Analysis of the CHD7 gene mutations in patients of congenital heart disease with extracardiac malformations.

Background: Congenital heart disease (CHD) is a common birth defect, and is frequently accompanied with extracardiac malformations (ECM). Uncovering the genetic etiology of CHD may have a meaningful impact on disease management. De novo variants have been proven to be associated with CHD. Methods: Whole exome sequencing was performed for 4 unrelated CHD families with extracardiac malformations, candidate genes were screened by using stringent bioinformatics analysis, and the obtained variants were confirmed by Sanger sequencing. RT-PCR and Sanger sequencing were used to investigate the influence of a splice variant on pre-mRNA splicing. Further targeted sequencing was conducted to investigate the association of CHD7 variants with sporadic CHD. Results: Four novel heterozygous loss-of-function CHD7 mutations were found by using stringent bioinformatics analysis: the frameshift mutation c.1951_1952delAAinsT (p.L651X) in family #1, the nonsense mutations c.2913C>G (p.Y971X) in family #2 and c.3106C>T (pA1036X) in family #3, and the splicing mutation c.4353+4_4353+12delinsGCCCA in family #4. Sanger sequencing confirmed that these were all de novo mutations and were absent in the healthy parents and siblings of the probands. Further studies revealed that the splice mutation c.4353+4_4353+12delinsGCCCA influenced CHD7 mRNA splicing in vivo. Targeted sequencing found 23 rare mutations in 1,155 sporadic CHD patients. Conclusions: The findings here confirm that de novo loss-of-function variants of the CHD7 gene are the genetic cause of familial CHD with extracardiac malformations and the spectrum of pathogenic CHD7 variants in sporadic CHD is expanded.

Cultural antecedents of virus transmission: Individualism is associated with lower compliance with social distancing rules during the COVID-19 pandemic.

In the context of COVID-19 government-ordered lockdowns, more individualistic people might be less willing to leave their homes to protect their own health, or they might be more willing to go out to relieve their boredom. Using an Australian sample, a pilot study found that people's lay theories were consistent with the latter possibility, that individualism would be associated with a greater willingness to violate lockdown orders. Using a longitudinal data set containing location records of about 18 million smartphones across the United States, Study 1 found that people in more individualistic states were less likely to comply with social distancing rules following lockdown orders. Additional analyses replicated this finding with reference to counties' residential mobility, which is associated with increased individualism. In a longitudinal data set containing mobility data across 79 countries and regions, Study 2 found that people in more individualistic countries and regions were also less likely to follow social distancing rules. Preregistered Study 3 replicated these findings at the individual level: People scoring higher on an individualism scale indicated that they had violated social distancing rules more often during the COVID-19 pandemic. Study 4 found that the effect of individualism on violating social distancing rules was mediated by people's selfishness and boredom. Overall, our findings document a cultural antecedent of individuals' socially responsible behavior during a pandemic and suggest an additional explanation for why the COVID-19 pandemic has been much harder to contain in some parts of the world than in others. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinical implications of respiratory ciliary dysfunction in heterotaxy patients with congenital heart disease: elevated risk of postoperative airway complications.

Objective: Cardiac surgery in Congenital Heart Disease-Heterotaxy (CHD-HTX) patients often leads to increased postoperative airway complications. Abnormal respiratory ciliary function, resembling primary ciliary dyskinesia, has been observed. We expanded the sample size by retrospectively reviewing Ciliary Dysfunction (CD) in CHD-HTX patients to verify the increased risk of post-surgical respiratory complications. Methods: We conducted a retrospective review of 69 CHD-HTX patients undergoing cardiac surgery, assessing abnormal respiratory function using nasal nitric oxide (nNO) levels and nasal ciliary motion observed in video microscopy. Data collected included demographics, surgical details, postoperative complications, length of stay, ICU hours, salvage procedures, intubation duration, and mortality. Results: The CD and no-CD cohorts exhibited notable similarities in risk adjustment in Congenital Heart Surgery-1 (RACHS-1) risk categories, age at the time of surgery, and the duration of follow-up evaluations. We observed a trend toward an increased length of post-operative stay in the CD group (15.0 vs. 14.0; P = 0.0017). CHD-HTX patients with CD showed significantly higher rates of respiratory complications (70% vs. 44.4%; P = 0.008). There were no notable variances observed in postoperative hospitalization duration, mechanical ventilation period, or surgical mortality. Conclusion: Our findings suggest that CHD-HTX patients with CD may face an elevated risk of respiratory complications. These results offer guidance for perioperative management and serve as a reference for further pathological studies.

An X-linked PLXNB3 mutation identified in patients with congenital heart disease with neurodevelopmental disabilities.

Background: Congenital heart disease (CHD) is the most common birth defect and is often accompanied by neurodevelopmental disabilities (NDD) which increase the associated mortality. Plexin families are known to play a key role in the development of heart and the occurrence of neurodevelopmental anomalies. However, there has been no report of PLXNB3 mutation in isolated CHD or CHD with concomitant NDD. Methods: We performed whole-exome sequencing (WES) on a proband with CHD with neurodevelopmental anomalies and his family members. Targeted sequencing, conservation analysis, AlphaFold, and PyRosetta were performed to identify more pathogenic mutations of PLXNB3. Scratch wound assay, Ki-67 assessment by flow cytometry, and gene expression analysis of heart development related pathway by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted after 24 h transfection in AC16 and HEK293T to investigate the effect of the target mutation. Results: We identified a pathogenic mutation in the X-linked PLXNB3 gene (c.A4319T p.E1440V). In addition, we found 4 other pathogenic mutations in a cohort of 75 patients with sporadic CHD with NDD. AlphaFold and PyRosetta predicted that these 4 mutations could cause dramatic changes of the PLXNB3 protein structure (root-mean-square deviation score >10 Å). Further functional analysis revealed that this p.E1440V variant inhibits cell migration and proliferation, and affects the activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways. Conclusions: These findings suggest that PLXNB3 and the p.E1440V variant may be related to the pathogenesis of CHD associated with NDD.

Salvage high intensity focused ultrasound for residual or recurrent cervical cancer after definitive chemoradiotherapy.

Objective: The treatment of residual/recurrent cervical cancer within a previously irradiated area is challenging and generally associated with a poor outcome. Local treatments such as salvage surgery and re-irradiation are usually traumatic and have limited efficacy. High intensity focused ultrasound (HIFU) treatment can directly ablate solid tumors without damaging neighboring healthy tissue. However, the HIFU studies for these patients are limited. Experience gained over the course of 10 years with the use of HIFU for the management of residual/recurrent cervical cancer after chemoradiotherapy is reported herein. Methods: 153 patients with residual/recurrent cervical cancer in a previously irradiated field who received HIFU treatment between 2010 and 2021 were retrospectively analyzed. Adverse effects, survival benefit and factors affecting prognosis were given particular attention. Results: A total of 36 patients (23.5%) achieved a partial response following HIFU treatment and 107 patients (69.9%) had stable disease. The objective response and disease control rates were 23.5% and 93.5%, respectively. The median progression-free survival (mPFS) and median overall survival (mOS) were 17.0 months and 24.5 months, respectively. Moreover, patients with lesions ≥1.40 cm before HIFU treatment and a shrinkage rate ≥ 30% after treatment had a higher mPFS and mOS, and patients with lesions ≤1.00 cm after HIFU treatment had a higher mPFS (P=<0.05). All the treatment-related adverse events were limited to minor complications, which included skin burns, abdominal pain and vaginal discharge. Conclusions: HIFU treatment is likely a preferred option for cervical cancer patients with residual disease or recurrence following CRT that can safely improve the local control rate and extend survival.

Copy number variant analysis for syndromic congenital heart disease in the Chinese population.

BACKGROUND: Syndromic congenital heart disease (CHD) is among the most severe conditions in the pediatric population. Copy number variant (CNV) is an important cause of syndromic CHD, but few studies focused on CNVs related to these patients in China. The present study aimed to identify pathogenic CNVs associated with syndromic CHD in the Chinese population. METHODS: A total of 109 sporadic patients with syndromic CHD were applied chromosomal microarray analysis (CMA). Phenotype spectrum of pathogenic or likely pathogenic CNVs was analyzed. CHD-related genes were prioritized from genes within pathogenic or likely pathogenic CNVs by VarElect, OVA, AMELIE, and ToppGene. RESULTS: Using CMA, we identified 43 candidate CNVs in 37/109 patients. After filtering CNVs present in the general population, 29 pathogenic/likely pathogenic CNVs in 24 patients were identified. The diagnostic yield of CMA for pathogenic/likely pathogenic CNVs was 23.1% (24/104), excluding 5 cases with aneuploidies or gross chromosomal aberrations. The overlapping analysis of CHD-related gene lists from different prioritization tools highlighted 16 CHD candidate genes. CONCLUSION: As the first study focused on CNVs in syndromic CHD from the Chinese population, this study reveals the importance of CMA in exploring the genetic etiology of syndromic CHD and expands our understanding of these complex diseases. The bioinformatic analysis of candidate genes suggests several CHD-related genes for further functional research.

Temperature-Compensated Multi-Point Strain Sensing Based on Cascaded FBG and Optical FMCW Interferometry.

We proposed a novel temperature-compensated multi-point strain sensing system based on cascaded FBG and optical FMCW interferometry. The former is used for simultaneous sensing of temperature and strain, and the latter is used for position information reading and multiplexing. In the experiment, a narrow linewidth laser with continuous frequency-sweeping was used as the light source. After demodulating the beat-frequency signal, the link information of the 16 m fiber was obtained, and the measured result was identical to the actual position. The measurement accuracy reached 50.15 mm, and the dynamic range was up to 22.68 dB. Meanwhile, we completed the sensing experiments for temperature range from 20 °C to 90 °C and strain range from 0 µÎµ to 7000 µÎµ. The sensitivity of the sensing system to temperature was 10.21 pm/°C, the sensitivity and accuracy to strain were as high as 1.163 pm/µÎµ and 10 µÎµ, respectively. Finally, the measured strain and temperature values were obtained using the sensing matrix. The sensing system has important practical significance in the field of quasi-distributed strain measurement.

Analysis of the Expression and Role of Keratin 17 in Human Tumors.

Objective: We aimed to explore the expression and carcinogenic effect of KRT17 in human tumors and provide useful information for the study of KRT17. Methods: We used databases including the Cancer Genome Atlas, Gene Expression Omnibus, GTEx, and GEPIA2 to analyze the expression, mutation, and prognosis of KRT17 in human tumors. Through webservers, including UALCAN, TIMER2.0, and STRING, we learned about the genetic variation, immune cell penetration, and enrichment analysis of KRT17-related genes. Results: KRT17 was highly expressed in most tumors (such as esophageal cancer, lung cancer, cervical cancer, etc.), and the high expression level correlated with tumor stage and prognosis. In addition, amplification was the main type of KRT17 tumor variation, with an amplification rate of about 9%, followed by mutation, with a mutation rate of 4%. Moreover, KRT17 was strongly associated with tumor-infiltrating immune cells (such as macrophages, CD8+T, Tregs, and cancer-associated fibroblasts). KEGG analysis suggested that KRT17 may play a role in tumor pathogenesis following human papillomavirus infection, and the gene ontology enrichment analysis indicated that the carcinogenicity of KRT17 can be attributed to cadherin binding, intermediate fibrocytoskeleton and epidermal development. Conclusion: KRT17 may play an important role in the occurrence, development, and prognosis of malignant tumors. We provided a relatively comprehensive description of the carcinogenic role of KRT17 in different tumors for the first time.

The Role of LncRNAs in the Regulation of Radiotherapy Sensitivity in Cervical Cancer.

Cervical cancer (CC) is one of the three majors gynecological malignancies, which seriously threatens women's health and life. Radiotherapy (RT) is one of the most common treatments for cervical cancer, which can reduce local recurrence and prolong survival in patients with cervical cancer. However, the resistance of cancer cells to Radiotherapy are the main cause of treatment failure in patients with cervical cancer. Long non-coding RNAs (LncRNAs) are a group of non-protein-coding RNAs with a length of more than 200 nucleotides, which play an important role in regulating the biological behavior of cervical cancer. Recent studies have shown that LncRNAs play a key role in regulating the sensitivity of radiotherapy for cervical cancer. In this review, we summarize the structure and function of LncRNAs and the molecular mechanism of radiosensitivity in cervical cancer, list the LncRNAs associated with radiosensitivity in cervical cancer, analyze their potential mechanisms, and discuss the potential clinical application of these LncRNAs in regulating radiosensitivity in cervical cancer.

[Effects of inhibiting the expression of lncRNA PVT1 on the proliferation, apoptosis and oxidative stress of vascular endothelial cells induced by hyperglycemia].

Objective: To investigate the effects of inhibition of lncRNA PVT1 on the proliferation, apoptosis and oxidative stress of vascular endothelial cells induced by hyperglycemic. Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and divided into four groups: control group (5.5 mmol/L glucose), high glucose group (30 mmol/L glucose), high glucose + siNC group (30 mmol/L glucose +siNC, negative control group), HG + siPVT1 group (30 mmol/L glucose + siPVT1, lncRNA PVT1 silencing group). The expression of PVT1 after transfection was detected by quantitative real-time PCR. MTT assay was used to detect the effect of siPVT1 (small interfering RNA PVT1) on the proliferation of HUVECs cells induced by high glucose. Flow cytometry was used to detect ROS and apoptosis of HUVECs cells induced by siPVT1. Western blot was used to detect the expression levels of apoptotic proteins such as Bax, Bcl-2, and cleaved caspase-3 in HUVECs cells. Results: Compared with the control group, after transfection with siPVT1, the expression level of PVT1 was decreased significantly (P＜0.05). MTT results showed that the proliferation activity of HUVECs cells in the high-glucose group was reduced significantly after 24 h and 48 h. Compared with the HG + siNC group, the proliferation activity of HUVECs cells in the HG + siPVT1 group was increased significantly (P＜0.05) after 24 h and 48 h. Flow cytometry results showed that ROS and apoptosis rate of HUVECs cells in the high-glucose group were increased significantly compared with the control group. Compared with the HG + siNC (negative control) group, ROS and apoptosis rates of HUVECs cells in the HG + siPVT1 group were reduced significantly. Compared with the control group, the expression levels of cleaved-caspase-3 and Bax in the high-glucose group were significantly up-regulated, while the expression level of Bcl-2 was down-regulated. Compared with the HG + siNC group, the expression levels of cleaved-caspase-3 and Bax were down-regulated, and the expression level of Bcl-2 was up-regulated. The differences were statistically significant (P＜0.05). Conclusion: Inhibition of lncRNA PVT1 can significantly increase the proliferation activity of HUVECs cells induced by hyperglycemia, reduce oxidative stress and inhibit cell apoptosis.

The decreased expression of GW2 homologous genes contributed to the increased grain width and thousand­grain weight in wheat-Dasypyrum villosum 6VS·6DL translocation lines.

KEY MESSAGE: This study demonstrated that the aberrant transcription of DvGW2 contributed to the increased grain width and thousand-grain weight in wheat-Dasypyrum villosum T6VS·6DL translocation lines. Due to the high immunity to powdery mildew, Dasypyrum villosum 6VS has been one of the most successful applications of the wild relatives in modern wheat breeding. Along with the desired traits, side-effects could be brought when large alien chromosome fragments are introduced into wheat, but little is known about effects of 6VS on agronomic traits. Here, we found that T6VS·6DL translocation had significantly positive effects on grain weight, plant heightand spike length, and small negative effects on total spikelet number and spikelet compactness using recipient and wheat-D. villosum T6VS·6DL allohexaploid wheats, Wan7107 and Pm97033. Further analysis showed that the 6VS segment might exert direct genetic effect on grain width, then driving the increase of thousand-grain weight. Furthermore, comparative transcriptome analysis identified 2549 and 1282 differentially expressed genes (DEGs) and 2220 and 1496 specifically expressed genes (SEGs) at 6 days after pollination (DAP) grains and 15 DAP endosperms, respectively. Enrichment analysis indicated that the process of cell proliferation category was over-represented in the DEGs. Notably, two homologous genes, TaGW2-D1 and DvGW2, were identified as putative candidate genes associated with grain weight and yield. The expression analysis showed that DvGW2 had an aberrant expression in Pm97033, resulting in significantly lower total expression level of GW2 than Wan7107, which drives the increase of grain weight and width in Pm97033. Collectively, our data indicated that the compromised expression of DvGW2 is critical for increased grain width and weight in T6VS·6DL translocation lines.

A Non-coding HES1 Variant Predisposes Children to Congenital Heart Disease in Chinese Population.

Background: As a key component in the NOTCH signaling pathway, HES1 plays an important role in vertebrate heart development. Variants in the HES1 coding sequence are known to be associated with congenital heart disease (CHD). However, little is known about HES1 non-coding sequence variants and their association with the risk of developing CHD. Method and Results: We initially analyzed the non-coding sequence of the HES1 gene in 12 unrelated CHD families by direct sequencing and identified a previously unreported promoter region variant (NM_005524.4: c.-1279-1278 insAC, rs148941464) in the HES1 gene in four CHD families. The homozygous variant in patients was inherited from carrier parents with normal phenotypes, indicating a likely recessive genetic model. Given that the HES1 gene is predicted to be likely to exhibit haploinsufficiency (%HI: 11.44), we hypothesized that the HES1 homozygous variant is a genetic risk factor underlying CHD. We then carried out sequencing of this HES1 variant in 629 sporadic non-syndromic CHD cases and 696 healthy controls and performed association analysis. Interestingly, we observed a significant association of the homozygous HES1 promoter variant with CHD (18.92% of cases vs. 9.91% of controls; OR: 2.291, 95% CI: 1.637-3.207, p = 9.72 × 10-7). No significant association with CHD was observed for the HES1 promoter heterozygous variant (p > 0.05). However, association analysis tests of the HES1 homozygous variant with each subtype of CHD revealed that this homozygous variant was strongly associated with transposition of the great arteries (TGA) (OR: 3.726, 95% CI: 1.745-7.956, p = 0.0003). Moreover, the prevalence of HES1 homozygous variants in CHD patients with TGA (27.66%) was significantly higher than that in patients with other CHD subtypes or controls. Similar results were observed in a replication group of TGA (n = 64). Functional studies demonstrated that the homozygous variant in the HES1 promoter can disrupt its ability to bind RXRA, an inhibitory transcription factor, which results in abnormally high expression of the HES1 gene, indicating that this variant harbors gain-of-function effects. Conclusions: Our findings reveal that the non-coding homozygous variant in the HES1 promoter has a gain-of-function effect and is associated with an increased risk of CHD development, especially the severe TGA subtype.

Clinical Analysis of Congenital Deficient Tracheal Cartilage Rings: Six Case Reports and a Literature Review.

Congenital deficiency of tracheal rings is a rare tracheal malformation that can cause central airway obstruction. Herein we reported the clinical data of six patients with symptomatic congenital deficient tracheal rings. There were five cases, with isolated short-segment absent cartilage ring located on the distal trachea (three cases), cervical trachea (one case), and distal trachea combined with bilateral bronchi (one case). Among them, four (4/5) received surgical tracheal resection, three fully recovered, and one died of severe infection. Besides that, one patient, who could not be weaned off the mechanical ventilation, died after rejecting surgery. One case had episodes of recurrent dyspnea and extubation failure due to long-segment tracheomalacia after repair of esophageal atresia and tracheoesophageal fistula. For this patient, deficient cartilage rings were suspected and confirmed at the age of 26 months. Moreover, the clinical characteristics of 12 cases with congenital deficient tracheal cartilage rings reported in previous literature were reviewed. The different characteristics between short- and long-segment deficient cartilage rings were discussed.

Using Machine Learning to Generate Novel Hypotheses: Increasing Optimism About COVID-19 Makes People Less Willing to Justify Unethical Behaviors.

How can we nudge people to not engage in unethical behaviors, such as hoarding and violating social-distancing guidelines, during the COVID-19 pandemic? Because past research on antecedents of unethical behavior has not provided a clear answer, we turned to machine learning to generate novel hypotheses. We trained a deep-learning model to predict whether or not World Values Survey respondents perceived unethical behaviors as justifiable, on the basis of their responses to 708 other items. The model identified optimism about the future of humanity as one of the top predictors of unethicality. A preregistered correlational study (N = 218 U.S. residents) conceptually replicated this finding. A preregistered experiment (N = 294 U.S. residents) provided causal support: Participants who read a scenario conveying optimism about the COVID-19 pandemic were less willing to justify hoarding and violating social-distancing guidelines than participants who read a scenario conveying pessimism. The findings suggest that optimism can help reduce unethicality, and they document the utility of machine-learning methods for generating novel hypotheses.

A Single Amino Acid Substitution in STKc_GSK3 Kinase Conferring Semispherical Grains and Its Implications for the Origin of Triticum sphaerococcum.

Six subspecies of hexaploid wheat (Triticum aestivum) have been identified, but the origin of Indian dwarf wheat (Triticum sphaerococcum), the only subspecies with round grains, is currently unknown. Here, we isolated the grain-shape gene Tasg-D1 in T sphaerococcum via positional cloning. Tasg-D1 encodes a Ser/Thr protein kinase glycogen synthase kinase3 (STKc_GSK3) that negatively regulates brassinosteroid signaling. Expression of TaSG-D1 and the mutant form Tasg-D1 in Arabidopsis (Arabidopsis thaliana) suggested that a single amino acid substitution in the Thr-283-Arg-284-Glu-285-Glu-286 domain of TaSG-D1 enhances protein stability in response to brassinosteroids, likely leading to formation of round grains in wheat. This gain-of-function mutation has pleiotropic effects on plant architecture and exhibits incomplete dominance. Haplotype analysis of 898 wheat accessions indicated that the origin of T sphaerococcum in ancient India involved at least two independent mutations of TaSG-D1 Our results demonstrate that modest genetic changes in a single gene can induce dramatic phenotypic changes.

A novel de novo PDE4D gene mutation identified in a Chinese patient with acrodysostosis.

Acrodysostosis is an extremely rare disorder at birth, that is, characterized by skeletal dysplasia with short stature and midfacial hypoplasia, which has been reported to be caused by PDE4D and PRKAR1A gene mutations. Here, a Chinese boy with acrodysostosis, ventricular septal defect, and pulmonary hypertension was recruited for our study, and his clinical and biochemical characteristics were analyzed. A novel de novo heterozygous missense mutation (NM_001104631: c.2030A>C, p.Tyr677Ser) of the PDE4D gene was detected by whole exome sequencing and confirmed by Sanger sequencing. The c.2030A>C (p.Tyr677Ser) variant was located in exon 15 of the PDE4D gene, predicted to be damaging by a functional prediction program and shown to be highly conserved among many species. Further functional analysis showed that the p.Tyr677Ser substitution changes the function of the PDE4D protein, affects its subcellular localization in transfected cells, increases PDE4 activity in the regulation of cAMP signaling and affects cell proliferation. Our study identified a novel de novo PDE4D mutation in acrodysostosis of Chinese origin that not only contributes a deeper appreciation of the phenotypic characteristics of patients with PDE4D mutations but also expands the spectrum of PDE4D mutations.

Association of a MiR-499 SNP and risk of congenital heart disease in a Chinese population.

MicroRNAs (miRNAs) play an important role in heart development. Single nucleotide polymorphisms (SNPs) in miRNAs have been shown to associate with congenital heart disease (CHD). Methionine synthase (MTR), a key enzyme of folate metabolism, is involved in the early embryonic development. In this study, we aimed to test whether MTR is a direct target of miR-499, and to estimate the associations between miR-499 polymorphisms and the risk of CHD in Chinese population. Gene polymorphisms were analyzed in 1615 subjects including 792 healthy controls and 823 CHD patients. The miR-499 SNP were genotyped and the associations between the SNP frequencies and CHD were assessed by computing odds ratios (ORs) and 95% confidence intervals (95% CIs), as well as by applying Chi-square tests. Dual reporter assay was carried out to test whether MTR is a direct target gene of miR-499. The miR-499 rs374644 AG genotype was not associated with the CHD risk (AG vs. AA. OR=1.27, 95%CI=0.85-1.81, p=0.20). The GG genotype was associated with a significantly increased CHD risk (GG vs. AA. OR=5.33, 95%CI=1.80-15.83, p=0.001). The AG/GG variants were associated with a significantly increased CHD risk, compared with the AA genotype (OR=1.56, 95%CI=1.16-2.10, p=0.003). MiR-499 mimics inhibits the expression of MTR. MiR-499 directly targeted on MTR. Thus, our study suggested that miR-499 directly targets on MTR and the polymorphisms of rs3746444 may be associated with CHD risk in Chinese individuals.

Characteristics of Pulmonary Vascular Remodeling in a Novel Model of Shunt-Associated Pulmonary Arterial Hypertension.

BACKGROUND Establishing a shunt-induced pulmonary arterial hypertension (PAH) model in mice would be of great scientific value, but no such models have been reported to date. Here, we established a shunt-associated PAH in mice to investigate the characteristics of pulmonary vascular remodeling, which provides a new platform for the in-depth study of PAH associated with congenital heart disease (CHD). MATERIAL AND METHODS Eighty mice were randomly divided into the heavy shunt group (n=32), the small shunt group (n=32), the sham operation group (n=8), and the control group (n=8). The septum of the abdominal aorta and inferior vena cava was cut directly to create a heavy abdominal aortocaval shunt. Pulmonary artery pressure, right ventricular hypertrophy index, and lung tissue morphology were evaluated in the 4th, 6th, 8th, and 12th weeks in the shunt groups. RESULTS Shunt-associated PAH by abdominal aortocaval shunt in mice was successfully established. The shunt patency rate was significantly higher in the heavy shunt group. Significant differences were observed between the heavy shunt group and other groups in terms of pulmonary artery pressure and the right ventricular hypertrophy index. Tissue sections revealed a thickened pulmonary intimal layer and muscular layer and stenosis of the lumen in the shunt groups. Immunofluorescent assay results showed significant proliferations of PAH smooth muscle cells and endothelial cells, consistent with the clinical pulmonary vascular remodeling seen in human patients with severe PAH. CONCLUSIONS Shunt-associated PAH established by directly cutting the septum between the abdominal aorta and inferior vena cava is a stable and reliable model for research on PAH associated with CHD.

A novel allele of TaGW2-A1 is located in a finely mapped QTL that increases grain weight but decreases grain number in wheat (Triticum aestivum L.).

KEY MESSAGE: A novel TaGW2-A1 allele was identified from a stable, robust QTL region, which is pleiotropic for thousand grain weight, grain number per spike, and grain morphometric parameters in wheat. Thousand grain weight (TGW) and grain number per spike (GNS) are two crucial determinants of wheat spike yield, and genetic dissection of their relationships can help to fine-tune these two components and maximize grain yield. By evaluating 191 recombinant inbred lines in 11 field trials, we identified five genomic regions on chromosomes 1B, 3A, 3B, 5B, or 7A that solely influenced either TGW or GNS, and a further region on chromosome 6A that concurrently affected TGW and GNS. The QTL of interest on chromosome 6A, which was flanked by wsnp_BE490604A_Ta_2_1 and wsnp_RFL_Contig1340_448996 and designated as QTgw/Gns.cau-6A, was finely mapped to a genetic interval shorter than 0.538 cM using near isogenic lines (NILs). The elite NILs of QTgw/Gns.cau-6A increased TGW by 8.33%, but decreased GNS by 3.05% in six field trials. Grain Weight 2 (TaGW2-A1), a well-characterized gene that negatively regulates TGW and grain width in wheat, was located within the finely mapped interval of QTgw/Gns.cau-6A. A novel and rare TaGW2-A1 allele with a 114-bp deletion in the 5' flanking region was identified in the parent with higher TGW, and it reduced TaGW2-A1 promoter activity and expression. In conclusion, these results expand our knowledge of the genetic and molecular basis of TGW-GNS trade-offs in wheat. The QTLs and the novel TaGW2-A1 allele are likely useful for the development of cultivars with higher TGW and/or higher GNS.