Amphiphilic shuttle peptide delivers base editor ribonucleoprotein to correct the CFTR R553X mutation in well-differentiated airway epithelial cells.

Base editing could correct nonsense mutations that cause cystic fibrosis (CF), but clinical development is limited by the lack of delivery methods that efficiently breach the barriers presented by airway epithelia. Here, we present a novel amphiphilic shuttle peptide based on the previously reported S10 peptide that substantially improved base editor ribonucleoprotein (RNP) delivery. Studies of the S10 secondary structure revealed that the alpha-helix formed by the endosomal leakage domain (ELD), but not the cell penetrating peptide (CPP), was functionally important for delivery.

Extended survival of 9- and 10-gene-edited pig heart xenografts with ischemia minimization and CD154 costimulation blockade-based immunosuppression.

Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, either alone or with addition of various human complement, coagulation, and anti-inflammatory ''transgenes''. Here we evaluated results associated with gene-edited (GE) pig hearts transplanted in baboons using an established costimulation-based immunosuppressive regimen and a cold-perfused graft preservation technique.

Methods: Eight baboons received heterotopic abdominal heart transplants from 3-GE (GalKO.

Conceptus estrogen and prostaglandins provide the maternal recognition of pregnancy signal to prevent luteolysis during early pregnancy in the pig†.

Conceptus estrogens and prostaglandins have long been considered the primary signals for maternal recognition of pregnancy (MRP) in the pig. However, loss-of-function studies targeting conceptus aromatase genes (CYP19A1 and CYP19A2) and prostaglandin-endoperoxide synthase 2 (PTGS2) indicated that conceptuses can not only signal MRP without estrogens or prostaglandins but can maintain early pregnancy. However, complete loss of estrogen production leads to abortion after day 25 of gestation.

Pigs: Large Animal Preclinical Cancer Models.

Pigs are playing an increasingly vital role as translational biomedical models for studying human pathophysiology. The annotation of the pig genome was a huge step forward in translatability of pigs as a biomedical model for various human diseases. Similarities between humans and pigs in terms of anatomy, physiology, genetics, and immunology have allowed pigs to become a comprehensive preclinical model for human diseases.

A Protocol for Evaluating Digital Technology for Monitoring Sleep and Circadian Rhythms in Older People and People Living with Dementia in the Community.

Sleep and circadian rhythm disturbance are predictors of poor physical and mental health, including dementia. Long-term digital technology-enabled monitoring of sleep and circadian rhythms in the community has great potential for early diagnosis, monitoring of disease progression, and assessing the effectiveness of interventions. Before novel digital technology-based monitoring can be implemented at scale, its performance and acceptability need to be evaluated and compared to gold-standard methodology in relevant populations.

Keeping Pathologists in the Loop and an Adaptive F1-Score Threshold Method for Mitosis Detection in Canine Perivascular Wall Tumours.

Performing a mitosis count (MC) is the diagnostic task of histologically grading canine Soft Tissue Sarcoma (cSTS). However, mitosis count is subject to inter- and intra-observer variability. Deep learning models can offer a standardisation in the process of MC used to histologically grade canine Soft Tissue Sarcomas.

septicemia presenting as endogenous endophthalmitis.

Purpose: To present a rarely reported systemic infection with (), transmitted from a horse, and to describe successful treatment when complicated by endogenous endophthalmitis.

Observations: We diagnosed suspected septicemia presenting as loss of vision in the right eye of an otherwise healthy polo player/horse trainer. He received immediate intravenous antibiotics and three vitrectomies with two intravitreal antibiotic injections during the first week, to cure infection and subsequent retinal detachment.

Response of pet owners to Whistle FIT activity monitor digital alerts of increased pruritic activity in their dogs: a retrospective observational study.

Pruritus is a common clinical sign in dogs and is often underrecognized by dog owners and veterinarians. The Whistle FIT, a wearable accelerometer paired with analytics, can detect changes in pruritic activity in dogs, which can be reported to owners in a smartphone/tablet application. The objectives of this retrospective observational study were to investigate the impact of digital alerts for increased pruritic behaviors received by dog owners in a real-life setting, on (1) the initiation of veterinary clinic visits, and (2) if such visits resulted in initiation of therapy for pruritus.

Porcine-specific expression of the three functional CYP19 paralogs in early conceptus, placenta, and gonads.

In Brief: Aromatase catalyzes the synthesis of estrogens and has been shown to have an important role during the establishment of pregnancy in the pig. This study confirmed the differential expression of the three aromatase isoforms.

Abstract: Although three porcine aromatase isoforms have been identified, their gene expression profiles in reproduction are still poorly understood.

Part of the gender gap in voting for Democrats arises because a higher proportion of women than men voters are Black.

Women voted for the Democratic candidate more than men did in each US presidential election since 1980. We show that part of the gender gap stems from the fact that a higher proportion of women than men voters are Black, and Black voters overwhelmingly choose Democratic candidates. Past research shows that Black men have especially high rates of death, incarceration, and disenfranchisement due to criminal convictions.

Detection of Necrosis in Digitised Whole-Slide Images for Better Grading of Canine Soft-Tissue Sarcomas Using Machine-Learning.

The definitive diagnosis of canine soft-tissue sarcomas (STSs) is based on histological assessment of formalin-fixed tissues. Assessment of parameters, such as degree of differentiation, necrosis score and mitotic score, give rise to a final tumour grade, which is important in determining prognosis and subsequent treatment modalities. However, grading discrepancies are reported to occur in human and canine STSs, which can result in complications regarding treatment plans.

Profiling development of abdominal organs in the pig.

The pig is an ideal model system for studying human development and disease due to its similarities to human anatomy, physiology, size, and genome. Further, advances in CRISPR gene editing have made genetically engineered pigs viable models for the study of human pathologies and congenital anomalies. However, a detailed atlas illustrating pig development is necessary for identifying and modeling developmental defects.

Improvements in pig agriculture through gene editing.

Genetic modification of animals via selective breeding is the basis for modern agriculture. The current breeding paradigm however has limitations, chief among them is the requirement for the beneficial trait to exist within the population. Desirable alleles in geographically isolated breeds, or breeds selected for a different conformation and commercial application, and more importantly animals from different genera or species cannot be introgressed into the population via selective breeding.

Deep learning for necrosis detection using canine perivascular wall tumour whole slide images.

Necrosis seen in histopathology Whole Slide Images is a major criterion that contributes towards scoring tumour grade which then determines treatment options. However conventional manual assessment suffers from inter-operator reproducibility impacting grading precision. To address this, automatic necrosis detection using AI may be used to assess necrosis for final scoring that contributes towards the final clinical grade.

Gene editing provides a tool to investigate genes involved in reproduction of pigs.

CRISPR-Cas9 gene editing technology provides a method to generate loss-of-function studies to investigate, in vivo, the specific role of specific genes in regulation of reproduction. With proper design and selection of guide RNAs (gRNA) designed to specifically target genes, CRISPR-Cas9 gene editing allows investigation of factors proposed to regulate biological pathways involved with establishment and maintenance of pregnancy. The advantages and disadvantages of using the current gene editing technology in a large farm species is discussed.

Chloride channel accessory 1 gene deficiency causes selective loss of mucus production in a new pig model.

Morbidity and mortality of respiratory diseases are linked to airway obstruction by mucus but there are still no specific, safe, and effective drugs to correct this phenotype. The need for better treatment requires a new understanding of the basis for mucus production. In that regard, studies of human airway epithelial cells in primary culture show that a mucin granule constituent known as chloride channel accessory 1 (CLCA1) is required for inducible expression of the inflammatory mucin MUC5AC in response to potent type 2 cytokines.

Disruption of anthrax toxin receptor 1 in pigs leads to a rare disease phenotype and protection from senecavirus A infection.

Senecavirus A (SVA) is a cause of vesicular disease in pigs, and infection rates are rising within the swine industry. Recently, anthrax toxin receptor 1 (ANTXR1) was revealed as the receptor for SVA in human cells. Herein, the role of ANTXR1 as a receptor for SVA in pigs was investigated by CRISPR/Cas9 genome editing.

Future of biomedical, agricultural, and biological systems research using domesticated animals.

Increased knowledge of reproduction and health of domesticated animals is integral to sustain and improve global competitiveness of U.S. animal agriculture, understand and resolve complex animal and human diseases, and advance fundamental research in sciences that are critical to understanding mechanisms of action and identifying future targets for interventions.

We Want You Back: Uncovering the Effects on In-Person Instructional Operations in Fall 2020.

Postsecondary institutions' responses to COVID-19 are a topic of immediate relevance. Emergent research suggests that partisanship was more strongly linked to institutions offering in-person instruction for Fall 2020 than was COVID-19. Using data from the College Crisis Initiative and a multiple group structural equation modeling approach, we tested the relationships between our outcome of interest (in-person instruction in Fall 2020) and state and county sociopolitical features, state and county COVID-19 rates, and state revenue losses.

Serologic titers to Leptospira in vaccinated pigs and interpretation for surveillance.

Diagnosis and surveillance of pathogenic Leptospira is difficult as organisms may be intermittently shed and in small numbers. Therefore, serologic testing by the microscopic agglutination test (MAT) is the primary screening method for leptospirosis. While a MAT titer ≥1:100 is considered to be a positive result, interpretation is complicated by the use of commercial vaccines in pigs.

Conceptus interferon gamma is essential for establishment of pregnancy in the pig†.

Establishment and maintenance of pregnancy in the pig is a complex process that relies on conceptus regulation of the maternal proinflammatory response to endometrial attachment. Following elongation, pig conceptuses secrete interferon gamma (IFNG) during attachment to the endometrial luminal epithelium. The objective here was to determine if conceptus production of IFNG is important for early development and establishment of pregnancy.

Disrupting porcine glutaminase does not block preimplantation development and elongation nor decrease mTORC1 activation in conceptuses†.

Elongation of pig conceptuses is a dynamic process, requiring adequate nutrient provisions. Glutamine is used as an energy substrate and is involved in the activation of mechanistic target of rapamycin complex 1 (mTORC1) during porcine preimplantation development. However, the roles of glutamine have not been extensively studied past the blastocyst stage.