Miracle-dz/UniFAR-FTUs huggingface dataset:
Experiences of interventions and rehabilitation activities in connection with return-to-work from a gender perspective. A focus group study among employees on sick leave for common mental disorders

Background Common mental disorders present the main reason for registered sick leave in Sweden today, and women are at a higher risk of such sick leave than men. The aim of this paper is to explore how employees on sick leave for common mental disorders experience interventions and rehabilitation activities during return-to-work, as well as to explore similarities and differences between the experiences of the interviewed women and men. Material and methods A qualitative design was applied with semi-structured focus group interviews. Seven focus groups were conducted with a total of 28 participants (13 women and 15 men). The focus group discussions were audiotaped and transcribed verbatim, and data analyzed with conventional content analysis. Similarities and differences in the women’s and men’s experiences were written down in reflective notes during all steps of the analysis. Results The results comprise of one main category, “To be met with respect and recognition”, and subcategories at two levels. Both similarities and differences emerged in how women and men sick-listed because of common mental disorders experienced return-to-work interventions and rehabilitation activities. It was important for both women and men to be met with respect and recognition, which was essential to all forms of help that the participants discussed during the focus group interviews. Women expressed a need for home-related interventions, whereas men expressed a need for organizational interventions to counter feelings of resignation at work. Women could also more easily understand their mental health condition as compared with men. Conclusion A key implication of this study is that research on interventions and rehabilitation activities during return-to-work among employees on sick leave for common mental disorders should consider whether the findings are relevant equally to both women and men. Similarly, return-to-work professionals may need to consider possible differences among women and men on sick leave for common mental disorders, and to further customize offered interventions and rehabilitation activities. Doing so may help enhance the effectiveness of such interventions.
Coronavirus disease 2019: update on coronavirus disease 2019 outcomes and vaccine efficacy in patients with immune-mediated inflammatory disease

Purpose of review Although the literature to date on COVID-19 outcomes in those with immune-mediated inflammatory disease has been largely reassuring there remain many unanswered questions. These include the impact of specific medications on outcomes and the antibody response after COVID-19 vaccination. Recent findings We summarized the current literature related to COVID-19 outcomes in immune-mediated inflammatory diseases in rheumatology, gastroenterology, dermatology, and neurology. Overall, we found either no difference or modest differences in risk for severe COVID-19 for people with immune-mediated diseases compared with the general population. When considering disease-specific factors, glucocorticoid use and underlying immune-mediated disease activity were generally associated with worse outcomes. Specific medications varied in associations: tumor necrosis factor inhibitors generally had lower odds for severe COVID-19 outcomes, whereas rituximab use generally had higher odds for severe outcomes. We also detailed the recent reports of antibody response to COVID-19 vaccination in people with immune-mediated inflammatory diseases. Summary Investigations of immune-mediated inflammatory diseases across several organ systems have offered important insight into the COVID-19 disease course. Overall, these studies have provided reassurance to patients and clinicians while also identifying groups who may be at higher risk for poor outcomes.
Increased long‐term mortality after open colorectal cancer surgery: A multicentre population‐based study

Unlike meta‐analyses of randomized controlled trials, population‐based studies in colorectal cancer (CRC) patients have shown a significant association between open surgery and increased 30‐ and 90‐day mortality compared with laparoscopic surgery. Long‐term mortality, however, is scarcely reported. This retrospective population‐based study aimed to compare long‐term mortality after open and laparoscopic surgery for CRC.
Systemic therapies for metastatic hormone‐sensitive prostate cancer: network meta‐analysis

To perform a systematic review and network meta‐analysis to compare the efficacy and safety of currently available treatments for the management of metastatic hormone‐sensitive prostate cancer (mHSPC), as there has been a paradigm shift with the use of next‐generation androgen receptor inhibitors (ARIs) and docetaxel.
Phytoplankton mortality in a changing thermal seascape

Predicting spatiotemporal distributions of phytoplankton biomass and community composition heavily relies on experimental studies that document how environmental conditions influence population growth rates. In unicellular phytoplankton, the net population growth rate is the difference between the cell division rate and the death rate. Along with predation and disease, phytoplankton mortality arises from abiotic stress. Although the effect of temperature on the net population growth rate is well understood, studies examining thermally induced death rates in phytoplankton are scarce. We investigated how cell division and death rates of the diatom Phaeodactylum tricornutum varied within its thermal tolerance limits (thermal niche), and at temperatures just above its upper thermal tolerance limit. We show that death rates were largely independent of temperature when P. tricornutum was grown within its thermal niche, but increased significantly at temperatures that approached or exceeded its upper thermal tolerance limit. Furthermore, the sensitivity of mortality increased with the duration of exposure to heat stress and was affected by the pre‐acclimation temperature. Heat waves can be expected to significantly affect phytoplankton mortality episodically. The increasing frequency of heat waves accompanying global warming can be expected to drive changes in phytoplankton community structure due to interspecific variability of thermal niches with potential implications for food web dynamics and biogeochemical cycles.
Pulsating fluid flow affects pre‐osteoblast behavior and osteogenic differentiation through production of soluble factors

Bone mass increases after error‐loading, even in the absence of osteocytes. Loaded osteoblasts may produce a combination of growth factors affecting adjacent osteoblast differentiation. We hypothesized that osteoblasts respond to a single load in the short‐term (minutes) by changing F‐actin stress fiber distribution, in the intermediate‐term (hours) by signaling molecule production, and in the long‐term (days) by differentiation. Furthermore, growth factors produced during and after mechanical loading by pulsating fluid flow (PFF) will affect osteogenic differentiation. MC3T3‐E1 pre‐osteoblasts were either/not stimulated by 60 min PFF (amplitude, 1.0 Pa; frequency, 1 Hz; peak shear stress rate, 6.5 Pa/s) followed by 0–6 h, or 21/28 days of post‐incubation without PFF. Computational analysis revealed that PFF immediately changed distribution and magnitude of fluid dynamics over an adherent pre‐osteoblast inside a parallel‐plate flow chamber (immediate impact). Within 60 min, PFF increased nitric oxide production (5.3‐fold), altered actin distribution, but did not affect cell pseudopodia length and cell orientation (initial downstream impact). PFF transiently stimulated Fgf2, Runx2, Ocn, Dmp1, and Col1⍺1 gene expression between 0 and 6 h after PFF cessation. PFF did not affect alkaline phosphatase nor collagen production after 21 days, but altered mineralization after 28 days. In conclusion, a single bout of PFF with indirect associated release of biochemical factors, stimulates osteoblast differentiation in the long‐term, which may explain enhanced bone formation resulting from mechanical stimuli.
Temperature Dependence and Structural Influence on the Thermophysical Properties of Eleven Commercial Ionic Liquids

Density, speed of sound, refractive index, and viscosity of the commercial ionic liquids 1-ethyl-3-methylpyridinium bis(trifluoromethylsulfonyl)imide, [EMpy][NTf2], 1-propyl-3-methylpyridinium bis(trifluoromethylsulfonyl)imide, [PMpy][NTf2], 1-butyl-3-methylpyridinium bis(trifluoromethylsulfonyl)imide, [BMpy][NTf2], 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [EMim][NTf2], 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [HMim][NTf2], 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, [BMpyr][NTf2], 1-butyl-1-methylpyrrolidinium trifluoromethanesulfonate, [BMpyr][TFO], 1-butyl-3-methylimidazolium trifluoromethanesulfonate, [BMim][TFO], 1-hexyl-3-methylimidazolium trifluoromethanesulfonate, [HMim][TFO], 1-butyl-3-methylimidazolium dicyanamide, [BMim][N(CN)2], and 1-hexyl-3-methylimidazolium dicyanamide, [HMim][N(CN)2] were measured as a function of temperature at atmospheric pressure. The density, speed of sound, and refractive index data were properly fitted .
Myristoylation and its effects on the human Golgi Reassembly and Stacking Protein 55

GRASP55 is a myristoylated protein localized in the medial/trans-Golgi faces and involved in the Golgi structure maintenance and the regulation of unconventional secretion pathways. It is believed that GRASP55 achieves its main functionalities in the Golgi organization by acting as a tethering factor and, when bound to the lipid bilayer, its orientation relative to the membrane surface is restricted to determine its proper trans-oligomerization. Despite the paramount role of myristoylation in GRASP function, the impact of such protein modification on the membrane-anchoring properties and the structural organization of GRASP remains elusive. Here, an optimized protocol for the myristoylation in E. coli of the membrane-anchoring domain of GRASP55 is presented. The biophysical properties of the myristoylated/non-myristoylated GRASP55 GRASP domain were characterized in a membrane-mimicking micellar environment. Although myristoylation did not cause any impact on the protein’s secondary structure, according to our circular dichroism data, it had a significant impact on the protein’s thermal stability and solubility. Electrophoresis of negatively charged liposomes incubated with the two GRASP55 constructions showed different electrophoretic mobility for the myristoylated anchored protein only, thus demonstrating that myristoylation is essential for the biological membrane anchoring. Molecular dynamics simulations were used to further explore the anchoring process in determining the restricted orientation of GRASPs in the membrane.
Oxidative Stress Is a Potential Cost of Synchronous Nesting in Olive Ridley Sea Turtles

Olive ridley sea turtles, Lepidochelys olivacea, exhibit a polymorphic reproductive behaviour nesting in solitary or in mass aggregations termed “arribadas”, where thousands of turtles nest at once. Arribadas may provide fitness benefits including mate finding during nearshore aggregations and predator satiation at the time of hatching, but the potential costs of arribada nesting remain understudied. To explore the potential trade-offs of the fitness benefits associated with arribada nesting, we collected blood from olive ridley turtles nesting in arribada and solitary. We measured reproductive and metabolic hormones (progesterone, estradiol, testosterone, thyroxine, and triiodothyronine), triglycerides (TG), non-esterified fatty acids (NEFA) and markers of oxidative damage (4-hydroxynonenal, malondialdehyde, protein carbonyls, and nitrotyrosine). Arribada nesters were bigger and had higher levels of progesterone than solitary nesters. Similarly, thyroid hormones were higher in individuals nesting in arribada than in solitary nesters, while TG and NEFA were positively correlated in arribada but not in solitary nesters. Nesting in arribada was associated with increased lipid peroxidation and protein carbonyls compared to solitary nesting. These results suggest that nesting in arribada is potentially more energetically expensive than nesting solitarily, and that oxidative stress may be a trade-off of the fitness benefits associated with arribada nesting.
Pseudomonas syringae addresses distinct environmental challenges during plant infection through the coordinated deployment of polysaccharides

Prior to infection, phytopathogenic bacteria face a challenging environment on the plant surface, where they are exposed to nutrient starvation and abiotic stresses. Pathways enabling surface adhesion, stress tolerance and epiphytic survival are important for successful plant pathogenesis. Understanding the roles and regulation of these pathways is therefore crucial to fully understand bacterial plant infections. The phytopathogen Pseudomonas syringae pv. tomato (Pst) encodes multiple polysaccharides that are implicated in biofilm formation, stress survival and virulence in other microbes. To examine how these polysaccharides impact Pst epiphytic survival and pathogenesis, we analysed mutants in multiple polysaccharide loci to determine their intersecting contributions to epiphytic survival and infection. In parallel, we used qRT-PCR to analyse the regulation of each pathway. Pst polysaccharides are tightly coordinated by multiple environmental signals. Nutrient availability, temperature and surface association strongly affect the expression of different polysaccharides under the control of the signalling proteins ladS and cbrB and the second messenger cyclic-di-GMP. Furthermore, functionally redundant, combinatorial phenotypes were observed for several polysaccharides. Exopolysaccharides and WapQ-mediated lipopolysaccharide production are important for leaf adhesion, while α-glucan and alginate together confer desiccation tolerance. Our results suggest that polysaccharides play important roles in overcoming environmental challenges to Pst during plant infection. Highlight Pseudomonas syringae uses the coordinated deployment of polysaccharides to address environmental challenges during plant colonization. Functional redundancy renders individual polysaccharides dispensable during plant infection, but their combined loss impedes pathogenicity.
Complexity of Genomic Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae Isolates in Colombia Urges the Reinforcement of Whole Genome Sequencing-Based Surveillance Programs

Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging public health problem. This study explores the specifics of CRKP epidemiology in Colombia based on whole genome sequencing (WGS) of the National Reference Laboratory at Instituto Nacional de Salud (INS)’s 2013-2017 sample collection. Methods A total of 425 CRKP isolates from 21 departments were analyzed by HiSeq-X10® Illumina high-throughput sequencing. Bioinformatic analysis was performed, primarily using the pipelines developed collaboratively by the National Institute for Health Research Global Health Research Unit (GHRU) on Genomic Surveillance of AMR, and AGROSAVIA. Results Of the 425 CRKP isolates, 91.5% were carbapenemase-producing strains. The data support a recent expansion and the endemicity of CRKP in Colombia with the circulation of 7 high-risk clones, the most frequent being CG258 (48.39% of isolates). We identified genes encoding carbapenemases blaKPC-3, blaKPC-2, blaNDM-1, blaNDM-9, blaVIM-2, blaVIM-4, and blaVIM-24, and various mobile genetic elements (MGE). The virulence of CRKP isolates was low, but colibactin (clb3) was present in 25.2% of isolates, and a hypervirulent CRKP clone (CG380) was reported for the first time in Colombia. ST258, ST512, and ST4851 were characterized by low levels of diversity in the core genome (ANI> 99.9%). Conclusions The study outlines complex CRKP epidemiology in Colombia. CG258 expanded clonally and carries specific carbapenemases in specific MGEs, while the other high-risk clones (CG147, CG307, and CG152) present a more diverse complement of carbapenemases. The specifics of the Colombian situation stress the importance of WGS-based surveillance to monitor evolutionary trends of STs, MGE, and resistance and virulence genes. summary In Colombia, the dissemination of carbapenemases in carbapenem-resistant Klebsiella pneumoniae is attributed to horizontal gene transfer and successful circulation of CG258, and, to a lesser extent, other clones such as ST307, ST147, and ST152.
Economic Choices under Simultaneous or Sequential Offers Rely on the Same Neural Circuit

A series of studies in which monkeys chose between two juices offered in variable amounts identified in the orbitofrontal cortex (OFC) different groups of neurons encoding the value of individual options (offer value), the binary choice outcome (chosen juice), and the chosen value. These variables capture both the input and the output of the choice process, suggesting that the cell groups identified in OFC constitute the building blocks of a decision circuit. Several lines of evidence support this hypothesis. However, in previous experiments offers were presented simultaneously, raising the question of whether current notions generalize to when goods are presented or are examined in sequence. Recently, Ballesta and Padoa-Schioppa (2019) examined OFC activity under sequential offers. An analysis of neuronal responses across time windows revealed that a small number of cell groups encoded specific sequences of variables. These sequences appeared analogous to the variables identified under simultaneous offers, but the correspondence remained tentative. Thus, in the present study, we examined the relation between cell groups found under sequential versus simultaneous offers. We recorded from the OFC while monkeys chose between different juices. Trials with simultaneous and sequential offers were randomly interleaved in each session. We classified cells in each choice modality, and we examined the relation between the two classifications. We found a strong correspondence; in other words, the cell groups measured under simultaneous offers and under sequential offers were one and the same. This result indicates that economic choices under simultaneous or sequential offers rely on the same neural circuit. SIGNIFICANCE STATEMENT Research in the past 20 years has shed light on the neuronal underpinnings of economic choices. A large number of results indicates that decisions between goods are formed in a neural circuit within the orbitofrontal cortex. In most previous studies, subjects chose between two goods offered simultaneously. Yet, in daily situations, goods available for choice are often presented or examined in sequence. Here we recorded neuronal activity in the primate orbitofrontal cortex alternating trials under simultaneous and under sequential offers. Our analyses demonstrate that the same neural circuit supports choices in the two modalities. Hence, current notions on the neuronal mechanisms underlying economic decisions generalize to choices under sequential offers.
A multiparametric activity profiling platform for neuron disease phenotyping and drug screening

Patient stem cell-derived models enable imaging of complex disease phenotypes and the development of scalable drug discovery platforms. Current preclinical methods for assessing cellular activity do not, however, capture the full intricacies of disease-induced disturbances, and instead typically focus on a single parameter, which impairs both the understanding of disease and the discovery of effective therapeutics. Here, we describe a cloud-based image processing and analysis platform that captures the intricate activity profile revealed by GCaMP fluorescent recordings of intracellular calcium changes and enables discovery of molecules that correct 153 parameters that define the amyotrophic lateral sclerosis motor neuron disease phenotype. In a high-throughput screen we identified compounds that revert the multiparametric disease profile to that found in healthy cells, a novel and robust measure of therapeutic potential quite distinct from unidimensional screening. This platform can guide the development of therapeutics that counteract the multifaceted pathological features of diseased cellular activity.
Switching an active site helix in dihydrofolate reductase reveals limits to sub-domain modularity

To what degree are individual structural elements within proteins modular such that similar structures from unrelated proteins can be interchanged? We study sub-domain modularity by creating 20 chimeras of an enzyme, E. coli dihydrofolate reductase (DHFR), in which a catalytically important, 10-residue α-helical sequence is replaced by α-helical sequences from a diverse set of proteins. The chimeras stably fold but have a range of diminished thermal stabilities and catalytic activities. Evolutionary coupling analysis indicates that the residues of this α-helix are under selection pressure to maintain catalytic activity in DHFR. We performed molecular dynamics simulations using replica exchange with solute-tempering. Chimeras with low catalytic activity exhibit non-helical conformations that block the binding site and disrupt the positioning of the catalytically essential residue D27. Simulation observables and in vitro measurements of thermal stability and substrate binding affinity are strongly correlated. Several E. coli strains with chromosomally integrated chimeric DHFRs can grow, with growth rates that follow predictions from a kinetic flux model that depends on the intracellular abundance and catalytic activity of DHFR. Our findings show that although α-helices are not universally substitutable, the molecular and fitness effects of modular segments can be predicted by the biophysical compatibility of the replacement segment. Statement of Significance α-helices are ubiquitous components of protein structure that exhibit a degree of independent folding behavior, making them plausible structural modules within proteins. Here, we assess the effects of switching the sequence of an α-helix in an essential enzyme for α-helical sequences from evolutionarily unrelated proteins. The resultant chimeric proteins can still fold but enzymatic activity, stability, and cellular growth rates are negatively affected. Computational investigations reveal how residues in an α-helix have been shaped by selection pressure to maintain catalytic activity and a specific, helical conformation of the protein. More broadly, we illustrate how molecular and fitness effects of switching protein segments depend on the protein and cellular context.
Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes, but the impacts of integration in tumorigenesis remain unclear. Analysis of 105 HPV-positive oropharyngeal cancers by whole genome sequencing detects viral integration in 77%, revealing five statistically significant integration hotspots near genes that regulate epithelial stem cell maintenance (i.e. SOX2, TP63, FGFR, MYC) and immune evasion (i.e. CD274). Somatic hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with local density of HPV integrants. Genes expressed at extreme outlier levels are increased 86-fold within +/- 150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking and/or de novo expression of noncoding or imprinted genes. We conclude that HPV integration contributes substantively to cancer development by causing extensive disruption of host genome structure and gene expression.