Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

A schema for coding health equity scholarship within pediatric research.

Introduction: Seattle Children's Research Institute is identifying the amount and type of health equity scholarship being conducted institution wide. However, methods for categorizing how scholarship is equity-focused are lacking. We developed and evaluated the reliability of a health equity scholarship coding schema applied to Seattle Children's affiliated scholarship.

Epigenomic and phenotypic characterization of DEGCAGS syndrome.

Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities syndrome (DEGCAGS, MIM #619488) is caused by biallelic, loss-of-function (LoF) ZNF699 variants, and is characterized by variable neurodevelopmental disability, discordant organ anomalies among full siblings and infant mortality. ZNF699 encodes a KRAB zinc finger protein of unknown function. We aimed to investigate the genotype-phenotype spectrum of DEGCAGS and the possibility of a diagnostic DNA methylation episignature, to facilitate the diagnosis of a highly variable condition lacking pathognomonic clinical findings.

Neuropsychology and Vascular Cognitive Impairment and Dementia.

Neuropsychology is an integral component of health care assessment for persons with vascular contributions to cognitive impairment and dementia. Since syndromes of vascular cognitive decline have multiple and varying pathophysiologies, anatomic brain locations, and levels of severity, neuropsychological assessment can be critical to clarify the cognitive manifestations of the disease, potential consequences for the patient and family, as well as the prognosis for future life planning. Cognitive profiles of vascular cognitive declines and relevant neuropsychological literature are reviewed here to provide the practicing physician with guidance for best clinical care practices.

Prognostic enrichment for early-stage Huntington's disease: An explainable machine learning approach for clinical trial.

Background: In Huntington's disease clinical trials, recruitment and stratification approaches primarily rely on genetic load, cognitive and motor assessment scores. They focus less on in vivo brain imaging markers, which reflect neuropathology well before clinical diagnosis. Machine learning methods offer a degree of sophistication which could significantly improve prognosis and stratification by leveraging multimodal biomarkers from large datasets.

Modeling properties of chromosome territories using polymer filaments in diverse confinement geometries.

Interphase chromosomes reside within distinct nuclear regions known as chromosome territories (CTs). Recent observations from Hi-C analyses, a method mapping chromosomal interactions, have revealed varied decay in contact probabilities among different chromosomes. Our study explores the relationship between this contact decay and the particular shapes of the chromosome territories they occupy.

Multiplexed immunohistochemical analysis of the immune microenvironment of biliary tract cancers pre- & post-neoadjuvant chemotherapy: case series.

Background: Neoadjuvant chemotherapy (NACT) is increasingly being used in the management of locally advanced biliary tract cancer (BTC). The evidence suggests a contributing role of tumor infiltrating immune cells in the prognosis and response. We set out to characterize immune modulation of tumor immune microenvironment in BTC following NACT.

Chronic oral LPS administration does not increase inflammation or induce metabolic dysregulation in mice fed a western-style diet.

Introduction: Lipopolysaccharides (LPS) present in the intestine are suggested to enter the bloodstream after consumption of high-fat diets and cause systemic inflammation and metabolic dysregulation through a process named "metabolic endotoxemia." This study aimed to determine the role of orally administered LPS to mice in the early stage of chronic low-grade inflammation induced by diet.

Methods: We supplemented the drinking water with derived LPS to mice fed either high-fat Western-style diet (WSD) or standard chow (SC) for 7 weeks ( = 16-17).

hictk: blazing fast toolkit to work with .hic and .cool files.

Motivation: Hi-C is gaining prominence as a method for mapping genome organization. With declining sequencing costs and a growing demand for higher-resolution data, efficient tools for processing Hi-C datasets at different resolutions are crucial. Over the past decade, the .

Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis.

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT).

Digital Pathology in the Detection of Infectious Microorganisms: An Evaluation of Its Strengths and Weaknesses Across a Panel of Immunohistochemical and Histochemical Stains Routinely Used in Diagnostic Surgical Pathology.

Context.—: The diagnosis of some infectious diseases requires their identification in tissue specimens. As institutions adopt digital pathology for primary diagnosis, the limits of microorganism detection from digital images must be delineated.

Loss of multi-level 3D genome organization during breast cancer progression.

Breast cancer entails intricate alterations in genome organization and expression. However, how three-dimensional (3D) chromatin structure changes in the progression from a normal to a breast cancer malignant state remains unknown. To address this, we conducted an analysis combining Hi-C data with lamina-associated domains (LADs), epigenomic marks, and gene expression in an model of breast cancer progression.

CAMTA1-related disorder: Phenotypic and molecular characterization of 26 new individuals and literature review.

Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53).

Twisting a Cylindrical Sheet Makes It a Tunable Locking Material.

A buckled sheet offers a reservoir of material that can be unfurled at a later time. For sufficiently thin yet stiff materials, this geometric process has a striking mechanical feature: when the slack runs out, the material locks to further extension. Here, we establish a simple route to a tunable locking material: a system with an interval where it is freely deformable under a given deformation mode, and where the endpoints of this interval can be changed continuously over a wide range.

The temporal event-based model: Learning event timelines in progressive diseases.

Timelines of events, such as symptom appearance or a change in biomarker value, provide powerful signatures that characterise progressive diseases. Understanding and predicting the timing of events is important for clinical trials targeting individuals early in the disease course when putative treatments are likely to have the strongest effect. However, previous models of disease progression cannot estimate the time between events and provide only an ordering in which they change.

The shape of chromatin: insights from computational recognition of geometric patterns in Hi-C data.

The three-dimensional organization of chromatin plays a crucial role in gene regulation and cellular processes like deoxyribonucleic acid (DNA) transcription, replication and repair. Hi-C and related techniques provide detailed views of spatial proximities within the nucleus. However, data analysis is challenging partially due to a lack of well-defined, underpinning mathematical frameworks.

Mixed longitudinal and cross-sectional analyses of deep gray matter and white matter using diffusion weighted images in premanifest and manifest Huntington's disease.

Changes in the brain of patients with Huntington's disease (HD) begin years before clinical onset, so it remains critical to identify biomarkers to track these early changes. Metrics derived from tensor modeling of diffusion-weighted MRIs (DTI), that indicate the microscopic brain structure, can add important information to regional volumetric measurements. This study uses two large-scale longitudinal, multicenter datasets, PREDICT-HD and IMAGE-HD, to trace changes in DTI of HD participants with a broad range of CAP scores (a product of CAG repeat expansion and age), including those with pre-manifest disease (i.

Simple plication alleviates physical symptoms in patients with post-gestational rectus diastasis.

Purpose: To evaluate our surgery for post-gestational rectus abdominis muscle diastasis using slowly absorbable monofilament suture and eight weeks of abdominal binder in terms of recurrence rate, complications, and effect on patients' physical and cosmetic complaints.

Method: In a retrospective cohort study, all 44 patients operated between 2014 and 2020 were invited to a follow-up using ultrasound, clinical examination, and questionnaires regarding symptoms before and after surgery.

Results: 89% of invited patients participated, with a median follow-up of 36 months.

Prognostic Factors Among Colonic Adenocarcinomas Invading Into the Muscularis Propria.

Depth of invasion through the intestinal wall, categorized as primary tumor stage (pT), is an important prognostic factor in colorectal cancer. However, additional variables that may affect clinical behavior among tumors involving the muscularis propria (pT2) have not been examined at length. We evaluated 109 patients with pT2 colonic adenocarcinomas (median age: 71 y, interquartile range: 59 to 79 y) along various clinicopathologic parameters, including invasion depth, regional lymph node involvement, and disease progression after resection.

Cross-sections of doubly curved sheets as confined elastica.

Although thin films are typically manufactured in planar sheets or rolls, they are often forced into three-dimensional (3D) shapes, producing a plethora of structures across multiple length scales. To understand this complex response, previous studies have either focused on the overall gross shape or the small-scale buckling that decorates it. A geometric model, which considers the sheet as inextensible yet free to compress, has been shown to capture the gross shape of the sheet.