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Background The use of extended criteria donors (ECD) in liver transplantation is increasing due to the organ shortage. Histological evaluation of the liver graft in the context of procurement is an important tool for extending the donor pool without affecting the quality of the transplanted organs. Macrovesicular steatosis is widely accepted as predictor of early allograft dysfunction (EAD), while other features, such as portal fibrosis, are poorly studied. Aim To identify morphological features, other than macrovesicular steatosis, that may affect recipients’ outcome. Methods Between 2014 and 2016, 132 donors with extended criteria underwent pre-transplant liver biopsy during procurement. Histological variables of the graft, donors’/recipients’ clinical data, EAD and patient/graft survival were registered. Results The recipients who received a graft with histological-proven portal fibrosis had a significant lower patient and graft survival in comparison to patients without fibrosis (P = 0.044 and P = 0.039, respectively). Donors’ dyslipidemia was significantly associated with the occurrence of EAD (P = 0.021). When dyslipidemia was combined with histological liver fibrosis a 54.5% incidence of EAD was observed (P = 0.012). Conclusions The histological assessment of liver fibrosis in pre-transplant biopsy of ECD grafts, together with donor’s clinical data, provides important information on recipients’ outcome.

Background: The availability of accurate and rapid diagnostic tools for COVID-19 is essential for tackling the ongoing pandemic. Our study aimed to quantify the performance of available antigen-detecting rapid diagnostic tests (Ag-RDTs) in a real-world hospital setting. Methods: In this retrospective analysis, the diagnostic performance of 7 Ag-RDTs was compared with real-time reverse transcription quantitative polymerase chain reaction assay in terms of sensitivity, specificity and expected predictive values. Results: A total of 321 matched Ag-RDTreal-time reverse transcription quantitative polymerase chain reaction samples were analyzed retrospectively. The overall sensitivity and specificity of the Ag-RDTs was 78.7% and 100%, respectively. However, a wide range of sensitivity estimates by brand (66.0%–93.8%) and cycle threshold (Ct) cut-off values (Ct

One of the hallmarks of Alzheimer's disease is the accumulation of toxic amyloid-β (Aβ) peptides in extracellular plaques. The direct precursor of Aβ is the carboxyl-terminal fragment β (or C99) of the amyloid precursor protein (APP). C99 is detected at elevated levels in Alzheimer's disease brains, and its intracellular accumulation has been linked to early neurotoxicity independently of Aβ. Despite this, the causes of increased C99 levels are poorly understood. Here, we demonstrate that APP interacts with the clathrin vesicle adaptor AP-1 (adaptor protein 1), and we map the interaction sites on both proteins. Using quantitative kinetic trafficking assays, established cell lines and primary neurons, we also show that this interaction is required for the transport of APP from the trans-Golgi network to endosomes. In addition, disrupting AP-1-mediated transport of APP alters APP processing and degradation, ultimately leading to increased C99 production and Aβ release. Our results indicate that AP-1 regulates the subcellular distribution of APP, altering its processing into neurotoxic fragments.

We analyze the extent of comovement between daily price returns of nine major cryptocurrencies during the first three main phases of their development, from April 2013 to November 2018. We assess its evolution using bivariate and multivariate modeling approaches and detect pronounced time variation. Generally, comovement is initially low and positive, but increases between early 2017 and late 2018. We then adopt a right-tail version of the Augmented Dickey-Fuller unit root test to identify periods of mildly explosive behavior (statistical instability) in the Network Value to Transactions (NVT) ratio (a measure of the dollar value of cryptocurrency transaction activity relative to network value) of six cryptocurrencies. We show evidence of significant mild explosiveness in all of them. At the end of 2017 and in 2018, several cryptocurrencies experience often simultaneous instability associated with rising NVT ratios. Instability is a dominant feature of these markets.

Selective transport of transmembrane proteins to different intracellular compartments often involves the recognition of sorting signals in the cytosolic domains of the proteins by components of membrane coats. Some of these coats have as their key components a family of heterotetrameric adaptor protein (AP) complexes named AP-1 through AP-5. AP complexes play important roles in all cells, but their functions are most critical in neurons because of the extreme compartmental complexity of these cells. Accordingly, various diseases caused by mutations in AP subunit genes exhibit a range of neurological abnormalities as their most salient features. In this article, we discuss the properties of the different AP complexes, with a focus on their roles in neuronal physiology and pathology.

Targeting of soluble lysosomal enzymes requires mannose 6-phosphate (M6P) signals whose formation is initiated by the hexameric N-acetylglucosamine (GlcNAc)-1-phosphotransferase complex (α(2)β(2)γ(2)). Upon proteolytic cleavage by site-1 protease, the α/β-subunit precursor is catalytically activated but the functions of γ-subunits (Gnptg) in M6P modification of lysosomal enzymes are unknown. To investigate this, we analyzed the Gnptg expression in mouse tissues, primary cultured cells, and in Gnptg reporter mice in vivo, and found high amounts in the brain, eye, kidney, femur, vertebra and fibroblasts. Consecutively we performed comprehensive quantitative lysosomal proteome and M6P secretome analysis in fibroblasts of wild-type and Gnptg(ko) mice mimicking the lysosomal storage disorder mucolipidosis III. Although the cleavage of the α/β-precursor was not affected by Gnptg deficiency, the GlcNAc-1-phosphotransferase activity was significantly reduced. We purified lysosomes and identified 29 soluble lysosomal proteins by SILAC-based mass spectrometry exhibiting differential abundance in Gnptg(ko) fibroblasts which was confirmed by Western blotting and enzymatic activity analysis for selected proteins. A subset of these lysosomal enzymes show also reduced M6P modifications, fail to reach lysosomes and are secreted, among them α-l-fucosidase and arylsulfatase B. Low levels of these enzymes correlate with the accumulation of non-degraded fucose-containing glycostructures and sulfated glycosaminoglycans in Gnptg(ko) lysosomes. Incubation of Gnptg(ko) fibroblasts with arylsulfatase B partially rescued glycosaminoglycan storage. Combinatorial treatments with other here identified missorted enzymes of this degradation pathway might further correct glycosaminoglycan accumulation and will provide a useful basis to reveal mechanisms of selective, Gnptg-dependent formation of M6P residues on lysosomal proteins.

The Golgi-resident site-1 protease (S1P) is a key regulator of cholesterol homeostasis and ER stress responses by converting latent transcription factors sterol regulatory element binding proteins (SREPBs) and activating transcription factor 6 (ATF6), as well as viral glycoproteins to their active forms. S1P is also essential for lysosome biogenesis via proteolytic activation of the hexameric GlcNAc-1-phosphotransferase complex required for modification of newly synthesized lysosomal enzymes with the lysosomal targeting signal, mannose 6-phosphate. In the absence of S1P, the catalytically inactive α/β-subunit precursor of GlcNAc-1-phosphotransferase fails to be activated and results in missorting of newly synthesized lysosomal enzymes, and lysosomal accumulation of non-degraded material, which are biochemical features of defective GlcNAc-1-phosphotransferase subunits and the associated pediatric lysosomal diseases mucolipidosis type II and III. The early embryonic death of S1P-deficient mice and the importance of various S1P-regulated biological processes, including lysosomal homeostasis, cautioned for clinical inhibition of S1P. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.

Industry 4.0 is moving factories towards a high level of collaboration between human workers and industrial robots, with the aim of improving efficiency and productivity. Among other technologies, Augmented Reality (AR) is one of the most researched in recent years to provide novel user interfaces that could easily blend the real world with additional information. This literature review aims at identifying the main strengths and weaknesses of AR with industrial robots in human–robot collaborative scenarios. The term industrial robot is meant according to the ISO 8373:2012 definition. To this end, starting from 3734 initial works, 63 papers have been selected and analysed. The results suggest that AR technology shows its effectiveness also in this particular domain. With respect to traditional approaches, AR systems are faster and more appreciated by users. Nonetheless, the use of AR in human–robot collaborative scenarios is so cutting edge that not all the considered works have properly evaluated the proposed user interfaces. Future research should improve the qualitative evaluation in order to clearly point out both limitations and strengths of the proposed systems, involving also expert users in tests.

High-fat diets are used to induce adverse alterations in the intestinal microbiota, or dysbiosis, generalized inflammation and metabolic stress, which ultimately may lead to obesity. The influence of dietary whey proteins, whether intact or hydrolyzed, has been reported to improve glucose homeostasis and reduce stress. Therefore, the purpose of this work was to test if dietary milk-whey proteins, both in the intact form and hydrolyzed, could have an effect on the compositional changes of the cecal microbiota that can be induced in mice when receiving a high-fat diet in combination with the standard casein. Male C57BL/6 mice were fed a control casein diet (AIN 93-G); high-fat-casein (HFCAS); high-fat-whey protein concentrate (HFWPC) and high-fat whey-protein hydrolysate (HFWPH) for 9 weeks. The intestinal microbiota composition was analyzed by 16S-rRNA of the invariant (V1–V3) gene, potentially endotoxemic lipopolysaccharide (LPS) release was determined colorimetrically, and liver fat infiltration assessed by light microscopy. The high-fat diet proved to induce dysbiosis in the animals by inverting the dominance of the phylum Firmicutes over Bacteroidetes, promoted the increase of LPS and resulted in liver fat infiltration. The whey proteins, whether intact or hydrolyzed, resisted the installation of dysbiosis, prevented the surge of circulating LPS and prevented fat infiltration in the liver. It is concluded that dietary whey proteins exert metabolic actions that tend to preserve the normal microbiota profile, while mitigating liver fat deposition in mice consuming a high-fat diet for nine weeks. Such beneficial effects were not seen when casein was the dietary protein. The hydrolyzed whey protein still differed from the normal whey protein by selectively protecting the Bacteroidetes phylum.

Using monthly data between 1970 and 2013, we provide a comprehensive analysis of the extent of co-movement (measured by correlation coefficients) among the nominal price returns of 11 major energy, agricultural, and food commodities. We study the degree and the time evolution of unconditional and conditional correlations using a uniform-spacings estimation and testing approach, multivariate dynamic conditional correlation models, and a rolling regression procedure. We find that (1) the price returns of energy and agricultural commodities are highly correlated; (2) the overall level of co-movement among commodities increased in recent years, especially between energy and agricultural commodities, and in particular in the cases of maize and soybean oil, which are important inputs in the production of biofuels; and (3) the stock market volatility is positively associated with the co-movement of price returns across markets, especially after 2007.

Objectives We tested the noninferiority of a fast-track rule-out protocol for the diagnosis of non-ST-segment elevation myocardial infarction vs noncoronary chest pain based on the single-sampling combined assessment of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin compared with the serial assessment of medium-sensitivity cardiac troponin I. Methods Ultra-sensitive copeptin and medium-sensitivity cardiac troponin I levels were measured at presentation in 196 consecutive patients admitted to the emergency department for acute nontraumatic chest pain within 6 hours from symptoms onset and without ST-segment elevation on a 12-lead electrocardiogram. The diagnostic performance for non-ST-segment elevation myocardial infarction diagnosis of the dual-marker single-sampling strategy with medium-sensitivity cardiac troponin I and ultra-sensitive copeptin on admission was compared with that of the serial 0- and 3-hour medium-sensitivity cardiac troponin I sampling in reference to the adjudicated postdischarge diagnosis, using both the comparison of area under the curve (AUC) receiver operating characteristic and the McNemar chi-square test. Results The diagnosis of non-ST-segment elevation myocardial infarction was adjudicated in 29 patients (14.8%). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin generated an AUC of 0.87 (95% confidence interval, 0.82-0.91), which was noninferior with respect to the 3-hour interval medium-sensitivity cardiac troponin I serial sampling ( P = .194 for AUC difference). The combination of medium-sensitivity cardiac troponin I and ultra-sensitive copeptin also yielded a numerically higher diagnostic sensitivity (100% vs 89.7%; P = not significant). Conclusions A single-sampling strategy of combined ultra-sensitive copeptin and medium-sensitivity cardiac troponin I is noninferior to a 0- and 3-hour serial medium-sensitivity cardiac troponin I sampling in ruling out non-ST-segment elevation myocardial infarction and thus may allow an earlier discharge of patients who are ruled out for non-ST-segment elevation myocardial infarction (ClinicalTrials.gov Identifier NCT01962506).

Due to the various beneficial effects attributed to propolis, which include anti-inflammatory and anti-bacterial infection properties, the objective of the study was to evaluate the effect of propolis supplementation on the composition of the intestinal microbiota and its anti-inflammatory action. Forty male C57BL/6 mice were fed either a standard diet (control), a high-fat (HF) diet, or a high-fat diet supplemented with 0.2% crude propolis (HFP) for 2 or 5 weeks prior to sacrifice. Blood samples were collected for the determination of lipopolysaccharide (LPS) and classical biochemical parameters. Expression of the TLR4 pathway in muscle, and DNA sequencing for the 16S rRNA of the gut microbiota were performed. The HF diet increased the proportion of the phylum Firmicutes and inflammatory biomarkers, while supplementation with propolis for five weeks rendered the microbiota profile nearly normal. Consistently with the above, the supplementation reduced levels of circulating LPS and down-regulated the TLR4 pathway and inflammatory cytokine expressions in muscle. Moreover, propolis improved such biochemical parameters as serum triacylglycerols and glucose levels. The data suggest that propolis supplementation reduces inflammatory response and endotoxemia by preventing dysbiosis in mice challenged with a high-fat diet.

Avian Pathogenic Escherichia coli (APEC) strains are extra-intestinal E. coli that infect poultry and cause diseases. Nitrite is a central branch-point in bacterial nitrogen metabolism and is used as a cytotoxin by macrophages. Unlike nitric oxide (NO), nitrite cannot diffuse across bacterial membrane cells. The NirC protein acts as a specific channel to facilitate the transport of nitrite into Salmonella and E. coli cells for nitrogen metabolism and cytoplasmic detoxification. NirC is also required for the pathogenicity of Salmonella by downregulating the production of NO by the host macrophages. Based on an in vitro microarray that revealed the overexpression of the nirC gene in APEC strain SCI-07, we constructed a nirC-deficient SCI-07 strain (ΔnirC) and evaluated its virulence potential using in vivo and in vitro assays. The final cumulative mortalities caused by mutant and wild-type (WT) were similar; while the ΔnirC caused a gradual increase in the mortality rate during the seven days recorded, the WT caused mortality up to 24 h post-infection (hpi). Counts of the ΔnirC cells in the spleen, lung and liver were higher than those of the WT after 48 hpi but similar at 24 hpi. Although similar number of ΔnirC and WT cells was observed in macrophages at 3 hpi, there was higher number of ΔnirC cells at 16 hpi. The cell adhesion ability of the ΔnirC strain was about half the WT level in the presence and absence of alpha- d -mannopyranoside. These results indicate that the nirC gene influences the pathogenicity of SCI-07 strain.

A multi-step setup for heavy-flavour studies in high-energy nucleus–nucleus collisions is presented. The initial hard production of Q Q ¯ pairs is simulated with the POWHEG pQCD event generator, interfaced with the PYTHIA parton shower. In a nucleus–nucleus collision the propagation of the heavy quarks in the medium is described through the relativistic Langevin equation. The numerical results are compared to experimental data from the RHIC and the LHC. In particular we show the comparisons of the nuclear modification factor of D-mesons, non-prompt J / ψ 's and heavy-flavour electrons. Furthermore, first results on azimuthal correlations of heavy quark pair and open charm/beauty meson pairs are presented.

We present a numerical code modeling the evolution of the medium formed in relativistic heavy ion collisions, ECHO-QGP. The code solves relativistic hydrodynamics in $(3+1)-$D, with dissipative terms included within the framework of Israel-Stewart theory; it can work both in Minkowskian and in Bjorken coordinates. Initial conditions are provided through an implementation of the Glauber model (both Optical and Monte Carlo), while freezeout and particle generation are based on the Cooper-Frye prescription. The code is validated against several test problems and shows remarkable stability and accuracy with the combination of a conservative (shock-capturing) approach and the high-order methods employed. In particular it beautifully agrees with the semi-analytic solution known as Gubser flow, both in the ideal and in the viscous Israel-Stewart case, up to very large times and without any ad hoc tuning of the algorithm., 4 pages, 6 figures, XXIV Quark Matter conference proceedings (2014)

We compared PECS and VOCA intervention strategies to promote communication opportunities for three girls with Rett syndrome and severe to profound developmental disabilities. The first aim of the study was to assess the effectiveness of both aforementioned strategies by enhancing request and choices of preferred items by the participants involved to a caregiver. The second goal of the study was to assess the effects of the intervention program by reducing stereotyped behaviors (i.e. body rocking and hand movements). Finally, the third purpose was to carry out the indices of happiness and monitor quality of life concerning the participants exposed to the intervention program. The study was carried out according to an alternating treatments design with a final preference check phase for each participant. Results showed an increasing of independent requested and chosen items as well as of indices of happiness during intervention phases for all participants. Moreover, two of them chose VOCA strategy during preference checks phase, while the third one equally chose both strategies. Furthermore, a decreasing of stereotypies was observed during intervention phases for the three participants. Clinical, educational and psychological implications of the findings are discussed.