Pharmacogenomics-Driven Prediction of Antidepressant Treatment Outcomes: A Machine-Learning Approach With Multi-trial Replication.

We set out to determine whether machine learning-based algorithms that included functionally validated pharmacogenomic biomarkers joined with clinical measures could predict selective serotonin reuptake inhibitor (SSRI) remission/response in patients with major depressive disorder (MDD). We studied 1,030 white outpatients with MDD treated with citalopram/escitalopram in the Mayo Clinic Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS; n = 398), Sequenced Treatment Alternatives to Relieve Depression (STAR*D; n = 467), and International SSRI Pharmacogenomics Consortium (ISPC; n = 165) trials. A genomewide association study for PGRN-AMPS plasma metabolites associated with SSRI response (serotonin) and baseline MDD severity (kynurenine) identified single nucleotide polymorphisms (SNPs) in DEFB1, ERICH3, AHR, and TSPAN5 that we tested as predictors.

Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in .

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase () that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy.

Non-equilibrium landscape and flux reveal how the central amygdala circuit gates passive and active defensive responses.

Uncovering the underlying physical principles of biology is important for understanding the biological function yet challenging. Take an example, the animals' defensive systems are very effective to threats. However, the underlying physical mechanisms are still unclear.

Electromechanical vibration of microtubules and its application in biosensors.

An electric field (EF) has the potential to excite the vibration of polarized microtubules (MTs) and thus enable their use as a biosensor for the biophysical properties of MTs or cells. To facilitate the development, this paper aims to capture the EF-induced vibration modes and the associated frequency for MTs. The analyses were carried out based on a molecular structural mechanics model accounting for the structural details of MTs.

Modulation of TARP 8-Containing AMPA Receptors as a Novel Therapeutic Approach for Chronic Pain.

Nonselective glutamate -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists are efficacious in chronic pain but have significant tolerability issues, likely arising from the ubiquitous expression of AMPA receptors in the central nervous system (CNS). Recently, LY3130481 has been shown to selectively block AMPA receptors coassembled with the auxiliary protein, transmembrane AMPA receptor regulatory protein (TARP) 8, which is highly expressed in the hippocampus but also in pain pathways, including anterior cingulate (ACC) and somatosensory cortices and the spinal cord, suggesting that selective blockade of 8/AMPA receptors may suppress nociceptive signaling with fewer CNS side effects. The potency of LY3130481 on recombinant 8-containing AMPA receptors was modulated by coexpression with other TARPs; 2 subunits affected activity more than 3 subunits.

Comparative genomic analysis of 127 Escherichia coli strains isolated from domestic animals with diarrhea in China.

Background: Escherichia coli is an important pathogen that causes diarrhea in both humans and animals. To determine the relationships between putative virulence factors and pathotypes or host taxa, many molecular studies on diarrhea-associated E. coli have been reported.

Graphical Depiction of Longitudinal Study Designs in Health Care Databases.

Pharmacoepidemiologic and pharmacoeconomic analysis of health care databases has become a vital source of evidence to support health care decision making and efficient management of health care organizations. However, decision makers often consider studies done in nonrandomized health care databases more difficult to review than randomized trials because many design choices need to be considered. This is perceived as an important barrier to decision making about the effectiveness and safety of medical products.

PEEK surface modification by fast ambient-temperature sulfonation for bone implant applications.

We develop a simple, fast and economical surface treatment under ambient temperature to improve the hydrophilicity and osteoconductivity of polyetheretherketone (PEEK) for bone implant applications. A major challenge in bone implants is the drastic difference in stiffness between traditional implant materials (such as titanium and stainless steel) and human bone. PEEK is biocompatible with an elastic modulus closely matching that of human bone, making it a highly attractive alternative.

Bioinspired polydopamine and polyphenol tannic acid functionalized titanium suppress osteoclast differentiation: a facile and efficient strategy to regulate osteoclast activity at bone-implant interface.

Osseointegration of metallic implants in porous osteoporotic bone remains a challenge. Surface modification of implants to reduce peri-implant osteoclastic bone resorption was explored in the study. Bioinspired polydopamine (pDOP) and polyphenol tannic acid (pTAN) are nature-derived universal coating systems that have emerged either as a sole coating or ad-layer for biomolecular conjugation on different biomaterials.

Accurate Patient-Specific Machine Learning Models of Glioblastoma Invasion Using Transfer Learning.

Background And Purpose: MR imaging-based modeling of tumor cell density can substantially improve targeted treatment of glioblastoma. Unfortunately, interpatient variability limits the predictive ability of many modeling approaches. We present a transfer learning method that generates individualized patient models, grounded in the wealth of population data, while also detecting and adjusting for interpatient variabilities based on each patient's own histologic data.

Time to Loading Dose and Risk of Recurrent Events in the SOCRATES Trial.

Background and Purpose- Recurrent ischemia risk is high in the acute period after cerebral ischemic events. Effects of antiplatelet agents may vary by time to loading dose (TLD). We explored the risk of recurrent events and safety and efficacy of ticagrelor versus aspirin in relation to TLD.

BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension.

Background: Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. BOLA3 (BolA Family Member 3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined.

Novel Paracrine Functions of Smooth Muscle Cells in Supporting Endothelial Regeneration Following Arterial Injury.

Rationale: Regeneration of denuded or injured endothelium is an important component of vascular injury response. Cell-cell communication between endothelial cells and smooth muscle cells (SMCs) plays a critical role not only in vascular homeostasis but also in disease. We have previously demonstrated that PKCδ (protein kinase C-delta) regulates multiple components of vascular injury response including apoptosis of SMCs and production of chemokines, thus is an attractive candidate for a role in SMC-endothelial cells communication.

Distribution of cerebral microbleeds in the East and West: Individual participant meta-analysis.

Objective: We investigated differences in the anatomical distribution of cerebral microbleeds (CMBs) on MRI, hypothesized to indicate the type of underlying cerebral small vessel disease (SVD), between Eastern and Western general populations.

Methods: We analyzed data from 11 studies identified by a PubMed search between 1996 and April 2014 according to the Preferred Reporting Items for a Systematic Review and Meta-analysis of Individual Participant Data. Study quality measures indicated low or medium risk of bias.

Spin current generation and relaxation in a quenched spin-orbit-coupled Bose-Einstein condensate.

Understanding the effects of spin-orbit coupling (SOC) and many-body interactions on spin transport is important in condensed matter physics and spintronics. This topic has been intensively studied for spin carriers such as electrons but barely explored for charge-neutral bosonic quasiparticles (including their condensates), which hold promises for coherent spin transport over macroscopic distances. Here, we explore the effects of synthetic SOC (induced by optical Raman coupling) and atomic interactions on the spin transport in an atomic Bose-Einstein condensate (BEC), where the spin-dipole mode (SDM, actuated by quenching the Raman coupling) of two interacting spin components constitutes an alternating spin current.

TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.

Purpose: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.

Methods: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes.

NHLBI-Sponsored Randomized Trial of Postconditioning During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction.

Rationale: Postconditioning at the time of primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit.

Objective: We performed the first National Heart, Lung, and Blood Institute-sponsored trial of postconditioning in the United States using strict enrollment criteria to optimize the early benefits of postconditioning and assess its long-term effects on left ventricular (LV) function.

Cost-Effectiveness of Transcatheter Versus Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Intermediate Risk.

Background: In patients with severe aortic stenosis (AS) at intermediate surgical risk, treatment with transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) results in similar rates of death or stroke at 2 years. Whether TAVR is cost-effective compared with SAVR for intermediate-risk patients remains uncertain.

Methods: Between 2011 and 2014, 3110 intermediate-risk AS patients were treated with TAVR or SAVR in the PARTNER 2 trial (Placement of Aortic Transcatheter Valves 2).

Computational Analysis of the Action of Chloroquine on Short QT Syndrome Variant 1 and Variant 3 in Human Ventricles.

Aims: The short QT syndrome (SQTS) is a rare genetic disorder associated with arrhythmias and sudden cardiac death (SCD). The SQTI and SQT3, SQTS variants, result from gain-of-function mutations (N588K and D172N, respectively) in the KCNH2-encoded and KCNJ2-encoded potassium channels, in which treatment with potassium channel blocking agents has demonstrated some efficacy. This study used in silico modelling to gain mechanistic insights into the actions of anti-malarial drug chloroquine (CQ) in the setting of SQTI and SQT3.

Broadly Neutralizing Antibody Mediated Clearance of Human Hepatitis C Virus Infection.

The role that broadly neutralizing antibodies (bNAbs) play in natural clearance of human hepatitis C virus (HCV) infection and the underlying mechanisms remain unknown. Here, we investigate the mechanism by which bNAbs, isolated from two humans who spontaneously cleared HCV infection, contribute to HCV control. Using viral gene sequences amplified from longitudinal plasma of the two subjects, we found that these bNAbs, which target the front layer of the HCV envelope protein E2, neutralized most autologous HCV strains.

Pillar versus dimple patterned surfaces for wettability and adhesion with varying scales.

Inspired by biological topographical surfaces, micropatterned elastomeric surfaces with square pillars and dimples of different geometry scales were fabricated. Their wettability and adhesion properties with various liquids were systematically investigated and compared with flat surfaces. Interesting results were obtained in the case of silicone oil (the toe-pad-like wetting case) in that the scale-dependent wettability and adhesion performed inversely for pillars and dimples.

Investigation on the Antibacterial and Anti-T3SS Activity of Traditional Myanmar Medicinal Plants.

Myanmar has a rich pool of, but less known, medicinal plants with traditional knowledge. In this study, we aimed to investigate the inhibitory activity of traditional Myanmar medicinal plants against the type III secretion system (T3SS) of serovar Typhimurium UK-1 8956 and the intestinal disease-caused by microbes including serovar Typhimurium UK-1 8956, CPCC 160013 CICC 10003, and ATCC 25923. The EtOH extracts of 93 samples were used to screen the inhibitory activities against the secretion of T3SS effector proteins SipA/B/C/D of and the antibacterial activity against , and Out of 71 crude drugs traditionally used, 18 were proofed to be effective either on the growth inhibition of tested bacteria and/or as inhibitors for the T3SS.

MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.

Background: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.

Methods: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.

Results: Analysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.