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Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive dementia. The detection of 14-3-3 protein in cerebrospinal fluid (CSF) is included in the WHO diagnostic criteria for the pre-mortem diagnosis of CJD. The aim of this study is to assess CSF 14-3-3 protein analytical and diagnostic performances using a new automated capillary Western technology (Simple Western technology-SW). For the validation of this assay, samples from a cohort of 268 patients suspected from sCJD were analyzed: 77 sCJD (including 40 definite sCJD) and 191 non-CJD samples were tested using both SW and the current Western Blot (WB) assays. Automated capillary Western determination provided better analytical performances than WB with a lower intra- and inter-assay variability. Analytical interferences such as hemolysis and high total protein concentration known to lead to false positive WB results were also assessed using SW assay: unfortunately, these interferences still remain confounders of CSF 14-3-3 protein determination. Finally, automated capillary Western assay’s sensitivity and specificity were superior to those of WB assay (93.5 and 95.3%, respectively, compared to 92.2 and 84.8% for WB). In conclusion, with a shorter time of analysis than WB assays’ (4 h versus 1.5 day), automated capillary Western assay is an excellent routine alternative method to the currently performed WB assay for CSF 14-3-3 protein detection in patients suspected of sporadic Creutzfeldt-Jakob disease.

Background Liver metastases are mainly supplied by the hepatic artery, allowing the administration of intra-arterial hepatic chemotherapy (IAHC) while preserving normal parenchyma. The progression-free survival and response rate are prolonged by IAHC which can improve the rate of secondary resectability. Severe abdominal pain requiring high-dose opioids can appear during HIAC administration. This pain is related to extrahepatic infusion and gastroduodenal ulceration. However, intense abdominal pain was observed under oxaliplatin IAHC specifically without any extrahepatic infusion. Method We retrospectively reviewed the charts of 68 patients who received IAHC in our center between 2011 and 2015. Patient’s demographics and disease characteristics were collected. Other variables such as the type, duration, and dosage of the chemotherapy administered, as well as the usage of painkillers before, during, or after intra-arterial administration, were also registered. Results The mean age of the patients was 59 years. 61.7% were male ( n  = 42). The mean dose of oxaliplatin administered was 162 mg per cure over 6.7-h course. Fifty percent were diagnosed with a left colon cancer, and 85.2% had synchronous liver metastasis. While 47% of patients received IAHC as a third-line therapy, the main chemotherapeutic drug was oxaliplatin (85.2% of cases; n  = 58), then OPTILIV protocol (5FU, irinotecan, oxaliplatin) (13.3%; n  = 9), and mitomycin C (1.5%; n  = 1). A dose reduction of 23.6% had been noted in 58.8% ( n  = 40) cases due to adverse effects. Among patients who received opioids during IAHC (n = 40), 20% required opioids in intercure. Before, during, and after IAHC administration, patients complained of abdominal pain in 8.8%, 58.8%, and 19.1%, and opioids were used in 10.2%, 57.3%, and 19.1%, respectively. The main onset of pain occurs during the third cycle of chemotherapy. Among our patients, 11.7% and 22% had ulcer and extrahepatic perfusion, respectively, while 7.3% of them were asymptomatic. The mean occurrence of these signs was during the fourth cycle of IAHC. 33.8% and 52.9% of patients had abdominal pain while an extended and short infusion time, respectively. Conclusion Lengthening of the infusion time did not prevent the occurrence of abdominal pain significantly but was nonetheless decreased compared with patients undergoing short infusion durations. Pain was more common in patients who did not have a dose reduction and who presented with ulcer and extrahepatic perfusion. Abdominal pain occurred on average one cycle before ulcer or extrahepatic perfusion diagnosis. In current practice, pain should be an alarming indicator in patients receiving IAHC, as it may be associated with ulcer or extrahepatic perfusion and thus requiring opioids.

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1 , 2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3 – 7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease. A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

The aim was to investigate the relation between urinary neopterin and the Crohn's Disease Activity Index (CDAI) and to compare its ability to discriminate active versus inactive CD with serum C-reactive protein (CRP).MethodsIn all, 217 urinary samples for neopterin measurement were obtained in a cohort of 93 consecutive patients with CD and 66 samples in 33 healthy volunteers. Clinical parameters were recorded and blood samples for CRP were collected as well.ResultsWhereas patients with inactive CD showed similar levels of urinary neopterin excretion than healthy volunteers (163 ± 8 versus 142 ± 7 nmol/mol of creatinine, respectively; P = 0.1), urinary neopterin excretion from mild to severe active CD was significantly higher (302 ± 15 nmol/mol of creatinine; P < 0.001). Serum CRP levels were higher in active CD (14.8 ± 2.1 mg/L) compared with inactive CD (5.6 ± 0.8 mg/L; P < 0.001). Urinary neopterin excretion, and to a lesser degree CRP, were positively and significantly correlated with CDAI (r = 0.64 and 0.43, respectively, P < 0.001). Based on the cutoff of 183 nmol/mol of creatinine for urinary neopterin, the sensitivity and specificity of urinary neopterin to discriminate between active and inactive CD were 73% and 82%, respectively, and the positive and negative predictive values were 80% and 78%, respectively.ConclusionsUrinary neopterin excretion is an objective, valuable, simple, and noninvasive biomarker to detect and follow fluctuations of CD activity. Further work is warranted to study its clinical value and relation to mucosal healing.

To investigate the intracellular transport of sterols in etiolated leek (Allium porrum L.) seedlings, in vivo pulse-chase experiments with [1-14C]acetate were performed. Then, endoplasmic reticulum-, Golgi-, and plasma membrane (PM)-enriched fractions were prepared and analyzed for the radioactivity incorporated into free sterols. In leek seedlings sterols are present as a mixture in which (24R)-24-ethylcholest-5-en-3beta-ol is by far the major compound (around 60%). The other sterols are represented by cholest-5-en-3beta-ol, 24-methyl-cholest-5-en-3beta-ol, (24S)-24-ethylcholesta-5,22E-dien-3beta-ol, and stigmasta-5,24(24(1))Z-dien-3Beta-ol. These compounds are shown to reside mainly in the PM. Our results clearly indicate that free sterols are actively transported from the endoplasmic reticulum to the PM during the first 60 min of chase, with kinetics very similar to that of phosphatidylserine. Such a transport was found to be decreased at low temperature (12 degrees C) and following treatment with monensin and brefeldin A. These data are consistent with a membrane-mediated process for the intracellular transport of sterols to the PM, which likely involves the Golgi apparatus

Despite the current wealth of sequencing data, one‐third of all biochemically characterized metabolic enzymes lack a corresponding gene or protein sequence, and as such can be considered orphan enzymes. They represent a major gap between our molecular and biochemical knowledge, and consequently are not amenable to modern systemic analyses. As 555 of these orphan enzymes have metabolic pathway neighbours, we developed a global framework that utilizes the pathway and (meta)genomic neighbour information to assign candidate sequences to orphan enzymes. For 131 orphan enzymes (37% of those for which (meta)genomic neighbours are available), we associate sequences to them using scoring parameters with an estimated accuracy of 70%, implying functional annotation of 16 345 gene sequences in numerous (meta)genomes. As a case in point, two of these candidate sequences were experimentally validated to encode the predicted activity. In addition, we augmented the currently available genome‐scale metabolic models with these new sequence–function associations and were able to expand the models by on average 8%, with a considerable change in the flux connectivity patterns and improved essentiality prediction. Many characterized metabolic enzymes currently lack associated gene and protein sequences. Here, pathway and genomic neighbour data are used to assign genes to these ‘orphan enzymes,’ and the predictions are validated with experimental assays and genome‐scale metabolic modelling. Synopsis Many characterized metabolic enzymes currently lack associated gene and protein sequences. Here, pathway and genomic neighbour data are used to assign genes to these ‘orphan enzymes,’ and the predictions are validated with experimental assays and genome‐scale metabolic modelling. A computational method is developed for assigning candidate sequences to orphan enzymes. The method uses metabolic pathway, genomic neighbourhood, genomic co‐occurrence, and protein domain information to predict genes that are likely to perform a particular enzymatic function. Benchmarking of the scoring scheme based on the 4 features above revealed that some combinations of parameters yielded greater than 70% accuracy, and that high‐confidence predictions could be generated for 131 orphan enzymes. Enzyme assay experiments confirmed the predicted enzymatic activity for two of the high‐confidence candidate sequences. Predicted functions can improve the annotation of genomic and metagenomic data, and can reveal putative genes for enzymes with potential biotechnological applications. Incorporating the predicted enzymatic reactions into genome‐scale metabolic models changed the flux connectivity and improved their ability to correctly predict gene essentiality, supporting the biological relevance of these predictions.

This paper discusses the distinct meanings of internalization and interiorization as ways of rendering intelligible the social constitution of the psychological in a line of research that started with Piaget and extended into a post-Piagetian reformulation of intelligence in successive generations of studies of the relations between social interaction and cognitive development. While the same clarity cannot be found in Vygotsky’s work, the emphasis on the cultural embeddedness of cognitive activity in contemporary cultural psychology has also been a significant influence on the evolution of this work. This paper proposes a further integration of these perspectives by developing the idea of operativity-in-context as a means of retaining the advantages of Piaget’s structural analysis of cognition whilst recognizing the situational and cultural constraints on cognitive functioning.

The current study explores the extent to which different processing strategies affect comprehension accuracy and integration of information across multiple texts. Reading comprehension of single texts is a difficult task, in which the challenges are compounded by the need to integrate information across texts. Processing strategies, such as self-explanation and source-evaluation, help reduce the challenges that readers face when attempting to comprehend texts. Self-explanation has been a successful strategy for coherence-building processes in single text comprehension, but the benefits for supporting inter-textual comprehension have not yet been explored. Source-evaluation supports identification of different sources, which helps resolve inconsistencies between texts; yet it remains unclear whether sourcing alone supports comprehension within as well as between texts. Think-aloud is a strategy intended to encourage further processing of the text without providing any explicit comprehension strategy. The differences between these two strategies prompts questions regarding the adequacy of either strategy for supporting inferencing and integration within and across texts. In this study, participants (n=80) were randomly assigned to one of three strategy conditions: self-explanation, source-evaluation, or think-aloud. Students read four texts after which they completed three types of open-ended comprehension questions (i.e., textbase, intra-textual inference, and inter-textual inference), a source memory task, and individual difference measures. Prior knowledge and reading skill were strongly correlated (r = .65) and showed moderate correlations (r = .31 to .60) with participants’ comprehension accuracy, total number of integrations within their responses, and their memory for sources. Participants were more likely to respond accurately and demonstrate integrations across texts for the text-based questions in comparison to the more challenging inference questions. There was a marginal effect of condition on comprehension question accuracy, wherein participants who self-explained responded more accurately than those who engaged in the think-aloud task. In addition, those in the self-explanation or source-evaluation conditions recalled more sources than those in the think-aloud condition. There were no significant differences in performance between the self-explanation and the source-evaluation conditions. Overall, the results of this study indicate that encouraging students to self-explain and/or evaluate sources while they read multiple documents enhances comprehension and memory for sources.

Bcl-2 and p53 genes may participate in a common pathway for regulation of apoptosis. The aims of this study were (1) to study the immunohistochemical expression of the bcl-2 oncoprotein in colorectal tumors, (2) to correlate it with that of p53 protein overexpression, and (3) to compare it with histopathologic prognostic factors, such as TNM classification and grade. Prospective study of expression of bcl-2 and p53 oncogenes in colorectal tumors. We examined 6 colorectal hyperplastic polyps, 33 adenomas, and 61 carcinomas. Regional academic medical center. An immunohistochemical study with bcl-2 and p53 antibodies was performed on frozen sections of colorectal tumors. The levels of bcl-2 and p53 expression were evaluated using a semiquantitative grading system. Two-color immunohistochemistry was performed to examine the intracellular colocalization of bcl-2 and p53 in all tumors with a strong positivity for both antigens. Bcl-2 was expressed in 28 (85%) of the 33 adenomas, whereas p53 was expressed in only one adenoma, which had areas of in situ carcinoma. Bcl-2 and p53 were each expressed in 43 (70.4%) of the 61 carcinomas. Thirty-one (50%) of the colorectal carcinomas coexpressed the two oncoproteins. There was no correlation between the number of cells expressing bcl-2 and the number expressing p53 in a given carcinoma. No correlation was observed between the expression of bcl-2 or p53 and the established prognostic factor. Abnormal bcl-2 oncoprotein expression appears earlier than p53 accumulation in colorectal carcinogenesis. This study suggests that there is more than one sequence and mechanism of bcl-2 and p53 gene deregulation in colorectal carcinomas.