Computer-aided design of Organophosphorus inhibitors of Urease

Based on the structure of the most potential inhibitor diamidophosphate, various novel groups of inhibitors were developed by knowledge-based design approach with covalent carbon-phosphorus or carbon-phosphorus-carbon bond to improve hydrolytic stability to inhibit the microbial ureases. Designed compounds were evaluated with 10 (LigScore1, LigScore2, PLP1, PLP2, JAIN, PMF, PMF04, LUDI_1, LUDI_2 and LUDI_3) different scoring functions implemented in Discovery Studio and conformation analysis by AutoDock package

The Nylon Scintillator Containment Vessels for the Borexino Solar Neutrino Experiment

Borexino is a solar neutrino experiment designed to observe the 0.86 MeV Be-7 neutrinos emitted in the pp cycle of the sun. Neutrinos will be detected by their elastic scattering on electrons in 100 tons of liquid scintillator. The neutrino event rate in the scintillator is expected to be low (~0.35 events per day per ton), and the signals will be at energies below 1.5 MeV, where background from natural radioactivity is prominent. Scintillation light produced by the recoil electrons is observed by an array of 2240 photomultiplier tubes. Because of the intrinsic radioactive contaminants in these PMTs, the liquid scintillator is shielded from them by a thick barrier of buffer fluid. A spherical vessel made of thin nylon film contains the scintillator, separating it from the surrounding buffer. The buffer region itself is divided into two concentric shells by a second nylon vessel in order to prevent inward diffusion of radon atoms. The radioactive background requirements for Borexino are challenging to meet, especially for the scintillator and these nylon vessels. Besides meeting requirements for low radioactivity, the nylon vessels must also satisfy requirements for mechanical, optical, and chemical properties. The present paper describes the research and development, construction, and installation of the nylon vessels for the Borexino experiment

Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α

Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures determined in the presence of reducing agents. These structures correspond to free forms and complexes with activators, substrates, and inhibitors. Here we report the conformation of an oxidized state with an intramolecular disulfide bond between Cys119 and Cys162 that is conserved in vertebrates. The structure of the oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by partially unwinding and displacing the short αD helix due to the movement of Cys119 towards Cys162. The transition between oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design that we describe in detail.© 2023. The Author(s)

An anatomical investigation of rare upper limb neuropathies due to the Struthers’ ligament or arcade: a meta-analysis

Background: The Struthers’ ligament (SL) is a fibrous band that originates fromthe supracondylar humeral process and inserts into the medial humeral epicondyle, potentially compressing both the median nerve and brachial artery. The controversial Struthers’ arcade (SA) is a musculotendinous band found in the distal end of the arm that might compress the ulnar nerve. This study aimed to evaluate the pooled prevalence estimate of the SL and SA, and their anatomical features. Materials and methods: A meticulous search of major electronic medical databases was carried out regarding both structures. Applicable articles (and all relevant references) were analysed. Data from the eligible articles was extracted and evaluated. The quality and the potential risk of bias in the included studies were assessed using the AQUA tool. Results: The arcade was reported in 13 studies (510 arms), whereas the ligament in 6 studies (513 arms). The overall pooled prevalence estimate of the ligament was 1.8%, and 52.6% for the arcade. Most frequently, the ulnar nerve was covered by a tendinous arcade (42.2%). In all cases, the ligament inserted into the medial humeral epicondyle, but had various origins. Only 1 study reported compression of the median nerve by the ligament, whilst another contradicted this view. Conclusions: Although the SL is rare, and the SA is a valid anatomical entity (though with a variable presentation), clinically meaningful neurovascular entrapments caused by these structures are infrequent. Nonetheless, a better understanding of each may be beneficial for the best patient outcomes

Earnings Management: The Effect of Ex Ante Earnings Expectations

Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions

Political transition and emergent forest-conservation issues in Myanmar.

Political and economic transitions have had substantial impacts on forest conservation. Where transitions are underway or anticipated, historical precedent and methods for systematically assessing future trends should be used to anticipate likely threats to forest conservation and design appropriate and prescient policy measures to counteract them. Myanmar is transitioning from an authoritarian, centralized state with a highly regulated economy to a more decentralized and economically liberal democracy and is working to end a long-running civil war. With these transitions in mind, we used a horizon-scanning approach to assess the 40 emerging issues most affecting Myanmar's forests, including internal conflict, land-tenure insecurity, large-scale agricultural development, demise of state timber enterprises, shortfalls in government revenue and capacity, and opening of new deforestation frontiers with new roads, mines, and hydroelectric dams. Averting these threats will require, for example, overhauling governance models, building capacity, improving infrastructure- and energy-project planning, and reforming land-tenure and environmental-protection laws. Although challenges to conservation in Myanmar are daunting, the political transition offers an opportunity for conservationists and researchers to help shape a future that enhances Myanmar's social, economic, and environmental potential while learning and applying lessons from other countries. Our approach and results are relevant to other countries undergoing similar transitions

Management earnings forecasts and IPO performance: evidence of a regime change

Companies undertaking initial public offerings (IPOs) in Greece were obliged to include next-year profit forecast in their prospectuses, until the regulation changed in 2001 to voluntary forecasting. Drawing evidence from IPOs issued in the period 1993–2015, this is the first study to investigate the effect of disclosure regime on management earnings forecasts and IPO long-term performance. The findings show mainly positive forecast errors (forecasts are lower than actual earnings) and higher long-term returns during the mandatory period, suggesting that the mandatory disclosure requirement causes issuers to systematically bias profit forecasts downwards as they opt for the safety of accounting conservatism. The mandatory disclosure requirement artificially improves IPO share performance. Overall, our results show that mandatory disclosure of earnings forecasts can impede capital market efficiency once it goes beyond historical financial information to involve compulsory projections of future performance

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD

Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia.

ABSTARCT: Hepatitis B virus (HBV) occult infection (OBI) is a risk factor to be taken into account in transfusion, hemodialysis and organ transplantation. The aim of this study was to identify and characterize at the molecular level OBI cases in patients with end-stage liver disease. METHODS: Sixty-six liver samples were obtained from patients with diagnosis of end-stage liver disease submitted to liver transplantation in Medellin (North West, Colombia). Samples obtained from patients who were negative for the surface antigen of HBV (n = 50) were tested for viral DNA detection by nested PCR for ORFs S, C, and X and confirmed by Southern-Blot. OBI cases were analyzed by sequencing the viral genome to determine the genotype and mutations; additionally, viral genome integration events were examined by the Alu-PCR technique. RESULTS: In five cases out of 50 patients (10%) the criteria for OBI was confirmed. HBV genotype F (subgenotypes F1 and F3), genotype A and genotype D were characterized in liver samples. Three integration events in chromosomes 5q14.1, 16p13 and 20q12 affecting Receptor-type tyrosine-protein phosphatase T, Ras Protein Specific Guanine Nucleotide Releasing Factor 2, and the zinc finger 263 genes were identified in two OBI cases. Sequence analysis of the viral genome of the 5 OBI cases showed several punctual missense and nonsense mutations affecting ORFs S, P, Core and X. CONCLUSIONS: This is the first characterization of OBI in patients with end-stage liver disease in Colombia. The OBI cases were identified in patients with HCV infection or cryptogenic cirrhosis. The integration events (5q14.1, 16p13 and 20q12) described in this study have not been previously reported. Further studies are required to validate the role of mutations and integration events in OBI pathogenesis