Response Of Human Tissue Research Articles

Hybrid biofabricated blood vessel for medical devices testing

ABSTRACT Current in vitro and in vivo tests applied to assess the safety of medical devices retain several limitations, such as an incomplete ability to faithfully recapitulate human features, and to predict the response of human tissues together with non-trivial ethical aspects. We here challenged a new hybrid biofabrication technique that combines bioprinting and Fast Diffusion-induced Gelation strategy to generate a vessel-like structure with the attempt to spatially organize fibroblasts, smooth-muscle cells, and endothelial cells. The introduction of Fast Diffusion-induced Gelation minimizes the endothelial cell mortality during biofabrication and produce a thin endothelial layer with tunable thickness. Cell viability, Von Willebrand factor, and CD31 expression were evaluated on biofabricated tissues, showing how bioprinting and Fast Diffusion-induced Gelation can replicate human vessels architecture and complexity. We then applied biofabricated tissue to study the cytotoxicity of a carbothane catheter under static condition, and to better recapitulate the effect of blood flow, a novel bioreactor named CuBiBox (Customized Biological Box) was developed and introduced in a dynamic modality. Collectively, we propose a novel bioprinted platform for human in vitro biocompatibility testing, predicting the impact of medical devices and their materials on vascular systems, reducing animal experimentation and, ultimately, accelerating time to market.

Reconstruction of the Permittivity of Ex Vivo Animal Tissues in the Frequency Range 1-20 GHz Using a Water-Based Dielectric Model.

Several medical techniques are based on the application of electromagnetic fields (EMFs) on the human body with therapeutic and/or diagnostic aims. The response of human tissues to the applied EMF is mediated by the tissues' dielectric properties, which must therefore be characterized at the frequencies of the considered technique. Due to the heterogeneity and complexity of biological tissues, it is necessary to know their properties in vivo for the specific condition of interest. Traditional techniques for the dielectric characterization of biological tissues are invasive and, as such, not adoptable for this aim. Accordingly, alternative sensors and/or sensing methods are needed. Recently, a new wideband spectroscopy technique was proposed, based on quantities derived from the Magnetic Resonance (MRI) signal. Among these quantities, the water content was proposed to evaluate the dielectric properties at frequencies around a few GHz. This work verifies the possibility of deriving tissues' dielectric properties in the frequency range of 1-20 GHz based on knowledge of the water content. The water content was retrieved through a dehydration procedure for five different ex vivo tissues. The achieved results were compared with references from the literature.

Investigating Snake-Venom-Induced Dermonecrosis and Inflammation Using an Ex Vivo Human Skin Model.

Snakebite envenoming is a neglected tropical disease that causes >100,000 deaths and >400,000 cases of morbidity annually. Despite the use of mouse models, severe local envenoming, defined by morbidity-causing local tissue necrosis, remains poorly understood, and human-tissue responses are ill-defined. Here, for the first time, an ex vivo, non-perfused human skin model was used to investigate temporal histopathological and immunological changes following subcutaneous injections of venoms from medically important African vipers (Echis ocellatus and Bitis arietans) and cobras (Naja nigricollis and N. haje). Histological analysis of venom-injected ex vivo human skin biopsies revealed morphological changes in the epidermis (ballooning degeneration, erosion, and ulceration) comparable to clinical signs of local envenoming. Immunostaining of these biopsies confirmed cell apoptosis consistent with the onset of necrosis. RNA sequencing, multiplex bead arrays, and ELISAs demonstrated that venom-injected human skin biopsies exhibited higher rates of transcription and expression of chemokines (CXCL5, MIP1-ALPHA, RANTES, MCP-1, and MIG), cytokines (IL-1β, IL-1RA, G-CSF/CSF-3, and GM-CSF), and growth factors (VEGF-A, FGF, and HGF) in comparison to non-injected biopsies. To investigate the efficacy of antivenom, SAIMR Echis monovalent or SAIMR polyvalent antivenom was injected one hour following E. ocellatus or N. nigricollis venom treatment, respectively, and although antivenom did not prevent venom-induced dermal tissue damage, it did reduce all pro-inflammatory chemokines, cytokines, and growth factors to normal levels after 48 h. This ex vivo skin model could be useful for studies evaluating the progression of local envenoming and the efficacy of snakebite treatments.

Inflammatory tissue response in human soft tissue is caused by a higher particle load near carbon fiber-reinforced PEEK compared to titanium plates

Titanium as the leading implant material in locked plating is challenged by polymers such as carbon fiber-reinforced polyetheretherketone (CFR-PEEK), which became the focus of interest of researchers and manufacturers in recent years. However, data on human tissue response to these new implant materials are rare.Osteosynthesis plates and peri‑implant soft tissue samples of 16 healed proximal humerus fractures were examined (n = 8 CFR-PEEK, n = 8 titanium). Soft tissue was analyzed by immunohistochemistry and µCT. The entrapped foreign bodies were further examined for their material composition by FTIR. To gain insight into their origin and formation mechanism, explanted and new plates were evaluated by SEM, EDX, profilometry and HR-CT.In the peri‑implant soft tissue of the CFR-PEEK plates, an inflammatory tissue reaction was detected. Tissues contained foreign bodies, which could be identified as tantalum wires, carbon fiber fragments and PEEK particles. Titanium particles were also found in the peri‑implant soft tissue of the titanium plates but showed a less intense surrounding tissue inflammation in immunohistochemistry. The surface of explanted CFR-PEEK plates was rougher and showed exposed and broken carbon fibers as well as protruding and deformed tantalum wires, especially in used screw holes, whereas scratches were identified on the titanium plate surfaces.Particles were present in the peri‑implant soft tissue neighboring both implant materials and could be clearly assigned to the plate material. Particles from both plate materials caused detectable tissue inflammation, with more inflammatory cells found in soft tissue over CFR-PEEK plates than over titanium plates. Statement of significanceOsteosynthesis plates are ubiquitously used in various medical specialties for the reconstruction of bone fractures and defects and are therefore indispensable for trauma surgeons, ENT specialists and many others. The leading implant material are metals such as titanium, but recently implants made of polymers such as carbon fiber-reinforced polyetheretherketone (CFR-PEEK) have become increasingly popular. However, little is known about human tissue reaction and particle generation related to these new implant types. To clarify this question, 16 osteosynthesis plates (n = 8 titanium and n = 8 CFR-PEEK) and the overlying soft tissue were analyzed regarding particle occurrence and tissue inflammation. Tissue inflammation is clinically relevant for the development of scar tissue, which is discussed to cause movement restrictions and thus contributes significantly to patient outcome.

Challenges in diagnosing canine spindle cell tumours using immunohistochemistry, illustrated by three nonpigmented malignant cases from the nictitating membrane

BackgroundNonpigmented malignant spindle cell tumours of the membrana nictitans are rare in dogs. In twenty-three years only three cases have been diagnosed in Scandinavia. This study describes the three cases of malignant tumours of the membrana nictitans recorded by the Eye Pathology Section, University of Copenhagen, Denmark, with reference to the clinical appearance and work-up, the treatment and prognosis, and the histopathological description including immunohistochemistry. The three cases are compared to previous publications on canine tumours of the nictitating membrane. We emphasize the importance of using protocols that are adapted to the specific species such as dogs. Opposite the human tissue responses, we even need more than one marker when diagnosing melanomas in dogs.ResultsThe dogs presented were an 8-year-old Dachshund, a 12-year-old Akita and a 14-year-old Shetland Sheepdog. All three dogs were entire females. All three nictitating membrane tumours developed on the right nictitating membrane as firm or multilobulated hyperaemic masses. Two of the tumours were macroscopically nonpigmented, the third being partly pigmented on the surface and ulcerated. According to the histopathology and for two of the cases immunohistochemistry with dog-adapted protocols the diagnoses included one hemangiosarcoma and two amelanotic melanomas. Tumour regrowth developed in all three cases and repeated resections were completed 1, 2 and 3 times, respectively, with recurrence experienced within 1.5 months − 3 years.ConclusionsNonpigmented malignant spindle cell tumours of the canine membrana nictitans are rare. Treatment of choice should be complete excision with a minimal histologic tumour-free distance and in case of a recurrence a full resection of the nictitating membrane. We strongly recommend a dog-adapted protocol for immunohistochemistry.

A novel investigational preclinical model to assess fluence rate for dental oral craniofacial tissues

ObjectivePhotodynamic Therapy (PDT) and Photobiomodulation (PBM) are recognized for their potential in treating head and neck conditions. The heterogeneity of human tissue optical properties presents a challenge for effective dosimetry. The porcine mandible cadaver serves as an excellent model and has several similarities to human tissues of the dental oral craniofacial complex. This study aims to validate a novel modeling system that will help refine PDT and PBM dosimetry for the head and neck region. Methods and MaterialsLight transmission was analyzed through several tissue combinations at distances of 2 mm to 10 mm. Maximum light fluence rates (mW/cm2) were compared across tissue types to reveal the effects of tissue heterogeneity. ResultsThe study revealed that light fluence is affected by tissue composition, with dentin/enamel showing reduced transmission and soft tissue regions exhibiting elevated values. The porcine model has proven to be efficient in mimicking human tissue responses to light, enabling the potential to optimize future protocols. ConclusionThe porcine mandible cadaver is a novel model to understand the complex interactions between light and tissue. This study provides a foundation for future investigations into dosimetry optimization for PDT and PBM.

Thermal responses of human tissues during nano-assisted hyperthermia for subcutaneous tumors

Non-invasive thermal therapy for subcutaneous tumors with the assistance of gold nanoparticles and surface cooling measures was proposed in the present study. To achieve real-time monitoring of 3-D temperature distribution and accurate measurement of thermal response, we developed a theoretical approach in which the dual-phase-lag (DPL) biological heat transfer model and Henriques' burn estimation model were employed. A closed-form solution for temperature distribution in the skin tissue can be obtained from this new model by employing the Green's function method. In addition, the influences of the embedment of gold nanoparticles, surface cooling, and non-Fourier effects on the temperature, thermal damage, and size of the burnt region were discussed in detail. The present model performs well in addressing the difficult issue of temperature and burn prediction inside human tissue. It is found that the combination of gold nanoparticles and surface cooling can concentrate thermal empyrosis in the subcutaneous tumor to enhance tumor elimination and protect both skin and deeper healthy tissue. This study provides theoretical support for the improvement and development of laser thermotherapy for subcutaneous tumors.

A lymph node slice culture model to characterize T cell activation dynamics and anti-viral responses in human tissue

Abstract T cell activation in the lymph node (LN) is critical to initiating adaptive immune responses to vaccination, tumors, and infection. We previously demonstrated that T cells from human tissue sites (blood, LNs, bone marrow, lung) undergo conserved cell state transitions during activation. However, these studies were performed in suspension culture from dissociated tissue, depleting the spatial and signaling contributions of the tissue microenvironment. To address this, we developed techniques for culture and single-cell analysis of human LN slices, which preserve tissue architecture, local signaling, and physiological cell frequencies. Single-cell RNA-seq (scRNA-seq) of matched LN suspension and slice cultures stimulated with anti-CD3/28 antibody tetramers revealed distinct activation patterns. While anti-CD3/28 stimulation is commonly used to study T cell activation, this reagent circumvents antigen presentation and may not fully recapitulate antigen-mediated signaling. Conversely, antigen-dependent stimulation with superantigen mimics require MHCII/TCR binding and may benefit from the intact microenvironment in slice culture. We discovered a distinct metabolic intermediate through scRNA-seq analysis of superantigen-stimulated LN suspension and slice cultures that is not observed with anti-CD3/28 stimulation. Overall, these studies demonstrate the utility of analyzing T cell responses in intact tissue and comparative analysis of distinct mechanisms of activation. 1T32GM145440-01 (MSTP Training Grant) U19AI128949 (NIAID)

Acoustic Sensing Response in Human Tissues for Theranostics and Implants

This letter investigates the impacts of high- and low-frequency acoustic waves on various human tissues. It is observed that low-frequency (4.6 kHz) acoustic energy works as a better alternative for acoustic power distribution across the tissues. Using a 4.6 kHz piezoelectric diaphragm transmitter and receiver, finite-element simulation was performed, and then, an experimental examination was done to evaluate the energy distribution. The average electrical output voltage produced by the low-frequency transducers was 0.758 V in the male subject's palm, 0.187 V in the wrist, and 0.015 V close to the elbow region. In comparison, it was 1.27 V in the female subject's palm, 0.534 V in the wrist, and 0.146 V close to the elbow region. The low-frequency response of the sensors was found to be equal to or a maximum of 39.7% better than that of the high-frequency alternative. The obtained output voltage can be used to power medical implants and extract medical data at great depths with minimal attenuation.

Dosimetric Double Network Hydrogel Based on Poly(vinyl-alcohol)/Phenylalanine-Derivatives with Enhanced Mechanical Properties

An innovative double network hydrogel based on poly(vinyl-alcohol) (PVA) cross-linked with glutaraldehyde (GTA) was obtained by the addition of self-assembling phenylalanine (Phe) derivatives with the aim to achieve improved mechanical-elastic properties exploitable to produce 3D dosimeters. The self-assembling ability in fibrous structures of Phe derivatives (FmocPhe-OH, A; FmocPhe-Phe-OMe, P) even within the PVA gel was proved by AFM and SEM imaging. The proposed matrices containing A and P were completely characterized from the physical-chemical point of view in order to deeply understand how the two molecules influenced the hydrogel properties. Mechanical tests proved that the addition of the Phe derivatives produce higher stiffness, toughness, and stretchability of the hydrogels. In particular, these properties appear in the peptide P matrix and could be appropriately tailored by regulating the concentration of the added molecule. Preliminary dosimetric studies were also performed by infusing the studied hydrogels with Fricke solution. The P type has been demonstrated to be suitable for dosimetric applications by avoiding any effect on the dose response of the hydrogel. This work presents an unconventional material that is able to provide clinicians and medical physicists with effective and reliable 3D dosimetric measurements for the development of anthropomorphic phantoms that mimic mechanical properties and the radiological response of human tissues.

Alternative transcription start sites contribute to acute-stress-induced transcriptome response in human skeletal muscle

BackgroundMore than half of human protein-coding genes have an alternative transcription start site (TSS). We aimed to investigate the contribution of alternative TSSs to the acute-stress-induced transcriptome response in human tissue (skeletal muscle) using the cap analysis of gene expression approach. TSSs were examined at baseline and during recovery after acute stress (a cycling exercise).ResultsWe identified 44,680 CAGE TSS clusters (including 3764 first defined) belonging to 12,268 genes and annotated for the first time 290 TSSs belonging to 163 genes. The transcriptome dynamically changes during the first hours after acute stress; the change in the expression of 10% of genes was associated with the activation of alternative TSSs, indicating differential TSSs usage. The majority of the alternative TSSs do not increase proteome complexity suggesting that the function of thousands of alternative TSSs is associated with the fine regulation of mRNA isoform expression from a gene due to the transcription factor-specific activation of various alternative TSSs. We identified individual muscle promoter regions for each TSS using muscle open chromatin data (ATAC-seq and DNase-seq). Then, using the positional weight matrix approach we predicted time course activation of “classic” transcription factors involved in response of skeletal muscle to contractile activity, as well as diversity of less/un-investigated factors.ConclusionsTranscriptome response induced by acute stress related to activation of the alternative TSSs indicates that differential TSSs usage is an essential mechanism of fine regulation of gene response to stress stimulus. A comprehensive resource of accurate TSSs and individual promoter regions for each TSS in muscle was created. This resource together with the positional weight matrix approach can be used to accurate prediction of TFs in any gene(s) of interest involved in the response to various stimuli, interventions or pathological conditions in human skeletal muscle.

Listening in on Multicellular Communication in Human Tissue Immunology.

Immune responses in human tissues rely on the concerted action of different cell types. Inter-cellular communication shapes both the function of the multicellular interaction networks and the fate of the individual cells that comprise them. With the advent of new methods to profile and experimentally perturb primary human tissues, we are now in a position to systematically identify and mechanistically dissect these cell-cell interactions and their modulators. Here, we introduce the concept of multicellular hubs, functional modules of immune responses in tissues. We outline a roadmap to discover multicellular hubs in human tissues and discuss how emerging technologies may further accelerate progress in this field.

Genome-wide evaluation of transcriptomic responses of human tissues to smoke: A systems biology study.

The harmful compounds in various sources of smoke threaten human health. So far, many studies have investigated the effects of compounds of smoke on transcriptome changes in different human tissues. However, no study has been conducted on the effects of these compounds on transcriptome changes in different human tissues simultaneously. Hence, the present study was conducted to identify smoke-related genes (SRGs) and their response mechanisms to smoke in various human cells and tissues using systems biology based methods. A total of 6,484 SRGs were identified in the studied tissues, among which 4,095 SRGs were up-regulated and 2,389 SRGs were down-regulated. Totally, 459 SRGs were smoke-related transcription factors (SRTFs). Gene regulatory network analysis showed that the studied cells and tissues have different gene regulation and responses to compounds of smoke. The comparison of different tissues revealed no common SRG among the all studied tissues. However, the CYP1B1 gene was common among seven cells and tissues, and had the same expression trend. Network analysis showed that the CYP1B1 is a hub gene among SRGs in various cells and tissues. To the best of our knowledge, for the first time, our results showed that compounds of smoke induce and increase the expression of CYP1B1 key gene in all target and non-target tissues of human. Moreover, despite the specific characteristics of CYP1B1 gene and its identical expression trend in target and non-target tissues, it can be used as a biomarker for diagnosis and prognosis.

Theoretical evaluation of bio-thermal response in human tissue subjected to pulse-laser induced hyperthermia therapy for cancer treatment

This paper aims to develop a theoretical estimation of thermal response in human tissues appearing in a hyperthermia treatment under the influence of laser-induced external heat sources. In general, to develop a theoretical investigation on bioheat transfer, the fundamental aspect is to adopt an appropriate thermal model for predicting the correct thermal response. Among the existing bioheat models, the two-temperature model is considered to be the most feasible one, as it takes into account the arterio-vascular architectural interaction in the analysis. This model is established based on the local thermal non-equilibrium (LTNE) approach. The exact solution of the two-temperature bioheat model has been established by the implementation of the combined scheme of Duhamel's theorem and the Finite integral transform method. A pulse laser heating applied externally as a therapeutic heat source is introduced newly in the area of the LTNE bioheat modelling whereas the existing research works were developed by utilizing scattering laser heat sources. The thermal response of the tissue is analyzed for different laser variables such as laser intensity, optical penetration depth, pulse laser time, and laser irradiation radius. A parametric study has been made to set a theoretical treatment protocol for hyperthermia therapy and correspondingly, the thermal field has been developed within the prescribed peak temperature spectrum for the hyperthermia treatment. The thermal field has also been investigated for various biological parameters, viz. blood perfusion rate, porosity, and pore diameter of the blood vessel. The present research outcome depicts that the hyperthermia temperature can be achieved at the optical penetration depth of 0.0005 m with the laser irradiation radius in the range of 0.004 m–0.008 m. From the present work, it can be highlighted that the health monitoring of infected tissues or the organ of the human body is necessary before processing therapeutic heating as the thermal field depends on the porosity of tissue significantly. A qualitative investigation between pulse heating and scattering laser heating depicts that pulse laser heating is a better option to choose for the thermal therapy for the curtailment of the possibility of thermally induced damage of healthy tissues. A successful verification and authentication study has been carried out between the present work and the published experimental and theoretical works.

Experimental Investigation on Thermal Conductivity and Thermal Diffusivity of Ex-Vivo Bovine Liver from Room Temperature down to -60 °C.

Ex vivo animal tissues (e.g., bovine liver) as well as water-agar gel are commonly used to simulate both experimentally and numerically the response of human tissues to cryoablation treatments. Data on the low temperature thermal properties of bovine liver are difficult to find in the literature and very often are not provided for the whole temperature range of interest. This article presents the thermal conductivity and thermal diffusivity measurements performed on ex-vivo bovine liver samples using the transient plane source method. Regression coefficients are provided to determine these properties in different temperature ranges except for the phase transition during which no results were obtained, which suggests an ad hoc calorimetric analysis. A quick procedure is also suggested to determine the water mass fraction in the tissue. Moreover, an attempt to estimate the liver density in the frozen state using measurements performed solely at room temperature is also presented. The measured thermal conductivity and thermal diffusivity values are compared with data reported in literature highlighting a spread up to 40%. Moreover, it emerges that water-agar gel usually made with 2% by weight of agar does not show the same thermal properties as the bovine liver.

A non-stationary relay-based 3D MIMO channel model with time-variant path gains for human activity recognition in indoor environments

Extensive research showed that the physiological response of human tissue to exposure to low-frequency electromagnetic fields is the induction of an electric current in the body segments. As a result, each segment of the human body behaves as a relay, which retransmits the radio-frequency (RF) signal. To investigate the impact of this phenomenon on the Doppler characteristics of the received RF signal, we introduce a new three-dimensional (3D) non-stationary channel model to describe the propagation phenomenon taking place in an indoor environment. Here, the indoor space is equipped with a multiple-input multiple-output (MIMO) system. A single person is moving in the indoor space and is modelled by a cluster of synchronized moving point scatterers, which behave as relays. We derive the time-variant (TV) channel transfer function (CTF) with TV path gains and TV path delays. The expression of the TV path gains is obtained from the instantaneous total received power at the receiver side. This TV total received power is expressed as the product of the TV power of the RF signal initially transmitted and received by a body segment and the TV received power of the redirected signal. These TV powers are determined according the free-space path-loss model. Also, a closed-form approximate solution to the spectrogram of the TVCTF is derived. Here, we analyse the effect of the motion of the person and the validity of the relay assumption on the spectrogram, the TV mean Doppler shift (MDS), and the TV Doppler shift (DS) of the TVCTF. Simulation results are presented to illustrate the proposed channel model.

Characterization of an engineered live bacterial therapeutic for the treatment of phenylketonuria in a human gut-on-a-chip

Engineered bacteria (synthetic biotics) represent a new class of therapeutics that leverage the tools of synthetic biology. Translational testing strategies are required to predict synthetic biotic function in the human body. Gut-on-a-chip microfluidics technology presents an opportunity to characterize strain function within a simulated human gastrointestinal tract. Here, we apply a human gut-chip model and a synthetic biotic designed for the treatment of phenylketonuria to demonstrate dose-dependent production of a strain-specific biomarker, to describe human tissue responses to the engineered strain, and to show reduced blood phenylalanine accumulation after administration of the engineered strain. Lastly, we show how in vitro gut-chip models can be used to construct mechanistic models of strain activity and recapitulate the behavior of the engineered strain in a non-human primate model. These data demonstrate that gut-chip models, together with mechanistic models, provide a framework to predict the function of candidate strains in vivo.

A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids.

SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.

Tissue Responses to Shiga Toxin in Human Intestinal Organoids.

Background & AimsShiga toxin (Stx)-producing Escherichia coli (eg, O157:H7) infection produces bloody diarrhea, while Stx inhibits protein synthesis and causes the life-threatening systemic complication of hemolytic uremic syndrome. The murine intestinal tract is resistant to O157:H7 and Stx, and human cells in culture fail to model the complex tissue responses to intestinal injury. We used genetically identical, human stem cell–derived intestinal tissues of varying complexity to study Stx toxicity in vitro and in vivo.MethodsIn vitro susceptibility to apical or basolateral exposure to Stx was assessed using human intestinal organoids (HIOs) derived from embryonic stem cells, or enteroids derived from multipotent intestinal stem cells. HIOs contain a lumen, with a single layer of differentiated epithelium surrounded by mesenchymal cells. Enteroids only contain epithelium. In vivo susceptibility was assessed using HIOs, with or without an enteric nervous system, transplanted into mice.ResultsStx induced necrosis and apoptotic death in both epithelial and mesenchymal cells. Responses that require protein synthesis (cellular proliferation and wound repair) also were observed. Epithelial barrier function was maintained even after epithelial cell death was seen, and apical to basolateral translocation of Stx was seen. Tissue cross-talk, in which mesenchymal cell damage caused epithelial cell damage, was observed. Stx induced mesenchymal expression of the epithelial marker E-cadherin, the initial step in mesenchymal–epithelial transition. In vivo responses of HIO transplants injected with Stx mirrored those seen in vitro.ConclusionsIntestinal tissue responses to protein synthesis inhibition by Stx are complex. Organoid models allow for an unprecedented examination of human tissue responses to a deadly toxin.

The impact of perceived stress on skin ageing.

Skin ageing can be divided according to phenotypical features into intrinsic (by the passage of time) and extrinsic (with the addition of the effects of environmental factors). Photoageing is by far the most researched factor of extrinsic ageing but the additional impact of other factors such as cigarette smoking and exposure to air pollution ought to be taken into account. One of the least researched topics in relation to extrinsic skin ageing is the impact of psychological stress. A contemporary review of response of human skin to stress describes the molecular mechanisms of extrinsic skin ageing, but has fallen short of explaining resilience to stress exhibited by people. Mechanisms to regulate gene expression, define cellular identity and promote functionality are responsible for the adaptive response to stressful events. Conversely, maladaptive response of human tissues to chronic stress appears to have an impact on gene regulation. Epigenetics is the study of heritable changes in organisms due to modifications in gene activity and expression, as opposed to the genetic code (DNA genome). Chronic stress appears to be an important factor in determining an individual's vulnerability to ageing and age-related comorbidities via epigenetic modifications. Forerunners in epigenetic research recognized the necessity of a reliable biomarker in order to develop a better understanding of the role of epigenomics in ageing. Genomic DNA methylation patterns (DNAm) appear to be valuable in age prediction but variability in specificity exists across species of mammals, human races and tissues. Neuroscience research appears to be leading the way in epigenomics whilst the lack of a valid and reliable DNAm-associated age predictor compatible with human skin tissue hinders research endeavours for the epigenetics of skin ageing.