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Background: We present our experience after the introduction of Advanced Trauma Life Support (ATLS)©, Trauma Team (TT) and Preperitoneal Pelvic Packing (PPP) protocols for the treatment of hemodynamically unstable pelvic blunt trauma. Methods: This is a retrospective study with historical controls: before (Control Group, CG) and after (Study Group SG) the introduction of the protocol. A single physician managed the CG and angiography was the emergency manoeuvre. A team with ATLS guidelines and PPP as an emergency manoeuvre managed the SG. Data were collected retrospectively. Patients were divided into two groups: before and after the introduction of protocols. Results: From January 2007 to October 2014, 36 patients were treated at our Centre. We consider patients from January 2007 to August 2011 (19 patients, CG) and from September 2011 to October 2014 (17 patients, SG). Median age was 54 years (43–69) in the CG vs. 47 (40–63) in the SG (p = 0.43), median initial SBP 90 mmHg (85–103) in the CG 94 (69–103) in the SG, (p = 0.60), heart rate was 90 (80–110) in the CG and 110 (95–130) in the SG, (p = 0.09). Median Injury Severity Score was 33 (21–41) in the CG and 34 (26–41) in the SG (p = 0.29). Time from arrival in the Emergency Department to first therapeutic manoeuvre was 132 minutes (109–180) in the CG and 87 minutes (51–204) in the SG (p = 0.4). The difference in mortality was statistically significant: 64.7% (11/17) in the CG and 23.5% (4/17) in the SG (p = 0.02). Conclusions: The introduction of protocols changed our approach in hemodynamically unstable pelvic trauma, achieving a remarkable improvement in early mortality.

TLQP-21, a peptide encoded by the prohormone VGF, is expressed in neuroendocrine cells and can modulate inflammatory processes. Since TLQP-21 can bind the complement 3a receptor 1 on macrophages, interest has risen in this peptide as a potential drug for the treatment of Acute Respiratory Distress Syndrome (ARDS), whose hospital mortality can reach 35–46%. Since no effective pharmacologic therapies are available, our aim was to exploit the potential of a short analog of TLQP-21(JMV5656) in order to modulate the inflammatory process in ARDS and the progression to pulmonary fibrosis in an experimental model of unilateral acid aspiration in mice. Mice were divided in 2 treatment groups. In the acute protocol, mice received intra-peritoneal injection of either vehicle or 0.6 mg/kg JMV5656 on experimental days 1 and 2, and ARDS was induced on day 3 under deep anesthesia by instillation of HCl (1.5 ml/kg of 0.1 M HCl in 0.9% NaCl) into the right lung; all measurements were performed 24 h later. In the subacute protocol, mice were treated as previously, but treatment with vehicle or JMV5656 was repeated also on day 4 and measurements were made 2 weeks later. Twenty-four hours after acid instillation, the total number of immune cell in the BAL rose sharply due primarily to an increase in the PMN population which increased from 1% up to 58% of total cell numbers. JMV5656 significantly reduced PMN recruitment into the alveolar space, but had no effects on cytokine levels in BAL. Two weeks after acid injury, static compliance of the right lung was significantly higher in the JMV5656-treated group compared to vehicle-treated group. Treatment with JMV5656 also blunted the acid-induced collagen deposition in the right lung. These results suggest that JMV5656 can ameliorate mechanical compliance, and reduce collagen deposition in acid-injured lungs in mice. This effect was likely due to the ability of JMV5656 to inhibit PMN recruitment in the injured lung.

VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca2+. This effect relies both on Ca2+ release from the endoplasmic reticulum (ER) and extracellular Ca2+ entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca2+ entry, the activation of outward K+-Ca2+-dependent currents, mainly the KCa3.1 currents, provides a membrane polarizing influence which offset the depolarizing action of Ca2+ elevation and indirectly maintains the driving force for optimal Ca2+ increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions.

After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Growth hormone secretagogues (GHS) are a family of synthetic molecules, first discovered in the late 1970s for their ability to stimulate growth hormone (GH) release. Many effects of GHS are mediated by binding to GHS-R1a, the receptor for the endogenous hormone ghrelin, a 28-amino acid peptide isolated from the stomach. Besides endocrine functions, both ghrelin and GHS are endowed with some relevant extraendocrine properties, including stimulation of food intake, anticonvulsant and anti-inflammatory effects, and protection of muscle tissue in different pathological conditions. In particular, ghrelin and GHS inhibit cardiomyocyte and endothelial cell apoptosis and improve cardiac left ventricular function during ischemia-reperfusion injury. Moreover, in a model of cisplatin-induced cachexia, GHS protect skeletal muscle from mitochondrial damage and improve lean mass recovery. Most of these effects are mediated by GHS ability to preserve intracellular Ca2+ homeostasis. In this review, we address the muscle-specific protective effects of GHS mediated by Ca2+ regulation, but also highlight recent findings of their therapeutic potential in pathological conditions characterized by skeletal or cardiac muscle impairment.

Background: Ventilator-induced diaphragmatic dysfunction (VIDD) is a common event during mechanical ventilation (MV) leading to rapid muscular atrophy and contractile dysfunction. Recent data show that renin-angiotensin system is involved in diaphragmatic skeletal muscle atrophy after MV. In particular, angiotensin-II can induce marked diaphragm muscle wasting, whereas angiotensin-(1–7) (Ang-(1–7)) could counteract this activity. This study was designed to evaluate the effects of the treatment with Ang-(1–7) in a rat model of VIDD with neuromuscular blocking agent infusion. Moreover, we studied whether the administration of A-779, an antagonist of Ang-(1–7) receptor (Mas), alone or in combination with PD123319, an antagonist of AT2 receptor, could antagonize the effects of Ang-(1–7). Methods: Sprague-Dawley rats underwent prolonged MV (8 h), while receiving an iv infusion of sterile saline 0.9% (vehicle) or Ang-(1–7) or Ang-(1–7) + A-779 or Ang-(1–7) + A-779 + PD123319. Diaphragms were collected for ex vivo contractility measurement (with electric stimulation), histological analysis, quantitative real-time PCR, and Western blot analysis. Results: MV resulted in a significant reduction of diaphragmatic contractility in all groups of treatment. Ang-(1–7)-treated rats showed higher muscular fibers cross-sectional area and lower atrogin-1 and myogenin mRNA levels, compared to vehicle treatment. Treatment with the antagonists of Mas and Ang-II receptor 2 (AT2R) caused a significant reduction of muscular contractility and an increase of atrogin-1 and MuRF-1 mRNA levels, not affecting the cross-sectional fiber area and myogenin mRNA levels. Conclusions: Systemic Ang-(1–7) administration during MV exerts a protective role on the muscular fibers of the diaphragm preserving muscular fibers anatomy, and reducing atrophy. The involvement of Mas and AT2R in the mechanism of action of Ang-(1–7) still remains controversial.

The Keck Observatory Archive (KOA), a collaboration between the NASA Exoplanet Science Institute and the W. M. Keck Observatory, serves science and calibration data for all current and retired instruments from the twin Keck Telescopes. In addition to the raw data, we publicly serve quick-look, reduced data products for four instruments (HIRES, LWS, NIRC2, NIRSPEC and OSIRIS), so that KOA users can easily assess the quality and scientific content of the data. In this paper we present the modernization of the Data Evaluation and Processing (DEP) Pipeline, our quality assurance tool to ensure science data is ready for archiving. Since there was no common infrastructure for data headers, the DEP pipeline had to evolve to accommodate new instruments through additional control paths each time an instrument was added or upgraded. Over time, new modules to assist with the processing were added in a variety of languages including IDL, C, CSH, PHP, and Python. The calls to multiple interpreters caused a lot of overhead. This project was an initiative to consolidate the DEP pipeline into a common language, Python, using an object-oriented approach. The object-oriented approach allows us to abstract out the differences and use common variables in place of instrument-specific values. As a result, new instruments only need a modified subclass with the differing values in order to work with the pipeline. By consolidating everything to Python, we have seen an increase in efficiency, ease of operation, and ease of maintenance.

Neurodegenerative diseases are characterized by the progressive functional loss of neurons in the brain, causing cognitive impairment and motoneuron disability. Although multifactorial interactions are evident, nutrition plays an essential role in the pathogenesis and evolution of these diseases. A systematic literature search was performed, and the prevalence of studies evaluated the effect of the Mediterranean diet (MeDiet), nutritional support, EPA and DHA, and vitamins on memory and cognition impairment. The data showed that malnutrition and low body mass index (BMI) is correlated with the higher development of dementia and mortality. MeDiet, nutritional support, and calorie-controlled diets play a protective effect against cognitive decline, Alzheimer’s disease (AD), Parkinson disease (PD) while malnutrition and insulin resistance represent significant risk factors. Malnutrition activates also the gut-microbiota-brain axis dysfunction that exacerbate neurogenerative process. Omega-3 and -6, and the vitamins supplementation seem to be less effective in protecting neuron degeneration. Insulin activity is a prevalent factor contributing to brain health while malnutrition correlated with the higher development of dementia and mortality.

TLQP-21 is a neuropeptide which has been implicated in regulation of nociception and other relevant physiologic functions. Although recent studies identified C3a and gC1q receptors as targets for TLQP-21, its intracellular molecular mechanisms of action remain largely unidentified. Our aim was (i) to explore the intracellular signaling pathway(s) activated by JMV5656, a novel derivative of TLQP-21, in RAW264.7 macrophages, and (ii) to assess linkages of these pathways with its purported receptors. JMV5656 stimulated, in a dose-dependent fashion, a rapid and transient increase in intracellular Ca2+ concentrations in RAW264.7 cells; repeated exposure to the peptide resulted in a lower response, suggesting a possible desensitization mechanism of the receptor. In particular, JMV5656 increased cytoplasmic Ca2+ levels by a PLC-dependent release of Ca2+ from the endoplasmic reticulum. STIM proteins and Orai Ca2+ channels were activated and played a crucial role. In fact, treatment of the cells with U73122 and thapsigargin modulated the increase of intracellular Ca2+ levels stimulated by JMV5656. Moreover, in RAW264.7 cells intracellular Ca2+ increases did not occur through the binding of JMV5656 to the C3a receptor, since the increase of intracellular Ca2+ levels induced by JMV5656 was not affected by specific siRNA against C3aR. In summary, our study provides new indications for the downstream effects of JMV5656 in macrophages, suggesting that it could activate receptors different from the C3aR

TLQP-21 is a neuropeptide that is involved in the control of several physiological functions, including energy homeostasis. Since TLQP-21 could oppose the early phase of diet-induced obesity, it has raised a huge interest, but very little is known about its mechanisms of action on peripheral tissues. Our aim was to investigate TLQP-21 distribution in brain and peripheral tissues after systemic administration using positron emission tomography. We report here the radiolabeling of NODA-methyl phenylacetic acid (MPAA) functionalized JMV5763, a short analog of TLQP-21, with [F-18]aluminum fluoride. Labeling of JMV5763 was initially performed manually, on a small scale, and then optimized and implemented on a fully automated radiosynthesis system. In the first experiment, mice were injected in the tail vein with [F-18]JMV5763, and central and peripheral tissues were collected 13, 30, and 60 min after injection. Significant uptake of [F-18]JMV5763 was found in stomach, intestine, kidney, liver, and adrenal gland. In the CNS, very low uptake values were measured in all tested areas, suggesting that the tracer does not efficiently cross the blood-brain barrier. Pretreatment with nonradioactive JMV5763 caused a significant reduction of tracer uptake only in stomach and intestine. In the second experiment, PET analysis was performed in vivo 10-120 min after i.v. [F-18]JMV5763 administration. Results were consistent with those of the ex vivo determinations. PET images showed a progressive increase of [F-18]JMV5763 uptake in intestine and stomach reaching a peak at 30 min, and decreasing at 120 min. Our results demonstrate that F-18-labeling of TLQP-21 analogs is a suitable method to study its distribution in the body.

Existing psycholinguistic models typically describe agreement relations as monolithic phenomena amounting to mechanisms that check mere feature consistency. This eye-tracking study aimed at widening this perspective by investigating the time spent reading subject-verb (number, person) and adverb-verb (tense) violations on an inflected verb during sentence comprehension in Spanish. Results suggest that (i) distinct processing mechanisms underlie the analysis of subject-verb and adverb-verb relations, (ii) the parser is sensitive to the different interpretive properties that characterise the person, number and tense features encoded in the verb (i.e. anchoring to discourse for person and tense interpretation, as opposed to anchoring to cardinality information for number), and (iii) the (local, distal) position of the agreement controller with respect to the verb affects the interpretation of these dependencies. An account is proposed that capitalises on the importance of enriching current sentence processing formalizations using a feature and relation-based approach.

To preserve high quality of a project, it is necessary to perform many refactoring steps during the development and maintenance phases. Code refactoring received a great attention in the literature, often directed to the refactoring of code smells. While at the architectural level, architectural smells received less attention. One of the most common architectural smell which may affect many parts of a software application is the Cyclic Dependency smell. This position paper presents a tool prototype that suggests which path a developer could follow to remove Cyclic Dependency smells in Java applications. The tool has been developed as an extension of the Arcan tool for architectural smells detection. In this paper we describe how the tool identifies the path to follow for the refactoring of Cyclic Dependency on real projects. The tool has been thought only to suggest a possible refactoring approach which a developer could considerate to resolve Cyclic Dependency.

Novel GnRH I and II analogues were designed and synthesized by Solid Phase Peptide Synthesis (SPPS), since GnRH has antiproliferative properties, but poor metabolic stability. To rationalize synthetic difficulties, molecular dynamics simulations were performed, showing the conformational behavior of three derivatives. Among the two series of peptidomimetics (Ie, f and IIe, f were GnRH I and GnRH II analogues, respectively), several compounds (Id-f and IIc-e) showed significant binding affinity. In particular, derivative Ie has an increased metabolic stability with respect to the physiological ligand (Ie t1/2 = 3.96 h versus GnRH I t1/2 = 2.63 h).

TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca2+ that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca2+ in the N9 microglia cells, and whether this Ca2+ elevation is coupled with the activation Ca2+ -sensitive K+ channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca2+ -activated potassium (K+) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K+ channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa 3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca2+, and, following extracellular Ca2+ entry, the opening of KCa 3.1 channels.

Background: Cachexia is a wasting condition associated with cancer types and, at the same time, is a serious and dose-limiting side effect of cancer chemotherapy. Skeletal muscle loss is one of the main characteristics of cachexia that significantly contributes to the functional muscle impairment. Calcium-dependent signaling pathways are believed to play an important role in skeletal muscle decline observed in cachexia, but whether intracellular calcium homeostasis is affected in this situation remains uncertain. Growth hormone secretagogues (GHS), a family of synthetic agonists of ghrelin receptor (GHS-R1a), are being developed as a therapeutic option for cancer cachexia syndrome; however, the exact mechanism by which GHS interfere with skeletal muscle is not fully understood. Methods: By a multidisciplinary approach ranging from cytofluorometry and electrophysiology to gene expression and histology, we characterized the calcium homeostasis in fast-twitch extensor digitorum longus (EDL) muscle of adult rats with cisplatin-induced cachexia and established the potential beneficial effects of two GHS (hexarelin and JMV2894) at this level. Additionally, in vivo measures of grip strength and of ultrasonography recordings allowed us to evaluate the functional impact of GHS therapeutic intervention. Results: Cisplatin-treated EDL muscle fibres were characterized by a ~18% significant reduction of the muscle weight and fibre diameter together with an up-regulation of atrogin1/Murf-1 genes and a down-regulation of Pgc1-a gene, all indexes of muscle atrophy, and by a two-fold increase in resting intracellular calcium, [Ca2+]i, compared with control rats. Moreover, the amplitude of the calcium transient induced by caffeine or depolarizing high potassium solution as well as the store-operated calcium entry were ~50% significantly reduced in cisplatin-treated rats. Calcium homeostasis dysregulation parallels with changes of functional ex vivo (excitability and resting macroscop