Recombinant probiotic Lactococcus lactis delivering P62 mitigates moderate colitis in mice.

Introduction and objective: p62 is a human multifunctional adaptor protein involved in key cellular processes such as tissue homeostasis, inflammation, and cancer. It acts as a negative regulator of inflammasome complexes. It may thus be considered a good candidate for therapeutic use in inflammatory bowel diseases (IBD), such as colitis. Probiotics, including recombinant probiotic strains producing or delivering therapeutic biomolecules to the host mucosal surfaces, could help prevent and mitigate chronic intestinal inflammation. The objective of the present study was to combine the intrinsic immunomodulatory properties of the probiotic Lactococcus lactis NCDO2118 with its ability to deliver health-promoting molecules to enhance its protective and preventive effects in the context of ulcerative colitis (UC). Material and methods: This study was realized in vivo in which mice were supplemented with the recombinant strain. The intestinal barrier function was analyzed by monitoring permeability, secretory IgA total levels, mucin expression, and tight junction genes. Its integrity was evaluated by histological analyses. Regarding inflammation, colonic cytokine levels, myeloperoxidase (MPO), and expression of key genes were monitored. The intestinal microbiota composition was investigated using 16S rRNA Gene Sequencing. Results and discussion: No protective effect of L. lactis NCDO2118 pExu:p62 was observed regarding mice clinical parameters compared to the L. lactis NCDO2118 pExu: empty. However, the recombinant strain, expressing p62, increased the goblet cell counts, upregulated Muc2 gene expression in the colon, and downregulated pro-inflammatory cytokines Tnf and Ifng when compared to L. lactis NCDO2118 pExu: empty and inflamed groups. This recombinant strain also decreased colonic MPO activity. No difference in the intestinal microbiota was observed between all treatments. Altogether, our results show that recombinant L. lactis NCDO2118 delivering p62 protein protected the intestinal mucosa and mitigated inflammatory damages caused by dextran sodium sulfate (DSS). We thus suggest that p62 may constitute part of a therapeutic approach targeting inflammation.

Evaluation of the Treatment with Akkermansia muciniphila BAA-835 of Chemotherapy-induced Mucositis in Mice.

Mucositis is a high-incidence side effect in cancer patients undergoing chemotherapy. Next-generation probiotics are emerging as new therapeutic tools for managing various disorders. Studies have demonstrated the potential of Akkermansia muciniphila to increase the efficiency of anticancer treatment and to mitigate mucositis. Due to the beneficial effect of A. muciniphila on the host, we evaluated the dose-response, the microorganism viability, and the treatment protocol of A. muciniphila BAA-835 in a murine model of chemotherapy-induced mucositis. Female Balb/c mice were divided into groups that received either sterile 0.9% saline or A. muciniphila by gavage. Mucositis was induced using a single intraperitoneal injection of 5-fluorouracil. The animals were euthanized three days after the induction of mucositis, and tissue and blood were collected for analysis. Prevention of weight loss and small intestine shortening and reduction of neutrophil and eosinophil influx were observed when animals were pretreated with viable A. muciniphila at 1010 colony-forming units per mL (CFU/mL). The A. muciniphila improved mucosal damage by preserving tissue architecture and increasing villus height and goblet cell number. It also improved the integrity of the epithelial barrier, decreasing intestinal permeability and bacterial translocation. In addition, the treatment prevented the expansion of Enterobacteriaceae. The immunological parameters were also improved by decreasing the expression of pro-inflammatory cytokines (IL6, IL1ß, and TNF) and increasing IL10. In conclusion, pretreatment with 1010 CFU/mL of viable A. muciniphila effectively controlled inflammation, protected the intestinal mucosa and the epithelial barrier, and prevented Enterobacteriaceae expansion in treated mice.

A Next-Generation Bacteria (Akkermansia muciniphila BAA-835) Presents Probiotic Potential Against Ovalbumin-Induced Food Allergy in Mice.

Next-generation microorganisms have recently gained prominence in the scientific community, mainly due to their probiotic and postbiotic potentials. However, there are few studies that investigate these potentials in food allergy models. Therefore, the present study was designed to evaluate the probiotic potential of Akkermansia muciniphila BAA-835 in an ovalbumin food allergy (OVA) model and also analyse possible postbiotic potential. To access the probiotic potential, clinical, immunological, microbiological, and histological parameters were evaluated. In addition, the postbiotic potential was also evaluated by immunological parameters. Treatment with viable A. muciniphila was able to mitigate weight loss and serum levels of IgE and IgG1 anti-OVA in allergic mice. In addition, the ability of the bacteria to reduce the injury of the proximal jejunum, the eosinophil and neutrophil influx, and the levels of eotaxin-1, CXCL1/KC, IL4, IL6, IL9, IL13, IL17, and TNF, was clear. Furthermore, A. muciniphila was able to attenuate dysbiotic signs of food allergy by mitigating Staphylococcus levels and yeast frequency in the gut microbiota. In addition, the administration of the inactivated bacteria attenuated the levels of IgE anti-OVA and eosinophils, indicating its postbiotic effect. Our data demonstrate for the first time that the oral administration of viable and inactivated A. muciniphila BAA-835 promotes a systemic immunomodulatory protective effect in an in vivo model of food allergy to ovalbumin, which suggests its probiotic and postbiotic properties.

Long-term outcomes for females with early-onset dystrophinopathy.

AIM: To study long-term disease course for females with early-onset dystrophinopathy, including common (female) symptoms, challenges in social participation, the need for care, and current healthcare management to support guideline development. METHOD: Twelve females with early-onset dystrophinopathy were followed for a median period of more than 17 years (range 1-36). RESULTS: One patient died owing to end-stage cardiac failure. Cardiac abnormalities were observed in three of the remaining 11 participants. Respiratory function was reduced in seven of 10 participants. Fatigue, myalgia, lower back pain, and arthralgia were reported in more than six of the participants. Functional status varied from exercise intolerance to wheelchair dependency. Most or all of the 10 participants reported restrictions in participation in work (n = 10), household duties (n = 10), sports (n = 9), and education (n = 8). Only a few participants received followed-up pulmonary (n = 2) or rehabilitation (n = 3) care. INTERPRETATION: Females with early-onset dystrophinopathy experience a wide range of impairments, comorbidities, limitations in activities, and restrictions in social participation. The whole spectrum should be acknowledged in the healthcare setting. Neuromuscular and cardiac follow-up are indispensable. Additional respiratory assessment and rehabilitation care are expected to improve health status and support daily activities and participation. WHAT THIS PAPER ADDS: No standard diagnostic procedures seem to exist for female patients suspected for dystrophinopathy. Female participants with early-onset dystrophinopathy experienced a broad scope of burdening symptoms, such as fatigue, myalgia, lower back pain, and arthralgia. None of participants worked full time, all felt restricted in paid work, and most felt restricted in education. Most participants showed decreased lung function, while only one was symptomatic. Availability of rehabilitation care may improve support for daily activities and participation for females with early-onset dystrophinopathy.

Evaluation of a Functional Craft Wheat Beer Fermented with Saccharomyces cerevisiae UFMG A-905 to treat Salmonella Typhimurium infection in mice.

Functional foods containing probiotics are generally administered as dairy products. Non-dairy beverages are another possibility, but probiotic functionality must be confirmed in such vehicles. In the present study, a craft wheat beer brewed with the probiotic yeast Saccharomyces cerevisiae UFMG A-905 (905) was evaluated in a murine model of Salmonella Typhimurium infection. Unfiltered or filtered beer brewed with 905, a commercial wheat beer used as a negative control, or saline were administered orally to mice before and during oral S. Typhimurium challenge. High fecal levels of yeast were only counted in mice treated with the unfiltered 905 beer, which also had reduced mortality and body weight loss due to S. Typhimurium infection. Increased levels of intestinal IgA, translocation to liver and spleen, liver and intestinal lesions, pro-inflammatory cytokines in liver and ileum, and hepatic and intestinal myeloperoxidase and eosinophilic peroxidase activities were observed in animals infected with S. Typhimurium. All these parameters were reduced by the treatment with unfiltered 905 beer. In conclusion, the results show that a craft wheat beer brewed with S. cerevisiae UFMG A-905 maintained the probiotic properties of this yeast when administered orally to mice challenged with S. Typhimurium.

Chronic Kidney Disease After Liver Transplantation.

Improved survival after liver transplantation has led to an aging cohort of recipients at risk of renal dysfunction. The etiology of renal dysfunction is typically multifactorial; calcineurin inhibitors nephrotoxicity, pretransplant renal dysfunction, and perioperative acute kidney injury are important risk factors. Metabolic complications such as hypertension, diabetes mellitus, and metabolic-associated fatty liver disease also contribute to the development of renal disease. Most LT recipients will eventually develop some degree of renal dysfunction. Criteria to select candidates for simultaneous liver and kidney transplantation have been established. Both delayed introduction of CNIs and renal-sparing immunosuppressive regimens may reduce progression of renal dysfunction.

Epigenetic Mechanisms Mediate Nicotine-Induced Reward and Behaviour in Zebrafish.

Nicotine induces long-term changes in the neural activity of the mesocorticolimbic reward pathway structures. The mechanisms involved in this process have not been fully characterized. The hypothesis discussed here proposed that epigenetic regulation participates in the installation of persistent adaptations and long-lasting synaptic plasticity generated by nicotine action on the mesolimbic dopamine neurons of zebrafish. The epigenetic mechanisms induced by nicotine entail histone and DNA chemical modifications, which have been described to lead to changes in gene expression. Among the enzymes that catalyze epigenetic chemical modifications, histone deacetylases (HDACs) remove acetyl groups from histones, thereby facilitating DNA relaxation and making DNA more accessible to gene transcription. DNA methylation, which is dependent on DNA methyltransferase (DNMTs) activity, inhibits gene expression by recruiting several methyl binding proteins that prevent RNA polymerase binding to DNA. In zebrafish, phenylbutyrate (PhB), an HDAC inhibitor, abolishes nicotine rewarding properties together with a series of typical reward-associated behaviors. Furthermore, PhB and nicotine alter long- and short-term object recognition memory in zebrafish, respectively. Regarding DNA methylation effects, a methyl group donor L-methionine (L-met) was found to dramatically reduce nicotine-induced conditioned place preference (CPP) in zebrafish. Simultaneous treatment with DNMT inhibitor 5-aza-2'-deoxycytidine (AZA) was found to reverse the L-met effect on nicotine-induced CPP as well as nicotine reward-specific effects on genetic expression in zebrafish. Therefore, pharmacological interventions that modulate epigenetic regulation of gene expression should be considered as a potential therapeutic method to treat nicotine addiction.

Patient selection for heart transplant: balancing risk.

PURPOSE OF REVIEW: Heart failure incidence continues to rise despite a relatively static number of available donor hearts. Selecting an appropriate heart transplant candidate requires evaluation of numerous factors to balance patient benefit while maximizing the utility of scarce donor hearts. Recent research has provided new insights into refining recipient risk assessment, providing additional tools to further define and balance risk when considering heart transplantation. RECENT FINDINGS: Recent publications have developed models to assist in risk stratifying potential heart transplant recipients based on cardiac and noncardiac factors. These studies provide additional tools to assist clinicians in balancing individual risk and benefit of heart transplantation in the context of a limited donor organ supply. SUMMARY: The primary goal of heart transplantation is to improve survival and maximize quality of life. To meet this goal, a careful assessment of patient-specific risks is essential. The optimal approach to patient selection relies on integrating recent prognostication models with a multifactorial assessment of established clinical characteristics, comorbidities and psychosocial factors.

Bifidobacterium longum subsp. longum 51A attenuates intestinal injury against irinotecan-induced mucositis in mice.

Intestinal mucositis (IM) is a critical side-effect associated with antineoplastic therapy. Treatment available is only palliative and often not effective. However, alternative therapeutic strategies, such as probiotics, have attracted significant attention due to their immune-modulatory action in several diseases. Thus, the present study aims to elucidate the therapeutic potential of the probiotic strain Bifidobacterium longum 51A in a murine model of mucositis induced by irinotecan. Due to the scarcity of studies on dose-response and viability (probiotic vs paraprobiotic), we first evaluated which dose and cell viability would be most effective in treating mucositis. In this study, the oral pretreatment with viable B. longum 51A at a concentration of 1 × 109 CFU/mL reduced the daily disease activity index (p < 0.01), protected the intestinal architecture, preserved the length of the intestine (p < 0.05), and reduced intestinal permeability (p < 0.01), inflammation, and oxidative damage (p < 0.01) induced by irinotecan. Also, treatment with B. longum 51A increased the production of secretory immunoglobulin A (p < 0.05) in the intestinal fluid of mice with mucositis. Furthermore, B. longum 51A reversed the mucositis-induced increase in Enterobacteriaceae bacterial group in the gut (p < 0.01). In conclusion, these results showed that oral administration of B. longum 51A protects mice against intestinal damage caused by irinotecan, suggesting its use as a potential probiotic in therapy during mucositis.

NPY Released From GABA Neurons of the Dentate Gyrus Specially Reduces Contextual Fear Without Affecting Cued or Trace Fear.

Disproportionate, maladapted, and generalized fear are essential hallmarks of posttraumatic stress disorder (PTSD), which develops upon severe trauma in a subset of exposed individuals. Among the brain areas that are processing fear memories, the hippocampal formation exerts a central role linking emotional-affective with cognitive aspects. In the hippocampus, neuronal excitability is constrained by multiple GABAergic interneurons with highly specialized functions and an extensive repertoire of co-released neuromodulators. Neuropeptide Y (NPY) is one of these co-transmitters that significantly affects hippocampal signaling, with ample evidence supporting its fundamental role in emotional, cognitive, and metabolic circuitries. Here we investigated the role of NPY in relation to GABA, both released from the same interneurons of the dorsal dentate gyrus (DG), in different aspects of fear conditioning. We demonstrated that activation of dentate GABA neurons specifically during fear recall reduced cue-related as well as trace-related freezing behavior, whereas inhibition of the same neurons had no significant effects. Interestingly, concomitant overexpression of NPY in these neurons did not further modify fear recall, neither under baseline conditions nor upon chemogenetic stimulation. However, potentially increased co-release of NPY substantially reduced contextual fear, promoted extinction learning, and long-term suppression of fear in a foreground context-conditioning paradigm. Importantly, NPY in the dorsal DG was not only expressed in somatostatin neurons, but also in parvalbumin-positive basket cells and axoaxonic cells, indicating intense feedback and feedforward modulation of hippocampal signaling and precise curtailing of neuronal engrams. Thus, these findings suggest that co-release of NPY from specific interneuron populations of the dorsal DG modifies dedicated aspects of hippocampal processing by sharpening the activation of neural engrams and the consecutive fear response. Since inappropriate and generalized fear is the major impediment in the treatment of PTSD patients, the dentate NPY system may be a suitable access point to ameliorate PTSD symptoms and improve the inherent disease course.

On the objectivity, reliability, and validity of deep learning enabled bioimage analyses.

Bioimage analysis of fluorescent labels is widely used in the life sciences. Recent advances in deep learning (DL) allow automating time-consuming manual image analysis processes based on annotated training data. However, manual annotation of fluorescent features with a low signal-to-noise ratio is somewhat subjective. Training DL models on subjective annotations may be instable or yield biased models. In turn, these models may be unable to reliably detect biological effects. An analysis pipeline integrating data annotation, ground truth estimation, and model training can mitigate this risk. To evaluate this integrated process, we compared different DL-based analysis approaches. With data from two model organisms (mice, zebrafish) and five laboratories, we show that ground truth estimation from multiple human annotators helps to establish objectivity in fluorescent feature annotations. Furthermore, ensembles of multiple models trained on the estimated ground truth establish reliability and validity. Our research provides guidelines for reproducible DL-based bioimage analyses.

Research in biology generates many image datasets, mostly from microscopy. These images have to be analyzed, and much of this analysis relies on a human expert looking at the images and manually annotating features. Image datasets are often large, and human annotation can be subjective, so automating image analysis is highly desirable. This is where machine learning algorithms, such as deep learning, have proven to be useful. In order for deep learning algorithms to work first they have to be 'trained'. Deep learning algorithms are trained by being given a training dataset that has been annotated by human experts. The algorithms extract the relevant features to look out for from this training dataset and can then look for these features in other image data. However, it is also worth noting that because these models try to mimic the annotation behavior presented to them during training as well as possible, they can sometimes also mimic an expert's subjectivity when annotating data. Segebarth, Griebel et al. asked whether this was the case, whether it had an impact on the outcome of the image data analysis, and whether it was possible to avoid this problem when using deep learning for imaging dataset analysis. For this research, Segebarth, Griebel et al. used microscopy images of mouse brain sections, where a protein called cFOS had been labeled with a fluorescent tag. This protein typically controls the rate at which DNA information is copied into RNA, leading to the production of proteins. Its activity can be influenced experimentally by testing the behaviors of mice. Thus, this experimental manipulation can be used to evaluate the results of deep learning-based image analyses. First, the fluorescent images were interpreted manually by a group of human experts. Then, their results were used to train a large variety of deep learning models. Models were trained either on the results of an individual expert or on the results pooled from all experts to come up with a consensus model, a deep learning model that learned from the personal annotation preferences of all experts. This made it possible to test whether training a model on multiple experts reduces the risk of subjectivity. As the training of deep learning models is random, Segebarth, Griebel et al. also tested whether combining the predictions from multiple models in a so-called model ensemble improves the consistency of the analyses. For evaluation, the annotations of the deep learning models were compared to those of the human experts, to ensure that the results were not influenced by the subjective behavior of one person. The results of all bioimage annotations were finally compared to the experimental results from analyzing the mice's behaviors in order to check whether the models were able to find the behavioral effect on cFOS. Segebarth, Griebel et al. concluded that combining the expert knowledge of multiple experts reduces the subjectivity of bioimage annotation by deep learning algorithms. Combining such consensus information in a group of deep learning models improves the quality of bioimage analysis, so that the results are reliable, transparent and less subjective.

Liberação miofascial no ganho de potência muscular do quadríceps: um estudo controlado e randomizado / Myfascial release in quadriceps muscle power gain: a controlled and randomized study

A prescrição de exercícios para o ganho de força e potência muscular é utilizado com o objetivo de ajudar na reabilitação de lesões musculares e para o aprimoramento físico nas práticas esportivas. Dentre as técnicas que são apontadas como possíveis condutas que poderiam auxiliar no fortalecimento muscular e potência destaca-se a Liberação Miofascial. Deste m o do, o estudo buscou analisar e comparar um programa de treinamento para ganho de potência muscular com fortalecimento muscular resistido isolado e os resultados de sua combinação com a Liberação Miofascial. Trata-se de um estudo quantitativo, transversal, analítico, de caráter experimental, comparativo, controlado e randomizado. A amostra foi composta por 11 mulheres com idade de 18 a 40 anos subdivididas em dois grupos de intervenção. As intervenções ocorerram 3 vezes por semana durante 4 semanas. Os membros do Grupo controle realizaram apenas o fortalecimento muscular com exercício de agachamento a partir de 0 º de flexão de joelhos até o limite de 90º de flexão e retornando ao grau 0. As voluntárias do Grupo Liberação Miofascial associado ao treino de força inicialmente foram submetidas a intervenções de Liberação Miofascial dos músculos quadríceps bilateralmente e posteriormente ao treino de fortalecimento muscular descrito no grupo controle. Foram avaliadas as variáveis distância do salto vertical e carga suportada em 1 Repetição Máxima. A estatística inferencial utilizada foi através do t este T de Student emparelhado para verificar a diferença entre as médias do antes e depois dos tratamentos em cada grupo. Para verificar as diferenças em relação às técnicas utilizadas em grupos diferentes foi realizado o teste T de Student não compartilhado. Os resultados demonstraram não haver diferença estatisticamente significante entre os grupos no que se refere a carga máxima suportada em 1 Repetição Máxima (p=0,484), mesmo sendo essa diferença numericamente de 3,31kg a mais de ganho para o Grupo que utilizou a Liberação Miofascial associada ao treino de força, e não foi encontrada diferença significativa (p=0,068) entre a distância de salto vertical nos grupos, apesar desta distânicia ser 4,35 cm maior também no grupo Liberação Miofascial associada ao treino de força. Foi possível demonstrar, desta form a, que a liberação miofascial não otimiza o ganho da potencia muscular associado ao exercício resistido . Desta forma, através dos resultados deste estudo, não é possível recomendar a utilização da LM como um recurso para ser utilizado pré treino com objetivo de ganho de potência muscular...(AU)

The prescription of exercises to gain muscle strength and power is used to help in the rehabilitation of muscle injuries and for physical improvement in sport practices. Among the techniques that are pointed as possible ways that could help in muscle strengthening and power, Myofascial Release stands out. Thus, the study sought to analyze and compare a training program for muscle power gain with isolated resistance muscle strengthening and the results of its combination with myofascial release. It is a quantitative, cross-sectional, analytical, experimental, comparative, controlled and randomized study. Our sample consisted of 11 women aged 18 to 40 years old, subdivided into two interventio n gro ups. Th e interventions occurred 3 times a week for 4 weeks. Control Group members only perform muscle strengthening with squats from 0º of knee flexion up to the limit of 90º of flexion and return of grade 0. As volunteers of the Myofascial Release Group associated with strength training, t hey were subm it ted t o Myofascial Release of the quadriceps muscles bilaterally and after the muscle st rengt hening t raining described in the control group. The variables vertical jump distance and load supported in 1 Maximum Repetition were evaluated. The inferential statistics used was through the paired Student's T test to verify the difference between the means of before and after treatments in each group. To verify the differences in relation to the techniques used in different groups, the Student's t-test was not shared. T here was n o statistically significant difference between the groups regarding the maximum load supported in 1 Maximum Repeat (p=0.484), even though this difference was numerically 3 .3 1kg m o re gain fo r t he Myofascial Release Group.No significant difference (p=0.068) was found either between t he v ertical jump distance, which was 4.35 cm higher ­ also in the Myofascial Release group. Thus, it was demonstrated that myofascial release does not optimize the gain in muscle power associat ed with resistance exercises. Thus, through the results of this study, it is not possible to recommend the use of SCI as a resource to be used pre-training in order to gain muscle power...(AU)

CRISPLD1: a novel conserved target in the transition to human heart failure.

Heart failure is a major health problem worldwide with a significant morbidity and mortality rate. Although studied extensively in animal models, data from patients at the compensated disease stage are lacking. We sampled myocardium biopsies from aortic stenosis patients with compensated hypertrophy and moderate heart failure and used transcriptomics to study the transition to failure. Sequencing and comparative analysis of analogous samples of mice with transverse aortic constriction identified 25 candidate genes with similar regulation in response to pressure overload, reflecting highly conserved molecular processes. The gene cysteine-rich secretory protein LCCL domain containing 1 (CRISPLD1) is upregulated in the transition to failure in human and mouse and its function is unknown. Homology to ion channel regulatory toxins suggests a role in Ca2+ cycling. CRISPR/Cas9-mediated loss-of-function leads to dysregulated Ca2+ handling in human-induced pluripotent stem cell-derived cardiomyocytes. The downregulation of prohypertrophic, proapoptotic and Ca2+-signaling pathways upon CRISPLD1-KO and its upregulation in the transition to failure implicates a contribution to adverse remodeling. These findings provide new pathophysiological data on Ca2+ regulation in the transition to failure and novel candidate genes with promising potential for therapeutic interventions.

P2X7 and A2A receptor endogenous activation protects against neuronal death caused by CoCl2 -induced photoreceptor toxicity in the zebrafish retina.

Injured retinas in mammals do not regenerate and heal with loss of function. The adult retina of zebrafish self-repairs after damage by activating cell-intrinsic mechanisms, which are regulated by extrinsic signal interactions. Among relevant regulatory extrinsic systems, purinergic signaling regulates progenitor proliferation during retinogenesis and regeneration and glia proliferation in proliferative retinopathies. ATP-activated P2X7 (P2RX7) and adenosine (P1R) receptors are involved in the progression of almost all retinopathies leading to blindness. Here, we examined P2RX7 and P1R participation in the retina regenerative response induced by photoreceptor damage caused by a specific dose of CoCl2 . First, we found that treatment of uninjured retinas with a potent agonist of P2RX7 (BzATP) provoked photoreceptor damage and mitotic activation of multipotent progenitors. In CoCl2 -injured retinas, blockade of endogenous extracellular ATP activity on P2RX7 caused further neurodegeneration, Müller cell gliosis, progenitor proliferation, and microglia reactivity. P2RX7 inhibition in injured retinas also increased the expression of lin28a and tnfα genes, which are related to multipotent progenitor proliferation. Levels of hif1α, vegf3r, and vegfaa mRNA were enhanced by blockade of P2RX7 immediately after injury, indicating hypoxic like damage and endothelial cell growth and proliferation. Complete depletion of extracellular nucleotides with an apyrase treatment strongly potentiated cell death and progenitor proliferation induced with CoCl2 . Blockade of adenosine P1 and A2A receptors (A2A R) had deleterious effects and deregulated normal timing for progenitor and precursor cell proliferation following photoreceptor damage. ATP via P2RX7 and adenosine via A2A R are survival extracellular signals key for retina regeneration in zebrafish.

Surgical resection for diverticulitis using robotic natural orifice intracorporeal anastomosis and transrectal extraction approach: the NICE procedure.

Numerous studies have confirmed significant benefits of intracorporeal anastomosis (ICA) following colorectal procedures; however technical challenges have limited this approach following conventional laparoscopic surgery. The robotic Xi platform serves as an enabling technology and has resulted in a surge of reports for right-sided ICA, however, there are no reports involving more complex left-sided procedures such as diverticulitis. Furthermore, there are no reports of natural orifice-assisted techniques using robotic Xi in which the specimen can be removed and the anvil can be placed transrectally, thereby completely eliminating the need for an abdominal wall incision other than for port sites. We present a pilot study to investigate the safety, feasibility and short-term outcomes of robotic Natural orifice-assisted IntraCorporeal anastomosis with transrectal Extraction of specimen, called the robotic NICE procedure. Consecutive patients presenting for elective resection for diverticulitis with formation of a colorectal anastomosis were entered into an IRB database. All patients underwent the robotic NICE procedure. Demographic data, intraoperative data and outcomes data were assessed and analyzed. Ten patients (five males and five females) underwent resection. The mean age and BMI were 56 years (43-66) and 29 kg/m2 (21-35). All procedures were successfully completed including transrectal extraction of the specimen and formation of an ICA. The mean operative time was 198 min (146-338) and mean EBL was 35 ml (15-50). Mean time to first flatus was 16 h (10-22) and mean length of stay was 1.9 days (1.6-2.6). There were no intraoperative or postoperative complications. There was no unexpected ICU stay, reoperation or readmission. Colorectal left-sided resections such as for diverticulitis were safely accomplished using natural orifice-assisted extraction of the specimen as well as complete intracorporeal anastomosis in this pilot study. The NICE procedure resulted in early return of bowel function, short length of stay and low complication. The complete elimination of abdominal wall incision likely accounts for these findings and larger cohorts of patients are to be investigated to explore this promising approach afforded by robotic technology.

Organ-specific small non-coding RNA responses in domestic (Sudani) ducks experimentally infected with highly pathogenic avian influenza virus (H5N1).

The duck represents an important reservoir of influenza viruses for transmission to other avian and mammalian hosts, including humans. The increased pathogenicity of the recently emerging clades of highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype in ducks features systemic viral spread and organ-to-organ variation in viral transcription and tissue damage. We previously reported that experimental infection of Sudani ducks (Cairina moschata) with an Egyptian HPAI (H5N1) virus (clade 2.2.1.2) features high viral replication and severe tissue damage in lung, but lower viral replication and only mild histological changes in brain. Little is known about the involvement of miRNA in organ-specific responses to H5N1 viruses in ducks, and involvement of the other classes of small noncoding RNA (sncRNA) has not been investigated so far. Following RNA sequencing, we have annotated the duck sncRNome and compared global expression changes of the four major sncRNA classes (miRNAs, piRNAs, snoRNAs, snRNAs) between duck lung and brain during a 120 h time course of infection with this HPAI strain. We find major organ-specific differences in miRNA, piRNA and snoRNA populations even before infection and substantial reprogramming of all sncRNA classes throughout infection, which was less pronounced in brain. Pathway prediction analysis of miRNA targets revealed enrichment of inflammation-, infection- and apoptosis-related pathways in lung, but enrichment of metabolism-related pathways (including tryptophan metabolism) in brain. Thus, organ-specific differences in sncRNA responses may contribute to differences in viral replication and organ damage in ducks infected with isolates from this emerging HPAI clade, and likely other strains.

Severe transient neonatal long QT syndrome due to maternal paroxetine usage: a case report.

A female neonate with in utero selective serotonin reuptake inhibitor exposure presented with bradycardia shortly after birth. Electrocardiography showed severe QT prolongation and second-degree atrioventricular block. Over time QT-times spontaneously normalised and genetic testing did not show mutations associated with long QT syndrome making maternal selective serotonin reuptake inhibitor usage the most likely explanation for the observed severe transient neonatal QT prolongation.

Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y.

Survival in a natural environment forces an individual into constantly adapting purposive behavior. Specified interoceptive neurons monitor metabolic and physiological balance and activate dedicated brain circuits to satisfy essential needs, such as hunger, thirst, thermoregulation, fear, or anxiety. Neuropeptides are multifaceted, central components within such life-sustaining programs. For instance, nutritional depletion results in a drop in glucose levels, release of hormones, and activation of hypothalamic and brainstem neurons. These neurons, in turn, release several neuropeptides that increase food-seeking behavior and promote food intake. Similarly, internal and external threats activate neuronal pathways of avoidance and defensive behavior. Interestingly, specific nuclei of the hypothalamus and extended amygdala are activated by both hunger and fear. Here, we introduce the relevant neuropeptides and describe their function in feeding and emotional-affective behaviors. We further highlight specific pathways and microcircuits, where neuropeptides may interact to identify prevailing homeostatic needs and direct respective compensatory behaviors. A specific focus will be on neuropeptide Y, since it is known for its pivotal role in metabolic and emotional pathways. We hypothesize that the orexigenic and anorexigenic properties of specific neuropeptides are related to their ability to inhibit fear and anxiety.

Robotic left-sided colorectal resection with natural orifice IntraCorporeal anastomosis with extraction of specimen: The NICE procedure. A pilot study of consecutive cases.

BACKGROUND: Despite numerous benefits, only a small fraction of laparoscopic left-sided colectomy is accomplished without the need for an abdominal incision to retrieve the specimen and prepare for anastomosis. We report our early experience with a robotic approach using Natural orifice IntraCorporeal anastomosis with Extraction of specimen (NICE) to help overcome the technical limitations and challenges of this approach. METHODS: Twenty consecutive patients presented for elective sigmoid or rectosigmoid resection for benign and malignant disease and underwent the NICE procedure. Safety, feasibility and post-operative outcomes were analyzed. RESULTS: Intracorporeal anastomosis was accomplished in all patients. One patient required an abdominal incision to extract a bulky tumor. Mean operative time was 222 min (146-344). Mean time to first flatus and length of stay was 23 and 49 h, respectively. All but 4 patients were discharged home on post-operative day 2. One patient was readmitted with a pelvic fluid collection. CONCLUSION: Robotic left-sided colorectal resection with NICE procedure is a safe and feasible minimally invasive approach and may facilitate greater adoption rates of this technique.

The codon sequences predict protein lifetimes and other parameters of the protein life cycle in the mouse brain.

The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.