Acute Tissue Damage Research Articles

PA22 Topical tacrolimus management of chronic recurrent skin reaction to mauve stinger jellyfish envenomation

Abstract Chronic skin eruptions may follow the acute reaction to envenomation by some jellyfish, the incidence and management of which are not well described. We describe management with topical tacrolimus of a chronic eruption following envenomation by Pelagia noctiluca (‘mauve stinger’), one of the most common stinging jellyfish in the Mediterranean Sea. An 8-year-old girl was stung on the arm by a P. noctiluca in Menorca, Spain. First-aid measures with vinegar and topical antihistamine were administered, and the discomfort settled within 24 h. Five days later, the sting site became increasingly painful and itchy, with superficial ulceration and arm swelling. A second sting site on the lower leg reacted in a similar manner. She was systemically well. She was treated with oral co-amoxiclav, fusidic acid and betamethasone valerate 0.1% cream, and nonadhesive dressings. She initially responded well, but was required to continue the use of potent topical steroid after 3 weeks, as the symptoms recurred within 48 h of halted application. The use of topical tacrolimus cream 0.03% achieved symptom control when used in a slowly weaning regime over 3 months, with a brief flare of skin symptoms around the time of contracting COVID-19. She has now been asymptomatic for 12 months, and the sting site is a maturing scar. Envenomation reactions to jellyfish of the phylum Cnidaria (including P. noctiluca) are the result of varying pathophysiological mechanisms. The tentacles and bell of P. noctiluca carry toxin-releasing epithelial organelles called nematocysts. When triggered, the stinging apparatus fires, injecting thousands of mineralized spine-covered tubules and toxins such as porins [Yanagihara AA, Wilcox C, Smith J, Surrett GW. Cubozoan envenomations: clinical features, pathophysiology and management. In: The Cnidaria, Past, Present and Future (Goffredo S, Dubinsky Z, eds). Cham: Springer, 2016; 637–52]. Acute tissue damage and inflammation are caused by physical trauma and venom effects. Vinegar used at the time of a sting may permanently prevent discharge from unfired and noninjected nematocysts. Hot-water immersion for 30 min inactivates venom, and topical steroids reduce inflammation. The delayed and prolonged skin response (presenting after the primary reaction to envenomation), as in our case, is likely to be an immunological response to the retained, embedded nematocyst structures and may include granulomatous reactions, and eventually scarring. Optimal acute first-aid measures (as above) are thought to reduce incidence of late skin sequelae. This report highlights the successful use of topical tacrolimus immunomodulation for an established delayed reaction.

Evidence of Antibiotic Resistance and Virulence Factors in Environmental Isolates of Vibrio Species.

The outbreak of waterborne diseases such as cholera and non-cholera (vibriosis) is continuously increasing in the environment due to fecal and sewage discharge in water sources. Cholera and vibriosis are caused by different species of Vibrio genus which are responsible for acute diarrheal disease and soft tissue damage. Although incidences of cholera and vibriosis have been reported from the Vaishali district of Bihar, India, clinical or environmental strains have not been characterized in this region. Out of fifty environmental water samples, twelve different biochemical test results confirmed the presence of twenty Vibrio isolates. The isolates were found to belong to five different Vibrio species, namely V. proteolyticus, V. campbellii, V. nereis, V. cincinnatiensis, and V. harveyi. From the identified isolates, 65% and 45% isolates were found to be resistant to ampicillin and cephalexin, respectively. Additionally, two isolates were found to be resistant against six and four separately selected antibiotics. Furthermore, virulent hlyA and ompW genes were detected by PCR in two different isolates. Additionally, phage induction was also noticed in two different isolates which carry lysogenic phage in their genome. Overall, the results reported the identification of five different Vibrio species in environmental water samples. The isolates showed multiple antibacterial resistance, phage induction, and virulence gene profile in their genome.

Distinct Alterations in Oxygenation, Ion Composition and Acid-Base Balance in Cerebral Collaterals During Large-Vessel Occlusion Stroke

PurposeDisturbances of blood gas and ion homeostasis including regional hypoxia and massive sodium (Na+)/potassium (K+) shifts are a hallmark of experimental cerebral ischemia but have not been sufficiently investigated for their relevance in stroke patients.MethodsWe report a prospective observational study on 366 stroke patients who underwent endovascular thrombectomy (EVT) for large-vessel occlusion (LVO) of the anterior circulation (18 December 2018–31 August 2020). Intraprocedural blood gas samples (1 ml) from within cerebral collateral arteries (ischemic) and matched systemic control samples were obtained according to a prespecified protocol in 51 patients.ResultsWe observed a significant reduction in cerebral oxygen partial pressure (−4.29%, paO2ischemic = 185.3 mm Hg vs. paO2systemic = 193.6 mm Hg; p = 0.035) and K+ concentrations (−5.49%, K+ischemic = 3.44 mmol/L vs. K+systemic = 3.64 mmol/L; p = 0.0083). The cerebral Na+:K+ ratio was significantly increased and negatively correlated with baseline tissue integrity (r = −0.32, p = 0.031). Correspondingly, cerebral Na+ concentrations were most strongly correlated with infarct progression after recanalization (r = 0.42, p = 0.0033). We found more alkaline cerebral pH values (+0.14%, pHischemic = 7.38 vs. pHsystemic = 7.37; p = 0.0019), with a time-dependent shift towards more acidotic conditions (r = −0.36, p = 0.055).ConclusionThese findings suggest that stroke-induced changes in oxygen supply, ion composition and acid-base balance occur and dynamically progress within penumbral areas during human cerebral ischemia and are related to acute tissue damage.

Regulation of myeloid cells and inflammation marks increased susceptibility in a genetic model of acute viral infection-induced tissue damage.

Abstract M.H2 k/bmice are identical to MA/My parent strain aside from a C57L-derived region within the MHC, which causes these mice to develop significant splenic tissue damage during acute murine cytomegalovirus (MCMV) infection. To understand how MCMV infection leads to the induction of tissue damage, we probed immunological differences between the M.H2 k/band MA/My mice over time. Using tissue imaging and flow cytometry, we observed increased infiltration of neutrophils to the marginal zones of the M.H2 k/bmice aligning with the appearance of necrosis at 2 days post infection (dpi). While TUNEL staining identified increased cell death within these clusters, apoptosis was reduced, suggesting an inflammatory death pathway in the M.H2 k/bneutrophils. In line with this hypothesis, multiplex ELISA identified increased IL-6 and TGF-β in the spleens of M.H2 k/bmice at this time. Intriguingly, depletion of neutrophils prior to infection did not alleviate M.H2 k/bhistopathology or inflammation. Seeing the differential regulation of neutrophils, we assessed the state of other myeloid populations in the spleen during acute MCMV infection. We observed significant loss of marginal zone and red pulp macrophages (MZMs, RPMs) beginning at 2dpi and worsening over time in the M.H2 k/bmice. Further exploration into how the loss of these populations may contribute to tissue damage identified buildup of toxic lipid peroxidation byproduct 4HNE early in the MZMs and progressing through the RPMs alongside the development of histopathology. In conclusion, we have identified increased inflammation, oxidative stress, and macrophage loss in M.H2 k/bspleens during acute MCMV infection that tracks with localization and temporal appearance of histopathology. NIH NIAID R01AI50072, Department of Medicine/Nephrology, Center for Immunity Inflammation and Regenerative Medicine, Beirne B Carter Center for Immunology Research.

Lung injury induces preferential expansion of Foxp3 +regulatory T cells over conventional T cells in self-antigen specific CD4 +T cell repertoire.

Abstract Self antigen-specific T cells are prevalent in the mature adaptive immune repertoire. At steady state, these T cells are regulated by various mechanisms of peripheral tolerance. Characterizing the activation of these self antigen-specific T cells during inflammation may shed crucial insights into the pathogenesis of autoimmunity. Utilizing an experimental animal model where mice express three model T cell epitopes (2W, gp66, and OVA) in a tissue restricted manner, we detect the exclusive expansion of autoreactive regulatory T cells (Tregs) following acute lung injury that is dependent on recognition of their cognate self antigen and IL-2 signaling. Conversely, conventional T cells of the same self antigen-specificity did not expand during inflammation, even following the depletion of endogenous Tregs. Therefore, our findings suggest that the self-antigen specific T cell repertoire may serve a regulatory function during acute tissue damage to regulate the ongoing immune response and limit the possibility of autoimmunity.

Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy.

To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) 4, a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC50 = 2.3 nM) and five mutant strains, such as K103N (EC50 = 8 nM) and E138K (EC50 = 6 nM), significantly better than 4. The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC50 = 40.77 μM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.

A dual-responsive ratiometric indicator designed for in vivo monitoring of oxidative stress and antioxidant capacity.

The imbalance between oxidative stress and antioxidant capacity is strongly associated with the development of numerous degenerative diseases, including cardiovascular diseases, diabetes, neurodegenerative diseases, and cancer. Therefore, monitoring oxidative stress and antioxidant capacity in vivo is crucial for maintaining cellular homeostasis and the stability of the organism's internal environment. Here, we present the findings of our study on DQ1, a dual-responsive indicator designed specifically for imaging H2O2 and NAD(P)H, which are critical indicators of oxidative stress and antioxidant capacity. DQ1 facilitated the colorimetric and fluorescence detection of H2O2 and NAD(P)H in two well-separated channels, exhibiting a detection limit of 1.0 μM for H2O2 and 0.21 nM for NAD(P)H, respectively. Experiments conducted on living cells and zebrafish demonstrated that DQ1 could effectively detect changes in H2O2 and NAD(P)H levels when exposed to exogenous hypoxic conditions and chemical stimuli. Furthermore, the effectiveness of the as-fabricated indicator was investigated in two distinct mouse models: evaluating H2O2 and NAD(P)H levels in myocardial cell dysfunction during acute myocardial infarction and liver tissue damage under trichloroethylene stress conditions. In vivo experiments demonstrated that the levels of the two cardiac biomarkers increase progressively with the development of myocardial infarction, eventually reaching a steady state after 7 days when the damaged cells in the infarcted region become depleted. Moreover, during 14 continuous days of exposure to trichloroethylene, the two biomarkers in liver tissue exhibited a sustained increase, indicating a significant enhancement in intracellular oxidative stress and antioxidant capacity attributed to the mouse liver's robust metabolic capacity. The aforementioned studies underscore the efficacy of DQ1 as a valuable tool for scrutinizing redox states at both the single-cell and biological tissue levels. It presents significant potential for investigating the dynamic alternations in oxidative stress and antioxidant capacity within disease models as the disease progresses, thereby facilitating a more profound comprehension of these processes across various disease models.

Laser-Microfabricated Polymer Multielectrodes for Intraspinal Microstimulation.

The overall goal of this study was to design, fabricate, and characterize a new polymer-based multielectrode for the spinal cord for the application of intraspinal microstimulation (ISMS). Three-channel multielectrodes were fabricated from modified poly(dimethylsiloxane) (PDMS) and platinum-iridium (Pt-Ir) foil using nanosecond laser microfabrication techniques. These devices were compared against traditional 50 μm diameter Pt-Ir microwire electrodes mechanically and electrochemically in bench environments, and were assessed electrochemically and functionally in vivo in a domestic pig model. Polymer-based multielectrodes were significantly more flexible than microwire electrodes (p < 0.05) and had greater charge storage capacities in phosphate buffered saline (p < 0.05). In a domestic pig model, multielectrodes had significantly greater charge injection limits than microwire electrodes (p < 0.05). When stimulating within the quadriceps motor pool in the spinal cord, multielectrodes generated strong knee extensor joint torques of up to 4.4 ± 0.3 Nm and were able to extend the knee by up to 26 ± 1°. However, histological analyses showed that polymer-based multielectrodes, implanted with half-needle insertion aids, produced greater acute tissue damage compared to microwire electrodes (p < 0.05). Alternative insertion methods for these flexible electrodes should be explored to reduce acute tissue damage. The PDMS-based three-channel multielectrodes demonstrated improved flexibility and charge injection capabilities over traditional microwire electrodes, and were able to produce functional responses in vivo. Polymer-based multielectrodes demonstrate improved functionality over microwire electrodes while remaining more flexible than silicon multielectrode designs. These features may in the future permit polymer-based multielectrodes to implement ISMS with greater efficacy and biocompatibility compared to traditional technologies.

Impact of fluoroquinolones and aminoglycosides on P. aeruginosa virulence factor production and cytotoxicity.

The opportunistic pathogen Pseudomonas aeruginosa is one of leading causes of disability and mortality worldwide and the world health organisation has listed it with the highest priority for the need of new antimicrobial therapies. P. aeruginosa strains responsible for the poorest clinical outcomes express either ExoS or ExoU, which are injected into target host cells via the type III secretion system (T3SS). ExoS is a bifunctional cytotoxin that promotes intracellular survival of invasive P. aeruginosa by preventing targeting of the bacteria to acidified intracellular compartments. ExoU is a phospholipase which causes destruction of host cell plasma membranes, leading to acute tissue damage and bacterial dissemination. Fluoroquinolones are usually employed as a first line of therapy as they have been shown to be more active against P. aeruginosa in vitrothan other antimicrobial classes. Their overuse over the past decade, however, has resulted in the emergence of antibiotic resistance. In certain clinical situations, aminoglycosides have been shown to be more effective then fluoroquinolones, despite their reduced potency towards P. aeruginosa in vitro. In this study, we evaluated the effects of fluoroquinolones (moxifloxacin and ciprofloxacin) and aminoglycosides (tobramycin and gentamycin) on T3SS expression and toxicity, in corneal epithelial cell infection models. We discovered that tobramycin disrupted T3SS expression and reduced both ExoS and ExoU mediated cytotoxicity, protecting infected HCE-t cells at concentrations below the minimal inhibitory concentration (MIC). The fluoroquinolones moxifloxacin and ciprofloxacin, however, up-regulated the T3SS and did not inhibit and may have increased the cytotoxic effects of ExoS and ExoU.

Effects of the New Thrombolytic Compound LT3001 on Acute Brain Tissue Damage After Focal Embolic Stroke in Rats.

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10mg/kg LT3001 or tPA at 1.5, 3, or 4.5h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke.

The Use of Campenot Trichambers for the Study of Peripheral Neuronal Growth and Survival in Presence of Thrombotic Factors and Serpins.

The mechanisms underlying nervous system injury, such as spinal cord injury (SCI), traumatic brain injury (TBI), and peripheral nerve injury are complex and not well understood. Following acute tissue damage and cell death, inflammatory processes cause ongoing damage. Many factors regulate this inflammation, including factors that modulate chemokine expression. Serine proteases, including those of the thrombotic and thrombolytic pathways (e.g., thrombin, tPA, uPA) are upregulated during nervous system damage and can modulate the release and bioavailability of many chemokines. Virus-derived immunomodulators, such as Serp-1, a serine protease inhibitor (serpin), have protective effects by reducing inflammation and tissue damage. However, the precise mechanisms of Serp-1 neuroprotection are still being studied. Compartmentalized in vitro neuron culture systems, such as the Campenot trichamber, are useful for such mechanistic studies. This chapter provides a protocol for assembling and culturing rodent embryonic superior cervical ganglion (SCG) and dorsal root ganglion (DRG) neurons in Campenot trichambers, as well as instructive examples of the types of experiments enabled by these methods.

Identification of 3-Phenylquinoline Derivative PQ1 as an Antagonist of p53 Transcriptional Activity.

Transcription factor p53 regulates cellular responses to environmental perturbations via the transcriptional activation of downstream target genes. Inappropriate p53 activation can trigger abnormal cellular responses, therefore leading to acute or chronic tissue damage, human developmental syndromes, and neurodegenerative diseases. Antagonists of p53 transcriptional activity provide prospective therapeutic applications and molecular probes. In this article, we identified five 3-phenylquinoline derivatives as potential p53 inhibitors through screening a chemical library consisting of 120 compounds, in which PQ1 was the most active compound. PQ1 had no effect on p53 protein levels and decreased the expression of p53 target gene p21. PQ1 thermally stabilizes the wild-type p53 protein. Further, transcriptomics confirmed that PQ1 exposure generated a similar regulatory effect to transcription profiles with a reported p53 transcriptional inhibitor pifithrin-α. However, compared to pifithrin-α, PQ1 increased the sensitivity of SW480 cells to 5FU. Taken together, PQ1 was a novel antagonist of p53 transcriptional activity. We propose that PQ1 could be developed as a chemical tool to pinpoint the physiological functions of p53 and a novel lead compound for targeting dysfunctional p53 activation.

Safety and feasibility of irreversible electroporation for the pancreatic head in a porcine model

BACKGROUNDIrreversible electroporation (IRE) is a local non-thermal ablative technique which has been suggested as a potential cancer therapy. However, the specific anatomic characteristics of the pancreatic head make it challenging to perform any local ablation in this region. Therefore, the safety and feasibility of IRE in the pancreatic head region should be further explored.AIMTo evaluate the safety of IRE in pancreatic head region including its effects on pancreatic ducts, vessels, and adjacent gastrointestinal organs.METHODSEight landrace miniature pigs underwent IRE of pancreatic head tissue successfully, with a total of 16 lesions created. Laboratory testing including white blood cell (WBC) count and serum amylase before IRE with follow-up laboratory analysis and pathological examination at 1, 7, 14, and 28 d postablation were performed. RESULTSAll pigs tolerated the ablation procedure without serious perioperative complications. Transiently elevated WBC count and amylase were observed at 24 h post-IRE, suggesting an acute pancreatic tissue damage which was confirmed by pathological observations. Vascular endothelial cells and pancreatic duct epithelial cells in ablation zone were also positive in terminal deoxynucleotidyl transferase dUTP nick end labeling staining. There was extensive duodenum mucosa damage with local hemorrhage 24 h after ablation, while regeneration of new villous structures were observed at 7 and 28 d post-IRE. Masson’s trichromatic staining showed that the extracellular matrix was still intact in vessels and pancreatic ducts, and even in the duodenum.CONCLUSIONIRE ablation to the pancreatic head may be safe and feasible without long-term damage to the surrounding vital structures. However, risks of stress injuries in acute phase should be taken into consideration to prevent severe perioperative complications.

Bio-inspired natural platelet hydrogels for wound healing

Wound healing has invariably been a fundamental health concern, demanding manpower and materials and causing financial burdens. In this research, inspired by the hemostatic function of platelets, we proposed a novel bionic hydrogel by covalent amidation crosslinking natural platelet and alginate for wound healing. With the natural functional groups, the platelet-derived hydrogel exhibited outstanding biocompatibility and blood compatibility. By changing the addition ratio of platelets to alginates, the mechanical properties of the achieved hydrogel were variable to cater to different wound environments. Furthermore, silver nanoparticles could be loaded into the void space of the hydrogel which endowed the composites with superior anti-infective properties. We have demonstrated that the bio-inspired platelet hydrogel could promote hemostasis of acute tissue damage, prevent bacterial proliferation, and promote angiogenesis, collagen deposition, and granulation tissue formation in wound healing. These features signify the potential values of the bio-inspired platelet hydrogel in clinical applications.

Discovery of novel biphenyl-substituted pyridone derivatives as potent non-nucleoside reverse transcriptase inhibitors with promising oral bioavailability

Adding to past success in developing non-nucleoside reverse transcriptase inhibitors (NNRTIs), we report herein our efforts to optimize an FDA-approved NNRTI, doravirine, into a series of novel biphenyl-substituted pyridone derivatives. A strategy focused on harnessing the X-ray crystal structure of doravirine, coupled with computer simulations, to guide the design of conformationally constrained analogs led to the discovery of ZLM-66, which provided comparable inhibitory potency to doravirine against wild-type HIV-1 (EC50 = 13 nM) and various single/double mutant strains. ZLM-66 possessed acceptable cytotoxicity and selectivity index. In vivo profiling indicated that ZLM-66 exhibited excellent pharmacokinetics with significantly improved oral bioavailability (F = 140.24%) and a more favorable half-life (T1/2 = 8.45 h), compared to that of doravirine (F = 57%, T1/2 = 4.4 h). In addition, ZLM-66 did not cause significant inhibition of CYP and hERG (>200 μM), as well as acute toxicity and tissue damage at a dose of 1.2 g/kg. Therefore, ZLM-66 can be used as a lead compound to further guide the development of orally active biphenyl-containing doravirine analogs for HIV therapy.

Cellular senescence

Cellular senescence defines a state of stable and generally irreversible proliferative arrest associated with various morphological, structural and functional changes (Figure 1), including enhanced expression and secretion of pro-inflammatory and tissue-remodelling mediators. This state is crucial in tissue physiology and pathology and arises as a response to potentially damaging stress signals. Whether the activation of a senescence state provides benefits or detriments for tissue function and homeostasis is strictly dependent on the context. Cell senescence acts as a potent tumour-suppressive mechanism limiting the proliferation of cells at risk of malignant transformation and supports the repair of acute tissue damage, but also represents a key driver of ageing and age-related diseases.

Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung carcinogenesis.

Our earlier work demonstrated varying potency of dihydromethysticin (DHM) as the active kava phytochemical for prophylaxis of tobacco carcinogen nicotine-derived nitrosamine ketone (NNK)-induced mouse lung carcinogenesis. Efficacy was dependent on timing of DHM gavage ahead of NNK insult. In addition to DNA adducts in the lung tissues mitigated by DHM in a time-dependent manner, our in vivo data strongly implicated the existence of DNA damage-independent mechanism(s) in NNK-induced lung carcinogenesis targeted by DHM to fully exert its anti-initiation efficacy. In the present work, RNA seq transcriptomic profiling of NNK-exposed (2 h) lung tissues with/without a DHM (8 h) pretreatment revealed a snap shot of canonical acute phase tissue damage and stress response signaling pathways as well as an activation of protein kinase A (PKA) pathway induced by NNK and the restraining effects of DHM. The activation of the PKA pathway by NNK active metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) at a concentration incapable of promoting DNA adduct was confirmed in a lung cancer cell culture model, potentially through NNAL binding to and activation of the β-adrenergic receptor. Our in vitro and in vivo data overall support the hypothesis that DHM suppresses PKA activation as a key DNA damage-independent mechanistic lead, contributing to its effective prophylaxis of NNK-induced lung carcinogenesis. Systems biology approaches with a detailed temporal dissection of timing of DHM intake versus NNK exposure are warranted to fill the knowledge gaps concerning the DNA damage-driven mechanisms and DNA damage-independent mechanisms to optimize the implementation strategy for DHM to achieve maximal lung cancer chemoprevention.

Immune translational control by CPEB4 regulates intestinal inflammation resolution and colorectal cancer development

SummaryUpon tissue injury, cytokine expression reprogramming transiently remodels the inflammatory immune microenvironment to activate repair processes and subsequently return to homeostasis. However, chronic inflammation induces permanent changes in cytokine production which exacerbate tissue damage and may even favor tumor development. Here, we address the contribution of post-transcriptional regulation, by the RNA-binding protein CPEB4, to intestinal immune homeostasis and its role in inflammatory bowel diseases (IBD) and colorectal cancer (CRC) development. We found that intestinal damage induces CPEB4 expression in adaptive and innate immune cells, which is required for the translation of cytokine mRNA(s) such as the one encoding interleukin-22. Accordingly, CPEB4 is required for the development of gut-associated lymphoid tissues and to maintain intestinal immune homeostasis, mediating repair and remodeling after acute inflammatory tissue damage and promoting the resolution of intestinal inflammation. CPEB4 is chronically overexpressed in inflammatory cells in patients with IBD and in CRC, favoring tumor development.

A Pneumatic-Based Mechanism for Inserting a Flexible Microprobe Into the Brain

Abstract Insertion of flexible microprobes into the brain requires withstanding the compressive penetration force by the microprobes. To aid the insertion of the microprobes, most of the existing approaches use pushing mechanisms to provide temporary stiffness increase for the microprobes to prevent buckling during insertion into the brain. However, increasing the microprobe stiffness may result in acute neural tissue damage during insertion. Moreover, any late or premature removal of the temporary stiffness after insertion may lead to further tissue damage due to brain micromotion or inaccuracy in the microprobe positioning. In this study, a novel pneumatic-based insertion mechanism is proposed which simultaneously pulls and pushes a flexible microprobe toward the brain. As part of the brain penetration force in the proposed mechanism is supplied by the tensile force, the applied compressive force, which the microprobe must withstand during insertion, is lower compared with the existing approaches. Therefore, the microprobes with a critical buckling force less than the brain penetration force can be inserted into the brain without buckling. Since there is no need for temporary stiffness increment, neural tissue damage during the microprobe insertion will be much lower compared with the existing insertion approaches. The pneumatic-based insertion mechanism is modeled analytically to investigate the effects of the microprobe configuration and the applied air pressure on the applied tensile and compressive forces to the microprobe. Next, finite element modeling is conducted, and its analysis results not only validate the analytical results but also confirm the efficiency of the mechanism.

Peripheral serotonin lacks effects on endothelial adhesion molecule expression in acute inflammation

BackgroundPeripheral, non‐neuronal serotonin promotes the recruitment of neutrophils to sites of acute inflammation and tissue damage. Direct effects of serotonin on neutrophil function were shown to be involved. However, the influence of serotonin on the endothelial counterpart is unknown. ObjectivesTo investigate whether serotonin alters the function of endothelial cells in leukocyte recruitment during acute inflammation. MethodsWe used two murine models of acute inflammation: intraperitoneal lipopolysaccharide (LPS) injection and mesenteric ischemia/reperfusion injury (I/R). To study effects of peripheral serotonin, leukocyte recruitment and endothelial adhesion molecule expression were compared in wild type (WT) and tryptophan hydroxylase 1 deficient (Tph1−/−) mice, which are unable to synthesize peripheral serotonin. ResultsAs expected, neutrophil transmigration into the peritoneal cavity following LPS injection was impaired in Tph1−/− mice. Abdominal blood vessels, however, showed no difference in adhesion molecule expression. In the early reperfusion phase after mesenteric I/R, the number of rolling leukocytes was significantly lower in Tph1−/− compared to WT. In line with the LPS model, endothelial adhesion molecule expression was independent of serotonin. In vitro experiments using human umbilical vein endothelial cells (HUVECs) confirmed that serotonin does not affect endothelial adhesion molecules. ConclusionsThe inflammatory release of peripheral serotonin is dispensable for the regulation of endothelial adhesion molecules.