TrpA1 is a shear stress mechanosensing channel regulating intestinal homeostasis in Drosophila

Adult stem cells are essential for maintaining normal tissue homeostasis and supporting tissue repair. Although genetic and biochemical programs controlling adult stem cell behavior have been extensively investigated, how mechanosensing regulates stem cells and tissue homeostasis is not well understood. Here, we show that shear stress can activate enteroendocrine cells, but not other gut epithelial cell types, to regulate intestine stem cell-mediated gut homeostasis. This shear stress sensing is mediated by transient receptor potential A1 (TrpA1), a Ca2+-permeable ion channel expressed only in enteroendocrine cells among all gut epithelial cells. Genetic depletion of TrpA1 or modification of its shear stress sensing function causes reduced intestine stem cell proliferation and intestine growth. We further show that among the TrpA1 splice variants, only select isoforms are activated by shear stress. Altogether, our results suggest the naturally occurring mechanical force such as fluid passing generated shear stress regulates intestinal stem cell-mediated tissue growth by activating enteroendocrine cells, and Drosophila TrpA1 as a new shear stress sensor.

Temporal control of the integrated stress response by a stochastic molecular switch

Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response, by integrating quantitative experiments with mathematical modeling, and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2alpha, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 mRNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.

Development of Multi-Scale Carbon Nanofiber and Nanotube-Based Cementitious Composites for Reliable Sensing of Tensile Stresses

In this work, multi-scale cementitious composites containing short carbon fibers (CFs) and carbon nanofibers (CNFs)/multi-walled carbon nanotubes (MWCNTs) were studied for their tensile stress sensing properties. CF-based composites were prepared by mixing 0.25, 0.5 and 0.75 wt.% CFs (of cement) with water using magnetic stirring and Pluronic F-127 surfactant and adding the mixture to the cement paste. In multi-scale composites, CNFs/MWCNTs (0.1 and 0.15 wt.% of cement) were dispersed in water using Pluronic F-127 and ultrasonication and CFs were then added before mixing with the cement paste. All composites showed a reversible change in the electrical resistivity with tensile loading; the electrical resistivity increased and decreased with the increase and decrease in the tensile load/stress, respectively. Although CF-based composites showed the highest stress sensitivity among all specimens at 0.25% CF content, the fractional change in resistivity (FCR) did not show a linear correlation with the tensile load/stress. On the contrary, multi-scale composites containing CNFs (0.15% CNFs with 0.75% CFs) and MWCNTs (0.1% MWCNTs with 0.5% CFs) showed good stress sensitivity, along with a linear correlation between FCR and tensile load/stress. Stress sensitivities of 6.36 and 11.82%/MPa were obtained for the best CNF and MWCNT-based multi-scale composite sensors, respectively.

Cellular Bioenergetics and AMPK and TORC1 Signalling in Blood Lymphoblasts Are Biomarkers of Clinical Status in FMR1 Premutation Carriers

Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder affecting carriers of premutation alleles (PM) of the X-linked FMR1 gene, which contain CGG repeat expansions of 55–200 range in a non-coding region. This late-onset disorder is characterised by the presence of tremor/ataxia and cognitive decline, associated with the white matter lesions throughout the brain, especially involving the middle cerebellar peduncles. Nearly half of older male and ~ 20% of female PM carriers develop FXTAS. While there is evidence for mitochondrial dysfunction in neural and some peripheral tissues from FXTAS patients (though less obvious in the non-FXTAS PM carriers), the results from peripheral blood mononuclear cells (PBMC) are still controversial. Motor, cognitive, and neuropsychiatric impairments were correlated with measures of mitochondrial and non-mitochondrial respiratory activity, AMPK, and TORC1 cellular stress-sensing protein kinases, and CGG repeat size, in a sample of adult FXTAS male and female carriers. Moreover, the levels of these cellular measures, all derived from Epstein- Barr virus (EBV)- transformed and easily accessible blood lymphoblasts, were compared between the FXTAS (N = 23) and non-FXTAS (n = 30) subgroups, and with baseline data from 33 healthy non-carriers. A significant hyperactivity of cellular bioenergetics components as compared with the baseline data, more marked in the non-FXTAS PMs, was negatively correlated with repeat numbers at the lower end of the CGG-PM distribution. Significant associations of these components with motor impairment measures, including tremor-ataxia and parkinsonism, and neuropsychiatric changes, were prevalent in the FXTAS subgroup. Moreover, a striking elevation of AMPK activity, and a decrease in TORC1 levels, especially in the non-FXTAS carriers, were related to the size of CGG expansion. The bioenergetics changes in blood lymphoblasts are biomarkers of the clinical status of FMR1 carriers. The relationship between these changes and neurological involvement in the affected carriers suggests that brain bioenergetic alterations are reflected in this peripheral tissue. A possible neuroprotective role of stress sensing kinase, AMPK, in PM carriers, should be addressed in future longitudinal studies. A decreased level of TORC1—the mechanistic target of the rapamycin complex, suggests a possible future approach to therapy in FXTAS.

Individualized stress detection using an unmodified car steering wheel

In-car passive stress sensing could enable the monitoring of stress biomarkers while driving and reach millions of commuters daily (i.e., 123 million daily commuters in the US alone). Here, we present a nonintrusive method to detect stress solely from steering angle data of a regular car. The method uses inverse filtering to convert angular movement data into a biomechanical Mass Spring Damper model of the arm and extracts its damped natural frequency as an approximation of muscle stiffness, which in turn reflects stress. We ran a within-subject study (N = 22), in which commuters drove a vehicle around a closed circuit in both stress and calm conditions. As hypothesized, cohort analysis revealed a significantly higher damped natural frequency for the stress condition (P = .023, d = 0.723). Subsequent automation of the method achieved rapid (i.e., within 8 turns) stress detection in the individual with a detection accuracy of 77%.