundation of Hunan, The Scientific Research Program of FuRong laboratory, and the Natural Science Project of the University of Anhui Province.

Classification of attention deficit/hyperactivity disorder based on EEG signals using a EEG-Transformer model ∗ ∗This work was supported in part by the National Key R&D Program of China (2022YFE0197500), National Natural Science Foundation of China (#81927804, #62101538), Science and Technology Planning Project of Shenzhen (#JSGG20210713091808027, #JSGG20211029095801002), China Postdoctoral Science Foundation (2022M710968), and the Science and Technology Program of Guangdong Province

Objective. Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in adolescents that can seriously impair a person’s attention function, cognitive processes, and learning ability. Currently, clinicians primarily diagnose patients based on the subjective assessments of the Diagnostic and Statistical Manual of Mental Disorders-5, which can lead to delayed diagnosis of ADHD and even misdiagnosis due to low diagnostic efficiency and lack of well-trained diagnostic experts. Deep learning of electroencephalogram (EEG) signals recorded from ADHD patients could provide an objective and accurate method to assist physicians in clinical diagnosis. Approach. This paper proposes the EEG-Transformer deep learning model, which is based on the attention mechanism in the traditional Transformer model, and can perform feature extraction and signal classification processing for the characteristics of EEG signals. A comprehensive comparison was made between the proposed transformer model and three existing convolutional neural network models. Main results. The results showed that the proposed EEG-Transformer model achieved an average accuracy of 95.85% and an average AUC value of 0.9926 with the fastest convergence speed, outperforming the other three models. The function and relationship of each module of the model are studied by ablation experiments. The model with optimal performance was identified by the optimization experiment. Significance. The EEG-Transformer model proposed in this paper can be used as an auxiliary tool for clinical diagnosis of ADHD, and at the same time provides a basic model for transferable learning in the field of EEG signal classification.

Association between ovarian reserve and spontaneous miscarriage and their shared genetic architecture.

Can potential mechanisms involved in the likely concurrence of diminished ovarian reserve (DOR) and miscarriage be identified using genetic data? Concurrence between ovarian reserve and spontaneous miscarriage was observed, and may be attributed to shared genetic risk loci enriched in antigen processing and presentation and autoimmune disease pathways. Previous studies have shown that lower serum anti-Müllerian hormone (AMH) levels are associated with increased risk of embryo aneuploidy and spontaneous miscarriage, although findings have not been consistent across all studies. A recent meta-analysis suggested that the association between DOR and miscarriage may not be causal, but rather a result of shared underlying causes such as clinical conditions or past exposure. Motivated by this hypothesis, we conducted the present analysis to explore the concurrence between DOR and miscarriage, and to investigate potential mechanisms using genetic data. Three data sources were used in the study: the clinical IVF data were retrospectively collected from an academically affiliated Reproductive Medicine Center (17786 cycles included); the epidemiological data from the UK Biobank (UKB), which is a large-scale, population-based, prospective cohort study (35 316 white women included), were analyzed; and individual-level genotype data from the UKB were extracted for further analysis. There were three modules of analysis. First, clinical IVF data were used to test the association between ovarian reserve biomarkers and the subsequent early spontaneous miscarriage risk. Second, the UKB data were used to test the association of spontaneous miscarriage history and early menopause. Third, individual-level genotype data from the UKB were analyzed to identify specific pleiotropic genes which affect the development of miscarriage and menopause. In the analysis of clinical IVF data, the risk of early spontaneous miscarriage was 1.57 times higher in the group with AMH < 1.1 ng/ml group (P < 0.001), 1.62 times for antral follicular count <5 (P < 0.001), and 1.39 times for FSH ≥10 mIU/ml (P < 0.001) in comparison with normal ovarian reserve groups. In the analysis of UKB data, participants with a history of three or more miscarriages had a one-third higher risk of experiencing early menopause (odds ratio: 1.30, 95% CI 1.13-1.49, P < 0.001), compared with participants without spontaneous miscarriage history. We identified 158 shared genetic risk loci that affect both miscarriage and menopause, which enrichment analysis showed were involved in antigen processing and presentation and autoimmune disease pathways. The analyses of the UKB data were restricted to participants of European ancestry, as 94.6% of the cohort were of white ethnicity. Further studies are needed in non-white populations. Additionally, maternal age at the time of spontaneous miscarriage was not available in the UKB cohort, therefore we adjusted for age at baseline assessment in the models instead. It is known that miscarriage rate in IVF is higher compared to natural conception, highlighting a need for caution when generalizing our findings from the IVF cohort to the general population. Our findings have implications for IVF clinicians in terms of patient counseling on the prognosis of IVF treatment, as well as for genetic counseling regarding miscarriage. Our results highlight the importance of further research on the shared genetic architecture and common pathophysiological basis of DOR and miscarriage, which may lead to new therapeutic opportunities. This work was supported by the Hunan Youth Science and Technology Innovation Talent Project (2020RC3060), the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220220), the fellowship of China Postdoctoral Science Foundation (2022M723564), and the Natural Science Foundation of Hunan Province, China (2023JJ41016). This work has been accepted for poster presentation at the 39th Annual Meeting of ESHRE, Copenhagen, Denmark, 25-28 June 2023 (Poster number: P-477). The authors declare no conflict of interest. N/A.

Association between female-specific reproductive factors and leukocyte telomere length.

What are the associations between female-specific reproductive factors and leukocyte telomere length (LTL)? Early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of oral contraceptives (OCs) and hormone replacement therapy (HRT) were associated with shorter LTL. Reproductive factors have been associated with age-related diseases, but their associations with cellular aging, as indicated by LTL, are unclear. This population-based study included 224 965 women aged 40-69 years from the UK Biobank between 2006 and 2010. Women aged 40-69 were included. Female-specific reproductive factors, including age at menarche, age at natural menopause, reproductive lifespan, number of live births, age at first live birth, history of stillbirth, history of miscarriage, and use of OCs and HRT were self-reported. LTL was measured using a validated polymerase chain reaction method. Multiple linear regression and restricted cubic spline models were applied to explore the association between each reproductive factor and LTL. After adjustment for potential confounders, early menarche (<12 years; percent change, per unit change in LTL Z score: -1.29%, 95% CI: -2.32%, -0.26%), early menopause (<45 years; percent change: -7.18%, 95% CI: -8.87%, -5.45%), short reproductive lifespan (<30 years; percent change: -6.10%, 95% CI: -8.14%, -4.01%), multiparity (percent change: -3.38%, 95% CI: -4.38%, -2.37%), early age at first live birth (<20 years; percent change: -4.46%, 95% CI: -6.00%, -2.90%), and use of OCs (percent change: -1.10%, 95% CI: -2.18%, -0.02%) and HRT (percent change: -3.72%, 95% CI: -4.63%, -2.80%) were all significantly associated with shorter LTL. However, no significant association was found for history of miscarriage and stillbirth. We observed nonlinear relationships of age at menarche, age at natural menopause, reproductive lifespan, and age at first live birth with LTL (Pnonlinear < 0.05). Considering that the participants were predominantly of European ethnicity, the findings may not be generalizable to women of other ethnic backgrounds. Our findings suggest that early menarche, early menopause, short reproductive lifespan, early age at first birth, multiparity, and use of OCs and HRT were associated with shorter LTL, which has been linked to various chronic diseases. The accelerated shortening of telomeres may potentially contribute to the development of chronic diseases related to reproductive factors. This study was funded by the National Natural Science Foundation of China (82003479, 82073660), Hubei Provincial Natural Science Foundation of China (2023AFB663), and the China Postdoctoral Science Foundation (2019M662646, 2020T130220). The authors have no competing interests to disclose. N/A.

Association between particulate matter (PM)2·5 air pollution and clinical antibiotic resistance: a global analysis

Antibiotic resistance is an increasing global issue, causing millions of deaths worldwide every year. Particulate matter (PM)2·5 has diverse elements of antibiotic resistance that increase its spread after inhalation. However, understanding of the contribution of PM2·5 to global antibiotic resistance is poor. Through univariate and multivariable analysis, we aimed to present the first global estimates of antibiotic resistance and burden of premature deaths attributable to antibiotic resistance resulting from PM2·5 pollution. For this global analysis, data on multiple potential predictors (ie, air pollution, antibiotic use, sanitation services, economics, health expenditure, population, education, climate, year, and region) were collected in 116 countries from 2000 to 2018 to estimate the effect of PM2·5 on antibiotic resistance via univariate and multivariable analysis. Data were obtained from ResistanceMap, European Centre for Disease Prevention and Control Surveillance Atlas (antimicrobial-resistance sources), and PLISA Health Information Platform for the Americas. Future global aggregate antibiotic resistance and premature mortality trends derived from PM2·5 in different scenarios (eg, 50% reduced antibiotic use or PM2·5 controlled to 5 μg/m3) were projected until 2050. The final dataset included more than 11·5 million tested isolates. Raw antibiotic-resistance data included nine pathogens and 43 types of antibiotic agents. Significant correlations between PM2·5 and antibiotic resistance were consistent globally in most antibiotic-resistant bacteria (R2=0·42-0·76, p<0·0001), and correlations have strengthened over time. Antibiotic resistance derived from PM2·5 caused an estimated 0·48 (95% CI 0·34-0·60) million premature deaths and 18·2 (13·4-23·0) million years of life lost in 2018 worldwide, corresponding to an annual welfare loss of US$395 (290-500) billion due to premature deaths. The 5 μg/m3 target of concentration of PM2·5 in the air quality guidelines set by WHO, if reached in 2050, was estimated to reduce antibiotic resistance by 16·8% (95% CI 15·3-18·3) and avoid 23·4% (21·2-25·6) of premature deaths attributable to antibiotic resistance, equivalent to a saving of $640 (580-671) billion. This analysis is the first to describe the association between PM2·5 and clinical antibiotic resistance globally. Results provide new pathways for antibiotic-resistance control from an environmental perspective. National Natural Science Foundation of China, Fundamental Research Funds for the Central Universities, Zhejiang University Global Partnership Fund, and China Postdoctoral Science Foundation.

Nucleons as modified Ising models* *S.M.H and J.X. are supported in part by the National Natural Science Foundation of China (12105247) and the China Postdoctoral Science Foundation (2021M702957). Y.S.L is supported in part by the National Natural Science Foundation of China (12002209)

In this paper, we propose a map that connects nucleons bound in nuclei and Ising spins in the Ising model. This proposal is based on the fact that the description of states of nucleons and Ising spins could share the same type of observables. We present a nuclear model corresponding to an explicit modified Ising model and qualitatively confirm the correctness of this map with a simulation on a two-dimensional square lattice. This map can help us understand the profound connections between different physical systems.

1563-P: Hepatic PHD3 Stimulates Gluconeogenesis and Aggravates Hyperglycemia and Type 2 Diabetes by Hydroxylating CRTC2 at Pro129 and Pro615

Hepatic gluconeogenesis is critical for metabolic adaption in response to fasting, and its abnormal elevation contributes to the pathogenesis of hyperglycemia and type 2 diabetes. However, whether and how protein hydroxylation regulates hepatic gluconeogenesis and glucose metabolism remains largely unknown. Here we report that PHD3 is identified as a fasting-induced factor and regulates hepatic gluconeogenesis through interaction and hydroxylation of CRTC2. Pro129 and Pro615 hydroxylation of CRTC2 following PHD3 activation is necessary for its nuclear translocation and association with CREB, and enhanced binding to promoters of gluconeogenic target genes in response to fasting or the cAMP activator forskolin. CRTC2 hydroxylation-stimulated gluconeogenic gene expression is independent of SIK-mediated phosphorylation of CRTC2. Liver-specific knockout of PHD3 (PHD3 LKO) mice or prolyl hydroxylase-deficient knockin mice with alanine mutation in PHD3 at Pro196 (PHD3 KI) show significant attenuated gluconeogenic genes, glycaemia and hepatic capacity to produce glucose during fasting or fed with high-fat, high-sucrose diet. The efficacies of glucagon or adenylyl cyclase activator forskolin on stimulating the expression of gluconeogenic enzymes, such as PEPCK and G6Pase, and on glucose output are abolished in PHD3-/- mouse primary hepatocytes. Importantly, Pro615 hydroxylation of CRTC2 by PHD3 is increased in livers of fasted mice, diet-induced insulin resistance or genetically obese ob/ob mice and humans with diabetes. Together, these findings increase our understanding of the molecular mechanisms linking protein hydroxylation to gluconeogenesis under physiological and insulin resistant conditions, and may offer therapeutic potential for treating sustained gluconeogenesis, hyperglycemia and type 2 diabetes. Disclosure Y.Xue: None. W.Su: None. J.Zhao: None. C.Gao: None. J.Wen: None. Y.Xu: None. W.Fu: None. J.C.Fang: None. Y.Li: None. A.Cui: None. S.Wei: None. F.Ma: None. Z.Liu: None. X.Fang: None. W.Li: None. Y.Liu: None. G.Cai: None. Funding National Key R&amp;D Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008, 82073061, 82170587, 32100943); Ministry of Science and Technology of China (2020YFA0803301); Open Project Program of Metabolic Vascular Diseases Key Laboratory of Sichuan Province (2022MVDKL-K2); Shandong Natural Science Foundation (ZR2020MH206); China Postdoctoral Science Foundation (2021M693273)

PTGDS PROMOTES TUMORIGENESIS OF PERIPHERAL T CELL LYMPHOMA THROUGH REGULATING IRON METABOLISM

Introduction: Accumulating evidence indicates that ferroptosis, an iron-dependent cell death, is involved in the development of tumors, and targeting ferroptosis offers great potential in tumor therapy. However, the regulatory networks of ferroptosis in peripheral T cell lymphoma (PTCL) remain unclear. Methods: Paraffin-embedded tissues of 112 PTCL patients and 38 reactive hyperplasia cases were collected with informed consents. Lentiviral vectors were stably transfected into PTCL cell lines. Tandem mass tag (TMT)-mass spectrometry and RNA-sequencing (RNA-seq) were performed for downstream analysis. Co-IP and confocal immunofluorescence were performed to verify protein–protein interaction. Xenograft models were established using SCID Beige mice. Results: Firstly, both mRNA and protein levels of PTGDS were found to be higher in PTCL cells and patients’ tissue (Figure 1A–C). Survival analysis revealed that the positive expression of PTGDS was closely associated with worse prognosis in PTCL patients (Figure 1D). PTGDS overexpression could significantly promote the proliferation of PTCL cells while PTGDS knockdown inhibited it in vitro and in vivo (Figure 2A,B). Besides, PTCL cells with PTGDS knockdown displayed a higher apoptosis rate (Figure 2C). PTGDS specific inhibitor AT56 could significantly inhibit the proliferation of PTCL cells, in a dose- and time-dependent manner (Figure 2D). Moreover, AT56 treatment induced the cell cycle arrest at G0/G1 phase in PTCL cells (Figure 2E). Analysis based on TMT-mass spectrometry found that AT56 treatment significantly regulated the expression of ferroptosis-related molecules (Figure 3A) in PTCL cells. The anti-tumor effects of sorafenib and erastin, classic ferroptosis inducers, was significantly enhanced by AT56 treatment, and Fer-1, ferroptosis inhibitor, rescued the inhibitory role of AT56 on cell proliferation (Figure 3B,C). Moreover, AT56 promoted erastin/sorafenib-induced accumulation of lipid ROS (Figure 3D), a classic biomarker of ferroptosis. Further in-vivo experiments observed that AT56 treatment enhanced the anti-tumor effects of sorafenib (Figure 3E). Mechanically, structure analysis of differentially expressed molecules in TMT-mass spectrometry identified HMOX1, a regulator of heme catabolism, as PTGDS interactive protein. Co-IP and confocal immunofluorescence assays verified their co-localization and interaction in PTCL cells (Figure 4A,B). Moreover, AT56 treatment increased the level of intracellular iron, and HMOX1 knockdown could rescue it (Figure 4C). Keywords: aggressive T-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers, molecular targeted therapies The research was funded by: National Natural Science Foundation (No. 82270200, No. 82170189, No. 82070203, No. 81800194, No. 81770210); Key Research and Development Program of Shandong Province (No. 2018CXGC1213); China Postdoctoral Science Foundation (No. 2021T1404223); Translational Research Grant of NCRCH (No. 2021WWB02, No. 2020ZKMB01); Shandong Provincial Natural Science Foundation (ZR2021YQ51); Taishan Scholars Program of Shandong Province; Shandong Provincial Engineering Research Center of Lymphoma; Academic Promotion Programme of Shandong First Medical University (No. 2019QL018). No conflicts of interests pertinent to the abstract.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Nanotherapeutics for solid organ transplantation: new kid onthe block.

Biallelic variants in KCTD19 associated with male factor infertility and oligoasthenoteratozoospermia.

Can whole-exome sequencing (WES) reveal new genetic factors responsible for male infertility characterized by oligozoospermia? We identified biallelic missense variants in the Potassium Channel Tetramerization Domain Containing 19 gene (KCTD19) and confirmed it to be a novel pathogenic gene for male infertility. KCTD19 is a key transcriptional regulator that plays an indispensable role in male fertility by regulating meiotic progression. Kctd19 gene-disrupted male mice exhibit infertility due to meiotic arrest. We recruited a cohort of 536 individuals with idiopathic oligozoospermia from 2014 to 2022 and focused on five infertile males from three unrelated families. Semen analysis data and ICSI outcomes were collected. WES and homozygosity mapping were performed to identify potential pathogenic variants. The pathogenicity of the identified variants was investigated in silico and in vitro. Male patients diagnosed with primary infertility were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Genomic DNA extracted from affected individuals was used for WES and Sanger sequencing. Sperm phenotype, sperm nuclear maturity, chromosome aneuploidy, and sperm ultrastructure were assessed using hematoxylin and eosin staining and toluidine blue staining, FISH and transmission electron microscopy. The functional effects of the identified variants in HEK293T cells were investigated via western blotting and immunofluorescence. We identified three homozygous missense variants (NM_001100915, c.G628A:p.E210K, c.C893T:p.P298L, and c.G2309A:p.G770D) in KCTD19 in five infertile males from three unrelated families. Abnormal morphology of the sperm heads with immature nuclei and/or nuclear aneuploidy were frequently observed in individuals with biallelic KCTD19 variants, and ICSI was unable to rescue these deficiencies. These variants reduced the abundance of KCTD19 due to increased ubiquitination and impaired its nuclear colocalization with its functional partner, zinc finger protein 541 (ZFP541), in HEK293T cells. The exact pathogenic mechanism remains unclear, and warrants further studies using knock-in mice that mimic the missense mutations found in individuals with biallelic KCTD19 variants. Our study is the first to report a likely causal relationship between KCTD19 deficiency and male infertility, confirming the critical role of KCTD19 in human reproduction. Additionally, this study provided evidence for the poor ICSI clinical outcomes in individuals with biallelic KCTD19 variants, which may guide clinical treatment strategies. This work was supported by the National Key Research and Developmental Program of China (2022YFC2702604 to Y.-Q.T.), the National Natural Science Foundation of China (81971447 and 82171608 to Y.-Q.T., 82101961 to C.T.), a key grant from the Prevention and Treatment of Birth Defects from Hunan Province (2019SK1012 to Y.-Q.T.), a Hunan Provincial Grant for Innovative Province Construction (2019SK4012), and the China Postdoctoral Science Foundation (2022M721124 to W.W.). The authors declare no conflicts of interest. N/A.

Sleep duration and testosterone levels in community older men: results from the West China Health and Aging Trend study.

Sleep duration and testosterone levels in community older men: results from the West China Health and Aging Trend study.

Creating high-resistant starch rice by simultaneous editing of SS3a and SS3b.

Creating high-resistant starch rice by simultaneous editing of SS3a and SS3b.

Association between accelerometer-measured amplitude of rest–activity rhythm and future health risk: a prospective cohort study of the UK Biobank

The health effects of rest-activity rhythm are of major interest to public health, but its associations with health outcomes remain elusive. We aimed to examine the associations between accelerometer-measured rest-activity rhythm amplitude and health risks among the general UK population. We did a prospective cohort analysis of UK Biobank participants aged 43-79 years with valid wrist-worn accelerometer data. Low rest-activity rhythm amplitude was defined as the first quintile of relative amplitude; all other quintiles were classified as high rest-activity rhythm amplitude. Outcomes of interest were defined using International Classification of Diseases 10th Revision codes and consisted of incident cancer and cardiovascular, infectious, respiratory, and digestive diseases, and all-cause and disease-specific (cardiovascular, cancer, and respiratory) mortality. Participants with a current diagnosis of any outcome of interest were excluded. We assessed the associations between decreased rest-activity rhythm amplitude and outcomes using Cox proportional hazards models. Between June 1, 2013, and Dec 23, 2015, 103 682 participants with available raw accelerometer data were enrolled. 92 614 participants (52 219 [56·4%] women and 40 395 [42·6%] men) with a median age of 64 years (IQR 56-69) were recruited. Median follow-up was 6·4 years (IQR 5·8-6·9). Decreased rest-activity rhythm amplitude was significantly associated with increased incidence of cardiovascular diseases (adjusted hazard ratio 1·11 [95% CI 1·05-1·16]), cancer (1·08 [1·01-1·16]), infectious diseases (1·31 [1·22-1·41]), respiratory diseases (1·26 [1·19-1·34]), and digestive diseases (1·08 [1·03-1·14]), as well as all-cause mortality (1·54 [1·40-1·70]) and disease-specific mortality (1·73 [1·34-2·22] for cardiovascular diseases, 1·32 [1·13-1·55] for cancer, and 1·62 [1·25-2·09] for respiratory diseases). Most of these associations were not modified by age older than 65 years or sex. Among 16 accelerometer-measured rest-activity parameters, low rest-activity rhythm amplitude had the strongest or second- strongest associations with nine health outcomes. Our results suggest that low rest-activity rhythm amplitude might contribute to major health outcomes and provide further evidence to promote risk-modifying strategies associated with rest-activity rhythm to improve health and longevity. National Natural Science Foundation of China and China Postdoctoral Science Foundation.

Cognitive adverse events in patients with lung cancer treated with checkpoint inhibitor monotherapy: a propensity score-matched analysis.

Cancer-related cognitive decline is a serious problem in long-term survival but no pivotal study has investigated whether checkpoint inhibitors (ICI) may be associated with cognitive adverse events. This propensity score-matched analysis recruited non-small cell lung cancer (NSCLC) patients prescribed with or without ICI monotherapy from three Chinese tertiary hospitals. Patients were excluded from study who developed brain metastasis or had disorders severely affecting cognitive abilities. Primary outcomes were changes in neuropsychological battery test (NBT) at baseline, 6- and 12-month sessions, and any NBT score changes that exceeded 3∗SD of baseline scores would be marked as objective cognitive adverse events (CoAE). Secondary endpoint was the 20-item Perceived Cognitive Impairment (PCI) sub-scale score change in Functional Assessment of Cancer Therapy-Cognitive Function questionnaire, administered at baseline, 3-, 6-, 9-, 12-, and 15-month follow-up session. Per-protocol ICI and control arms were matched with propensity scores that incorporated baseline variables to compare both NBT and PCI assessment results. Patients participating in PCI assessments were analysed in intention-to-treat analysis. Kaplan-Meier survival curves with log-rank tests were adopted to analyse incidence of perceived cognitive decline events (PCDE). Between March 12, 2020, and March 28, 2021, 908 participants were enrolled. Compared to control, 3 of 4 subtest of NBT scores in ICI arm showed significant cognitive decline in 6- and 12-month sessions, in which Trail Making Test score change (13.56±11.73) reached threshold of cognitive deficit diagnosis in the 12-month session. In 1:1 matched 292 pairs from 908 patients, PCI score changes in ICI arms were-4.26±8.54 (3rd month),-4.72±11.83 (6th month),-6.16±15.41 (9th month),-6.07±15.71 (12th month), and-7.96±13.97 (15th month). The scores were significantly lower than control arm in 3-, 6-, and 12-session follow-up. The result was validated after adjusting quality of life scores and in intention-to-treat analysis. Mean PCI change exceeded 1/2 SD of baseline PCI score (5.81) in 9-, 12-, and 15-month sessions in ICI arm, but not in control arm. PCDE incidence/prevalence was significantly higher in ICI arm (incidence 26.4% vs. 5.1%, and prevalence 16.2% vs. 1.7%). Immune-related adverse events related to incidence of PCDE after adjusting for baseline variables. ICI monotherapy seemed to relate to higher cognitive decline represented by score changes and incidence/prevalence rates. The decline deteriorated as treatment progressed, and immune-related adverse events seemed to be associated with higher cognitive adverse events incidence in the ICI treatment. The Fellowship of China Postdoctoral Science Foundation and National Natural Science Foundation of China Youth Science Fund Project.