Interplay of the physical microenvironment, contact guidance, and intracellular signaling in cell decision making [Research]

The peritumoral physical microenvironment consists of complex topographies that influence cell migration. Cell decision making, upon encountering anisotropic, physiologically relevant physical cues, has yet to be elucidated. By integrating microfabrication with cell and molecular biology techniques, we provide a quantitative and mechanistic analysis of cell decision making in a variety of well-defined physical microenvironments. We used MDA-MB-231 breast carcinoma and HT1080 fibrosarcoma as cell models. Cell decision making after lateral confinement in 2-dimensional microcontact printed lines is governed by branch width at bifurcations. Cells confined in narrow feeder microchannels prefer to enter wider branches at bifurcations. In contrast, in feeder channels that are wider than the cell body, cells elongate along one side wall of the channel and are guided by contact with the wall to the contiguous branch channel independent of its width. Knockdown of β1-integrins or inhibition of cellular contractility suppresses contact guidance. Concurrent, but not individual, knockdown of nonmuscle myosin isoforms IIA and IIB also decreases contact guidance, which suggests the existence of a compensatory mechanism between myosin IIA and myosin IIB. Conversely, knockdown or inhibition of cell division control protein 42 homolog promotes contact guidance–mediated decision making. Taken together, the dimensionality, length scales of the physical microenvironment, and intrinsic cell signaling regulate cell decision making at intersections.—Paul, C. D., Shea, D. J., Mahoney, M. R., Chai, A., Laney, V., Hung, W.-C., Konstantopoulos, K. Interplay of the physical microenvironment, contact guidance, and intracellular signaling in cell decision making.

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Talin: a mechanosensitive molecule in health and disease [Review]

Talin is a ubiquitous, large focal adhesion protein that links intracellular networks with the extracellular matrix (ECM) via its connection with the actin cytoskeleton and membrane integrins. It is one of a handful molecules that can expose new recognition sites when undergoing force-induced mechanical unfolding, and it can bind and recruit cytoskeletal proteins that are involved in mechanotransduction. Talin has attracted great interest in the field of mechanobiology because of its plasticity in undergoing conformational changes under force stimulation as well as its cellular localization that bridges the cytoskeleton with the ECM. In addition to these roles in healthy cells, the dysregulation of talin activators can lead to disease states in which aberrant integrin activation and mechanotransduction precipitate changes in cell spreading, migration, and survival. New data have implicated a role for talin in diseases that are highly regulated by mechanical cues. In this review, we present the current understanding of talin structure, its relationship to binding partners, and its role in disease states.—Haining, A. W. M., Lieberthal, T. J., del Río Hernández, A. Talin: a mechanosensitive molecule in health and disease.

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Is the worsening of psychosocial exposures associated with mental health? Comparing two population-based cross-sectional studies in Spain, 2005–2010

Aims

To analyze whether associations between workplace psychosocial exposures and the mental health of the working population in Spain changed between 2005 and 2010.

Methods

Two representative samples of the Spanish working population have been analyzed, 2005 (n = 5073) and 2010 (n = 3544).

Results

In 2010 there was a significant association between poor mental health and exposure to high Demands, low Social Support and high Insecurity over working conditions, and exposure to high Insecurity over losing the job only for men. In 2005 there was a significant association with exposure to high Demands and low Social Support.

Conclusion

Changes in the associations between psychosocial risks and mental health may be related to the socioeconomic context marked by the rise in unemployment and the destruction of jobs as a result of the 2008 economic crisis. Am. J. Ind. Med. © 2016 Wiley Periodicals, Inc.

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Job stress, inflammation, and atherosclerosis: A reflection

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Long term symptomatic, functional, and work outcomes of carpal tunnel syndrome among construction workers

Background

The long-term outcomes of carpal tunnel syndrome (CTS) including symptoms, functional status, work disability, and economic impact are unknown.

Methods

We conducted a retrospective study of 234 active construction workers with medical claims for CTS and 249 workers without CTS claims; non-cases were matched on age, trade, and insurance eligibility. We conducted telephone interviews with cases and non-cases and collected administrative data on work hours.

Results

Compared to non-cases, CTS cases were more likely to report recurrent hand symptoms, decreased work productivity/quality, decreased performance of physical work demands, and greater functional limitations. Surgical cases showed larger improvements on multiple outcomes than non-surgical cases. Minimal differences in paid work hours were seen between cases and non-cases in the years preceding and following CTS claims.

Conclusions

Persistent symptoms and functional impairments were present several years after CTS diagnosis. Long-term functional limitations shown by this and other studies indicate the need for improved prevention and treatment. Am. J. Ind. Med. © 2016 Wiley Periodicals, Inc.

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Central nervous system diseases of organic solvents exposed workers based on nationwide medical surveillance-data in Korea

Background

New light is being shed on the relationship between chronic neurotoxicity of the central nervous system (CNS) and exposure to low-level organic solvents (OS). However, there are few longitudinal studies with a large sample size.

Methods

A cohort of OS-exposed male workers was selected who had undergone an OS-associated specialized medical check-up at least once between 2000 and 2004 in Korea. The standardized admission ratios (SAR) for CNS diseases were calculated with reference to the Korean adult male population. Adjusted relative risks (ARR) were also estimated in comparison to noise-exposed male workers.

Results

There were 238,574 OS-exposed workers, yielding 954,772 person-years of exposure. OS-exposed workers were at elevated risk of “other extrapyramidal and movement disorders” (G25) with a SAR = 2.95 (95% CI: 1.41–5.42) and “systemic atrophies primarily affecting the CNS” (G10–G13) SAR = 2.08 (95% CI: 1.03–3.74). There were no significant differences between the OS-exposed workers and noise-exposed workers.

Conclusions

A limited number of CNS diseases identified through hospital admissions data and short observation periods reduced statistical power to determine effect size. OS exposure was positively associated with “other extrapyramidal and movement disorder and systemic atrophies primarily affecting the CNS. Am. J. Ind. Med. © 2016 Wiley Periodicals, Inc.

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A Case of Thanatophoric Dysplasia Type I with Fetal Hydrops in the First Trimester

During a routine prenatal exam, a 36-year-old female in her third pregnancy was diagnosed with fetal hydrops at 11 weeks of gestation. The pregnancy was monitored with periodic ultrasounds; however, spontaneous resolution was not observed. Amniotic fluid examination at 16 weeks of gestation showed a normal karyotype; however, macrocephaly, a narrow thorax, and shortening of the long bones were observed on ultrasonography. With the strong suspicion of a fetal skeletal disease, specifically thanatophoric dysplasia (TD), and after extensive genetic counseling, termination of the pregnancy was performed per the parents’ wishes with mechanical cervical dilation and gemeprost (PGE1) administration. Following delivery, the fetus was found to have macrocephaly, a narrow bell-shaped thorax, and a protuberant abdomen, as well as curved long bones, H-shaped platyspondyly, and curved clavicles on skeletal radiography. As a result, the fetus was diagnosed with TD type I. This case illustrates that although TD is a rare disease, an accurate prenatal diagnosis can be made with the use of ultrasonography.

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Colonic Mucosal Epigenome and Microbiome Development in Children and Adolescents

Epigenetic and microbiome changes during pediatric development have been implicated as important elements in the developmental origins of inflammatory bowel diseases (IBDs) including Crohn’s disease (CD) and ulcerative colitis (UC), which are linked to early onset colorectal cancer (CRC). Colonic mucosal samples from 22 control children between 3.5 and 17.5 years of age were studied by Infinium HumanMethylation450 BeadChips and, in 10 cases, by 454 pyrosequencing of the bacterial 16S rRNA gene. Intercalating age-specific DNA methylation and microbiome changes were identified, which may have significant translational relevance in the developmental origins of IBD and CRC.

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Deletion of Herpud1 Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease

Herp is an endoplasmic reticulum- (ER-) resident membrane protein that plays a role in ER-associated degradation. We studied the expression of Herp and its effect on neurodegeneration in a mouse model of Parkinson’s disease (PD), in which both the oxidative stress and the ER stress are evoked. Eight hours after administering a PD-related neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), to mice, the expression of Herp increased at both the mRNA and the protein levels. Experiments using Herpud1+/+ and Herpud1−/− mice revealed that the status of acute degeneration of nigrostriatal neurons and reactive astrogliosis was comparable between two genotypes after MPTP injection. However, the expression of a potent antioxidant, heme oxygenase-1 (HO-1), was detected to a higher degree in the astrocytes of Herpud1−/− mice than in the astrocytes of Herpud1+/+ mice 24 h after MPTP administration. Further experiments using cultured astrocytes revealed that the stress response against MPP+, an active form of MPTP, and hydrogen peroxide, both of which cause oxidative stress, was comparable between the two genotypes. These results suggest that deletion of Herpud1 may cause a slightly higher level of initial damage in the nigrastrial neurons after MPTP administration but is compensated for by higher induction of antioxidants such as HO-1 in astrocytes.

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