Notes

Lin_F9: A new Linear Empirical Scoring Purpose for Protein-Ligand Docking.
Deletions covering the entire or partial JARID2 gene as well as pathogenic single nucleotide variants leading to haploinsufficiency of JARID2 have recently been shown to cause a clinically distinct neurodevelopmental syndrome. Here, we present a previously undescribed partial de novo duplication of the JARID2 gene in a patient displaying features similar to those of patients with JARID2 loss-of-function variants.

The index patient presents with abnormalities in gross motor skills and speech development as well as neuropsychiatric disorders. The patient has markedly dark infraorbital circles and slightly prominent supraorbital ridges.Whole-genome sequencing and array comparative genomic hybridization revealed a novel disease-causing variant type, a partial tandem duplication of JARID2, covering the exons 1-7. Furthermore, RNA sequencing validated the increased expression of these exons. Expression alterations were also detected in target genes of the PRC2 complex, in which JARID2 acts as an essential member.

Our data add to the variety of different pathogenic variants associated with JARID2 neurodevelopmental syndrome.
Our data add to the variety of different pathogenic variants associated with JARID2 neurodevelopmental syndrome.Soil salinity is a significant threat to global agriculture. Understanding salt exclusion mechanisms in halophyte species may be instrumental in improving salt tolerance in crops. Puccinellia tenuiflora is a typical salt-excluding halophytic grass often found in potassium-deprived saline soils. Our previous work showed that P. tenuiflora possesses stronger selectivity for K+ than for Na+ ; however, the mechanistic basis of this phenomenon remained elusive. Here, P. tenuiflora PutHKT1;5 was cloned and the functions of PutHKT1;5 and PutSOS1 were characterized using heterologous expression systems. Yeast assays showed that PutHKT1;5 possessed Na+ transporting capacity and was highly selective for Na+ over K+ . PutSOS1 was located at the plasma membrane and operated as a Na+ /K+ exchanger, with much stronger Na+ extrusion capacity than its homolog from Arabidopsis. PutHKT2;1 mediated high-affinity K+ and Na+ uptake and its expression levels were upregulated by mild salinity and K+ deprivation. Salinity-induced changes of root PutHKT1;5 and PutHKT1;4 transcript levels matched the expression pattern of root PutSOS1, which was consistent with root Na+ efflux. The transcript levels of root PutHKT2;1 and PutAKT1 were downregulated by salinity. Taken together, these findings demonstrate that the functional activity of PutHKT1;5 and PutSOS1 in P. tenuiflora roots is fine-tuned under saline conditions as well as by operation of other ion transporters/channel (PutHKT1;4, PutHKT2;1, and PutAKT1). This leads to the coordination of radial Na+ and K+ transport processes, their loading to the xylem, or Na+ retrieval and extrusion under conditions of mild salinity and/or K+ deprivation.A problem in developmental toxicology is the massive loss of life from fertilization through gastrulation, and the surprising lack of knowledge of causes of miscarriage. Half to two-thirds of embryos are lost, and environmental and genetic causes are nearly equal. Simply put, it can be inferred that this is a difficult period for normal embryos, but that environmental stresses may cause homeostatic responses that move from adaptive to maladaptive with increasing exposures. At the lower 50% estimate, miscarriage causes greater loss-of-life than all cancers combined or of all cardio- and cerebral-vascular accidents combined. Surprisingly, we do not know if miscarriage rates are increasing or decreasing. Overshadowed by the magnitude of miscarriages, are insufficient data on teratogenic or epigenetic imbalances in surviving embryos and their stem cells. Superimposed on the difficult normal trajectory for peri-gastrulation embryos are added malnutrition, hormonal, and environmental stresses. An overarching hypothesis is that high throughput screens (HTS) using cultured viable reporter embryonic and placental stem cells (e.g., embryonic stem cells [ESC] and trophoblast stem cells [TSC] that report status using fluorescent reporters in living cells) from the pre-gastrulation embryo will most rapidly test a range of hormonal, environmental, nutritional, drug, and diet supplement stresses that decrease stem cell proliferation and imbalance stemness/differentiation. A second hypothesis is that TSC respond with greater sensitivity in magnitude to stress that would cause miscarriage, but ESC are stress-resistant to irreversible stemness loss and are best used to predict long-term health defects. DevTox testing needs more ESC and TSC HTS to model environmental stresses leading to miscarriage or teratogenesis and more research on epidemiology of stress and miscarriage. This endeavor also requires a shift in emphasis on pre- and early gastrulation events during the difficult period of maximum loss by miscarriage.Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
Food insecurity is an important social determinant of health, but there is limited understanding of its relationship with adult oral health. This study examined the associations between food insecurity and dental diseases (caries and periodontitis) among middle-aged and older adults in the United States and South Korea.

This study focused on middle-aged (40-59 years) and older adults (>59 years) who participated in the 2011-2016 US National Health and Nutrition Examination Surveys (NHANES) or the 2013-2015 South Korean NHANES. The exposure was food insecurity severity (food secure/early-stage food insecurity/middle-stage or severe food insecurity) assessed using the 18-item US Household Food Security Survey Module. The two outcomes were any untreated tooth decay and periodontitis measured using the Modified Community Periodontal Index of Treatment Needs. Covariate-adjusted odds ratios (OR) with 95% confidence intervals (CI) were generated using multivariable logistic regression models.

Middle or seve oral health of middle-aged and older adults in diverse sociocultural contexts.Identifying novel curative and preventive approaches that can specifically target the osteosarcoma cells (OS) without affecting the normal cells is appreciable. The aim of this study is to investigate the combined effect of chrysin as an apigenin analog with high therapeutic potential and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on the treatment of Saos-2 and MG-63 cells. Cell viability were determined using MTT method. The rate of apoptosis was assessed by enzyme-linked immunosorbent assay (ELISA) cell death assay and caspase 8 activity assays. The messenger RNA (mRNA) and protein evaluation of candidate genes include Bcl-2, XIAP, c-IAP1, c-IAP2, and c-FLIP were accomplished before and after the treatment by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis, respectively. Our results showed that chrysin synergistically increased the cytotoxic effects of TRAIL as follows Chrysin plus TRAIL > TRAIL > Chrysin. Chrysin could sensitize both cells against the TRAIL-induced apoptosis, amplify the caspase 8 activity and this outcome is achieved by decreasing the expression levels of antiapoptotic genes. Our findings suggest that Chrysin can sensitize the OS cell lines against TRAIL through induction of the death receptor pathway. Moreover, the combinational therapy of these agents might be the promising therapeutic regimen for improving the clinical efficacy of TRAIL-induced apoptosis in patients with OS.
Congenital anomalies affect over 2% of pregnancies, with congenital heart disease (CHD) the most common. Understanding of causal factors is limited. Micronutrients are essential trace elements with key roles in growth and development. We aimed to investigate whether maternal micronutrient deficiencies increase the risk of fetal CHD through systematic review of published literature.

We performed a systematic review registered at PROSPERO as CRD42021276699. Ovid-MEDLINE, Ovid-EMBASE, and Cochrane Library were searched from their inception until September 7, 2021. Case control trials were included with a population of biological mothers of fetuses with and without CHD. The exposure was maternal micronutrient level measured in pregnancy or the postpartum period. Data extraction was performed by one author and checked by a second. Risk of bias assessment was performed according to the Scottish Intercollegiate Guidelines Network guidance. We performed a narrative synthesis for analysis.

726 articles were identified of which 8 met our inclusion criteria. Final analysis incorporated data from 2,427 pregnancies, 1,199 of which were complicated by fetal CHD assessing 8 maternal micronutrients vitamin D, vitamin B12, folate, vitamin A, zinc, copper, selenium, and ferritin. Studies were heterogenous with limited sample sizes and differing methods and timing of maternal micronutrient sampling. Definitions of deficiency varied and differed from published literature. Published results were contradictory.

There is not enough evidence to confidently conclude if maternal micronutrient deficiencies increase the risk of fetal CHD. Further large-scale prospective study is required to answer this question.
There is not enough evidence to confidently conclude if maternal micronutrient deficiencies increase the risk of fetal CHD. Further large-scale prospective study is required to answer this question.
Pulmonary vein isolation (PVI) using high-power-short-duration (HPSD) radiofrequency ablation (RF) is emerging as the standard of care for treatment of atrial fibrillation (AF). While procedural short-term to midterm efficacy and efficiency are very promising, this registry aims to investigate esopahgeal safety using an optimized ablation approach.

In a single-center experience, 388 consecutive standardized first-time AF ablation were performed using a CLOSE-guided-fixed-50 W-circumferential PVI and substrate modification without intraprocedural esophageal temperature measurement. Immunology inhibitor Three hundred patients underwent postprocedural esophageal endoscopy to diagnose and grade endoscopically detected esophageal lesions (EDEL) and were included in the analysis.

EDEL were detected in 35 of 300 patients (11.6%), 25 of 35 were low-grade Kansas-city-classification(KCC) 1 lesions with fast healing tendencies. Sixpatients suffered KCC 2a lesions, 4 patients had KCC 2b lesions (1.3% of all patients). No esophageal perforation or fistula formation was observed.
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