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The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.
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The Arabidopsis thaliana glycosyl transferases SPINDLY (SPY) and SECRET AGENT (SEC) modify nuclear and cytosolic proteins with O-linked fucose or O-linked N-acetylglucosamine (O-GlcNAc), respectively. O-fucose and O-GlcNAc modifications can occur at the same sites. SPY interacts physically and genetically with GIGANTEA (GI), suggesting that it could be modified by both enzymes. Previously, we found that, when co-expressed in Escherichia coli, SEC modifies GI; however, the modification site was not determined. By analyzing the overlapping sub-fragments of GI, we identified a region that was modified by SEC in E. coli. Modification was undetectable when threonine 829 (T829) was mutated to alanine, while the T834A and T837A mutations reduced the modification, suggesting that T829 was the primary or the only modification site. Mapping using mass spectrometry detected only the modification of T829. Previous studies have shown that the positions modified by SEC in E. coli are modified in planta, suggesting that T829 is O-GlcNAc modified in planta.
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In the course of researching and writing the first-ever book length biography of Edward Graeme Robertson's (1903-1975) eventful life and career in Australasian neurology, a rare 1933 cinema film recording of National Hospital staff at Queen Square has recently been rediscovered. Graeme completed his residency in neurology at Queen Square in the early 1930s and maintained close connections with his colleagues in London, thoughtfully recording them at different times using early movie cameras. Two versions of Graeme's 1933 film have been preserved, and there are also other color clips of his colleagues from later in life in the UCL Neurology archives and Robertson family collection. These remarkable films contain images of several historically significant neurologists, including Gordon Morgan Holmes (1876-1965), Samuel Alexander Kinnier Wilson (1878-1937), Derek Denny-Brown (1901-1981), Macdonald Critchley (1900-1997), and several others. We provide a contextual summary of the many clips recorded alongside an in-depth inventory of all the personalities represented in the 1933 film. Selected photographs are used to indicate the contents of these remarkable films.
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INTRODUCTION: Friedreich's Ataxia (FRDA) is a multi-system disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM. METHODS: Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer MRI) were assessed. RESULTS: Participants included 11 individuals with FRDA (4 female), median age 27y (IQR 23, 39), BMI 26.9kg/m2 (24.1, 29.4), and 24 controls (11 female), 29y (26, 39), 24.4kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA (91 vs. 83mg/dL (5.0 vs. 4.6mmol/L), p<0.05). Individuals with FRDA had lower insulin sensitivity (WBISI 2.8 vs. 5.3, p<0.01), higher post-prandial insulin secretion (insulin secretory rate iAUC 30-180 minutes, 24,652 vs. 17,858, p<0.05), and more suppressed post-prandial endogenous glucose production (-0.9% vs. 26.9% of fasting EGP, p<0.05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different. CONCLUSIONS: Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.
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Recent accumulation of evidence across taxa indicates that the ecological impacts of invasive alien species are predictable from their functional response (FR; e.g. the maximum feeding rate) and functional response ratio (FRR; the FR attack rate divided by handling time). Here, we experimentally derive these metrics to predict the ecological impacts of both juvenile and adult lionfish (Pterois volitans), one of the world's most damaging invaders, across representative and likely future prey types. Potentially prey-population destabilizing Type II FRs were exhibited by both life stages of lionfish towards four prey species: Artemia salina, Gammarus oceanicus, Palaemonetes varians and Nephrops norvegicus. FR magnitudes revealed ontogenetic shifts in lionfish impacts where juvenile lionfish displayed similar if not higher consumption rates than adult lionfish towards prey, apart from N. norvegicus, where adult consumption rate was considerably higher. Additionally, lionfish FRR values were very substantially higher than mean FRR values across known damaging invasive taxa. Thus, both life stages of lionfish are predicted to contribute to differing but high ecological impacts across prey communities, including commercially important species. With lionfish invasion ranges currently expanding across multiple regions globally, efforts to reduce lionfish numbers and population size structure, with provision of prey refugia through habitat complexity, might curtail their impacts. Nevertheless, the present study indicates that management programmes to support early detection and complete eradication of lionfish individuals when discovered in new regions are advised.
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As a part of a study of suicide in children aged 17 years and under in three centers-Hennepin County in the United States (US), Auckland in New Zealand (NZ), and South Australia in Australia (AUS) from 2008 to 2017 it was decided to characterize potential risk factors and to determine whether these differed by jurisdiction. Reviewed data included a history of psychiatric illness, symptoms prior to suicide, events preceding suicide, previous suicidal ideation or suicide attempts, and communication of suicidal intent. The most common events preceding suicide were arguments with family/friends and relationship issues; in addition depression with or without expressed suicidal ideation, self-harming behavior, sadness, distress, drug/substance abuse, and anorexia were documented. Suicidal intent was on occasion communicated via technological means. In 79.5% of cases in South Australia decedents had a previously diagnosed psychiatric illness, with 62% in Hennepin County. This compared to a much lower proportion of cases in Auckland (23.8%). Whether this reflects more limited access to psychiatric services or a reluctance to seek support and therapy in Auckland is unclear. It does, however, demonstrate that risk factors for child suicide are not uniform among communities and so extrapolation of data from one area to another may not be appropriate. Disturbingly parents/carers were not aware of the decedent's suicidal intent in 84-87.2% of cases.
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No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) impacting cognitive function in long-term testicular cancer survivors (TC-survivors). TC-survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those which assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC-survivors [median age: 46 (IQR: 38, 54); median time-since-chemotherapy: 10.9 years (IQR = 7.9, 15.9)], 13.7% reported cognitive dysfunction. Hearing loss (OR = 2.02; P = .040), neuropathic-pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P<.001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive declines. Factors associated with impaired cognition identify TC-survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic-pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC-survivors.
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PURPOSE: Post-exercise passive heating has been reported to augment adaptations associated with endurance training. The current study evaluated the effect of a 4-week remotely administered, post-exercise passive leg heating protocol, using an electrically heated layering ensemble, on determinants of endurance performance. METHODS: Thirty recreationally trained participants were randomly allocated to either a post-exercise passive leg heating (PAH, n = 16) or unsupervised training only control group (CON, n = 14). The PAH group wore the passive heating ensemble for 90-120 min/day, completing a total of 20 (16 post-exercise and 4 stand-alone leg heating) sessions across 4 weeks. Whole-body (peak oxygen uptake, gas exchange threshold, gross efficiency and pulmonary oxygen uptake kinetics), single-leg exercise (critical torque and NIRS-derived muscle oxygenation), resting vascular characteristics (flow-mediated dilation) and angiogenic blood measures (nitrate, vascular endothelial growth factor and hypoxia inducible factor 1-α) were recorded to characterize the endurance phenotype. All measures were assessed before (PRE), at 2 weeks (MID) and after (POST) the intervention. RESULTS: There was no effect of the intervention on test of whole-body endurance capacity, vascular function or blood markers (p > 0.05). However, oxygen kinetics were adversely affected by PAH, denoted by a slowing of the phase II time constant; τ (p = 0.02). Furthermore, critical torque-deoxygenation ratio was improved in CON relative to PAH (p = 0.03). CONCLUSION: We have demonstrated that PAH had no ergogenic benefit but instead elicited some unfavourable effects on sub-maximal exercise characteristics in recreationally trained individuals.
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PURPOSE: The purpose of this study was to determine the effect of acute nicotinamide riboside (NR) supplementation on cerebral nicotinamide adenine dinucleotide (NAD+) levels in the human brain in vivo by means of downfield proton MRS (DF 1H MRS). METHODS: DF 1H MRS was performed on 10 healthy volunteers in a 7.0 T MRI scanner with spectrally selective excitation and spatially selective localization to determine cerebral NAD+ levels on two back-to-back days: once after an overnight fast (baseline) and once 4 h after oral ingestion of nicotinamide riboside (900 mg). Additionally, two more baseline scans were performed following the same paradigm to assess test-retest reliability of the NAD+ levels in the absence of NR. RESULTS: NR supplementation increased mean NAD+ concentration compared to the baseline (0.458 ± 0.053 vs. 0.392 ± 0.058 mM; p < 0.001). The additional two baseline scans demonstrated no differences in mean NAD+ concentrations (0.425 ± 0.118 vs. 0.405 ± 0.082 mM; p = 0.45), and no difference from the first baseline scan (F(2, 16) = 0.907; p = 0.424). CONCLUSION: These preliminary results confirm that acute NR supplementation increases cerebral NAD+ levels in healthy human volunteers and shows the promise of DF 1H MRS utility for robust detection of NAD+ in humans in vivo.
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Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening. We sequenced DNA from 509 individuals with CLL or monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, using a targeted sequencing panel of 59 recurrently mutated genes in CLL and additional amplicons across regions affected by clinically relevant CNAs [i.e., del(17p), del(11q), del(13q), and trisomy 12]. We used the PatternCNV algorithm to call CNA and compared the concordance of calling clinically relevant CNAs by targeted sequencing to that of FISH. We found a high accuracy of calling CNAs via sequencing compared to FISH. With FISH as the gold standard, the specificity of targeted sequencing was >95%, sensitivity was >86%, positive predictive value was >90%, and negative predictive value was >84% across the clinically relevant CNAs. Using targeted sequencing, we were also able to identify other common CLL-associated CNAs, including del(6q), del(14q), and gain 8q, as well as complex karyotype, defined as the presence of 3 or more chromosomal abnormalities, in 26 patients. In a single and cost-effective assay that can be performed on stored DNA samples, targeted sequencing can simultaneously detect CNAs, somatic mutations, and complex karyotypes, which are all important prognostic features in CLL.
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PURPOSE: To compare disease-free survival (DFS), overall survival (OS), and adverse events (AEs) among muscle-invasive urothelial carcinoma (MIUC) patients receiving adjuvant immune checkpoint inhibitors (ICIs) versus placebo/observation following radical surgery. METHODS: This was a systematic review/meta-analysis of all published phase 3 randomized controlled trials. MEDLINE, EMBASE, and Cochrane were searched from inception until April 4, 2024. Pooled hazard ratios (HR) and relative risks (RR), plus confidence intervals (CI), were generated using frequentist random-effects modeling. RESULTS: Three trials were identified: IMvigor010, CheckMate 274, and AMBASSADOR. In the overall cohort, adjuvant ICIs significantly improved DFS by 23% (HR = 0.77, 95% CI = 0.65-0.90). No DFS benefit was observed in patients with upper tract disease (HR = 1.19, 95% CI = 0.86-1.64). The highest magnitude of DFS benefit was observed among patients who had received prior neoadjuvant chemotherapy (HR = 0.69) and pathologic node-positive disease (HR = 0.75). A similar DFS benefit was observed irrespective of tumor PD-L1 status. Pooled OS demonstrated a 13% non-significant benefit (HR = 0.87, 95% CI = 0.75-1.01). Grade ≥ 3 immune-mediated AEs occurred in 8.6% and 2.1% of ICI and placebo/observation patients, respectively (RR = 4.35, 95% CI = 1.02-18.5). AEs leading to treatment discontinuation occurred in 14.3% and 0.9% of patients, respectively. CONCLUSION: Adjuvant ICIs confer a DFS benefit following radical surgery for MIUC, particularly among node-positive patients and those who received prior neoadjuvant chemotherapy. The lack of benefit for upper tract disease suggests that alternate adjuvant approaches, including chemotherapy, should be considered for these patients. Tumor PD-L1 status is not a predictive biomarker, highlighting the need for biomarkers in this setting.
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Carcinoma de Células de Transição , Inibidores de Checkpoint Imunológico , Neoplasias da Bexiga Urinária , Humanos , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgiaRESUMO
To understand the potential exposure to tobacco smoke in Washoe County (Reno/Sparks), Nevada casinos by measuring air quality in smoking areas relative to non-smoking/non-gaming areas in which minors may be present. To act as a pilot study in community-based health research and policy campaigns by evaluating low-cost air monitors to measure personal secondhand smoke (SHS) exposure. We used customized mobile apps, AtmoTube PRO Air Monitors, and hand clickers to measure the timing and minute-by-minute levels of PM2.5 (a tobacco smoke marker). The app was used to record the number of smokers, minors, and total patrons associated with ~10-minute sequential time periods in standardized casino locations, including outdoor areas, slots, tables, restaurants, bars/lounges, arcades, among others. Between April and May 2022, we successfully visited 14 casinos and 18 distinct types of indoor casino locations. We found high PM2.5 peaks in casino locations even with zero, or a low percentage of, observed active smokers, including in both gaming/non-gaming areas. Indoor areas, regardless of smoking/non-smoking areas, consistently had higher PM2.5 levels than outdoor background levels. Indoor locations had median PM2.5 levels up to 18 times higher than the lowest outdoor background levels. Minors were present throughout all casino locations, and thus were likely exposed to elevated PM2.5 levels. Potential PM2.5 exposures due to smoking can be high regardless of ventilation systems. Small proportions of smokers in a location can lead to high levels of exposure. Establishing comprehensive smoke-free casinos is the only way to protect against SHS harms.
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Pigments provide a simple means to rapidly visually ascertain the quantities or presence of specific microbes in a complex community. The selection of pigment-producing colonies that are simple to differentiate from common colony phenotypes provides a high degree of certainty for the identity of pigment-tagged strains. Successful employment of pigment production is dependent on various intrinsic factors related to proper levels of gene expression and pigment production that are not always easy to predict and vary within each microbe. We have constructed a simple transposon system that incorporates the genes for the production of deoxyviolacein, a pigment produced from intracellular reserves of the amino acid tryptophan, to randomly insert these genes throughout the genome. This tool allows the user to select from many thousands of potential sites throughout a bacterial genome for an ideal location to generate the desired amount of pigment. We have applied this system to a small selection of endophytes and other model bacteria to differentiate these strains from complex communities and confirm their presence after several weeks in natural environments. We provide two examples of applications using the pigments to trace strains following introduction into plant tissues or to produce a reporter strain for extracellular nitrogen compound sensing. We recognize that this tool could have far broader utility in other applications and microbes, and describe the methodology for use by the greater scientific community.
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Elementos de DNA Transponíveis , Pigmentos Biológicos , Elementos de DNA Transponíveis/genética , Pigmentos Biológicos/metabolismo , Mutagênese Insercional/métodos , Vetores Genéticos/genética , Bactérias/genética , Bactérias/metabolismo , Bactérias/classificação , Triptofano/metabolismo , Endófitos/genética , Endófitos/metabolismoRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. METHODS: The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. RESULTS: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p = .47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p = .10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. CONCLUSIONS: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.
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Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2+ γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4+ T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4+ T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4+ T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4+ T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.
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Despite the growing popularity of women's rugby, there is a lack of research understanding the contribution of place-kicking to match outcomes. This study aims to establish the characteristics and contribution of place-kicking to women's international Rugby Union and evaluate the performance of place-kickers while accounting for factors that contribute to kick difficulty. Data from 674 place-kicks across 80 matches were analysed. A binomial generalised linear mixed model (GLMM) was used to predict the probability of kick success. 60.5% of place-kicks were successful, and they contributed 23.9% of all points scored; conversions accounted for 16.8% and penalties 7.1%. Kick success percentages for conversions (56.9%) and penalties (78.3%) significantly differed (p < 0.01). Kick distance and angle were significant (p < 0.01) predictors of kick success and the GLMM had a prediction accuracy of 73.6%. The performance rankings of kickers changed when comparing observed and expected success, highlighting the need to consider contextual factors contributing to kick difficulty when evaluating performance. The GLMM results provide valuable insights for coaches and players to make informed decisions, for example, whether to attempt a place-kick when a penalty is awarded, by enabling predictions of place-kick success. This could enhance a team's chances of winning matches.
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Previous studies involving workers at brick kilns in the Kathmandu Valley of Nepal have investigated chronic exposure to hazardous levels of fine particulate matter (PM2.5) common in ambient and occupational environments. Such exposures are known to cause and/or exacerbate chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. However, there is a paucity of data regarding the status of systemic inflammation observed in exposed workers at brick manufacturing facilities within the country. In the current study, we sought to elucidate systemic inflammatory responses by quantifying the molecular cytokine/chemokine profiles in serum from the study participants. A sample of participants were screened from a kiln in Bhaktapur, Nepal (n = 32; 53% female; mean ± standard deviation: 28.42 ± 11.47 years old) and grouped according to job category. Blood was procured from participants on-site, allowed to clot at room temperature, and centrifuged to obtain total serum. A human cytokine antibody array was used to screen the inflammatory mediators in serum samples from each of the participants. For the current study, four job categories were evaluated with n = 8 for each. Comparisons were generated between a control group of administration workers vs. fire master workers, administration workers vs. green brick hand molders, and administration workers vs. top loaders. We discovered significantly increased concentrations of eotaxin-1, eotaxin-2, GCSF, GM-CSF, IFN-γ, IL-1α, IL-1ß, IL-6, IL-8, TGF-ß1, TNF-α, and TIMP-2 in serum samples from fire master workers vs. administration workers (p < 0.05). Each of these molecules was also significantly elevated in serum from green brick hand molders compared to administration workers (p < 0.05). Further, each molecule in the inflammatory screening with the exception of TIMP-2 was significantly elevated in serum from top loaders compared to administration workers (p < 0.05). With few exceptions, the fire master workers expressed significantly more systemic inflammatory molecular abundance when compared to all other job categories. These results reveal an association between pulmonary exposure to PM2.5 and systemic inflammatory responses likely mediated by cytokine/chemokine elaboration. The additional characterization of a broader array of inflammatory molecules may provide valuable insight into the susceptibility to lung diseases among this population.