Long-term ambient air pollution exposure and renal function and biomarkers of renal disease.

BACKGROUND: Despite accumulating evidence of an association between air pollution and renal disease, studies on the association between long-term exposure to air pollution and renal function are still contradictory. This study aimed to investigate this association in a large population with relatively low exposure and with improved estimation of renal function as well as renal injury biomarkers. METHODS: We performed a cross-sectional analysis in the middle-aged general population participating in the Swedish CardioPulmonary bioImaging Study (SCAPIS; n = 30 154). Individual 10-year exposure to total and locally emitted fine particulate matter (PM2.5), inhalable particulate matter (PM10), and nitrogen oxides (NOx) were modelled using high-resolution dispersion models. Linear regression models were used to estimate associations between exposures and estimated glomerular filtration rate (eGFR, combined creatinine and cystatin C) and serum levels of renal injury biomarkers (KIM-1, MCP-1, IL-6, IL-18, MMP-2, MMP-7, MMP-9, FGF-23, and uric acid), with consideration of potential confounders. RESULTS: Median long-term PM2.5 exposure was 6.2 µg/m3. Almost all participants had a normal renal function and median eGFR was 99.2 mL/min/1.73 m2. PM2.5 exposure was associated with 1.3% (95% CI 0.6, 2.0) higher eGFR per 2.03 µg/m3 (interquartile range, IQR). PM2.5 exposure was also associated with elevated serum matrix metalloproteinase 2 (MMP-2) concentration, with 7.2% (95% CI 1.9, 12.8) higher MMP-2 per 2.03 µg/m3. There was a tendency towards an association between PM10 and higher levels of uric acid, but no associations were found with the other biomarkers. Associations with other air pollutants were null or inconsistent. CONCLUSION: In this large general population sample at low exposure levels, we found a surprising association between PM2.5 exposure and a higher renal filtration. It seems unlikely that particle function would improve renal function. However, increased filtration is an early sign of renal injury and may be related to the relatively healthy population at comparatively low exposure levels. Furthermore, PM2.5 exposure was associated with higher serum concentrations of MMP-2, an early indicator of renal and cardiovascular pathology.

Long-term exposure to transportation noise and obesity: A pooled analysis of eleven Nordic cohorts.

Background: Available evidence suggests a link between exposure to transportation noise and an increased risk of obesity. We aimed to assess exposure-response functions for long-term residential exposure to road traffic, railway and aircraft noise, and markers of obesity. Methods: Our cross-sectional study is based on pooled data from 11 Nordic cohorts, including up to 162,639 individuals with either measured (69.2%) or self-reported obesity data. Residential exposure to transportation noise was estimated as a time-weighted average Lden 5 years before recruitment. Adjusted linear and logistic regression models were fitted to assess beta coefficients and odds ratios (OR) with 95% confidence intervals (CI) for body mass index, overweight, and obesity, as well as for waist circumference and central obesity. Furthermore, natural splines were fitted to assess the shape of the exposure-response functions. Results: For road traffic noise, the OR for obesity was 1.06 (95% CI = 1.03, 1.08) and for central obesity 1.03 (95% CI = 1.01, 1.05) per 10 dB Lden. Thresholds were observed at around 50-55 and 55-60 dB Lden, respectively, above which there was an approximate 10% risk increase per 10 dB Lden increment for both outcomes. However, linear associations only occurred in participants with measured obesity markers and were strongly influenced by the largest cohort. Similar risk estimates as for road traffic noise were found for railway noise, with no clear thresholds. For aircraft noise, results were uncertain due to the low number of exposed participants. Conclusion: Our results support an association between road traffic and railway noise and obesity.

Loss of bmp15 function in the seasonal spawner Atlantic salmon results in ovulatory failure.

Bone morphogenetic protein 15 (BMP15) is an oocyte-specific growth factor important for successful female reproduction in mammals. While mutations in BMP15/Bmp15 cause ovulatory deficiency and/or infertility in certain mammalian species, loss of bmp15 in zebrafish, a continuous spawner and the only bmp15 knockout model in fish to date, results in complete arrest of follicle development and later female-to-male sex reversal, preventing to examine effects on ovulation/fertilization. Here, we used Atlantic salmon, a seasonal spawner, and generated bmp15 mutants to investigate ovarian development and fertility. Histological and morphometric analyses revealed that in biallelic frameshift (bmp15 fs/fs) mutant ovaries, folliculogenesis started earlier, resulting in an advanced development compared to wild-type (WT) controls, accompanied by a weaker expression of the (early) oocyte-specific factor figla. This precocious ovarian development was followed in bmp15 fs/fs females by enhanced follicle atresia during vitellogenic stages. Although genes involved in steroid synthesis and signaling (star, cyp11b, cyp17a1 and esr1) were dramatically higher in late vitellogenic bmp15 fs/fs mutant ovaries, estradiol-17ß plasma levels were lower than in WT counterparts, potentially reflecting compensatory changes at the level of ovarian gene expression. At spawning, bmp15 fs/fs females displayed lower gonado-somatic index values and reduced oocyte diameter, and the majority (71.4%), showed mature non-ovulating ovaries with a high degree of atresia. The remaining (28.6%) females spawned eggs but they either could not be fertilized or, upon fertilization, showed severe malformations and embryonic mortality. Our results show that Bmp15 is required for proper follicle recruitment and growth and later ovulatory success in Atlantic salmon, providing an alternative candidate target to induce sterility in farmed salmon. Moreover, since loss of bmp15 in salmon, in contrast to zebrafish, does not result in female-to-male sex change, this is the first mutant model in fish allowing further investigations on Bmp15-mediated functions in the ovulatory period.

Long-term ambient air pollution and coronary atherosclerosis: Results from the Swedish SCAPIS study.

BACKGROUND AND AIMS: Despite firm evidence for an association between long-term ambient air pollution exposure and cardiovascular morbidity and mortality, results from epidemiological studies on the association between air pollution exposure and atherosclerosis have not been consistent. We investigated associations between long-term low-level air pollution exposure and coronary atherosclerosis. METHODS: We performed a cross-sectional analysis in the large Swedish CArdioPulmonary bioImaging Study (SCAPIS, n = 30 154), a random general population sample. Concentrations of total and locally emitted particulate matter <2.5 µm (PM2.5), <10 µm (PM10), and nitrogen oxides (NOx) at the residential address were modelled using high-resolution dispersion models. We estimated associations between air pollution exposures and segment involvement score (SIS), coronary artery calcification score (CACS), number of non-calcified plaques (NCP), and number of significant stenoses, using ordinal regression models extensively adjusted for potential confounders. RESULTS: Median 10-year average PM2.5 exposure was 6.2 µg/m3 (range 3.5-13.4 µg/m3). 51 % of participants were women and 51 % were never-smokers. None of the assessed pollutants were associated with a higher SIS or CACS. Exposure to PM2.5 was associated with NCP (adjusted OR 1.34, 95 % CI 1.13, 1.58, per 2.05 µg/m3). Associations with significant stenoses were inconsistent. CONCLUSIONS: In this large, middle-aged general population sample with low exposure levels, air pollution was not associated with measures of total burden of coronary atherosclerosis. However, PM2.5 appeared to be associated with a higher prevalence of non-calcified plaques. The results suggest that increased risk of early-stage atherosclerosis or rupture, but not increased total atherosclerotic burden, may be a pathway for long-term air pollution effects on cardiovascular disease.

Occupational particle exposure and chronic kidney disease: a cohort study in Swedish construction workers.

OBJECTIVES: Increasing epidemiological and experimental evidence suggests that particle exposure is an environmental risk factor for chronic kidney disease (CKD). However, only a few case-control studies have investigated this association in an occupational setting. Hence, our objective was to investigate associations between particle exposure and CKD in a large cohort of Swedish construction workers. METHODS: We performed a retrospective cohort study in the Swedish Construction Workers' Cohort, recruited 1971-1993 (n=286 089). A job-exposure matrix was used to identify workers exposed to nine different particulate exposures, which were combined into three main categories (inorganic dust and fumes, wood dust and fibres). Incident CKD and start of renal replacement therapy (RRT) were obtained from validated national registries until 2021 and analysed using adjusted Cox proportional hazards models. RESULTS: Exposure to inorganic dust and fumes was associated with an increased risk of CKD and RRT during working age (adjusted HR for CKD at age <65 years 1.15, 95% CI 1.05 to 1.26). The elevated risk did not persist after retirement age. Exposure to cement dust, concrete dust and diesel exhaust was associated with CKD. Elevated HRs were also found for quartz dust and welding fumes. CONCLUSIONS: Workers exposed to inorganic particles seem to be at elevated risk of CKD and RRT. Our results are in line with previous evidence of renal effects of ambient air pollution and warrant further efforts to reduce occupational and ambient particle exposure.

Reliability in Novel Field-Based Fitness Measurements and Postexercise Scores from a Physical Fitness Test Battery in Older Adults.

INTRODUCTION: Physical fitness is strongly associated with daily physical function, health, and longevity in older adults. Field-based tests may provide a reasonable alternative compared to advanced laboratory testing. Separating postexercise test scores from reactivity measurements requires sufficient test-retest reliability. Postexercise test scores with reliability analyses of field-based fitness tests in older adults are lacking. The present study aimed to examine the test-retest reliability of some novel easily accommodated fitness test measurements and compare pretest scores with postexercise results in these tests along with other field-based fitness tests in older adults. METHODS: Totally 1,407 community-dwelling older adults (69% female), x̄ = 71.5 ± 5.0 (65-84 years), performed twelve field-based fitness tests at pretest 1, pretest 2 and a posttest after an 8-week exercise period (twice weekly 1 h of combined strength and aerobic training). T tests, intra-class correlation, limits of agreement, standard error of measurement, and coefficient of variance were performed between pre-1 and pre-2 tests, and repeated measures ANOVA and partial eta squared effect size for postexercise differences for men and women in 5-year age groups ranging from 65 to 84 years. RESULTS: Between pre-1 and pre-2 tests a significant difference was noted in some of the novel fitness test measurements but generally not, e.g., in isometric trunk flexion and step-up height on either leg among all sex and age groups. In most of these novel fitness test measurements, no significant differences occurred between the two pretests. Examples of results from the pre-2 test to the posttest were isometric trunk flexion 45° endurance and isometric trunk extension endurance improved significantly for both sexes in age groups 65-74 years. Women, but not men, improved the maximal step-up height for both legs in most age groups. The speed in the 50 sit-to-stand improved significantly for most age groups in both sexes. Six-min walk distance improved significantly for most age groups in women but among men only in 65-69 years. In the timed-up-and-go test, significant improvements were seen for all age groups in women and in men 70-79 years. No postexercise improvements were generally observed for grip strength or balance. CONCLUSIONS: In most of the novel fitness test measures, no significant difference was noted between the two pretests in the assessed sex and age groups. Results after the 8-week exercise period varied between sex and age groups, with significant improvements in several of the twelve studied fitness tests. These findings may be valuable for future projects utilizing easily accommodated physical fitness tests in older adults.

Folded Alpha Helical Putative New Proteins from Apilactobacillus kunkeei.

The emergence of new proteins is a central question in biology. Most tertiary protein folds known to date appear to have an ancient origin, but it is clear from bioinformatic analyses that new proteins continuously emerge in all organismal groups. However, there is a paucity of experimental data on new proteins regarding their structure and biophysical properties. We performed a detailed phylogenetic analysis and identified 48 putative open reading frames in the honeybee-associated bacterium Apilactobacillus kunkeei for which no or few homologs could be identified in closely-related species, suggesting that they could be relatively new on an evolutionary time scale and represent recently evolved proteins. Using circular dichroism-, fluorescence- and nuclear magnetic resonance (NMR) spectroscopy we investigated six of these proteins and show that they are not intrinsically disordered, but populate alpha-helical dominated folded states with relatively low thermodynamic stability (0-3 kcal/mol). The NMR and biophysical data demonstrate that small new proteins readily adopt simple folded conformations suggesting that more complex tertiary structures can be continuously re-invented during evolution by fusion of such simple secondary structure elements. These findings have implications for the general view on protein evolution, where de novo emergence of folded proteins may be a common event.

Loss of Fshr Prevents Testicular Maturation in Atlantic Salmon (Salmo salar L.).

Early puberty poses a significant challenge for male Atlantic salmon in aquaculture due to its negative impact on growth and welfare. The regulation of puberty in vertebrates involves 2 key reproductive hormones: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and their gonadal receptors. In male mice lacking FSH receptor, testes size is reduced, but fertility is maintained, while medaka and zebrafish with a disrupted fshr gene exhibit near normal testis size and fertility. In these fishes both Fsh and Lh are present during puberty and Lh may rescue fertility, while in salmonid fish only Fsh is present in the circulation during puberty. Using CRISPR-Cas9, we produced crispants with a high prevalence of fshr mutations at the target site, which remained fertile, although more than half showed a testis development deviating from wild-type (wt) males. Crossing out these F0 crispants to each other produced a viable F1 generation showing frameshift (fshr-/-) or in-frame mutations (fshrif/if). Nearly all wt males matured while all fshr-/- males remained immature with small testes containing A spermatogonia as the furthest developed germ cell type and prepubertal plasma androgen levels. Also, the pituitary transcript levels of gnrhr2bba and lhb, but not for fshb, were reduced in the fshr-/- males compared with maturing males. More than half of the fshrif/if mutant males showed no or a delayed maturation. In conclusion, Atlantic salmon show the unique characteristic that loss of Fshr function alone results in male infertility, offering new opportunities to control precocious puberty or fertility in salmon.

Conservation of Affinity Rather Than Sequence Underlies a Dynamic Evolution of the Motif-Mediated p53/MDM2 Interaction in Ray-Finned Fishes.

The transcription factor and cell cycle regulator p53 is marked for degradation by the ubiquitin ligase MDM2. The interaction between these 2 proteins is mediated by a conserved binding motif in the disordered p53 transactivation domain (p53TAD) and the folded SWIB domain in MDM2. The conserved motif in p53TAD from zebrafish displays a 20-fold weaker interaction with MDM2, compared to the interaction in human and chicken. To investigate this apparent difference, we tracked the molecular evolution of the p53TAD/MDM2 interaction among ray-finned fishes (Actinopterygii), the largest vertebrate clade. Intriguingly, phylogenetic analyses, ancestral sequence reconstructions, and binding experiments showed that different loss-of-affinity changes in the canonical binding motif within p53TAD have occurred repeatedly and convergently in different fish lineages, resulting in relatively low extant affinities (KD = 0.5 to 5 µM). However, for 11 different fish p53TAD/MDM2 interactions, nonconserved regions flanking the canonical motif increased the affinity 4- to 73-fold to be on par with the human interaction. Our findings suggest that compensating changes at conserved and nonconserved positions within the motif, as well as in flanking regions of low conservation, underlie a stabilizing selection of "functional affinity" in the p53TAD/MDM2 interaction. Such interplay complicates bioinformatic prediction of binding and calls for experimental validation. Motif-mediated protein-protein interactions involving short binding motifs and folded interaction domains are very common across multicellular life. It is likely that the evolution of affinity in motif-mediated interactions often involves an interplay between specific interactions made by conserved motif residues and nonspecific interactions by nonconserved disordered regions.

Blood cadmium is associated with increased fracture risk in never-smokers - results from a case-control study using data from the Malmö Diet and Cancer cohort.

BACKGROUND: Several studies have shown associations between cadmium (Cd) exposure and an increased risk of fractures. However, the size of the risk is still unclear and proper adjustment for smoking is a challenge. The aim of this study was to quantify the association between dietary cadmium measured in blood and fracture risk in the general Swedish population through a large population-based case-control study in never-smokers. METHODS: The study included 2113 incident cases with osteoporosis-related fractures and the same number of age- and sex-matched controls in never-smokers from the Swedish population-based Malmö Diet and Cancer study cohort. Cd in blood (B-Cd) was analyzed at baseline (1991-1996). Incident osteoporosis-related fractures (of the hip, distal radius, and proximal humerus) up to the year 2014 were identified using the National Patient Register. Associations between B-Cd and fractures were analyzed using logistic regression. RESULTS: Median B-Cd was 0.22 µg/L (P25 = 0.16, P75 = 0.31) among 2103 cases and 0.21 (P25 = 0.15, P75 = 0.30) among 2105 controls. The risk of fracture was significantly increased (OR 1.58; 95 % confidence interval 1.08-2.31, per µg/L of B-Cd), after adjustment for age, sex, BMI, physical activity, and fiber consumption. In analyses by cadmium quartiles, the OR increased monotonically and was significant in the highest quartile of B-Cd (for B-Cd > 0.31 versus B-Cd < 0.15 µg/L; OR 1.21; 95 % confidence interval 1.01-1.45). CONCLUSION: Even modestly increased blood cadmium in never-smokers is associated with increased risk of incident osteoporosis-related fractures.

Effects of dapagliflozin and dapagliflozin-saxagliptin on erythropoiesis, iron and inflammation markers in patients with type 2 diabetes and chronic kidney disease: data from the DELIGHT trial.

BACKGROUND: This post-hoc analysis of the DELIGHT trial assessed effects of the SGLT2 inhibitor dapagliflozin on iron metabolism and markers of inflammation. METHODS: Patients with type 2 diabetes and albuminuria were randomized to dapagliflozin, dapagliflozin and saxagliptin, or placebo. We measured hemoglobin, iron markers (serum iron, transferrin saturation, and ferritin), plasma erythropoietin, and inflammatory markers (urinary MCP-1 and urinary/serum IL-6) at baseline and week 24. RESULTS: 360/461 (78.1%) participants had available biosamples. Dapagliflozin and dapagliflozin-saxagliptin, compared to placebo, increased hemoglobin by 5.7 g/L (95%CI 4.0, 7.3; p < 0.001) and 4.4 g/L (2.7, 6.0; p < 0.001) and reduced ferritin by 18.6% (8.7, 27.5; p < 0.001) and 18.4% (8.7, 27.1; p < 0.001), respectively. Dapagliflozin reduced urinary MCP-1/Cr by 29.0% (14.6, 41.0; p < 0.001) and urinary IL-6/Cr by 26.6% (9.1, 40.7; p = 0.005) with no changes in other markers. CONCLUSIONS: Dapagliflozin increased hemoglobin and reduced ferritin and urinary markers of inflammation, suggesting potentially important effects on iron metabolism and inflammation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02547935.

Identification of motif-based interactions between SARS-CoV-2 protein domains and human peptide ligands pinpoint antiviral targets.

The virus life cycle depends on host-virus protein-protein interactions, which often involve a disordered protein region binding to a folded protein domain. Here, we used proteomic peptide phage display (ProP-PD) to identify peptides from the intrinsically disordered regions of the human proteome that bind to folded protein domains encoded by the SARS-CoV-2 genome. Eleven folded domains of SARS-CoV-2 proteins were found to bind 281 peptides from human proteins, and affinities of 31 interactions involving eight SARS-CoV-2 protein domains were determined (KD ∼ 7-300 µM). Key specificity residues of the peptides were established for six of the interactions. Two of the peptides, binding Nsp9 and Nsp16, respectively, inhibited viral replication. Our findings demonstrate how high-throughput peptide binding screens simultaneously identify potential host-virus interactions and peptides with antiviral properties. Furthermore, the high number of low-affinity interactions suggest that overexpression of viral proteins during infection may perturb multiple cellular pathways.

Stress and recurrent abdominal pain.

We discuss the aetiology of recurrent abdominal pain of non-organic origin, according to the Rome Criteria for Functional Gastrointestinal Disorders and a psychogenic hypothesis. Stress activates the brain-gut axis, which is important for local gut symptoms, such as abdominal pain, but it also causes pain in other areas, including the head, back and chest. Our research has indicated that the startle reflex plays a dominant role in this stress-induced pain pattern, which is manifested in the whole body. Localised abdominal pain can be part of a general negative stress reaction that causes multiple pains in other areas of the body.

Effects of bile salt-stimulated lipase on blood cells and associations with disease activity in human inflammatory joint disorders.

The bile salt-stimulated lipase (BSSL) was originally recognized as a lipolytic enzyme expressed by the exocrine pancreas and in some species, notably humans, the lactating mammary gland, being secreted into the duodenum and with the mother's milk, respectively. However, BSSL is also present in the blood and has been assigned additional functions, even beyond the gastrointestinal tract. Conventional BSSL knockout mice are protected from developing disease in animal models of arthritis, and antibodies directed towards BSSL prevent or mitigate disease in similar models. The aim of this study was to investigate the role of BSSL as a newly discovered player in inflammation and specifically in inflammatory joint disorders. As part of mechanism of action, we here show that BSSL is secreted by neutrophils, interacts with monocytes and stimulates their migration in vitro. An anti-BSSL antibody that blocks the human BSSL-monocyte interaction was shown to simultaneously prevent the signaling pathway by which BSSL induce cell migration. Moreover, in this cohort study we show that BSSL levels are significantly higher in blood samples from patients with rheumatoid arthritis and psoriatic arthritis compared to healthy controls. The BSSL levels in patients' blood also correlated with disease activity scores and established inflammatory markers. Hence, although the mode of action is not yet fully clarified, we conclude that BSSL could be considered a proinflammatory component in the innate immune system and thus a possible novel target for treatment of chronic inflammation.

Intrinsically Disordered Flanking Regions Increase the Affinity of a Transcriptional Coactivator Interaction across Vertebrates.

Interactions between two proteins are often mediated by a disordered region in one protein binding to a groove in a folded interaction domain in the other one. While the main determinants of a certain interaction are typically found within a well-defined binding interface involving the groove, recent studies show that nonspecific contacts by flanking regions may increase the affinity. One example is the coupled binding and folding underlying the interaction between the two transcriptional coactivators NCOA3 (ACTR) and CBP, where the flanking regions of an intrinsically disordered region in human NCOA3 increases the affinity for CBP. However, it is not clear whether this flanking region-mediated effect is a peculiarity of this single protein interaction or if it is of functional relevance in a broader context. To further assess the role of flanking regions in the interaction between NCOA3 and CBP, we analyzed the interaction across orthologs and paralogs (NCOA1, 2, and 3) in human, zebra fish, and ghost shark. We found that flanking regions increased the affinity 2- to 9-fold in the six interactions tested. Conservation of the amino acid sequence is a strong indicator of function. Analogously, the observed conservation of increased affinity provided by flanking regions, accompanied by moderate sequence conservation, suggests that flanking regions may be under selection to promote the affinity between NCOA transcriptional coregulators and CBP.

Physical Exercise and Serum BDNF Levels: Accounting for the Val66Met Polymorphism in Older Adults.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) expression, which can be measured in blood serum, has been found to increase with aerobic exercise. The link between BDNF level, physical exercise, and genetic status (Val66Met polymorphism) has not been well researched in older adults. OBJECTIVE: To investigate the possible link between BDNF expression, acute aerobic exercise, and the Val66Met polymorphism in older adults. METHOD: Twenty-three healthy older adults participated in one session of acute aerobic exercise. Their serum BDNF levels were measured both at baseline and post exercise. Saliva samples were collected to identify each individual's genetic status. RESULTS: At baseline, the individuals' mean serum BDNF level was 16.03 ng/mL (Val66Val = 15.89 ng/mL; Val66Met = 16.34 ng/mL); post exercise, the individuals' mean serum BDNF level was 16.81 ng/mL (Val66Val = 16.14 ng/mL; Val66Met = 18.34 ng/mL). CONCLUSION: One session of acute aerobic exercise significantly increased the individuals' mean serum BDNF level. Males had higher BDNF levels than females. There was a significant interaction between gender and BDNF expression post exercise and a significant between-group effect of gender. The Val66Met carriers had a more positive response to the acute aerobic exercise compared with the Val66Val carriers, although without a significant difference between the two groups.

Cancer incidence among workers in soft paper mills: A cohort study.

OBJECTIVES: To elucidate whether occupational exposure to soft paper dust increases the incidence of cancer. METHODS: We studied 7988 workers in Swedish soft paper mills from 1960 to 2008, of whom 3233 (2 187 men and 1046 women) had more than 10 years of employment. They were divided into high exposure (>5 mg/m3 for >1 year) or lower exposure to soft paper dust based on a validated job-exposure matrix. They were followed from 1960 to 2019, and person-years at risk were stratified according to gender, age, and calendar-year. The expected numbers of incident tumors were calculated using the Swedish population as the reference, and standardized incidence ratios (SIR) with 95% confidence intervals (95% CI) were assessed. RESULTS: Among high-exposure workers with more than 10 years of employment, there was an increased incidence of colon cancer (SIR 1.66, 95% CI 1.20-2.31), small intestine cancer (SIR 3.27, 95% CI 1.36-7.86), and thyroid gland cancer (SIR 2.68, 95% CI 1.11-6.43), as well as lung cancer (SIR 1.56, 95% CI 1.12-2.19). Among the lower-exposed workers there was an increased incidence of connective tissue tumors (sarcomas) (SIR 2.26, 95% CI 1.13-4.51) and pleural mesothelioma (SIR 3.29, 95% CI 1.37-7.91). CONCLUSION: Workers in soft paper mills with high exposure to soft paper dust have an increased incidence of large and small intestine tumors. Whether the increased risk is caused by paper dust exposure or some unknown associated factors is unclear. The increased incidence of pleural mesothelioma is probably linked to asbestos exposure. The reason for increased incidence of sarcomas is unknown.

Occupational exposure to noise and dust in Swedish soft paper mills and mortality from ischemic heart disease and ischemic stroke: a cohort study.

OBJECTIVE: To elucidate whether occupational noise exposure increases the mortality from ischemic heart disease (IHD) and stroke, and if exposure to paper dust modified the risks. METHODS: We studied 6686 workers from soft paper mills, with occupational noise exposure, < 85 dBA, 85-90 dBA and > 90 dBA, and high (> 5 mg/m3) exposure to paper dust. Person-years 1960-2019 were stratified according to gender, age, and calendar-year. Expected numbers of deaths were calculated using the Swedish population as the reference and standardized mortality ratios (SMR) with 95% confidence intervals (95% CI) were assessed. RESULTS: SMR for IHD was 1.12 (95% CI 0.88-1.41) for noise < 85 dBA, 1.18 (95% CI 0.90-1.55) for 85-90 dBA, and 1.27 (95% CI 1.10-1.47) among workers exposed > 90 dBA. Joint exposure to high noise exposure and high exposure to paper dust resulted in slightly higher IHD mortality (SMR 1.39, 95% CI 1.15-1.67). SMR for ischemic stroke was 0.90 (95% CI 0.37-2.15) for noise < 85 dBA, 1.08 (95% CI 0.45-2.59) for 85-90 dBA, and 1.48 (95% CI 0.99-2.00) among workers exposed > 90 dBA. High noise exposure and high exposure to paper dust resulted in higher ischemic stroke mortality (SMR 1.83, 95% CI 1.12-2.98). CONCLUSION: Noise levels > 90 dBA was associated with increased IHD mortality. Combined exposures of noise and paper dust may further increase the risks. Our results do not provide support for a causal relationship for ischemic stroke. Residual confounding from smoking has to be considered. Workers need to be protected from occupational noise levels exceeding 90 dBA.

Evolution of affinity between p53 transactivation domain and MDM2 across the animal kingdom demonstrates high plasticity of motif-mediated interactions.

The interaction between the transcription factor p53 and the ubiquitin ligase MDM2 results in the degradation of p53 and is well-studied in cancer biology and drug development. Available sequence data suggest that both p53 and MDM2-family proteins are present across the animal kingdom. However, the interacting regions are missing in some animal groups, and it is not clear whether MDM2 interacts with, and regulates p53 in all species. We used phylogenetic analyses and biophysical measurements to examine the evolution of affinity between the interacting protein regions: a conserved 12-residue intrinsically disordered binding motif in the p53 transactivation domain (TAD) and the folded SWIB domain of MDM2. The affinity varied significantly across the animal kingdom. The p53TAD/MDM2 interaction among jawed vertebrates displayed high affinity, in particular for chicken and human proteins (KD around 0.1 µM). The affinity of the bay mussel p53TAD/MDM2 complex was lower (KD = 15 µM) and those from a placozoan, an arthropod, and a jawless vertebrate were very low or non-detectable (KD > 100 µM). Binding experiments with reconstructed ancestral p53TAD/MDM2 variants suggested that a micromolar affinity interaction was present in the ancestral bilaterian animal and was later enhanced in tetrapods while lost in other linages. The different evolutionary trajectories of p53TAD/MDM2 affinity during speciation demonstrate high plasticity of motif-mediated interactions and the potential for rapid adaptation of p53 regulation during times of change. Neutral drift in unconstrained disordered regions may underlie the plasticity and explain the observed low sequence conservation in TADs such as p53TAD.

Large-scale phage-based screening reveals extensive pan-viral mimicry of host short linear motifs.

Viruses mimic host short linear motifs (SLiMs) to hijack and deregulate cellular functions. Studies of motif-mediated interactions therefore provide insight into virus-host dependencies, and reveal targets for therapeutic intervention. Here, we describe the pan-viral discovery of 1712 SLiM-based virus-host interactions using a phage peptidome tiling the intrinsically disordered protein regions of 229 RNA viruses. We find mimicry of host SLiMs to be a ubiquitous viral strategy, reveal novel host proteins hijacked by viruses, and identify cellular pathways frequently deregulated by viral motif mimicry. Using structural and biophysical analyses, we show that viral mimicry-based interactions have similar binding strength and bound conformations as endogenous interactions. Finally, we establish polyadenylate-binding protein 1 as a potential target for broad-spectrum antiviral agent development. Our platform enables rapid discovery of mechanisms of viral interference and the identification of potential therapeutic targets which can aid in combating future epidemics and pandemics.