Unraveling lexical semantics in the brain: Comparing internal, external, and hybrid language models.

To explain how the human brain represents and organizes meaning, many theoretical and computational language models have been proposed over the years, varying in their underlying computational principles and in the language samples based on which they are built. However, how well they capture the neural encoding of lexical semantics remains elusive. We used representational similarity analysis (RSA) to evaluate to what extent three models of different types explained neural responses elicited by word stimuli: an External corpus-based word2vec model, an Internal free word association model, and a Hybrid ConceptNet model. Semantic networks were constructed using word relations computed in the three models and experimental stimuli were selected through a community detection procedure. The similarity patterns between language models and neural responses were compared at the community, exemplar, and word node levels to probe the potential hierarchical semantic structure. We found that semantic relations computed with the Internal model provided the closest approximation to the patterns of neural activation, whereas the External model did not capture neural responses as well. Compared with the exemplar and the node levels, community-level RSA demonstrated the broadest involvement of brain regions, engaging areas critical for semantic processing, including the angular gyrus, superior frontal gyrus and a large portion of the anterior temporal lobe. The findings highlight the multidimensional semantic organization in the brain which is better captured by Internal models sensitive to multiple modalities such as word association compared with External models trained on text corpora.

Small bowel neuroendocrine tumors: Unique features and low lethality compared with small bowel adenocarcinoma.

BACKGROUND AND AIM: Population-based studies comparing clinical characteristics and survival disparities between patients with small bowel adenocarcinoma (SBA) and small bowel neuroendocrine tumors (SBNETs) in the United States are limited. METHODS: Data for patients with SBA or SBNETs, obtained from the Surveillance, Epidemiology, and End Results database for the years between 2000 and 2018 were analyzed. RESULTS: Between 2000 and 2018, the age-adjusted incidence of SBA experienced a marginal increase whereas SBNETs demonstrated a significant increase, emerging as the predominant subtype of small bowel cancer (SBC). Diagnoses peaked at ages 65-69 years for SBA and 60-64 years for SBNETs, with the latter exhibiting a heightened age-specific incidence and maintaining equilibrium in gender distribution. Clinicopathologic disparities revealed SBA's duodenal predilection, larger tumor size, and advanced stages, contrasting with SBNETs' ileal predilection, early-stage presentation, and superior outcomes. SBNETs patients underwent surgery more frequently but received less chemotherapy and radiation than SBA patients. Factors intricately correlated with a diagnosis of SBNETs included female gender, White race, advanced age, marital status, recent diagnoses, superior tumor differentiation, smaller size, distal location, and early-stage presentation. Survival analysis unveiled a remarkable 79% reduction in the mortality risk for SBNETs compared with SBA. Subgroup analysis further confirmed the consistently favorable survival advantages of SBNETs, highlighting the clinical relevance of histological classification in prognostication. CONCLUSION: Compared with SBA, SBNETs exhibited distinctive clinicopathological features characterized by a higher inclination toward low-grade and early-stage manifestations, thereby contributing to superior survival outcomes.

CCLOOW: Chinese children's lexicon of oral words.

In this article, we introduce the Chinese Children's Lexicon of Oral Words (CCLOOW), the first lexical database based on animated movies and TV series for 3-to-9-year-old Chinese children. The database computes from 2.7 million character tokens and 1.8 million word tokens. It contains 3920 unique character and 22,229 word types. CCLOOW reports frequency and contextual diversity metrics of the characters and words, as well as length and syntactic categories of the words. CCLOOW frequency and contextual diversity measures correlated well with other Chinese lexical databases, particularly well with that computed from children's books. The predictive validity of CCLOOW measures were confirmed with Grade 2 children's naming and lexical decision experiments. Further, we found that CCLOOW frequencies could explain a considerable proportion in adults' written word recognition, indicating that early language experience might have lasting impacts on the mature lexicon. CCLOOW provides validated frequency and contextual diversity estimates that complements current children's lexical database based on written language samples. It is freely accessible online at https://www.learn2read.cn/ccloow .

Aberrant NAD synthetic flux in podocytes under diabetic conditions and effects of indoleamine 2,3-dioxygenase on promoting de novo NAD synthesis.

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme in the kidney. The first step in de novo NAD synthesis is regulated by indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme. Here, we investigated NAD synthetic flux and NAD levels in podocytes under diabetic conditions. We also studied the effects of IDO overexpression on NAD synthetic flux and high glucose (HG)-induced podocyte injury. NAD synthetases in the de novo, Preiss-Handler and salvage pathways were analyzed using in vivo single-nucleus RNA sequencing datasets (GSE131882) of control and diabetic kidney disease (DKD). The mRNA levels of these NAD synthetases were measured in vitro in HG-treated podocytes. The effects of IDO on NAD synthesis were examined by transducing cultured podocytes with an adenovirus encoding IDO, and apoptosis, podocyte markers and mobility were investigated. Cellular transcriptome analysis revealed that control podocytes had relatively low levels of NAD synthetases. In DKD podocytes, de novo NAD synthetase levels were further downregulated. IDO levels were virtually undetectable and did not increase in DKD. In vitro experiments confirmed aberrant de novo NAD synthetic flux and decreased IDO levels in HG-treated podocytes. Overexpression of IDO promoted NAD de novo synthesis, reduced NAD-bypass metabolic enzyme, increased NAD content and recovered podocyte injury markers under diabetic conditions. Taken together, our findings suggest that the de novo NAD synthetic flux is aberrant in DKD, and IDO promotes de novo NAD synthesis and NAD levels, as well as alleviates injury in HG-treated podocytes.

Growth associated protein 43 deficiency promotes podocyte injury by activating the calmodulin/calcineurin pathway under hyperglycemia.

Podocyte injury is a crucial factor in the pathogenesis of diabetic kidney disease (DKD), and finding potential therapeutic interventions that can mitigate podocyte injury holds significant clinical relevance. This study was to elucidate the role of growth associated protein-43(Gap43) in podocyte injury of high glucose (HG). We confirmed the expression of Gap43 in human glomerulus and found that Gap43 expression was downregulated in podocytes of patients with DKD and HG-treated podocytes in vitro. Gap43 knockdown in podocytes promoted podocyte apoptosis, increased migration ability and decreased nephrin expression, while overexpression of Gap43 markedly suppressed HG-induced injury. Moreover, the increased expression and activity of calcineurin (CaN) were also abrogated by overexpression Gap43 in HG. Pretreatment with a typical CaN inhibitor FK506 in Gap43 knockdown podocytes restored the injury. Mechanistically, co-immunoprecipitation experiments suggested that Gap43 could bind to calmodulin (CaM). Pull-down assay further demonstrated that Gap43 and CaM directly interacts with each other via amino acids 30-52 of Gap43 and amino acids 133-197 of CaM. In addition, we also identified Pax5 as potential transcription inhibitor factor mediating Gap43 expression. In conclusion, the study indicated that the Gap43/CaM-CaN pathway may be exploited as a promising therapeutic target for protecting against podocyte injury in high glucose.

Role of TFEB in regulation of the podocyte actin cytoskeleton.

Podocyte injury is linked to the pathogenesis and progression of renal disease. The Transcription Factor EB (TFEB), a master regulator of the autophagy and lysosomal pathways, has been found to exert cell- and tissue-specific biological function. To explore TFEB function and underlying mechanisms in podocytes, a total of 4645 differentially expressed genes (DEGs) were detected in TFEB-knockdown mouse podocytes by transcriptome sequencing. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis showed that, apart from the enrichment in autophagy and lysosomal pathways, DEGs were enriched in cytoskeleton structure (Actin Cytoskeleton, Focal Adhesion, and Adherens Junction), as well as cytoskeleton regulatory molecular signaling (Hippo and Rho GTPase Signaling). In vitro, TFEB knockdown resulted in podocyte cytoskeletal rearrangement, which was disorganized with cortical distribution of actin filaments. Further, TFEB knockdown decreased mRNA and protein levels of Synaptopodin and led to the rearrangement of Synaptopodin. Inhibition of TFEB decreased mRNA levels for proteins involved in actin cytoskeleton dynamics. Moreover, apoptosis was increased by TFEB knockdown in podocyte. In summary, this study initiated a comprehensive analysis of the role of TFEB in podocyte function and the potential underlying mechanisms, and identified a novel role for TFEB in regulation of the podocyte actin cytoskeleton.

CCLOWW: A grade-level Chinese children's lexicon of written words.

In this article, we present the Chinese Children's Lexicon of Written Words (CCLOWW), the first grade-level database that provides frequency statistics of simplified Chinese characters and words for children. The database computes from a corpus of 34,671,424 character tokens and 22,427,010 word tokens (including single- and multicharacter words), extracted from 2131 books. It contains 6746 different character types and 153,079 different word types. CCLOWW provides several frequency indices of simplified Chinese for three grade levels (grade 2 and below, grades 3-4, grades 5-6) to profile children's experience with written Chinese in and outside of school. We describe in this article the distributions of frequency and contextual diversity of the characters and words, as well as word length and syntactic categories of the words in the corpus and the subcorpora. We also report results of correlation analyses with other written corpora and of several naming and lexicon decision experiments. The findings suggest that CCLOWW frequency measures correlate well with other corpora. Importantly, they could reliably predict children's and adults' naming and lexical decision performances. They could also explain variance in adults' visual word recognition, in addition to frequency measures computed in an adult corpus, indicating that early print exposure might influence readers' lexical processing later on beyond an age of acquisition effect. CCLOWW will help researchers in language processing and development as well as educators with selecting language materials appropriate for children's developmental stages. The database is freely available online at https://www.learn2read.cn/database/ .

Analysis of the prevalence, risk factors, and clinical characteristics of osteoporosis in patients with essential hypertension.

BACKGROUND: The present study investigated the prevalence of osteoporosis (OP) among patients with essential hypertension (EH) in the Changchun community and analysed the correlation between EH and OP. METHODS: The study included 425 subjects with EH and 425 age- and sex-matched healthy controls. Bone mineral density (BMD) and serum creatinine (CR) levels were measured, and the subjects' current EH and OP statuses were surveyed to analyse the correlation between EH and OP. RESULTS: The EH group exhibited lower BMD and a higher rate of having OP than the control group, and this difference was statistically significant (p < 0.05). A significant sex difference in the BMD T-score was observed among the subjects (male: - 1.19 ± 1.55, female: - 1.70 ± 1.34). In both the EH group and the control group, the rate of having OP in females was greater than that in males. However, the OP prevalence among subjects with EH varied significantly by age, body weight, fracture history, nocturnal urination frequency, depression and anxiety status, duration of hypertension, and antihypertensive medication use (p < 0.05). Two-way analysis of variance suggested an effect of the interaction between different EH statuses and bone mass conditions on the serum CR values (F = 3.584, p = 0.028, bias η2 = 0.008). CONCLUSIONS: The prevalence of OP and low BMD were significantly higher among subjects with EH than among healthy controls. Additionally, the findings indicate that age, weight, fracture history, nocturnal urination frequency, depression and anxiety, duration of hypertension and antihypertensive drug use may be correlated to having OP in EH subjects, requiring further studies. Moreover, serum CR levels in subjects with different bone mass profiles were strongly influenced by the presence or absence of EH, and the serum CR levels differed significantly with the interaction of these two factors.

Comprehensive analysis of immune-related prognostic genes in the tumour microenvironment of hepatocellular carcinoma.

BACKGROUND: The mortality rate of hepatocellular carcinoma (HCC) remains high worldwide despite surgery and chemotherapy. Immunotherapy is a promising treatment for the rapidly expanding HCC spectrum. Therefore, it is necessary to further explore the immune-related characteristics of the tumour microenvironment (TME), which plays a vital role in tumour initiation and progression. METHODS: In this research, 866 immune-related differentially expressed genes (DEGs) were identified by integrating the DEGs of samples from The Cancer Genome Atlas (TCGA)-HCC dataset and the immune-related genes from databases (InnateDB; ImmPort). Afterwards, 144 candidate prognostic genes were defined through weighted gene co-expression network analysis (WGCNA). RESULTS: Seven immune-related prognostic DEGs were identified using the L1-penalized least absolute shrinkage and selection operator (LASSO) Cox proportional hazards (PH) model, and the ImmuneRiskScore model was constructed on this basis. The prognostic index of the ImmuneRiskScore model was then validated in the relevant dataset. Patients were divided into high- and low-risk groups according to the ImmuneRiskScore. Differences in the immune cell infiltration of patients with different ImmuneRiskScore values were clarified, and the correlation of immune cell infiltration with immunotherapy biomarkers was further explored. CONCLUSION: The ImmuneRiskScore of HCC could be a prognostic marker and can reflect the immune characteristics of the TME. Furthermore, it provides a potential biomarker for predicting the response to immunotherapy in HCC patients.

Evaluation of Endovascular Therapy Combined with Bowel Resection Treatment on Patients with Acute Mesenteric Venous Thrombosis.

BACKGROUND: This retrospective study aims to investigate the effects of the endovascular and surgical strategy for treating patients with acute mesenteric venous thrombosis (AMVT). METHODS: We retrospectively studied 68 patients with AMVT who underwent treatment in Jinling Hospital during the period from January 2009 to December 2014. The mean age was 45 ± 12 years (range 20-72 years). All patients were treated by using the combined treatment that included endovascular treatment, damage control surgery, surgical intensive care, and intestinal rehabilitation treatment. Clinical outcomes and complications were compared during the follow-up period. RESULTS: All the 68 cases received anticoagulant treatment. However, only 24 received the endovascular intervention, 19 received surgical resection, and 25 patients received endovascular treatment combined with bowel resection. The overall mortality rate was 2.94% (2 cases). Bowel resection range significantly decreased (92 ± 14 cm vs. 162 ± 27 cm, t = -2.377, P = 0.022) in the combination therapy group, when compared with the surgery group. During the 1-year follow-up period, 4 cases suffered from short bowel syndrome. CONCLUSIONS: Our study indicates that AMVT can be successfully treated with the early improvement of intestinal blood circulation. Further, our applied combined approach showed a favorable outcome in mesenteric thrombosis patients and reduced the mortality rate by improving the prognosis significantly.

Pediatric allergy and immunology in China.

Over the past 30 years, China has enjoyed rapid economic development along with urbanization at a massive scale that the world has not experienced before. Such development has also been associated with a rapid rise in the prevalence of allergic disorders. Because of the large childhood population in the country, the burden of childhood allergic disorders has become one of the major challenges in the healthcare system. Among the Chinese centers participating in the International Study of Asthma and Allergies in Childhood, the data clearly showed a continuing rise in the prevalence of asthma, allergic rhinitis, and atopic eczema. However, the discipline of pediatric allergy in mainland China is still in its infancy due to the lack of formal training program and subspecialty certification. Clinicians and researchers are increasingly interested in providing better care for patients with allergies by establishing pediatric allergy centers in different regions of the country. Many of them have also participated in national or international collaborative projects hoping to answer the various research questions related to the discipline of pediatric allergy and immunology. It is our hope that the research findings from China will not only improve the quality of care of affected children within this country but also the millions of patients with allergies worldwide.

Acoustic Radiation Force Impulse Imaging for Assessing Liver Fibrosis Preoperatively in Infants With Biliary Atresia: Comparison With Liver Fibrosis Biopsy Pathology.

OBJECTIVES: The purpose of this study was to investigate the diagnostic performance of acoustic radiation force impulse (ARFI) in assessing liver fibrosis preoperatively in infants with biliary atresia (BA). METHODS: A total of 50 consecutive infants with BA and 50 healthy infants who underwent ARFI examination were recruited. Siemens Acuson S2000 in Virtual Touch Quantification mode (Siemens Medical Solutions, Mountain View, CA) was used to measure shear wave speeds (SWSs). All infants with BA underwent a liver biopsy within 3 days after ARFI imaging. The liver fibrosis stages of specimens were defined according to the Batts-Ludwig scoring system. The correlation analysis was performed between SWSs and pathological findings. Cut-off values were determined using receiver operating characteristic (ROC) curves. RESULTS: The mean SWS in the BA group was significantly higher than controls (mean ± standard deviation): 1.89 ± 0.45 versus 1.12 ± 0.06 m/s; P < .001). A significant correlation was found between the SWSs and fibrosis stages (r = 0.719, P < .001). The cut-off value for predicting significant fibrosis (F ≥ 2), severe fibrosis (F ≥ 3), and cirrhosis (F = 4) was 1.53, 1.80 and 2.16 m/s, respectively, and the area under the ROC curve was 0.823, 0.884 and 0.917, respectively. CONCLUSIONS: Acoustic radiation force impulse imaging showed significant correlation with the severity of liver fibrosis by comparing it with liver fibrosis biopsy pathology. It may be an effective method for liver fibrosis assessment, prognosis prediction, and clinical management in infants with BA.

The flagellin hypervariable region is a potential flagella display domain in probiotic Escherichia coli strain Nissle 1917.

The most studied probiotic, Escherichia coli strain Nissle 1917 (EcN) possesses flagella of serotype H1. To explore the potential to use EcN flagellin in flagella display applications, we investigated the effect of deleting amino acids in the hypervariable region of flagellin on EcNc (EcN cured of its two cryptic plasmids pMUT1 and pMUT2). Two EcNc flagellin isogenic mutants with deletions of amino acid residual from 277 to 286 and from 287 to 296 in the hypervariable domain were constructed. Both mutants were flagellated, adherent to IPEC-J2 cells, and colonized BALB/c mice. These hypervariable regions may have future utility in the display of heterologous epitopes.

Rupatadine inhibits colorectal cancer cell proliferation through the PIP5K1A/Akt/CDK2 pathway.

BACKGROUND: Phosphatidylinositol-4-phosphate 5-kinase type 1 alpha (PIP5K1A) acts upstream of the Akt regulatory pathway and is abnormally expressed in many types of malignancies. However, the role and mechanism of PIP5K1A in colorectal cancer (CRC) have not yet been reported. In this study, we aimed to determine the association between PIP5K1A and progression of CRC and assess the efficacy and mechanism by which rupatadine targets PIP5K1A. METHODS: Firstly, expression and function of PIP5K1A in CRC were investigated by human colon cancer tissue chip analysis and cell proliferation assay. Next, rupatadine was screened by computational screening and cytotoxicity assay and interactions between PIP5K1A and rupatadine assessed by kinase activity detection assay and bio-layer interferometry analysis. Next, rupatadine's anti-tumor effect was evaluated by in vivo and in vitro pharmacodynamic assays. Finally, rupatadine's anti-tumor mechanism was explored by quantitative real-time reverse-transcription polymerase chain reaction, western blot, and immunofluorescence. RESULTS: We found that PIP5K1A exerts tumor-promoting effects as a proto-oncogene in CRC and aberrant PIP5K1A expression correlates with CRC malignancy. We also found that rupatadine down-regulates cyclin-dependent kinase 2 and cyclin D1 protein expression by inhibiting the PIP5K1A/Akt/GSK-3ß pathway, induces cell cycle arrest, and inhibits CRC cell proliferation in vitro and in vivo. CONCLUSIONS: PIP5K1A is a potential drug target for treating CRC. Rupatadine, which targets PIP5K1A, could serve as a new option for treating CRC, its therapeutic mechanism being related to regulation of the Akt/GSK-3ß signaling pathway.

Distinct roles of Kif6 and Kif9 in mammalian ciliary trafficking and motility.

Ciliary beat and intraflagellar transport depend on dynein and kinesin motors. The kinesin-9 family members Kif6 and Kif9 are implicated in motile cilia motilities across protists and mammals. How they function and whether they act redundantly, however, remain unclear. Here, we show that Kif6 and Kif9 play distinct roles in mammals. Kif6 forms puncta that move bidirectionally along axonemes, whereas Kif9 appears to oscillate regionally on the ciliary central apparatus. Consistently, only Kif6 displays microtubule-based motor activity in vitro, and its ciliary localization requires its ATPase activity. Kif6 deficiency in mice disrupts coordinated ciliary beat across ependymal tissues and impairs cerebrospinal fluid flow, resulting in severe hydrocephalus and high mortality. Kif9 deficiency causes mild hydrocephalus without obviously affecting the ciliary beat or the lifespan. Kif6-/- and Kif9-/- males are infertile but exhibit oligozoospermia with poor sperm motility and defective forward motion of sperms, respectively. These results suggest Kif6 as a motor for cargo transport and Kif9 as a central apparatus regulator.

Autophagic inhibitor ROC-325 ameliorates glomerulosclerosis and podocyte injury via inhibiting autophagic flux in experimental FSGS mice.

BACKGROUND: Autophagy plays an important role in the pathogenesis of focal segmental glomerulosclerosis (FSGS). Podocyte-specific Yes-associated protein (YAP) deletion mice, referred to as YAP-KO mice, is considered a new animal model to study the underlying mechanism of FSGS. ROC-325 is a novel small-molecule lysosomal autophagy inhibitor that is more effective than chloroquine (CQ) and hydroxychloroquine (HCQ) in suppressing autophagy. In this study, we sought to determine the therapeutic benefit and mechanism of action of ROC-325 in YAP-KO mice, an experimental FSGS model. METHODS AND RESULTS: YAP-KO mice were treated with ROC-325 (50 mg/kg, p.o.) daily for one month. Our results revealed that albuminuria, mesangial matrix expension, and focal segmental glomerulosclerosis in YAP-KO mice were significantly attenuated by ROC-325 administration. Transmission electron microscopy and immunofluorescence staining showed that ROC-325 treatment significantly inhibited YAP-KO-induced autophagy activation by decreasing autophagosome-lysosome fusion and increasing LC3A/B and p62/SQSTM. Meanwhile, Immunofluorescence staining revealed that preapplication of ROC-325 in podocyte with YAP-targeted siRNA and mRFP-GFP-LC3 adenovirus markedly suppressed autophagic flux in vitro, suggesting that autophagy intervention may serve as a target for FSGS. CONCLUSIONS: These results showed that the role of autophagic activity in FSGS mice model and ROC-325 could be a novel and promising agent for the treatment of FSGS.

Is it worthwhile to screen the hip in infants born with clubfeet?

PURPOSE: There is some disagreement about whether idiopathic congenital talipes equinovarus (CTEV) increases the risk of neonatal developmental dysplasia of the hip (DDH). This study aimed to investigate the incidence of DDH in our infants with idiopathic CTEV. METHODS: We conducted an observational cohort study over a three-year period to assess the relationship between idiopathic CTEV and DDH. All neonates younger than six weeks with idiopathic CTEV who were treated in our medical centre were admitted to this study. Each subject underwent hip ultrasound examination using the Graf method at the age of six weeks. DDH was diagnosed when a hip was type IIa(-) or worse according to the Graf classification of sonographic hip type. RESULTS: A total of 184 patients were diagnosed with idiopathic CTEV and underwent hip sonography. In total, seven hips of five individuals underwent treatment (four girls and one boy). The results indicated that 2.7% of babies (five of 184) with idiopathic CTEV had DDH. However, we did not find any statistically significant difference (p = 0.5776) in the Pirani scores between the DDH group and group with normal hips. CONCLUSIONS: This study revealed that the idiopathic CTEV group had a greater incidence of DDH in comparison with the general population. It is recommended that hip sonography be undertaken particularly in patients with idiopathic CTEV.

Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients with HCC. It is necessary to study the mechanism of kinase inhibitor resistance and explore possible solutions to overcome this resistance to improve clinical benefits. In this study, we reviewed the mechanisms of resistance to multi-target kinase inhibitors in HCC and discussed strategies that can be used to improve treatment outcomes.

Maternal and neonatal blood vitamin D status and neurodevelopment at 24 months of age: a prospective birth cohort study.

BACKGROUND: This study aimed to explore the relationship of 25-hydroxyvitamin D [25(OH)D] in three trimesters and at birth with neurodevelopment at 24 months of age. METHODS: From 2013 to 2016, pregnant women from the Shanghai Birth Cohort in China were recruited for the study. Altogether, 649 mother-infant pairs were included. Serum 25(OH)D was measured with mass spectrometry in three trimesters, and cord blood was divided into deficiency (< 20 and < 12 ng/mL, respectively), insufficiency (20-30 and 12-20 ng/mL, respectively), and sufficiency (≥ 30 and ≥ 20 ng/mL, respectively). Bayley-III scale was used to assess cognitive, language, motor, social-emotional, and adaptive behavior development at 24 months of age. The Bayley-III scores were grouped into quartiles, and scores within the lowest quartile were defined as suboptimal development. RESULTS: After adjusting for confounding factors, cord blood 25(OH)D in the sufficient group was positively correlated with cognitive [ß = 11.43, 95% confidence interval (CI) = 5.65-17.22], language (ß = 6.01, 95% CI = 1.67-10.3), and motor scores (ß = 6.43, 95% CI = 1.73-11.1); cord blood 25(OH)D in the insufficient group was also positively correlated with cognitive scores (ß = 9.42, 95% CI = 3.74-15.11). Additionally, sufficient vitamin D status in the four periods and persistent 25(OH)D ≥ 30 ng/mL throughout pregnancy were associated with a lower risk of suboptimal cognitive development in adjusted models, although the effects were attenuated after applying the false discovery rate adjustment. CONCLUSIONS: Cord blood 25(OH)D ≥ 12 ng/mL has a significant positive association with cognitive, language, and motor development at 24 months of age. Sufficient vitamin D status in pregnancy might be a protective factor for suboptimal neurocognition development at 24 months of age.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats.

AIM: Sacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. METHODS: The AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. RESULTS: Sac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. CONCLUSION: Sac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.