Recessive variants in the intergenic NOS1AP-C1orf226 locus cause monogenic kidney disease responsive to anti-proteinuric treatment.

In genetic disease, an accurate expression landscape of disease genes and faithful animal models will enable precise genetic diagnoses and therapeutic discoveries, respectively. We previously discovered that variants in NOS1AP , encoding nitric oxide synthase 1 (NOS1) adaptor protein, cause monogenic nephrotic syndrome (NS). Here, we determined that an intergenic splice product of N OS1AP / Nos1ap and neighboring C1orf226/Gm7694 , which precludes NOS1 binding, is the predominant isoform in mammalian kidney transcriptional and proteomic data. Gm7694 -/- mice, whose allele exclusively disrupts the intergenic product, developed NS phenotypes. In two human NS subjects, we identified causative NOS1AP splice variants, including one predicted to abrogate intergenic splicing but initially misclassified as benign based on the canonical transcript. Finally, by modifying genetic background, we generated a faithful mouse model of NOS1AP -associated NS, which responded to anti-proteinuric treatment. This study highlights the importance of intergenic splicing and a potential treatment avenue in a mendelian disorder.

Bounding the Amount of Entanglement from Witness Operators.

We present an approach to estimate the operational distinguishability between an entangled state and any separable state directly from measuring an entanglement witness. We show that this estimation also implies bounds on a variety of other well-known entanglement quantifiers. This approach for entanglement estimation is then extended to both the measurement-device-independent scenario and the fully device-independent scenario, where we obtain nontrivial but suboptimal bounds. The procedure requires no numerical optimization and is easy to compute. It offers ways for experimenters to not only detect, but also quantify, entanglement from the standard entanglement witness procedure.

Social isolation and the risk of Parkinson disease in the UK biobank study.

Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91-1.10) for the moderately isolated group and 1.19 (1.05-1.36) for the most isolated group (P-trend = 0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.

Development and experimental validation of an energy metabolism-related gene signature for diagnosing of osteoporosis.

Osteoporosis is usually caused by excessive bone resorption and energy metabolism plays a critical role in the development of osteoporosis. However, little is known about the role of energy metabolism-related genes in osteoporosis. This study aimed to explore the important energy metabolism-related genes involved in the development of osteoporosis and develop a diagnosis signature for osteoporosis. The GSE56814, GSE62402, and GSE7158 datasets were downloaded from the NCBI Gene Expression Omnibus. The intersection of differentially expressed genes between high and low levels of body mineral density (BMD) and genes related to energy metabolism were screened as differentially expressed energy metabolism genes (DE-EMGs). Subsequently, a DE-EMG-based diagnostic model was constructed and differential expression of genes in the model was validated by RT-qPCR. Furthermore, a receiver operating characteristic curve and nomogram model were constructed to evaluate the predictive ability of the diagnostic model. Finally, the immune cell types in the merged samples and networks associated with the selected optimal DE-EMGs were constructed. A total of 72 overlapped genes were selected as DE-EMGs, and a five DE-EMG based diagnostic model consisting B4GALT4, ADH4, ACAD11, B4GALT2, and PPP1R3C was established. The areas under the curve of the five genes in the merged training dataset and B4GALT2 in the validation dataset were 0.784 and 0.790, respectively. Moreover, good prognostic prediction ability was observed using the nomogram model (C index = 0.9201; P = 5.507e-14). Significant differences were observed in five immune cell types between the high- and low-BMD groups. These included central memory, effector memory, and activated CD8 T cells, as well as regulatory T cells and activated B cells. A network related to DE-EMGs was constructed, including hsa-miR-23b-3p, DANCR, 17 small-molecule drugs, and two Kyoto Encyclopedia of Genes and Genomes pathways, including metabolic pathways and pyruvate metabolism. Our findings highlighted the important roles of DE-EMGs in the development of osteoporosis. Furthermore, the DANCR/hsa-miR-23b-3p/B4GALT4 axis might provide novel molecular insights into the process of osteoporosis development.

High Entropy Alloys Enable Durable and Efficient Lithium-Mediated CO2 Redox Reactions.

Designing electrocatalysts with high activity and durability for multistep reduction and oxidation reactions is challenging. High-entropy alloys (HEAs) are intriguing due to their tunable geometric and electronic structure through entropy effects. However, understanding the origin of their exceptional performance and identifying active centers is hindered by the diverse microenvironment in HEAs. Herein, NiFeCoCuRu HEAs designed with an average diameter of 2.17 nm, featuring different adsorption capacities for various reactants and intermediates in Li-mediated CO2 redox reactions, are introduced. The electronegativity-dependent nature of NiFeCoCuRu HEAs induces significant charge redistribution, shifting the d-band center closer to Fermi level and forming highly active clusters of Ru, Co, and Ni for Li-based compounds adsorptions. This lowers energy barriers and simultaneously stabilizes *LiCO2 and LiCO3+CO intermediates, enhancing the efficiency of both CO2 reduction and Li2CO3 decomposition over extended periods. This work provides insights into specific active site interactions with intermediates, highlighting the potential of HEAs as promising catalysts for intricate CO2 redox reactions.

Highly efficient field-free switching of perpendicular yttrium iron garnet with collinear spin current.

Yttrium iron garnet, a material possessing ultralow magnetic damping and extraordinarily long magnon diffusion length, is the most widely studied magnetic insulator in spintronics and magnonics. Field-free electrical control of perpendicular yttrium iron garnet magnetization with considerable efficiency is highly desired for excellent device performance. Here, we demonstrate such an accomplishment with a collinear spin current, whose spin polarization and propagation direction are both perpendicular to the interface. Remarkably, the field-free magnetization switching is achieved not only with a heavy-metal-free material, Permalloy, but also with a higher efficiency as compared with a typical heavy metal, Pt. Combined with the direct and inverse effect measurements, we ascribe the collinear spin current to the anomalous spin Hall effect in Permalloy. Our findings provide a new insight into spin current generation in Permalloy and open an avenue in spintronic devices.

Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.

Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation.

Olive oil intake and cardiovascular disease, cancer, and all-cause mortality: a systematic review and dose-response meta-analysis of prospective cohort studies.

Background: Currently, the reported links between olive oil intake and cardiovascular disease (CVD), cancer morbidity and mortality, and all-cause mortality are inconsistent. The aim of this meta-analysis is to study the reported correlations of olive oil intake with CVD, coronary heart disease (CHD), stroke and cancer incidence and mortality, and all-cause mortality. Methods: PubMed, Embase, and Web of Science were searched until March 7, 2024. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the random-effects model. Nonlinear dose-response relationships were modeled with restricted cubic splines. This study has been registered at PROSPERO (CRD42023419001). Results: Overall, 30 articles covering 2 710 351 participants were identified. Higher olive oil intake was linked with a reduced risk of CVD incidence (RR: 0.85; 95% CI: 0.77, 0.93), CHD incidence (RR: 0.85; 95% CI: 0.72, 0.99), CVD mortality (RR: 0.77; 95% CI: 0.67, 0.88), and all-cause mortality (RR: 0.85; 95% CI: 0.81, 0.89). For a 10 g d-1 increment of olive oil intake, the risk of CVD incidence, stroke incidence, CVD mortality, and all-cause mortality decreased by 7%, 5%, 8%, and 8%, respectively. No association was found between olive oil intake and cancer incidence and mortality. Nonlinear relationships between olive oil intake and CVD and all-cause mortality were observed, with a reduced risk from intakes ranging from 0 to 18 g d-1 and 0 to 22 g d-1, respectively. Conclusion: Our study found that high olive oil intake was related to a lower risk of CVD and CHD incidence and CVD mortality and all-cause mortality.

Range-Intensity-Profile-Guided Gated Light Ranging and Imaging Based on a Convolutional Neural Network.

Three-dimensional (3D) range-gated imaging can obtain high spatial resolution intensity images as well as pixel-wise depth information. Several algorithms have been developed to recover depth from gated images such as the range-intensity correlation algorithm and deep-learning-based algorithm. The traditional range-intensity correlation algorithm requires specific range-intensity profiles, which are hard to generate, while the existing deep-learning-based algorithm requires large number of real-scene training data. In this work, we propose a method of range-intensity-profile-guided gated light ranging and imaging to recover depth from gated images based on a convolutional neural network. In this method, the range-intensity profile (RIP) of a given gated light ranging and imaging system is obtained to generate synthetic training data from Grand Theft Auto V for our range-intensity ratio and semantic network (RIRS-net). The RIRS-net is mainly trained on synthetic data and fine-tuned with RIP data. The network learns both semantic depth cues and range-intensity depth cues in the synthetic data, and learns accurate range-intensity depth cues in the RIP data. In the evaluation experiments on both a real-scene and synthetic test dataset, our method shows a better result compared to other algorithms.

ATP Citrate Lyase is a General Tumour Biomarker and Contributes to the Development of Cutaneous Squamous Cell Carcinoma.

ATP citrate lyase, the first rate-limiting enzyme in de novo lipogenesis, plays a crucial role in tumour progression. This study explores ATP citrate lyase's potential as a tumour biomarker and its role in cutaneous squamous cell carcinoma. ATP citrate lyase expression patterns were analysed using TCGA and TIMER databases, and patient skin specimens were collected for immunohistochemistry to determine ATP citrate lyase levels. Cell proliferation, cell cycle, apoptosis, and c-Myc expression were assessed in A431 and SCL-1 cells. Stable cell lines with reduced ATP citrate lyase expression were obtained and subcutaneously implanted into nude mice to evaluate in vivo tumour growth. Ki67, c-Myc expression and TUNEL staining were analysed in subcutaneous tumours. ATP citrate lyase exhibited upregulation in various tumours, and showed significant associations with prognosis and immune infiltrate. Moreover, ATP citrate lyase was highly expressed in cutaneous squamous cell carcinoma. After ATP citrate lyase silencing, cutaneous squamous cell carcinoma cell growth decelerated, the cell cycle halted, cell apoptosis increased, and c-Myc expression decreased. Animal experiments revealed that, following ATP citrate lyase knockdown, tumour tissue growth slowed down, and there was a reduction in Ki-67 and c-Myc expression, accompanied by enhanced TUNEL staining. In conclusion, ATP citrate lyase may serve as a tumour biomarker. It is highly expressed in cutaneous squamous cell carcinoma and may serve as a therapeutic target.

Comparison and evaluation of overcoring and hydraulic fracturing stress measurements.

The stress measurements determined by both the overcoring (OC) and hydraulic fracturing (HF) methods in the Shuichang iron mine and Sanshandao gold mine were compared and evaluated, respectively. The results indicate that the independent OC and HF data in the two mines reveal the same dominant faulting stress regime. The σH orientations derived from the OC and HF methods in the Shuichang iron mine are dominantly oriented in the N81.1°W-N89.4°W and N77.0°E-N88.0°E, respectively, and the σH orientations yielded from the OC and HF techniques in the Sanshandao gold mine are predominantly in the N30°W-N90°W and N55.5°W-N60.4°W, respectively; hence, the σH orientations obtained by the two different methods in the two mines are comparatively similar. In addition, the shapes of the probability density diagrams using an improved Bayesian regression approach of the three principal stresses measured by the OC and HF methods in the same mine are quite similar, and all the obtained Kolmogorov-Smirnov test p-values are larger than the selected significance level of 0.01, indicating that the stress data interpreted by the two methods approximately follow the same distribution law. Thus, the performance of the two techniques and the reliability of the measured data are satisfactory.

Dose-response associations of triglyceride to high-density lipoprotein cholesterol ratio and triglyceride-glucose index with arterial stiffness risk.

BACKGROUND: The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and triglyceride-glucose (TyG) index are novel indexes for insulin resistance (IR). We aimed to evaluate associations of TG/HDL-C and TyG with arterial stiffness risk. METHODS: We enrolled 1979 participants from the Rural Chinese Cohort Study, examining arterial stiffness by brachial-ankle pulse wave velocity (baPWV). Logistic and linear regression models were employed to calculate effect estimates. For meta-analysis, we searched relevant articles from PubMed, Embase and Web of Science up to August 26, 2023. The fixed-effects or random-effects models were used to calculate the pooled estimates. We evaluated dose-response associations using restricted cubic splines. RESULTS: For cross-sectional studies, the adjusted ORs (95%CIs) for arterial stiffness were 1.12 (1.01-1.23) and 1.78 (1.38-2.30) for per 1 unit increment in TG/HDL-C and TyG. In the meta-analysis, the pooled ORs (95% CIs) were 1.26 (1.14-1.39) and 1.57 (1.36-1.82) for per 1 unit increment of TG/HDL-C and TyG. Additionally, both TG/HDL-C and TyG were positively related to PWV, with ß of 0.09 (95% CI 0.04-0.14) and 0.57 (95% CI 0.35-0.78) m/s. We also found linear associations of TG/HDL-C and TyG with arterial stiffness risk. CONCLUSIONS: High TG/HDL-C and TyG were related to increased arterial stiffness risk, indicating TG/HDL-C and TyG may be convincing predictors of arterial stiffness.

Enteric glia regulate Paneth cell secretion and intestinal microbial ecology.

Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro . Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1 + cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1 + glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.

Tunable Interfacial Electric Field-Mediated Cobalt-Doped FeSe/Fe3Se4 Heterostructure for High-Efficiency Potassium Storage.

The interfacial electric field (IEF) in the heterostructure can accelerate electron transport and ion migration, thereby enhancing the electrochemical performance of potassium-ion batteries (PIBs). Nevertheless, the quantification and modulation of the IEF for high-efficiency PIB anodes currently remains a blank slate. Herein, we achieve for the first time the quantification and tuning of IEF via amorphous carbon-coated undifferentiated cobalt-doped FeSe/Fe3Se4 heterostructure (denoted UN-CoFe4Se5/C) for efficient potassium storage. Co doping can increase the IEF in FeSe/Fe3Se4, thereby improving the electron transport, promoting the potassium adsorption capacity, and lowering the diffusion barrier. As expected, the IEF magnitude in UN-CoFe4Se5/C is experimentally quantified as 62.84 mV, which is 3.65 times larger than that of amorphous carbon-coated FeSe/Fe3Se4 heterostructure (Fe4Se5/C). Benefiting from the strong IEF, UN-CoFe4Se5/C as a PIB anode exhibits superior rate capability (145.8 mAh g-1 at 10.0 A g-1) and long cycle lifespan (capacity retention of 95.1% over 3000 cycles at 1.0 A g-1). Furthermore, this undifferentiated doping strategy can universally regulate the IEF magnitude in CoSe2/Co9Se8 and FeS2/Fe7S8 heterostructures. This work can provide fundamental insights into the design of advanced PIB electrodes.

Catalytic role of in-situ formed C-N species for enhanced Li2CO3 decomposition.

Sluggish kinetics of the CO2 reduction/evolution reactions lead to the accumulation of Li2CO3 residuals and thus possible catalyst deactivation, which hinders the long-term cycling stability of Li-CO2 batteries. Apart from catalyst design, constructing a fluorinated solid-electrolyte interphase is a conventional strategy to minimize parasitic reactions and prolong cycle life. However, the catalytic effects of solid-electrolyte interphase components have been overlooked and remain unclear. Herein, we systematically regulate the compositions of solid-electrolyte interphase via tuning electrolyte solvation structures, anion coordination, and binding free energy between Li ion and anion. The cells exhibit distinct improvement in cycling performance with increasing content of C-N species in solid-electrolyte interphase layers. The enhancement originates from a catalytic effect towards accelerating the Li2CO3 formation/decomposition kinetics. Theoretical analysis reveals that C-N species provide strong adsorption sites and promote charge transfer from interface to *CO22- during discharge, and from Li2CO3 to C-N species during charge, thereby building a bidirectional fast-reacting bridge for CO2 reduction/evolution reactions. This finding enables us to design a C-N rich solid-electrolyte interphase via dual-salt electrolytes, improving cycle life of Li-CO2 batteries to twice that using traditional electrolytes. Our work provides an insight into interfacial design by tuning of catalytic properties towards CO2 reduction/evolution reactions.

PAFAH1B3 is a KLF9 target gene that promotes proliferation and metastasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. Uncontrolled cell proliferation, invasion and migration of pancreatic cancer cells are the fundamental causes of death in PDAC patients. Our previous studies showed that KLF9 inhibits the proliferation, invasion and migration of pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In this study, we found that platelet-activating factor acetylhydrolase IB3 (PAFAH1B3) is highly expressed in pancreatic cancer tissues and cells. In vitro and in vivo studies showed that overexpression of PAFAH1B3 promoted the proliferation and invasion of pancreatic cancer cells, while downregulation of PAFAH1B3 inhibited these processes. We found that KLF9 expression is negatively correlated with PAFAH1B3 expression in pancreatic cancer tissues and cells. Western blotting revealed that KLF9 negatively regulates the expression of PAFAH1B3 in pancreatic cancer tissues and cells. Rescue experiments showed that overexpression of PAFAH1B3 could partially attenuate the suppression of pancreatic cancer cell proliferation, invasion and migration induced by KLF9 overexpression. Finally, chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays were carried out, and the results showed that KLF9 directly binds to the promoter of PAFAH1B3 and inhibits its transcriptional activity. In conclusion, our study indicated that KLF9 can inhibit the proliferation, invasion, migration and metastasis of pancreatic cancer cells by inhibiting PAFAH1B3.

A fully validated LC­MS/MS method for quantifying bevacizumab in plasma samples from patients with NSCLC and its implications in therapeutic drug monitoring.

Given the increasing use of bevacizumab in combinatorial drug therapy for a multitude of different cancer types, there is a need for therapeutic drug monitoring to analyze the possible correlation between drug trough concentration, and therapeutic effect and adverse reactions. An ultra-performance liquid chromatography tandem-mass spectrometry method was then developed and validated to determine bevacizumab levels in human plasma samples. Chromatographic separation was achieved on a Shimadzu InertSustainBio C18 HP column, whereas subsequent mass spectrometric analysis was performed using a Shimadzu 8050CL triple quadrupole mass spectrometer equipped with an electro-spray ionization source in the positive ion mode. In total, three multiple reaction monitoring transitions of each of the surrogate peptides were chosen with 'FTFSLDTSK' applied as the quantification peptide whereas 'VLIYFTSSLHSGVPSR' and 'STAYLQMNSLR' were designated as the verification peptides using the Skyline software. This analytical method was then fully validated, with specificity, linearity, lower limit of quantitation, accuracy, precision, stability, matrix effect and recovery calculated. The linearity of this method was developed to be within the concentration range 5-400 µg/ml for bevacizumab in human plasma. Subsequently, eight patients with non-small cell lung cancer (NSCLC) were recruited and injected with bevacizumab over three periods of treatment to analyze their steady-state trough concentration and differences. To conclude, the results of the present study suggest that bevacizumab can be monitored in a therapeutic setting in patients with NSCLC.

Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission.

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

Safety of an inactivated COVID-19 vaccine (CoronaVac) in children aged 7-14 years in Taizhou, China.

Our study aimed to evaluate the safety of CoronaVac, an inactivated vaccine made by Sinovac, in children aged 7-14. We conducted a parent-administered online survey to monitor adverse reactions after vaccinating children in Taizhou, China, from February 15, 2021, to January 19, 2022. 767 parents completed the survey after receiving a questionnaire via WeChat. Overall, 15.3 % (117/767) of children experienced adverse effects after the first dose, and 12.2 % (88/724) after the second. Muscle pain was the most common adverse reaction post-first dose (10.0 %), while localized pain or itching at the injection site was most common after the second dose (7.6 %). In conclusion, the vaccine has a low incidence of side effects. The mild to moderate, transient, and common nature of these effects further boosts parents' confidence in vaccinating their children.