Porterhigh4383

The first systematic study of ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) on aryl α-chloro β-keto esters was performed, and 15 structurally diverse chiral anti-aryl α-chloro β-hydroxy esters were synthesized in 74-98% isolated yields, along with moderate-to-excellent diastereoselectivity (up to >99  1 dr) and good-to-excellent enantioselectivity (mostly >99% ee). LfSDR1-catalyzed complete reduction of 100 g L-1 of substrate 6b at a ten-gram scale was achieved with a continuous fed-batch strategy, affording anti-(2S,3S)-1b, the key intermediate of diltiazem, in a record-breaking space-time yield of 96 g L-1 d-1. An eight-step synthesis of diltiazem, clentiazem, and siratiazem was accomplished in 32-45% overall yields, featuring this versatile biocatalytic reduction reaction as well as an efficient, green chlorination reaction in flow.Protein profiling of major bovine milk proteins (i.e., whey and casein proteins) is of great interest in food science and technology. This complex set of protein proteoforms may vary with breed, genetics, lactation stage, health, and nutritional status of the animal. Current routine methods for bovine milk protein profiling at the intact level are typically based on capillary electrophoresis-ultraviolet, which does not allow confirming unequivocally the identity of the separated proteins. As an alternative, in this study, we describe for the first time a novel and simple capillary electrophoresis-mass spectrometry method in positive electrospray ionization mode. Under the optimized conditions, capillary electrophoresis-mass spectrometry allowed the separation and identification at the intact level of major bovine milk whey and casein proteins in less than 15 min. Furthermore, high-resolution mass spectrometry confirmed its importance in the reliable characterization of bovine milk protein proteoforms, especially those with slight molecular mass differences, such as β-casein A1 and A2, which are relevant to unequivocally identify milk with specific β-casein compositions (e.g., A2A2 milk, which is widely known as A2 milk). This differentiation was not possible by matrix-assisted laser desorption/ionization mass spectrometry, which provided rapidly and easily a rich but less accurate fingerprint of bovine milk proteins due to the lower mass resolution.Glucagon is a prominent peptide hormone, playing central roles in the regulation of glucose blood-level and lipid metabolism. Formation of glucagon amyloid fibrils has been previously reported, although no biological functions of such fibrils are known. Here, we demonstrate that glucagon amyloid fibrils catalyze biologically important reactions, including esterolysis, lipid hydrolysis, and dephosphorylation. In particular, we found that glucagon fibrils catalyze dephosphorylation of adenosine triphosphate (ATP), a core metabolic reaction in cell biology. Comparative analysis of several glucagon variants allowed mapping the catalytic activity to an enzymatic pocket-like triad formed at the glucagon fibril surface, comprising the histidyl-serine domain at the N-terminus of the peptide. This study may point to previously unknown physiological roles and pathological consequences of glucagon fibrillation and supports the hypothesis that catalytic activities of native amyloid fibrils play functional roles in human physiology and disease.The production of mannosylerythritol lipids (MELs) has been reported on different smut fungi. These biomolecules possess four typical conformations to which key commercially interesting properties have been attributed. In vivo, MEL production could only be explained by the chain-shortening pathway, a new route, unlike the main three fatty acid synthesis pathways described. The production of MELs requires nitrogen starvation and a carbon source, usually a fatty acid, the principals. The first MEL biosynthetic gene cluster was elucidated in U. maydis by the combination of different methodologies, which resulted in a reference genome, on which five genes comprising the MEL cluster were annotated. Subsequently, the evolution of DNA sequencing technologies advanced genome and transcriptome assembly, allowing the annotation of more MEL producers' genomes. These, in combination with different experimental techniques, coupled to bioinformatic methods offer a plethora of genomic resources for further manipulation and commercial exploitation. In this review, we present the main findings, which unraveled MEL production and multi-omics studies, leading to molecular tools for further genomic manipulation and exploitation in smut fungi.

The Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) conducted a retrospective study on the disease course and clinical management of ganglioneuromas.

Ganglioneuromas are rare tumors derived from neural crest cells. Data on these tumors remain limited to case reports and single-institution case series.

Patients of all ages with pathologically confirmed primary retroperitoneal, intra-abdominal, and pelvic ganglioneuromas between January 1, 2000 and January 1, 2020 were included. selleck inhibitor We examined demographic, clinicopathologic, radiologic characteristics as well as clinical management.

Overall, 328 patients from 29 institutions were included. The median age at diagnosis was 37 years with 59.1% of patients being female. Symptomatic presentation comprised 40.9% of cases, and tumors were often located in the extra-adrenal retroperitoneum (67.1%). At baseline, the median maximum tumor diameter was 7.2cm. One hundred sixteen (35.4%) patients underwent active surveillance while 212 (64.6%owing tumors, resection may be curative.

Randomized controlled trials (RCTs) yield the highest level of evidence but are notoriously difficult to perform in surgery. Surgical RCTs may be hampered by slow accrual, the surgical learning curve, and lack of financial support. Alternative RCT designs such as stepped-wedge randomized controlled trials (SW-RCTs), registry-based randomized controlled trials (RB-RCTs), and trials-within-cohorts (TwiCs) may overcome several of these difficulties. This review provides an overview of alternative RCT designs used in surgical research.

We systematically searched PubMed, EMBASE, and Cochrane Central for surgical SW-RCTs, RB-RCTs, and TwiCs. A surgical RCT was defined as a randomized trial that studied interventions in patients undergoing general surgery, regardless of the affiliation of the corresponding author. Exponential regression analysis was performed to assess time trends.

Overall, 41 surgical RCTs using alternative designs were identified, including 17 published final RCT reports and 24 published prociated with surgical RCTs.

The aim of this study was to explore the incidence, risk factors, clinical course and treatment of perforation and fistula of the gastrointestinal tract in a large unselected cohort of patients with necrotizing pancreatitis.

Perforation and fistula of the gastrointestinal (GI)-tract may occur in necrotizing pancreatitis. Data from large unselected patient populations on the incidence, risk factors, clinical outcomes, and treatment are lacking.

We performed a post-hoc analysis of a nationwide prospective database of 896 patients with necrotizing pancreatitis. GI-tract perforation and fistula were defined as spontaneous or iatrogenic discontinuation of the gastrointestinal wall. Multivariable logistic regression was used to explore risk factors and to adjust for confounders to explore associations of the GI-tract perforation and fistula on the clinical course.

A perforation or fistula of the GI-tract was identified in 139 (16%) patients, located in the stomach in 23 (14%), duodenum in 56 (35%), jejunum ntervention was identified as a risk factor for perforation or fistula of the lower GI-tract. The clinical course was mostly affected by involvement of the lower GI-tract.

Perforation and fistula of the GI-tract occurred in one out of six patients with necrotizing pancreatitis. Risk factors were high C-reactive protein within 48 hours and early organ-failure. Prior intervention was identified as a risk factor for perforation or fistula of the lower GI-tract. The clinical course was mostly affected by involvement of the lower GI-tract.

Atrial fibrillation (AF) and stable coronary artery disease (SCAD) frequently coexist. This study aimed to assess the long-term outcome of catheter ablation in patients with paroxysmal AF and SCAD.

In total, 12,104 patients with paroxysmal AF underwent catheter ablation in the Chinese Atrial Fibrillation Registry between 2011 and 2019 were screened. A total of 441 patients with SCAD were matched with patients without SCAD in a 14 ratio. The primary endpoint was AF recurrence after single ablation. The composite secondary endpoints were thromboembolism, coronary events, major bleeding, all-cause death.

Over a mean follow-up of 46.0±18.9 months, the recurrence rate in patients with SCAD was significantly higher after a single ablation (49.0%vs. 41.9%, p=.03). The very late recurrence rate of AF in the SCAD group was also significantly higher than that in the control group (38.9%vs. 31.2%;p=.04). In multivariate analysis, adjusted with the female, smoking, duration of AF, previous thromboembolism, COPD, and statins, SCAD was independently associated with AF recurrence (adjusted HR, 1.19 [1.02-1.40], p=.03). The composite secondary endpoints were significantly higher in the SCAD group (12.70%vs. 8.54%, p=.02), mainly due to thromboembolism events (8.16%vs. 4.41%, p<.01).

SCAD significantly increased the risk of recurrence after catheter ablation of paroxysmal AF. The incidence of thromboembolic events after catheter ablation of paroxysmal AF in the patients with SCAD was significantly higher than that in those without SCAD.

SCAD significantly increased the risk of recurrence after catheter ablation of paroxysmal AF. The incidence of thromboembolic events after catheter ablation of paroxysmal AF in the patients with SCAD was significantly higher than that in those without SCAD.

To determine the prevalence of metastases to the cervical and recurrent laryngeal cervicothoracic (CT) nodes as well as survival and recurrence patterns after esophagectomy with three-field lymph node dissection (TFD) in patients with predominately adenocarcinoma (AC) of the esophagus.

Although esophagectomy with TFD is commonly practiced in Japan and Southeast Asia for squamous cell cancer of the esophagus (SCC), there are only a handful of reports about its' utilization and survival benefit in North American patients.

This is a retrospective case series of patients who had an esophagectomy with TFD. The primary outcomes of interest were the prevalence of nodal metastases to the CT nodes as well as overall (OS) and disease-free survival (DFS). Secondary outcomes included time to recurrence, recurrence patterns, operative morbidity as well as 30 and 90-day mortality.

242 patients with esophageal cancer (AC67%) underwent esophagectomy with TFD. Metastases to the CT nodes were present in 56 patients (23% AC 20% and SCC 30%). Positive CT nodes were present in 14% of pT1/T2 tumors and 30% of pT3 tumors. For the 56 patients with CT positive nodes, 5-year OS was 25% (AC16%; SCC39%). Fifteen of 56 (26.7%) patients with metastases to the CT nodes were alive and disease-free at a minimum of five years postoperatively. Ten-year OS was 43% for all patients with SCC and 28% for patients with AC.

Metastases to the CT nodes are common in both SCC and AC of the esophagus and may be present in at least 14% of early lesions. Five-year survival is encouraging particularly for patients with esophageal SCC cancer.

Metastases to the CT nodes are common in both SCC and AC of the esophagus and may be present in at least 14% of early lesions. Five-year survival is encouraging particularly for patients with esophageal SCC cancer.