Biophysical characterization of the outer membrane polysaccharide export protein and the polysaccharide co-polymerase protein from Xanthomonas campestris

This study investigated the structural and biophysical characteristics of GumB and GumC, two Xanthomonas campestris membrane proteins that are involved in xanthan biosynthesis. Xanthan is an exopolysaccharide that is thought to be a virulence factor that contributes to bacterial in planta growth. It also is one of the most important industrial biopolymers. The first steps of xanthan biosynthesis are well understood, but the polymerization and export mechanisms remain unclear. For this reason, the key proteins must be characterized to better understand these processes. Here we characterized, by biochemical and biophysical techniques, GumB, the outer membrane polysaccharide export protein, and GumC, the polysaccharide co-polymerase protein of the xanthan biosynthesis system. Our results suggested that recombinant GumB is a tetrameric protein in solution. On the other hand, we observed that both native and recombinant GumC present oligomeric conformation consistent with dimers and higher-order oligomers. The transmembrane segments of GumC are required for GumC expression and/or stability. These initial results provide a starting point for additional studies that will clarify the roles of GumB and GumC in the xanthan polymerization and export processes and further elucidate their functions and mechanisms of action.Fil: Bianco, María Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Jacobs, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Salinas, Silvina Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Salvay, Andrés Gerardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Ielmini, M. V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ielpi, Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentin

Biophysical characterization of the outer membrane polysaccharide export protein and the polysaccharide co-polymerase protein from <i>Xanthomonas campestris</i>

This study investigated the structural and biophysical characteristics of GumB and GumC, two Xanthomonas campestris membrane proteins that are involved in xanthan biosynthesis. Xanthan is an exopolysaccharide that is thought to be a virulence factor that contributes to bacterial in planta growth. It also is one of the most important industrial biopolymers. The first steps of xanthan biosynthesis are well understood, but the polymerization and export mechanisms remain unclear. For this reason, the key proteins must be characterized to better understand these processes. Here we characterized, by biochemical and biophysical techniques, GumB, the outer membrane polysaccharide export protein, and GumC, the polysaccharide co-polymerase protein of the xanthan biosynthesis system. Our results suggested that recombinant GumB is a tetrameric protein in solution. On the other hand, we observed that both native and recombinant GumC present oligomeric conformation consistent with dimers and higher-order oligomers. The transmembrane segments of GumC are required for GumC expression and/or stability. These initial results provide a starting point for additional studies that will clarify the roles of GumB and GumC in the xanthan polymerization and export processes and further elucidate their functions and mechanisms of action.Instituto de Física de Líquidos y Sistemas Biológico

Multilevel HfO2-based RRAM devices for low-power neuromorphic networks

Training and recognition with neural networks generally require high throughput, high energy efficiency, and scalable circuits to enable artificial intelligence tasks to be operated at the edge, i.e., in battery-powered portable devices and other limited-energy environments. In this scenario, scalable resistive memories have been proposed as artificial synapses thanks to their scalability, reconfigurability, and high-energy efficiency, and thanks to the ability to perform analog computation by physical laws in hardware. In this work, we study the material, device, and architecture aspects of resistive switching memory (RRAM) devices for implementing a 2-layer neural network for pattern recognition. First, various RRAM processes are screened in view of the device window, analog storage, and reliability. Then, synaptic weights are stored with 5-level precision in a 4 kbit array of RRAM devices to classify the Modified National Institute of Standards and Technology (MNIST) dataset. Finally, classification performance of a 2-layer neural network is tested before and after an annealing experiment by using experimental values of conductance stored into the array, and a simulation-based analysis of inference accuracy for arrays of increasing size is presented. Our work supports material-based development of RRAM synapses for novel neural networks with high accuracy and low-power consumption. (C) 2019 Author(s)

Standards for the Characterization of Endurance in Resistive Switching Devices

Resistive switching (RS) devices are emerging electronic components that could have applications in multiple types of integrated circuits, including electronic memories, true random number generators, radiofrequency switches, neuromorphic vision sensors, and artificial neural networks. The main factor hindering the massive employment of RS devices in commercial circuits is related to variability and reliability issues, which are usually evaluated through switching endurance tests. However, we note that most studies that claimed high endurances >106 cycles were based on resistance versus cycle plots that contain very few data points (in many cases even <20), and which are collected in only one device. We recommend not to use such a characterization method because it is highly inaccurate and unreliable (i.e., it cannot reliably demonstrate that the device effectively switches in every cycle and it ignores cycle-to-cycle and device-to-device variability). This has created a blurry vision of the real performance of RS devices and in many cases has exaggerated their potential. This article proposes and describes a method for the correct characterization of switching endurance in RS devices; this method aims to construct endurance plots showing one data point per cycle and resistive state and combine data from multiple devices. Adopting this recommended method should result in more reliable literature in the field of RS technologies, which should accelerate their integration in commercial products

Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction: Information on the off–label use of Long–Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on– vs off–label LAIs and predictors of off–label First– or Second–Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method: In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off– or on–label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off–label group. Results: SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on– and off–label use. Approximately 1 in 4 patients received an off–label prescription. In the off–label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p&nbsp;= 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p&nbsp;= 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion: Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off–label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co–morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Comparing Long-Acting Antipsychotic Discontinuation Rates Under Ordinary Clinical Circumstances: A Survival Analysis from an Observational, Pragmatic Study

Background: Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective: Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods: The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results: The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p&nbsp;=&nbsp;0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p&nbsp;=&nbsp;0.049). Conclusions: Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation

Omission of Radiotherapy in Primary Mediastinal B-Cell Lymphoma: IELSG37 Trial Results

\ua9 2024 by American Society of Clinical Oncology. PURPOSE The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial. METHODS The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned. RESULTS The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, -0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively). CONCLUSION This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation

Modeling and Compensation of IR Drop in Crosspoint Accelerators of Neural Networks

In-memory computing (IMC) has the potential of accelerating data-intensive computing tasks, such as inference and training of neural networks, by the matrix vector multiplication (MVM) in the crosspoint array. As the array size increases, however, a significant problem arises due to the parasitic IR drop at row and column lines. Understanding and compensating IR drop is essential to enable high-density accelerators of MVM. This work presents an analytical model for the IR drop and a numerical algorithm capable of accelerating the nodal analysis of crosspoint arrays up to five orders of magnitude with respect to SPICE analysis. The numerical algorithm is used to study the impact of array size, data density, device/wire resistance, and nonlinearity on the IR drop and the related loss of accuracy in IMC. We also derive two simple compensation schemes and an architectural solution for the mitigation of IR drop that are able to increase the accuracy of neural networks from 59% up to 96.6%, compared to an ideal accuracy of 97%