Injury-induced MAPK activation triggers body axis formation in Hydra by default Wnt signaling.

Hydra's almost unlimited regenerative potential is based on Wnt signaling, but so far it is unknown how the injury stimulus is transmitted to discrete patterning fates in head and foot regenerates. We previously identified mitogen-activated protein kinases (MAPKs) among the earliest injury response molecules in Hydra head regeneration. Here, we show that three MAPKs-p38, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases (ERKs)-are essential to initiate regeneration in Hydra, independent of the wound position. Their activation occurs in response to any injury and requires calcium and reactive oxygen species (ROS) signaling. Phosphorylated MAPKs hereby exhibit cross talk with mutual antagonism between the ERK pathway and stress-induced MAPKs, orchestrating a balance between cell survival and apoptosis. Importantly, Wnt3 and Wnt9/10c, which are induced by MAPK signaling, can partially rescue regeneration in tissues treated with MAPK inhibitors. Also, foot regenerates can be reverted to form head tissue by a pharmacological increase of ß-catenin signaling or the application of recombinant Wnts. We propose a model in which a ß-catenin-based stable gradient of head-forming capacity along the primary body axis, by differentially integrating an indiscriminate injury response, determines the fate of the regenerating tissue. Hereby, Wnt signaling acquires sustained activation in the head regenerate, while it is transient in the presumptive foot tissue. Given the high level of evolutionary conservation of MAPKs and Wnts, we assume that this mechanism is deeply embedded in our genome.

Molecular characterization of the immediate wound response of the solitary ascidian Polycarpa mytiligera.

BACKGROUND: Injury response is key to successful regeneration. Yet, transcriptome analyses of injury response were performed only on a handful of regenerative organisms. Here, we studied the injury response of the solitary ascidian Polycarpa mytiligera, an emerging model system, capable of regenerating any body part. We used the siphon as a model for studying transcriptional changes following injury, and identified genes that were activated in the initial 24 hours post amputation (hpa). RESULTS: Highly conserved genes, such as bone morphogenetic protein-1 (BMP1), growth hormone secretagogue receptor (GHSR) and IL-17, were upregulated by 12 hpa, yet their expression was sustained only in non-regenerating tissue fragments. We optimized fluorescent in situ hybridization, and found that the majority of BMP1+ cells were localized to the rigid tunic that covers the animal. This highlights the importance of this tissue, particularly during injury response. BMP1 was overexpressed following injuries to other body regions, suggesting that it was a part of a common injury-induced program. CONCLUSION: Our study suggests that, initially, specific injury-induced genes were upregulated in P. mytiligera organs, yet, later, a unique transcriptional profile was observed only in regenerating tissues. These findings highlight the importance of studying diverse regenerating and non-regenerating organisms for complete understanding of regeneration.

An RNA-sequencing transcriptome of the rodent Schwann cell response to peripheral nerve injury.

BACKGROUND: The important contribution of glia to mechanisms of injury and repair of the nervous system is increasingly recognized. In stark contrast to the central nervous system (CNS), the peripheral nervous system (PNS) has a remarkable capacity for regeneration after injury. Schwann cells are recognized as key contributors to PNS regeneration, but the molecular underpinnings of the Schwann cell response to injury and how they interact with the inflammatory response remain incompletely understood. METHODS: We completed bulk RNA-sequencing of Schwann cells purified acutely using immunopanning from the naïve and injured rodent sciatic nerve at 3, 5, and 7 days post-injury. We used qRT-PCR and in situ hybridization to assess cell purity and probe dataset integrity. Finally, we used bioinformatic analysis to probe Schwann cell-specific injury-induced modulation of cellular pathways. RESULTS: Our data confirm Schwann cell purity and validate RNAseq dataset integrity. Bioinformatic analysis identifies discrete modules of genes that follow distinct patterns of regulation in the 1st days after injury and their corresponding molecular pathways. These findings enable improved differentiation of myeloid and glial components of neuroinflammation after peripheral nerve injury and highlight novel molecular aspects of the Schwann cell injury response such as acute downregulation of the AGE/RAGE pathway and of secreted molecules Sparcl1 and Sema5a. CONCLUSIONS: We provide a helpful resource for further deciphering the Schwann cell injury response and a depth of transcriptional data that can complement the findings of recent single cell sequencing approaches. As more data become available on the response of CNS glia to injury, we anticipate that this dataset will provide a valuable platform for understanding key differences in the PNS and CNS glial responses to injury and for designing approaches to ameliorate CNS regeneration.

Functions of histone modifications and histone modifiers in Schwann cells.

Schwann cells (SCs) are the main glial cells present in the peripheral nervous system (PNS). Their primary functions are to insulate peripheral axons to protect them from the environment and to enable fast conduction of electric signals along big caliber axons by enwrapping them in a thick myelin sheath rich in lipids. In addition, SCs have the peculiar ability to foster axonal regrowth after a lesion by demyelinating and converting into repair cells that secrete neurotrophic factors and guide axons back to their former target to finally remyelinate regenerated axons. The different steps of SC development and their role in the maintenance of PNS integrity and regeneration after lesion are controlled by various factors among which transcription factors and chromatin-remodeling enzymes hold major functions. In this review, we discussed how histone modifications and histone-modifying enzymes control SC development, maintenance of PNS integrity and response to injury. The functions of histone modifiers as part of chromatin-remodeling complexes are discussed in another review published in the same issue of Glia.

The Trichoderma atroviride Strains P1 and IMI 206040 Differ in Their Light-Response and VOC Production.

Trichoderma atroviride is a strong necrotrophic mycoparasite antagonizing and feeding on a broad range of fungal phytopathogens. It further beneficially acts on plants by enhancing growth in root and shoot and inducing systemic resistance. Volatile organic compounds (VOCs) are playing a major role in all those processes. Light is an important modulator of secondary metabolite biosynthesis, but its influence has often been neglected in research on fungal volatiles. To date, T. atroviride IMI 206040 and T. atroviride P1 are among the most frequently studied T. atroviride strains and hence are used as model organisms to study mycoparasitism and photoconidiation. However, there are no studies available, which systematically and comparatively analyzed putative differences between these strains regarding their light-dependent behavior and VOC biosynthesis. We therefore explored the influence of light on conidiation and the mycoparasitic interaction as well as the light-dependent production of VOCs in both strains. Our data show that in contrast to T. atroviride IMI 206040 conidiation in strain P1 is independent of light. Furthermore, significant strain- and light-dependent differences in the production of several VOCs between the two strains became evident, indicating that T. atroviride P1 could be a better candidate for plant protection than IMI 206040.

The retinal environment induces microglia-like properties in recruited myeloid cells.

BACKGROUND: Microglia are essential to the development of the CNS and its homeostasis. Our prior findings suggested a niche model to describe the behaviors of retinal microglia. Here, we ask whether new myeloid cells recruited to the retina are constrained to resemble endogenous microglia morphologically and functionally. METHODS: Use of CD11cDTR/GFP transgenic mouse allowed identification of two niches of retinal microglia distinguished by being GFPlo or GFPhi. We also used transgenic mice in which CX3CR1+ cells expressed YFP and were depletable following tamoxifen-induced expression of diphtheria toxin subunit A. We employed several ablation and injury stimulation protocols to examine the origin and fate of myeloid cells repopulating the retina. Analysis of retinal myeloid cells was done by microscopy, flow cytometry, and qRT-PCR. RESULTS: We found that the origin of new GFPhi and GFPlo myeloid cells in the retina of CD11cDTR/GFP mice, whether recruited or local, depended on the ablation and stimulation protocols. Regardless of origin, new GFPlo and GFPhi retinal myeloid cells were CD45medCD11b+Ly6G-Ly6CloIba1+F4/80+, similar to endogenous microglia. Following tamoxifen-induced diphtheria toxin ablation, myeloid cell repopulation differed in the retina compared to the brain and optic nerve. Stimulation of replacement GFPhi cells was substantially attenuated in repopulating retinas after tamoxifen-induced diphtheria toxin ablation compared to control or radiation-ablated mice. In radiation bone marrow chimeric mice, replacement GFPhi myeloid cells from the circulation were slow to repopulate the retina unless stimulated by an optic nerve crush injury. However, once stimulated, recruited GFPhi cells were found to concentrate on injured retinal ganglion cells and were morphologically similar to GFPhi cells in non-ablated control CD11cDTR/GFP mice. CONCLUSIONS: The results support the idea that GFPhi cells in the CD11cDTR/GFP mouse, whether recruited or from resident microglia, mark a unique niche of activated retinal myeloid cells. We conclude that the retinal environment has a potent influence on the function, morphology, and proliferative capacity of new myeloid cells regardless of their origin, compelling them to be equivalent to the endogenous microglia.

Injury affects coelomic fluid proteome of the common starfish, Asterias rubens.

Echinoderms, possessing outstanding regenerative capabilities, provide a unique model system for the study of response to injury. However, little is known about the proteomic composition of coelomic fluid, an important biofluid circulating throughout the animal's body and reflecting the overall biological status of the organism. In this study, we used LC-MALDI tandem mass spectrometry to characterize the proteome of the cell-free coelomic fluid of the starfish Asterias rubens and to follow the changes occurring in response to puncture wound and blood loss. In total, 91 proteins were identified, of which 61 were extracellular soluble and 16 were bound to the plasma membrane. The most represented functional terms were 'pattern recognition receptor activity' and 'peptidase inhibitor activity'. A series of candidate proteins involved in early response to injury was revealed. Ependymin, ß-microseminoprotein, serum amyloid A and avidin-like proteins, which are known to be involved in intestinal regeneration in the sea cucumber, were also identified as injury-responsive proteins. Our results expand the list of proteins potentially involved in defense and regeneration in echinoderms and demonstrate dramatic effects of injury on the coelomic fluid proteome.

Pericytes in Cutaneous Wound Healing.

Most of the studies on cutaneous wound healing are focused on epidermal closure. This is obviously important, as the epidermis constitutes the main barrier that separates the inner organism from the environment. However, dermal remodeling is key to achieve long-lasting healing of the area that was originally wounded. In this chapter, we summarize what is known on the stromal components that strongly influence the outcome of healing and postulate that dedifferentiation of stably differentiated cells plays a major role in the initial response to wounding, as well as in long-term wound remodeling. Specifically, we explore the available evidence implicating skin pericytes, endothelial cells, Schwann cells, and macrophages as major players in a complex symphony of cellular plasticity and signaling events whose balance will promote healing (by tissue regeneration or repair) or fibrosis.

Are Gastric and Esophageal Metaplasia Relatives? The Case for Barrett's Stemming from SPEM.

Chronic injury and inflammation in the esophagus can cause a change in cellular differentiation known as metaplasia. Most commonly, the differentiation changes manifest as Barrett's esophagus (BE), characterized by the normal stratified squamous epithelium converting into a cuboidal-columnar, glandular morphology. BE cells can phenotypically resemble specific normal cell types of the stomach or intestine, or they can have overlapping phenotypes in disorganized admixtures. The stomach can also undergo metaplasia characterized by aberrant gastric or intestinal differentiation patterns. In both organs, it has been argued that metaplasia may represent a recapitulation of the embryonic or juvenile gastrointestinal tract, as cells access a developmental progenitor genetic program that can help repair damaged tissue. Here, we review the normal development of esophagus and stomach, and describe how BE represents an intermixing of cells resembling gastric pseudopyloric (SPEM) and intestinal metaplasia. We discuss a cellular process recently termed "paligenosis" that governs how mature, differentiated cells can revert to a proliferating progenitor state in metaplasia. We discuss the "Cyclical Hit" theory in which paligenosis might be involved in the increased risk of metaplasia for progression to cancer. However, somatic mutations might occur in proliferative phases and then be warehoused upon redifferentiation. Through years of chronic injury and many rounds of paligenosis and dedifferentiation, eventually a cell with a mutation that prevents dedifferentiation may arise and clonally expand fueling stable metaplasia and potentially thereafter acquiring additional mutations and progressing to dysplasia and cancer.

Adhesion G-protein coupled receptors and extracellular matrix proteins: Roles in myelination and glial cell development.

Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders. Developmental Dynamics 246:275-284, 2017. © 2016 Wiley Periodicals, Inc.

ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates.

Motoneuron death after transection of the axons (axotomy) in neonates is believed to share the same mechanistic bases as naturally occurring programmed cell death during development. The c-Jun N-terminal kinase pathway is activated in both forms of motoneuron death, but it remains unknown to what extent these two forms of motoneuron death depend on this pathway and which upstream kinases are involved. We found that numbers of facial motoneurons are doubled in neonatal mice deficient in either ZPK/DLK (zipper protein kinase, also known as dual leucine zipper kinase), a mitogen-activated protein kinase kinase kinase, or in MKK4/MAP2K4, a mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, and that the facial motoneurons in those mutant mice are completely resistant to axotomy-induced death. Conditional deletion of MKK4/MAP2K4 in neurons further suggested that ZPK/DLK and MKK4/MAP2K4-dependent mechanisms underlying axotomy-induced death are motoneuron autonomous. Nevertheless, quantitative analysis of facial motoneurons during embryogenesis revealed that both ZPK/DLK and MKK4/MAP2K4-dependent and -independent mechanisms contribute to developmental elimination of excess motoneurons. In contrast to MKK4/MAP2K4, mice lacking MKK7/MAP2K7, another mitogen-activated protein kinase kinase directly downstream of ZPK/DLK, conditionally in neurons did not have excess facial motoneurons. However, some MKK7/MAP2K7-deficient facial motoneurons were resistant to axotomy-induced death, indicating a synergistic effect of MKK7/MAP2K7 on axotomy-induced death of these facial motoneurons. Together, our study provides compelling evidence for the pivotal roles of the ZPK/DLK and MKK4/MAP2K4-dependent mechanism in axotomy-induced motoneuron death in neonates and also demonstrates that axotomy-induced motoneuron death is not identical to developmental motoneuron death with respect to the involvement of ZPK/DLK, MKK4/MAP2K4 and MKK7/MAP2K7.

SkpA restrains synaptic terminal growth during development and promotes axonal degeneration following injury.

The Wallenda (Wnd)/dual leucine zipper kinase (DLK)-Jnk pathway is an evolutionarily conserved MAPK signaling pathway that functions during neuronal development and following axonal injury. Improper pathway activation causes defects in axonal guidance and synaptic growth, whereas loss-of-function mutations in pathway components impairs axonal regeneration and degeneration after injury. Regulation of this pathway is in part through the E3 ubiquitin ligase Highwire (Hiw), which targets Wnd/DLK for degradation to limit MAPK signaling. To explore mechanisms controlling Wnd/DLK signaling, we performed a large-scale genetic screen in Drosophila to identify negative regulators of the pathway. Here we describe the identification and characterization of SkpA, a core component of SCF E3 ubiquitin ligases. Mutants in SkpA display synaptic overgrowth and an increase in Jnk signaling, similar to hiw mutants. The combination of hypomorphic alleles of SkpA and hiw leads to enhanced synaptic growth. Mutants in the Wnd-Jnk pathway suppress the overgrowth of SkpA mutants demonstrating that the synaptic overgrowth is due to increased Jnk signaling. These findings support the model that SkpA and the E3 ligase Hiw function as part of an SCF-like complex that attenuates Wnd/DLK signaling. In addition, SkpA, like Hiw, is required for synaptic and axonal responses to injury. Synapses in SkpA mutants are more stable following genetic or traumatic axonal injury, and axon loss is delayed in SkpA mutants after nerve crush. As in highwire mutants, this axonal protection requires Nmnat. Hence, SkpA is a novel negative regulator of the Wnd-Jnk pathway that functions with Hiw to regulate both synaptic development and axonal maintenance.

Divergent and dynamic activity of endogenous retroviruses in burn patients and their inflammatory potential.

Genes constitute ~3% of the human genome, whereas human endogenous retroviruses (HERVs) represent ~8%. We examined post-burn HERV expression in patients' blood cells, and the inflammatory potentials of the burn-associated HERVs were evaluated. Buffy coat cells, collected at various time points from 11 patients, were screened for the expression of eight HERV families, and we identified their divergent expression profiles depending on patient, HERV, and time point. The population of expressed HERV sequences was patient-specific, suggesting HERVs' inherent genomic polymorphisms and/or differential expression potentials depending on characteristics of patients and courses of injury response. Some HERVs were shared among the patients, while the others were divergent. Interestingly, one burn-associated HERV gag gene from a patient's genome induced IL-6, IL-1ß, Ptgs-2, and iNOS. These findings demonstrate that injury stressors initiate divergent HERV responses depending on patient, HERV, and disease course and implicate HERVs as genetic elements contributing to polymorphic injury pathophysiology.

Validated numerical unrestrained occupant-seat crash scenarios for high-speed trains integrating experimental, computational, and inverse methods.

OBJECTIVE: Occupant impact safety is critical for train development. This paper proposes a systematic procedure for developing validated numerical occupant crash scenarios for high-speed trains by integrating experimental, computational, and inverse methods. METHODS: As the train interior is the most potentially injury-causing factor, the material properties were acquired by mechanical tests, and constitutive models were calibrated using inverse methods. The validity of the seat material constitutive model was further verified via drop tower tests. Finite element (FE) and multibody (MB) models of train occupant-seat interactions in frontal impact were established in LS-DYNA and MADYMO software, respectively, using the experimentally acquired materials/mechanical characteristics. Three dummy sled crash tests with different folding table and backrest configurations were conducted to validate the numerical occupant-seat models and to further assess occupant injury in train collisions. The occupant impact responses between dummy tests and simulations were quantitatively compared using a correlation and analysis (CORA) objective rating method. RESULTS: Results indicated that the experimentally calibrated numerical seat-occupant models could effectively reproduce the occupant responses in bullet train collisions (CORA scores >80%). Compared with the train seat-occupant MB model, the FE model could simulate the head acceleration with slightly more acceptable fidelity, however, the FE model CORA scores were slightly less than for the MB models. The maximum head acceleration was 30 g but the maximum HIC score was 17.4. When opening the folding table, the occupant's chest injury was not obvious, but the neck-table contact and "chokehold" may potentially be severe and require further assessment. CONCLUSIONS: This study demonstrates the value of experimental data for occupant-seat model interactions in train collisions and provides practical help for train interior safety design and formulation of standards for rolling stock interior passive safety.

Glycosaminoglycans: Roles in wound healing, formation of corneal constructs and synthetic corneas.

Maintaining the clarity of the cornea is essential for vision, and is achieved through an exquisite array of collagen fibrils and proteoglycans in the corneal stroma. Alterations in the identity and modifications of the glycosaminoglycans (GAGs) are seen both throughout the normal wound healing process and in pathological conditions resulting in corneal opacity. Understanding these changes has been essential for the development of corneal prostheses and corneal reconstruction. The goal of this review article is to summarize and consolidate research in the alterations seen in glycosaminoglycans in injured and hypoxic states, address the role of proteins that can regulate glycosaminoglycans in the corneal wound healing process, and apply these findings to the context of corneal restoration through reconstruction or the insertion of synthetic devices.

From injury to patterning-MAPKs and Wnt signaling in Hydra.

Hydra has a regenerative capacity that is not limited to individual organs but encompasses the entire body. Various global and integrative genome, transcriptome and proteome approaches have shown that many of the signaling pathways and transcription factors present in vertebrates are already present in Cnidaria, the sister group of Bilateria, and are also activated in regeneration. It is now possible to investigate one of the central questions of regeneration biology, i.e., how does the patterning system become activated by the injury signals that initiate regeneration. This review will present the current data obtained in Hydra and draw parallels with regeneration in Bilateria. Important findings of this global analysis are that the Wnt signaling pathway has a dual function in the regeneration process. In the early phase Wnt is activated generically and in a second phase of pattern formation it is activated in a position specific manner. Thus, Wnt signaling is part of the generic injury response, in which mitogen-activated protein kinases (MAPKs) are initially activated via calcium and reactive oxygen species (ROS). The MAPKs, p38, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERK) are essential for Wnt activation in Hydra head and foot regenerates. Furthermore, the antagonism between the ERK signaling pathway and stress-induced MAPKs results in a balanced induction of apoptosis and mitosis. However, the early Wnt genes are activated by MAPK signaling rather than apoptosis. Early Wnt gene activity is differentially integrated with a stable, ß-Catenin-based gradient along the primary body axis maintaining axial polarity and activating further Wnts in the regenerating head. Because MAPKs and Wnts are highly evolutionarily conserved, we hypothesize that this mechanism is also present in vertebrates but may be activated to different degrees at the level of early Wnt gene integration.

Chemistry and Function of Glycosaminoglycans in the Nervous System.

Proteoglycans, and especially their GAG components, participate in numerous biologically significant interactions with growth factors, chemokines, morphogens, guidance molecules, survival factors, and other extracellular and cell-surface components. These interactions are often critical to the basic developmental processes of cellular proliferation and differentiation, as well as to both the onset of disease sequelae and prevention of disease progression. In many tissues, proteoglycans and especially their glycosaminoglycan (GAG) components are mediators of these processes. The GAG family is characterized by covalently linked repeating disaccharides forming long unbranched polysaccharide chains. Thus far in higher eukaryotes, the family consists of chondroitin sulfate (CS), heparin/heparan sulfate (HS), dermatan sulfate (DS), keratan sulfate (KS) and hyaluronan (HA). All GAG chains (except HA) are characteristically modified by varying amounts of esterified sulfate. One or more GAG chains are usually found in nature bound to polypeptide backbones in the form of proteoglycans; HA is the exception. In the nervous system, GAG/proteoglycan-mediated interactions participate in proliferation and synaptogenesis, neural plasticity, and regeneration. This review focuses on the structure, chemistry and function of GAGs in nervous system development, disease, function and injury response.

A novel approach to investigate effects of front-end structures on injury response of e-bike riders: Combining Monte Carlo sampling, automatic operation, and data mining.

Transportation safety related to e-bikes is becoming more problematic with the growing popularity in recent decade years, however, rare studies focused on the protection for e-bike riders in traffic accidents. This paper aimed to investigate the relationship between vehicle front-end structures and rider's injury based on a novel approach including modeling, sampling, and analyzing. Firstly, a parametrized model for front-end structures of the vehicle was developed with nine parameters to realize the standardization of multi-body models of car to e-bike collision considering three stature riders and different impacting velocities. Secondly, a framework, combining Monte Carlo sampling for twelve initial variables and automatic operation for 1000 impact simulations, was built to obtain valid results automatically and then to construct a big dataset. Finally, according to the sensitive variables to riders' vulnerable regions, the decision tree algorithm was further adopted to develop the decision or prediction model on injuries. The novel approach achieved the stochastical generation of vehicle shapes and the automatic operation of multi-body models. The results showed that the rider's head, pelvis, and thighs were more vulnerable to being injured in the car to e-bike perpendicular accidents. The three decision tree models (HIC15, lateral force of pelvis, bending moment of upper leg) were validated to be accurate and reliable according to the confusion matrix with the precision of more than 80% and the receiver operating characteristic curves (ROC) with the under area more than 85%. Based on decision tree models, not only the effects of front-end structural parameters on the corresponding injury but also the interaction mechanism between various variables can be clearly interpreted. Each route from the same root node to hierarchical middle nodes then to various leaf nodes represented a decision-making process. And the different branches under the same decision node directly illustrated the correlation between variables, which is highly readable and comprehensible. During the safety performance design of front-end structures, the rational value of variables could be decided according to decision routes that resulted in lower injury levels; Even if the accident was inevitable, the collision parameters could be controlled within a certain range for the least injury according to the prediction rules. Based on the novel framework coupling Monte Carlo sampling and automatic operation, it's foreseeable to apply the parametric and standard car-to-e-bike collision models to develop the virtual test system and to optimize front-end shapes for rider's protection.

Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury.

Homoeostasis and health of multicellular organisms with multiple organs depends on interorgan communication. Tissue injury in one organ disturbs this homoeostasis and can lead to disease in multiple organs, or multiorgan failure. Many routes of interorgan crosstalk during homoeostasis are relatively well known, but interorgan crosstalk in disease still lacks understanding. In particular, how tissue injury in one organ can drive injury at remote sites and trigger multiorgan failure with high mortality is poorly understood. As examples, acute kidney injury can trigger acute lung injury and cardiovascular dysfunction; pneumonia, sepsis or liver failure conversely can cause kidney failure; lung transplantation very frequently triggers acute kidney injury. Mechanistically, interorgan crosstalk after tissue injury could involve soluble mediators and their target receptors, cellular mediators, in particular immune cells, as well as newly identified neuro-immune connections. In this review, I will focus the discussion of deleterious interorgan crosstalk and its mechanistic concepts on one example, acute kidney injury-induced remote lung injury.

A Comparison of the Mid-Size Male THOR and Hybrid III ATDs in Vehicle Frontal Crash Tests.

In order to evaluate the THOR-50M as a front impact Anthropomorphic Test Device (ATD) for vehicle safety design, the ATD was compared to the H3-50M in matching vehicle crash tests for 20 unique vehicle models from 2 vehicle manufacturers. For the belted driver condition, a total of fifty-four crash tests were investigated in the 56.3 km/h (35 mph) front rigid barrier impact condition. Four more tests were compared for the unbelted driver and right front passenger at 40.2 km/h (25 mph) in the flat frontal and 30-degree right oblique rigid barrier impact conditions. The two ATDs were also evaluated for their ability to predict injury risk by comparing their fleet average injury risk to Crash Investigation Sampling System (CISS) accident data for similar conditions. The differences in seating position and their effect on ATD responses were also investigated. This study showed that the belted THOR-50M injury responses were higher than the H3-50M by 25%-180%, in all reported ATD responses, except chest acceleration. For one unbelted condition, the THOR-50M reported 200%-300% higher neck responses than the H3-50M, primarily due to head contact to the roof structure in a mid-sized sedan. The THOR-50M overpredicted the injury risk based on chest deflection compared to the CISS accident data by at least a factor of 4 times. The THOR-50M also overpredicted the injury risk based on BrIC by at least a factor of 10 times. Future work is needed to investigate these overpredictions with respect to ATD construction, injury risk curves, and seating procedures.