Testing the shock protection performance of Type I construction helmets using impactors of different masses.

BACKGROUND: Wearing protective helmets is an important prevention strategy to reduce work-related traumatic brain injuries. The existing standardized testing systems are used for quality control and do not provide a quantitative measure of the helmet performance. OBJECTIVE: To analyze the failure characterizations of Type I industrial helmets and develop a generalized approach to quantify the shock absorption performance of Type I industrial helmets based on the existing standardized setups. METHODS: A representative basic Type I construction helmet model was selected for the study. Top impact tests were performed on the helmets at different drop heights using two different impactor masses (3.6 and 5.0 kg). RESULTS: When the helmets were impacted with potential impact energies smaller than the critical potential impact energy values, there was a consistent relationship between the peak impact force and the potential impact energy. When the helmets were impacted under potential impact energies greater than the critical potential impact energy values, the peak impact forces increased steeply with increasing potential impact energy. CONCLUSION: A concept of safety margin for construction helmets based on potential impact energy was introduced to quantify the helmets' shock absorption performance. The proposed method will help helmet manufacturers improve their product quality.

Breaking NGF-TrkA immunosuppression in melanoma sensitizes immunotherapy for durable memory T cell protection.

Melanoma cells, deriving from neuroectodermal melanocytes, may exploit the nervous system's immune privilege for growth. Here we show that nerve growth factor (NGF) has both melanoma cell intrinsic and extrinsic immunosuppressive functions. Autocrine NGF engages tropomyosin receptor kinase A (TrkA) on melanoma cells to desensitize interferon γ signaling, leading to T and natural killer cell exclusion. In effector T cells that upregulate surface TrkA expression upon T cell receptor activation, paracrine NGF dampens T cell receptor signaling and effector function. Inhibiting NGF, either through genetic modification or with the tropomyosin receptor kinase inhibitor larotrectinib, renders melanomas susceptible to immune checkpoint blockade therapy and fosters long-term immunity by activating memory T cells with low affinity. These results identify the NGF-TrkA axis as an important suppressor of anti-tumor immunity and suggest larotrectinib might be repurposed for immune sensitization. Moreover, by enlisting low-affinity T cells, anti-NGF reduces acquired resistance to immune checkpoint blockade and prevents melanoma recurrence.

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

Antagonizing the irreversible thrombomodulin-initiated proteolytic signaling alleviates age-related liver fibrosis via senescent cell killing.

Cellular senescence is a stress-induced, stable cell cycle arrest phenotype which generates a pro-inflammatory microenvironment, leading to chronic inflammation and age-associated diseases. Determining the fundamental molecular pathways driving senescence instead of apoptosis could enable the identification of senolytic agents to restore tissue homeostasis. Here, we identify thrombomodulin (THBD) signaling as a key molecular determinant of the senescent cell fate. Although normally restricted to endothelial cells, THBD is rapidly upregulated and maintained throughout all phases of the senescence program in aged mammalian tissues and in senescent cell models. Mechanistically, THBD activates a proteolytic feed-forward signaling pathway by stabilizing a multi-protein complex in early endosomes, thus forming a molecular basis for the irreversibility of the senescence program and ensuring senescent cell viability. Therapeutically, THBD signaling depletion or inhibition using vorapaxar, an FDA-approved drug, effectively ablates senescent cells and restores tissue homeostasis in liver fibrosis models. Collectively, these results uncover proteolytic THBD signaling as a conserved pro-survival pathway essential for senescent cell viability, thus providing a pharmacologically exploitable senolytic target for senescence-associated diseases.

Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression.

BACKGROUND AND AIMS: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. APPROACH AND RESULTS: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress. CONCLUSION: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. APPROACH AND RESULTS: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. CONCLUSION: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.

EPDR1 is a noncanonical effector of insulin-mediated angiogenesis regulated by an endothelial-specific TGF-ß receptor complex.

Insulin signaling in blood vessels primarily functions to stimulate angiogenesis and maintain vascular homeostasis through the canonical PI3K and MAPK signaling pathways. However, angiogenesis is a complex process coordinated by multiple other signaling events. Here, we report a distinct crosstalk between the insulin receptor and endoglin/activin receptor-like kinase 1 (ALK1), an endothelial cell-specific TGF-ß receptor complex essential for angiogenesis. While the endoglin-ALK1 complex normally binds to TGF-ß or bone morphogenetic protein 9 (BMP9) to promote gene regulation via transcription factors Smad1/5, we show that insulin drives insulin receptor oligomerization with endoglin-ALK1 at the cell surface to trigger rapid Smad1/5 activation. Through quantitative proteomic analysis, we identify ependymin-related protein 1 (EPDR1) as a major Smad1/5 gene target induced by insulin but not by TGF-ß or BMP9. We found endothelial EPDR1 expression is minimal at the basal state but is markedly enhanced upon prolonged insulin treatment to promote cell migration and formation of capillary tubules. Conversely, we demonstrate EPDR1 depletion strongly abrogates these angiogenic effects, indicating that EPDR1 is a crucial mediator of insulin-induced angiogenesis. Taken together, these results suggest important therapeutic implications for EPDR1 and the TGF-ß pathways in pathologic angiogenesis during hyperinsulinemia and insulin resistance.

ßIV-spectrin as a stalk cell-intrinsic regulator of VEGF signaling.

Defective angiogenesis underlies over 50 malignant, ischemic and inflammatory disorders yet long-term therapeutic applications inevitably fail, thus highlighting the need for greater understanding of the vast crosstalk and compensatory mechanisms. Based on proteomic profiling of angiogenic endothelial components, here we report ßIV-spectrin, a non-erythrocytic cytoskeletal protein, as a critical regulator of sprouting angiogenesis. Early loss of endothelial-specific ßIV-spectrin promotes embryonic lethality in mice due to hypervascularization and hemorrhagic defects whereas neonatal depletion yields higher vascular density and tip cell populations in developing retina. During sprouting, ßIV-spectrin expresses in stalk cells to inhibit their tip cell potential by enhancing VEGFR2 turnover in a manner independent of most cell-fate determining mechanisms. Rather, ßIV-spectrin recruits CaMKII to the plasma membrane to directly phosphorylate VEGFR2 at Ser984, a previously undefined phosphoregulatory site that strongly induces VEGFR2 internalization and degradation. These findings support a distinct spectrin-based mechanism of tip-stalk cell specification during vascular development.

Cancer-cell-derived GABA promotes ß-catenin-mediated tumour growth and immunosuppression.

Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3ß activity, leading to enhanced ß-catenin signalling. This GABA-mediated ß-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.

Evaluation of the Fall Protection of Type I Industrial Helmets.

The performance of Type I industrial helmets for fall protection is not required to be tested in standardized tests. The current study analyzed the fall protection performance of Type I industrial helmets and evaluated if the use of a chin strap and the suspension system tightness have any effect on protection performance. Head impact tests were performed using an instrumented manikin. There were 12 combinations of test conditions: with or without chin strap usage, three levels of suspension system tightness, and two impact surfaces. Four representative helmet models (two basic and two advanced models) were selected for the study. Impact tests without a helmet under all other applicable test conditions were used as a control group. There were four replicates for each test condition-a total of 192 impact tests with helmets and eight impact tests for the control group. The peak acceleration and the calculated head impact criteria (HIC) were used to evaluate shock absorption performance of the helmets. The results showed that all four helmet models demonstrated excellent performance for fall protection compared to the barehead control group. The fall protection performance of the advanced helmet models was substantially better than the basic helmet models. However, the effects of the use of chin straps and suspension system tightness on the helmets' fall protection performance were statistically not significant.

Biomechanical assessment while using production tables on mast climbing work platforms.

The objective of this study was to assess the impact of using alternative mast climbing work platform (MCWP) designs on trunk motion and postural stability with masonry workers while performing bricklaying and stepping down tasks using a conventional MCWP setting (i.e. with a step deck) as well as two types of production tables (straight- and L-shaped). The trunk angles and postural sway parameters of twenty-five masonry workers were recorded for the following tasks: (1) standing on a simulated MCWP and laying bricks on an adjacent wall, and (2) stepping down onto the step deck to get into position for doing the bricklaying task. Results indicated that the use of the L-shaped production table resulted in the lowest trunk ranges of motion and significantly reduced the workers' trunk angles in all three planes when compared to both the straight-shaped production table and the conventional approach of not using a production table. Data showed that both body sway velocity and area were significantly reduced when using either one of the production tables. The use of production tables significantly reduced impact sway forces when workers stepped from the main platform to the step deck. The use of production tables on MCWPs improved workers' postures and overall stability, which could reduce the risk of injury.

Application of polyethylene air-bubble cushions to improve the shock absorption performance of Type I construction helmets for repeated impacts.

BACKGROUND: The use of helmets was considered to be one of the important prevention strategies employed on construction sites. The shock absorption performance of a construction (or industrial) helmet is its most important performance parameter. Industrial helmets will experience cumulative structural damage when being impacted repeatedly with impact magnitudes greater than its endurance limit. OBJECTIVE: The current study is to test if the shock absorption performance of Type I construction helmets subjected to repeated impacts can be improved by applying polyethylene air-bubble cushions to the helmet suspension system. METHODS: Drop impact tests were performed using a commercial drop tower test machine following the ANSI Z89.1 Type I drop impact protocol. Typical off-the-shelf Type I construction helmets were evaluated in the study. A 5 mm thick air-bubble cushioning liner was placed between the headform and the helmet to be tested. Helmets were impacted ten times at different drop heights from 0.61 to 1.73 m. The effects of the air-bubble cushioning liner on the helmets' shock absorption performance were evaluated by comparing the peak transmitted forces collected from the original off-the-shelf helmet samples to the helmets equipped with air-bubble cushioning liners. RESULTS: Our results showed that a typical Type I construction helmet can be subjected to repeated impacts with a magnitude less than 22 J (corresponding to a drop height 0.61 m) without compromising its shock absorption performance. In comparison, the same construction helmet, when equipped with an air-bubble cushioning liner, can be subjected to repeated impacts of a magnitude of 54 J (corresponding to a drop height 1.52 m) without compromising its shock absorption performance. CONCLUSIONS: The results indicate that the helmet's shock absorbing endurance limit has been increased by 145% with addition of an air-bubble cushioning liner.

An Approach to Characterize the Impact Absorption Performance of Construction Helmets in Top Impact.

The helmets used by construction site workers are mainly designed for head protection when objects are dropped from heights. Construction helmets are also casually called "hard hats" in industries. Common construction helmets are mostly categorized as type 1 according to different standards. All type 1 helmets have to pass type 1 standard impact tests, which are top impact tests-the helmet is fixed and is impacted by a free falling impactor on the top crown of the helmet shell. The purpose of this study was to develop an approach that can determine the performance characterization of a helmet. A total of 31 drop impact tests using a representative type 1 helmet model were performed at drop heights from 0.30 to 2.23 m, which were estimated to result in impact speeds from 2.4 to 6.6 m/s. Based on our results, we identified a critical drop height that was used to evaluate the performance of helmets. The peak impact forces and peak accelerations varied nonproportionally with the drop height. When the drop height is less than the critical height, the peak force and peak acceleration increase gradually and slowly with increasing drop height. When the drop height is greater than the critical height, the peak force and peak acceleration increase steeply with even a slight increase in drop height. Based on the critical drop height, we proposed an approach to determine the safety margin of a helmet. The proposed approach would make it possible to determine the performance characteristics of a helmet and to estimate the safety margin afforded by the helmet, if the helmet first passes the existing standardized tests. The proposed test approach would provide supplementary information for consumers to make knowledgeable decisions when selecting construction helmets.

Evaluation of the shock absorption performance of construction helmets under repeated top impacts.

It is accepted in industries that an industrial helmet should be disposed of when it is subjected to a significant impact. There is no scientific evidence that supports this well-accepted belief. The current study was intended to evaluate the shock absorption performance of industrial helmets under repeated impacts. Common industrial or construction helmets are categorized as Type I according to ANSI Z89.1 and they are designed to mainly protect top impacts. A representative basic Type I construction helmet model was selected in the study. Helmets were repeatedly impacted ten times using a commercial drop tower tester with an impactor (mass 3.6 kg) at different drop heights from 0.30 to 2.03 m. A total of 80 impact trials were performed in the study. The relationships of the transmitted force with the drop height and with impact number were analyzed. A new parameter - the endurance limit - was proposed to evaluate the shock absorption performance of a helmet. The helmets were observed to experience cumulative structural damage with increasing impact number, resulting in a degrading shock absorption performance, when being impacted repeatedly with magnitudes greater than the endurance limit. Repeated impacts with magnitudes smaller than the endurance limit did not cause measurable cumulative structural damage to the helmets in our study.

CD36 initiates the secretory phenotype during the establishment of cellular senescence.

Cellular senescence is a unique cell fate characterized by stable proliferative arrest and the extensive production and secretion of various inflammatory proteins, a phenomenon known as the senescence-associated secretory phenotype (SASP). The molecular mechanisms responsible for generating a SASP in response to senescent stimuli remain largely obscure. Here, using unbiased gene expression profiling, we discover that the scavenger receptor CD36 is rapidly upregulated in multiple cell types in response to replicative, oncogenic, and chemical senescent stimuli. Moreover, ectopic CD36 expression in dividing mammalian cells is sufficient to initiate the production of a large subset of the known SASP components via activation of canonical Src-p38-NF-κB signaling, resulting in the onset of a full senescent state. The secretome is further shown to be ligand-dependent, as amyloid-beta (Aß) is sufficient to drive CD36-dependent NF-κB and SASP activation. Finally, loss-of-function experiments revealed a strict requirement for CD36 in secretory molecule production during conventional senescence reprogramming. Taken together, these results uncover the Aß-CD36-NF-κB signaling axis as an important regulator of the senescent cell fate via induction of the SASP.

TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth.

Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although αTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-ß-activated kinase 1 (TAK1) as a key activator of αTAT1. TAK1 directly interacts with and phosphorylates αTAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types. Using a custom phospho-αTAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent αTAT1 activity, which, accordingly, is diminished rapidly upon intra-cerebral injection of a TAK1 inhibitor. Lastly, we show that TAK1 selectively inhibits AKT to suppress mitogenic and metabolism-related pathways through MT-based mechanisms in culture and in vivo. Collectively, our findings support a fundamental new role for TGF-ß signaling in MT-related functions and disease.

Evaluating the stability of a freestanding Mast Climbing Work Platform.

Mast Climbing Work Platforms (MCWPs) are becoming more common at construction sites and are being used as an alternative to traditional scaffolding. Although their use is increasing, little to no published information exists on the potential safety hazards they could pose for workers. As a last line of defense, a personal fall-arrest system can be used to save a worker in a fall incident from the platform. There has been no published information on whether it is safe to use such a personal fall-arrest system with MCWPs. In this study, the issues of concern for occupational safety included: (a) the overall stability of the freestanding mast climber during a fall-arrest condition and (b) whether that fall-arrest system could potentially present safety hazards to other workers on the platform during a fall-arrest condition. This research project investigated those safety concerns with respect to the mast climber stability and the workers using it by creating fall-arrest impact forces that are transmitted to the equipment and by subsequently observing the movement of the mast climber and the working deck used by the workers. This study found that when the equipment was erected and used according to the manufacturer's recommendations during a fall-arrest condition, destabilizing forces were very small and there were no signs of potential of MCWP collapse. However, potential fall hazards could be presented to other workers on the platform during a fall arrest. Workers near an open platform are advised to wear a personal fall-arrest system to reduce the risk of being ejected. Due to the increasing use of MCWPs at construction sites, there is a corresponding need for evidence and science-based safety guidelines or regulations and further research should be conducted to continue to fill the knowledge gap with MCWP equipment.

Evaluation of postural sway and impact forces during ingress and egress of scissor lifts at elevations.

Workers are at risk when entering (ingress) or exiting (egress) elevated scissor lifts. In this study, we recorded ground impact forces and postural sway from 22 construction workers while they performed ingress and egress between a scissor lift and an adjacent work surface with varying conditions: lift opening designs, horizontal and vertical gaps, and sloped work surfaces. We observed higher peak ground shear forces when using a bar-and-chain opening, with larger horizontal gap, with the lift surface more than 0.2 m below the work surface, and presence of a sloped (26°) work surface. Similar trends were observed for postural sway, except that the influence of vertical distance was not significant. To reduce slip/trip/fall risk and postural sway of workers while ingress or egress of an elevated scissor lift, we suggest scissor lifts be equipped with a gate-type opening instead of a bar-and-chain design. We also suggest the lift surface be placed no more than 0.2 m lower than the work surface and the horizontal gap between lift and work surfaces be as small as possible. Selecting a non-sloped surface to ingress or egress a scissor lift is also preferred to reduce risk.

An improved finite element modeling of the cerebrospinal fluid layer in the head impact analysis.

The finite element (FE) method has been widely used to investigate the mechanism of traumatic brain injuries (TBIs), because it is technically difficult to quantify the responses of the brain tissues to the impact in experiments. One of technical challenges to build a FE model of a human head is the modeling of the cerebrospinal fluid (CSF) of the brain. In the current study, we propose to use membrane elements to construct the CSF layer. Using the proposed approach, we demonstrate that a head model can be built by using existing meshes available in commercial databases, without using any advanced meshing software tool, and with the sole use of native functions of the FE package Abaqus. The calculated time histories of the intracranial pressures at frontal, posterior fossa, parietal, and occipital positions agree well with the experimental data and the simulations in the literature, indicating that the physical effects of the CSF layer have been accounted for in the proposed modeling approach. The proposed modeling approach would be useful for bioengineers to solve practical problems.