Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges.

Design principles and therapeutic applications of novel synthetic WNT signaling agonists.

Wingless-related integration site or Wingless and Int-1 or Wingless-Int (WNT) signaling is crucial for embryonic development, and adult tissue homeostasis and regeneration, through its essential roles in cell fate, patterning, and stem cell regulation. The biophysical characteristics of WNT ligands have hindered efforts to interrogate ligand activity and prevented their development as therapeutics. Recent breakthroughs have enabled the generation of synthetic WNT signaling molecules that possess characteristics of natural ligands and potently activate the pathway, while also providing distinct advantages for therapeutic development and manufacturing.

Ocular Manifestations and Outcomes in Children With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Comparison With Adult Patients.

Purpose: To compare the clinical features and visual outcomes in children and adults with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).

Design: Retrospective comparative case series.

Methods: This retrospective study included 280 eyes of 140 patients (35 children and 105 adults) with SJS/TEN treated between 2010 and 2020.

Novel Frizzled-specific antibody-based Wnt mimetics and Wnt superagonists selectively activate WNT/β-catenin signaling in target tissues.

WNTs are essential factors for stem cell biology, embryonic development, and for maintaining homeostasis and tissue repair in adults. Difficulties in purifying WNTs and their lack of receptor selectivity have hampered research and regenerative medicine development. While breakthroughs in WNT mimetic development have overcome some of these difficulties, the tools developed so far are incomplete and mimetics alone are often not sufficient.

Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD-selective WNT surrogate in mice.

Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD/TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD-selective ligand Norrin.

Methicillin-Resistant Staphylococcus aureus Ocular Infection in Taiwan: Potential Role of Panton-Valentine Leukocidin Gene.

Purpose: The relationship between Panton-Valentine leucocidin (PVL), a major virulence factor of Staphylococcus aureus, and disease severity and clinical outcomes remains unclear. We investigated the molecular characteristics and role of the PVL gene in methicillin-resistant S. aureus (MRSA) ocular infection in Taiwan.

Benefits, harms, and costs of newborn genetic screening for hypertrophic cardiomyopathy: Estimates from the PreEMPT model.

Purpose: Population newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain.

Methods: We developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns.

Paradoxical mortality of high estimated glomerular filtration rate reversed by 24-h urine creatinine excretion rate adjustment: sarcopenia matters.

Background: Muscle wasting may explain the paradoxical mortality of patients with high estimated glomerular filtration rates (eGFRs) derived from equation methods. However, empirical evidence and solutions remain insufficient.

Methods: In this retrospective cohort study, we compared the performance of equation methods for predicting all-cause mortality; we used 24-h creatinine clearance (24-h CrCl), equation-based eGFRs, and a new eGFR estimating equation weighting for population 24-h urine creatinine excretion rate (U-CER).

Glomerular disease classification and lesion identification by machine learning.

Background: Classification of glomerular diseases and identification of glomerular lesions require careful morphological examination by experienced nephropathologists, which is labor-intensive, time-consuming, and prone to interobserver variability. In this regard, recent advance in machine learning-based image analysis is promising.

Methods: We combined Mask Region-based Convolutional Neural Networks (Mask R-CNN) with an additional classification step to build a glomerulus detection model using human kidney biopsy samples.

De novo design of modular and tunable protein biosensors.

Naturally occurring protein switches have been repurposed for the development of biosensors and reporters for cellular and clinical applications. However, the number of such switches is limited, and reengineering them is challenging. Here we show that a general class of protein-based biosensors can be created by inverting the flow of information through de novo designed protein switches in which the binding of a peptide key triggers biological outputs of interest.

Therapeutic Potential of Tpl2 (Tumor Progression Locus 2) Inhibition on Diabetic Vasculopathy Through the Blockage of the Inflammasome Complex.

Objective: Diabetic retinopathy, one of retinal vasculopathy, is characterized by retinal inflammation, vascular leakage, blood-retinal barrier breakdown, and neovascularization. However, the molecular mechanisms that contribute to diabetic retinopathy progression remain unclear. Approach and Results: Tpl2 (tumor progression locus 2) is a protein kinase implicated in inflammation and pathological vascular angiogenesis.

Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.

Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis.

Development of Potent, Selective Surrogate WNT Molecules and Their Application in Defining Frizzled Requirements.

WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective WNT molecules. Soluble WNT surrogates have been reported, but they demonstrate relatively weak WNT signaling activity.

Smoking Paradox in Stroke Survivors?: Uncovering the Truth by Interpreting 2 Sets of Data.

Background and Purpose- The observation that smokers with stroke could have better outcome than nonsmokers led to the term "smoking paradox." The controversy of such a complex claim has not been fully settled, even though different case mix was noted. Analyses were conducted on 2 independent data sets to evaluate and determine whether such a paradox truly exists.

Inhibition of Advanced Glycation End Products Formation Attenuates Cardiac Electrical and Mechanical Remodeling and Vulnerability to Tachyarrhythmias in Diabetic Rats.

Diabetic patients with cardiomyopathy show a higher incidence of arrhythmias and sudden death. Chronic hyperglycemia induces the formation of advanced glycation end products (AGEs), which contribute to the pathogenesis of diabetic cardiomyopathy. This study investigated whether inhibition of AGEs formation by aminoguanidine (AG) could prevent cardiac electromechanical and arrhythmogenic remodeling in diabetes mellitus.

Impact of Clopidogrel Therapy on Mortality and Cancer in Patients With Cardiovascular and Cerebrovascular Disease: A Patient-Level Meta-Analysis.

Background: Clinical trial data associate extended clopidogrel therapy with increased mortality and cancer. We sought to determine the impact of continued clopidogrel use on mortality and cancer within a patient-level meta-analysis of randomized clinical trials.

Methods And Results: Meta-analytic clinical event rates for all-cause, cardiovascular, noncardiovascular, and cancer-related mortality; cancer; myocardial infarction; stroke; and fatal and major nonfatal bleeding were generated using patient-level data from 6 randomized trials comparing prolonged versus no or short-duration clopidogrel on a background of aspirin in patients with cardiovascular and cerebrovascular disease.

1-(2,4-Dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one: A Novel Opioid Receptor Agonist with Less Accompanying Gastrointestinal Dysfunction than Morphine.

Background: The authors investigated the pharmacology and signaling pathways of the opioid receptors modulated by compound 1, 1-(2,4-dibromophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one.

Methods: In vitro studies of compound 1 were assessed by using a radioligand-binding assay (n = 3), a cyclic adenosine monophosphate assay (n = 3), a β-arrestin assay (n = 3), an internalization assay (n = 3), and an immunohistochemistry (n = 8). In vivo studies of compound 1 were characterized using a tail-flick test (n = 5 to 6), tail-clip test (n = 7), von Frey hair test (n = 5), and charcoal meal test (n = 5).

Adipocyte Browning and Higher Mitochondrial Function in Periadrenal But Not SC Fat in Pheochromocytoma.

Context: Patients with pheochromocytoma (pheo) show presence of multilocular adipocytes that express uncoupling protein 1 within periadrenal (pADR) and omental (OME) fat depots. It has been hypothesized that this is due to adrenergic stimulation by catecholamines produced by the pheo tumors.

Objective: To characterize the prevalence and respiratory activity of brown-like adipocytes within pADR, OME, and SC fat depots in human adult pheo patients.

Carpal tunnel syndrome: US strain imaging for diagnosis.

Purpose: To determine the feasibility of two-dimensional (2D) ultrasonographic (US) strain imaging for quantifying and mapping mechanical behaviors of the median nerve, flexor retinaculum, and flexor tendons within the carpal tunnel in normal and carpal tunnel syndrome (CTS) disease states during active finger motion.

Materials And Methods: This prospective study was approved by the institutional review board; all subjects gave written informed consent and had both of their hands examined. Ten wrists in 10 healthy volunteers (age range, 35-51 years) and 16 wrists in 12 patients with CTS (age range, 37-55 years) were examined.

Acute uterine irritation provokes colonic motility via transient receptor potential A(1)-dependent spinal NR2B phosphorylation in rats.

Background: Patients with inflammatory gynecological/obstetrical problems often complain of irritable bowel syndrome. The authors examined whether acute uterus irritation reflexively provokes colonic motility in rat preparations.

Methods: A modified colon manometry and striated abdominal muscle electromyogram activity in response to mustard oil (MO) instillation into the uterine horn were continuously recorded in anesthetized rats.