Design, Synthesis, And Evaluation Of A Novel Serine Protease Inhibitor Based On Monocyclic β-Lactams

Serine proteases are a large family of proteolytic enzymes which utilize a serine residue as a reactive nucleophile in the active site. Some of the more common serine proteases are chymotrypsin, trypsin, thrombin, human leukocyte elastase (HLE), human cathepsin G, and human cytomegalovirus protease (HCMV protease). Unregulated serine protease activity has been implicated in several common ailments, including rheumatoid arthritis, emphysema, pancreatitis, atherosclerosis, cystic fibrosis, and Alzheimer’s disease. Since serine proteases are responsible for the onset of such a wide range of diseases, there is an equivalent need for a large library of synthetic serine protease inhibitors to selectively counteract these conditions. To date, several serine protease inhibitors have been developed with reactive functionality. Additionally, compounds which have incorporated the monocyclic b-lactam into their structure have also been reported to inhibit some serine proteases. To date, all reported monocyclic b-lactam inhibitors take advantage of the reactivity of the b-lactam ring, however, none of the previously synthesized inhibitors attempt to deliberately mimic the natural substrates of serine proteases. The inhibitors proposed in this project will incorporate the reactive b-lactam functionality into the peptide backbone of a serine protease substrate. Molecules will be synthesized and tested in an inhibition assay with chymotrypsin, the prototypical serine protease. These monocyclic b-lactam inhibitors will theoretically be recognized by the serine protease as a substrate, and bind in a manner which places the b-lactam at the active site. These inhibitors have been rationally designed to inhibit serine proteases by this mechanism, however, previous research involving b-lactam type inhibitors of serine proteases,has shown that inhibitors sharing the same functionality often behave differently in enzyme assays. Because of this, the exact mode of inhibition of these compounds will need to be determined experimentally. If these rationally designed compounds are found to successfully inhibit chymotrypsin, the library of reactive functionality that can be used to combat serine protease activity will be expanded. Unlike many of their predecessors, these inhibitors will have the distinction of being able to exploit interactions with the enzyme on both sides of the scissile bond

Cost effectiveness after a pancreaticoduodenectomy: bolstering the volume argument

AbstractBackgroundThe cost implication of variability in pancreatic surgery is not well described. It was hypothesized that for a pancreaticoduodenectomy (PD), lower volume centres demonstrate worse peri-operative outcomes at higher costs.MethodsFrom 2009–2011, 9883 patients undergoing a PD were identified from the University HealthSystems Consortium (UHC) database and stratified into quintiles by annual hospital case volume. A decision analytic model was constructed to assess cost effectiveness. Total direct cost data were based on Medicare cost/charge ratios and included readmission costs when applicable.ResultsThe lowest volume centres demonstrated a higher peri-operative mortality rate (3.5% versus 1.3%, P < 0.001) compared with the highest volume centres. When both index and readmission costs were considered, the per-patient total direct cost at the lowest volume centres was $23 005, or 10.9$2263 per case) more than at the highest volume centres. One-way sensitivity analyses adjusting for peri-operative mortality (1.3% at all centres) did not materially change the cost effectiveness analysis. Differences in cost were largely recognized in the index admission; readmission costs were similar across quintiles.ConclusionsFor PD, low volume centres have higher peri-operative mortality rates and 10.9% higher cost per patient. Performance of PD at higher volume centres can lead to both better outcomes and substantial cost savings

The <i>Rosetta</i> Mission and the Chemistry of Organic Species in Comet 67P/Churyumov–Gerasimenko

Comets are regarded as probably the most primitive of solar system objects, preserving a record of the materials from which the solar system aggregated. Key amongst their components are organic compounds – molecules that may trace their heritage to the interstellar medium from which the protosolar nebula eventually emerged. The most recent cometary space mission, Rosetta, carried instruments designed to characterize, in unprecedented detail, the organic species in comet 67P/Churyumov–Gerasimenko (67P). Rosetta was the first mission to match orbits with a comet and follow its evolution over time, and also the first mission to land scientific instruments on a comet surface. Results from the mission revealed a greater variety of molecules than previously identified and indicated that 67P contained both primitive and processed organic entities

CoRoT/ESTA-TASK 1 and TASK 3 comparison of the internal structure and seismic properties of representative stellar models: Comparisons between the ASTEC, CESAM, CLES, GARSTEC and STAROX codes

We compare stellar models produced by different stellar evolution codes for the CoRoT/ESTA project, comparing their global quantities, their physical structure, and their oscillation properties. We discuss the differences between models and identify the underlying reasons for these differences. The stellar models are representative of potential CoRoT targets. Overall we find very good agreement between the five different codes, but with some significant deviations. We find noticeable discrepancies (though still at the per cent level) that result from the handling of the equation of state, of the opacities and of the convective boundaries. The results of our work will be helpful in interpreting future asteroseismology results from CoRoT.Comment: 26 pages, 21 figures, accepted for publication in Astrophysics and Space Science, CoRoT/ESTA Volum

Forest biodiversity, ecosystem functioning and the provision of ecosystem services

Forests are critical habitats for biodiversity and they are also essential for the provision of a wide range of ecosystem services that are important to human well-being. There is increasing evidence that biodiversity contributes to forest ecosystem functioning and the provision of ecosystem services. Here we provide a review of forest ecosystem services including biomass production, habitat provisioning services, pollination, seed dispersal, resistance to wind storms, fire regulation and mitigation, pest regulation of native and invading insects, carbon sequestration, and cultural ecosystem services, in relation to forest type, structure and diversity. We also consider relationships between forest biodiversity and multifunctionality, and trade-offs among ecosystem services. We compare the concepts of ecosystem processes, functions and services to clarify their definitions. Our review of published studies indicates a lack of empirical studies that establish quantitative and causal relationships between forest biodiversity and many important ecosystem services. The literature is highly skewed; studies on provisioning of nutrition and energy, and on cultural services, delivered by mixed-species forests are under-represented. Planted forests offer ample opportunity for optimising their composition and diversity because replanting after harvesting is a recurring process. Planting mixed-species forests should be given more consideration as they are likely to provide a wider range of ecosystem services within the forest and for adjacent land uses. This review also serves as the introduction to this special issue of Biodiversity and Conservation on various aspects of forest biodiversity and ecosystem services

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase&nbsp;1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation&nbsp;disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age&nbsp; 6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score&nbsp; 652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc&nbsp;= 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N&nbsp;= 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in&nbsp;Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in&nbsp;Asia&nbsp;and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Conservation Analysis in the Municipality of Toa Baja

In Puerto Rico, ongoing economic and population growth is causing widespread urbanization at the expense of valuable forest ecosystems. The community of el Plantio faced this issue when a cherished range of forested hills was threatened by local developers. We assessed the situation through interviews, explored the area to compile scientific arguments for preservation, and surveyed local educators regarding use of the area for educational purposes. Our findings will help the community justify re-zoning the hills as a protected area and suggest educational uses as an alternative to development. With the assistance of the Department of Natural and Environmental Resources, we used the example of el Plantio to adapt the USFS Wildland-Urban Interface Assessment to a Puerto Rican context