Mutations in FUS lead to synaptic dysregulation in ALS-iPSC derived neurons.

Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset neurodegenerative disorder characterized by progressive muscular weakness due to the selective loss of motor neurons. Mutations in the gene Fused in Sarcoma (FUS) were identified as one cause of ALS. Here, we report that mutations in FUS lead to upregulation of synaptic proteins, increasing synaptic activity and abnormal release of vesicles at the synaptic cleft. Consequently, FUS-ALS neurons showed greater vulnerability to glutamate excitotoxicity, which raised neuronal swellings (varicose neurites) and led to neuronal death. Fragile X mental retardation protein (FMRP) is an RNA-binding protein known to regulate synaptic protein translation, and its expression is reduced in the FUS-ALS lines. Collectively, our data suggest that a reduction of FMRP levels alters the synaptic protein dynamics, leading to synaptic dysfunction and glutamate excitotoxicity. Here, we present a mechanistic hypothesis linking dysregulation of peripheral translation with synaptic vulnerability in the pathogenesis of FUS-ALS.

Climate change and cancer: an oncology nurse perspective in two Colombian regions.

Given the lack of publications and public policies addressing the relationship between climate change and cancer care in Colombia, we present an exploration of the perspectives and communication practices of a group of nurses from Valle del Cauca and Antioquia. We provide a context based on the available literature on climate change and general health then provide an overview of cancer in the country. Next, we present how oncology nurses have incorporated information about strategies their patients can use to mitigate the effects of climate change on their health. We highlight the centrality of patient-centered communication using a framework from the US National Cancer Institute) and the fundamental role nurses have in patients' experiences throughout their treatment. We conclude with the need to investigate oncology nurse communication practices in other Colombian hospitals, with consideration of culture, cancer stigma, barriers to care and other factors that may influence successful climate change mitigation and to better understand how other Latin American oncology nurses are addressing this serious challenge.

Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia.

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 'tethering' proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3ß (GSK3ß), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity.

Differential effects of photobiomodulation interval schedules on brain cytochrome c-oxidase and proto-oncogene expression.

Significance: Transcranial photobiomodulation (PBM) is a noninvasive neuromodulation technique capable of producing changes in the mitochondrial cytochrome c-oxidase (CCO) activity of neurons. Although the application of PBM in clinical practice and as a neurophysiological tool is increasing, less is known about how different treatment time intervals may result in different outcomes. Aim: We evaluated the effects of different PBM treatment intervals on brain metabolic activity through the CCO and proto-oncogene expression (c-Fos). Approach: We studied PBM effects on brain CCO and c-Fos expression in three groups of animals: Control (CN, n = 8 ), long interval PBM treatment (LI, n = 5 ), and short interval PBM treatment (SI, n = 5 ). Results: Increased CCO activity in the LI group, compared to the SI and CN groups, was found in the prefrontal cortices, dorsal and ventral striatum, and hippocampus. Regarding c-Fos expression, we found a significant increase in the SI group compared to LI and CN, whereas LI showed increased c-Fos expression compared to CN in the cingulate and infralimbic cortices. Conclusions: We show the effectiveness of different PBM interval schedules in increasing brain metabolic activity or proto-oncogene expression.

The Relationship between Choline Bioavailability from Diet, Intestinal Microbiota Composition, and Its Modulation of Human Diseases.

Choline is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which, upon absorption by the host is converted into trimethylamine-N-oxide (TMAO) in the liver. A high accumulation of both components is related to cardiovascular disease, inflammatory bowel disease, non-alcoholic fatty liver disease, and chronic kidney disease. However, the relationship between the microbiota production of these components and its impact on these diseases still remains unknown. In this review, we will address which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., the genotype) and diet affect TMA production, and the colonization of these microbes and the reversal of dysbiosis as a therapy for these diseases.

Metabolism in Acute-On-Chronic Liver Failure: The Solution More than the Problem.

Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.

Global Palliative Care and Cross-National Comparison: How Is Palliative Care Development Assessed?

Background: Indicators assessing national-level palliative care (PC) development used for cross-national comparison depict progress on this field. There is current interest on its inclusion in global monitoring frameworks. Objective: Identify and conceptualize those most frequently used for international PC development reporting. Design: Systematic review. Data Sources: PubMed, CINAHL, Google Scholar, and Google targeting national-level development indicators used for cross-national comparison. Additional search requesting experts' suggestions on key studies and "snow-balling" on reference section of all included studies. Identified indicators were listed and categorized in dimensions: services, use of medicines, policy, and education. Results: Fifty-four studies were included. Development has been evaluated using 480 different formulations of 165 indicators, 38 were highly reported. Thirty-two fell into proposed dimensions, 11 for use of medicines, 9 for policy, 7 for services, and 5 for education. Six into complementary dimensions: research, professional activity, and international cooperation. Six were the most frequently used indicators: number of PC services per population (40 reports), existence of PC national plan, strategy, or program (25), existence of palliative medicine specialization (22), availability and allocation of funds for PC (13), medical schools, including PC, in undergraduate curricula (13), and total use of opioids-morphine equivalents (11). Conclusion: There is a clear pattern for national-level PC development evaluation repeatedly using a small number of indicators. Indicators addressing generalistic provision, integration into health systems, and specific fields such as pediatric lack. This study invites international discussion on a global consensus on PC-development assessment.

The gestational power of mast cells in the injured tissue.

The inflammatory response expressed after wound healing would be the recapitulation of systemic extra-embryonic functions, which would focus on the interstitium of the injured tissue. In the injured tissue, mast cells, provided for a great functional heterogeneity, could play the leading role in the re-expression of extra-embryonic functions, i.e., coelomic-amniotic and trophoblastic-vitelline. Moreover, mast cells would favor the production of a gastrulation-like process, which in certain tissues and organs would induce the regeneration of the injured tissue. Therefore, the engraftment of mesenchymal stem cells and mast cells, both with an extra-embryonic regenerative phenotype, would achieve a blastema, from the repaired and regenerated injured tissue, rather than by fibrosis, which is commonly made through wound-healing.

Disregulación emocional y síntomas alimentarios: Análisis de sesiones de terapia grupal en pacientes con trastorno alimentario / Emotion dysregulation and eating symptoms: Analysis of group sessions in patients with eating disorder

El objetivo de este estudio fue explorar y analizar la relación entre emociones, sentimientos y estados de ánimo con el comportamiento, principalmente el alimentario, en pacientes con trastornos de la conducta alimentaria (TCA). Participaron 43 mujeres, de entre 14 y 45 años de edad (M= 19.8, DE= 6.8), 19 con el diagnóstico de anorexia nerviosa, 22 con bulimia nerviosa, y dos con trastorno por atracón). Todas asistían a un programa ambulatorio intensivo. Con base en una metodología cualitativa, se analizaron los contenidos de una sesión de terapia grupal conductual dialéctica. Frente a emociones negativas, se observó que estas pacientes —independientemente del tipo de TCA— usan preferentemente estrategias de supresión más que de reinterpretación. Específicamente, las pacientes con anorexia nerviosa suelen afrontar las emociones negativas con base en la expresión de síntomas restrictivos; mientras que aquellas con síntomas bulímicos, lo realizan a través de atracones y/o purgas. Fue notoria la dificultad de todas las pacientes para nombrar y discriminar sus emociones, o asociarlas con sus comportamientos maladaptativos. El tratamiento de los TCA requiere del uso de técnicas terapéuticas enfocadas a fortalecer en estas pacientes la tolerancia al malestar inducido por emociones negativas, pero que además promuevan la reinterpretación de estas.

The aim of this article was to explore and analyze the relationship between emotions, feelings and moods, with eating behavior and other behaviors in patients with eating disorders (ED). A total of 43 women aged among 14 to 45 years (M= 19.8, SD= 6.8), 19 were diagnosed with anorexia nervosa, 22 with bulimia nervosa and two with binge eating disorder. All participants attended to an ambulatory intensive program. Based on a qualitative methodology, it was analyzed the content of a dialectical behavior therapy group session. Before negative emotions it was observed that patients —regardless of the ED diagnostic— preferentially use suppression strategies rather than re-appraisal. Specifically, patients with anorexia nervosa tend to face negative emotions based on the expression of restrictive symptoms while bulimic ones tend to binge and/or purge. It was notorious the difficulty of all patients to name and discriminate emotions or associate them with maladaptive behaviors. ED treatment requires therapeutic techniques aimed to strength tolerance when discomfort is induced by negative emotions, but also promoting re-appraisal of these emotions.

Assessing the brain through the eye: New ways to explore hepatic encephalopathy.

BACKGROUND & AIMS: Minimal hepatic encephalopathy (mHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments in mHE. We studied one of its precipitating factors, portal hypertension which is driving the inflammatory process behind mHE. The purpose was to describe an indirect diagnostic method able to detect the pathology at early stages based on the study of the vascularization and mast cells conjunctival hyperplasia as secondary inflammatory response associated to portal hypertension. Finally, we correlated the presence of histological changes in the eye in mHE with deficits in behavioral task acquisition. METHODS: Rats were trained on a stimulus-response task and a spatial working memory task using the Morris water maze. Two groups of animals were used: a SHAM (sham-operated) group (n=10) and a portal hypertension (HT) group (n=10). The triple portal vein ligation method was used to create an animal model of mHE. Latencies to reach the platform, number of glial fibrillary acidic protein-immunoreactive astrocytes (GFAP-IR), mast cell expression and presence/absence of blood and lymphatic vessels were examined. RESULTS: There were differences in stimulus-response behavioral performance, with a deficit in the acquisition in the HT group. However, no differences between groups were found on the spatial working memory task. At the same time, differences between groups were found in the GFAP-IR density, which was lower in the HT group, and in the number of mast cells and the presence of vessels, which were higher in the HT group. CONCLUSIONS: In this study, we provide the first preliminary insight into the validity of exploring the eye as a possible tool to assess the diagnosis of mHE conditions.

Low-light-level therapy as a treatment for minimal hepatic encephalopathy: behavioural and brain assessment.

Minimal hepatic encephalopathy (MHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. However, little is known about treating or diagnosing early impairments involved in MHE. We studied one of its precipitating factors, portal hypertension. The purpose was to evaluate an enhancement in neuronal metabolism through low-light-level therapy (LLLT) and whether this therapy has effects on behavioural task acquisition. Rats were trained to perform a stimulus-response task using the Morris water maze. Three groups of animals were used: a SHAM (sham-operated) group (n = 7), a portal hypertension (PH) group (n = 7) and a PH + LLLT group (n = 7). The triple portal vein ligation method was used to create an animal model of the early developmental phase of HE, and then the animals were exposed to 670 + 10 nm LED light at a dose of 9 J/cm2 once a day for 7 days. The metabolic activity of the brains was studied with cytochrome c oxidase histochemistry. There were differences in behavioural performance, with an improvement in the PH + LLLT group. Energetic brain metabolism revealed significant differences between the groups in all the brain structures analysed, except the anterodorsal thalamus. At the same time, in different brain networks, the PH group showed a more complicated relationship among the structures, while the SHAM and PH + LLLT groups had similar patterns. In this study, we provide the first preliminary insights into the validity of LLLT as a possible intervention to improve memory under minimal hepatic encephalopathy conditions.

Finding the place without the whole: Timeline involvement of brain regions.

Mastering the Morris water maze (MWM) requires the animal to consolidate, retain and retrieve spatial localizations of relevant visual cues. However, it is necessary to investigate whether a reorganization of the neural networks takes place when part of the spatial information is removed. We conducted four experiments using the MWM. A classical reference memory procedure was performed over five training days, RM5 (n=7), and eight days, RM8 (n=7), with the whole room and all the spatial cues presented. Another group of animals were trained in the same protocol, but they received an additional day of training with only partial cues, PC (n=8). Finally, a third group of animals performed the classical task, followed by an overtraining with partial cues for four more days, OPC (n=8). After completing these tasks, cytochrome c-oxidase activity (CO) in several brain limbic system structures was compared between groups. In addition, c-Fos positive cells were measured in the RM5, RM8, PC and OPC groups. No significant differences were found among the four groups in escape latencies or time spent in the target quadrant. CO revealed involvement of the prefrontal and parietal cortices, dorsal and ventral striatum, CA1 and CA3 subfields of the dorsal hippocampus, basolateral and lateral amygdala, and mammillary nuclei in the PC group, compared to the RM group. In the OPC group, involvement of the ventral striatum and anteroventral thalamus and the absence of amygdala involvement were revealed, compared to the PC group. C-Fos results highlighted the role of the prefrontal cortex, dorsal striatum, anterodorsal thalamus and CA3 in the PC group, compared to the OPC, RM5 and RM8 groups. The animals were able to find the escape platform even when only a portion of the space where the cues were placed was available. Although the groups did not differ behaviorally, energetic brain metabolism and immediate early gene expression revealed the engagement of different neural structures in the groups that received more training without the entire surrounding space.

c-Fos expression correlates with performance on novel object and novel place recognition tests.

In rodents, many studies have been carried out using novelty-preference paradigms. The results show that the perirhinal cortex and the hippocampus are involved in the recognition of a novel object, "what", and its new position, "where", respectively. We employed these two variants of a novelty-preference paradigm to assess whether the expression of the immediate-early gene c-fos in the dorsal hippocampus and perirhinal cortex correlates with the performance discrimination ratio (d2), on the respective versions of the novelty preference tests. A control group (CO) was added to explore c-fos activation not specific to recognition. The results showed different patterns of c-Fos protein expression in the hippocampus and perirhinal cortex. The Where Group presented more c-Fos positive nuclei than the What and CO groups in the CA1 and CA3 regions, whereas in the perirhinal cortex, the What Group showed more c-Fos positive nuclei than the Where and CO groups. The correlation results indicate that levels of c-Fos in the CA1 area and perirhinal cortex correlate with effective exploration, d2, on the respective versions of the novelty preference tests, novel place and novel object recognition. These data suggest that the hippocampal CA1 and perirhinal cortex are specifically related to the level of recognition of place and objects, respectively.

Main target of minimal hepatic encephalopathy: Morphophysiological, inflammatory and metabolic view.

Although often not considered clinically relevant and, therefore, not diagnosed or treated, minimal hepatic encephalopathy (MHE) has been shown to affect daily functioning, quality of life, driving and overall mortality. To discover early impairments involved in MHE, we studied one of its precipitating factors, portal hypertension. Rats were trained on a stimulus-response task using the Morris water maze. Two groups of animals were used: a SHAM (sham-operated) group (n= 13) and a portal hypertension (PH) group (n= 13). The triple portal vein ligation method was used to create an animal model of an early developmental phase of HE. Brain metabolic activity was studied with cytochrome c-oxidase histochemistry (C.O.). Neuronal nuclear volume was assessed by nucleator probe; the number of glial fibrillary acidic protein-immunoreactive astrocytes (GFAP-IR) and proinflammatory mediators was measured. The results revealed that the PH group was not able to reach the behavioural criterion, in contrast to the SHAM group. The metabolic brain consumption revealed decreased C.O. activity in the ventral striatum. The PH group showed lower density of GFAP-IR and an increase in the tumour necrotic factor-α (TNF-α). The PH group showed decreased neuronal nuclear volume in the dorsal striatum. On the contrary, increased neuronal nuclear volume was found in the ventral striatum. For the first time, a relationship has been established between inflammation, astrocytic and neural damage, and brain metabolic impairment in a model of MHE. Disruption of the striatum and related structures was highlighted as the main target in early stages of HE. Finally, a simple task was presented to assess the subtle impairments found in the clinic, which could provide fresh insights into the development of new tools for the assessment of MHE.

Sexual metabolic differences in the rat limbic brain.

BACKGROUND: There is actually limited evidence about the influence of estrogens on neuronal energy metabolism or functional cerebral asymmetry. In order to evaluate this relationship, eight male and sixteen female adult Wistar rats, divided into estrus and diestrus phase, were used to measure basal neuronal metabolic activity in some of the structures involved in the Papez circuit, using cytochrome c oxidase (C.O.) histochemistry. METHOD: We used C.O. histochemistry because cytochrome oxidase activity can be considered as a reliable endogenous marker of neuronal activity. RESULTS: We found higher C.O. activity levels in diestrus as compared to estrus and male groups in the prefrontal cortex and thalamus. Conversely, neuronal oxidative metabolism was significantly higher in estrus than in diestrus and male groups in the dorsal and ventral hippocampus (CA1 and CA3) and in the mammillary bodies. However, no hemispheric functional lateralization was found in estrus, diestrus or male groups by C.O. activity. CONCLUSIONS: These results suggest a modulatory effect of estrogens on neuronal oxidative metabolism.

Coupling inflammation with evo-devo.

Inflammation integrates diverse mechanisms that are associated not only with pathological conditions, such as cardiovascular diseases, type 2 diabetes, obesity, neurodegenerative diseases and cancer, but also with physiological processes like reproduction i.e. oogenesis and embryogenesis as well as aging. In the current review we firstly propose that the inflammatory response could recapitulate the phylogenia. In this way, highly conserved inflammatory mechanisms that play a main role in the evolutive development of different animal species, both invertebrates as well as vertebrates, are identified. Therefore, we also hypothesize that inflammation could represent a key tool used by nature to modulate organisms according to the environmental conditions in which these develop. Thus, inflammation could be the pathway by which the environmental factors could be related to the evolutionary development. If so, the diverse human chronic inflammatory diseases that nowadays the Western society suffer would represent the way for adapting to the abrupt changes in their lifestyle. Nonetheless, the distribution of the different pathological conditions varies in terms of intensity and magnitude among Western country populations depending on their genetic polymorphism. In this case, it should be considered that this set of diseases, distributed between all the individuals that constitute the Westernized society, would represent a true Social Inflammatory Syndrome whose final result is its remodeling. In this context, the use of inflammation by the Western society could represent the camouflaged expression of efficient mechanisms of evolution and development. In addition, if the different types of the inflammatory response involved in these diverse chronic pathological conditions could trace the biochemical origins of life, perhaps inflammation could represent an archaeological tool of unsuspected usefulness for understanding our own origin.

Distinct immune effector pathways contribute to the full expression of peanut-induced anaphylactic reactions in mice.

BACKGROUND: Food-induced anaphylaxis is often a severe allergic reaction characterized by multiorgan dysfunction and a potentially fatal outcome. OBJECTIVES: We sought to investigate the relative contribution of immunoglobulin-dependent effector pathways to anaphylactic responses to food (ie, peanut). METHODS: Wild-type and various mutant mice were sensitized with peanut protein and cholera toxin by means of oral gavage weekly for 4 weeks. Mice were subjected to different cellular depletion and Fc receptor blocking strategies before challenge with peanut 1 week after the last sensitization. RESULTS: Our data indicate that pathways other than the classical mast cell (MC)-IgE pathway contribute to the full spectrum of anaphylactic reactions to peanut. We show that the single deletion of MCs, basophils, or phagocytes (ie, macrophages) prevents the most significant clinical outcome: death. Remarkably, the combined deficiency of MCs and phagocytes, but not MCs and basophils, averted nearly all clinical and physiological signs of anaphylaxis. Furthermore, blockade of both IgE and IgG1 signaling was necessary to abolish anaphylactic responses to peanut. Although MC responses occurred through IgE and IgG1, phagocyte responses were fully mediated through IgG1. CONCLUSIONS: Peanut-induced anaphylaxis is a process that involves the concerted action of multiple immune effector pathways, and thus interventions targeting a single pathway (eg, MC-IgE) might not be sufficient to fully prevent anaphylactic responses.