Single-Stranded Hairpin Loop RNAs (loopmeRNAs) Potently Induce Gene Silencing through the RNA Interference Pathway.

Synthetic small interfering RNAs conjugated to trivalent -acetylgalactosamine (GalNAc) are clinically validated drugs for treatment of liver diseases. Incorporation of phosphorothioate linkages and ribose modifications are necessary for stability, potency, and duration of pharmacology. Although multiple alternative siRNA designs such as Dicer-substrate RNA, shRNA, and circular RNA have been evaluated in vitro and in preclinical studies with some success, clinical applications of these designs are limited as it is difficult to incorporate chemical modifications in these designs.

The differential proteomic response to ischemic stroke in appalachian subjects treated with mechanical thrombectomy.

Introduction: The Appalachia region of North America is known to have significant health disparities, specifically, worse risk factors and outcomes for stroke. Appalachians are more likely to have comorbidities related to stroke, such as diabetes, obesity, and tobacco use, and are often less likely to have stroke interventions, such as mechanical thrombectomy (MT), for emergent large vessel occlusion (ELVO). As our Comprehensive Stroke Center directly serves stroke subjects from both Appalachian and non-Appalachian areas, inflammatory proteomic biomarkers were identified associated with stroke outcomes specific to subjects residing in Appalachia.

Enhancing undergraduate education and research in aging to eliminate health disparities (ENGAGED) - A pipeline program to advance diversity in aging research.

The Enhancing Undergraduate Education and Research in Aging to Eliminate Health Disparities (ENGAGED) program takes advantage of the broad, multidisciplinary research established in the area of aging at Wake Forest University School of Medicine and its partner institutions, Wake Forest University and Winston-Salem State University. The ENGAGED program is designed to provide undergraduate students who are underrepresented in the biomedical sciences an opportunity to participate in educational and research training in aging and health disparities. Funded since August 2019, ENGAGED has provided 73 academic year internships and 46 summer internships, with another 8 internships starting in Fall 2023.

The Association of Gabapentin Initiation with Cognitive and Behavioral Changes in Older Adults with Cognitive Impairment: A Retrospective Cohort Study.

Background: Although gabapentin has been increasingly prescribed to older adults, the relation between gabapentin initiation and longer-term neurocognitive changes is not well understood. Thus, this study aimed to examine the association of gabapentin initiation with cognitive and motor function decline in older adult participants with cognitive impairment.

Methods: A retrospective cohort study was conducted using the National Alzheimer's Coordinating Center Uniform Data Set (2005-March 2023).

Structure and Stability of Ago2 MID-Nucleotide Complexes: All-in-One (Drop) His-SUMO Tag Removal, Nucleotide Binding, and Crystal Growth.

The middle (MID) domain of eukaryotic Argonaute (Ago) proteins and archaeal and bacterial homologues mediates the interaction with the 5'-terminal nucleotide of miRNA and siRNA guide strands. The MID domain of human Ago2 (hAgo2) is comprised of 139 amino acids with a molecular weight of 15.56 kDa.

Heat Tolerance Testing and the Return to Duty Decision: A Two-Year Case Cohort Analysis.

Background: Among individuals with prior exertional heat illness (EHI), heat tolerance testing (HTT) may inform risk and return to duty/activity. However, little is known about HTT's predictive validity, particularly for EHI recurrence. Our project sought to demonstrate the predictive validity of HTT in EHI recurrence and HTT's utility as a diagnostic tool in exertional heat stroke (EHS).

Alzheimer's disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort.

Introduction: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia.

Methods: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer's Disease Research Center cohort. We evaluated six Alzheimer's disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p-tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform.

Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency.

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin.

Performance Validity Testing on the NIH Toolbox Cognition Battery: Base Rates of Failed Embedded Validity Indicators in the Adult Normative Sample.

Objective: The goal of this study was to determine the base rates of failing proposed embedded validity indicators (EVIs) for the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB) in the normative sample.

Method: Participants included adults in the NIHTB-CB normative sample with data to calculate age-adjusted standard scores (n = 855; ages: M(SD) = 46.9(17.

Shorter Is Better: The α-(l)-Threofuranosyl Nucleic Acid Modification Improves Stability, Potency, Safety, and Ago2 Binding and Mitigates Off-Target Effects of Small Interfering RNAs.

Chemical modifications are necessary to ensure the metabolic stability and efficacy of oligonucleotide-based therapeutics. Here, we describe analyses of the α-(l)-threofuranosyl nucleic acid (TNA) modification, which has a shorter 3'-2' internucleotide linkage than the natural DNA and RNA, in the context of small interfering RNAs (siRNAs). The TNA modification enhanced nuclease resistance more than 2'--methyl or 2'-fluoro ribose modifications.

Cognitive, imaging, and psychiatric changes associated with chronic toluene use: case report and literature review.

Inhalant misuse and inhalant use disorder are global public health concern that impacts adolescents but can occur throughout life. Toluene is the most commonly misused inhalant. Toluene use leads to significant neuroanatomic, cognitive, and psychiatric deficits.

Inflammatory-associated proteomic predictors of cognitive outcome in subjects with ELVO treated by mechanical thrombectomy.

Background: Emergent Large Vessel Occlusion (ELVO) stroke causes devastating vascular events which can lead to significant cognitive decline and dementia. In the subset of ELVO subjects treated with mechanical thrombectomy (MT) at our institution, we aimed to identify systemic and intracranial proteins predictive of cognitive function at time of discharge and at 90-days. These proteomic biomarkers may serve as prognostic indicators of recovery, as well as potential targets for novel/existing therapeutics to be delivered during the subacute stage of stroke recovery.

Development of a Skin-Directed Scoring System for Stevens-Johnson Syndrome and Epidermal Necrolysis: A Delphi Consensus Exercise.

Importance: Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent.

Objectives: To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN.

Evidence Review: A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement.

The Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D) at the Spallation Neutron Source (invited).

The Oak Ridge National Laboratory is planning to build the Second Target Station (STS) at the Spallation Neutron Source (SNS). STS will host a suite of novel instruments that complement the First Target Station's beamline capabilities by offering an increased flux for cold neutrons and a broader wavelength bandwidth. A novel neutron imaging beamline, named the Complex, Unique, and Powerful Imaging Instrument for Dynamics (CUPI2D), is among the first eight instruments that will be commissioned at STS as part of the construction project.

Base excision repair of the N-(2-deoxy-d-erythro-pentofuranosyl)-urea lesion by the hNEIL1 glycosylase.

The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and subsequent hydrolysis. It interconverts between α and β deoxyribose anomers. Synthetic oligodeoxynucleotides containing this adduct are efficiently incised by unedited (K242) and edited (R242) forms of the hNEIL1 glycosylase.

Synthesis and Biophysical Properties of Phosphorodiamidate Piperidino Oligomers.

We report the synthesis of piperidino nucleoside phosphoramidates functionalized with uracil, cytosine, guanine, and adenine and their incorporation into oligomers. High-performance liquid chromatography analyses demonstrated that a phosphorodiamidate piperidino oligomer (PPO) is more lipophilic than a phosphorodiamidate morpholino oligomer (PMO) of the same tetrameric sequence. A PMO containing piperidino residues formed duplexes with both DNA and RNA, and the PPO had higher stability at endosomolytic pH and higher hydrophobicity than the PMO.

Examining the Effects of Formal Education Level on the Montreal Cognitive Assessment.

METHODS: RESULTS: CONCLUSIONS:

Observational study of sterile field bioburden levels during orthopedic arthroplasty surgery in operating rooms complying with current United States ventilation specifications.

Background: Airborne contamination from microbe carrying particles (MCPs) is a risk factor for devastating early onset periprosthetic joint infection(PJIs). There are no published guidelines to quantify this risk factor for PJI events. This observational cohort project addresses this gap and utilizes a simple passive system to produce quantitative data from 80 total joint replacement cases performed in operating rooms built to current USA standards.