Validation and in silico function prediction of circtial1 as a novel marker of abnormal lung development in nitrofen-induced congenital diaphragmatic hernia (CDH).

Purpose: Circular RNAs (circRNAs) are stable, non-coding RNAs with tissue- and developmental-specific expression making them suitable biomarkers for congenital anomalies. Current circRNA discovery pipelines have focused on human and mouse. We aim to bridge this gap by combining bioinformatics resources and used circtial1 as a model candidate in the nitrofen rat model of congenital diaphragmatic hernia (CDH).

Diabetic Deformities of the Lesser Toes.

The United States Centers for Disease Control and the National Institute of Diabetic, Digestive and Kidney Disorders now estimates that there are now over 34.2 million patients with diabetes in the United Sates, or over 10.2% of our population.

The urotensin II receptor triggers an early meningeal response and a delayed macrophage-dependent vasospasm after subarachnoid hemorrhage in male mice.

Subarachnoid hemorrhage (SAH) can be associated with neurological deficits and has profound consequences for mortality and morbidity. Cerebral vasospasm (CVS) and delayed cerebral ischemia affect neurological outcomes in SAH patients, but their mechanisms are not fully understood, and effective treatments are limited. Here, we report that urotensin II receptor UT plays a pivotal role in both early events and delayed mechanisms following SAH in male mice.

G protein selectivity profile of GPR56/ADGRG1 and its effect on downstream effectors.

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13.

G protein selectivity profile of GPR56/ADGRG1 and its effect on downstream effectors.

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13.

Rational Design of Selective TMPRSS6 Peptidomimetic Inhibitors via Exploitation of the S2 Subpocket.

TMPRSS6 is a potential therapeutic target for the treatment of iron overload due to its role in regulating levels of hepcidin. Although potent TMPRSS6 inhibitors have been previously developed, their lack of specificity requires optimization to avoid potential side effects before pursuing preclinical development with models. Here, using computer-aided drug design based on a TMPRSS6 homology model, we reveal that the S2 position of TMPRSS6 offers a potential avenue to achieve selectivity against other members of the TTSP family.

Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals.

SARS-CoV-2 Omicron subvariants with increased transmissibility and immune evasion are spreading globally with alarming persistence. Whether the mutations and evolution of spike (S) Omicron subvariants alter the viral hijacking of human TMPRSS2 for viral entry remains to be elucidated. This is particularly important to investigate because of the large number and diversity of mutations of S Omicron subvariants reported since the emergence of BA.

Preliminary Experience With Commercially Available Trabecular Metal Tibial Cones Combined With a Retrograde Locked Intramedullary Nail for Bony Defects in Tibiotalocalcaneal Arthrodesis.

Critical sized bone defects in the ankle are becoming increasingly more common in patients undergoing limb reconstruction with tibiotalocalcaneal arthrodesis. Bulk allografts have not fared well over time. There have been scattered preliminary reports using custom spinal cages or 3D-printed Titanium Implants to address the critical bony defect; however, the cost of these devices is prohibitive in many clinical practice settings.

Quality of Outcomes Research in Total Ankle Arthroplasty.

Total ankle arthroplasty is a topic that has recently gained increasing interest, largely due to the improved outcomes, which have been demonstrated by short- and mid-term research studies on the newer, third-generation implant designs. The purpose of this review is to provide an updated assessment of the quality of outcomes research on total ankle arthroplasty.

Optimization of Ketobenzothiazole-Based Type II Transmembrane Serine Protease Inhibitors to Block H1N1 Influenza Virus Replication.

Human influenza viruses cause acute respiratory symptoms that can lead to death. Due to the emergence of antiviral drug-resistant strains, there is an urgent requirement for novel antiviral agents and innovative therapeutic strategies. Using the peptidomimetic ketobenzothiazole protease inhibitor RQAR-Kbt (IN-1, aka N-0100) as a starting point, we report how substituting P2 and P4 positions with natural and unnatural amino acids can modulate the inhibition potency toward matriptase, a prototypical type II transmembrane serine protease (TTSP) that acts as a priming protease for influenza viruses.

Amyloid β Proteoforms Elucidated by Quantitative LC/MS in the 5xFAD Mouse Model of Alzheimer's Disease.

Numerous Aβ proteoforms, identified in the human brain, possess differential neurotoxic and aggregation propensities. These proteoforms contribute in unknown ways to the conformations and resultant pathogenicity of oligomers, protofibrils, and fibrils in Alzheimer's disease (AD) manifestation owing to the lack of molecular-level specificity to the exact chemical composition of underlying protein products with widespread interrogating techniques, like immunoassays. We evaluated Aβ proteoform flux using quantitative top-down mass spectrometry (TDMS) in a well-studied 5xFAD mouse model of age-dependent Aβ-amyloidosis.

A novel class of broad-spectrum active-site-directed 3C-like protease inhibitors with nanomolar antiviral activity against highly immune-evasive SARS-CoV-2 Omicron subvariants.

Antivirals with broad coronavirus activity are important for treating high-risk individuals exposed to the constantly evolving SARS-CoV-2 variants of concern (VOCs) as well as emerging drug-resistant variants. We developed and characterized a novel class of active-site-directed 3-chymotrypsin-like protease (3CLpro) inhibitors (). Our lead direct-acting antiviral (DAA), , is a non-covalent, non-peptide with a dissociation constant of 170 nM against recombinant SARS-CoV-2 3CLpro.

Unraveling allostery within the angiotensin II type 1 receptor for Gα and β-arrestin coupling.

G protein-coupled receptors engage both G proteins and β-arrestins, and their coupling can be biased by ligands and mutations. Here, to resolve structural elements and mechanisms underlying effector coupling to the angiotensin II (AngII) type 1 receptor (AT1R), we combined alanine scanning mutagenesis of the entire sequence of the receptor with pharmacological profiling of Gα and β-arrestin engagement to mutant receptors and molecular dynamics simulations. We showed that Gα coupling to AT1R involved a large number of residues spread across the receptor, whereas fewer structural regions of the receptor contributed to β-arrestin coupling regulation.

Cruciate-Retaining Versus Cruciate-Substituting Total Knee Arthroplasty: A Meta-Analysis.

Background: Primary total knee arthroplasty (TKA) can be performed using cruciate-retaining (CR), cruciate-substituting (CS), or posterior-stabilized (PS) total knee arthroplasty designs. While there have been many studies comparing the outcomes of CR versus PS TKA, the current literature is lacking in systematic reviews and meta-analyses that compare outcomes of CR knees versus CS TKAs.

Methods: This study is a systematic review and meta-analysis of the literature comparing CR and CS knees with regard to survivorship, functional, and patient-reported outcomes, range of motion (ROM), biomechanics, and revision rate.

Surgical smoke and the orthopedic surgeon: a non-systematic review of the hazards and strategies for mitigating risk.

Introduction: Surgical smoke generated through the use of electrical surgical devices poses a risk to the surgeon, medical personnel in the operating room, and the patient by exposing them to environmentally hazardous particulate matter. Previous investigation has shown that surgical smoke leads to an increased risk of pulmonary conditions, circulatory disorders, and irritation of the eyes, nose, and throat. Transmission of infectious disease can occur through inhalation of viral particles, and the presence of carcinogens are also of major concern.

Omics approaches for the assessment of biological responses to nanoparticles.

Nanotechnology has enabled the development of innovative therapeutics, diagnostics, and drug delivery systems. Nanoparticles (NPs) can influence gene expression, protein synthesis, cell cycle, metabolism, and other subcellular processes. While conventional methods have limitations in characterizing responses to NPs, omics approaches can analyze complete sets of molecular entities that change upon exposure to NPs.

Preoperative and Perioperative Management of Diabetics Undergoing Elective Foot and Ankle Surgery.

Diabetics are a highly comorbid population with an elevated risk profile when undergoing surgery. Proper preparation and management of modifiable risk factors can optimize outcomes in diabetics. A multidisciplinary approach to preoperative optimization, including surgeons, primary care providers, and anesthesiologists, ensures diabetic patients receive comprehensive evaluation before elective surgery.

Adductor Canal Nerve Block versus Intra-articular Anesthetic in Knee Arthroscopy: A Single-Blinded Prospective Randomized Trial.

Effective perioperative pain control following knee arthroscopy allows patients to reduce narcotic intake, avoid side effects of these medications, and recover more quickly. Adductor canal nerve blockade (ACB) and intra-articular injection of local anesthetic have been described as adjuvant treatments for postoperative pain control following surgery of the knee. This study directly compares the effect of each of these treatment modalities.

Bone cutting efficiency and heat generation using a traditional fluted Burr and a novel fluteless resurfacing tool.

Background: Powered instrumentation is often used for bone preparation and/or removal in many orthopaedic procedures but does risk thermogenesis. This study compares biomechanical properties of a fluted burr and a novel fluteless resurfacing tool.

Methods: Twenty cadaveric metatarsals were tested with four predetermined cutting forces to evaluate heat generation and cutting rate for the fluted burr and fluteless resurfacing tool over 40 s or until a depth of 4 mm was reached.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs.