Haplotype editing with CRISPR/Cas9 as a therapeutic approach for dominant-negative missense mutations in .

Inactivation of disease alleles by allele-specific editing is a promising approach to treat dominant-negative genetic disorders, provided the causative gene is haplo-sufficient. We previously edited a dominant missense mutation with inactivating frameshifts and rescued disease-relevant phenotypes in induced pluripotent stem cell (iPSC)-derived motor neurons. However, a multitude of different missense mutations cause disease.

Sequence-Based Machine Learning Reveals 3D Genome Differences between Bonobos and Chimpanzees.

The 3D structure of the genome is an important mediator of gene expression. As phenotypic divergence is largely driven by gene regulatory variation, comparing genome 3D contacts across species can further understanding of the molecular basis of species differences. However, while experimental data on genome 3D contacts in humans are increasingly abundant, only a handful of 3D genome contact maps exist for other species.

Integrin αvβ3 Limits Cytokine Production by Plasmacytoid Dendritic Cells and Restricts TLR-Driven Autoimmunity.

Plasmacytoid dendritic cells (pDCs) are strongly implicated as a major source of IFN-I in systemic lupus erythematosus (SLE), triggered through TLR-mediated recognition of nucleic acids released from dying cells. However, relatively little is known about how TLR signaling and IFN-I production are regulated in pDCs. In this article, we describe a role for integrin αvβ3 in regulating TLR responses and IFN-I production by pDCs in mouse models.

Gene loss and relaxed selection of in vertebrates adapted to low-light environments.

Gene loss is an important mechanism for evolution in low-light or cave environments where visual adaptations often involve a reduction or loss of eyesight. The gene family are phospholipases essential for the degradation of organelles in the lens of the eye. They translocate to damaged organelle membranes, inducing them to rupture.

Dialysis and a plant-based diet to achieve physiologic urea levels for fetal benefit: Normal pregnancy outcome despite chronic kidney disease and hypertension.

Chronic kidney disease significantly increases the risk of adverse maternal and perinatal outcomes. A growing body of evidence suggests that intensive dialysis, achieving physiologic pre-dialysis blood urea, is associated with decreased morbidity. We report a case of a successful pregnancy outcome in a 32-year-old nulliparous woman with stage 4 chronic kidney disease who underwent haemodialysis from 11 to 31 weeks' gestation for fetal benefit and concurrently trialled a plant-based diet.

Sequence-based machine learning reveals 3D genome differences between bonobos and chimpanzees.

Phenotypic divergence between closely related species, including bonobos and chimpanzees (genus ), is largely driven by variation in gene regulation. The 3D structure of the genome mediates gene expression; however, genome folding differences in are not well understood. Here, we apply machine learning to predict genome-wide 3D genome contact maps from DNA sequence for 56 bonobos and chimpanzees, encompassing all five extant lineages.

B Cell αv Integrins Regulate TLR-Driven Autoimmunity.

Systemic lupus erythematosus (SLE) is defined by loss of B cell tolerance, resulting in production of autoantibodies against nucleic acids and other cellular Ags. Aberrant activation of TLRs by self-derived RNA and DNA is strongly associated with SLE in patients and in mouse models, but the mechanism by which TLR signaling to self-ligands is regulated remains poorly understood. In this study, we show that αv integrin plays a critical role in regulating B cell TLR signaling to self-antigens in mice.

Long-Term Impact of Vascular Surgery Stress on Frail Older Patients.

Background: Frailty is a syndrome where the ability to cope with acute physiological stress is compromised, although it is unclear what impact this stress has on long-term outcomes. Vascular-Physiological and Operative Severity Score for enumeration of Mortality and Morbidity is a validated method for calculating levels of stress associated with vascular procedures. We designed this study to evaluate the long-term impact of different levels of surgical stress among frail older patients undergoing vascular surgery procedures.

Compartment Syndrome in Tibial Plateau Fractures: Do Previously Established Predictors Have External Validity?

Objective: To test previously established radiographic predictors of compartment syndrome in tibial plateau fractures and determine whether novel measurements may further improve a surgeon's ability to identity patients at high risk for developing this outcome.

Design: Retrospective review.

Setting: Academic Level I trauma center.

Burden of Care and Quality of Life Among Caregivers for Adults Receiving Maintenance Dialysis: A Systematic Review.

Rationale & Objective: Dialysis is a burdensome and complex treatment for which many recipients require support from caregivers. The impact of caring for people dependent on dialysis on the quality of life of the caregivers has been incompletely characterized.

Study Design: Systematic review of quantitative studies of quality of life and burden to caregivers.

Primary Hyperparathyroidism in Pregnancy: Maternofetal Outcomes at a Quaternary Referral Obstetric Hospital, 2000 Through 2015.

Context: Primary hyperparathyroidism (PHPT) in pregnancy has historically been associated with substantial maternofetal morbidity and mortality rates. The optimal treatment and timing of surgical intervention in pregnancy remain contested.

Objective: To compare maternofetal outcomes of medically and surgically treated patients with PHPT in pregnancy.

Implicit Self-Importance in an Interpersonal Pronoun Categorization Task.

Object relations theories emphasize the manner in which the salience/importance of implicit representations of self and other guide interpersonal functioning. Two studies and a pilot test (total = 304) sought to model such representations. In dyadic contexts, the self is a "you" and the other is a "me", as verified in a pilot test.

American medical home runs.

Four primary care sites in the United States constitute "medical home runs" because their patients incur 15-20 percent less (risk-adjusted) total health care spending per year than patients treated by regional peers, without evidence of reduced quality. The sites achieved this result in a U.S.

Tendon pathology in the foot. The use of corticosteroid injection therapy.

Corticosteroids have been used extensively in the practice of orthopedics and podiatry. It is the authors' opinion that the issue of corticosteroids and their effect on the healing of tendon pathology has not been addressed sufficiently or answered adequately. Few studies have used a well-controlled injury model.

Super potent topical corticosteroid use associated with adrenal suppression: clinical considerations.

The potential for a variety of local and systemic side effects from the use of potent topical corticosteroids has long been recognized. However, adrenal suppression has only rarely been documented. We describe two patients with profound hypothalamic-pituitary-adrenal axis suppression resulting from the unregulated use of super potent topical corticosteroids.

Vesiculopustular eruption of Crohn's disease.

We report a 16-year-old Hispanic girl with gastrointestinal complaints and an unusual cutaneous eruption consisting of vesiculopustules and blanching erythematous plaques with peripheral scale. Diagnostic workup showed collections of neutrophils in the upper epidermis and subcorneal layer on the skin biopsy specimen, and deep ulcerations, crypt abscesses, and granulomas on endoscopy, diagnostic of Crohn disease. The skin findings are consistent with a vesiculopustular eruption without vasculitis, previously only reported in association with ulcerative colitis.

Development of the basal forebrain cholinergic system: phenotype expression prior to target innervation.

We measured choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities in the rat to determine the time course of development, maturity, and senescence of ChAT activity. Tissue was obtained from Sprague-Dawley rats ranging in age from embryonic day 14 through 23 months. Seven regions were examined, including the magnocellular preoptic/substantia innominata region, frontal cortex, medial septal region, hippocampus, diagnoal band, and medial and lateral striatum.