MiRNA-34 and stress response

Psychiatric disorders are known to result from a strong interaction between genetic predisposition and environmental factors, mainly exposure to stressful events. Environmental events can modulate genes expression, possibly via epigenetic mechanisms, and affect onset/expression of a disease [1]. Epigenetic mechanisms include, among others, post-transcriptional regulation by non-coding RNAs such as microRNAs (miRNAs). MiRNAs are small non-coding RNAs predicted to regulate hundreds of targets and to be engaged in every biological process [2]. Thanks to their ability to fine-tune gene expression, miRNAs can control gene expression patterns favoring organism’s adaptation to internal and environmental (external) factors [3], such as stressful events

Effects of lack of microRNA-34 on the neural circuitry underlying the stress response and anxiety

Stress-related psychiatric disorders, including anxiety, are complex diseases that have genetic, and environmental causes. Stressful experiences increase the release of prefrontal amygdala neurotransmitters, a response that is relevant to cognitive, emotional, and behavioral coping. Moreover, exposure to stress elicits anxiety-like behavior and dendritic remodeling in the amygdala. Members of the miR-34 family have been suggested to regulate synaptic plasticity and neurotransmission processes, which mediate stress-related disorders. Using mice that harbored targeted deletions of all 3 members of the miR-34-family (miR-34-TKO), we evaluated acute stress-induced basolateral amygdala (BLA)-GABAergic and medial prefrontal cortex (mpFC) aminergic outflow by intracerebral in vivo microdialysis. Moreover, we also examined fear conditioning/extinction, stress-induced anxiety, and dendritic remodeling in the BLA of stress-exposed TKO mice. We found that TKO mice showed resilience to stress-induced anxiety and facilitation in fear extinction. Accordingly, no significant increase was evident in aminergic prefrontal or amygdala GABA release, and no significant acute stress-induced amygdalar dendritic remodeling was observed in TKO mice. Differential GRM7, 5-HT2C, and CRFR1 mRNA expressionwas noted in the mpFC and BLA between TKO andWT mice. Our data demonstrate that the miR-34 has a critical function in regulating the behavioral and neurochemical response to acute stress and in inducing stress-related amygdala neuroplasticity

The Acute Porphyric Attack: A Difficult Diagnosis for a Potential Lethal Event in Emergency Medicine

The porphyrias are a heterogeneous group of metabolic disorders due to an inherited (but in some forms the disturbance may also be acquired) enzymatic deficiency in the metabolic pathway of heme biosynthesis. The variable degree of block in the heme biosynthetic pathway due to the enzyme deficiency results in accumulation of different metabolic intermediates, whose toxicity is responsible for the peculiar (cutaneous and/or neurovisceral) clinical pictures observed in each of these diseases. According to the clinical features, the porphyrias are classified as \u201cacute\u201d (or neuropsychic) [characterized by acute neurovisceral crises (the acute porphyric attack) involving the autonomic and/or central nervous system, but also the liver and the kidney] and \u201con acute\u201d (or dermatological) (mostly presenting with cutaneous lesions, due to photosensitivity). The acute porphyrias are often misdiagnosed diseases: the acute porphyric attack may in fact mimic many other more common medical and neuropsychiatric conditions; its delayed diagnosis and treatment (or its inappropriate treatment) may result in a fatal outcome. For these reasons, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially in those cases presenting with acute and life-threatening clinical features. An early and definitive diagnosis is mandatory to improve outcomes and to assure that potentially harmful drugs are avoided. To date, the availability of an adequate treatment has significantly improved the outcome of the acute porphyric attacks, so the knowledge about the management of these events may be relevant for the physicians working in internal and emergency medicine units

Mechanisms of Neuronal Damage in Acute Hepatic Porphyrias

Porphyrias are a group of congenital and acquired diseases caused by an enzymatic impairment in the biosynthesis of heme. Depending on the specific enzyme involved, different types of porphyrias (i.e., chronic vs. acute, cutaneous vs. neurovisceral, hepatic vs. erythropoietic) are described, with different clinical presentations. Acute hepatic porphyrias (AHPs) are characterized by life-threatening acute neuro-visceral crises (acute porphyric attacks, APAs), featuring a wide range of neuropathic (central, peripheral, autonomic) manifestations. APAs are usually unleashed by external “porphyrinogenic” triggers, which are thought to cause an increased metabolic demand for heme. During APAs, the heme precursors -aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate in the bloodstream and urine. Even though several hypotheses have been developed to explain the protean clinical picture of APAs, the exact mechanism of neuronal damage in AHPs is still a matter of debate. In recent decades, a role has been proposed for oxidative damage caused by ALA, mitochondrial and synaptic ALA toxicity, dysfunction induced by relative heme deficiency on cytochromes and other hemeproteins (i.e., nitric oxide synthases), pyridoxal phosphate functional deficiency, derangements in the metabolic pathways of tryptophan, and other factors. Since the pathway leading to the biosynthesis of heme is inscribed into a complex network of interactions, which also includes some fundamental processes of basal metabolism, a disruption in any of the steps of this pathway is likely to have multiple pathogenic effects. Here, we aim to provide a comprehensive review of the current evidence regarding the mechanisms of neuronal damage in AHPs

Evaluation of an additive efficacy in broiler litter microbial level control in field: preliminary results

The present study was conducted to evaluate in field the efficacy of an additive (SOP® C POULTRY), as an agent for the control of micro-organisms in broiler litter. The Total aerobic Microbial Count (TMC), Staphylococcus species (spp.), Coliforms, and Salmonella spp. in broiler litter samples of both the Houses, 2 (H2) and 3 (H3), were determined, and also at the end of each cycle the mortality rate was recorded. The results showed significant reduction of all the microbial counts: P= 0.0078 (CMT), 0,0021 (Staphylococcus spp.) and 0.0541 (Coliforms), and mortality (P= 0.00106) in treated litter samples H2 and the control H3

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives

Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, -aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations

Animal models of compulsive eating behavior

In industrialized nations, overeating is a significant problem leading to overweight, obesity, and a host of related disorders; the increase in these disorders has prompted a significant amount of research aimed at understanding their etiology. Eating disorders are multifactorial conditions involving genetic, metabolic, environmental, and behavioral factors. Considering that compulsive eating in the face of adverse consequences characterizes some eating disorders, similar to the way in which compulsive drug intake characterizes drug-addiction, it might be considered an addiction in its own right. Moreover, numerous review articles have recently drawn a connection between the neural circuits activated in the seeking/intake of palatable food and drugs of abuse. Based on this observation, “food addiction” has emerged as an area of intense scientific research and accumulating evidence suggests it is possible to model some aspects of food addiction in animals. The development of well-characterized animal models would advance our understanding of the etiologic neural factors involved in eating disorders, such as compulsive overeating, and it would permit to propose targeted pharmacological therapies. However, to date, little evidence has been reported of continued food seeking and intake despite its harmful consequences in rats and mice

Model to simulate the behaviour of RC beams shear strengthened with ETS bars

To predict correctly the deformational and the cracking behavior of reinforced concrete elements failing in shear using a smeared crack approach, the strategy adopted to simulate the crack shear stress transfer is crucial. For this purpose, several strategies for modeling the fracture mode II were implemented in a smeared crack model already existing in the FEM-based computer program, FEMIX. Special development was given to a softening shear stress-shear strain diagram adopted for modeling the crack shear stress transfer. The predictive performance of the implemented constitutive model was assessed by simulating up to failure a series of eight beams tested to appraise the effectiveness of a new strengthening technique to increase the shear resistance of reinforced concrete beams. According to this strengthening technique, designated as Embedded Through-Section (ETS), holes are opened through the beam’s section, with the desired inclinations, and bars are introduced into these holes and bonded to the concrete substrate with adhesive materials. The strengthening elements are composed of steel bars bonded to the surrounding concrete with an epoxy adhesive. By using the properties obtained from the experimental programs for the characterization of the relevant properties of the intervening materials, and deriving from inverse analysis the data for the crack shear softening diagram, the simulations carried out have fitted with high accuracy the deformational and cracking behavior of the tested beams, as well as the strain fields in the reinforcements. The constitutive model is briefly described, and the simulations are presented and analyzed.Fundação para a Ciência e a Tecnologia (FCT

Extension of analytical indicial aerodynamics to generic trapezoidal wings in subsonic flow

Analytical indicial aerodynamic functions are calculated for several trapezoidal wings in subsonic flow, with a Mach number 0.3≤ Ma≤ 0.7. The formulation herein proposed extends well-known aerodynamic theories, which are limited to thin aerofoils in incompressible flow, to generic trapezoidal wing planforms. Firstly, a thorough study is executed to assess the accuracy and limitation of analytical predictions, using unsteady results from two state-of-the-art computational fluid dynamics solvers as cross-validated benchmarks. Indicial functions are calculated for a step change in the angle of attack and for a sharp-edge gust, each for four wing configurations and three Mach numbers. Then, analytical and computational indicial responses are used to predict dynamic derivatives and the maximum lift coefficient following an encounter with a one-minus-cosine gust. It is found that the analytical results are in excellent agreement with the computational results for all test cases. In particular, the deviation of the analytical results from the computational results is within the scatter or uncertainty in the data arising from using two computational fluid dynamics solvers. This indicates the usefulness of the developed analytical theories