Clinical and genetic characterization of 47 Chinese pediatric patients with Pitt-Hopkins syndrome: a retrospective study.

Background: Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder that remains underdiagnosed and its clinical presentations and mutation profiles in a diverse population are yet to be evaluated. This retrospective study aims to investigate the clinical and genetic characteristics of Chinese patients with PTHS.

Methods: The clinical, biochemical, genetic, therapeutic, and follow-up data of 47 pediatric patients diagnosed with PTHS between 2018 and 2021 were retrospectively analyzed.

Multivariate analysis and model building for classifying patients in the peroxisomal disorders X-linked adrenoleukodystrophy and Zellweger syndrome in Chinese pediatric patients.

Background: The peroxisome is a ubiquitous single membrane-enclosed organelle with an important metabolic role. Peroxisomal disorders represent a class of medical conditions caused by deficiencies in peroxisome function and are segmented into enzyme-and-transporter defects (defects in single peroxisomal proteins) and peroxisome biogenesis disorders (defects in the peroxin proteins, critical for normal peroxisome assembly and biogenesis). In this study, we employed multivariate supervised and non-supervised statistical methods and utilized mass spectrometry data of neurological patients, peroxisomal disorder patients (X-linked adrenoleukodystrophy and Zellweger syndrome), and healthy controls to analyze the role of common metabolites in peroxisomal disorders, to develop and refine a classification models of X-linked adrenoleukodystrophy and Zellweger syndrome, and to explore analytes with utility in rapid screening and diagnostics.

FVC as an adaptive and accurate method for filtering variants from popular NGS analysis pipelines.

The quality control of variants from whole-genome sequencing data is vital in clinical diagnosis and human genetics research. However, current filtering methods (Frequency, Hard-Filter, VQSR, GARFIELD, and VEF) were developed to be utilized on particular variant callers and have certain limitations. Especially, the number of eliminated true variants far exceeds the number of removed false variants using these methods.

Status of AI-Enabled Clinical Decision Support Systems Implementations in China.

Background: AI-enabled Clinical Decision Support Systems (AI + CDSSs) were heralded to contribute greatly to the advancement of health care services. There is an increased availability of monetary funds and technical expertise invested in projects and proposals targeting the building and implementation of such systems. Therefore, understanding the actual system implementation status in clinical practice is imperative.

Pitt-Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations.

Pitt-Hopkins syndrome is an underdiagnosed neurodevelopmental disorder which is characterized by specific facial features, early-onset developmental delay, and moderate to severe intellectual disability. The genetic cause, a deficiency of the TCF4 gene, has been established; however, the underlying pathological mechanisms of this disease are still unclear. Herein, we report four unrelated children with different de novo mutations (T606A, K607E, R578C, and V617I) located at highly conserved sites and with clinical phenotypes which present variable degrees of developmental delay and intellectual disability.

Demographics, in-hospital analysis, and prevalence of 33 rare diseases with effective treatment in Shanghai.

Background: Rare diseases are ailments which impose a heavy burden on individual patients and global society as a whole. The rare disease management landscape is not a smooth one-a rare disease is quite often hard to diagnose, treat, and investigate. In China, the country's rapid economic rise and development has brought an increased focus on rare diseases.

Evaluation Framework for Successful Artificial Intelligence-Enabled Clinical Decision Support Systems: Mixed Methods Study.

Background: Clinical decision support systems are designed to utilize medical data, knowledge, and analysis engines and to generate patient-specific assessments or recommendations to health professionals in order to assist decision making. Artificial intelligence-enabled clinical decision support systems aid the decision-making process through an intelligent component. Well-defined evaluation methods are essential to ensure the seamless integration and contribution of these systems to clinical practice.

RePhine: An Integrative Method for Identification of Drug Response-related Transcriptional Regulators.

Transcriptional regulators (TRs) participate in essential processes in cancer pathogenesis and are critical therapeutic targets. Identification of drug response-related TRs from cell line-based compound screening data is often challenging due to low mRNA abundance of TRs, protein modifications, and other confounders (CFs). In this study, we developed a regression-based pharmacogenomic and ChIP-seq data integration method (RePhine) to infer the impact of TRs on drug response through integrative analyses of pharmacogenomic and ChIP-seq data.

Nuclear Segmentation in Histopathological Images Using Two-Stage Stacked U-Nets With Attention Mechanism.

Nuclei segmentation is a fundamental but challenging task in histopathological image analysis. One of the main problems is the existence of overlapping regions which increases the difficulty of independent nuclei separation. In this study, to solve the segmentation of nuclei and overlapping regions, we introduce a nuclei segmentation method based on two-stage learning framework consisting of two connected Stacked U-Nets (SUNets).

Correlations Between Phenotypes and Biological Process Ontologies in Monogenic Human Diseases.

A substantial body of research is focused to improve the understanding of the relationship between genotypes and phenotypes. Genotype-phenotype studies have shown promise in improving disease diagnosis in humans and identification of specific clinical phenotypes may be helpful in developing more effective therapeutic and diagnostic strategies. To expand on the existing paradigm of evaluating genotypes and phenotypes, we present an investigation of the correlation between biological processes as represented by genomic information and phenotypes in human disease.

Molecular dynamics provides new insights into the mechanism of calcium signal transduction and interdomain interactions in cardiac troponin.

Understanding the regulation of cardiac muscle contraction at a molecular level is crucial for the development of therapeutics for heart conditions. Despite the availability of atomic structures of the protein components of cardiac muscle thin filaments, detailed insights into their dynamics and response to calcium are yet to be fully depicted. In this study, we used molecular dynamics simulations of the core domains of the cardiac muscle protein troponin to characterize the equilibrium dynamics of its calcium-bound and calcium-free forms, with a focus on elements of cardiac muscle contraction activation and deactivation, that is, calcium binding to the cardiac troponin Ca -binding subunit (TnC) and the release of the switch region of the troponin inhibitory subunit (TnI) from TnC.

Integrative Analysis of Membrane Proteome and MicroRNA Reveals Novel Lung Cancer Metastasis Biomarkers.

Lung cancer is one of the most common human cancers both in incidence and mortality, with prognosis particularly poor in metastatic cases. Metastasis in lung cancer is a multifarious process driven by a complex regulatory landscape involving many mechanisms, genes, and proteins. Membrane proteins play a crucial role in the metastatic journey both inside tumor cells and the extra-cellular matrix and are a viable area of research focus with the potential to uncover biomarkers and drug targets.

Improving the Diagnosis of Phenylketonuria by Using a Machine Learning-Based Screening Model of Neonatal MRM Data.

Phenylketonuria (PKU) is a common genetic metabolic disorder that affects the infant's nerve development and manifests as abnormal behavior and developmental delay as the child grows. Currently, a triple-quadrupole mass spectrometer (TQ-MS) is a common high-accuracy clinical PKU screening method. However, there is high false-positive rate associated with this modality, and its reduction can provide a diagnostic and economic benefit to both pediatric patients and health providers.

Closing Human Reference Genome Gaps: Identifying and Characterizing Gap-Closing Sequences.

Despite continuous updates of the human reference genome, there are still hundreds of unresolved gaps which account for about 5% of the total sequence length. Given the availability of whole genome assemblies, especially those derived from long-read sequencing data, gap-closing sequences can be determined. By comparing 17 long-read sequencing assemblies with the human reference genome, we identified a total of 1,125 gap-closing sequences for 132 (16.

Analysis of economic burden and its associated factors of twenty-three rare diseases in Shanghai.

Background: It is estimated that at present there are over 10 million rare disease patients in China. Recently an increased focus from policy perspective has been placed on rare diseases management. Improved disease definitions and the releases of local and national rare disease lists are some of the steps taken already.

Functional Site Discovery From Incomplete Training Data: A Case Study With Nucleic Acid-Binding Proteins.

Function annotation efforts provide a foundation to our understanding of cellular processes and the functioning of the living cell. This motivates high-throughput computational methods to characterize new protein members of a particular function. Research work has focused on discriminative machine-learning methods, which promise to make efficient, predictions of protein function.

A Herpes Simplex Virus Thymidine Kinase-Induced Mouse Model of Hepatocellular Carcinoma Associated with Up-Regulated Immune-Inflammatory-Related Signals.

Inflammation and fibrosis in human liver are often precursors to hepatocellular carcinoma (HCC), yet none of them is easily modeled in animals. We previously generated transgenic mice with hepatocyte-specific expressed herpes simplex virus thymidine kinase (). These mice would develop hepatitis with the administration of ganciclovir (GCV)(Zhang, 2005 #1).

Transcription Factors Contribute to Differential Expression in Cellular Pathways in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.

Lung cancers are broadly classified into small cell lung cancers and non-small cell lung cancers (NSCLC). Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are two common subtypes of NSCLC, and despite the fact that both occur in lung tissues, these two subtypes show a number of different pathological characteristics. To investigate the differences and seek potential therapy targets, we used bioinformatics methods to analyze RNA-Seq data from different aspects.

Multi-omics facilitated variable selection in Cox-regression model for cancer prognosis prediction.

Motivation: New developments in high-throughput genomic technologies have enabled the measurement of diverse types of omics biomarkers in a cost-efficient and clinically-feasible manner. Developing computational methods and tools for analysis and translation of such genomic data into clinically-relevant information is an ongoing and active area of investigation. For example, several studies have utilized an unsupervised learning framework to cluster patients by integrating omics data.

Regenerative nano-hybrid coating tailored for autonomous corrosion protection.

A novel bilayer coating system for autonomous corrosion-triggered self-healing is demonstrated. The storage of the encapsulated monomer and the catalyst is separated in two different layers. The encapsulated catalyst is stored inside a metallic coating, which ensures its activity even for an extended exposure time.

Synthesis of ultrathin poly(methyl methacrylate) model coatings bound via organosilanes to zinc and investigation of their delamination kinetics.

Polymer coatings are widely used to protect metals from corrosion. Coating adhesion to the base material is critical for good protection, but coatings may fail because of cathodic delamination. Most of the experimental studies on cathodic delamination use polymers to study the corrosion behavior under conditions where the interfacial chemistry at the metal(oxide)/polymer interface is not well-defined.

Calcium induced regulation of skeletal troponin--computational insights from molecular dynamics simulations.

The interaction between calcium and the regulatory site(s) of striated muscle regulatory protein troponin switches on and off muscle contraction. In skeletal troponin binding of calcium to sites I and II of the TnC subunit results in a set of structural changes in the troponin complex, displaces tropomyosin along the actin filament and allows myosin-actin interaction to produce mechanical force. In this study, we used molecular dynamics simulations to characterize the calcium dependent dynamics of the fast skeletal troponin molecule and its TnC subunit in the calcium saturated and depleted states.

Mechanically untying a protein slipknot: multiple pathways revealed by force spectroscopy and steered molecular dynamics simulations.

Protein structure is highly diverse when considering a wide range of protein types, helping to give rise to the multitude of functions that proteins perform. In particular, certain proteins are known to adopt a knotted or slipknotted fold. How such proteins undergo mechanical unfolding was investigated utilizing a combination of single molecule atomic force microscopy (AFM), protein engineering, and steered molecular dynamics (SMD) simulations to show the mechanical unfolding mechanism of the slipknotted protein AFV3-109.