Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of working conditions on non-work-related sickness absence.

BACKGROUND There is limited evidence of the role of working conditions as prognostic factors for non-work-related sickness absence (i.e. absence due to injuries or diseases of non-occupational origin). AIMS To analyse the association between working conditions and time to return to work (RTW) in workers with long-term (>15 days) non-work-related sickness absence. METHODS We followed up a total of 655 workers, who completed a baseline questionnaire including physical and psychosocial work factors, until their non-work-related long-term sickness absence ended. Time to RTW was determined based on the health insurance company register. Cox proportional hazard models were constructed to evaluate the associations between working conditions and time to RTW. RESULTS A self-perceived high level of physical activity at work and work with back twisted or bent were related to longer duration of sickness absence. We did not find any strong evidence of associations between psychosocial work factors and time to RTW, although higher job insecurity and low reward showed marginal statistical significance. CONCLUSIONS Hazardous physical working conditions are associated with longer duration of non-work-related sickness absence. Workplace ergonomic interventions could conceivably shorten the length of sickness absence that has not originated at work.
Large nonsaturating magnetoresistance and signature of nondegenerate Dirac nodes in ZrSiS

Significance Topological semimetals provide the opportunity to explore the fundamental physics of relativistic particles and offer the possibility of technological applications. However, finding robust systems with a sufficiently large range of linearly dispersing bands remains elusive. Recently discovered Dirac semimetal ZrSiS hosts multiple Dirac cones with the largest reported energy range of linear band dispersion (∼2 eV). In this work, we report transport measurements on ZrSiS, exploring extreme and anisotropic magnetoresistance with distinct quantum oscillations, enabling us to quantitatively analyze the Fermi surface properties. We have also observed the unique signature of chiral anomaly in longitudinal magnetoresistance. Our work comprehensively confirms the recent theoretical and angle-resolved photoemission spectroscopy results on ZrSiS and suggests a large family of materials as potential topological semimetals. Whereas the discovery of Dirac- and Weyl-type excitations in electronic systems is a major breakthrough in recent condensed matter physics, finding appropriate materials for fundamental physics and technological applications is an experimental challenge. In all of the reported materials, linear dispersion survives only up to a few hundred millielectronvolts from the Dirac or Weyl nodes. On the other hand, real materials are subject to uncontrolled doping during preparation and thermal effect near room temperature can hinder the rich physics. In ZrSiS, angle-resolved photoemission spectroscopy measurements have shown an unusually robust linear dispersion (up to ∼2 eV) with multiple nondegenerate Dirac nodes. In this context, we present the magnetotransport study on ZrSiS crystal, which represents a large family of materials (WHM with W = Zr, Hf; H = Si, Ge, Sn; M = O, S, Se, Te) with identical band topology. Along with extremely large and nonsaturating magnetoresistance (MR), ∼1.4 × 105% at 2 K and 9 T, it shows strong anisotropy, depending on the direction of the magnetic field. Quantum oscillation and Hall effect measurements have revealed large hole and small electron Fermi pockets. A nontrivial π Berry phase confirms the Dirac fermionic nature for both types of charge carriers. The long-sought relativistic phenomenon of massless Dirac fermions, known as the Adler–Bell–Jackiw chiral anomaly, has also been observed.
Prospective relationships between workplace sexual harassment and psychological distress.

BACKGROUND Exposure to workplace sexual harassment (SH) has been associated with impaired mental health, but longitudinal studies confirming the relationship are lacking. AIMS To examine gender differences in prospective associations between SH and psychological distress. METHODS Baseline questionnaire survey data were collected in 2005 in a representative sample of Norwegian employees. Follow-up data were collected in 2007. SH was measured with the Bergen Sexual Harassment Scale. Psychological distress was measured with the 25 item Hopkins Symptom Checklist (HSCL-25) with cases of psychological distress defined as having a mean score of <1.75. Variables were measured at both baseline and follow-up. Logistic regression analysis was used to analyse data. RESULTS Response rates were 57% in 2005 and 75% in 2007 when the final cohort comprised 1775 respondents. After adjusting for baseline distress and age, exposure to SH at baseline was associated with psychological distress at follow-up among women [odds ratio (OR): 2.03; 95% confidence interval (CI): 1.2-3.39] but not men (OR: 1.32; 95% CI: 0.72-2.43). Baseline distress was significantly related to SH at follow-up among men (OR: 3.03; 95% CI: 1.74-5.26) but not women (OR: 1.15; 95% CI: 0.69-1.92). CONCLUSIONS The study found that SH contributed to subsequent psychological distress among women. Workplace measures against SH would be expected to lead to a reduction in mental disorders. The finding that psychological distress predicts SH among men may indicate either a vulnerability factor or a negative perception mechanism.
Altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) prior to insulin deficiency

Approximately 10% of the patients diagnosed with type 2 diabetes (T2D) have detectable serum levels of glutamic acid decarboxylase 65 autoantibodies (GADA). These patients usually progress to insulin dependency within a few years, and are classified as being latent autoimmune diabetes in adults (LADA). A decrease in the frequency of peripheral blood natural killer (NK) cells has been reported recently in recent‐onset T1D and in high‐risk individuals prior to the clinical onset. As NK cells in LADA patients have been investigated scarcely, the aim of this study was to use multicolour flow cytometry to define possible deficiencies or abnormalities in the frequency or activation state of NK cells in LADA patients prior to insulin dependency. All patients were GADA‐positive and metabolically compensated, but none were insulin‐dependent at the time blood samples were taken. LADA patients exhibited a significant decrease in NK cell frequency in peripheral blood compared to healthy individuals (P = 0·0018), as reported previously for recent‐onset T1D patients. Interestingly, NKG2D expression was increased significantly (P < 0·0001), whereas killer cell immunoglobulin‐like receptor (KIR)3DL1 expression was decreased (P < 0·0001) within the NK cell population. These observations highlight a defect in both frequency and activation status of NK cells in LADA patients and suggest that this immunological alteration may contribute to the development of autoimmune diabetes by affecting peripheral tolerance. Indeed, recent evidence has demonstrated a regulatory function for NK cells in autoimmunity. Moreover, the decrease in NK cell number concords with observations obtained in recent‐onset T1D, implying that similar immunological dysfunctions may contribute to the progression of both LADA and T1D.
Comprehensive and quantitative mapping of RNA–protein interactions across a transcribed eukaryotic genome

Significance High-throughput sequencing has transformed modern biology, but its repertoire is currently confined to reading DNA molecules. Here, we report hardware and software adaptations that allow the very methods that enabled the genomic sequencing revolution to be applied to fluorescence-based biochemical assays, on a massive scale. We demonstrate the unique value of this approach by finding previously unknown features of an ancient developmental regulator, Vts1 (Smaug in metazoans), despite its extensive study with previously available techniques. Our work couples transcriptome-wide measurements of binding affinity, sequence, and structural determinants of binding, and phenotypic outcomes to provide a comprehensive portrait of Vts1 function. Our technology is easily extensible to other RNA-binding proteins involved in disease and development, and facilitates diverse applications in systems biochemistry. RNA-binding proteins (RBPs) control the fate of nearly every transcript in a cell. However, no existing approach for studying these posttranscriptional gene regulators combines transcriptome-wide throughput and biophysical precision. Here, we describe an assay that accomplishes this. Using commonly available hardware, we built a customizable, open-source platform that leverages the inherent throughput of Illumina technology for direct biophysical measurements. We used the platform to quantitatively measure the binding affinity of the prototypical RBP Vts1 for every transcript in the Saccharomyces cerevisiae genome. The scale and precision of these measurements revealed many previously unknown features of this well-studied RBP. Our transcribed genome array (TGA) assayed both rare and abundant transcripts with equivalent proficiency, revealing hundreds of low-abundance targets missed by previous approaches. These targets regulated diverse biological processes including nutrient sensing and the DNA damage response, and implicated Vts1 in de novo gene “birth. ” TGA provided single-nucleotide resolution for each binding site and delineated a highly specific sequence and structure motif for Vts1 binding. Changes in transcript levels in vts1Δ cells established the regulatory function of these binding sites. The impact of Vts1 on transcript abundance was largely independent of where it bound within an mRNA, challenging prevailing assumptions about how this RBP drives RNA degradation. TGA thus enables a quantitative description of the relationship between variant RNA structures, affinity, and in vivo phenotype on a transcriptome-wide scale. We anticipate that TGA will provide similarly comprehensive and quantitative insights into the function of virtually any RBP.
ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations

Significance Ankylosing spondylitis (AS) is a common inflammatory arthritis of the spine. It is associated with two genes involved in antigen processing and presentation to the immune system, HLA-B*27 and ERAP1 (endoplasmic reticulum aminopeptidase 1), which act synergistically in AS. Previous reports have suggested that rare ERAP1 variants associated with dramatically altered antigen processing function are responsible. In contrast, we show here conclusively that it is common variants of ERAP1 that are mainly responsible for protection/susceptibility in AS rather than rare ERAP1 variants and/or unusual combinations of ERAP1 variants. This has important potential implications for future studies addressing the development of ERAP1 inhibitors as new treatments not only for AS but also in other diseases genetically associated with ERAP1. We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)—rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher’s exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes (“VRNQE,” “MKDRQ,” “MRDRE,” and “MKDRE”) in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination (“*001/*005”) previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10–24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.
Two-metal versus one-metal mechanisms of lysine adenylylation by ATP-dependent and NAD+-dependent polynucleotide ligases

Significance This season marks the 50th anniversary of the discovery of polynucleotide ligases, the sine qua non enzymes of nucleic acid repair and the enabling reagents of molecular biology, reported in a series of seminal papers in PNAS. Ligases react with ATP or NAD+ to form a covalent enzyme–adenylate intermediate in which AMP is linked via a P–N bond to a lysine. This work reports crystal structures of the Michaelis complexes of an exemplary ATP-dependent RNA ligase (bacteriophage T4 Rnl1) and an NAD+-dependent DNA ligase (Escherichia coli LigA) that illuminate the chemical and structural basis for lysine adenylylation, via distinctive two-metal (ATP) and one-metal (NAD+) mechanisms. Polynucleotide ligases comprise a ubiquitous superfamily of nucleic acid repair enzymes that join 3′-OH and 5′-PO4 DNA or RNA ends. Ligases react with ATP or NAD+ and a divalent cation cofactor to form a covalent enzyme-(lysine-Nζ)–adenylate intermediate. Here, we report crystal structures of the founding members of the ATP-dependent RNA ligase family (T4 RNA ligase 1; Rnl1) and the NAD+-dependent DNA ligase family (Escherichia coli LigA), captured as their respective Michaelis complexes, which illuminate distinctive catalytic mechanisms of the lysine adenylylation reaction. The 2.2-Å Rnl1•ATP•(Mg2+)2 structure highlights a two-metal mechanism, whereby: a ligase-bound “catalytic” Mg2+(H2O)5 coordination complex lowers the pKa of the lysine nucleophile and stabilizes the transition state of the ATP α phosphate; a second octahedral Mg2+ coordination complex bridges the β and γ phosphates; and protein elements unique to Rnl1 engage the γ phosphate and associated metal complex and orient the pyrophosphate leaving group for in-line catalysis. By contrast, the 1.55-Å LigA•NAD+•Mg2+ structure reveals a one-metal mechanism in which a ligase-bound Mg2+(H2O)5 complex lowers the lysine pKa and engages the NAD+ α phosphate, but the β phosphate and the nicotinamide nucleoside of the nicotinamide mononucleotide (NMN) leaving group are oriented solely via atomic interactions with protein elements that are unique to the LigA clade. The two-metal versus one-metal dichotomy demarcates a branchpoint in ligase evolution and favors LigA as an antibacterial drug target.
B cell‐targeted therapy with anti‐CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism

Graves' disease is a B cell‐mediated and T cell‐dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti‐thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen‐presenting/immune‐modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti‐mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A‐subunit (Ad‐TSHR289). We observe that a single injection of 250 µg/mouse anti‐mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR‐specific splenocyte secretion of interferon (IFN)‐γ, anti‐TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time‐point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN‐γ. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody‐producing cells but also as antigen‐presenting/immune‐modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development.
Large-scale heterochromatin remodeling linked to overreplication-associated DNA damage

Significance Heterochromatin is a challenging environment in which to repair DNA damage. In addition to dense packaging, heterochromatin often contains repetitive DNA that can lead to errors in homologous recombination-based repair. One strategy to address this problem has been reported in animals. In Drosophila, heterochromatic double-strand breaks are translocated out of the heterochromatin into nearby euchromatin for repair. Here, we show that ARABIDOPSIS TRITHORAX-RELATED 5,6 (atxr5,6) mutants use an interesting variation of the approach used by animals. Rather than translocating heterochromatic breaks into euchromatin, heterochromatic aggregations, called “chromocenters,” are remodeled to create specialized compartments with reduced chromatin density. These compartments contain double-strand breaks and DNA-repair enzymes and therefore are likely to play a role in facilitating heterochromatic DNA repair. Previously, we have shown that loss of the histone 3 lysine 27 (H3K27) monomethyltransferases ARABIDOPSIS TRITHORAX-RELATED 5 (ATXR5) and ATXR6 (ATXR6) results in the overreplication of heterochromatin. Here we show that the overreplication results in DNA damage and extensive chromocenter remodeling into unique structures we have named “overreplication-associated centers” (RACs). RACs have a highly ordered structure with an outer layer of condensed heterochromatin, an inner layer enriched in the histone variant H2AX, and a low-density core containing foci of phosphorylated H2AX (a marker of double-strand breaks) and the DNA-repair enzyme RAD51. atxr5,6 mutants are strongly affected by mutations in DNA repair, such as ATM and ATR. Because of its dense packaging and repetitive DNA sequence, heterochromatin is a challenging environment in which to repair DNA damage. Previous work in animals has shown that heterochromatic breaks are translocated out of the heterochromatic domain for repair. Our results show that atxr5,6 mutants use a variation on this strategy for repairing heterochromatic DNA damage. Rather than being moved to adjacent euchromatic regions, as in animals, heterochromatin undergoes large-scale remodeling to create a compartment with low chromatin density.
Smoking and periodontal disease: discrimination of antibody responses to pathogenic and commensal oral bacteria

Smoking is an independent risk factor for the initiation, extent and severity of periodontal disease. This study examined the ability of the host immune system to discriminate commensal oral bacteria from pathogens at mucosal surfaces, i.e. oral cavity. Serum immunoglobulin (Ig)G antibody reactive with three pathogenic and five commensal oral bacteria in 301 current smokers (age range 21–66 years) were examined by enzyme‐linked immunosorbent assay. Clinical features of periodontal health were used as measures of periodontitis. Antibody to the pathogens and salivary cotinine levels were related positively to disease severity; however, the antibody levels were best described by the clinical disease unrelated to the amount of smoking. The data showed a greater immune response to pathogens than commensals that was related specifically to disease extent, and most noted in black males. Significant correlations in individual patient responses to the pathogens and commensals were lost with an increasing extent of periodontitis and serum antibody to the pathogens. Antibody to Porphyromonas gingivalis was particularly distinct with respect to the discriminatory nature of the immune responses in recognizing the pathogens. Antibody responses to selected pathogenic and commensal oral microorganisms differed among racial groups and genders. The antibody response to the pathogens was related to disease severity. The level of antibody to the pathogens, and in particular P. gingivalis, was correlated with disease severity in black and male subsets of patients. The amount of smoking did not appear to impact directly serum antibody levels to these oral bacteria.
Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin

Significance Mutant form of p53 (mutp53) proteins are expressed at high levels in many human cancers and can promote tumor cell growth. However, their mechanisms of action have not been fully understood. Elucidation of the mechanisms may identify new therapeutic strategies for treating many cancers that contain mutp53s. We describe a role for several hotspot mutp53s in reducing the checkpoint response to replication stress through interacting with TopBP1. This finding provides a rationale for a synthetic lethality strategy to treat mutp53-harboring cancer cells with inhibitors of another ATR activator, DNA2. We also find that certain mutp53s directly promote DNA replication by bridging the interaction between TopBP1 and Treslin. These results uncover mechanisms by which mutp53 enhances DNA replication. Accumulating evidence supports the gain-of-function of mutant forms of p53 (mutp53s). However, whether mutp53 directly perturbs the DNA replication checkpoint remains unclear. Previously, we have demonstrated that TopBP1 forms a complex with mutp53s and mediates their gain-of-function through NF-Y and p63/p73. Akt phosphorylates TopBP1 and induces its oligomerization, which inhibits its ATR-activating function. Here we show that various contact and conformational mutp53s bypass Akt to induce TopBP1 oligomerization and attenuate ATR checkpoint response during replication stress. The effect on ATR response caused by mutp53 can be exploited in a synthetic lethality strategy, as depletion of another ATR activator, DNA2, in mutp53-R273H–expressing cancer cells renders cells hypersensitive to cisplatin. Expression of mutp53-R273H also makes cancer cells more sensitive to DNA2 depletion or DNA2 inhibitors. In addition to ATR-activating function during replication stress, TopBP1 interacts with Treslin in a Cdk-dependent manner to initiate DNA replication during normal growth. We find that mutp53 also interferes with TopBP1 replication function. Several contact, but not conformational, mutp53s enhance the interaction between TopBP1 and Treslin and promote DNA replication despite the presence of a Cdk2 inhibitor. Together, these data uncover two distinct mechanisms by which mutp53 enhances DNA replication: (i) Both contact and conformational mutp53s can bind TopBP1 and attenuate the checkpoint response to replication stress, and (ii) during normal growth, contact (but not conformational) mutp53s can override the Cdk2 requirement to promote replication by facilitating the TopBP1/Treslin interaction.