The evolution of autonomy from two cooperative specialists in fluctuating environments.

From microbes to humans, organisms perform numerous tasks for their survival, including food acquisition, migration, and reproduction. A complex biological task can be performed by either an autonomous organism or by cooperation among several specialized organisms. However, it remains unclear how autonomy and cooperation evolutionarily switch. Specifically, it remains unclear whether and how cooperative specialists can repair deleted genes through direct genetic exchange, thereby regaining metabolic autonomy. Here, we address this question by experimentally evolving a mutualistic microbial consortium composed of two specialists that cooperatively degrade naphthalene. We observed that autonomous genotypes capable of performing the entire naphthalene degradation pathway evolved from two cooperative specialists and dominated the community. This evolutionary transition was driven by the horizontal gene transfer (HGT) between the two specialists. However, this evolution was exclusively observed in the fluctuating environment alternately supplied with naphthalene and pyruvate, where mutualism and competition between the two specialists alternated. The naphthalene-supplied environment exerted selective pressure that favors the expansion of autonomous genotypes. The pyruvate-supplied environment promoted the coexistence and cell density of the cooperative specialists, thereby increasing the likelihood of HGT. Using a mathematical model, we quantitatively demonstrate that environmental fluctuations facilitate the evolution of autonomy through HGT when the relative growth rate and carrying capacity of the cooperative specialists allow enhanced coexistence and higher cell density in the competitive environment. Together, our results demonstrate that cooperative specialists can repair deleted genes through a direct genetic exchange under specific conditions, thereby regaining metabolic autonomy.

Clonal evolution dissection reveals that a high MSI2 level promotes chemoresistance in T-cell acute lymphoblastic leukemia.

ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5' single-cell RNA with paired T-cell receptor (TCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the 2 contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemotherapy resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemotherapy resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.

The transcriptional hub SHORT INTERNODES1 integrates hormone signals to orchestrate rice growth and development.

Plants have evolved sophisticated mechanisms to coordinate their growth and stress responses via integrating various phytohormone signaling pathways. However, the precise molecular mechanisms orchestrating integration of the phytohormone signaling pathways remain largely obscure. In this study, we found that the rice (Oryza sativa) short internodes1 (shi1) mutant exhibits typical auxin-deficient root development and gravitropic response, brassinosteroid (BR)-deficient plant architecture and grain size as well as enhanced abscisic acid (ABA)-mediated drought tolerance. Additionally, we found that the shi1 mutant is also hyposensitive to auxin and BR treatment but hypersensitive to ABA. Further, we showed that OsSHI1 promotes the biosynthesis of auxin and BR by activating the expression of OsYUCCAs and D11, meanwhile dampens ABA signaling by inducing the expression of OsNAC2, which encodes a repressor of ABA signaling. Furthermore, we demonstrated that 3 classes of transcription factors, AUXIN RESPONSE FACTOR 19 (OsARF19), LEAF AND TILLER ANGLE INCREASED CONTROLLER (LIC), and OsZIP26 and OsZIP86, directly bind to the promoter of OsSHI1 and regulate its expression in response to auxin, BR, and ABA, respectively. Collectively, our results unravel an OsSHI1-centered transcriptional regulatory hub that orchestrates the integration and self-feedback regulation of multiple phytohormone signaling pathways to coordinate plant growth and stress adaptation.

A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation.

Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH; however, the molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) alters Trim71's mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. Mutant Trim71, but not wild-type Trim71, binds Lsd1 (Kdm1a) mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.

CircularSTAR3D: a stack-based RNA 3D structural alignment tool for circular matching.

The functions of non-coding RNAs usually depend on their 3D structures. Therefore, comparing RNA 3D structures is critical in analyzing their functions. We noticed an interesting phenomenon that two non-coding RNAs may share similar substructures when rotating their sequence order. To the best of our knowledge, no existing RNA 3D structural alignment tools can detect this type of matching. In this article, we defined the RNA 3D structure circular matching problem and developed a software tool named CircularSTAR3D to solve this problem. CircularSTAR3D first uses the conserved stacks (consecutive base pairs with similar 3D structures) in the input RNAs to identify the circular matched internal loops and multiloops. Then it performs a local extension iteratively to obtain the whole circular matched substructures. The computational experiments conducted on a non-redundant RNA structure dataset show that circular matching is ubiquitous. Furthermore, we demonstrated the utility of CircularSTAR3D by detecting the conserved substructures missed by regular alignment tools, including structural motifs and conserved structures between riboswitches and ribozymes from different classes. We anticipate CircularSTAR3D to be a valuable supplement to the existing RNA 3D structural analysis techniques.

LINC00941 is a diagnostic biomarker for lung adenocarcinoma and promotes tumorigenesis through cell autophagy.

Non-small cell lung cancer (NSCLC) is a lethal malignancy. There is mounting evidence indicating that lncRNAs are crucial players with dual roles as both biomarkers and regulators across various cancers. It was reported that LINC00941 plays a cancer-promoting role in NSCLC. However, its impact on tumour autophagy remains poorly understood. In this study, we developed a risk assessment model and identified an autophagy-related lncRNA LINC00941, which has independent predictive and early diagnostic potential. Using RT-qPCR analysis, we confirmed the upregulation of LINC00941 in tumour tissues and cell lines of human lung adenocarcinoma (LUAD). Functional assays, such as CCK8, colony formation and xenograft models, demonstrated the cancer-promoting activity of LINC00941 both in vitro and in vivo. Further analysis using Western blotting analysis, mRFP-GFP-LC3 double fluorescence lentivirus vector and transmission electron microscopy (TEM) confirmed that the knockdown of LINC00941 triggered autophagy. These results indicate that knockdown of LINC00941 induces autophagy and impairs the proliferation of LUAD. Therefore, we propose LINC00941 as an independent biomarker for early diagnosis as well as a therapeutic target in LUAD.

Confirming the enzymatic activity and neurodevelopmental trajectory of PYCR1 mutation in one child with autosomal-recessive cutis laxa type 2.

Autosomal-recessive cutis laxa type 2 (ARCL2) is a rare genetic disorder caused by pyrroline-5-carboxylate reductase 1 (PYCR1) mutations and characterized by loose and sagging skin, typical facial features, intrauterine growth retardation, and developmental delay. To study the effect of PYCR1 mutations on protein function and clinical features, we identified a homozygous missense mutation c.559G > A (p.Ala187Thr) in PYCR1 in a Chinese child with typical clinical features, especially severe developmental delays. The three-dimensional (3D) model showed the modification of the hydrogen bonds produce a misfolding in the mutant PYCR1 protein. Mutagenesis and enzyme assay study revealed decreased activity of the mutant protein in vitro, indicating that this mutation impairs PYCR1 function. Our findings confirmed abnormal enzymatic activity and neurodevelopmental trajectory of this PYCR1 mutation.

Analysis of PROS1 mutations and clinical characteristics in three Chinese families with hereditary protein S deficiency.

We report three heterozygous PROS1 mutations that caused type I protein S deficiency in three unrelated Chinese families. We measured protein S activity and antigen levels for all participants, screened them for mutations in the PROS1 gene. And we employed the calibrated automated thrombin generation (CAT) method to investigate thrombin generation. Numerous bioinformatics tools were utilized to analyze the conservation, pathogenicity of mutation, and spatial structure of the protein S. Phenotyping analysis indicated that all three probands exhibited simultaneous reduced levels of PS:A, TPS:Ag, and FPS:Ag. Genetic testing revealed that proband A harbored a heterozygous c.458_458delA (p.Lys153Serfs*6) mutation in exon 5, proband B carried a heterozygous c.1687C>T (p.Gln563stop) mutation in exon 14, and proband C exhibited a heterozygous c.200A>C (p.Glu67Ala) mutation in exon 2. Bioinformatic analysis predicted that the p.Lys153Serfs*6 frameshift mutation and the p.Gln563stop nonsense mutation in the protein S were classified as "disease-causing." The identification of the novel mutation p.Lys153Serfs*6 in PROS1 enriches the Human Genome Database. Our research suggests that these three mutations (p.Lys153Serfs*6, p.Gln563stop, and p.Glu67Ala) are possibly responsible for the decreased level of protein S in the three families. Furthermore, the evidence also supports the notion that individuals who are asymptomatic but have a family history of PSD can benefit from genetic analysis of the PROS1 gene.

Cut-off values of haemoglobin and clinical outcomes in incident peritoneal dialysis: the PDTAP study.

BACKGROUND: To explore the cut-off values of haemoglobin (Hb) on adverse clinical outcomes in incident peritoneal dialysis (PD) patients based on a national-level database. METHODS: The observational cohort study was from the Peritoneal Dialysis Telemedicine-assisted Platform (PDTAP) dataset. The primary outcomes were all-cause mortality, major adverse cardiovascular events (MACE) and modified MACE (MACE+). The secondary outcomes were the occurrences of hospitalization, first-episode peritonitis and permanent transfer to haemodialysis (HD). RESULTS: A total of 2591 PD patients were enrolled between June 2016 and April 2019 and followed up until December 2020. Baseline and time-averaged Hb <100 g/l were associated with all-cause mortality, MACE, MACE+ and hospitalizations. After multivariable adjustments, only time-averaged Hb <100 g/l significantly predicted a higher risk for all-cause mortality {hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.19-281], P = .006}, MACE [HR 1.99 (95% CI 1.16-3.40), P = .012] and MACE+ [HR 1.77 (95% CI 1.15-2.73), P = .010] in the total cohort. No associations between Hb and hospitalizations, transfer to HD and first-episode peritonitis were observed. Among patients with Hb ≥100 g/l at baseline, younger age, female, use of iron supplementation, lower values of serum albumin and renal Kt/V independently predicted the incidence of Hb <100 g/l during the follow-up. CONCLUSION: This study provided real-world evidence on the cut-off value of Hb for predicting poorer outcomes through a nation-level prospective PD cohort.

Targeted phytogenic compounds against Vibrio parahaemolyticus biofilms.

As one of main culprit of seafood-associated human illness, Vibrio parahaemolyticus can readily accumulate on biotic or abiotic surfaces to form biofilms in the seafood processing environment. Biofilm formation on various surfaces can provide a protective barrier for viable bacterial cells that are resistant to most traditional bacteriostatic measures. This underscores the necessity and urgency of developing effective alternative strategies to control V. parahaemolyticus biofilms. Plants have always provided an extensive and infinite source of biologically active compounds for "green" antibiofilm agents. This review summarizes recent developments in promising multitargeted phytogenic compounds against V. parahaemolyticus biofilms. This review provides valuable insights into potential research targets that can be pursued further to identify potent natural antibiofilm agents in the food industry.

Synergies between diabetes and hyperhomocysteinaemia: New insights to predict and prevent adverse cardiovascular effects.

AIM: To explore the association of hyperhomocysteinaemia (HHcy) and diabetes synergies with cardiovascular events in the adult population of northern China. METHODS: Data were collected from the Asymptomatic Polyvascular Abnomalities Community study for 2010 to 2019. Serum homocysteine (Hcy) levels were determined by enzyme-linked immunosorbent assay. The participants were categorized into four groups based on their Hcy levels and diabetes status: non-diabetes/non-HHcy, non-diabetes/HHcy, diabetes/non-HHcy and diabetes/HHcy. The composite endpoint consisted of the occurrence of first-ever stroke, myocardial infraction (MI) or all-cause mortality. Cox regression analyses were performed to evaluate the associations of diabetes and HHcy with cardiovascular disease (CVD) events. RESULTS: In total, 5278 participants were eligible (average age 55.1 years, 60% male). Over a follow-up of 9.1 years, 618 events were identified, 202 stroke, 52 MI and 406 all-cause deaths. Compared with the non-diabetes/non-HHcy group, hazard ratios with 95% confidence intervals in the diabetes/HHcy group for stroke, MI, major adverse cardiovascular event (MACE), all-cause death and composite endpoint were 1.85 (1.12-3.04), 1.33 (0.42-4.23), 1.78 (1.13-2.80), 2.24 (1.56-3.23) and 1.97 (1.47-2.65), respectively. Significant interactions between HHcy and diabetes status were found for stroke, MI and MACE (P for interaction = .002, .027 and .044, respectively). In addition, the association of diabetes/HHcy with stroke was modified by age (< 60 and ≥ 60 years; P for interaction = .016). CONCLUSIONS: The findings highlight the synergistic impact of diabetes and HHcy on CVD. Joint assessments of diabetes and Hcy levels should be emphasized for risk stratification and primary prevention of CVD.

Intricate microbe-plant-metabolic remodeling mediated by intercropping enhances the quality of Panax quinquefolius L.

Improving the cultivation mode and technology for traditional Chinese medicine has become important for its sustainable development. Monoculture enhances plant diseases, which decreases yield and quality. Intercropping is an effective measure to counterbalance that negative effect. In this study, we focused on Panax quinquefolium L. (ginseng) and four treatments were set up: the control without intercropping, P. quinquefolius + ryegrass (Lolium perenne L.), P. quinquefolius + red clover (Trifolium pratense L.), and P. quinquefolius + ryegrass + red clover. An LC-MS/MS system was used to detect the changes in the P. quinquefolius secondary metabolites, and high-throughput sequencing technology was used to determine the changes in the P. quinquefolius' rhizosphere soil microorganisms. Ginsenoside content, soil enzyme activities, and arbuscular mycorrhizal infection rate of P. quinquefolius were also measured using HPLC, ELISA kits, and microscopy, respectively. Co-intertia and Pearson's analysis were performed to explore the relationship between the metabolites and the P. quinquefolius microorganisms. Intercropping significantly increased the content of ginsenoside metabolites and recruited a large number of beneficial bacteria to the P. quinquefolius rhizosphere. The P. quinquefolius secondary metabolites were associated with the rhizosphere microbial community. For example, the dominant microorganisms, such as Acidobacteriota and Chloroflexi, played a key role in promoting the synthesis of ginsenoside Rd and (20R) ginsenoside Rg3 by P. quinquefolius. Intercropping led to changes in the P. quinquefolius secondary metabolites by driving and reshaping the rhizosphere microorganisms. These findings revealed the potential application of intercropping for improving the quality of P. quinquefolius.

Utilizing metagenomic next-generation sequencing for pathogen detection and diagnosis in lower respiratory tract infections in real-world clinical practice.

BACKGROUND: Infectious etiologies of lower respiratory tract infections (LRTIs) by the conventional microbiology tests (CMTs) can be challenging. Metagenomic next-generation sequencing (mNGS) has great potential in clinical use for its comprehensiveness in identifying pathogens, particularly those difficult-to-culture organisms. METHODS: We analyzed a total of 205 clinical samples from 201 patients with suspected LRTIs using mNGS in parallel with CMTs. mNGS results were used to guide treatment adjustments for patients who had negative CMT results. The efficacy of treatment was subsequently evaluated in these patients. RESULTS: mNGS-detected microorganisms in 91.7% (188/205) of the clinical samples, whereas CMTs demonstrated a lower detection rate, identifying microorganisms in only 37.6% (77/205) of samples. Compared to CMT results, mNGS exhibited a detection sensitivity of 93.5% and 95.4% in all 205 clinical samples and 180 bronchoalveolar lavage fluid (BALF) samples, respectively. A total of 114 patients (114/201; 56.7%) showed negative CMT results, among which 92 received treatment adjustments guided by their positive mNGS results. Notably, 67.4% (62/92) of patients demonstrated effective treatment, while 25% (23/92) experienced a stabilized condition. Subgroup analysis of cancer patients revealed that 41.9% (13/31) exhibited an effective response to treatment, and 35.5% (11/31) maintained a stable condition following medication adjustments guided by mNGS. CONCLUSION: mNGS demonstrated great potential in identifying microorganisms of clinical significance in LRTIs. The rapid turnaround time and reduced susceptibility to the impact of antimicrobial administration make mNGS a valuable supplementary tool for diagnosis and treatment decision-making for suspected LRTIs in clinical practice.

Multifunctional Lanthanide Metal-Organic Frameworks Are Used for Fluorescence Sensing of Bi3+, HPO42-, Flu, and PNBA and Application.

Using a nitrogen-containing tricarboxylic acid ligand (imidazole-1-yl) benzene-2,4,6-tricarboxylic acid (H3ttc) and lanthanide metal elements (Dy, Eu, Nd, and Gd), four lanthanide metal organic frameworks (Ln-MOFs) with the same structure, namely, {[Dy2 (Httc)3]·1.5DMF}n(1), {[Eu2 (Httc)3]·1.5DMF}n(2), {[Nd2 (Httc)3]·1.5DMF}n(3), and {[Gd2 (Httc)3]·1.5DMF}n(4), were synthesized under solvothermal conditions. The characterization analysis showed that the four isomorphic Ln-MOFs were trigonal crystals of the R3̅c space group, with good phase purity and thermal stability. Fluorescence analysis showed that complex 1 can be an excellent fluorescence sensor for Bi3+, HPO42-, and fluridine (Flu), while complex 2 can be an excellent fluorescence sensor for p-nitrobenzoic acid (PNBA). And their sensing mechanisms were discussed in detail. The fluorescent test paper and fluorescent seal were prepared by using the excellent luminescence properties of 1 and 2, and the pesticide on the surface of cherry tomato was detected. The applicability of these MOFs as fluorescence sensors was proved. Therefore, Ln-MOFs are expected to have unpredictable application prospects in the field of environmental detection.

Excessive dietary iron exposure increases the susceptibility of largemouth bass (Micropterus salmoides) to Aeromonas hydrophila by interfering with immune response, oxidative stress, and intestinal homeostasis.

Iron is an essential cofactor in the fundamental metabolic pathways of organisms. Moderate iron intake can enhance animal growth performance, while iron overload increases the risk of pathogen infection. Although the impact of iron on the pathogen-host relationship has been confirmed in higher vertebrates, research in fish is extremely limited. The effects and mechanisms of different levels of iron exposure on the infection of Aeromonas hydrophila in largemouth bass (Micropterus salmoides) remain unclear. In this study, experimental diets were prepared by adding 0, 800, 1600, and 3200 mg/kg of FeSO4∙7H2O to the basal feed, and the impact of a 56-day feeding period on the mortality rate of largemouth bass infected with A. hydrophila was analyzed. Additionally, the relationships between mortality rate and tissue iron content, immune regulation, oxidative stress, iron homeostasis, gut microbiota, and tissue morphology were investigated. The results showed that the survival rate of largemouth bass infected with A. hydrophila decreased with increasing iron exposure levels. Excessive dietary iron intake significantly increased iron deposition in the tissues of largemouth bass, reduced the expression and activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, increased the content of lipid peroxidation product malondialdehyde, and thereby induced oxidative stress. Excessive iron supplementation could influence the immune response of largemouth bass by upregulating the expression of pro-inflammatory cytokines in the intestine and liver, while downregulating the expression of anti-inflammatory cytokines. Additionally, excessive iron intake could also affect iron metabolism by inducing the expression of hepcidin, disrupt intestinal homeostasis by interfering with the composition and function of the gut microbiota, and induce damage in the intestinal and hepatic tissues. These research findings provide a partial theoretical basis for deciphering the molecular mechanisms underlying the influence of excessive iron exposure on the susceptibility of largemouth bass to pathogenic bacteria.

Analysis of risk factors for long-term mortality in patients with stage II and III tuberculous meningitis.

OBJECTIVE: To investigate risk factors associated with long-term mortality in patients with stage II and III tuberculous meningitis (TBM). METHODS: This retrospective analysis examined patients who were first diagnosed with stage II and III TBM at West China Hospital of Sichuan University between January 1, 2018 and October 1, 2019. Patients were followed via telephone and categorized into survival and mortality groups based on 4-year outcomes. Multivariate logistic regression identified independent risk factors for long-term mortality in stage II and III TBM. RESULTS: In total, 178 patients were included, comprising 108 (60.7%) males and 36 (20.2%) non-survivors. Mean age was 36 ± 17 years. Compared to survivors, non-survivors demonstrated significantly higher age, heart rate, diastolic blood pressure, blood glucose, rates of headache, neurological deficits, cognitive dysfunction, impaired consciousness, hydrocephalus, and basal meningeal inflammation. This group also exhibited significantly lower Glasgow Coma Scale (GCS) scores, blood potassium, albumin, and cerebrospinal fluid chloride. Multivariate analysis revealed age (OR 1.042; 95% CI 1.015-1.070; P = 0.002), GCS score (OR 0.693; 95% CI 0.589-0.814; P < 0.001), neurological deficits (OR 5.204; 95% CI 2.056-13.174; P < 0.001), and hydrocephalus (OR 2.680; 95% CI 1.081-6.643; P = 0.033) as independent mortality risk factors. The ROC curve area under age was 0.613 (95% CI 0.506-0.720; P = 0.036) and 0.721 (95% CI 0.615-0.826; P < 0.001) under GCS score. CONCLUSION: Advanced age, reduced GCS scores, neurological deficits, and hydrocephalus were identified as independent risk factors for mortality in stage II and III TBM patients.

COVID-19 in the Tibet, China, the roof of the world: a comparative analysis of high-altitude residents and newcomers.

BACKGROUND: After a 920-day hiatus, COVID-19 resurged in the Tibet Autonomous Region of China in August 2022. This study compares the characteristics of COVID-19 between high-altitude residents and newcomers, as well as between newcomers and lowlanders. METHODS: This multi-center cohort study conducted at the Third People's Hospital of Tibet Autonomous Region and Beijing University Shenzhen Hospital, included 520 high-altitude resident patients, 53 high-altitude newcomer patients, and 265 lowlander patients infected with the Omicron variant. Initially, we documented epidemiological, clinical, and treatment data across varying residency at admission. We compared the severity of COVID-19 and various laboratory indicators, including hemoglobin concentration and SpO2%, over a 14-day period from the date of the first positive nucleic acid test, as well as the differences in treatment methods and disease outcomes between highlanders and high-altitude newcomers. We also compared several characteristics of COVID-19 between high-altitude newcomers and lowlanders. Univariate analysis, multivariable logistic regression, and the generalized linear mixed model were utilized for the analysis. RESULTS: No fatalities were observed. The study found no significant differences in COVID-19 severity or in the physiological measures of hemoglobin concentration and SpO2% between high-altitude and lowland residents. Similarly, there were no statistically significant differences in the values or trends of hemoglobin and SpO2% between high-altitude residents and newcomers throughout the 14-day observation period. However, compared to age- and sex-matched lowlander patients (1:5 ratio), high-altitude newcomers exhibited higher heart rates, respiratory rates, and average hemoglobin concentrations, along with lower platelet counts. There were no significant differences in hospital stays between the two groups. CONCLUSIONS: High-altitude residents and newcomer patients exhibit clinical similarities. However, the clinical characteristics of high-altitude newcomers and lowlander patients differ due to the impact of the high-altitude environment. These results highlight potential considerations for public health strategies in high-altitude regions such as Tibet.

Haplotype-specific MAPK3 expression in 16p11.2 deletion contributes to variable neurodevelopment.

Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del neurodevelopmental disorders cohort and generated human induced pluripotent stem cells for two 16p11.2del families with distinct residual haplotypes and variable neurodevelopmental disorder phenotypes. Using transcriptomic profiles and cellular phenotypes of the human induced pluripotent stem cell-differentiated cortex neuronal cells, we revealed MAPK3 to be a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied on the basis of a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype were mapped to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with neurodevelopmental disorder phenotypes in 16p11.2del carriers.

Correlation between hyperuricemia and thickened left ventricular wall in hypertensive young adults.

BACKGROUND: In this study, we examine the association between the hyperuricemia(HU) and hypertension(HTN) in Chinese young adults. Besides, the correlation between the occurrence of thickened left ventricular wall and HU was identified in patients with HTN. METHODS: In all, 360 patients with HTN and 1991 young adults with normal blood pressure(NBP) were enrolled in the study. Participant characteristics were collected. Univariable and multivariable logistic regression tests were utilized to identify the correlation between the presence of HU and HTN, and the correlation between the occurrence of thickened ventricular septum and HU in patients with HTN. RESULTS: The prevalence of HU in Chinese young adults with HTN was significantly higher than young adults with NBP(36.39% vs. 16.93%). Univariable analyses revealed that 8 factors were related with the presence of HTN with p value < 0.001, including HU, male, body mass index(BMI) ≥ 24 kg/m2, total cholesterol(TC) > 5.17mmol/L, triglyceride(TG) > 1.70mmol/L, high density lipoprotein cholesterol(HDL-C) < 1.0mmol/L, fasting blood glucose(FBG) > 6.10mmol/L and fatty liver. After adjusting these covariates, multivariable analysis revealed that HU[odds ratio(OR):1.47, 95% confidence interval(CI): 1.10-1.95, p = 0.008] remained independent association with HTN in young adults. Additionally, univariable and multivariable logistic analyses revealed that HU kept the independent effect on the presence of thickened interventricular septum(adjusted OR = 1.81, 95% CI: 1.05-3.11, P = 0.03) and thickened left ventricular posterior wall(adjusted OR = 2.28, 95% CI: 1.28-4.08, P = 0.005) in young adults with HTN. CONCLUSION: HU was independently associated with HTN in young adults. HU was independently correlated with thickened left ventricular wall, including interventricular septum and left ventricular posterior wall, in young adults with HTN.

Fecal calprotectin: A novel predictor of ulcerated esophageal injury after atrial fibrillation catheter ablation.

BACKGROUND: Atrial esophageal fistula (AEF) is a lethal complication that can occur post atrial fibrillation (AF) ablation. Esophageal injury (EI) is likely to be the initial lesion leading to AEF. Endoscopic examination is the gold standard for a diagnosis of EI but extensive endoscopic screening is invasive and costly. This study was conducted to determine whether fecal calprotectin (Fcal), a marker of inflammation throughout the intestinal tract, may be associated with the existence of esophageal injury. METHODS: This diagnostic study was conducted in a cohort of 166 patients with symptomatic AF undergoing radiofrequency catheter ablation from May 2020 to June 2021. Fcal tests were performed 1-7 days after ablation. All patients underwent endoscopic ultrasonography 1 or 2 days after ablation. RESULTS: The levels of Fcal were significantly different between the EI and non-EI groups (404.9 µg/g (IQR 129.6-723.6) vs. 40.4 µg/g (IQR 15.0-246.2), p < .001). Analysis of ROC curves revealed that a Fcal level of 125 µg/g might be the optimal cut-off value for a diagnosis of EI, giving a 78.8% sensitivity and a 65.4% specificity. The negative predictive value of Fcal was 100% for ulcerated EI. CONCLUSIONS: The level of Fcal is associated with EI post AF catheter ablation. 125 µg/g might be the optimal cut-off value for a diagnosis of EI. Negative Fcal could predict the absence of ulcerated EI, which could be considered a precursor to AEF.