Metagenomic next-generation sequencing of rectal swabs for the surveillance of antimicrobial-resistant organisms on the Illumina Miseq and Oxford MinION platforms.

Antimicrobial resistance (AMR) is a public health threat where efficient surveillance is needed to prevent outbreaks. Existing methods for detection of gastrointestinal colonization of multidrug-resistant organisms (MDRO) are limited to specific organisms or resistance mechanisms. Metagenomic next-generation sequencing (mNGS) is a more rapid and agnostic diagnostic approach for microbiome and resistome investigations.

Decreased lymphatic HIF-2α accentuates lymphatic remodeling in lymphedema.

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1 α (HIF-1α), but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2α exacerbated lymphedema pathology.

Quantitative proteomic analysis of the frontal cortex in Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by intracellular formation of neurofibrillary tangles and extracellular deposition of β-amyloid protein (Aβ) in the extracellular matrix. The pathogenesis of AD has not yet been fully elucidated and little is known about global alterations in the brain proteome that are related to AD. To identify and quantify such AD-related changes in the brain, we employed a tandem mass tags approach coupled to high-resolution mass spectrometry.

Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.

Background: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

Methods: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15% Black; 30% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

Familial Aggregation in Idiopathic Subglottic Stenosis.

Objective: To evaluate inheritance patterns and define the familial clustering rate of idiopathic subglottic stenosis (iSGS).

Study Design: Retrospective observational study.

Setting: International multicenter collaborative of >30 tertiary care centers.

Mapping the Relationship between Dysmorphology and Cognitive, Behavioral, and Developmental Outcomes in Children with Autism Spectrum Disorder.

Previous studies investigating the association between dysmorphology and cognitive, behavioral, and developmental outcomes among individuals with autism spectrum disorder (ASD) have been limited by the binary classification of dysmorphology and lack of comparison groups. We assessed the association using a continuous measure of dysmorphology severity (DS) in preschool children aged 2-5 years (322 with ASD and intellectual disability [ID], 188 with ASD without ID, and 371 without ASD from the general population [POP]). In bivariate analyses, an inverse association between DS and expressive language, receptive language, fine motor, and visual reception skills was observed in children with ASD and ID.

-associated mitochondrial disease: A case report of a patient with prolonged survival and literature review.

Biallelic pathogenic variants in mitochondrial aminoacyl-tRNA synthetase (mt-aaRS) are associated with mitochondrial cytopathy. Here, we report the tenth case of an individual with biallelic pathogenic variants, detected by exome sequencing (ES), and a literature review of ten cases of mutations. Our patient displayed symptoms and clinical and laboratory findings similar to those reported previously with normal lactate levels.

Programmed switch in the mitochondrial degradation pathways during human retinal ganglion cell differentiation from stem cells is critical for RGC survival.

Retinal ganglion cell (RGC) degeneration is the root cause for vision loss in glaucoma as well as in other forms of optic neuropathy. A variety of studies have implicated abnormal mitochondrial quality control (MQC) as contributing to RGC damage and degeneration in optic neuropathies. The ability to differentiate human pluripotent stem cells (hPSCs) into RGCs provides an opportunity to study RGC MQC in great detail.

Parietal-Prefrontal Feedforward Connectivity in Association With Schizophrenia Genetic Risk and Delusions.

Objective: Conceptualizations of delusion formation implicate deficits in feedforward information updating across the posterior to prefrontal cortices, resulting in dysfunctional integration of new information about contexts in working memory and, ultimately, failure to update overfamiliar prior beliefs. The authors used functional MRI and machine learning models to address individual variability in feedforward parietal-prefrontal information updating in patients with schizophrenia. They examined relationships between feedforward connectivity, and delusional thinking and polygenic risk for schizophrenia.

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.

Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia.

Beyond being one the most widely used psychoactive drugs in the world, cannabis has been identified as an environmental risk factor for psychosis. Though the relationship between cannabis use and psychiatric disorders remains controversial, consistent association between early adolescent cannabis use and the subsequent risk of psychosis suggested adolescence may be a particularly vulnerable period. Previous findings on gene by environment interactions indicated that cannabis use may only increase the risk for psychosis in the subjects who have a specific genetic vulnerability.

CFTR variant testing: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods.

Development of a novel method for the quantification of tyrosine 39 phosphorylated α- and β-synuclein in human cerebrospinal fluid.

Background: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Biomarkers that can help monitor the progression of PD or response to disease-modifying agents will be invaluable in making appropriate therapeutic decisions. Further, biomarkers that could be used to distinguish PD from other related disorders with PD-like symptoms will be useful for accurate diagnosis and treatment.

Variation of Human Neural Stem Cells Generating Organizer States In Vitro before Committing to Cortical Excitatory or Inhibitory Neuronal Fates.

Better understanding of the progression of neural stem cells (NSCs) in the developing cerebral cortex is important for modeling neurogenesis and defining the pathogenesis of neuropsychiatric disorders. Here, we use RNA sequencing, cell imaging, and lineage tracing of mouse and human in vitro NSCs and monkey brain sections to model the generation of cortical neuronal fates. We show that conserved signaling mechanisms regulate the acute transition from proliferative NSCs to committed glutamatergic excitatory neurons.

Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer.

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation.

Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk.

Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data.

Neural substrates of smoking and reward cue reactivity in smokers: a meta-analysis of fMRI studies.

Smoking is partly attributed to alterations of reward processing. However, findings on the neurobiological mechanisms that underlie smoking-related and smoking-unrelated reward processing in smokers have been inconsistent. Neuroimaging experiments that used functional magnetic resonance imaging (fMRI) and reported brain responses to smoking-related cues and nonsmoking reward-related cues in smokers and healthy controls as coordinates in a standard anatomic reference space were identified by searching the PubMed, Embase, and Web of Science databases up to December 2018.

Multiplexed Phosphoproteomic Study of Brain in Patients with Alzheimer's Disease and Age-Matched Cognitively Healthy Controls.

Alzheimer's disease (AD) is the most common neurodegenerative disorder caused by neuronal loss that results in cognitive and functional impairment. Formation of neurofibrillary tangles composed of abnormal hyperphosphorylation of tau protein is one of the major pathological hallmarks of AD. Importantly, several neurodegenerative disorders, including AD, are associated with abnormal protein phosphorylation events.

Safety and outcome of gastrostomy tube placement in patients with Loeys-Dietz syndrome.

Background: Loeys-Dietz syndrome (LDS) is a systemic connective tissue disease (CTD) associated with a predisposition for intestinal inflammation, food allergy, and failure to thrive, often necessitating nutritional supplementation via gastrostomy tube. Poor wound healing has also been observed in in some patients with CTD, potentially increasing the risk of surgical interventions. We undertook to determine the safety and efficacy of gastrostomy tube placement in this population.

Midazolam and isoflurane combination reduces late brain damage in the paraoxon-induced status epilepticus rat model.

Organophosphates (OPs) are widely used as pesticides and have been employed as warfare agents. OPs inhibit acetylcholinesterase, leading to over-stimulation of cholinergic synapses and can cause status epilepticus (SE). OPs poisoning can result in irreversible brain damage and death.

Human transposon insertion profiling by sequencing (TIPseq) to map LINE-1 insertions in single cells.

Long interspersed element-1 (LINE-1, L1) sequences, which comprise about 17% of human genome, are the product of one of the most active types of mobile DNAs in modern humans. LINE-1 insertion alleles can cause inherited and de novo genetic diseases, and LINE-1-encoded proteins are highly expressed in some cancers. Genome-wide LINE-1 mapping in single cells could be useful for defining somatic and germline retrotransposition rates, and for enabling studies to characterize tumour heterogeneity, relate insertions to transcriptional and epigenetic effects at the cellular level, or describe cellular phylogenies in development.