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1.
Int Arch Occup Environ Health ; 96(4): 607-619, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36692547

RESUMO

PURPOSE: This study examined whether job satisfaction and job security moderate the path from physical demands and job strain to impaired work performance via musculoskeletal symptoms in the upper extremities (MSUE). Moderation effects on five paths were examined: (1) from job strain to MSUE; (2) from job strain to work performance; (3) from physical demands to MSUE; (4) from physical demands to work performance; (5) from MSUE to work performance. METHODS: This was a cross-sectional study of 669 full-time workers from 9 manufacturing and 3 healthcare facilities. Data were collected via health interviews, on-site physical exposure assessments, and computation of the Strain Index by ergonomists, and self-administered questionnaires on psychosocial factors. Structural equation modeling and zero-inflated negative binomial regression analysis were performed to examine the moderation effect on each path. RESULTS: Job satisfaction moderated the relationship between MSUE and impaired work performance (B = - 0.09, 95% CI: - 0.15, - 0.04) and job security moderated the relationship between physical demands and MSUE (B = - 0.64, 95% CI: - 1.17, - 0.11). Interaction between job satisfaction and MSUE was significant on both the occurrence (OR: 0.92, 95% CI: 0.87, 0.97) and the degrees of impaired work performance (mean ratio: 0.99, 95% CI: 0.97, 0.99), while the interaction between job security and physical demands was significant only on the degrees of MSUE (mean ratio: 0.94, 95% CI: 0.89, 0.99). CONCLUSION: Job satisfaction and job security can, respectively, mitigate the adverse impacts of working with MSUE and physical demands on work performance. Workplace interventions to improve workers' job satisfaction and job security can contribute to their musculoskeletal health and work performance.


Assuntos
Desempenho Profissional , Humanos , Satisfação no Emprego , Estudos Transversais , Local de Trabalho/psicologia , Inquéritos e Questionários
2.
Ergonomics ; 66(1): 34-48, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35301937

RESUMO

This study investigated the interaction between physical demands and job strain on musculoskeletal symptoms in upper extremities (MSUE) and work performance. Two years of prospective data were analysed from 713 full-time workers from twelve manufacturing and healthcare facilities in Washington in the United States. Physical exposure was measured by the Strain Index and Threshold Limit Value for hand activity, giving rise to safe, action, and hazardous physical demand groups. Job strain was calculated as the ratio of psychological job demands to job control. Multilevel modelling analysis showed that job strain affected MSUE and limited work performance less in the high physical demand group than the safe group because the protective effect of job control was smaller in these groups. Findings may suggest that high physical demand jobs are structured such that workers have low job control or high physical demand groups experience job strain not adequately captured by psychosocial variables.Practitioner Summary: The effects of job strain and job control on musculoskeletal symptoms in upper extremities and work performance were smaller among workers with higher physical demands. This could imply that high physical demand jobs limit job control or psychosocial variables may not adequately capture job strain among high physical demand groups.


Assuntos
Doenças Profissionais , Desempenho Profissional , Humanos , Estados Unidos , Estresse Psicológico/psicologia , Estudos Prospectivos , Ocupações , Análise Multinível , Doenças Profissionais/etiologia , Fatores de Risco
3.
Thorax ; 77(2): 123-128, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33927021

RESUMO

BACKGROUND: Inability to return to work (RTW) is common after acute respiratory distress syndrome (ARDS). Mismatch in an individual's job workload and his or her functional ability, termed work ability imbalance, is negatively associated with RTW, but has not been evaluated in ARDS survivors. OBJECT: We examine associations between work ability imbalance at 6 months and RTW at 6 months and 12 months, as well as the ability to sustain employment in ARDS survivors. METHODS: Previously employed participants from the ARDS Network Long-Term Outcomes Study (N=341) were evaluated. Pre-ARDS workload was determined based on the US Occupational Information Network classification. Post-ARDS functional ability was assessed using self-reported 36-Item Short Form Health Survey (SF-36) physical functioning, social functioning and mental health subscales, and Mini-Mental State Examination. ARDS survivors were categorised into four work ability imbalance categories: none, psychosocial, physical, and both psychosocial and physical. RESULTS: Almost 90% of ARDS survivors had a physical and/or psychosocial work ability imbalance at both 6-month and 12-month follow-up. Compared with survivors with no imbalance at 6 months, those with both physical and psychosocial imbalance had lower odds of RTW (6 months: OR=0.33, 95% CI=0.13 to 0.82; 12 months: OR=0.22, 95% CI=0.07 to 0.65). Thirty-eight (19%) of those who ever RTW were subsequently jobless at 12 months. CONCLUSION: Interventions aimed at rebalancing ARDS survivors' work ability by addressing physical and psychosocial aspects of their functional ability and workload should be explored as part of efforts to improve RTW, maintain employment and reduce the financial impact of joblessness.


Assuntos
Síndrome do Desconforto Respiratório , Retorno ao Trabalho , Atividades Cotidianas , Feminino , Humanos , Masculino , Sobreviventes , Carga de Trabalho
4.
J Occup Rehabil ; 31(2): 275-284, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33025272

RESUMO

Purpose People with Parkinson's disease (PwP) exit the workforce on average 5 years earlier than people without Parkinson's due to motor, cognitive, communicative, and affective symptoms. Decreased employment results in significant individual and societal costs. The objectives of this study were to identify strengths and weaknesses of employment resources and assess the needs of consumer and clinical stakeholders to improve job retention. Methods The study used a qualitative content analysis and Quasi Needs Assessment Framework. Sixteen PwP and 10 clinician stakeholders participated in two rounds of stakeholder discussion panels. Main outcomes included (1) the resources identified through the online content search and themes derived from those resources, and (2) the information gained from discussion panels and themes derived from their conversations. Results Literature review and online searches yielded 59 resources (30 consumer-focused documents, 17 peer-reviewed articles, and 12 documents supplied by key informants who are experts in Parkinson's disease and/or employment). Themes frequently found in the consumer-focused content but not the peer-reviewed literature included diagnosis disclosure decision-making, the benefits of retiring compared to working, and workplace accommodations. Stakeholders identified three key needs with regard to employment-related support for PwP: (1) knowledge about employment support options; (2) a clinician to start the discussion about employment challenges; and (3) an individualized and flexible approach to employment-related interventions. Conclusions Many people with Parkinson's experience unmet employment-related resource and process needs. An individually-tailored interdisciplinary intervention care path could facilitate decisions regarding disclosure and accommodations.


Assuntos
Doença de Parkinson , Revelação , Emprego , Humanos , Avaliação das Necessidades , Local de Trabalho
5.
Gynecol Oncol ; 159(2): 527-533, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32977988

RESUMO

OBJECTIVE: Measure the size and shape of talc particles in talcum powder and compare this data to the size and shape of talc particles found in surgically resected tissues from patients with ovarian carcinoma. METHODS: Using polarized light microscopy (PLM) and scanning electron microscopy (SEM), we measured the size and shape of talc particles in samples of talc-containing baby powder (TCBP) and surgically resected pelvic tissues (hysterectomies) from talc-exposed patients with ovarian carcinoma. RESULTS: The most frequent class of particles in TCBP can be unequivocally identified as talc, using both polarized light microscopy and scanning electron microscopy with energy dispersive X-ray analysis (SEM/EDX). The talc particles found in resected tissues from ovarian carcinoma patients are similar in size and shape to the most abundant morphological class of particles in TCBP. CONCLUSIONS: This finding, combined with previous epidemiological literature and tissue-based analytical studies, provides further evidence that the small, isodiametric particles that dominate TCBP can migrate from the perineum and become lodged in distal structures in the female reproductive tract, where they may lead to an increased risk of developing ovarian carcinoma.


Assuntos
Linfonodos/química , Omento/química , Ovário/química , Talco/análise , Adulto , Idoso , Carcinoma Epitelial do Ovário/patologia , Feminino , Humanos , Linfonodos/ultraestrutura , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Omento/ultraestrutura , Neoplasias Ovarianas/patologia , Ovário/ultraestrutura , Talco/efeitos adversos , Talco/farmacocinética
6.
Arch Phys Med Rehabil ; 101(1S): S63-S70, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-29050789

RESUMO

OBJECTIVE: To examine trajectories of satisfaction with life (SWL) of burn survivors over time and their clinical, demographic, and other predictors. DESIGN: Longitudinal survey. SETTING: Not applicable. PARTICIPANTS: Individuals ≥18 years of age who underwent burn-related surgery and met one of the following criteria: (1) >10% total body surface area (TBSA) burn and ≥65 years of age; (2) >20% TBSA burn and 18 to 64 years of age; (3) electrical high voltage/lightning injury; or (4) burn injury to the hands, face, or feet. The participants (N=378) had data on all variables of interest and were included in the analyses. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Satisfaction With Life Scale. RESULTS: Growth mixture modeling identified 2 classes with different trajectories of SWL. The mean SWL of the unchanged class (n=224, 60%) was flat over 2 years with high initial SWL scores. The SWL of the dissatisfied class (n=154, 40%) was at the low end of average and got progressively worse over time. CONCLUSIONS: SWL after burn injury can be described by 2 different trajectories with substantially different outcomes. Older age, worse mental health, and unemployment prior to injury predicted membership in the dissatisfied class. Additional services could be provided to those at high risk for low SWL to achieve better outcomes.


Assuntos
Queimaduras/psicologia , Satisfação Pessoal , Qualidade de Vida/psicologia , Pesquisa de Reabilitação/organização & administração , Sobreviventes/psicologia , Adulto , Fatores Etários , Queimaduras/reabilitação , Pessoas com Deficiência/psicologia , Pessoas com Deficiência/reabilitação , Feminino , Humanos , Vida Independente , Tempo de Internação , Estudos Longitudinais , Masculino , Saúde Mental , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Fatores Socioeconômicos , Índices de Gravidade do Trauma
7.
Matern Child Health J ; 24(8): 960-965, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32350731

RESUMO

INTRODUCTION: With shifting demographics and declining response rates, state and national health surveys are considering mixed mode approaches. Most states field the Pregnancy Risk Assessment Monitoring System (PRAMS) surveillance project, but few have studied the effect of encouraging online responses. METHODS: Like PRAMS, the 2016 Ohio Pregnancy Assessment Survey interviewed new mothers 2-4 months after delivery (n = 3382). Fielding included a traditional mailed paper questionnaire with telephone follow-up protocol and two experiments: a rotating web invitation added a web survey link at different points during the mail protocol, and a push-to-web protocol asked women to complete the survey online before mailing a questionnaire. This analysis examined the responses rates and tested for unweighted demographic differences using Pearson's chi-square. RESULTS: The unweighted response rate was highest with the traditional contact protocol (30.0%) and slightly lower among the rotating web invite (27.4%) and the push-to-web (25.5%) groups. Nearly two-thirds (64%) of push-to-web protocol respondents completed the survey online, with 70% of those web surveys submitted before the first paper questionnaire was mailed. Women who responded to the web versus mail surveys were similar on most characteristics, although in both experimental groups, women who completed the web version were more likely to be college educated. Among the push-to-web group, 60% of web and 36% of mail respondents had a 4-year college degree (p < .001). DISCUSSION: Given the potential for push-to-web to shift respondents to an online survey without greatly impacting response rates, researchers should continue to examine the utility of incorporating a web mode in surveys of new mothers.


Assuntos
Mães/psicologia , Seleção de Pacientes , Adulto , Feminino , Humanos , Internet , Ohio , Medição de Risco , Inquéritos e Questionários
8.
Proc Natl Acad Sci U S A ; 112(46): E6301-10, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26578790

RESUMO

Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.


Assuntos
Adipócitos/enzimologia , Senescência Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Janus Quinases/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia , Transdução de Sinais/efeitos dos fármacos , Adipócitos/citologia , Tecido Adiposo/citologia , Tecido Adiposo/enzimologia , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Senescência Celular/genética , Matriz Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/citologia , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Macrófagos/citologia , Macrófagos/enzimologia , Camundongos , RNA Interferente Pequeno/genética , Transdução de Sinais/genética
9.
Artigo em Inglês | MEDLINE | ID: mdl-38511844

RESUMO

The influence of posterior cruciate ligament (PCL) tension on the clinical outcome of cruciate-retaining total knee replacement (CR-TKR) remains controversial. Various numerical approaches have been used to study this influence systematically, but the models used are limited by certain assumptions and simplifications. Therefore, the objective of this computational study was to develop a combined musculoskeletal multibody and finite-element simulation during a squat motion to 90° knee flexion with a CR-TKR design to overcome previous limitations regarding model inputs. In addition, different PCL tensions (tight, lax, resected) were modeled and the influence on tibiofemoral and resurfaced patellofemoral joint dynamics and contact stresses was evaluated. The effect of the PCL on knee joint dynamics and contact stresses was more pronounced at higher flexion angles. Tibiofemoral joint dynamics were influenced and a tight PCL induced increased posterior femoral translation during flexion. The maximum contact stress in the tibial insert increased from 20.6 MPa to 22.5 MPa for the resected and tightest PCL at 90° knee flexion. Patellofemoral joint dynamics were only slightly affected by PCL tension. However, the maximum contact stress in the patellar component decreased from 58.0 MPa to 53.7 MPa for the resected and tightest PCL at 90° knee flexion. The combination of musculoskeletal multibody and finite-element simulation is a sufficient method to comprehensively investigate knee joint dynamics and contact stresses in CR-TKR. The PCL tension after CR-TKR affects joint dynamics and contact stresses at the articulating implant surfaces.

10.
bioRxiv ; 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38645053

RESUMO

In the last decade cellular senescence, a hallmark of aging, has come into focus for pharmacologically targeting aging processes. Senolytics are one of these interventive strategies that have advanced into clinical trials, creating an unmet need for minimally invasive biomarkers of senescent cell load to identify patients at need for senotherapy. We created a landscape of miRNA and mRNA expression in five human cell types induced to senescence in-vitro and provide proof-of-principle evidence that miRNA expression can track senescence burden dynamically in-vivo using transgenic p21 high senescent cell clearance in HFD fed mice. Finally, we profiled miRNA expression in seven different tissues, total plasma, and plasma derived EVs of young and 25 months old mice. In a systematic analysis, we identified 22 candidate senomiRs with potential to serve as circulating biomarkers of senescence not only in rodents, but also in upcoming human clinical senolytic trials.

11.
Qual Life Res ; 22(10): 2769-76, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23539469

RESUMO

INTRODUCTION: To help researchers in multiple sclerosis (MS) take advantage of the measurement properties of the PROMIS Pain Interference instrument while maintaining continuity with previous research, we developed and tested a crosswalk table to transform Brief Pain Inventory pain interference scale (BPI-PI) scores to PROMIS-PI short form (PROMIS-PI SF) scores. METHODS: The BPI-PI and the PROMIS-PI SF were administered in two studies that included persons with MS. One sample of 369 participants served as a developmental calibration sample, and a separate sample of 360 served as a validation sample. The crosswalk development included dimensionality assessment, item-level parameter estimation, and assessment of accuracy. BPI-PI and PROMIS-PI T scores were obtained from participants' item responses, and using the crosswalk table, PROMIS-PI T scores were derived from responses to the BPI-PI items. Differences between observed and crosswalked T scores were compared in both samples. RESULTS: For BPI-PI summary scores ranging from 0 to 10, corresponding T scores ranged from 38.6 to 81.2. The mean difference between observed and crosswalked T scores was 0.51 (SD = 3.9) in the calibration sample and -1.47 (SD = 4.2) in the validation sample. Approximately 80 % of crosswalked scores in the calibration sample were within four score points of the observed PROMIS-PI SF scores, and 70 % were within four points in the validation sample. In both samples, the largest differences were at lower levels of the pain interference continuum. CONCLUSIONS: Crosswalked pain interference scores adequately approximated observed PROMIS-PI SF scores in both the calibration and validation samples. MS researchers and clinicians interested in adopting the PROMIS instruments can use this table to transform BPI-PI scores to enable comparisons with other studies and to maintain continuity with previous research.


Assuntos
Dor Crônica/diagnóstico , Esclerose Múltipla/complicações , Medição da Dor/instrumentação , Dor Crônica/psicologia , Feminino , Humanos , Masculino , Manejo da Dor , Psicometria/estatística & dados numéricos , Qualidade de Vida , Inquéritos e Questionários
12.
Hum Immunol ; 84(4): 286-289, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36764862

RESUMO

Autoantibodies to Angiotensin II type 1 receptor (AT1R) are associated with detrimental outcomes in organ transplants. However, reports showed that adsorption with latex beads reduced positive anti-AT1R antibodies, suggesting possible false reactivity. To investigate this conundrum, we studied 11 samples positive for AT1R antibodies with an ELISA kit before and after adsorption. Adsorption significantly reduced the measurable level of AT1R antibodies (28.3 ± 9.8 vs. 6.3 ± 3.0 U/ml, p < 0.001). AT1R antibodies were lower when post-adsorption serum was added back at 1:1 ratio to the neat serum compared to the diluent control (8.6 ± 4.2 vs. 18.1 ± 10.3 U/ml, p = 0.02). Sham adsorption with the buffer from Adsorb Out™ kit without beads also suppressed the detection of anti-AT1R antibodies (32.7 ± 9.1 vs. 8.1 ± 3.9 U/ml, p < 0.001). Thus, rather than actively removing nonspecific antibodies by the beads, the adsorption process introduces soluble factors that interfere with the detection of anti-AT1R antibodies with the ELISA kit.


Assuntos
Transplante de Órgãos , Receptor Tipo 1 de Angiotensina , Humanos , Adsorção , Ensaio de Imunoadsorção Enzimática , Autoanticorpos , Rejeição de Enxerto
13.
Clin Park Relat Disord ; 9: 100225, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965070

RESUMO

Introduction: Motor and nonmotor Parkinson's disease (PD) symptoms can negatively influence employment, which may contribute to financial hardship. This article explores the association between financial hardship, employment challenges, and quality of life in people with early PD. Methods: We measured financial hardship with a validated summary item (5-point scale, lower score - less hardship) and the Comprehensive Score for Financial Toxicity (0-44, lower score worse toxicity) in a cohort of 60 employed individuals with early PD (<5 years). We used Spearman's Correlations and nonparametric tests to identify associations between financial hardship, demographic characteristics, PD-related factors, employment factors, and quality of life (Neuro-QOL computer adapted measures). Results: The sample was mostly white (93 %) and male (65 %). The plurality were highly-educated with graduate degrees (42 %). Of the 60 participants, 23 (38 %) reported a little bit and 14 (23 %) reported somewhat or more hardship. Comprehensive financial toxicity (22.0 ± 8.7) was correlated moderately (ρ = -0.56) with the single-item summary score. High financial hardship was associated with reduced confidence in job retention (ρ = -0.43, p = 0.001) and reduced perceived workplace success (ρ = -0.352, p = 0.006). Financial hardship was also associated with poorer quality of life in five Neuro-QOL domains: lower extremity function, satisfaction with social roles and activities, depression, anxiety, and stigma (p < 0.05). Conclusion: Financial hardship was common and was associated with employment challenges and poor quality of life. Further work should explore the effects of medical and psychosocial interventions to alleviate financial and employment challenges in individuals with early PD.

14.
Arch Phys Med Rehabil ; 93(8 Suppl): S177-84, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22840882

RESUMO

A systematic review (SR) is an essential component of evidence-based practice, because it synthesizes information on a particular topic that is necessary to inform health-related decision making. The purpose of this article is to document the process of producing a high-quality SR within the field of rehabilitation in contrast to other fields (eg, pharmaceutic research). We describe the notable methodologic challenges to producing high-quality SRs for rehabilitation researchers. Broadly, we outline how the quality of SRs is evaluated and suggest mechanisms for researchers to address potential pitfalls. Because meaningful SRs can and should be conducted in this field, we provide practical guidance regarding how to conduct such an SR. We outline a series of 8 important steps in the production of an SR: forming a committee, creating a development plan, conducting a literature review, selecting articles for inclusion, extracting data, preparing tables of evidence, facilitating external review and publication, and forming conclusions and recommendations. For each step of the SR process, we provide detailed description about the methodologic decisions involved and recommended strategies that researchers can implement to produce a high-quality SR. Using these preestablished steps and procedures as a guideline will not only help to increase the efficiency of the SR process, but also to improve the quality. The availability of high-quality SRs with plain language summaries promotes access to the best quality information for all involved in decision making.


Assuntos
Medicina Baseada em Evidências , Reabilitação/métodos , Reabilitação/normas , Literatura de Revisão como Assunto , Humanos
15.
PLoS One ; 17(1): e0262218, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35020751

RESUMO

Public lands in the United States are those land areas managed by federal, state, and county governments for public purposes such as preservation and recreation. Protecting carbon resources and increasing carbon sequestration capacity are compatible with public land management objectives for healthy and resilient habitats, i.e., managing habitats for the benefit of wildlife and ecosystem services can simultaneously capture and store carbon. To evaluate the effect of public land management on carbon storage and review carbon management as part of the land management objectives, we used existing data of carbon stock and net ecosystem carbon balance in a study of the National Wildlife Refuge System (NWRS), a public land management program of the U.S. Fish and Wildlife Service (Service). Total carbon storage of the 364 refuges studied was 16.6 PgC, with a mean value 42,981 gCm-2. We used mixed modeling with Bonferroni adjustment techniques to analyze the effect of time since refuge designation on carbon storage. In general, older refuges store more carbon per unit area than younger refuges. In addition to the age factor, carbon resources are variable by regions and habitat types protected in the refuges. Mean carbon stock and the rate of sequestration are higher within refuges than outside refuges, but the statistical comparison of 364 refuges analyzed in this study was not significant. We also used the social cost of carbon to analyze the annual benefits of sequestrating carbon in these publicly managed lands in the United States, which is over $976 million per year in avoided CO2 emissions via specific conservation management actions. We examine case studies of management, particularly with respect to Service cooperation activities with The Conservation Fund (TCF) Go Zero® Program, Trust for Public Land (TPL) and individuals. Additional opportunities exist in improving techniques to maximize carbon resources in refuges, while continuing to meet the core purpose and need of the NWRS.


Assuntos
Sequestro de Carbono , Carbono/análise , Mudança Climática , Conservação dos Recursos Naturais/métodos , Ecossistema , Animais , Animais Selvagens , Estados Unidos
16.
EBioMedicine ; 77: 103912, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35292270

RESUMO

BACKGROUND: α-Klotho is a geroprotective protein that can attenuate or alleviate deleterious changes with ageing and disease. Declines in α-Klotho play a role in the pathophysiology of multiple diseases and age-related phenotypes. Pre-clinical evidence suggests that boosting α-Klotho holds therapeutic potential. However, readily clinically-translatable, practical strategies for increasing α-Klotho are not at hand. Here, we report that orally-active, clinically-translatable senolytics can increase α-Klotho in mice and humans. METHODS: We examined α-Klotho expression in three different human primary cell types co-cultured with conditioned medium (CM) from senescent or non-senescent cells with or without neutralizing antibodies. We assessed α-Klotho expression in aged, obese, and senescent cell-transplanted mice treated with vehicle or senolytics. We assayed urinary α-Klotho in patients with idiopathic pulmonary fibrosis (IPF) who were treated with the senolytic drug combination, Dasatinib plus Quercetin (D+Q). FINDINGS: We found exposure to the senescent cell secretome reduces α-Klotho in multiple nonsenescent human cell types. This was partially prevented by neutralizing antibodies against the senescence-associated secretory phenotype (SASP) factors, activin A and Interleukin 1α (IL-1α). Consistent with senescent cells' being a cause of decreased α-Klotho, transplanting senescent cells into younger mice reduced brain and urine α-Klotho. Selectively removing senescent cells genetically or pharmacologically increased α-Klotho in urine, kidney, and brain of mice with increased senescent cell burden, including naturally-aged, diet-induced obese (DIO), or senescent cell-transplanted mice. D+Q increased α-Klotho in urine of patients with IPF, a disease linked to cellular senescence. INTERPRETATION: Senescent cells cause reduced α-Klotho, partially due to their production of activin A and IL-1α. Targeting senescent cells boosts α-Klotho in mice and humans. Thus, clearing senescent cells restores α-Klotho, potentially opening a novel, translationally-feasible avenue for developing orally-active small molecule, α-Klotho-enhancing clinical interventions. Furthermore, urinary α-Klotho may prove to be a useful test for following treatments in senolytic clinical trials. FUNDING: This work was supported by National Institute of Health grants AG013925 (J.L.K.), AG062413 (J.L.K., S.K.), AG044271 (N.M.), AG013319 (N.M.), and the Translational Geroscience Network (AG061456: J.L.K., T.T., N.M., S.B.K., S.K.), Robert and Arlene Kogod (J.L.K.), the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.), and the Noaber Foundation (J.L.K.). The previous IPF clinical trial was supported by the Claude D. Pepper Older Americans Independence Centers at WFSM (AG021332: J.N.J., S.B.K.), UTHSCA (AG044271: A.M.N.), and the Translational Geroscience Network.


Assuntos
Envelhecimento , Senoterapia , Idoso , Animais , Encéfalo , Senescência Celular , Humanos , Camundongos , Quercetina/farmacologia
17.
Nat Commun ; 13(1): 5671, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167854

RESUMO

Cellular senescence is a plausible mediator of inflammation-related tissue dysfunction. In the aged brain, senescent cell identities and the mechanisms by which they exert adverse influence are unclear. Here we used high-dimensional molecular profiling, coupled with mechanistic experiments, to study the properties of senescent cells in the aged mouse brain. We show that senescence and inflammatory expression profiles increase with age and are brain region- and sex-specific. p16-positive myeloid cells exhibiting senescent and disease-associated activation signatures, including upregulation of chemoattractant factors, accumulate in the aged mouse brain. Senescent brain myeloid cells promote peripheral immune cell chemotaxis in vitro. Activated resident and infiltrating immune cells increase in the aged brain and are partially restored to youthful levels through p16-positive senescent cell clearance in female p16-InkAttac mice, which is associated with preservation of cognitive function. Our study reveals dynamic remodeling of the brain immune cell landscape in aging and suggests senescent cell targeting as a strategy to counter inflammatory changes and cognitive decline.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina , Rejuvenescimento , Envelhecimento , Animais , Encéfalo/metabolismo , Senescência Celular/fisiologia , Fatores Quimiotáticos , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Masculino , Camundongos
18.
Proc Biol Sci ; 278(1719): 2737-44, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21270033

RESUMO

Transcontinental dispersals by organisms usually represent improbable events that constitute a major challenge for biogeographers. By integrating molecular phylogeny, historical biogeography and palaeoecology, we test a bold hypothesis proposed by Vladimir Nabokov regarding the origin of Neotropical Polyommatus blue butterflies, and show that Beringia has served as a biological corridor for the dispersal of these insects from Asia into the New World. We present a novel method to estimate ancestral temperature tolerances using distribution range limits of extant organisms, and find that climatic conditions in Beringia acted as a decisive filter in determining which taxa crossed into the New World during five separate invasions over the past 11 Myr. Our results reveal a marked effect of the Miocene-Pleistocene global cooling, and demonstrate that palaeoclimatic conditions left a strong signal on the ecology of present-day taxa in the New World. The phylogenetic conservatism in thermal tolerances that we have identified may permit the reconstruction of the palaeoecology of ancestral organisms, especially mobile taxa that can easily escape from hostile environments rather than adapt to them.


Assuntos
Migração Animal , Borboletas/fisiologia , Clima , Ecossistema , Paleontologia , Filogeografia , América , Animais , Ásia , Borboletas/classificação , Borboletas/genética , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase/métodos , Análise de Sequência de DNA
19.
J Phys Chem A ; 115(15): 3218-26, 2011 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-21446659

RESUMO

The photodissociation of NO(3) has been studied using velocity map ion imaging. Measurements of the NO(2) + O channel reveal statistical branching ratios of the O((3)P(J)) fine-structure states, isotropic angular distributions, and low product translational energy consistent with barrierless dissociation along the ground state potential surface. There is clear evidence for two distinct pathways to the formation of NO + O(2) products. The dominant pathway (>70% yield) is characterized by vibrationally excited O(2)((3)Σ(g)(-), v = 5-10) and rotationally cold NO((2)Π), while the second pathway is characterized by O(2)((3)Σ(g)(-), v = 0-4) and rotationally hotter NO((2)Π) fragments. We speculate the first pathway has many similarities to the "roaming" dynamics recently implicated in several systems. The rotational angular momentum of the molecular fragments is positively correlated for this channel, suggesting geometric constraints in the dissociation. The second pathway results in almost exclusive formation of NO((2)Π, v = 0). Although product state correlations support dissociation via an as yet unidentified three-center transition state, theoretical confirmation is needed.


Assuntos
Nitratos/química , Termodinâmica , Radicais Livres/química , Íons/química , Óxido Nítrico/química , Oxigênio/química , Processos Fotoquímicos
20.
J Chem Phys ; 135(9): 094201, 2011 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-21913756

RESUMO

We present analytical expressions relating the bipolar moment ß(Q)(K)(k(1)k(2)) parameters of Dixon to the measured anisotropy parameters of different pump/probe geometry sliced ion images. In the semi-classical limit, when there is no significant coherent contribution from multiple excited states to fragment angular momentum polarization, the anisotropy of the images alone is sufficient to extract the ß(Q)(K)(k(1)k(2)) parameters with no need to reference relative image intensities. The analysis of sliced images is advantageous since the anisotropy can be directly obtained from the image at any radius without the need for 3D-deconvolution, which is not applicable for most pump/probe geometries. This method is therefore ideally suited for systems which result in a broad distribution of fragment velocities. The bipolar moment parameters are obtained for NO(2) dissociation at 355 nm using these equations, and are compared to the bipolar moment parameters obtained from a proven iterative fitting technique for crushed ion images. Additionally, the utility of these equations in extracting speed-dependent bipolar moments is demonstrated on the recently investigated NO(3) system.

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