Pittsdugan4156

Pre-Structured Motifs (PreSMos) are transient secondary structures observed in many intrinsically disordered proteins (IDPs) and serve as protein target-binding hot spots. The prefix "pre" highlights that PreSMos exist a priori in the target-unbound state of IDPs as the active pockets of globular proteins pre-exist before target binding. Therefore, a PreSMo is an "active site" of an IDP; it is not a spatial pocket, but rather a secondary structural motif. The classical and perhaps the most effective approach to understand the function of a protein has been to determine and investigate its structure. Ironically or by definition IDPs do not possess structure (here structure refers to tertiary structure only). Are IDPs then entirely structureless? The PreSMos provide us with an atomic-resolution answer to this question. For target binding, IDPs do not rely on the spatial pockets afforded by tertiary or higher structures. Instead, they utilize the PreSMos possessing particular conformations that highly presage the target-bound conformations. PreSMos are recognized or captured by targets via conformational selection (CS) before their conformations eventually become stabilized via structural induction into more ordered bound structures. Using PreSMos, a number of, if not all, IDPs can bind targets following a sequential pathway of CS followed by an induced fit (IF). This chapter presents several important PreSMos implicated in cancers, neurodegenerative diseases, and other diseases along with discussions on their conformational details that mediate target binding, a structural rationale for unstructured proteins.Intrinsically disordered proteins (IDPs) lack a well-defined three-dimensional structure but do exhibit some dynamical and structural ordering. The structural plasticity of IDPs indicates that entropy-driven motions are crucial for their function. Many IDPs undergo function-related disorder-to-order transitions upon by their interaction with specific binding partners. Approaches that are based on both experimental and theoretical tools enable the biophysical characterization of IDPs. Molecular simulations provide insights into IDP structural ensembles and disorder-to-order transition mechanisms. However, such studies depend strongly on the chosen force field parameters and simulation techniques. In this chapter, we provide an overview of IDP characteristics, review all-atom force fields recently developed for IDPs, and present molecular dynamics-based simulation methods that allow IDP ensemble generation as well as the characterization of disorder-to-order transitions. In particular, we introduce metadynamics, replica exchange molecular dynamics simulations, and also kinetic models resulting from Markov State modeling, and provide various examples for the successful application of these simulation methods to IDPs.The well-defined roles and specific protein-protein interactions of many integral membrane proteins (IMPs), such as those functioning as receptors for extracellular matrix proteins and soluble growth factors, easily align with considering IMP structure as a classical "lock-and-key" concept. Nevertheless, continued advances in understanding protein conformation, such as those which established the widespread existence of intrinsically disordered proteins (IDPs) and especially intrinsically disordered regions (IDRs) in otherwise three-dimensionally organized proteins, call for ongoing reevaluation of transmembrane proteins. Here, we present basic traits of IDPs and IDRs, and, for some select single-span IMPs, consider the potential functional advantages intrinsic disorder might provide and the possible conformational impact of disease-associated mutations. For transmembrane proteins in general, we highlight several investigational approaches, such as biophysical and computational methods, stressing the importance of integrating them to produce a more-complete mechanistic model of disorder-containing IMPs. These procedures, when synergized with in-cell assessments, will likely be key in translating in silico and in vitro results to improved understanding of IMP conformational flexibility in normal cell physiology as well as disease, and will help to extend their potential as therapeutic targets.After four decades of prion protein research, the pressing questions in the literature remain similar to the common existential dilemmas. Who am I? Some structural characteristics of the cellular prion protein (PrPC) and scrapie PrP (PrPSc) remain unknown there are no high-resolution atomic structures for either full-length endogenous human PrPC or isolated infectious PrPSc particles. Why am I here? It is not known why PrPC and PrPSc are found in specific cellular compartments such as the nucleus; while the physiological functions of PrPC are still being uncovered, the misfolding site remains obscure. Where am I going? The subcellular distribution of PrPC and PrPSc is wide (reported in 10 different locations in the cell). This complexity is further exacerbated by the eight different PrP fragments yielded from conserved proteolytic cleavages and by reversible post-translational modifications, such as glycosylation, phosphorylation, and ubiquitination. Moreover, about 55 pathological mutations and 16 polymorphisms on the PrP gene (PRNP) have been described. Prion diseases also share unique, challenging features strain phenomenon (associated with the heterogeneity of PrPSc conformations) and the possible transmissibility between species, factors which contribute to PrP undruggability. However, two recent concepts in biochemistry-intrinsically disordered proteins and phase transitions-may shed light on the molecular basis of PrP's role in physiology and disease.

Pre-hospital anaesthesia is a core competency of helicopter emergency medical services (HEMS). Whether physician pre-hospital anaesthesia case volume affects outcomes is unknown in this setting. We aimed to investigate whether physician case volume was associated with differences in mortality or medical management.

We conducted a registry-based cohort study of patients undergoing drug-facilitated intubation by HEMS physician from January 1, 2013 to August 31, 2019. The primary outcome was 30-day mortality, analysed using multivariate logistic regression controlling for patient-dependent variables. Case volume for each patient was determined by the number of pre-hospital anaesthetics the attending physician had managed in the previous 12 months. The explanatory variable was physician case volume grouped by low (0-12), intermediate (13-36), and high (≥37) case volume. Secondary outcomes were characteristics of medical management, including the incidence of hypoxaemia and hypotension.

In 4818 patients, the physician case volume was 511, 2033, and 2274 patients in low-, intermediate-, and high-case-volume groups, respectively. Higher physician case volume was associated with lower 30-day mortality (odds ratio 0.79 per logarithmic number of cases [95% confidence interval 0.64-0.98]). High-volume physician providers had shorter on-scene times (median 28 [25th-75th percentile 22-38], compared with intermediate 32 [23-42] and lowest 32 [23-43] case-volume groups; P<0.001) and a higher first-pass success rate for tracheal intubation (98%, compared with 93% and 90%, respectively; P<0.001). The incidence of hypoxaemia and hypotension was similar between groups.

Mortality appears to be lower after pre-hospital anaesthesia when delivered by physician providers with higher case volumes.

Mortality appears to be lower after pre-hospital anaesthesia when delivered by physician providers with higher case volumes.

Recently, Rommens and Hoffman introduced a CT-based classification system for fragility fractures of the pelvis (FFP). Although fracture characteristics have been described, the relationship with clinical outcome is lacking. The purpose of this study was to get insight into the type of treatment and subsequent clinical outcome after all types of FFP.

A cross-sectional cohort study was performed including all elderly patients (≥ 65 years) with a CT-diagnosed FFP, between 2007-2019 in two level 1 trauma centers. Data regarding treatment, mortality and clinical outcome was gathered from the electronic patient files. Patients were asked to complete patient-reported outcome measures (PROMs) regarding physical functioning (SMFA) and quality of life (EQ-5D). Additionally, a standardized multidisciplinary treatment algorithm was constructed.

A total of 187 patients were diagnosed with an FFP of whom 117 patients were available for follow-up analysis and 58 patients responded. FFP type I was most common (60%), fwith FFP type I and II. Mortality rates at one year were substantial in all patients. Physical functioning and quality of life was about 20-30% decreased compared to the general population.Little is known about how frequently do-not-resuscitate (DNR) orders are placed in patients with acute myocardial infarction (AMI), the types of patients in which they are placed, treatment strategies or clinical outcomes of such patients. Using the United States (US) National Inpatient Sample (NIS) database from 2015 to 2018, we identified 2,767,549 admissions that were admitted to US hospitals and during the hospitalization received a principle diagnosis of AMI, of which 339,270 (12.3%) patients had a DNR order (instigated both preadmission and during in-hospital stay). Patients with a DNR status were older (median age 83 vs 65, p less then 0.001), more likely to be female (53.4% vs 39.3%, p less then 0.001) and White (81.0% vs 73.3%, p less then 0.001). Predictors of DNR status included comorbidities such as heart failure (OR 1.47, 95% CI 1.45 to 1.48), dementia (OR 2.53, 95% CI 2.50 to 2.55), and cancer. Patients with a DNR order were less likely to undergo invasive management or be discharged home (13.5% vs 52.8%), with only 1/3 receiving palliative consultation. Selleck Sotrastaurin In hospital mortality (32.7% vs 4.6%, p less then 0.001) and MACCE (37.1% vs 8.8%, p less then 0.001) were higher in the DNR group. Factors independently associated with in-hospital mortality among patients with a DNR order included a STEMI presentation (OR 2.90, 95% CI 2.84 to 2.96) and being of Black (OR 1.29, 95% CI 1.26 to 1.33), Hispanic (OR 1.36, 95% CI 1.32 to 1.41) or Asian/Pacific Islander (OR 1.56, 95% CI1.49-race. In conclusion, AMI patients with a DNR status were older, multimorbid, less likely to receive invasive management, with only one third of patients with DNR status referred for palliative care.Dronedarone may increase exposure and the risk of major bleeding when prescribed with a direct oral anticoagulant (DOAC). This retrospective cohort study examined the risk of the first occurrence of major bleeding (hospitalization or emergency room visit for gastrointestinal [GI] bleeding, intracranial hemorrhage [ICH], or bleeding at other sites) among new users of apixaban, dabigatran, and rivaroxaban in patients with AF ≥18 years (January 1, 2007 to September 30, 2017) from the United States Truven Health MarketScan claims, comparing concomitant users of dronedarone to DOAC alone users in patients with atrial fibrillation (AF). No increased risk of major bleeding was associated with use of dronedarone and apixaban (adjusted Hazard Ratio [aHR] 0.69 [95% confidence interval [CI] 0.40, 1.17], p = 0.16), a modestly increased risk of GI bleeding but not overall bleeding was associated with use of dronedarone and dabigatran (aHR bleeding 1.18 [95% CI 0.89, 1.56], p = 0.26; aHR GI bleeding 1.40 [95% CI 1.01, 1.93]; p = 0.