Markov state models (MSM) are used to model the kinetics of processes sampled by molecular dynamics (MD) simulations. MSM reduce the high dimensionality inherent to MD simulations as they partition ...the free energy landscape into discrete states, generating a kinetic model as a series of uncorrelated jumps between states. Here, we detail a new method, called GRadient Adaptive Decomposition, which optimizes coarse-grained MSM by refining borders with respect to the gradient along the free energy surface. The proposed method requires only a small number of initial microstates because it corrects for errors produced by limited sampling. Whereas many methods rely on fuzzy partitions for proper statistics, GRAD retains a crisp decomposition. Two test studies are presented to illustrate the method and assess its accuracy: the first analyzes MSM of idealized model potentials, while the second is a study of the dynamics of unstacking of the deoxyribose adenosine monophosphate dinucleotide.
To evaluate the types and mechanisms of stroke in a large population of HIV-infected patients.
We reviewed records of consecutive HIV-infected patients with acute stroke admitted to a large ...metropolitan hospital between 1996 and 2004. Stroke mechanism was defined by consensus between two cerebrovascular neurologists using TOAST classification.
A total of 82 patients were included, 77 with ischemic stroke and 5 with intracerebral hemorrhage. Mean age was 42 years and 89% were African American. Previous diagnosis of HIV infection was documented in 91% and AIDS diagnosis in 80%. Mean CD4 count was 113 cells/mm(3) and 85% had CD4 count <200 cells/mm(3). A total of 61% of patients had received combination antiretroviral treatment (CART). The mechanism of ischemic stroke was large artery atherosclerosis in 12%, cardiac embolism in 18%, small vessel occlusion in 18%, other determined etiology in 23%, and undetermined in 29% (including 19% with incomplete evaluation). Vasculitis was deemed responsible for the stroke in 10 patients (13%) and hypercoagulability in 7 (9%). Protein S deficiency was noted in 10/22 (45%) and anticardiolipin antibodies in 9/31 (29%) tested patients. When comparing patients with large or small vessel disease (atherothrombotic strokes) vs the rest of the population, there were no differences in exposure to CART or CD4 count, but patients with non-atherothrombotic strokes were younger (p = 0.04). Recent cocaine exposure was less common among patients with atherothrombotic strokes (p = 0.02). Strokes were fatal or severely disabling in 35% of cases.
Stroke mechanisms are variable in HIV-infected patients, with a relatively high incidence of vasculitis and hypercoagulability. In our population of severely immunodepressed patients, exposure to combination antiretroviral treatment did not significantly influence the mechanism of stroke.
In this paper, we illustrate laboratory experiments whose purpose is to study the vertical segregations that are commonly observed in deposits of dense geophysical flows (such as pyroclastic flows ...and rock avalanches). In these experiments, we use rock cuboids with 5mm long edges as matrix and rock cuboids with 2cm long edges as segregating clasts. A rotating disk is used to apply frictional stresses at the base of the granular masses. In our experiments, segregating cuboids with density smaller than or equal to that of the matrix particles rise whereas segregating cuboids with density larger than that of the matrix particles sink. The granular flows are imaged through the glass container of the experimental apparatus by a high-speed video camera at 2000fps. By means of particle image velocimetry analysis of the movies, we study the vertical gradient of particle agitation that exists within the granular flows where agitation increases downward because of the interaction with the subsurface asperities. The high-speed movies show that it is the particle agitation within the flows that exerts an upward force and that, when this force is larger than the weight of the segregating clast, the clast rises whereas, when it is smaller, the clast sinks. The most important result in our set of experiments is that the threshold which separates the values of density of the segregating clasts that segregate upward and the values of density of the segregating clasts that segregate downward is larger than the density of the matrix particles. This explains the upward segregation of dense lithics that is frequently observed in deposits of geophysical flows. This upward segregation is due to the fact that the resultant of the collisions exerted by the matrix particles is a force strong enough to push upward also dense and heavy fragments.
•The direction of segregation depends on the sum of the forces acting on the clast.•These forces are collisional, gravitational and retarding forces.•The resultant of the collisional forces points upward.•The collisional forces are due to the agitation gradient within the flows.•Dense clasts segregate upward when collisional forces can support them.
•Heat transfer and fluid flow in micro-channels are investigated.•Two serpentine cells are considered and compared with a straight parallel channel.•In order to improve the efficiency of the cells ...different flow conditions are studied.•Thermal behavior is evaluated on the Nu-Re diagram and through efficiency parameters.•µPIV measurements were performed to detail the observed global thermal performances.
The future technological horizons for engineering applications (Automotive, Energy, Bio-Engineering) require the use of limited size heat exchangers with high efficiency. In the present work, the flow field in small scale channels of different geometries is investigated experimentally using µPIV (micro Particle Image Velocimetry) and thermal measurements. The Reynolds number in the channels is changed as also the wall temperature, in order to investigate and improve the thermal efficiency at different flow rates, temperatures and geometrical configurations. The main result of this investigation is that a serpentine cell attains the highest efficiency regardless of flow regime, getting high Nusselt numbers combined with low pressure losses, as derived by the observation of quite high local velocities and few recirculation regions.
Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary ...resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients.
ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks.
Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) 95% confidence interval (CI) 0.86 0.62-1.19, P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC 11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017, and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002).
In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.
•The study compared survival with cancer vaccine OSE2101 versus CT in NSCLC patients after immunotherapy failure.•In patients with secondary resistance to sequential CT-ICB, survival was improved with OSE2101 compared to CT.•Quality of life, preservation of ECOG performance status 0 or 1 and safety were statistically better with OSE2101 compared to CT.•OSE2101 had a favorable benefit/risk versus CT in NSCLC patients with secondary resistance that merits further evaluation.
This article focuses on the process of contract renegotiation by an Italian wastewater utility, commenced with the goal of tariff revision. The main aim of this paper is to identify the conditions ...that lead to contract renegotiation. It also develops new tools and operations that can facilitate this process. We utilized the action research method that involves organizations in changing situations supported by professional researchers who assume the role of change agents. The study provides some interesting insights on contract management and renegotiation, and highlights conditions that lead to the failure of contract-based regulation.
•The incompleteness of contracts determines the risk of default of one of the counterparts.•Concession contracts without an active role for a regulatory agency have a high rate of collapse.•The lack of clear rules for tariff estimation generates information asymmetries.•The ambiguity in the tariff method has weakened the wholesalers.•The process of renegotiation is helped by the involvement of an independent actor.
An experimental investigation of the flow inside a rectangular cylinder with air injected continuously along the wall is performed. This kind of flow is a two-dimensional approximation of what ...happens inside a solid rocket motor, where the lateral grain burns expelling exhaust gas or in processes with air filtration or devices to attain uniform flows. We propose a brief derivation of some analytical solutions and a comparison between these solutions and experimental data, which are obtained using the particle image velocimetry technique, to provide a global reconstruction of the flowfield. The flow, which enters orthogonal to the injecting wall, turns suddenly its direction being pushed towards the exit of the chamber. Under the incompressible and inviscid flow hypothesis, two analytical solutions are reported and compared. The first one, known as Hart–McClure solution, is irrotational and the injection velocity is non-perpendicular to the injecting wall. The other one, due to Taylor and Culick, has non-zero vorticity and constant, vertical injection velocity. The comparison with laminar solutions is useful to assess whether transition to turbulence is reached and how the disturbance thrown in by the porous injection influences and modifies those solutions.
The Arabidopsis Cyclophilin Gene Family Patrick G. N. Romano; Horton, Peter; Gray, Julie E.
Plant physiology (Bethesda),
04/2004, Letnik:
134, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Database searching has allowed the identification of a number of previously unreported single and multidomain isoform members of the Arabidopsis cyclophilin gene family. In addition to the ...cyclophilin-like peptidyl-prolyl cis-trans isomerase domain, the latter contain a variety of other domains with characterized functions. Transcriptional analysis showed they are expressed throughout the plant, and different isoforms are present in all parts of the cell including the cytosol, nucleus, mitochondria, secretory pathway, and chloroplast. The abundance and diversity of cyclophilin isoforms suggests that, like their animal counterparts, plant cyclophilins are likely to be important proteins involved in a wide variety of cellular processes. As well as fulfilling the basic role of protein folding, they may also play important roles in mRNA processing, protein degradation, and signal transduction and thus may be crucial during both development and stress responsiveness.
Colorectal cancer survivors have many problems affecting their quality of life (QOL). Traditional follow-up focuses on the detection of recurrence rather than QOL. Efforts are being made to assess ...patient-reported outcomes (PROMS) more formally. Such changes may enable patients to consider QOL factors when deciding on treatment.
Patients who underwent laparoscopic surgery for rectal cancer between 2005 and 2015 at a single institution were identified and sent European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29 QOL questionnaires. QOL and the impact of radiotherapy, chemotherapy and formation of end colostomy were assessed.
Some 141 patients were identified: 12 died and 118 (83.7%) responded, of whom 101 completed the questionnaires and 17 declined to participate; 11 were lost to follow-up. Mean age was 67 years, median follow-up was 58 months. Median QOL score was 6 (maximum 7) and 4.5% of patients reported a poor QOL score (<4). Significant rectal/perianal pain, sexual dysfunction and urinary symptoms were reported in 3.6%, 10.9% and 2.7% of respondents, respectively. Significant differences between treatment groups were uncommon. All cohorts reported similar QOL, functional and symptom scores.
These results compare favourably with the published data. Future studies may benefit from baseline assessment to better assess treatment impact, prescient in an increasingly elderly and comorbid population. This paper establishes that good PROMs are achievable with laparoscopic surgery for rectal cancer. It identifies limited differences in QOL between treatment modalities. Restoration of intestinal continuity and end colostomy result in similar QOL. This may address common concerns regarding stomata, sexual function and low anterior resection syndrome in this cohort.
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