DNA unzipped under a constant force exhibits multiple metastable intermediates

Single molecule studies, at constant force, of the separation of double-stranded DNA into two separated single strands may provide information relevant to the dynamics of DNA replication. At constant applied force, theory predicts that the unzipped length as a function of time is characterized by jumps during which the strands separate rapidly, followed by long pauses where the number of separated base pairs remains constant. Here, we report previously uncharacterized observations of this striking behavior carried out on a number of identical single molecules simultaneously. When several single lphage molecules are subject to the same applied force, the pause positions are reproducible in each. This reproducibility shows that the positions and durations of the pauses in unzipping provide a sequence-dependent molecular fingerprint. For small forces, the DNA remains in a partially unzipped state for at least several hours. For larger forces, the separation is still characterized by jumps and pauses, but the double-stranded DNA will completely unzip in less than 30 min

Clinical Psychology and the COVID-19 Pandemic: A Mixed Methods Survey Among Members of the European Association of Clinical Psychology and Psychological Treatment (EACLIPT)

Background: The COVID-19 pandemic has affected people globally both physically and psychologically. The increased demands for mental health interventions provided by clinical psychologists, psychotherapists and mental health care professionals, as well as the rapid change in work setting (e.g., from face-to-face to video therapy) has proven challenging. The current study investigates European clinical psychologists and psychotherapists' views on the changes and impact on mental health care that occurred due to the COVID-19 pandemic. It further aims to explore individual and organizational processes that assist clinical psychologists' and psychotherapists' in their new working conditions, and understand their needs and priorities. Method: Members of the European Association of Clinical Psychology and Psychological Treatment (EACLIPT) were invited (N = 698) to participate in a survey with closed and open questions covering their experiences during the first wave of the pandemic from June to September 2020. Participants (n = 92) from 19 European countries, mostly employed in universities or hospitals, completed the online survey. Results: Results of qualitative and quantitative analyses showed that clinical psychologists and psychotherapists throughout the first wave of the COVID-19 pandemic managed to continue to provide treatments for patients who were experiencing emotional distress. The challenges (e.g., maintaining a working relationship through video treatment) and opportunities (e.g., more flexibleflexibleflexibleworking hours) of working through this time were identified. Conclusions: Recommendations for mental health policies and professional organizations are identified, such as clear guidelines regarding data security and workshops on conducting video therapy

Theory of biopolymer stretching at high forces

We provide a unified theory for the high force elasticity of biopolymers solely in terms of the persistence length, $\xi_p$, and the monomer spacing, $a$. When the force f>\fh \sim k_BT\xi_p/a^2 the biopolymers behave as Freely Jointed Chains (FJCs) while in the range \fl \sim k_BT/\xi_p < f < \fh the Worm-like Chain (WLC) is a better model. We show that $\xi_p$ can be estimated from the force extension curve (FEC) at the extension $x\approx 1/2$ (normalized by the contour length of the biopolymer). After validating the theory using simulations, we provide a quantitative analysis of the FECs for a diverse set of biopolymers (dsDNA, ssRNA, ssDNA, polysaccharides, and unstructured PEVK domain of titin) for $x \ge 1/2$. The success of a specific polymer model (FJC or WLC) to describe the FEC of a given biopolymer is naturally explained by the theory. Only by probing the response of biopolymers over a wide range of forces can the $f$-dependent elasticity be fully described.Comment: 20 pages, 4 figure

Cognitive-behaviour therapy for patients with Abridged Somatization Disorder (SSI 4,6) in primary care: a randomized, controlled study

Abstract Background Somatoform disorders are characterized by the presence of multiple somatic symptoms without an organic cause that completely explains their symptoms. These patients generate a high cost in health services. We aim to evaluate the effectiveness and feasibility of a cognitive-behaviour therapy (CBT) programme, administered in group and individual formats in primary care for patients who are diagnosed with abridged somatization disorder. Method/design Design: Multicentre, randomized, controlled trial involving 3 groups, one of which is the control group consisting of standardized recommended treatment for somatization disorder in primary care (Smith's norms) and the 2 others, the intervention groups, consisting of cognitive-behavioural therapy (10 sessions) administered in individual format (intervention group 1) or in group format (intervention group 2). Setting: 29 primary care health centres in the province of Zaragoza and 3 primary care health centres in the province of Mallorca, Spain. Sample: N = 204 patients, (68 in each of the three groups), aged 18–65 years, able to understand and read Spanish, who fulfil Escobar's criteria of Abridgged Somatization Disorder (SSI 4,6), stable with pharmacotherapy over the previous month, and who will remain stable for the next 3 months in the doctor's opinion, having signed informed consent. Intervention: Control group: Standardized recommended treatment for somatization disorder in primary care (Smith's norms). Intervention group: 10 weekly sessions of CBT, following a protocol designed by Prof. Escobar's group at UMDNJ, USA. There are 2 different treatment conditions: individual and group format. Measurements: Survey on the use of health services, number and severity of somatic symptoms, anxiety, depression, quality of life and clinical global impression. The interviewers will not know which group the patient belongs to (blind). The assessments will be carried out at baseline, post-treatment, 6 months and 12 post-treatment. Main variables: Utilization of health services, number and severity of somatic symptoms. Analysis: The analysis will be per intent to treat. We will use the general linear models of the SPSS v.15 statistical package, to analyse the effect of treatment on the result variable (utilization of health services, number and severity of somatic symptoms). Discussion It is necessary to develop more effective psychological treatments for somatoform disorders. This randomised clinical trial will determine whether cognitive behaviour therapy, both in group or in individual format, is effective for the treatment of these patients. Trial registration Current controlled trials ISRCTN69944771</p

Rapid overview of systematic reviews of nocebo effects reported by patients taking placebos in clinical trials

Background Trial participants in placebo groups report experiencing adverse events (AEs). Existing systematic reviews have not been synthesized, leaving questions about why these events occur as well as their prevalence across different conditions unanswered. Objectives (1) To synthesize the evidence of prevalence of AEs in trial placebo groups across different conditions. (2) To compare AEs in trial placebo groups with AEs reported in untreated groups within a subset of randomized trials. Search methods We searched PubMed for records with the word “nocebo” in the title and “systematic” in any field. We also contacted experts and hand-searched references of included studies. Study eligibility We included any systematic review of randomized trials where nocebo effects were reported. We excluded systematic reviews of non-randomized studies. Participants and interventions We included studies in any disease area. Study appraisal and synthesis methods We appraised the quality of the studies using a shortened version of the Assessment of Multiple Systematic Reviews tool (AMSTAR) tool. We reported medians and interquartile ranges (IQRs) of AEs. Among the trials within the review that included untreated groups, we compared the prevalence of AEs in untreated groups with the prevalence of AEs in placebo groups. Results We identified 20 systematic reviews. These included 1271 randomized trials and 250,726 placebo-treated patients. The median prevalence of AEs in trial placebo groups was 49.1% (IQR 25.7–64.4%). The median rate of dropouts due to AEs was 5% (IQR 2.28–8.4%). Within the 15 of trials that reported AEs in untreated groups, we found that the AE rate in placebo groups (6.51%) was higher than that reported in untreated groups (4.25%). Limitations This study was limited by the quality of included reviews and the small number of trials that included untreated groups. Conclusions and implications of key findings AEs in trial placebo groups are common and cannot be attributed entirely to natural history. Trial methodologies that reduce AEs in placebo groups while satisfying the requirement of informed consent should be developed and implemented

Mechanically activated rupture of single covalent bonds: evidence of force induced bond hydrolysis.

We have used temperature-dependent single molecule force spectroscopy to stretch covalently anchored carboxymethylated amylose (CMA) polymers attached to an amino-functionalized AFM cantilever. Using an Arrhenius kinetics model based on a Morse potential as a one-dimensional representation of covalent bonds, we have extracted kinetic and structural parameters of the bond rupture process. With 35.5 kJ mol−1, we found a significantly smaller dissociation energy and with 9.0 × 102 s−1 to 3.6 × 103 s−1 also smaller Arrhenius pre-factors than expected for homolytic bond scission. One possible explanation for the severely reduced dissociation energy and Arrhenius pre-factors is the mechanically activated hydrolysis of covalent bonds. Both the carboxylic acid amide and the siloxane bond in the amino-silane surface linker are in principle prone to bond hydrolysis. Scattering, slope and curvature of the scattered data plots indicate that in fact two competing rupture mechanisms are observed

Computational case-based redesign for people with ability impairment: Rethinking, reuse and redesign learning for home modification practice

Home modification practice for people with impairments of ability involves redesigning existing residential environments as distinct from the creation of a new dwelling. A redesigner alters existing structures, fittings and fixtures to better meet the occupant's ability requirements. While research on case-based design reasoning and healthcare informatics are well documented, the reasoning and process of redesign and its integration with individual human functional abilities remains poorly understood. Developing a means of capturing redesign knowledge in the form of case documentation online provides a means for integrating and learning from individual case-based redesign episodes where assessment and interventions are naturally linked. A key aim of the research outlined in this thesis was to gain a better understanding of the redesign of spaces for individual human ability with the view to computational modelling. Consequently, the foundational knowledge underpinning the model development includes design, redesign, case-based building design and human functional ability. Case-based redesign as proposed within the thesis, is a method for capturing the redesign context, the residential environment, the modification and the transformational knowledge involved in the redesign. Computational simulation methods are traditionally field dependent. Consequently, part of the research undertaken within this thesis involved the development of a framework for analysing cases within an online case-studies library to validate redesign for individuals and a method of acquiring reuse information so as to be able to estimate the redesign needs of a given population based on either their environment or ability profile. As home modification for people with functional impairments was a novel application field, an explorative action-based methodological approach using computational modelling was needed to underpin a case-based reasoning method. The action-based method involved a process of articulating and examining existing knowledge, suggesting new case-based computational practices, and evaluating the results. This cyclic process led to an improvement cycle that included theory, computational tool development and practical application. The rapid explosion of protocols and online redesign communities that utilise Web technologies meant that a web-based prototype capable of acquiring cases directly from home modification practitioners online and in context was both desirable and achievable. The first online version in 1998-99, encoded home modification redesigns using static WebPages and hyperlinks. This motivated the full-scale more dynamic and robust HMMinfo casestudies prototype whose action-based development is detailed within this thesis. The home modification casestudies library results from the development and integration of a novel case-based redesign model in combination with a Human- Activity-Space computational ontology. These two models are then integrated into a relational database design to enable online case acquisition, browsing, case reuse and redesign learning. The application of the redesign ontology illustrates case reuse and learning, and presents some of the implementation issues and their resolution. Original contributions resulting from this work include: extending case-based design theory to encompass redesign and redesign models, distinguishing the importance of human ability in redesign and the development of the Human-Activity-Space ontology. Additionally all data models were combined and their associated inter-relationships evaluated within a prototype made available to redesign practitioners. v Reflective and practitioner based evaluation contributed enhanced understanding of redesign case contribution dynamics in an online environment. Feedback from redesign practitioners indicated that gaining informed consent to share cases from consumers of home modification and maintenance services, in combination with the additional time required to document a case online, and reticence to go public for fear of critical feedback, all contributed to a less than expected case library growth. This is despite considerable interest in the HMMinfo casestudies website as evidenced by web usage statistics. Additionally the redesign model described in this thesis has practical implications for all design practitioners and educators who seek to create new work by reinterpreting, reconstructing and redesigning spaces

Differences in trauma history and psychopathology between PTSD patients with and without co-occurring dissociative disorders

Wabnitz P, Gast U, Catani C. Differences in trauma history and psychopathology between PTSD patients with and without co-occurring dissociative disorders. European Journal of Psychotraumatology. 2013;2013(4): 21452.Background: The interplay between different types of potentially traumatizing events, posttraumatic symptoms, and the pathogenesis of PTSD or major dissociative disorders (DD) has been extensively studied during the last decade. However, the phenomenology and nosological classification of posttraumatic disorders is currently under debate. The current study was conducted to investigate differences between PTSD patients with and without co-occurring major DD with regard to general psychopathology, trauma history, and trauma-specific symptoms. Methods: Twenty-four inpatients were administered the Clinician-Administered PTSD Scale for DSM-IV (CAPS) and the Mini-Structured Clinical Interview for DSM-IV Dissociative Disorders (MINI-SKID-D) to assess DD and PTSD. Additionally, participants completed questionnaires to assess general psychopathology and health status. Results: Symptom profiles and axis I comorbidity were similar in all patients. Traumatic experiences did not differ between the two groups, with both reporting high levels of childhood trauma. Only trauma-specific avoidance behavior and dissociative symptoms differed between groups. Conclusion: Results support the view that PTSD and DD are affiliated disorders that could be classified within the same diagnostic category. Our results accord with a typological model of dissociation in which profound forms of dissociation are specific to DD and are accompanied with higher levels of trauma-specific avoidance in DD patients

Knotting and unknotting of a protein in single molecule experiments.

Spontaneous folding of a polypeptide chain into a knotted structure remains one of the most puzzling and fascinating features of protein folding. The folding of knotted proteins is on the timescale of minutes and thus hard to reproduce with atomistic simulations that have been able to reproduce features of ultrafast folding in great detail. Furthermore, it is generally not possible to control the topology of the unfolded state. Single-molecule force spectroscopy is an ideal tool for overcoming this problem: by variation of pulling directions, we controlled the knotting topology of the unfolded state of the 52-knotted protein ubiquitin C-terminal hydrolase isoenzyme L1 (UCH-L1) and have therefore been able to quantify the influence of knotting on its folding rate. Here, we provide direct evidence that a threading event associated with formation of either a 31 or 52 knot, or a step closely associated with it, significantly slows down the folding of UCH-L1. The results of the optical tweezers experiments highlight the complex nature of the folding pathway, many additional intermediate structures being detected that cannot be resolved by intrinsic fluorescence. Mechanical stretching of knotted proteins is also of importance for understanding the possible implications of knots in proteins for cellular degradation. Compared with a simple 31 knot, we measure a significantly larger size for the 52 knot in the unfolded state that can be further tightened with higher forces. Our results highlight the potential difficulties in degrading a 52 knot compared with a 31 knot.N.C.H.L. is supported by a UBD Chancellor’s Scholarship from the Brunei Government. W.N. was supported by the Ministry of Education (MoE) Singapore. S.S.M acknowledges funding from the Alexander von Humboldt Foundation. This work was supported by an SFB 863 A2 grant of Deutsche Forschungsgemeinschaft to M.R