Airways Abnormalities in a Prospective Cohort of Patients With Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) affects roughly 1% of the population and commonly involves the lungs. Of lung involvement in RA, interstitial lung disease (ILD) is well known; however, airways disease in RA is relatively understudied.

Research Question: What are the baseline airways abnormalities in a prospective cohort of patients with RA based on pulmonary function testing (PFT) results, high-resolution CT (HRCT) scans, and computational imaging analysis and are there associations between these abnormalities and respiratory symptoms?

Study Design And Methods: In this single-center study, 188 patients with RA without a clinical diagnosis of ILD underwent HRCT imaging and PFT.

BiliQML: a supervised machine-learning model to quantify biliary forms from digitized whole slide liver histopathological images.

The progress of research focused on cholangiocytes and the biliary tree during development and following injury is hindered by limited available quantitative methodologies. Current techniques include two-dimensional standard histological cell-counting approaches, which are rapidly performed, error prone, and lack architectural context or three-dimensional analysis of the biliary tree in opacified livers, which introduce technical issues along with minimal quantitation. The present study aims to fill these quantitative gaps with a supervised machine-learning model (BiliQML) able to quantify biliary forms in the liver of anti-keratin 19 antibody-stained whole slide images.

Site-Specific Dolasynthen Antibody-Drug Conjugates Exhibit Consistent Pharmacokinetic Profiles across a Wide Range of Drug-to-Antibody Ratios.

Key defining attributes of an antibody-drug conjugate (ADC) include the choice of the targeting antibody, linker, payload, and the drug-to-antibody ratio (DAR). Historically, most ADC platforms have used the same DAR for all targets, regardless of target characteristics. However, recent studies and modeling suggest that the optimal DAR can depend on target expression level and intratumoral heterogeneity, target internalization and trafficking, and characteristics of the linker and payload.

Quantifying the Effect of Body Habitus on Cardiac Auscultation Via Computational Hemoacoustics.

The effect of body habitus on auscultation of heart murmurs is investigated via computational hemoacoustic modeling. The source of the heart murmur is first obtained from a hemodynamic simulation of blood flow through a stenosed aortic valve. This sound source is then placed at the aortic valve location in four distinct human thorax models, and the propagation of the murmur in each thorax model is simulated by solving the elastic wave equations in the time-domain.

Determining the Stoichiometry of a Protein-Polymer Conjugate Using Multisignal Sedimentation Velocity Analytical Ultracentrifugation.

Advances in polymer science have broadened the applications of protein-polymer conjugates as biopharmaceuticals and biotechnology reagents. The complex nature of these conjugates makes characterization challenging. Here, we describe the use of multisignal sedimentation velocity analytical ultracentrifugation to measure the polymer-to-protein ratio.

Simultaneous quantification of total antibody and antibody-conjugated drug for XMT-1522 in human plasma using immunocapture-liquid chromatography/mass spectrometry.

XMT-1522, an antibody-drug conjugate (ADC) currently in Phase I clinical development, represents the first Dolaflexin®-based, cleavable ADC with a high drug-antibody ratio (DAR). In this work, a novel immunocapture LC-MS/MS method was successfully developed for the simultaneous quantification of both total antibody and cleavable antibody-conjugated drug auristatin F-hydroxypropylamide (AF-HPA) in human plasma. This method utilized microwave-assisted enzymatic digestion for the total antibody and chemical release of the drug from ADC on a 96-well based immunocapture sample preparation platform.

A Cardiology Exhibit at a Science Museum, Viewed as Speech Acts in Sequence.

An exhibit about cardiology at a science museum is an elaborate form of health communication, with messaging happening across text, pictures, models, and videos. This qualitative case study uses concepts of speech act sequencing and interpellation to explain a series of multimodal exhibits about cardiovascular health. Health exhibits are described as verbal and audiovisual arguments combining assertions of information; directives to change behavior, and designations of risk candidacy-or sequences of assertive, directive, and declarative speech acts.

Detection of Alkynes via Click Chemistry with a Brominated Coumarin Azide by Simultaneous Fluorescence and Isotopic Signatures in Mass Spectrometry.

Alkynes are a key component of click chemistry and used for a wide variety of applications including bioconjugation, selective tagging of protein modifications, and labeling of metabolites and drug targets. However, challenges still exist for detecting alkynes because most 1,2,3-triazole products from alkynes and azides do not possess distinct intrinsic properties that can be used for their facile detection by either fluorescence or mass spectrometry. To address this critical need, a novel brominated coumarin azide was used to tag alkynes and detect alkyne-conjugated biomolecules.

Discovery at the interface: Toward novel anti-proliferative agents targeting human estrogen receptor/S100 interactions.

Estrogen Receptor Alpha (ER) is expressed in about 70% of breast cancer and mediates various cellular signaling events including cell cycle. The antiestrogen tamoxifen is currently administered to patients in order to induce regression of the tumor growth of estrogen receptor positive (ER+) breast cancer. However, upon continued administration, patients develop resistance to tamoxifen.

Parallel Pbx-Dependent Pathways Govern the Coalescence and Fate of Motor Columns.

The clustering of neurons sharing similar functional properties and connectivity is a common organizational feature of vertebrate nervous systems. Within motor networks, spinal motor neurons (MNs) segregate into longitudinally arrayed subtypes, establishing a central somatotopic map of peripheral target innervation. MN organization and connectivity relies on Hox transcription factors expressed along the rostrocaudal axis; however, the developmental mechanisms governing the orderly arrangement of MNs are largely unknown.

Hox Proteins Coordinate Motor Neuron Differentiation and Connectivity Programs through Ret/Gfrα Genes.

The accuracy of neural circuit assembly relies on the precise spatial and temporal control of synaptic specificity determinants during development. Hox transcription factors govern key aspects of motor neuron (MN) differentiation; however, the terminal effectors of their actions are largely unknown. We show that Hox/Hox cofactor interactions coordinate MN subtype diversification and connectivity through Ret/Gfrα receptor genes.

A T cell extrinsic mechanism by which IL-2 dampens Th17 differentiation.

Genetic variants in il2 and il2ra have been associated with autoimmune disease susceptibility in both genome-wide association studies (GWAS) in humans and in genetic linkage studies in experimental models of autoimmunity. Specifically, genetic variants resulting in a low IL-2 phenotype are susceptibility alleles while variants resulting in a high IL-2 phenotype are resistance alleles. The association of high IL-2 phenotypes with resistance has been attributed primarily to the T cell intrinsic promotion of regulatory T cell development, maintenance, and function; however, IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells.

Biologically inspired strategy for programmed assembly of viral building blocks with controlled dimensions.

Facile fabrication of building blocks with precisely controlled dimensions is imperative in the development of functional devices and materials. We demonstrate the assembly of nanoscale viral building blocks of controlled lengths using a biologically motivated strategy. To achieve this we exploit the simple self-assembly mechanism of Tobacco mosaic virus (TMV), whose length is solely governed by the length of its genomic mRNA.

A transgenic model of central nervous system autoimmunity mediated by CD4+ and CD8+ T and B cells.

Experimental autoimmune encephalomyelitis (EAE) is a widely used model of multiple sclerosis. In NOD mice, EAE develops as a relapsing-remitting disease that transitions to a chronic progressive disease, making the NOD model the only mouse model that recapitulates the full clinical disease course observed in most multiple sclerosis patients. We have generated a TCR transgenic mouse that expresses the α- and β-chains of a myelin oligodendrocyte glycoprotein (MOG) 35-55-reactive TCR (1C6) on the NOD background.

Differential IL-21 signaling in APCs leads to disparate Th17 differentiation in diabetes-susceptible NOD and diabetes-resistant NOD.Idd3 mice.

Type 1 diabetes (T1D) is an autoimmune disease that shows familial aggregation in humans and likely has genetic determinants. Disease linkage studies have revealed many susceptibility loci for T1D in mice and humans. The mouse T1D susceptibility locus insulin-dependent diabetes susceptibility 3 (Idd3), which has a homologous genetic interval in humans, encodes cytokine genes Il2 and Il21 and regulates diabetes and other autoimmune diseases; however, the cellular and molecular mechanisms of this regulation are still being elucidated.

INK4a deletion results in improved kidney regeneration and decreased capillary rarefaction after ischemia-reperfusion injury.

The molecular mechanisms that lead to tubular atrophy, capillary loss, and fibrosis following acute kidney injury are not very clear but may involve cell cycle inhibition by increased expression of cyclin kinase inhibitors. The INK4a/ARF locus encodes overlapping genes for two proteins, a cyclin kinase inhibitor, p16(INK4a), and a p53 stabilizer, p19(ARF), from independent promoters. To determine if decreased INK4a gene expression results in improved kidney regeneration, INK4a knockout (KO) and wild-type (WT) mice were subjected to ischemia-reperfusion injury (IRI).

Chemical activation of MEK1--a redox trigger for evaluating the effects of phosphorylation.

An approach to generate mimics of phosphorylated serine proteins chemically through site-specific sulfonation of cysteine is presented. This chemical modification is reversible in the presence of reducing agent and therefore is analogous to the kinase/phosphatase system used in nature.

Comparability analysis of protein therapeutics by bottom-up LC-MS with stable isotope-tagged reference standards.

Comparability studies lie at the heart of assessments that evaluate differences amongst manufacturing processes and stability studies of protein therapeutics. Low resolution chromatographic and electrophoretic methods facilitate quantitation, but do not always yield detailed insight into the effect of the manufacturing change or environmental stress. Conversely, mass spectrometry (MS) can provide high resolution information on the molecule, but conventional methods are not very quantitative.

INK4a knockout mice exhibit increased fibrosis under normal conditions and in response to unilateral ureteral obstruction.

The INK4a proteins p16(INK4a) and p19(ARF) regulate cell cycle arrest and senescence. However, the role of these proteins in controlling these processes in the normal kidney and following injury is unknown. We performed unilateral ureteral obstruction (UUO) to induce fibrosis in 2- to 3-mo-old wild-type (WT) C57/B6 and INK4a knockout mice.

Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells.

IFN-gamma plays a central role in antitumor immunity. T cell Ig and mucin domain (Tim-3) is expressed on IFN-gamma-producing Th1 cells; on interaction with its ligand, galectin-9, Th1 immunity is terminated. In this study, we show that transgenic overexpression of Tim-3 on T cells results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis.

Background: The clinical value of antibiotic prophylaxis in preventing Lyme disease remains uncertain, owing to a meta-analysis lacking sufficient power to demonstrate efficacy and a more recent trial showing effectiveness but lacking precision. Our objective was to update our prior meta-analysis on antibiotic prophylaxis for the prevention of Lyme disease, to obtain a more precise estimate of treatment effect.

Methods: Clinical trials were identified by searching MEDLINE, Embase, the Cochrane Library and trial registries, and by an assessment of the bibliographies of retrieved articles and reviews.

T-bet, a Th1 transcription factor regulates the expression of Tim-3.

T-cell immunoglobulin, mucin domain-3 (Tim-3) is a membrane protein expressed at late stages of IFN-gamma secreting CD4(+) Th1 cell differentiation and constitutively on DC. Ligation of Tim-3 on Th1 cells terminates Th1 immune responses. In addition, Tim-3 plays a role in tolerance induction, although the mechanism by which this is accomplished has yet to be elucidated.

Cutting edge: the Idd3 genetic interval determines regulatory T cell function through CD11b+CD11c- APC.

The Idd3 genetic interval confers protection against multiple autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis. The favored candidate gene in this interval is Il2, which is polymorphic between susceptible and resistant strains of mice. IL-2 regulates the growth/death of effector T cells as well as the generation/maintenance of regulatory T cells (Tregs), and recent studies have shown that NOD.

The oligomeric structure of high molecular weight adiponectin.

There is great interest in the structure of adiponectin as its oligomeric state may specify its biological activities. It occurs as a trimer, a hexamer and a high molecular weight complex. Epidemiological data indicate that the high molecular weight form is significant with low serum levels in type 2 diabetics but to date, has not been well-defined.