The Effect of Depression on Total Knee Arthroplasty.

Introduction: Depression is among the most common mental illnesses, with an estimated 8.1% of adults in the United States living with the condition. Despite its prevalence, the effect of depression on surgical outcomes is not well studied.

Predictive modeling of atmospheric nuclear fallout microphysics.

The capability to predict size, composition, and transport of nuclear fallout enables public officials to determine immediate and prolonged guidance in the event of a nuclear incident. Predictive computer models of fallout can also provide useful insight for nuclear forensic response when detailed radiochemical processes can be reliably included. Current post-detonation nuclear fallout models prescribe particle size distributions empirically or semi-empirically, based on measurements across limited conditions pertaining to tests conducted primarily in Nevada and the Pacific.

The Impact of Cardiac Arrhythmias on Total Knee Arthroplasty Outcomes.

Background: Cardiac comorbidities are common in patients undergoing total knee arthroplasty (TKA). While there is an abundance of research showing an association between cardiac abnormalities and poor postoperative outcomes, relatively little is published on specific pathologies. The aim of this study was to assess the impact of cardiac arrhythmias on postoperative outcomes in the setting of TKA.

Metabolomic profiles of intact tissues reflect clinically relevant prostate cancer subtypes.

Background: Prostate cancer (PC) is a heterogenous multifocal disease ranging from indolent to lethal states. For improved treatment-stratification, reliable approaches are needed to faithfully differentiate between high- and low-risk tumors and to predict therapy response at diagnosis.

Methods: A metabolomic approach based on high resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) analysis was applied on intact biopsies samples (n = 111) obtained from patients (n = 31) treated by prostatectomy, and combined with advanced multi- and univariate statistical analysis methods to identify metabolomic profiles reflecting tumor differentiation (Gleason scores and the International Society of Urological Pathology (ISUP) grade) and subtypes based on tumor immunoreactivity for Ki67 (cell proliferation) and prostate specific antigen (PSA, marker for androgen receptor activity).

A partial human LCK defect causes a T cell immunodeficiency with intestinal inflammation.

Lymphocyte-specific protein tyrosine kinase (LCK) is essential for T cell antigen receptor (TCR)-mediated signal transduction. Here, we report two siblings homozygous for a novel LCK variant (c.1318C>T; P440S) characterized by T cell lymphopenia with skewed memory phenotype, infant-onset recurrent infections, failure to thrive, and protracted diarrhea.

Examining the effects of soil entrainment during nuclear cloud rise on fallout predictions using a multiscale atmospheric modeling framework.

Current operational models for nuclear cloud rise over land were developed and validated using observations from shallow-buried or surface detonations, where lofted soil quickly mixed with fission products from the detonation. These models poorly predict fallout from elevated detonations near the fallout-free height of burst (FFHOB), where interactions with the ground are limited and the mixing of fission products and lofted soil is incomplete. Fallout-free is a misnomer at this HOB, as fallout was observed in these cases, but was below the levels of concern, especially off-grounds of the nuclear test site.

Point Mutations in TbpA Abrogate Human Transferrin Binding in Neisseria gonorrhoeae.

TonB-dependent transporters (TDTs) are essential proteins for metal acquisition, an important step in the growth and pathogenesis of many pathogens, including Neisseria gonorrhoeae, the causative agent of gonorrhea. There is currently no available vaccine for gonorrhea; TDTs are being investigated as vaccine candidates because they are highly conserved and expressed . Transferrin binding protein A (TbpA) is an essential virulence factor in the initiation of experimental infection in human males and functions by acquiring iron upon binding to host transferrin (human transferrin [hTf]).

Modeling intermediates of BamA folding an outer membrane protein.

BamA, the core component of the β-barrel assembly machinery complex, is an integral outer-membrane protein (OMP) in Gram-negative bacteria that catalyzes the folding and insertion of OMPs. A key feature of BamA relevant to its function is a lateral gate between its first and last β-strands. Opening of this lateral gate is one of the first steps in the asymmetric-hybrid-barrel model of BamA function.

A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B.

Recent reports of antiepileptic activity of the fungal alkaloid TMC-120B have renewed the interest in this natural product. Previous total syntheses of TMC-120B comprise many steps and have low overall yields (11-17 steps, 1.5-2.

Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM.

In Gram-negative bacteria, the biogenesis of β-barrel outer membrane proteins is mediated by the β-barrel assembly machinery (BAM). The mechanism employed by BAM is complex and so far- incompletely understood. Here, we report the structures of BAM in nanodiscs, prepared using polar lipids and native membranes, where we observe an outward-open state.

Fragment-Based Drug Discovery for RNA Targets.

Rapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR spectroscopy, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small-molecule RNA binders provides an overview on both the currently limited guidelines within RNA-targeting fragment library design, and future possibilities.

Structure Determination of Membrane Proteins Using X-Ray Crystallography.

Membrane proteins serve essential roles in all aspects of life and make up roughly one-third of all genomes from prokaryotes to eukaryotes. Their responsibilities include mediating cell signaling, nutrient import, waste export, cellular communication, trafficking, and immunity. For their critical role in many cellular processes, membrane proteins serve as targets for up to 50% of drugs currently on the market and remain primary targets in new therapeutics being developed.

Clinical Pathways of Patients Denied Total Knee Arthroplasty Due to an Institutional BMI Cutoff.

Out of concern for the increased risk of complications with morbid obesity, institutional body mass index (BMI) cutoffs for total knee arthroplasty (TKA) have become commonplace. We sought to answer the questions: what percentage of morbidly obese patients with knee osteoarthritis who present to an arthroplasty clinic will, within 2 years, undergo TKA at (1) a BMI less than 40 kg/m or (2) at a BMI greater than 40 kg/m? Of those who do not undergo surgery, (3) what percentage lose enough weight to become TKA-eligible, and (4) what percentage do not? We performed an observational study of 288 patients, of which 256 had complete follow-up. Institutional electronic medical record review and patient follow-up by telephone were conducted to determine which patients underwent surgery, and at what BMI.

Presence of Incipient Fungal Infection in Atypical Squamous Lesions of the Lip.

Epidermal barrier disruption caused by atypical squamous proliferations of the lip (SOL) creates an ideal environment for fungal growth. Histologic features of SOL include parakeratosis overlying partial- or full-thickness keratinocyte atypia with or without invasion of the dermis, dermal solar elastosis, and scattered inflammatory cells which are predominantly lymphocytes. Histologic features of SOL with fungal superinfections overlap those seen in primary fungal cheilitis with reactive atypia, creating a diagnostic challenge.

The assembly of β-barrel membrane proteins by BAM and SAM.

Gram-negative bacteria, mitochondria, and chloroplasts all possess an outer membrane populated with a host of β-barrel outer-membrane proteins (βOMPs). These βOMPs play crucial roles in maintaining viability of their hosts, and therefore, it is essential to understand the biogenesis of this class of membrane proteins. In recent years, significant structural and functional advancements have been made toward elucidating this process, which is mediated by the β-barrel assembly machinery (BAM) in Gram-negative bacteria, and by the sorting and assembly machinery (SAM) in mitochondria.

Incision site fat thickness and 90-day complications for direct anterior and posterior approach total hip arthroplasty.

Background: Defining the distribution of subcutaneous fat around the hip in relation to different approaches for total hip arthroplasty (THA) may lead to a better understanding of the relationship between obesity and complications. The purpose of this study was to: (1) describe the intraoperative thickness of subcutaneous fat at the incision site for direct anterior (DAA) and posterior approaches (PA) for THA; and (2) examine the relationship between fat thickness and 90-day postoperative complications.

Methods: Intraoperative fat measurements were obtained at the anterior incision site (AT-IS) of the DAA ( = 60) and the lateral incision site (LT-IS) of the PA ( = 64).

Structural insight into toxin secretion by contact-dependent growth inhibition transporters.

Bacterial contact-dependent growth inhibition (CDI) systems use a type Vb secretion mechanism to export large CdiA toxins across the outer membrane by dedicated outer membrane transporters called CdiB. Here, we report the first crystal structures of two CdiB transporters from and . CdiB transporters adopt a TpsB fold, containing a 16-stranded transmembrane β-barrel connected to two periplasmic domains.

Gene knockdown via electroporation of short hairpin RNAs in embryos of the marine hydroid Hydractinia symbiolongicarpus.

Analyzing gene function in a broad range of research organisms is crucial for understanding the biological functions of genes and their evolution. Recent studies have shown that short hairpin RNAs (shRNAs) can induce gene-specific knockdowns in two cnidarian species. We have developed a detailed, straightforward, and scalable method to deliver shRNAs into fertilized eggs of the hydrozoan cnidarian Hydractinia symbiolongicarpus via electroporation, yielding effective gene-targeted knockdowns that can last throughout embryogenesis.

Molecular Insight into TdfH-Mediated Zinc Piracy from Human Calprotectin by Neisseria gonorrhoeae.

, responsible for the sexually transmitted infection gonorrhea, is an obligate human pathogen exquisitely adapted for survival on mucosal surfaces of humans. This host-pathogen relationship has resulted in evolution by of pathways that enable the use of host metalloproteins as required nutrients through the deployment of outer membrane-bound TonB-dependent transporters (TdTs). Recently, a TdT called TdfH was implicated in binding to calprotectin (CP) and in removal of the bound zinc (Zn), enabling gonococcal growth.

Comprehensive metabolomics analysis of prostate cancer tissue in relation to tumor aggressiveness and TMPRSS2-ERG fusion status.

Background: Prostate cancer (PC) can display very heterogeneous phenotypes ranging from indolent asymptomatic to aggressive lethal forms. Understanding how these PC subtypes vary in their striving for energy and anabolic molecules is of fundamental importance for developing more effective therapies and diagnostics. Here, we carried out an extensive analysis of prostate tissue samples to reveal metabolic alterations during PC development and disease progression and furthermore between TMPRSS2-ERG rearrangement-positive and -negative PC subclasses.

BamA is required for autotransporter secretion.

Background: In Gram-negative bacteria, type Va and Vc autotransporters are proteins that contain both a secreted virulence factor (the "passenger" domain) and a β-barrel that aids its export. While it is known that the folding and insertion of the β-barrel domain utilize the β-barrel assembly machinery (BAM) complex, how the passenger domain is secreted and folded across the membrane remains to be determined. The hairpin model states that passenger domain secretion occurs independently through the fully-formed and membrane-inserted β-barrel domain via a hairpin folding intermediate.

Lymphoplasmacytic Granulomatosis Cheilitis Treated with Cheiloplasty.

Orofacial granulomatous (OFG) also known as granulomatous cheilitis, is a condition that causes the lips or mouth to become edematous due to a granulomatous inflammatory process. The underlying cause of the disease is unknown; however, it has been linked to other granulomatous pathologies, including sarcoidosis and Crohn's disease. Due to the lack of evidence regarding the etiology of OFG, treatment options vary depending on the symptoms associated with the presentation of OFG and patient medical history.

Presence of substrate aids lateral gate separation in LptD.

Lipopolysaccharides (LPS) provide the outer membrane (OM) of Gram-negative bacteria with a strong protective barrier. The periplasm-spanning Lpt machinery is responsible for the transport of LPS molecules across the periplasm, culminating in insertion by the outer-membrane proteins LptD and LptE. In order to elucidate the mechanisms of LPS insertion by LptDE, we performed over 14 microseconds of equilibrium molecular dynamics simulations.