MendelianRandomization v0.5.0: updates to an R package for performing Mendelian randomization analyses using summarized data.

The MendelianRandomization package is a software package written for the R software environment that implements methods for Mendelian randomization based on summarized data. In this manuscript, we describe functions that have been added to the package or updated in recent years. These features can be divided into four categories: robust methods for Mendelian randomization, methods for multivariable Mendelian randomization, functions for data visualization, and the ability to load data into the package seamlessly from the PhenoScanner web-resource. We provide examples of the graphical output produced by the data visualization commands, as well as syntax for obtaining suitable data and performing a Mendelian randomization analysis in a single line of code

Comparative Genomics and Transcriptional Analysis of Prophages Identified in the Genomes of Lactobacillus gasseri, Lactobacillus salivarius, and Lactobacillus casei

Lactobacillus gasseri ATCC 33323, Lactobacillus salivarius subsp. salivarius UCC 118, and Lactobacillus casei ATCC 334 contain one (LgaI), four (Sal1, Sal2, Sal3, Sal4), and one (Lca1) distinguishable prophage sequences, respectively. Sequence analysis revealed that LgaI, Lca1, Sal1, and Sal2 prophages belong to the group of Sfi11-like pac site and cos site Siphoviridae, respectively. Phylogenetic investigation of these newly described prophage sequences revealed that they have not followed an evolutionary development similar to that of their bacterial hosts and that they show a high degree of diversity, even within a species. The attachment sites were determined for all these prophage elements; LgaI as well as Sal1 integrates in tRNA genes, while prophage Sal2 integrates in a predicted arginino-succinate lyase-encoding gene. In contrast, Lca1 and the Sal3 and Sal4 prophage remnants are integrated in noncoding regions in the L. casei ATCC 334 and L. salivarius UCC 118 genomes. Northern analysis showed that large parts of the prophage genomes are transcriptionally silent and that transcription is limited to genome segments located near the attachment site. Finally, pulsed-field gel electrophoresis followed by Southern blot hybridization with specific prophage probes indicates that these prophage sequences are narrowly distributed within lactobacilli

A protein–leucine supplement increases branched-chain amino acid and nitrogen turnover but not performance

Purpose: This study aimed to determine the effect of postexercise protein–leucine coingestion with CHO–lipid on subsequent high-intensity endurance performance and to investigate candidate mechanisms using stable isotope methods and metabolomics. Methods: In this double-blind, randomized, crossover study, 12 male cyclists ingested a leucine/protein/CHO/fat supplement (LEUPRO 7.5/20/89/22 g·h−1, respectively) or isocaloric CHO/fat control (119/22 g·h−1) 1–3 h after exercise during a 6-d training block (intense intervals, recovery, repeated-sprint performance rides). Daily protein intake was clamped at 1.9 g·kg−1·d−1 (LEUPRO) and 1.5 g·kg−1·d−1 (control). Stable isotope infusions (1-13C-leucine and 6,6-2H2-glucose), mass spectrometry–based metabolomics, and nitrogen balance methods were used to determine the effects of LEUPRO on whole-body branched-chain amino acid (BCAA) and glucose metabolism and protein turnover. Results: After exercise, LEUPRO increased BCAA levels in plasma (2.6-fold; 90% confidence limits = ×/÷1.1) and urine (2.8-fold; ×/÷1.2) and increased products of BCAA metabolism plasma acylcarnitine C5 (3.0-fold; ×/÷0.9) and urinary leucine (3.6-fold; ×/÷1.3) and β-aminoisobutyrate (3.4-fold; ×/÷1.4), indicating that ingesting ∼10 g leucine per hour during recovery exceeds the capacity to metabolize BCAA. Furthermore, LEUPRO increased leucine oxidation (5.6-fold; ×/÷1.1) and nonoxidative disposal (4.8-fold; ×/÷1.1) and left leucine balance positive relative to control. With the exception of day 1 (LEUPRO = 17 ± 20 mg N·kg−1, control = −90 ± 44 mg N·kg−1), subsequent (days 2–5) nitrogen balance was positive for both conditions (LEUPRO = 130 ± 110 mg N·kg−1, control = 111 ± 86 mg N·kg−1). Compared with control feeding, LEUPRO lowered the serum creatine kinase concentration by 21%–25% (90% confidence limits = ±14%), but the effect on sprint power was trivial (day 4 = 0.4% ± 1.0%, day 6 = −0.3% ± 1.0%). Conclusions: Postexercise protein–leucine supplementation saturates BCAA metabolism and attenuates tissue damage, but effects on subsequent intense endurance performance may be inconsequential under conditions of positive daily nitrogen balance

Measuring cognitive complaints in breast cancer survivors: psychometric properties of the patient’s assessment of own functioning inventory

PURPOSE: Cognitive complaints are a concern for breast cancer survivors. Among various published measures for cognitive complaints, the Patient’s Assessment of Own Functioning Inventory (PAOFI) is one of the few assessing a spectrum of cognitive abilities, including those most commonly reported by breast cancer survivors. This study aimed to examine the psychometric properties of the PAOFI in breast cancer survivors. METHODS: An exploratory factor analysis was conducted with a sample of breast cancer survivors (n=189) who had completed all primary cancer treatments. Construct validity was examined by correlating factor scores with valid measures of cognitive complaints, fatigue, and quality of life. Reliability was measured by internal consistency of the items in each factor within this sample, a separate sample of breast cancer survivors with high persistent cognitive complaints (n=72), and healthy controls (n=63). Factor scores were compared across the three samples. RESULTS: A five-factor structure similar to the PAOFI standardization study was found, with factors related to executive functioning (accounting for most of the variance), two aspects of memory functioning, language, motor/sensory-perceptual abilities. Factor scores highly correlated with measures of cognitive complaints, fatigue, and quality of life. Executive functioning and memory-related factors achieved adequate reliability across samples. Scores were significantly different across the three samples as expected. CONCLUSIONS: The PAOFI is a reliable and valid tool for measuring cognitive complaints in breast cancer survivors

Effect of post-exercise protein–leucine feeding on neutrophil function, immunomodulatory plasma metabolites and cortisol during a 6-day block of intense cycling

Whey protein and leucine ingestion following exercise increases muscle protein synthesis and could influence neutrophil function during recovery from prolonged intense exercise. We examined the effects of whey protein and leucine ingestion post-exercise on neutrophil function and immunomodulators during a period of intense cycling. In a randomized double-blind crossover, 12 male cyclists ingested protein/leucine/carbohydrate/fat (LEUPRO 20/7.5/89/22 g h−1, respectively) or isocaloric carbohydrate/fat control (CON 119/22 g h−1) beverages for 1–3 h post-exercise during 6 days of high-intensity training. Blood was taken pre- and post-exercise on days 1, 2, 4 and 6 for phorbol myristate acetate (PMA)-stimulated neutrophil superoxide (O2 −) production, immune cell counts, amino acid and lipid metabolism via metabolomics, hormones (cortisol, testosterone) and cytokines (interleukin-6, interleukin-10). During recovery on day 1, LEUPRO ingestion increased mean concentrations of plasma amino acids (glycine, arginine, glutamine, leucine) and myristic acid metabolites (acylcarnitines C14, myristoylcarnitine; and C14:1-OH, hydroxymyristoleylcarnitine) with neutrophil priming capacity, and reduced neutrophil O2 production (15–17 mmol O2 − cell−1 ± 90 % confidence limits 20 mmol O2 − cell−1). On day 2, LEUPRO increased pre-exercise plasma volume (6.6 ± 3.8 %) but haematological effects were trivial. LEUPRO supplementation did not substantially alter neutrophil elastase, testosterone, or cytokine concentrations. By day 6, however, LEUPRO reduced pre-exercise cortisol 21 % (±15 %) and acylcarnitine C16 (palmitoylcarnitine) during exercise, and increased post-exercise neutrophil O2 − (33 ± 20 mmol O2 − cell−1), relative to control. Altered plasma amino acid and acylcarnitine concentrations with protein–leucine feeding might partly explain the acute post-exercise reduction in neutrophil function and increased exercise-stimulated neutrophil oxidative burst on day 6, which could impact neutrophil-dependent processes during recovery from intense training

Design and Synthesis of Novel and Selective Glycine Transporter‑1 (GlyT1) Inhibitors with Memory Enhancing Properties

We report here the identification and optimization of a novel series of potent GlyT1 inhibitors. A ligand design campaign that utilized known GlyT1 inhibitors as starting points led to the identification of a novel series of pyrrolo­[3,4-<i>c</i>]­pyrazoles amides (<b>21</b>–<b>50</b>) with good in vitro potency. Subsequent optimization of physicochemical and in vitro ADME properties produced several compounds with promising pharmacokinetic profiles. In vivo inhibition of GlyT1 was demonstrated for select compounds within this series by measuring the elevation of glycine in the cerebrospinal fluid (CSF) of rats after a single oral dose of 10 mg/kg. Ultimately, an optimized lead, compound <b>46</b>, demonstrated in vivo efficacy in a rat novel object recognition (NOR) assay after oral dosing at 0.1, 1, and 3 mg/kg