Human gut microbiome is a promising target for managing type 2 diabetes (T2D). Measures altering gut microbiota like oral intake of probiotics or berberine (BBR), a bacteriostatic agent, merit metabolic homoeostasis. We hence conducted a randomized, double-blind, placebo-controlled trial with newly diagnosed T2D patients from 20 centres in China. Four-hundred-nine eligible participants were enroled, randomly assigned (1:1:1:1) and completed a 12-week treatment of either BBR-alone, probiotics+BBR, probiotics-alone, or placebo, after a one-week run-in of gentamycin pretreatment. The changes in glycated haemoglobin, as the primary outcome, in the probiotics+BBR (least-squares mean [95% CI], −1.04[−1.19, −0.89]%) and BBR-alone group (−0.99[−1.16, −0.83]%) were significantly greater than that in the placebo and probiotics-alone groups (−0.59[−0.75, −0.44]%, −0.53[−0.68, −0.37]%, P < 0.001). BBR treatment induced more gastrointestinal side effects. Further metagenomics and metabolomic studies found that the hypoglycaemic effect of BBR is mediated by the inhibition of DCA biotransformation by Ruminococcus bromii. Therefore, our study reports a human microbial related mechanism underlying the antidiabetic effect of BBR on T2D. (Clinicaltrial.gov Identifier: NCT02861261).

The PAH1-encoded phosphatidate (PA) phosphatase in Saccharomyces cerevisiae is a pivotal enzyme that produces diacylglycerol for the synthesis of triacylglycerol (TAG) and simultaneously controls the level of PA used for phospholipid synthesis. Quantitative lipid analysis showed that the pah1⌬ mutation caused a reduction in TAG mass and an elevation in the mass of phospholipids and free fatty acids, changes that were more pronounced in the stationary phase. The levels of unsaturated fatty acids in the pah1⌬ mutant were unaltered, although the ratio of palmitoleic acid to oleic acid was increased with a similar change in the fatty acid composition of phospholipids. The pah1⌬ mutant exhibited classic hallmarks of apoptosis in stationary phase and a marked reduction in the quantity of cytoplasmic lipid droplets. Cells lacking PA phosphatase were sensitive to exogenous fatty acids in the order of toxicity palmitoleic acid > oleic acid > palmitic acid. In contrast, the growth of wild type cells was not inhibited by fatty acid supplementation. In addition, wild type cells supplemented with palmitoleic acid exhibited an induction in PA phosphatase activity and an increase in TAG synthesis. Deletion of the DGK1-encoded diacylglycerol kinase, which counteracts PA phosphatase in controlling PA content, suppressed the defect in lipid droplet formation in the pah1⌬ mutant. However, the sensitivity of the pah1⌬ mutant to palmitoleic acid was not rescued by the dgk1⌬ mutation. Overall, these findings indicate a key role of PA phosphatase in TAG synthesis for protection against fatty acid-induced toxicity.PA 2 phosphatase (EC 3.1.3.4), which was first discovered by Kennedy and co-workers (1) in 1957, catalyzes the dephosphorylation of PA to produce DAG and P i (1) (Fig. 1). The reaction is dependent on Mg 2ϩ ions and is based on a DXDX(T/V) catalytic motif within a haloacid dehalogenase-like domain in the enzyme (2-4). 3 The DAG produced by PA phosphatase is used for the synthesis of TAG and for the synthesis of PE and PC via the Kennedy pathway (4 -7) (Fig. 1). PA, the enzyme substrate, is utilized for the synthesis of phospholipids via the liponucleotide intermediate CDP-DAG (7) (Fig. 1). Moreover, both PA (e.g. activation of cell growth, membrane proliferation, transcription, and vesicular trafficking) and DAG (e.g. activation of protein kinase C) have lipid signaling functions (8 -17), and PA phosphatase plays a role in controlling their cellular concentrations (2, 18). Thus, it is generally recognized that PA phosphatase is a key regulatory enzyme for controlling lipid metabolism and cell physiology (4, 7, 19 -21).The biochemistry and physiological roles of PA phosphatase emanated from studies in the model eukaryote yeast Saccharomyces cerevisiae and latterly in mammalian cells (4,7,19,21,22). PA phosphatase was first purified and characterized from yeast in 1989 (23), and the PAH1 4 gene encoding the enzyme was identified in 2006 (2). The discovery that PAH1 encodes PA phosphatase in yeast led to the revelation that the ...

Supplementary data are available at Bioinformatics online.

Motivation: Principal component analysis (PCA) is a crucial step in quality control of genomic data and a common approach for understanding population genetic structure. With the advent of large genotyping studies involving hundreds of thousands of individuals, standard approaches are no longer computationally feasible. We present FlashPCA2, a tool that can perform PCA on 1 million individuals faster than competing approaches, while requiring substantially less memory.