Miracle-dz/UniFAR-FTUs huggingface dataset:
Manipulation of mRNA translation elongation influences the fragmentation of a biotherapeutic Fc‐fusion protein produced in CHO cells

Mammalian cells, particularly Chinese hamster ovary cells, are the dominant system for the production of protein‐based biotherapeutics, however, product degradation, particularly of Fc‐fusion proteins, is sometimes observed that impacts the quality of the protein generated. Here, we identify the site of fragmentation of a model immunoglobulin G1 Fc‐fusion protein, show that the observed clipping and aggregation are decreased by reduced temperature culturing, that the fragmentation/clipping is intracellular, and that reduced clipping at a lower temperature (<37°C) relates to mesenger RNA (mRNA) translation elongation. We subsequently show that reduced fragmentation can be achieved at 37°C by addition of chemical reagents that slow translation elongation. We then modified mRNA translation elongation speeds by designing different transcript sequences for the Fc‐fusion protein based on alternative codon usage and improved the product yield at 37°C, and the ratio of intact to a fragmented product. Our data suggest that rapid elongation results in misfolding that decreases product fidelity, generating a region susceptible to degradation/proteolysis, whilst the slowing of mRNA translation improves the folding, reducing susceptibility to fragmentation. Manipulation of mRNA translation and/or the target Fc‐fusion transcript is, therefore, an approach that can be applied to potentially reduce fragmentation of clipping‐prone Fc‐fusion proteins.
Can we have a second helping? A preregistered direct replication study on the neurobiological mechanisms underlying self‐control

Self‐control is of vital importance for human wellbeing. Hare et al. (2009) were among the first to provide empirical evidence on the neural correlates of self‐control. This seminal study profoundly impacted theory and empirical work across multiple fields. To solidify the empirical evidence supporting self‐control theory, we conducted a preregistered replication of this work. Further, we tested the robustness of the findings across analytic strategies. Participants underwent functional magnetic resonance imaging while rating 50 food items on healthiness and tastiness and making choices about food consumption. We closely replicated the original analysis pipeline and supplemented it with additional exploratory analyses to follow‐up on unexpected findings and to test the sensitivity of results to key analytical choices. Our replication data provide support for the notion that decisions are associated with a value signal in ventromedial prefrontal cortex (vmPFC), which integrates relevant choice attributes to inform a final decision. We found that vmPFC activity was correlated with goal values regardless of the amount of self‐control and it correlated with both taste and health in self‐controllers but only taste in non‐self‐controllers. We did not find strong support for the hypothesized role of left dorsolateral prefrontal cortex (dlPFC) in self‐control. The absence of statistically significant group differences in dlPFC activity during successful self‐control in our sample contrasts with the notion that dlPFC involvement is required in order to effectively integrate longer‐term goals into subjective value judgments. Exploratory analyses highlight the sensitivity of results (in terms of effect size) to the analytical strategy, for instance, concerning the approach to region‐of‐interest analysis.
Developing Action Plans Based on Machine Learning Analysis to Prevent Sick Leave in a Manufacturing Plant

This article describes a process of action plan development to prevent sick leave using a machine learning model at a Japanese manufacturing plant. Stress response scores in the Brief Job Stress Questionnaire, workers’ age, and departments were important factors, and thus, we developed plans to address each of these factors. Objective We aimed to develop action plans for employees' health promotion based on a machine learning model to predict sick leave at a Japanese manufacturing plant. Methods A random forest model was developed to predict sick leave. We developed plans for workers' health promotion based on variable importance and partial dependence plots. Results The model showed an area under the receiving operating characteristic curve of 0.882. The higher scores on the Brief Job Stress Questionnaire stress response, younger age, and certain departments were important predictors for sick leave due to mental disorders. We proposed plans to effectively use the Brief Job Stress Questionnaire and provide more support for younger workers and managers of high-risk departments. Conclusions We described a process of action plan development using a machine learning model, which may be beneficial for occupational health practitioners.
Treatments and interventions for compulsive sexual behavior disorder with a focus on problematic pornography use: A preregistered systematic review

Abstract Background and aims Compulsive sexual behavior disorder (CSBD) which includes problematic pornography use (PPU) is a clinically relevant syndrome that has been included in the ICD-11 as impulse control disorder. The number of studies on treatments in CSBD and PPU increased in the last years. The current preregistered systematic review aimed for identifying treatment studies on CSBD and PPU as well as treatment effects on symptom severity and behavior enactment. Methods The study was preregistered at Prospero International Prospective Register of Systematic Reviews (CRD42021252329). The literature search done in February 2022 at PubMed, Scopus, Web of Science, and PsycInfo, included original research published in peer-reviewed journals between 2000 to end 2021. The risk of bias was assessed with the CONSORT criteria. A quantitative synthesis based on effect sizes was done. Results Overall 24 studies were identified. Four of these studies were randomized controlled trials. Treatment approaches included settings with cognitive behavior therapy components, psychotherapy methods, and psychopharmacological therapy. Receiving treatment seems to improve symptoms of CSBD and PPU. Especially, evidence for the efficacy of cognitive behavior therapy is present. Discussion and conclusions There is first evidence for the effectiveness of treatment approaches such as cognitive behavior therapy. However, strong conclusions on the specificity of treatments should be drawn with caution. More rigorous and systematic methodological approaches are needed for future studies. Results may be informative for future research and the development of specific treatment programs for CSBD and PPU.
Coping profiles and differences in well‐being during the COVID‐19 pandemic: A latent profile analysis

Abstract During the current COVID‐19 pandemic, people need to cope with multiple stressors which may affect their well‐being. This study aimed (1) to identify latent coping profiles in the German general population, and (2) to investigate differences between these profiles in well‐being. In total, N = 2326 German participants were recruited as part of the European Society of Traumatic Stress Studies (ESTSS) ADJUST study from June to September 2020 using an online survey. Coping strategies were assessed using the Brief‐COPE and the Pandemic Coping Scale; well‐being was assessed using the WHO‐5 Well‐Being Index. Coping profiles were identified using latent profile analysis; differences between profiles were examined using the automatic BCH method and multiple group analyses. Five coping profiles were identified that included different types and numbers of coping strategies: (1) High functional coping (17.84%), (2) Moderate functional coping (40.63%), (3) High functional and religious coping (9.07%), (4) Low functional coping (22.06%), (5) Moderate functional and dysfunctional coping (10.40%). The identified profiles significantly differed in well‐being (χ 2 = 503.68, p <0.001). Coping profiles indicating high functional coping were associated with greater well‐being compared to coping profiles indicating low (χ 2 = 82.21, p <0.001) or primarily dysfunctional (χ 2 = 354.33, p <0.001) coping. These results provide insight into how people differ in their coping strategies when dealing with stressors in an early phase of the COVID‐19 pandemic. The study indicates higher levels of well‐being in coping profiles with more frequent use of functional strategies. To promote well‐being in the general population, it might be beneficial to train functional coping strategies in appropriate interventions that are associated with increased well‐being.
Validation of the Spanish Versions of FACIT-PAL and FACIT-PAL-14 in Palliative Patients

Palliative patients require several types of care to improve their quality of life as much as possible, and valid and reliable assessment instruments are essential. The objective of this study is the Spanish validation of the Functional Assessment Chronic Illness Therapy-Palliative Care (FACIT-PAL) and its abbreviated version, FACIT-PAL-14, in palliative care patients. FACIT-PAL and FACIT-PAL-14 were translated into Spanish and administered to 131 terminal oncology patients in home palliative care units, hospital palliative care units, health center teams, and social health centers. The European Organization for Research and Treatment of Cancer questionnaire, EORTC-QLQ-C15-PAL version, was used to evaluate the criterion validity. The EORTC-QLQ-C15-PAL was employed as a “gold standard”, and it obtained significant results with FACIT scales. FACIT-PAL-14, FACIT-PAL, and its subscales reported high internal consistency, from 0.640 to 0.816. The exploratory factor analysis for FACIT-PAL-14 found a structure in three factors that explained the 70.10% variance, and the FACIT-PAL scale found a structure of five factors. Physical wellbeing from FACIT-PAL highly correlated to the EORTC-QLQ-C15-PAL (r = 0.700), but social and family wellbeing was correlated to a lesser extent (r = −0.323). FACIT-PAL and the TOI (Toi Outcome Index) were also highly correlated with the EORTC-QLQ-C15-PAL, with values of r = −0.708 and r = −0.709, respectively. The Spanish versions of FACIT-PAL and FACIT-PAL-14 were demonstrated to be valid and reliable scales in palliative care patients.
Treatment strategies for low-risk papillary thyroid carcinoma: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM)

ABSTRACT Increasingly sensitive diagnostic methods, better understanding of molecular pathophysiology, and well-conducted prospective studies have changed the current approach to patients with thyroid cancer, requiring the implementation of individualized management. Most patients with papillary thyroid carcinoma (PTC) are currently considered to have a low risk of mortality and disease persistence/recurrence. Consequently, current treatment recommendations for these patients include less invasive or intensive therapies. We used the most recent evidence to prepare a position statement providing guidance for decisions regarding the management of patients with low-risk PTC (LRPTC). This document summarizes the criteria defining LRPTC (including considerations regarding changes in the TNM staging system), indications and contraindications for active surveillance, and recommendations for follow-up and surgery. Active surveillance may be an appropriate initial choice in selected patients, and the criteria to recommend this approach are detailed. A section is dedicated to the current evidence regarding lobectomy versus total thyroidectomy and the potential pitfalls of each approach, considering the challenges during long-term follow-up. Indications for radioiodine (RAI) therapy are also addressed, along with the benefits and risks associated with this treatment, patient preparation, and dosage. Finally, this statement presents the best follow-up strategies for LRPTC after lobectomy and total thyroidectomy with or without RAI.
Preliminary single-arm study of brain effects during transcutaneous auricular vagus nerve stimulation treatment of recurrent depression by resting-state functional magnetic resonance imaging.

OBJECTIVE To examine the brain effects of transcutaneous auricular vagus nerve stimulation (taVNS) treatment of recurrent depression based on the functional brain network by using resting-state functional magnetic resonance imaging (fMRI). METHODS Twenty-five patients with recurrent depression were enrolled in a single-arm trial of taVNS treatment for eight weeks. Clinical results were assessed by 17-item Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Scale (HAMA), Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), and Ruminative Response Scale (RRS) scales. Resting-state fMRI was conducted to explore the brain effects before and after treatment. For the functional connectivity (FC) analysis, the bilateral nucleus accumbens, globus pallidus, caudate, and putamen were selected as seeds. Finally, the correlations between FC and the clinical scale scores were calculated. RESULTS After treatment, the patients' scores of HAMD-17, HAMA, SDS, SAS, and RRS were significantly decreased ( < 0.05). FC was considerably decreased between the following areas: the left globus pallidus and the right postcentral gyrus, inferior parietal gyrus, the right globus pallidus and the left superior marginal gyrus, postcentral gyrus, superior parietal gyrus, inferior parietal gyrus, precuneus, right postcentral gyrus, superior marginal gyrus, and inferior parietal gyrus, between the right caudate and the right lingual gyrus, calcarine gyrus, and cerebellum. Changes in FC between the right globus pallidus and the left inferior parietal gyrus, between the left globus pallidus and the right postcentral gyrus were negatively correlated with HAMD-17 scores change before and after treatment (before, = 0.003, = -0.6; after, 0.009,= -0.54). The change of FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SDS (= 0.026,= -0.474). The difference in FC between the right globus pallidus and the right postcentral gyrus was negatively correlated with the change in SAS (= 0.016,= -0.513). CONCLUSIONS Recurrent depression could be effectively treated with taVNS. The changes in brain FC involving the basal ganglia, default mode, and sensorimotor networks provide insight into the effects of taVNS treatment on recurrent depression.
Theory of Nonequilibrium Superconductivity

PART I: GREEN'S FUNCTIONS IN THE BCS THEORY 1. Introduction 2. Green's Functions 3. The BCS Model 4. Superconducting Alloys PART II: THE QUASICLASSICAL METHOD 5. General Principles of the Quasiclassical Approximation 6. Quasiclassical Methods in Stationary Problems 7. Quasiclassical Methods for Layered Superconductors PART III: NONEQUILIBRIUM SUPERCONDUCTIVITY 8. Nonstationary Theory 9. Quasiclassical Methods for Nonstationary Phenomena 10. Kinetic Equations 11. The Time-Dependent Ginzburg-Landau Theory PART IV: VORTEX DYNAMICS 12. Time-Dependent Ginzburg-Landau Analysis 13. Vortex Dynamics in Dirty Superconductors 14. Vortex Dynamics in Clean Superconductors 15. Boltzmann's Kinetic Equation References Index
Polycystic ovary syndrome and leukocyte telomere length: cross-sectional and longitudinal changes

Objective Telomeres are DNA–protein complexes that protect chromosome ends from DNA damage and are surrogate biomarkers of cellular aging. Current evidence, almost entirely from cross-sectional observations, supports negative associations between leukocyte telomere length (LTL) and adverse lifestyle factors and cardiometabolic risk factors. Polycystic ovary syndrome (PCOS), the most common gynecological endocrine disorder, is associated with inflammation and oxidative stress, both factors associated with accelerated telomere attrition. We therefore hypothesized that LTL would be shorter and decrease more rapidly in women with PCOS in comparison to a control population. Design This is a population-based cohort study comprising women of Northern Finland Birth Cohort 1966, with clinical examinations at ages 31 and 46. The sample included self-reported PCOS (age 31, n = 190; age 46, n = 207) and referent women (age 31, n = 1054; age 46, n = 1324) with data on LTL. Methods The association between LTL and PCOS at ages 31 and 46 was analyzed by linear regression models adjusted for BMI, smoking, alcohol consumption and socioeconomic status at the corresponding age. Results Women with PCOS had similar mean LTL at ages 31 and 46 (P > 0.4 for both). The mean LTL change between ages 31 and 46 did not differ between groups (P = 0.19). However, we observed a significant LTL attrition between ages 31 and 46 in the reference population (P < 0.001), but not in women with PCOS (P = 0.96). Conclusions This finding may suggest a difference in the LTL attrition rate in women with PCOS, an unexpected finding that might affect their risk of age-related disease. Further research is needed to clarify the underlying mechanisms.
A large multi-country outbreak of monkeypox across 41 countries in the WHO European Region, 7 March to 23 August 2022

Following the report of a non-travel-associated cluster of monkeypox cases by the United Kingdom in May 2022, 41 countries across the WHO European Region have reported 21,098 cases and two deaths by 23 August 2022. Nowcasting suggests a plateauing in case notifications. Most cases (97%) are MSM, with atypical rash-illness presentation. Spread is mainly through close contact during sexual activities. Few cases are reported among women and children. Targeted interventions of at-risk groups are needed to stop further transmission.
Dimmed gene knockout shortens larval growth and reduces silk yield in the silkworm, Bombyx mori

The bHLH domain transcription factor, Bombyx mori‐derived dimmed (Bmdimm), is directly regulated by the JH‐BmMet/BmSRC‐BmKr‐h1 pathway and plays a key role in regulating the expression of FibH, which codes the main component of silk protein. However, the other roles of Bmdimm in silk protein synthesis remain unclear. Here, we established a Bmdimm knockout (KO) line containing a 7‐bp deletion via CRISPR/Cas9 system, which led to the absence of the bHLH domain. The expression level of silk protein genes and silk yield decreased significantly in the Bmdimm KO line. Moreover, knocking out Bmdimm led to shortened larval stages and significant weight loss in larvae and adults. Bmdimm was found to be highly expressed in the silk gland, but it was also expressed in the fat body. The expression level of Bmkr‐h1 in the fat body was significantly downregulated in the Bmdimm KO line. Exogenous JHA treatment upregulated Bmkr‐h1 and rescued the phenotype of larval growth in the Bmdimm KO line. In conclusion, knocking out Bmdimm led to a shortened larval stage via the inhibition of Bmkr‐h1 expression, then reduced silk yield. These findings help to elucidate the regulatory mechanism of fibroin synthesis and larval development in silkworms.
Astrocytes show increased levels of Ero1α in multiple sclerosis and its experimental autoimmune encephalomyelitis animal model

Multiple sclerosis (MS) and its animal models are characterized by cellular inflammation within the central nervous system (CNS). The sources and consequences of this inflammation are currently not completely understood. Critical signs and mediators of CNS inflammation are reactive oxygen species (ROS) that promote inflammation. ROS originate from a variety of redox‐reactive enzymes, one class of which catalyses oxidative protein folding within the endoplasmic reticulum (ER). Here, the unfolded protein response and other signalling mechanisms maintain a balance between ROS producers such as ER oxidoreductin 1α (Ero1α) and antioxidants such as glutathione peroxidase 8 (GPx8). The role of ROS production within the ER has so far not been examined in the context of MS. In this manuscript, we examined how components of the ER redox network change upon MS and experimental autoimmune encephalomyelitis (EAE). We found that unlike GPx8, Ero1α increases within both MS and EAE astrocytes, in parallel with an imbalance of other oxidases such of GPx7, and that no change was observed within neurons. This imbalance of ER redox enzymes can reduce the lifespan of astrocytes, while neurons are not affected. Therefore, Ero1α induction makes astrocytes vulnerable to oxidative stress in the MS and EAE pathologies.
Oxidative stress mediated immunosuppression caused by ammonia gas via antioxidant/oxidant imbalance in broilers

ABSTRACT 1. Ammonia is one of major air pollutants in intensive poultry houses, where it causes immunosuppression in broilers. Although previous studies have focused on a particular organ, data on multiple organs have not been reported. 2. In the following work, broilers were exposed to environmental ammonia (0, 10, 20, and 40 mg/m3 from 1–21 d old; and 0, 15, 30, and 60 mg/m3 from 22–42 d old). 3. Ammonia exposure reduced bird spleen index at 42 d and thymus index at 14, 28, 35 and 42 d, meaning that ammonia caused immunosuppression in birds. Moreover, high ammonia exposure down-regulated the expression of toll-like receptor 4 (TLR4) in lung tissue at 21 d, as well as TLR4 in lung and tracheal mucosa at 42 d when analysed using qRT-PCR. It increased SIgA in saliva at 42 d when analysed by ELISA. Ammonia increased interleukin-6 (IL-6), IL-1β, interferon-α (IFN-α), and IFN-γ in serum at 28 d from the ELISA assay, which indicated that all of these factors took part in ammonia-immunosuppression in birds. 4. Three antioxidants (CAT, SOD, T-AOC) decreased, and one oxidant MDA increased after ammonia exposure in the liver and blood, which indicated that ammonia caused oxidative stress via the imbalance of antioxidants/oxidants in birds. 5. Correlation analysis showed that TLR4 and TLR15 in the tracheal mucosa were significantly positively related to IFN-γ and negatively related to IL-6. TLR2 in the lung was significantly positively related to IL-1β, and TLR2 in bird tracheal mucosa was negatively related to IL-6 in serum. 6. The results suggested that oxidative stress mediated immunosuppression caused by ammonia gas via antioxidant/oxidant imbalance in broilers.
High throughput genome scale modeling predicts microbial vitamin requirements contribute to gut microbiome community structure

ABSTRACT Human gut microbiome structure and emergent metabolic outputs impact health outcomes. However, what drives such community characteristics remains underexplored. Here, we rely on high throughput genomic reconstruction modeling, to infer the metabolic attributes and nutritional requirements of 816 gut strains, via a framework termed GEMNAST. This has been performed in terms of a group of human vitamins to examine the role vitamin exchanges have at different levels of community organization. We find that only 91 strains can satisfy their vitamin requirements (prototrophs) while the rest show various degrees of auxotrophy/specialization, highlighting their dependence on external sources, such as other members of the microbial community. Further, 79% of the strains in our sample were mapped to 11 distinct vitamin requirement profiles with low phylogenetic consistency. Yet, we find that human gut microbial community enterotype indicators display marked metabolic differences. Prevotella strains display a metabolic profile that can be complemented by strains from other genera often associated with the Prevotella enterotype and agrarian diets, while Bacteroides strains occupy a prototrophic profile. Finally, we identify pre-defined interaction modules (IMs) of gut species from human and mice predicted to be driven by, or highly independent of vitamin exchanges. Our analysis provides mechanistic grounding to gut microbiome stability and to co-abundance-based observations, a fundamental step toward understanding emergent processes that influence health outcomes. Further, our work opens a path to future explorations in the field through applications of GEMNAST to additional nutritional dimensions.