In vivo base editing extends lifespan of a humanized mouse model of prion disease.

Prion disease is a fatal neurodegenerative disease caused by the misfolding of prion protein (PrP) encoded by the PRNP gene. While there is currently no cure for the disease, depleting PrP in the brain is an established strategy to prevent or stall templated misfolding of PrP. Here we developed in vivo cytosine and adenine base strategies delivered by adeno-associated viruses to permanently modify the PRNP locus to achieve PrP knockdown in the mouse brain.

Diversity of Culturable Bacteria from Endemic Medicinal Plants of the Highlands of the Province of Parinacota, Chile.

Endemic medicinal plants that grow at altitudes in northern Chile have been traditionally used for therapeutic applications by Aymara doctors. Several studies have analyzed the biological properties of these plants for therapeutic purposes. The aim was to characterize at molecular and biochemical levels the bacteria that live in the rhizosphere and roots from endemic medicinal plants that grow between 3681-5104 m.

Stability of ACE2 Peptide Mimetics and Their Implications on the Application for SARS-CoV2 Detection.

The SARS-CoV-2 worldwide outbreak prompted the development of several tools to detect and treat the disease. Among the new detection proposals, the use of peptides mimetics has surged as an alternative to avoid the use of antibodies, of which there has been a shortage during the COVID-19 pandemic. However, the use of peptides in detection systems still presents some questions to be answered, mainly referring to their stability under different environmental conditions.

Positron Emission Tomography Imaging of Vessel Wall Matrix Metalloproteinase Activity in Abdominal Aortic Aneurysm.

Background: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, Cu-RYM2.

High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER breast cancer.

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89).

Contemporary Trends in Hospital Admissions and Outcomes in Patients With Critical Limb Ischemia: An Analysis From the National Inpatient Sample Database.

Background: Critical limb ischemia (CLI) morbidity and mortality rates have historically been disproportionately higher than for other atherosclerotic diseases, however, recent trends have not been reported. In patients admitted with CLI, we aimed to examine trends in in-hospital mortality, major amputations, length of stay, and cost of hospitalizations overall and stratified by type of revascularization procedures.

Methods: Using 2011 to 2017 National Inpatient Sample data, we identified CLI-related admissions based on codes.

Initial Invasive Versus Conservative Management of Stable Ischemic Heart Disease in Patients With a History of Heart Failure or Left Ventricular Dysfunction: Insights From the ISCHEMIA Trial.

Background: Whether an initial invasive strategy in patients with stable ischemic heart disease and at least moderate ischemia improves outcomes in the setting of a history of heart failure (HF) or left ventricular dysfunction (LVD) when ejection fraction is ≥35% but <45% is unknown.

Methods: Among 5179 participants randomized into ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches), all of whom had left ventricular ejection fraction (LVEF) ≥35%, we compared cardiovascular outcomes by treatment strategy in participants with a history of HF/LVD at baseline versus those without HF/LVD. Median follow-up was 3.

Abdominal aortic and junctional tourniquet versus zone III resuscitative endovascular balloon occlusion of the aorta in a swine junctional hemorrhage model.

Background: Junctional hemorrhage is a leading contributor to battlefield mortality. The Abdominal Aortic and Junctional Tourniquet (AAJT) and infrarenal (zone III) resuscitative endovascular balloon occlusion of the aorta (REBOA) are emerging strategies for controlling junctional hemorrhage, with AAJT currently available in select forward deployed settings and increasing interest in applying REBOA in the military prehospital environment. This study compared the hemostatic, hemodynamic, and metabolic effects of these devices used for junctional hemorrhage control.

Effect of partial and complete aortic balloon occlusion on survival and shock in a swine model of uncontrolled splenic hemorrhage with delayed resuscitation.

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is accepted as a resuscitation adjunct and bridge to definitive hemostasis. The ischemic burden of REBOA may be mitigated by a partial REBOA (P-REBOA) strategy permitting longer occlusion times and military use for combat trauma. We evaluated REBOA and P-REBOA in a swine multiple trauma model with uncontrolled solid organ hemorrhage and delayed resuscitation and surgical hemostasis.

Cannabinoid Type-2 Receptor Drives Neurogenesis and Improves Functional Outcome After Stroke.

Background And Purpose: Stroke is a leading cause of adult disability characterized by physical, cognitive, and emotional disturbances. Unfortunately, pharmacological options are scarce. The cannabinoid type-2 receptor (CB2R) is neuroprotective in acute experimental stroke by anti-inflammatory mechanisms.

Dietary Flaxseed Reduces Central Aortic Blood Pressure Without Cardiac Involvement but Through Changes in Plasma Oxylipins.

Unlabelled: In the year-long FlaxPAD clinical trial (Flaxseed for Peripheral Artery Disease), dietary flaxseed generated a powerful reduction in brachial systolic and diastolic blood pressure in patients with peripheral artery disease. Oxylipins were implicated as potential mechanistic mediators. However, the ability of flaxseed to impact central aortic hypertension, arterial stiffness, or cardiac performance was not investigated.

Flaxseed consumption reduces blood pressure in patients with hypertension by altering circulating oxylipins via an α-linolenic acid-induced inhibition of soluble epoxide hydrolase.

Unlabelled: In a randomized, double-blinded, controlled clinical trial, participants with peripheral arterial disease (75% hypertensive) consumed 30 g of milled flaxseed/d for 6 months. The flaxseed group exhibited significant reductions in systolic (-10 mm Hg) and diastolic (-7 mm Hg) blood pressure. Flaxseed contains the n3 fatty acid α-linolenic acid.

Dengue specific immunoglobulins M, A, and E in primary and secondary dengue 4 infected Salvadorian children.

El Salvador is a Central American country that has been affected by several dengue outbreaks. This study investigated the levels of IgM, IgA, and IgE anti-dengue antibodies in serum samples from children in El Salvador, with a clinical and serological diagnosis of dengue infection during the dengue 4 outbreak in 2002-2003. Seventy one serum samples were tested by ELISA and cases were classified in three groups: 13 primary dengue fever (PDF), 21 secondary dengue fever (SDF), and 37 secondary dengue hemorrhagic fever (SDHF).

Forebrain deletion of the vesicular acetylcholine transporter results in deficits in executive function, metabolic, and RNA splicing abnormalities in the prefrontal cortex.

One of the key brain regions in cognitive processing and executive function is the prefrontal cortex (PFC), which receives cholinergic input from basal forebrain cholinergic neurons. We evaluated the contribution of synaptically released acetylcholine (ACh) to executive function by genetically targeting the vesicular acetylcholine transporter (VAChT) in the mouse forebrain. Executive function was assessed using a pairwise visual discrimination paradigm and the 5-choice serial reaction time task (5-CSRT).

Inhibitory effects of various L-type and T-type calcium antagonists on electrically generated, potassium-induced and carbachol-induced contractions of porcine detrusor muscle.

The inhibitory effects of different calcium antagonists on contractions of isolated porcine detrusor muscle were investigated. Suppression of the maximum potassium-induced contraction and electrically generated contractions by nifedipine, verapamil and diltiazem were investigated. Furthermore, concentration-response curves of carbachol after pretreatment with the L-type antagonists nifedipine, verapamil, diltiazem, nimodipine and the T-type antagonist mibefradil at different concentrations were performed.