The Rosetta de novo structure prediction and loop modeling protocols begin with coarse grained Monte Carlo searches in which the moves are based on short fragments extracted from a database of known ...structures. Here we describe a new object oriented program for picking fragments that greatly extends the functionality of the previous program (nnmake) and opens the door for new approaches to structure modeling. We provide a detailed description of the code design and architecture, highlighting its modularity, and new features such as extensibility, total control over the fragment picking workflow and scoring system customization. We demonstrate that the program provides at least as good building blocks for ab-initio structure prediction as the previous program, and provide examples of the wide range of applications that are now accessible.
Solid electrolytes can potentially address three key limitations of the organic electrolytes used in today’s lithium-ion batteries, namely, their flammability, limited electrochemical stability and ...low cationic transference number. The pioneering works of Wright and Armand, suggesting the use of solid poly(ethylene oxide)-based polymer electrolytes (PE) for lithium batteries, paved the way to the development of solid-state batteries based on PEs. Yet, low cationic mobility–low Li
+
transference number in polymer materials coupled with sufficiently high room-temperature conductivity remains inaccessible. The current strategies employed for the production of single-ion polymer conductors include designing new lithium salts, bonding of anions with the main polyether chain or incorporating them into the side chains of comb-branched polymers, plasticizing, adding inorganic fillers and anion receptors. Glass and crystalline superionic solids are classical single-ion-conducting electrolytes. However, because of grain boundaries and poor electrode/electrolyte interfacial contacts, achieving electrochemical performance in solid-state batteries comprising polycrystalline inorganic electrolytes, comparable to the existing batteries with liquid electrolytes, is particularly challenging. Quasi-elastic polymer-in-ceramic electrolytes provide good alternatives to the traditional lithium-ion-battery electrolytes and are believed to be the subject of extensive current research. This review provides an account of the advances over the past decade in the development of single-ion-conducting electrolytes and offers some directions and references that may be useful for further investigations.
Purpose
This study assessed the clinical and immunological outcomes of SARS-CoV-2-infected patients with risk factors for severe disease depending on their immunological status.
Methods
In this ...retrospective study with single follow-up visit, clinical outcome and humoral immunity was monitored in SARS-CoV-2 infected patients at risk. The results were compared based on the patients’ initial immunological status: unvaccinated (UV), patients who did not develop neutralizing antibodies after vaccination (vaccine non-responders, VNR), and patients who expressed neutralizing antibodies after vaccination (vaccine responders, VR). Patients who lacked neutralizing antibodies (VNR and UV) were treated with nMABs.
Results
In total, 113 patients at risk of severe COVID-19 consented to participate in the study. VR and UV were not admitted to the hospital. During the observation period, UVs had the highest rate of SARS-CoV-2 re-infections. Three of 41 VNRs (7.3%) were hospitalized due to severe COVID-19, with two of them having undergone iatrogenic B-cell depletion. The humoral immune response after infection was significantly lower in the VNR group than in the VR group in terms of anti-N, anti-receptor-binding domain (RBD), anti-S antibody titers, and anti-S antibody avidity. In a sub-analysis of VNR, B cell-deficient non-responders had significantly lower levels of anti-N antibodies and anti-S avidity after infection than other VNRs.
Conclusion
VNR, particularly B-cell-depleted VNR, remained at risk of hospitalization due to COVID-19. In the VR group, however, no clinical complications or severe disease were observed, despite not receiving nMAbs. Tailoring the administration of nMABs according to patient vaccination and immunological status may be advisable.
Measures of psychological constructs are validated by testing whether they relate to measures of other constructs as specified by theory. Each test of relations between measures reflects on the ...validity of both the measures and the theory driving the test. Construct validation concerns the simultaneous process of measure and theory validation. In this article, we review the recent history of validation efforts in clinical psychological science that has led to this perspective, and we review the following recent advances in validation theory and methodology of importance for clinical researchers. These are: the emergence of nonjustificationist philosophy of science; an increasing appreciation for theory and the need for informative tests of construct validity; valid construct representation in experimental psychopathology; the need to avoid representing multidimensional constructs with a single score; and the emergence of effective new statistical tools for the evaluation of convergent and discriminant validity.
Background and purpose
Individuals with radiologically isolated syndrome (RIS) are at increased risk of converting to multiple sclerosis (MS). Early identification of later converters is crucial for ...optimal treatment decisions. The purpose of this study was to assess the predictive potential of optical coherence tomography (OCT) measures in individuals with RIS regarding conversion to MS.
Methods
This prospective observational cohort study included 36 individuals with RIS and 36 healthy controls recruited from two German MS centers. All individuals received baseline OCT and clinical examination and were longitudinally followed over up to 6 years. The primary outcome measure was the conversion to MS.
Results
During clinical follow‐up of 46 (26–58) months (median, 25%–75% interquartile range), eight individuals with RIS converted to MS. Individuals converting to MS showed a thinning of the peripapillary retinal nerve fiber layer (pRNFL) and the common ganglion cell and inner plexiform layer (GCIP) at baseline and during follow‐up. Individuals with a pRNFL of 99 µm or lower or a GCIP of 1.99 mm3 or lower were at a 7.5‐ and 8.0‐fold risk for MS conversion, respectively, compared to individuals with higher measures. After correction for other known risk factors, Cox proportional hazards regression revealed a hazard ratio of 1.08 for conversion to MS for each 1 µm decline in pRNFL.
Conclusions
Reduction of the pRNFL might be a novel and independent risk factor for conversion to MS in individuals with RIS. OCT might be useful for risk stratification and therapeutic decision‐making in individuals with RIS.
Aims/hypothesis Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account ...glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. Methods A dementia-free cohort (n = 1,248) aged >=75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition DSM-III-R criteria). The Alzheimer's disease diagnoses were subdivided into Alzheimer's disease with stroke and Alzheimer's disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level >=11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level >=11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8-11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. Results During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer's disease (of the 320 Alzheimer's disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20-8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20-9.01) for Alzheimer's disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer's disease without vascular comorbidities. Conclusions/interpretation Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.
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Objective. We aimed to disentangle the effect of chronic multimorbidity and disability on 3‐year functional decline and survival in the elderly.
Design. Prospective cohort study with a mean of ...follow‐up of 2.8 years.
Setting. Swedish elderly persons from the Kungsholmen Project (1987–2000).
Subjects. A total of 1099 subjects, 77–100 years old, living in the community and institutions.
Main outcome measurements. Medical diagnoses (based on clinical examination, drug use, medical records and blood tests), and functional assessment (according to Katz Index) at baseline were investigated in relation to functional decline and death occurring during follow‐up.
Results. At baseline, 12.1% of participants had disability, and 52.3% were affected by multimorbidity. During follow‐up, 363 persons died and 85 worsened in functioning. The number of chronic conditions incrementally increased the risk of functional decline hazard ratio (HR) increased from 1.5 in subjects with one disease to 6.2 in persons with 4+ diseases. However, this was not the case for mortality, as the HR of death was the same for people with one disease as well as 4+ diseases (HR = 2.3). Baseline disability had the highest impact on survival, independently of number of diseases HR = 8.1; 95% confidence interval (CI) = 4.8–13.7 in subjects with one disease and HR = 7.7; 95% CI = 4.7–12.6 in those with 2+ diseases.
Conclusions. In the elderly subjects, chronic disability rather than multimorbidity emerged as the strongest negative prognostic factor for functionality and survival.
Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and ...adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
Abstract
Motivation
A number of pseudotime methods have provided point estimates of the ordering of cells for scRNA-seq data. A still limited number of methods also model the uncertainty of the ...pseudotime estimate. However, there is still a need for a method to sample from complicated and multi-modal distributions of orders, and to estimate changes in the amount of the uncertainty of the order during the course of a biological development, as this can support the selection of suitable cells for the clustering of genes or for network inference.
Results
In applications to scRNA-seq data we demonstrate the potential of GPseudoRank to sample from complex and multi-modal posterior distributions and to identify phases of lower and higher pseudotime uncertainty during a biological process. GPseudoRank also correctly identifies cells precocious in their antiviral response and links uncertainty in the ordering to metastable states. A variant of the method extends the advantages of Bayesian modelling and MCMC to large droplet-based scRNA-seq datasets.
Availability and implementation
Our method is available on github: https://github.com/magStra/GPseudoRank.
Supplementary information
Supplementary data are available at Bioinformatics online.
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