Production of 1,3-propanediol from glycerol under haloalkaline conditions by halanaerobium hydrogeniformans

With increased demands around the world to make modern lifestyles more environmentally friendly, the chemical commodity market has rapidly shifted. Through new technologies in chemical production, certain high value products have oversaturated the market and have become high-volume, low value waste products. The expansion of biodiesel production offers a prime example; high volumes of glycerol byproduct from this process have shifted glycerol from a high priced commodity to a common waste product. A number of microorganisms are known to synthesize the polymeric precursor 1,3-propanediol from glycerol; however, crude glycerol from biodiesel production creates a harsh environment for most microbes, and must go through expensive pre-treatment steps to lower alkaline pH values and salt concentrations before it can be considered a suitable feedstock. Halanaerobium hydrogeniformans has been identified to convert glycerol into 1,3-propanediol under haloalkaline conditions. Samples were grown over five days at pH 11 and at 7% (w/v) NaCL. The growth medium was amended with vitamin B12 to stimulate 1,3-propanediol production. HPLC analysis indicated statistically significant production of 1,3-propanediol, with the vitamin B12 amended bottles having a significant increase in 1,3-propanediol production compared to glycerol-only cultures. Data indicated a 0.6mol/mol conversion for vitamin B12 amended samples, while glycerol-only cultures had a conversion rate of 0.32mol/mol. H. hydrogeniformans, and potentially other haloalkaliphilic bacteria, provides a unique opportunity to develop new chemical processes that can overcome traditional problems and increase profitability by reducing the need for pH neutralization and dilution of residual salts in wastes such as crude glycerol --Abstract, page iv

Conversion of Glycerol to 1,3-propanediol under Haloalkaline Conditions

A method of producing 1,3-propanediol. The method comprises fermenting a haloalkaliphilic species of Halanaerobium with a source of glycerol into 1,3-propanediol, at a pH of greater than about 10 and at a salt concentration of greater than about 5% w/v. Furthermore, with supplementation of vitamin B12, the yield of 1,3-propanediol to glycerol can be increased

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Enantio- and Diastereoselective Synthesis of <i>syn</i>-β-Hydroxy-α-vinyl Carboxylic Esters via Reductive Aldol Reactions of Ethyl Allenecarboxylate with 10-TMS-9-Borabicyclo[3.3.2]decane and DFT Analysis of the Hydroboration Pathway

An enantio- and diastereoselective synthesis of <i>syn</i>-β-hydroxy-α-vinyl carboxylate esters <b>3</b> via the reductive aldol reaction of ethyl allenecarboxylate (<b>2</b>) with 10-trimethylsilyl-9-borabicyclo[3.3.2]decane (<b>1R</b>) has been developed. Density functional theory calculations suggest that the allene hydroboration involves the 1,4-reduction of <b>2</b> with the <b>1R</b>, leading directly to dienolborinate <i>Z</i>-(O)-<b>8a</b>

Casein Kinase 1δ Is an APC/CCdh1 Substrate that Regulates Cerebellar Granule Cell Neurogenesis

SummaryAlthough casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1) ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target