Mortality from lung cancer in workers exposed to sulfur dioxide in the pulp and paper industry.

Our objective in this study was to evaluate the mortality of workers exposed to sulfur dioxide in the pulp and paper industry. The cohort included 57,613 workers employed for at least 1 year in the pulp and paper industry in 12 countries. We assessed exposure to SO(2) at the level of mill and department, using industrial hygiene measurement data and information from company questionnaires; 40,704 workers were classified as exposed to SO(2). We conducted a standardized mortality ratio (SMR) analysis based on age-specific and calendar period-specific national mortality rates. We also conducted a Poisson regression analysis to determine the dose-response relations between SO(2) exposure and cancer mortality risks and to explore the effect of potential confounding factors. The SMR analysis showed a moderate deficit of all causes of death [SMR = 0.89; 95% confidence interval (CI), 0.87-0.96] among exposed workers. Lung cancer mortality was marginally increased among exposed workers (SMR = 1.08; 95% CI, 0.98-1.18). After adjustment for occupational coexposures, the lung cancer risk was increased compared with unexposed workers (rate ratio = 1.49; 95% CI, 1.14-1.96). There was a suggestion of a positive relationship between weighted cumulative SO(2) exposure and lung cancer mortality (p-value of test for linear trend = 0.009 among all exposed workers; p = 0.3 among workers with high exposure). Neither duration of exposure nor time since first exposure was associated with lung cancer mortality. Mortality from non-Hodgkin lymphoma and from leukemia was increased among workers with high SO(2) exposure; a dose-response relationship with cumulative SO(2) exposure was suggested for non-Hodgkin lymphoma. For the other causes of death, there was no evidence of increased mortality associated with exposure to SO(2). Although residual confounding may have occurred, our results suggest that occupational exposure to SO(2) in the pulp and paper industry may be associated with an increased risk of lung cancer

Extracellular LGALS3BP regulates neural progenitor position and relates to human cortical complexity.

Basal progenitors (BPs), including intermediate progenitors and basal radial glia, are generated from apical radial glia and are enriched in gyrencephalic species like humans, contributing to neuronal expansion. Shortly after generation, BPs delaminate towards the subventricular zone, where they further proliferate before differentiation. Gene expression alterations involved in BP delamination and function in humans are poorly understood. Here, we study the role of LGALS3BP, so far known as a cancer biomarker, which is a secreted protein enriched in human neural progenitors (NPCs). We show that individuals with LGALS3BP de novo variants exhibit altered local gyrification, sulcal depth, surface area and thickness in their cortex. Additionally, using cerebral organoids, human fetal tissues and mice, we show that LGALS3BP regulates the position of NPCs. Single-cell RNA-sequencing and proteomics reveal that LGALS3BP-mediated mechanisms involve the extracellular matrix in NPCs' anchoring and migration within the human brain. We propose that its temporal expression influences NPCs' delamination, corticogenesis and gyrification extrinsically

From Young to Old: AMPylation Hits the Brain

Protein post-translational modifications (PTMs) are implicated in numerous physiological processes and significantly contribute to complex regulatory networks of protein functions. Recently, a protein PTM called AMPylation was found to play a role in modulation of neurodevelopment and neurodegeneration. Combination of biochemical and chemical proteomic studies has uncovered the prevalence of this PTM in regulation of diverse metabolic pathways. In metazoans, thus far two protein AMP transferases have been identified to introduce AMPylation: FICD and SELO. These two proteins were found to be involved in unfolded protein response and redox homeostasis on the cellular level and in the case of FICD to adjust the development of glial cells and neurons in Drosophila and cerebral organoids, respectively. Together with findings on AMPylation and its association with toxic protein aggregation, we summarize in this Perspective the knowledge and putative future directions of protein AMPylation research

A Pronucleotide Probe for Live-Cell Imaging of Protein AMPylation

Conjugation of proteins to AMP (AMPylation) is a prevalent post-translational modification (PTM) in human cells, involved in the regulation of unfolded protein response and neural development. Here we present a tailored pronucleotide probe suitable for in situ imaging and chemical proteomics profiling of AMPylated proteins. Using straightforward strain-promoted azide-alkyne click chemistry, the probe provides stable fluorescence labelling in living cells

Differences among the coloured, white, black, and other South African populations in smoking-attributed mortality at ages 35-74 years: a case-control study of 481,640 deaths.

BACKGROUND: The full eventual effects of current smoking patterns cannot yet be seen in Africa. In South Africa, however, men and women in the coloured (mixed black and white ancestry) population have smoked for many decades. We assess mortality from smoking in the coloured, white, and black (African) population groups. METHODS: In this case-control study, 481,640 South African notifications of death at ages 35-74 years between 1999 and 2007 yielded information about age, sex, population group, education, smoking 5 years ago (yes or no), and underlying disease. Cases were deaths from diseases expected to be affected by smoking; controls were deaths from selected other diseases, excluding only HIV, cirrhosis, unknown causes, external causes, and mental disorders. Disease-specific case-control comparisons yielded smoking-associated relative risks (RRs; diluted by combining some ex-smokers with the never-smokers). These RRs, when combined with national mortality rates, yielded smoking-attributed mortality rates. Summation yielded RRs and smoking-attributed numbers for overall mortality. FINDINGS: In the coloured population, smoking prevalence was high in both sexes and smokers had about 50% higher overall mortality than did otherwise similar non-smokers or ex-smokers (men, RR 1·55, 95% CI 1·43-1·67; women, 1·49, 1·38-1·60). RRs were similar in the white population (men, 1·37, 1·29-1·46; women, 1·51, 1·40-1·62), but lower among Africans (men, 1·17, 1·15-1·19; women, 1·16, 1·13-1·20). If these associations are largely causal, smoking-attributed proportions for overall male deaths at ages 35-74 years were 27% (5608/20,767) in the coloured, 14% (3913/28,951) in the white, and 8% (20,398/264,011) in the African population. For female deaths, these proportions were 17% (2728/15,593) in the coloured, 12% (2084/17,899) in the white, and 2% (4038/205,623) in the African population. Because national mortality rates were also substantially higher in the coloured than in the white population, the hazards from smoking in the coloured population were more than double those in the white population. INTERPRETATION: The highest smoking-attributed mortality rates were in the coloured population and the lowest were in Africans. The substantial hazards already seen among coloured South Africans suggest growing hazards in all populations in Africa where young adults now smoke. FUNDING: South African Medical Research Council, UK Medical Research Council, Cancer Research UK, British Heart Foundation, New South Wales Cancer Council

Differences among the coloured, white, black, and other South African populations in smoking-attributed mortality at ages 35-74 years: a case-control study of 481,640 deaths

BACKGROUND: The full eventual effects of current smoking patterns cannot yet be seen in Africa. In South Africa, however, men and women in the coloured (mixed black and white ancestry) population have smoked for many decades. We assess mortality from smoking in the coloured, white, and black (African) population groups. METHODS: In this case-control study, 481,640 South African notifications of death at ages 35-74 years between 1999 and 2007 yielded information about age, sex, population group, education, smoking 5 years ago (yes or no), and underlying disease. Cases were deaths from diseases expected to be affected by smoking; controls were deaths from selected other diseases, excluding only HIV, cirrhosis, unknown causes, external causes, and mental disorders. Disease-specific case-control comparisons yielded smoking-associated relative risks (RRs; diluted by combining some ex-smokers with the never-smokers). These RRs, when combined with national mortality rates, yielded smoking-attributed mortality rates. Summation yielded RRs and smoking-attributed numbers for overall mortality. FINDINGS: In the coloured population, smoking prevalence was high in both sexes and smokers had about 50% higher overall mortality than did otherwise similar non-smokers or ex-smokers (men, RR 1.55, 95% CI 1.43-1.67; women, 1.49, 1.38-1.60). RRs were similar in the white population (men, 1.37, 1.29-1.46; women, 1.51, 1.40-1.62), but lower among Africans (men, 1.17, 1.15-1.19; women, 1.16, 1.13-1.20). If these associations are largely causal, smoking-attributed proportions for overall male deaths at ages 35-74 years were 27% (5608/20,767) in the coloured, 14% (3913/28,951) in the white, and 8% (20,398/264,011) in the African population. For female deaths, these proportions were 17% (2728/15,593) in the coloured, 12% (2084/17,899) in the white, and 2% (4038/205,623) in the African population. Because national mortality rates were also substantially higher in the coloured than in the white population, the hazards from smoking in the coloured population were more than double those in the white population. INTERPRETATION: The highest smoking-attributed mortality rates were in the coloured population and the lowest were in Africans. The substantial hazards already seen among coloured South Africans suggest growing hazards in all populations in Africa where young adults now smoke. FUNDING: South African Medical Research Council, UK Medical Research Council, Cancer Research UK, British Heart Foundation, New South Wales Cancer Counci

FICD activity and AMPylation remodelling modulate human neurogenesis.

Posttranslational modification (PTM) of proteins represents an important cellular mechanism for controlling diverse functions such as signalling, localisation or protein-protein interactions. AMPylation (also termed adenylylation) has recently been discovered as a prevalent PTM for regulating protein activity. In human cells AMPylation has been exclusively studied with the FICD protein. Here we investigate the role of AMPylation in human neurogenesis by introducing a cell-permeable propargyl adenosine pronucleotide probe to infiltrate cellular AMPylation pathways and report distinct modifications in intact cancer cell lines, human-derived stem cells, neural progenitor cells (NPCs), neurons and cerebral organoids (COs) via LC-MS/MS as well as imaging methods. A total of 162 AMP modified proteins were identified. FICD-dependent AMPylation remodelling accelerates differentiation of neural progenitor cells into mature neurons in COs, demonstrating a so far unknown trigger of human neurogenesis

AMPylation profiling during neuronal differentiation reveals extensive variation on lysosomal proteins.

Protein AMPylation is a posttranslational modification with an emerging role in neurodevelopment. In metazoans two highly conserved protein AMP-transferases together with a diverse group of AMPylated proteins have been identified using chemical proteomics and biochemical techniques. However, the function of AMPylation remains largely unknown. Particularly problematic is the localization of thus far identified AMPylated proteins and putative AMP-transferases. We show that protein AMPylation is likely a posttranslational modification of luminal lysosomal proteins characteristic in differentiating neurons. Through a combination of chemical proteomics, gel-based separation of modified and unmodified proteins, and an activity assay, we determine that the modified, lysosomal soluble form of exonuclease PLD3 increases dramatically during neuronal maturation and that AMPylation correlates with its catalytic activity. Together, our findings indicate that AMPylation is a so far unknown lysosomal posttranslational modification connected to neuronal differentiation and it may provide a molecular rationale behind lysosomal storage diseases and neurodegeneration