Miracle-dz/UniFAR-FTUs huggingface dataset:
Interleukin-22 orchestrates a pathological endoplasmic reticulum stress response transcriptional programme in colonic epithelial cells

Objective The functional role of interleukin-22 (IL22) in chronic inflammation is controversial, and mechanistic insights into how it regulates target tissue are lacking. In this study, we evaluated the functional role of IL22 in chronic colitis and probed mechanisms of IL22-mediated regulation of colonic epithelial cells. Design To investigate the functional role of IL22 in chronic colitis and how it regulates colonic epithelial cells, we employed a three-dimentional mini-gut epithelial organoid system, in vivo disease models and transcriptomic datasets in human IBD. Results As well as inducing transcriptional modules implicated in antimicrobial responses, IL22 also coordinated an endoplasmic reticulum (ER) stress response transcriptional programme in colonic epithelial cells. In the colon of patients with active colonic Crohn’s disease (CD), there was enrichment of IL22-responsive transcriptional modules and ER stress response modules. Strikingly, in an IL22-dependent model of chronic colitis, targeting IL22 alleviated colonic epithelial ER stress and attenuated colitis. Pharmacological modulation of the ER stress response similarly impacted the severity of colitis. In patients with colonic CD, antibody blockade of IL12p40, which simultaneously blocks IL12 and IL23, the key upstream regulator of IL22 production, alleviated the colonic epithelial ER stress response. Conclusions Our data challenge perceptions of IL22 as a predominantly beneficial cytokine in IBD and provide novel insights into the molecular mechanisms of IL22-mediated pathogenicity in chronic colitis. Targeting IL22-regulated pathways and alleviating colonic epithelial ER stress may represent promising therapeutic strategies in patients with colitis. Trial registration number NCT02749630.
Gender analysis of nurses' attitude towards care of the elderly with dementia in Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State, Nigeria

ABSTRACT This study assessed nurses’ knowledge and attitudes by gender toward the care of elderly patients with dementia and explored gender differences in attitudes and associated factors in Obafemi Awolowo University Teaching Hospital, Ile-Ife. The study adopted a sequential explanatory mixed method design to obtain data from 100 nurses selected through a multistage sampling technique. Data analysis was done at univariate, bivariate, and multivariate levels with a significance at P < . 05. Findings revealed that a majority of the nurses have good knowledge and attitudes toward the care of elderly patients with dementia. Previous experience in a specialized unit (Odd = 2.879, CI = 0.013–8.287, P = .047) was the main predictor for the nurses’ attitude.
Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling*

SILAC proteomics was applied to isogenic cell lines to identify cell surface proteins upregulated by mTORC1 signaling, which identified the proteases neprilysin and aminopeptidase N as the most highly induced. Validation and functional studies showed that the proliferation of cancer cells with hyperactive mTORC1 are sensitized to neprilysin and aminopeptidase N inhibition. These studies introduce a new paradigm for the treatment of cancer cells driven by mTORC1 that may overcome the well-established limitations of kinase inhibitors. Graphical Abstract Highlights Quantitative proteomes of the cellular surface changes induced by mTORC1 signaling. Hit validation in human cancer cell lines and biopsies. Functional studies showing new drug targets to which cancer cells with hyperactive mTORC1 may be addicted. A new paradigm for drug development, namely targeting cell surface proteins regulated by mTORC1. Aberrantly high mTORC1 signaling is a known driver of many cancers and human disorders, yet pharmacological inhibition of mTORC1 rarely confers durable clinical responses. To explore alternative therapeutic strategies, herein we conducted a proteomics survey to identify cell surface proteins upregulated by mTORC1. A comparison of the surfaceome from Tsc1−/− versus Tsc1+/+ mouse embryonic fibroblasts revealed 59 proteins predicted to be significantly overexpressed in Tsc1−/− cells. Further validation of the data in multiple mouse and human cell lines showed that mTORC1 signaling most dramatically induced the expression of the proteases neprilysin (NEP/CD10) and aminopeptidase N (APN/CD13). Functional studies showed that constitutive mTORC1 signaling sensitized cells to genetic ablation of NEP and APN, as well as the biochemical inhibition of APN. In summary, these data show that mTORC1 signaling plays a significant role in the constitution of the surfaceome, which in turn may present novel therapeutic strategies.
Hydrogen produced in rat colon improves in vivo reduction–oxidation balance due to induced regeneration of α-tocopherol

Abstract We investigated whether non-digestible saccharide fermentation-derived hydrogen molecules (H2) in rat colon could improve the in vivo reduction–oxidation (redox) balance via regeneration of α-tocopherol, by assessing their effect on hydroxyl radicals, the α-tocopherol concentration and the redox balance. In Expt 1, a Fenton reaction with phenylalanine (0 or 1·37 mmol/l of H2) was conducted. In Expt 2, rats received intraperitoneally maize oil containing phorone (400 mg/kg) 7 d after drinking ad libitum water containing 0 or 4 % fructo-oligosaccharides (FOS) (groups CP and FP, respectively). In Expt 3, rats unable to synthesise ascorbic acid drank ad libitum for 14 d water with 240 mg ascorbic acid/l (group AC), 20 mg of ascorbic acid/l (group DC) or 20 mg of ascorbic acid/l and 4 % FOS (group DCF). In the Fenton reaction, H2 reduced tyrosine produced from phenylalanine to 72 % when platinum was added and to 92 % when platinum was excluded. In Expt 2, liver glutathione was depleted by administration of phorone to rats. However, compared with CP, no change in the m-tyrosine concentration in the liver of FP was detected. In Expt 3, net H2 excretion was higher in DCF than in the other rats after 3 d of the experiment. Furthermore, the concentrations of H2 and α-tocopherol and the redox glutathione ratio in perirenal adipose tissue of rats were significantly higher in DCF than in DC. To summarise, in rat colon, fermentation-derived H2 further shifted the redox balance towards a more reducing status in perirenal adipose tissue through increased regeneration of α-tocopherol.
Transfusion errors — can they be eliminated?

The Serious Hazards of Transfusion haemovigilance scheme has documented adverse transfusion incidents for 22 years. Transmission of infection (three in 2018), transfusion‐related lung injury (one in 2018) and transfusion‐associated graft‐versus‐host disease (none since 2012) are rare. Despite national recommendations, guidelines and protocols, most incidents more than 85% of incidents are still due to errors in the transfusion process. European regulation and mandatory competency assessments have been associated with a reduction in ABO‐incompatible transfusion, but errors continue to put patients at risk. What can be done? Errors are reduced by the use of electronic identification systems. Exploration of human factors and ergonomics (HFE) results in amended approaches away from blaming individuals to a full review of the systems and environment. Research examining how transfusion is performed (work‐as‐done) compared to work‐as‐imagined (set out in protocols and guidelines) discovers where variability results in either resilience or error. All staff require HFE training, but this should be alongside employment of suitably qualified and experienced HFE professionals. Good teamwork is key and is undermined by insufficient staffing and poor morale. The five choosing wisely recommendations for transfusion (to ensure appropriate use) need to be widely disseminated to medical staff in all specialties to ensure patients participate in the decision‐making.
Vasodilator‐stimulated phosphoprotein (VASP) is recruited into dendritic spines via G‐actin‐dependent mechanism and contributes to spine enlargement and stabilization

Actin organization and dynamics are modulated by diverse actin regulators during dendritic spine development. To understand the molecular network that regulates actin organization and spine morphology, it is important to investigate dynamic redistribution of actin regulators during spine development. One of the actin regulators, vasodilator‐stimulated phosphoprotein (VASP), has multiple functions in actin regulation and is known to regulate spine morphology. However, dynamics and temporal regulation of VASP during spine development have not been clarified. In this study, we performed time‐lapse imaging of mouse hippocampal dissociated neurons to analyse the change in localization of VASP during spine development. We found that accumulation of VASP within spines precedes the start of persistent F‐actin increase, which are temporally coupled with spine enlargement. Using domain deletion or mutation constructs of VASP, we revealed that the interaction with G‐actin is important for the preceding accumulation of VASP. Furthermore, we showed that accumulation of VASP contributes to actin enrichment within spines and stabilization of spine morphology by dominant negative experiments. These data suggest that G‐actin‐dependent VASP recruitment has dual functions in spine development, enlargement and stabilization, through the interaction with actin and other cytoskeletal regulators.
The development and use of Actiphage® to detect viable mycobacteria from bovine tuberculosis and Johne’s disease‐infected animals

Here, we describe the development of a method that exploits bacteriophage D29 as a lysis agent for efficient DNA extraction from low numbers of mycobacterial cells. This method (Actiphage®) used in combination with PCR achieved rapid and sensitive (LOD ≤ 10 cell ml−1) detection and identification of viable, pathogenic mycobacteria in blood samples within 6 h. We demonstrate that mycobacteriophage D29 can be used to detect a range of mycobacteria from clinical blood samples including both Mycobacterium tuberculosis complex and Mycobacterium avium subsp. paratuberculosis without the need for culture and confirms our earlier observations that a low‐level bacteraemia is associated with these infections in cattle. In a study of M. bovis‐infected cattle (n = 41), the sensitivity of the Actiphage® method was 95 % (95 % CI; 0.84–0.99) and specificity was 100 % (95% CI; 0.92–1). We further used Actiphage® to demonstrate viable Mycobacterium avium subsp. paratuberculosis is present in the blood of Johne’s infected cattle. This method provides a revolutionary new tool for the study of infections caused by these difficult to grow pathogens.
Intestinal hydrolysis and microbial biotransformation of diacetoxyscirpenol-α-glucoside, HT-2-β-glucoside and N-(1-deoxy-d-fructos-1-yl) fumonisin B1 by human gut microbiota in vitro

Abstract Fusarium mycotoxins are common contaminants in cereals and often co-occur with plant-derived mycotoxin sugar conjugates. Several of these modified mycotoxins are not degraded in the small intestine and hence carried through to the large intestine where microbial transformation may occur. This study aims to assess the gastrointestinal stability of the trichothecenes HT-2 toxin (HT-2), HT-2-β-glucoside (HT-2-Glc), diacetoxyscirpenol (DAS), DAS-α-glucoside (DAS-Glc) and fumonisin B1 (FB1), N-(1-deoxy-d-fructos-1-yl) fumonisin-B1 (NDF-FB1). All tested modified mycotoxins were stable under upper gastrointestinal (GI) conditions. In faecal batch culture experiments, HT-2-Glc was hydrolysed efficiently and no further microbial biotransformation of HT-2 was observed. DAS-Glc hydrolysis was slow and DAS was de-acetylated to 15-monoacetoxyscripenol. NDF-FB1 was hydrolysed at the slowest rate and FB1 accumulation varied between donor samples. Our results demonstrate that all tested modified mycotoxins are stable in the upper GI tract and efficiently hydrolysed by human gut microbiota, thus potentially contributing to colonic toxicity. Hence the microbial biotransformation of any novel modified mycotoxins needs to be carefully evaluated.
Research on the courses of competence cultivation of basic logistics management talents

The purpose of this study is to explore the courses of competence cultivation of basic logistics management talents, and to analyze the importance of competence cultivation of basic logistics management talents. First of all, the Fuzzy Delphi Method is adopted to screen out the key dimensions and criteria for the courses of competence cultivation of basic logistics management talents. Second, a quantitative method is used to further investigate the opinions of experts in the industry, officials and scholars, and the Fuzzy method is used to resolve the ambiguity between dimensions and criteria. Then, the DANP method is adopted to clarify the causal relationship of key factors. In this study, the dimensions and criteria for the courses of competence cultivation of basic logistics management talents are screened and identified by means of literature and expert questionnaire, and then the DEMATEL method is used to explore the correlation between the dimensions and their related criteria. Finally, the weights of key dimensions and criteria are calculated by means of the DANP method, so as to provide some references for the logistics-related disciplines to arrange and design the courses of competence cultivation of basic logistics management talents.
The effect of inhibition on rate code efficiency indicators

In this paper we investigate the rate coding capabilities of neurons whose input signal are alterations of the base state of balanced inhibitory and excitatory synaptic currents. We consider different regimes of excitation-inhibition relationship and an established conductance-based leaky integrator model with adaptive threshold and parameter sets recreating biologically relevant spiking regimes. We find that given mean post-synaptic firing rate, counter-intuitively, increased ratio of inhibition to excitation generally leads to higher signal to noise ratio (SNR). On the other hand, the inhibitory input significantly reduces the dynamic coding range of the neuron. We quantify the joint effect of SNR and dynamic coding range by computing the metabolic efficiency—the maximal amount of information per one ATP molecule expended (in bits/ATP). Moreover, by calculating the metabolic efficiency we are able to predict the shapes of the post-synaptic firing rate histograms that may be tested on experimental data. Likewise, optimal stimulus input distributions are predicted, however, we show that the optimum can essentially be reached with a broad range of input distributions. Finally, we examine which parameters of the used neuronal model are the most important for the metabolically efficient information transfer.
Strategies for inducing effective neutralizing antibody responses against HIV-1

ABSTRACT Introduction: Despite intensive research efforts, there is still no effective prophylactic vaccine available against HIV-1. Currently, substantial efforts are devoted to the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs), which are capable of neutralizing most HIV-1 strains. All bNAbs target the HIV-1 envelope glycoprotein (Env), but Env immunizations usually only induce neutralizing antibodies (NAbs) against the sequence-matched virus and not against other strains. Areas covered: We describe the different strategies that have been explored to improve the breadth and potency of anti-HIV-1 NAb responses. The discussed strategies include the application of engineered Env immunogens, optimization of (bNAb) epitopes, different cocktail and sequential vaccination strategies, nanoparticles and nucleic acid-based vaccines. Expert opinion: A combination of the strategies described in this review and future approaches are probably needed to develop an effective HIV-1 vaccine that can induce broad, potent and long-lasting NAb responses.
Development of container free sample exposure for synchrotron X-ray footprinting.

The method of X-ray Footprinting and Mass Spectrometry (XFMS) on large protein assemblies and membrane protein samples requires high flux density to overcome the hydroxyl radical scavenging reactions produced by the buffer constituents and the total protein content. Previously, we successfully developed microsecond XFMS using microfluidic capillary flow and a micro-focused broadband X-ray source at the Advanced Light Source synchrotron beamlines, but the excessive radiation damage incurred when using capillaries prevented the full usage of a high-flux density beam. Here we present another significant advance for the XFMS method: the instrumentation of a liquid injection jet to deliver container free samples to the X-ray beam. Our preliminary experiments with a liquid jet at a bending magnet X-ray beamline demonstrate the feasibility of the approach, and show a significant improvement in the effective dose for both the Alexa fluorescence assay and protein samples compared to conventional capillary flow methods. The combination of precisely controlled high dose delivery, shorter exposure times, and elimination of radiation damage due to capillary effects significantly increases the signal quality of the hydroxyl radical modification products and the dose-response data. This new approach is the first application of container free sample handling for XFMS, and opens up the method for even further advances, such as high-quality microsecond time-resolved XFMS studies.
Impaired lysosomal acidification triggers iron deficiency and inflammation in vivo

Lysosomal acidification is a key feature of healthy cells. Inability to maintain lysosomal acidic pH is associated with aging and neurodegenerative diseases. However, the mechanisms elicited by impaired lysosomal acidification remain poorly understood. We show here that inhibition of lysosomal acidification triggers cellular iron deficiency, which results in impaired mitochondrial function and non-apoptotic cell death. These effects are recovered by supplying iron via a lysosome-independent pathway. Notably, iron deficiency is sufficient to trigger inflammatory signaling in cultured primary neurons. Using a mouse model of impaired lysosomal acidification, we observed a robust iron deficiency response in the brain, verified by in vivo magnetic resonance imaging. Furthermore, the brains of these mice present a pervasive inflammatory signature associated with instability of mitochondrial DNA (mtDNA), both corrected by supplementation of the mice diet with iron. Our results highlight a novel mechanism linking impaired lysosomal acidification, mitochondrial malfunction and inflammation in vivo.
Generalized multiple contrast tests in dose‐response studies

In the process of developing drugs, proof‐of‐concept studies can be helpful in determining whether there is any evidence of a dose‐response relationship. A global test for this purpose that has gained popularity is a component of the multiple comparisons procedure with modeling techniques (MCP‐Mod), which involves the specification of a candidate set of several plausible dose‐response models. For each model, a test is performed for significance of an optimally chosen contrast among the sample means. An overall P‐value is obtained from the distribution of the maximum of the contrast statistics. This is equivalent to basing the test on the minimum of the P‐values arising from these contrast statistics and, hence, can be viewed as a method for combining dependent P‐values. We generalize this idea to the use of different statistics for combining the dependent P‐values, such as Fisher's combination method or the inverse normal combination method. Simulation studies show that the generalized multiple contrast tests (GMCTs) based on the Fisher and inverse normal methods are generally more powerful than the MCP‐Mod procedure based on the minimum of the P‐values except for cases where the true dose‐response model is, in a sense, near the extremes of the candidate set of dose‐response models. The proposed GMCTs can also be used for model selection and dosage selection by employing a closed testing procedure.
Recherche de corrélation entre l’intensité de fixation de la 18F-FDOPA en TEP et l’expression du transporteur LAT1 en immunohistochimie dans les tumeurs cérébrales

Introduction : La TEP/TDM a la 18F-FDOPA est une technique d’imagerie de plus en plus utilisee dans l’exploration des tumeurs cerebrales. La surexpression du transporteur transmembranaire d’acides amines LAT1 par les tumeurs cerebrales serait responsable de leur hyperfixation de la 18F-FDOPA, mais les mecanismes responsables de cette fixation restent encore mal connus. L’objectif de notre etude etait de rechercher s’il existait une correlation entre l’intensite de fixation de la 18F-FDOPA en TEP/TDM et l’expression du transporteur LAT1 en immunohistochimie dans les tumeurs cerebrales primitive ou secondaires. Materiels et methodes : 28 patients ayant beneficie d’une TEP/TDM a la 18F-FDOPA dans un delai de deux mois avant chirurgie d’une tumeur cerebrale ont ete inclus. La population etait composee de 19 gliomes (5 grade II, 1 grade III et 13 grade IV) et 9 metastases. 22 tumeurs avaient ete prealablement irradiees. L’intensite de fixation en TEP a ete mesuree aux temps precoce (20min) et tardif (90min) avec different index (SUVmax, SUVpeak, SUVmean) normalises par un niveau de fixation endogene (striatum contro-lateral ou bruit de fond cerebral). L’expression de LAT1 a ete mesuree en immunohistochimie et rapportee selon deux scores (score de Hirsch et un score quantitatif). Resultats : Quel que soit l’index de quantification de l’intensite de fixation de la 18F-FDOPA et le score de marquage de LAT1 utilises, au temps precoce comme au temps tardif, nous n’avons pas mis en evidence de correlation entre ces deux parametres. On rapporte notamment 5 cas dont l’expression de LAT1 etait seulement cytoplasmique, donc a priori non fonctionnelle, mais dont l’intensite de la fixation de la 18F-FDOPA etait moyenne ou elevee. Aussi, il existait 4 cas avec un score de marquage faible et une intensite de fixation de la 18F-FDOPA elevee et 4 cas avec un score de marquage eleve et une intensite de fixation faible. Par ailleurs, la cinetique d’elimination de la 18F-FDOPA (calculee par le ratio SUVmax T/S Tardif / SUVmax T/S Precoce) etaient significativement plus rapide dans les tumeurs gliales que les metastases (p=0,047). Aussi, plus l’expression de LAT1 etait forte, plus la cinetique d’elimination du radiopharmaceutique etait lente (p=0,038). Conclusion : Dans notre etude ou la majorite des lesions avait ete prealablement irradiees, il n’existait pas de correlation entre l’intensite de fixation de la 18F-FDOPA et l’expression de LAT1 en immunohistochimie. Ce resultat suggere que LAT1 n’est probablement pas le seul facteur implique dans la fixation de la 18F-FDOPA par les tumeurs cerebrales. D’autres etudes semblent necessaires pour comprendre les mecanismes d’accumulation de la 18F-FDOPA dans les tumeurs cerebrales et notamment pour mieux caracteriser l’influence de l’irradiation.