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PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational changes that promote its membrane interaction and catalytic activity, yet the effects of ATP-site directed inhibitors on the PI3Kα membrane interaction are unknown. Using FRET and biolayer interferometry assays, we show that a class of ATP-site directed inhibitors represented by GSK2126458 block the growth factor activated PI3KαWT membrane interaction, an activity dependent on the ligand forming specific ATP-site interactions. The membrane interaction for hot spot oncogenic mutations that bypass normal p85α regulatory mechanisms was insensitive to GSK2126458, while GSK2126458 could regulate mutations found outside of these hot spot regions. Our data show that the effect of GSK126458 on the membrane interaction requires the enzyme to revert from its growth factor activated state to a basal state. We find that an ATP substrate analogue can increase the wild type PI3Kα membrane interaction, uncovering a substrate based regulatory event that can be mimicked by different inhibitor chemotypes. Our findings, together with the discovery of small molecule allosteric activators of PI3Kα illustrate that PI3Kα membrane interactions can be modulated by factors related to ligand binding both within the ATP site and at allosteric sites. [ABSTRACT FROM AUTHOR]

Owing to variation of moisture content, the larch wood basic density near-infrared (NIR) prediction model shows reduced accuracy and robustness, or even model failure. To solve this technical problem, a multi-verse-algorithm-optimized BP neural network (MVO-BPNN) prediction model is proposed to improve the accuracy of the model. The preprocessing effects of the Savitzky–Golay smoothing, detrending, and 15-point moving average smoothing method were compared. The synergy interval partial least squares was used to extract the feature bands of the NIR spectra. Results showed that the prediction model based on MVO-BPNN was better than those based on BPNN and the genetic algorithm-optimized BPNN. It indicated that the NIR model based on the MVO-BPNN could effectively predict the basic density of wood with different moisture contents. [ABSTRACT FROM AUTHOR]

Forest ecosystem attributes and their spatial variation across the landscape have the potential to subsequently influence variations in fire behavior. Understanding this variation is critical to fire managers in their ability to predict fire behavior and rate of spread. However, a fine-scale description of fuel patterns and their relationship with overstory and understory attributes for north-central Appalachia is lacking due to the complicated quantification of variations in topography, forest attributes, and their interactions. To better understand the fire environment in north-central Appalachia and provide a comprehensive evaluation based on fine-scale topography, ninety-four plots were established across different aspects and slope positions within an oak–hickory forest located in southeast Ohio, USA, which historically fell within fire regime group I with a fire return interval ranging from 7 to 26 years. The data collected from these plots were analyzed by four components of the fire environment, which include the overstory, understory, shrub and herbaceous layers, surface fuels, and fuel conditions. The results reveal that fuel bed composition changed across aspects and slope position, and it is a primary factor that influences the environment where fire occurs. Specifically, the oak fuel load was highest on south-facing slopes and in upper slope positions, while maple fuel loads were similar across all aspects and slope positions. Oak and maple basal areas were the most significant factors in predicting the oak and maple fuel load, respectively. In the shrub and undergrowth layers, woody plant coverage was higher in upper slope positions compared to lower slope positions. Overstory canopy closure displayed a significant negative correlation with understory trees/ha and woody plant variables. The findings in this study can provide a better understanding of fine-scale fuel bed and vegetation characteristics, which can subsequently feed into fire behavior modeling research in north-central Appalachia based on the different characterizations of the fire environment by landscape position. [ABSTRACT FROM AUTHOR]

Pulp feedstock components (including extractives, lignin and holocellulose) are major products of the pulp and paper industry, and their proportion in production feedstock (e.g., wood) greatly impact pulp yield and pulp production costs. Near-infrared (NIR) spectroscopy offers a potential solution for rapid characterizing physical and chemical properties of woody biomass. However, NIR models are highly specific to the physical form and species of the samples used in the production process. Traditional calibration transfer (CT) methods usually fail to adapt NIR models to significant differences between spectra. Adversarial transfer learning (ATL) strategies, an emerging algorithm in computer imaging, align source and target distributions by introducing adversarial mechanisms. For the first time, deep ATL architecture, coupled with NIR spectroscopy (collected from ASD LabSpecPro spectrometer), was applied to quantitatively predict the pulpwood feedstock component content for adapting models of different physical forms (wood blocks, wood meals) and tree species to each other without the need for constructing a new model. It was discovered that ATL methods, including domain adversarial neural networks (DANN), domain separation networks (DSN), and dynamic adversarial adaptation networks (DAAN) not only remove the differences between wood block and wood meal spectral data sources (i.e., domains), but also make desired predictions for cross-species domain adaptation. The robustness and stability of the transferred models exceed those of traditional CT and transfer learning methods. Our results suggest that ATL models could be effectively adapted to polymorphic, multi-species pulp feedstock data, and can be extended to the detection and inversion of other feedstock properties. [ABSTRACT FROM AUTHOR]

Blueberries are a nutritious and popular berry worldwide. The physical and chemical properties of blueberries constantly change through the cycle of the supply chain (from harvest to sale). The purpose of this study was to develop a rapid method for detecting the properties of packaged blueberries based on near‐infrared (NIR) spectroscopy. NIR was applied to quantitatively determine the soluble solid content (SSC) of polyethylene (PE)‐packaged blueberries. An orthogonal partial least squares discriminant analysis model was established to show the correlation between spectral data and the measured SSC. Multiplicative scattering correction, standard normal variable, Savitzky–Golay convolution first derivative, and normalization (Normalize) were used for spectra preprocessing. Uninformative variables elimination, competitive adaptive reweighted sampling, and iteratively retaining informative variables were jointly used for wavelength optimization. NIR‐based SSC prediction models for unpacked blueberries and PE‐packaged blueberries were developed using partial least squares (PLS). The prediction model for PE‐packaged samples (RP2= 0.876, root mean square error of prediction [RMSEP] = 0.632) had less precision than the model for unpacked samples (RP2= 0.953, RMSEP = 0.611). To reduce the effect of PE, the back propagation (BP) neural network and PLS were combined into the BP–PLS algorithm based on the residual learning algorithm. The model of BP–PLS (RP2= 0.947, RMSEP = 0.414) was successfully developed to improve the prediction accuracy of SSC for PE‐packaged blueberries. The results suggested a promising way of using the BP–PLS method in tandem with NIR for the rapid detection of the SSC of PE‐packaged blueberries. Practical Application: Most of the NIR‐based research used unpacked blueberries as samples, while the use of packaged blueberries would provide researchers with a better understanding of the crucial factors at different phases of the blueberry supply chain (from harvest to sale). To meet market demands and minimize losses, NIR spectroscopy has been proven to be a rapid and nondestructive method for the determination of the SSC of PE‐packaged blueberries. This study provides an effective method for monitoring the properties of blueberries in the entire supply chain. [ABSTRACT FROM AUTHOR]

Assessing the characteristics of fuel flammability during fire is of major significance regarding fire intensity and fire spread control. Under the background of shifting forest composition from heliophytic to mesophytic species in mixed-oak forests, our objective is to determine the impacts of species-driven changes in fuel flammability characteristics and the specific relationships between fuel ignition variations at the species level. Oak and maple fuels were collected from ninety-four plots established in Zaleski State Forest, Ohio. A total of 30 combustion samples were separated (15 oak samples and 15 maple samples), with each combustion sample weighing 20 g to ignite under a laboratory fume hood. Our results determined that oak fuel showed significantly higher flame temperatures than maple fuel, and the fuel consumption and combustion duration time both varied between oak and maple fuel. These findings indicated that the shift from oak forest to mesophytic species could change a fire's behavior. Combined with the cooler, moister, and less-flammable forest conditions generated by these mesophytic species, fires may not be able to reach their historical fire intensities, suggesting that updated data and new insights are needed for fire management. [ABSTRACT FROM AUTHOR]

Tropical forest loss has been a prominent concern in Madagascar, portrayed by a highly fragmented landscape of forests surrounded by small-scale agricultural patches along the northwestern and eastern regions. This paper seeks to identify priority areas for forest landscape restoration at a landscape scale using a geospatial land suitability analysis approach. The study area is the watershed of Mahavavy, home to one of the most biodiverse ecosystems in the island but also an important agriculture region. The suitability analysis method comprises five major steps: (1) the identification of a set of restoration criteria, (2) the acquisition of available environmental datasets for each criterion, (3) generating suitability maps for each criterion, (4) the conception of a suitability analysis model, and (5) the design of potential sites for restoration. The specific suitability criteria combine both landscape composition and soil characteristics, including (i) distance from protected sites and forest patches, (ii) land cover classes, (iii) distance from settlements, (iv) distance from roads, (v) risk of soil erosion. We found 143,680 ha (27.9%) that were highly suitable areas for forest landscape restoration, 159127 (30.9%) moderately suitable and138031 ha (26.6%) not suitable areas. High potential suitable areas are observed in close proximity of forest patches and protected areas, and low restoration feasibility in all areas that are easily accessible and thus subjected to exploitation. [ABSTRACT FROM AUTHOR]

We report severe acute respiratory syndrome coronavirus 2 antibody positivity among market and city bus depot workers in Lima, Peru. Among 1285 vendors from 8 markets, prevalence ranged from 27% to 73%. Among 488 workers from 3 city bus depots, prevalence ranged from 11% to 47%. Self-reported symptoms were infrequent. [ABSTRACT FROM AUTHOR]

Phenotypic diversity in urinary metabolomes of different geographical populations has been recognized recently. In this study, urinary metabolic signatures from Western (United Kingdom) and South-East Asian (Thai) cholangiocarcinoma patients were characterized to understand spectral variability due to host carcinogenic processes and/or exogenous differences (nutritional, environmental and pharmaceutical). Urinary liquid chromatography mass spectroscopy (LC–MS) spectral profiles from Thai (healthy = 20 and cholangiocarcinoma = 14) and UK cohorts (healthy = 22 and cholangiocarcinoma = 10) were obtained and modelled using chemometric data analysis. Healthy metabolome disparities between the two distinct populations were primarily related to differences in dietary practices and body composition. Metabolites excreted due to drug treatment were dominant in urine specimens from cholangiocarcinoma patients, particularly in Western individuals. Urine from participants with sporadic (UK) cholangiocarcinoma contained greater levels of a nucleotide metabolite (uridine/pseudouridine). Higher relative concentrations of 7-methylguanine were observed in urine specimens from Thai cholangiocarcinoma patients. The urinary excretion of hippurate and methyladenine (gut microbial-host co-metabolites) showed a similar pattern of lower levels in patients with malignant biliary tumours from both countries. Intrinsic (body weight and body composition) and extrinsic (xenobiotic metabolism) factors were the main causes of disparities between the two populations. Regardless of the underlying aetiology, biological perturbations associated with cholangiocarcinoma urine metabolome signatures appeared to be influenced by gut microbial community metabolism. Dysregulation in nucleotide metabolism was associated with sporadic cholangiocarcinoma, possibly indicating differences in mitochondrial energy production pathways between cholangiocarcinoma tumour subtypes. Mapping population-specific metabolic disparities may aid in interpretation of disease processes and identification of candidate biomarkers. [ABSTRACT FROM AUTHOR]

A wildfire occurred in Shawnee State Forest located in southern Ohio that consumed 1215 hectares. Based on earlier forest inventories it was known that paulownia (Paulownia tomentosa), a non-native invasive tree species, occurred in the forest. The objective of this study was to determine if paulownia heavily colonized areas two years after the fire where the burn occurred, and if its presence had a negative impact on the regeneration (<137 cm height) of native species--red and white oaks (Quercus sp.), red maple (Acer rubrum), and yellow-poplar (Liriodendron tulipifera). Two years after the fire, paulownia had invaded the burned areas but not at significantly higher densities than occurred in the unburned areas. Fire significantly reduced the number of regenerating stems of white oak and red maple two years after the fire, whereas the number of regenerating stems of red oak increased slightly and that of yellow-poplar increased significantly. In areas where paulownia occurred that experienced wildfire, all species studied displayed a reduction in the number of regenerating stems compared to paulownia's absence in the burn areas. Where paulownia occurred in areas not affected by the wildfire, all the native species studied displayed a reduction in the number of regenerating stems. The average heights of red oak, white oak, and red maple were significantly taller when growing in areas affected by the wildfire due to a more open canopy. However, there was no significant change in the average heights of yellow-poplar. The presence of paulownia in both the burned and unburned areas reduced the number of regenerating stems of the native species studied. [ABSTRACT FROM AUTHOR]

Autophagy is a process through which intracellular cargoes are catabolised inside lysosomes. It involves the formation of autophagosomes initiated by the serine/threonine kinase ULK and class III PI3 kinase VPS34 complexes. Here, unbiased phosphoproteomics screens in mouse embryonic fibroblasts deleted for Ulk1/2 reveal that ULK loss significantly alters the phosphoproteome, with novel high confidence substrates identified including VPS34 complex member VPS15 and AMPK complex subunit PRKAG2. We identify six ULK‐dependent phosphorylation sites on VPS15, mutation of which reduces autophagosome formation in cells and VPS34 activity in vitro. Mutation of serine 861, the major VPS15 phosphosite, decreases both autophagy initiation and autophagic flux. Analysis of VPS15 knockout cells reveals two novel ULK‐dependent phenotypes downstream of VPS15 removal that can be partially recapitulated by chronic VPS34 inhibition, starvation‐independent accumulation of ULK substrates and kinase activity‐regulated recruitment of autophagy proteins to ubiquitin‐positive structures. SYNOPSIS: Serine/threonine kinase ULK is the sole protein kinase in the autophagic signalling cascade and a key autophagy regulator. This study identifies the VPS34 complex component VPS15 as a novel ULK substrate in mammalian cells, and reveals a role for ULK‐VPS15 signalling in autophagosome formation. Unbiased phosphoproteomics and in vitro kinase assays identify several novel ULK substrates.ULK phosphorylates VPS15 and PRKAG2, components of VPS34 and AMPK complexes, respectively.The ULK‐VPS15 signalling axis regulates VPS34 complex activity in vitro, and autophagy in cells.VPS15 knockout cells accumulate subsets of ULK phospho‐substrates.Upon VPS15 loss, autophagy proteins redistribute to ubiquitin‐positive condensates in an ULK‐ and VPS34‐dependent manner. [ABSTRACT FROM AUTHOR]

Background and Aim: Liver disease mortality rates continue to rise due to late diagnosis. We need noninvasive tests to be made available in the community that can identify patients at risk from a serious liver‐related event (SLE). We examine the performance of a blood test, the liver traffic light test (LTLT), with regard to its ability to predict survival and SLEs. Methods: Using routinely gathered clinical data, sequential LTLT test results from 4854 individuals with suspected liver disease were prospectively analyzed (median follow‐up 41 months). An SLE was defined as the development of cirrhosis, liver failure, ascites, or varices. Patients were graded as follows: red (high risk), amber (intermediate risk), and green (low risk). Results: Overall, 565 individuals experienced an SLE (11.6%). The area under the curve (AUC) for the continuous LTLT variable was 0.87 (95% confidence interval 0.85–0.89) for prediction of an SLE and 0.81 (0.78–0.84) for mortality. When categorized into red/amber/green grades, a red LTLT result predicted an SLE with negative and positive predictive values of 0.97 and 0.29, respectively. A red LTLT score predicted mortality with negative and positive predictive values of 0.98 and 0.18, respectively. Kaplan–Meier plots demonstrated increased mortality and SLEs in the red group versus the green and amber groups (P < 0.001) and an increase in SLEs in the amber versus green group (P < 0.001). Conclusion: Here, the LTLT is further validated for the prediction of survival and SLE development. The LTLT could aid primary care risk management and referral pathways with the aim of detecting and treating liver disease earlier in the general population. [ABSTRACT FROM AUTHOR]

The lipid phosphatidylinositol-3-phosphate (PI3P) is a regulator of two fundamental but distinct cellular processes, endocytosis and autophagy, so its generation needs to be under precise temporal and spatial control. PI3P is generated by two complexes that both contain the lipid kinase VPS34: complex II on endosomes (VPS34/VPS15/Beclin 1/UVRAG), and complex I on autophagosomes (VPS34/VPS15/Beclin 1/ATG14L). The endosomal GTPase Rab5 binds complex II, but the mechanism of VPS34 activation by Rab5 has remained elusive, and no GTPase is known to bind complex I. Here we show that Rab5a–GTP recruits endocytic complex II to membranes and activates it by binding between the VPS34 C2 and VPS15 WD40 domains. Electron cryotomography of complex II on Rab5a-decorated vesicles shows that the VPS34 kinase domain is released from inhibition by VPS15 and hovers over the lipid bilayer, poised for catalysis. We also show that the GTPase Rab1a, which is known to be involved in autophagy, recruits and activates the autophagy-specific complex I, but not complex II. Both Rabs bind to the same VPS34 interface but in a manner unique for each. These findings reveal how VPS34 complexes are activated on membranes by specific Rab GTPases and how they are recruited to unique cellular locations. The phosphatidylinositol-3-phosphate (PI3P) is generated by the lipid kinase VPS34, in the context of VPS34 complex I on autophagosomes or complex II on endosomes. Biochemical and structural analyses provide insights into the mechanism of both VPS34 complexes recruitment to and activation on membranes by specific Rab GTPases. [ABSTRACT FROM AUTHOR]

Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly via ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail. [ABSTRACT FROM AUTHOR]

How to activate PI3Kγ in neutrophils: A critical effector of GPCRs in neutrophils is PI3Kγ, but how the two PI3Kγ complexes are activated by Gβγ has been controversial, likely due to a reliance on in vitro assays using cultured cells. Rynkiewicz et al. generated mice with knock-in mutations in the Gβγ-binding sites in the PI3Kγ catalytic subunit p110γ or in the regulatory subunit p101. Loss of Gβγ binding to p110γ had greater effects on signaling in response to different GPCR agonists than loss of Gβγ binding to p101. Although the migration of isolated neutrophils was affected only by loss of Gβγ binding to p110γ, neutrophil migration in mouse models of neutrophilic inflammation was strongly impaired by defective Gβγ binding to either p110γ or p101. These results refine our understanding of how PI3Kγ is activated in neutrophils and emphasize the importance of investigating signaling pathways in physiologically relevant contexts. The PI3Kγ isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3Kγ, p101/p110γ and p84/p110γ, receive direct regulation through Gβγ or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent Gβγ binding to p110γ (RK552DD) or to p101 (VVKR777AAAA) and investigated the effects of these mutations in primary neutrophils and in mouse models of neutrophilic inflammation. Loss of Gβγ binding to p110γ substantially reduced the activation of both p101/p110γ and p84/p110γ in neutrophils by various GPCR agonists. Loss of Gβγ binding to p101 caused more variable effects, depending on both the agonist and cellular response, with the biggest reductions seen in PIP3 production by primary neutrophils in response to LTB4 and MIP-2 and in the migration of neutrophils during thioglycolate-induced peritonitis or MIP2-induced ear pouch inflammation. We also observed that p101VVKR777AAAA neutrophils showed enhanced p84-dependent ROS responses to fMLP and C5a, suggesting that competition may exist between p101/p110γ and p84/p110γ for Gβγ subunits downstream of GPCR activation. GPCRs did not activate p110γ in neutrophils from mice lacking both the p101 and p84 regulatory subunits, indicating that RAS binding to p110γ is insufficient to support GPCR activation in this cell type. These findings define a direct role for Gβγ subunits in activating both of the endogenous PI3Kγ complexes and indicate that the regulatory PI3Kγ subunit biases activation toward different GPCRs. [ABSTRACT FROM AUTHOR]

The Selwyn Waihora Project was a research project supporting a collaborative policy-making process to set environmental limits in the Selwyn Waihora catchment in New Zealand's South Island. In this Design Report we reflect on this project based on data collected from a range of project participants approximately two years after project completion. The data collection was guided by the Integration and Implementation Sciences framework (i2S). On the basis of participant responses, and the authors' first-hand experiences working on the project, we present insights for transdisciplinary research. Through the questions asked by the i2S framework insights emerged on: what it means to honour community values; the importance of context but that projects can pay too much attention to it; boundary objects to foster integration across multiple knowledge systems; the value of intra-team narratives for translation; the importance of considering the losers of the research; and sharing the burden of uncertainty. [ABSTRACT FROM AUTHOR]

Despite the prominence of sexual health concerns in the spinal cord injury (SCI) population, education regarding sexual functioning and related matters is not well integrated into rehabilitation processes or ongoing care in SCI. Conceptual sexual health care frameworks encompass a range of biopsychosocial factors and recommend utilizing an interdisciplinary approach to meet the diverse needs of individuals with disabilities. Yet, it is rare to have a truly integrated treatment team dedicated to sexual health and functioning in SCI rehabilitative settings. The program described in this article attempts to align itself with proposed recommendations regarding sexual health assessment, intervention, education, and provision of resources for those living with SCI. The aim is to provide individualized and better-coordinated sexual health interventions specific to the cultural, religious, physical, emotional, cognitive, sexual orientation, and gender identity needs of the patients served. Three case reports illustrate how the interdisciplinary sexual health rehabilitation program operated. A review of program challenges and future directions are also discussed. [ABSTRACT FROM AUTHOR]

Background: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria‐shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. Methods: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin‐1‐like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision‐cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). Results: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short‐term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. Conclusions: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE. [ABSTRACT FROM AUTHOR]

Background & Aims: Dietary changes can modulate gut microbiota and interact with cirrhosis. Our prior study demonstrated that microbial diversity was higher in cirrhotics from Turkish vs the USA, which was associated with lower risk of 90‐day hospitalizations. We aimed to define gut microbial functional and metabolomic changes to increase insight into benefits of the Mediterranean compared to Western diets. Methods: In all, 139 Turkish (46 controls/50 compensated/43 decompensated) and 157 American subjects (48 controls/59 compensated/50 decompensated) were studied. Turkish subjects consumed a modified Mediterranean diet with daily fermented milk intake, whereas Americans consumed a Western diet. Predicted gut microbial functionalities and plasma metabolomics were compared between/within countries. Correlation network differences between microbiota and metabolites in cirrhotics from Turkey vs the USA were evaluated. Results: Predicted microbial function showed lower amino acid, bioenergetics and lipid pathways, with functions related to vitamin B, glycan, xenobiotic metabolism, DNA/RNA synthesis, in cirrhotics from Turkey compared to the USA. Plasma metabolomics demonstrated higher relative lactate levels in Turkey vs the USA. The metabolite changes in decompensated cirrhosis, compared to controls, showed similar trends in Turkey and the USA, with reduced lipids and phosphocholines. Phosphocholines were significantly lower in patients hospitalized in 90 days (P =.03). Correlation networks in cirrhotics demonstrated linkage differences between beneficial taxa, Blautia and Oscillispira, and lactate and unsaturated lipids, in Turkey compared to American patients. Conclusions: A modified Mediterranean diet was associated with altered plasma metabolomics and beneficially alters microbiota functionality and correlations compared to Western diet in cirrhosis. These altered diet‐microbial interactions could potentially affect the 90‐day hospitalization risk. [ABSTRACT FROM AUTHOR]

High levels of antimicrobial drug resistance deleteriously affecting the outcome of treatment with antibacterial agents are causing increasing concern worldwide. This is particularly worrying in patients with cirrhosis with a depressed immune system and heightened susceptibility to infection. Antibiotics have to be started early before results of microbiological culture are available. Current guidelines for the empirical choice of antibiotics in this situation are not very helpful, and embracing antimicrobial stewardship including rapid de-escalation of therapy are not sufficiently emphasised. Multi-drug resistant organism rates to quinolone drugs of up to 40% are recorded in patients with spontaneous bacterial peritonitis on prophylactic antibiotics, leading to a break-through recurrence of intra-peritoneal infection. Also considered in this review is the value of rifaximin-α, non-selective beta-blockers, and concerns around proton pump inhibitor drug use. Fecal microbial transplantation and other gut-targeting therapies in lessening gut bacterial translocation are a promising approach, and new molecular techniques for determining bacterial sensitivity will allow more specific targeted therapy. [ABSTRACT FROM AUTHOR]

The effects of fall and spring prescribed fires on large seedlings (0.3 to 1.3 m height) of oak and other hardwood species three years after a shelterwood harvest were examined in Richland Furnace and Zaleski State Forests in southern Ohio. Fall and spring burns appeared to be more deleterious to red oaks (Quercus rubra L., Q. velutina Lam., Q. coccinea Muenchh.) than white oaks (Q. alba L., Q. prinus L.). Red oak experienced reductions in numbers and canopy volume after spring burns, and canopy reductions after fall burns. White oak experienced small increases in numbers of stems after both fall and spring burns, and an increase in the canopy volume after fall burns, but a slight decrease after spring burns. Yellow-poplar (Liriodendron tulipifera L.), a major oak competitor prior to fire, experienced dramatic reductions in the number of regenerating stems and canopy volume after both fall and spring burns. On the other hand, red maple (Acer rubrum L.) experienced large increases in the number of regenerating stems and canopy volume after both fall and spring burns. Based on importance value, the oak species remained relatively unchanged after both fall and spring burns. Yellow-poplar became the least dominant species after spring burns and the second to last dominant species after fall burns. [ABSTRACT FROM AUTHOR]

Introduction: Healthcare systems in Africa suffer from neglect and underfunding, leading to severe challenges across the six World Health Organization (WHO) pillars of healthcare delivery. We conducted this study to identify the principal challenges in the health sector in Africa and their solutions for evidence-based decisions, policy development and program prioritization. Methods: The study was conducted as part of a recent African Epidemiological Association Meeting in Maputo, Mozambique with participants drawn from 11 African countries, Cuba, Portugal and the United Kingdom. Participants were divided into 10 groups, consisting of 7 to 10 persons each. Brainstorming approaches were used in a structured, modified nominal group process exercise to identify key challenges and strategies to mitigate healthcare service challenges in Africa. Identified challenges and solutions were prioritised by ranking 1–5, with 1 most important and 5 being least important. Results: The first three challenges identified were inadequate human resources (34.29%), inadequate budgetary allocation to health (30%) and poor leadership and management (8.45%). The leading solutions suggested included training and capacity building for health workers (29.69%), increase budgetary allocation to health (20.31%) and advocacy for political support and commitment (12.31%). Conclusion: The underdeveloped healthcare systems in Africa need radical solutions with innovative thought to break the current impasse in service delivery. For example, public-private initiatives should be sought, where multinational companies extracting resources from Africa might be encouraged to plough some of the profits back into healthcare for the communities providing the workforce for their commercial activities. Most problems and their solutions lie within human resources, budget allocation and management. These should be accorded the highest priority for better health outcomes. [ABSTRACT FROM AUTHOR]

Gastric bypass surgery, an operation that restricts the stomach and bypasses the duodenum and part of the jejunum, results in major improvement or remission of type 2 diabetes. Duodenual-jejunal bypass was developed by one of the authors (FR) as an experimental, stomach-sparing variant of gastric bypass surgery to investigate weight-independent mechanisms of surgical control of diabetes. Duodenual-jejunal bypass has been shown to improve various aspects of glucose homeostasis in rodents and in humans, thus providing an experimental model for investigating mechanisms of action of surgery and elusive aspects of gastrointestinal physiology. Performing duodenual-jejunal bypass in rodents, however, is associated with a steep learning curve. Here we report our experience with duodenual-jejunal bypass and provide practical tips for successful surgery in rats. Duodenual-jejunal bypass was performed on 50 lean rats as part of a study aimed at investigating the effect of the procedure on the physiologic mechanisms of glucose homeostasis. During the study, we have progressively refined details of anatomic exposure, technical aspects of duodeno-jejunostomy and peri-operative care. We analysed the role of such refinements in improving operative time and post-operative mortality. We found that refinement of exposure methods of the gastro-duodenal junction aimed at minimizing tension on small visceral vasculature, technical aspects of duodeno-jejunal anastomosis and peri-operative management played a major role in improving the survival rate and operative time. Overall, an experimental model of duodenual-jejunal bypass was successfully reproduced. Based on this experience, we describe here what we believe are the most important technical tips to reduce the learning curve for the procedure. [ABSTRACT FROM AUTHOR]

The rapidity of the increase in the global burden of liver disease covered in this review with estimates worldwide of 2 million deaths from cirrhosis and with no signs of effective controls being introduced for two of the main causes, namely, excess alcohol consumption and obesity, is of great concern. The 25% prevalence of non-alcoholic fatty liver disease in many population groups and the recent description of primary hepatocellular cancer (HCC) in obese subjects without underlying severe fibrosis/cirrhosis also raises many questions. In addition, covered in this review are more encouraging areas including techniques for machine preservation of donor organs enabling previously marginal organs to be used for transplantation. Greater knowledge of gut microbiome and gut bacterial translocation is defining the inflammatory reaction underlying multi-organ failure in decompensated cirrhosis. The gut microbiome also influences the response of HCC patients to the new check-point inhibitor drugs which restore immunological responses of its host. [ABSTRACT FROM AUTHOR]

Background: Outside South-East Asia, most cases of cholangiocarcinoma (CCA) have an obscure etiology. There is often diagnostic uncertainty. Metabolomics using ultraperformance liquid chromatography mass spectrometry (UPLC-MS) offers the portent to distinguish disease-specific metabolic signatures. We aimed to define such a urinary metabolic signature in a patient cohort with sporadic CCA and investigate whether there were characteristic differences from those in patients with hepatocellular carcinoma (HCC), metastatic secondary liver cancer, pancreatic cancer and ovarian cancer (OCA). Methods: Spot urine specimens were obtained from 211 subjects in seven participating centers across the UK. Samples were collected from healthy controls and from patients with benign hepatic disease (gallstone, biliary strictures, sphincter of Oddi dysfunction and viral hepatitis) and patients with malignant conditions (HCC, pancreatic cancer, OCA and metastatic cancer in the liver). The spectral metabolite profiles were generated using a UPLC-MS detector and data were analyzed using multivariate and univariate statistical analyses. Results: The greatest class differences were seen between the metabolic profiles of disease-free controls compared to individuals with CCA with altered acylcarnitine, bile acid and purine levels. Individuals with benign strictures showed comparable urine profiles to patients with malignant bile duct lesions. The metabolic signatures of patients with bile duct tumors were distinguishable from patients with hepatocellular and ovarian tumors, but no difference was observed between CCA cases and patients with pancreatic cancer or hepatic secondary metastases. Conclusion: CCA causes subtle but detectable changes in the urine metabolic profiles. The findings point toward potential applications of metabonomics in early tumor detection. However, it is key to utilize both global and targeted metabonomics in a larger cohort for in-depth characterization of the urine metabolome in hepato-pancreato-biliary disease. [ABSTRACT FROM AUTHOR]

Cells dynamically adjust their protein translation profile to maintain homeostasis in changing environments. During nutrient stress, the kinase general control nonderepressible 2 (GCN2) phosphorylates translation initiation factor eIF2α, initiating the integrated stress response (ISR). To examine the mechanism of GCN2 activation, we have reconstituted this process in vitro, using purified components. We find that recombinant human GCN2 is potently stimulated by ribosomes and, to a lesser extent, by tRNA. Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) mapped GCN2-ribosome interactions to domain II of the uL10 subunit of the ribosomal P-stalk. Using recombinant, purified P-stalk, we showed that this domain of uL10 is the principal component of binding to GCN2; however, the conserved 14-residue C-terminal tails (CTTs) in the P1 and P2 P-stalk proteins are also essential for GCN2 activation. The HisRS-like and kinase domains of GCN2 show conformational changes upon binding recombinant P-stalk complex. Given that the ribosomal P-stalk stimulates the GTPase activity of elongation factors during translation, we propose that the P-stalk could link GCN2 activation to translational stress, leading to initiation of ISR. [ABSTRACT FROM AUTHOR]

Focuses on the decline of the British science empire. Prescriptions for beneficial change; National attitude toward trade and manufacturing; Defense component of British public research and development spending.

Phosphatidylinositol-3-phosphate (PtdIns3P) is essential for generating autophagosomes and regulating endocytic trafficking. Recently, we have shown that the activities of human PIK3C3/VPS34-containing complexes I and II, which synthesize PtdIns3P, are greatly affected by three membrane physicochemical parameters: lipid unsaturation, membrane curvature, and negative charge. Both complexes are more active on membranes composed of unsaturated lipids than saturated lipids, and high membrane curvature can compensate for the negative effect of high lipid saturation. Negatively charged phosphatidylserine (PS) activates the complexes, as well as PIK3C3/VPS34 alone. The kinase activity of complex I depends critically on the ATG14 BATS domain, whereas complex II relies on the BECN1 BARA domain. Our findings highlight the importance of the membrane character as sensed by the unique membrane binding motifs/domain of the complexes for regulating PIK3C3/VPS34 activity. [ABSTRACT FROM AUTHOR]

Virus-specific T cells are critical in mediating the pathogenesis of hepatitis B virus (HBV) infection. Interferon gamma (IFNγ)-producing T cells are associated with resolution; in contrast, interleukin-17 (IL-17)-producing T cells are linked to exacerbation of liver inflammation and injury. Checkpoint receptors stringently regulate T cell functions, with their expression profiles varying on different T cell subsets. Blockade of checkpoint receptors may be an effective therapeutic strategy for chronic hepatitis B (CHB); however, blockade may also inadvertently exacerbate proinflammatory responses. In this study, we sought to determine the balance of inflammatory and antiviral T cells and determine their inhibitory receptor profile. The frequency of total and HBV antigen-specific Th17 and Tc17 cells was higher in CHB patients compared with healthy controls (HCs). Th17 and Tc17 cells in CHB patients had significantly lower expression of T cell immunoglobulin and mucin domain protein-3 (TIM-3) compared with HCs, with no difference in programmed death-1 (PD-1) or CD244 expression. Conversely, Th1 and Tc1 cells in CHB patients hyperexpressed PD-1 and CD244, while TIM-3 expression was comparable in both cohorts. During CHB, antiviral IFNγ T cells hyperexpress multiple immune inhibitory receptors driving their functional impairment. In contrast, inflammatory Th17/Tc17 cells hypoexpress TIM-3, but not PD-1 or CD244. Checkpoint inhibitors for CHB should target PD-1 or CD244 to allow restoration of IFNγ responses without affecting inflammatory IL-17 production. [ABSTRACT FROM AUTHOR]

The King’s prognostic criteria for patients with acute liver failure (ALF) introduced in 1989 have been used worldwide. This distinguished for the first time cases with ‘hyper-acute’ course (characteristically paracetamol overdose) where there is a better chance of recovery with medical supportive care alone from those etiologies with a less acute course and paradoxically lower chances of ‘spontaneous’ recovery. Ongoing use showed the limited sensitivity of the criteria to constitute a significant practical limitation. Subsequent models including the MELD score and composite ones with markers of necrosis, an apoptotic liver cell death, proposed to improve sensitivity did not have the required high specificity. Two recent models utilizing new availability of web- and app-based computing delivering outcome predication through sophisticated algorithms are described. The first is a dynamic model described for paracetamol-induced ALF based upon admission findings and sequential variables over the first 2 days. The new model of the US Acute Liver Failure group was devised to cover all etiologies of ALF for predicting ‘transplant-free’ survival and accurately predicated spontaneous survival in two-thirds of cases. Improved survival results with medical management, particularly in hyper-acute cases, now approach those obtained with successful liver transplant and have raised the question of transplant benefit. Also considered in the review are new non-transplant approaches to treatment including the use of plasma exchange and based on successful results in acute-on-chronic liver failure, agents to modulate and improve hepatic regeneration. [ABSTRACT FROM AUTHOR]

Background: Genealogy and molecular genetic studies of a Swedish river valley population resulted in a large pedigree, showing that the hereditary hemochromatosis (HH) HFE/p.C282Y mutation is inherited with other recessive disorders such as Wilson's disease (WND), a rare recessive disorder of copper overload. The population also contain individuals with the Swedish long QT syndrome (LQTS1) founder mutation (KCNQ1/p.Y111C) which in homozygotes causes the Jervell & Lange Nielsen syndrome (JLNS) and hearing loss (HL). Aims of the study were to test whether the Swedish long QT founder mutation originated in an ancestral HFE family and if carriers had an increased risk for hemochromatosis (HH), a treatable disorder. We also aimed to identify the pathogenic mutation causing the hearing loss disorder segregating in the pedigree. Methods: LQTS patients were asked about their ancestry and possible origin in a HH family. They were also offered a predictive testing for the HFE genotype. Church books were screened for families with hearing loss. One HH family had two members with hearing loss, who underwent molecular genetic analysis of the LQTS founder mutation, connexin 26 and thereafter exome sequencing. Another family with hearing loss in repeat generations was also analyzed for connexin 26 and underwent exome sequencing. Results: Of nine LQTS patients studied, four carried a HFE mutation (two p.C282Y, two p.H63D), none was homozygous. Three LQTS patients confirmed origin in a female founder (b 1694, identical to AJ b 1694, a HFE pedigree member from the Fax river. Her descent of 44 HH families, included also 29 families with hearing loss (HL) suggesting JLNS. Eleven LQTS probands confirmed origin in a second founder couple (b 1614/1605) in which the woman b 1605 was identical to a HFE pedigree member from the Fjällsjö river. In her descent there were not only 64 HH, six WND families, one JLNS, but also 48 hearing loss families. Most hearing loss was non syndromic and caused by founder effects of the late 16th century. One was of Swedish origin carrying the WHRN, c.1977delC, (p.S660Afs*30) mutation, the other was a TMC1(NM_138691),c. 1814T>C,(p.L605P) mutation, possibly of Finnish origin. Conclusions: Deep human HFE genealogies show HFE to be associated with other genetic disorders like Wilson's disease, LQTS, JLNS, and autosomal recessive hearing loss. Two new homozygous HL mutations in WHRN/p. S660Afs*30 and TMC1/p.L605P were identified, none of them previously reported from Scandinavia. The rarity of JLNS was possibly caused by miscarriage or intrauterine death. Most hearing loss (81.7%) was seen after 1844 when first cousin marriages were permitted. However, only 10 (10.3%) came from 1st cousin unions and only 2 (2.0 %) was born out of wedlock. [ABSTRACT FROM AUTHOR]