Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state

The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged

Morphology of two dimensional fracture surface

We consider the morphology of two dimensional cracks observed in experimental results obtained from paper samples and compare these results with the numerical simulations of the random fuse model (RFM). We demonstrate that the data obey multiscaling at small scales but cross over to self-affine scaling at larger scales. Next, we show that the roughness exponent of the random fuse model is recovered by a simpler model that produces a connected crack, while a directed crack yields a different result, close to a random walk. We discuss the multiscaling behavior of all these models.Comment: slightly revise

Nitrogen deprivation induces triacylglycerol accumulation, drug tolerance and hypervirulence in mycobacteria.

Mycobacteria share with other actinomycetes the ability to produce large quantities of triacylglycerol (TAG), which accumulate as intracytoplasmic lipid inclusions (ILI) also known as lipid droplets (LD). Mycobacterium tuberculosis (M. tb), the etiologic agent of tuberculosis, acquires fatty acids from the human host which are utilized to synthesize TAG, subsequently stored in the form of ILI to meet the carbon and nutrient requirements of the bacterium during long periods of persistence. However, environmental factors governing mycobacterial ILI formation and degradation remain poorly understood. Herein, we demonstrated that in the absence of host cells, carbon excess and nitrogen starvation promote TAG accumulation in the form of ILI in M. smegmatis and M. abscessus, used as surrogate species of M. tb. Based on these findings, we developed a simple and reversible in vitro model to regulate ILI biosynthesis and hydrolysis in mycobacteria. We also showed that TAG formation is tgs1 dependent and that lipolytic enzymes mediate TAG breakdown. Moreover, we confirmed that the nitrogen-deprived and ILI-rich phenotype was associated with an increased tolerance towards several drugs used for treating mycobacterial infections. Importantly, we showed that the presence of ILI substantially enhanced the bacterial burden and granuloma abundance in zebrafish embryos infected with lipid-rich M. abscessus as compared to embryos infected with lipid-poor M. abscessus, suggesting that ILI are actively contributing to mycobacterial virulence and pathogenesis

Total- and semi-bare noble metal nanoparticles@silica core@shell catalysts for hydrogen generation by formic acid decomposition

Catalysts are involved in a number of established and emerging chemical processes as well as in environmental remediation and energy conversion. Nanoparticles (NPs) can offer several advantages over some conventional catalysts, such as higher efficiency and selectivity. Nowadays, versatile and scalable nanocatalysts that combine activity and stability are still lacking. Here, we report a comprehensive investigation on the production and characterization of hybrid nano-architectures bringing a partial or total bare surface together with their catalytic efficiency evaluation on, as a proof-of-concept, the formic acid decomposition reaction. In this regard, formic acid (FA) is a convenient and safe hydrogen carrier with appealing features for mobile applications, fuel cells technologies, petrochemical processes and energetic applications. Thus, the design of robust catalysts for FA dehydrogenation is strongly demanded. Due to this, we produced and evaluated nano-architectures with various equilibrium between the size-increase of the active part and the barer catalytic surface. Overall, this work paves the way for the development of new approaches for green energy storage and safe delivery

Headache attributed to aeroplane travel: the first multicentric survey in a paediatric population affected by primary headaches

BACKGROUND: This multicentric survey investigates the prevalence and characteristics of Airplane Headache in children affected by primary headaches. METHODS: Patients with symptoms of Airplane Headache were recruited from nine Italian Pediatric Headache Centres. Each patient was handed a structured questionnaire which met the ICHD-III criteria. RESULTS: Among 320 children suffering from primary headaches who had flights during their lifetime, 15 (4.7%) had Airplane Headache, with mean age of 12.4 years. Most of the patients were females (80%). The headache was predominantly bilateral (80%) and localized to the frontal area (60%); it was mainly pulsating, and lasted less than 30 min in all cases. Accompanying symptoms were tearing, photophobia, phonophobia in most of the cases (73.3%). More than 30% of patients used medications to treat the attacks, with good results. CONCLUSION: Our study shows that Airplane Headache is not a rare disorder in children affected by primary headaches and highlights that its features in children are peculiar and differ from those described in adults. In children Airplane Headache prevails in females, is more often bilateral, has frequently accompanying symptoms and occurs at any time during the flight. Further studies are needed to confirm the actual frequency of Airplane Headache in the general pediatric population not selected from specialized Headache Centres, with and without other concomitant headache condition, and to better clarify the clinical characteristics, pathophysiology and potential therapies

The morbidity of urethral stricture disease among male Medicare beneficiaries

<p>Abstract</p> <p>Background</p> <p>To date, the morbidity of urethral stricture disease among American men has not been analyzed using national datasets. We sought to analyze the morbidity of urethral stricture disease by measuring the rates of urinary tract infections and urinary incontinence among men with a diagnosis of urethral stricture.</p> <p>Methods</p> <p>We analyzed Medicare claims data for 1992, 1995, 1998, and 2001 to estimate the rate of dual diagnoses of urethral stricture with urinary tract infection and with urinary incontinence occurring in the same year among a 5% sample of beneficiaries. Male Medicare beneficiaries receiving co-incident ICD-9 codes indicating diagnoses of urethral stricture and either urinary tract infection or urinary incontinence within the same year were counted.</p> <p>Results</p> <p>The percentage of male patients with a diagnosis of urethral stricture who also were diagnosed with a urinary tract infection was 42% in 2001, an increase from 35% in 1992. Eleven percent of male Medicare beneficiaries with urethral stricture disease in 2001 were diagnosed with urinary incontinence in the same year. This represents an increase from 8% in 1992.</p> <p>Conclusions</p> <p>Among male Medicare beneficiaries diagnosed with urethral stricture disease in 2001, 42% were also diagnosed with a urinary tract infection, and 11% with incontinence. Although the overall incidence of stricture disease decreased over this time period, these rates of dual diagnoses increased from 1992 to 2001. Our findings shed light into the health burden of stricture disease on American men. In order to decrease the morbidity of stricture disease, early definitive management of strictures is warranted.</p

Reduced Graphene Oxide: fundamentals and applications

In this paper we report our recent studies on the fundamental physical/chemical properties of supported reduced Graphene Oxide (rGO) obtained either via standard thermal annealing or under extreme-UV (EUV) light exposure alongside with investigations on its possible technological applications. rGO has been studied by X-ray Photoelectron Spectroscopy (XPS), micro-Raman Spectroscopy (μRS), and Optical Microscopy. rGO reduction degree has been calibrated on the basis of its color contrast (CC) providing a handy tool to quantitatively determine the fraction of sp The original choice of using EUV instead of UV light to photo-reduce supported GO is not only advantageous in terms of reduction efficiency but it also allows to introduce the concept of EUV photolithography (today limited to the silicon technology only) for the processing of graphene-based materials. Here we demonstrate resistless sub-micrometer GO photo-patterning over large areas ( 10 mm 2 ) This result is a relevant upgrade for the graphene-based technology that can take advantage, in this way, from the entire know-how of the EUV-based technology in view of an eco-sustainable all-carbon technology

Nucleon Decay, Atmospheric Neutrinos, and Cosmic Rays at DUNE: September 2016 Progress Report

We report on the progress made within the Nucleon Decay, Atmospheric Neutrinos, and Cosmogenics Physics Working Groups since the DUNE CDR, and in particular in the period September 2015 { September 2016. This note is also intended to provide input for the September 2016 Preliminary Report of the Far Detector Task Force. We report jointly for the three WGs since they are tightly coupled. They make use of the same DUNE Far Detector for their physics studies, they share the same energy regime, and they are all characterized by random, non-beam triggers. Finally, cosmogenic events are a background for atmospheric neutrino physics, and both cosmogenic events and atmospheric neutrinos are a background for nucleon decay physics. Recent progress within the Nucleon Decay, Atmospheric Neutrinos and Cosmogenics Physics Working Groups is reported in Secs. II, III and IV, respectively