Aged complement factor H knockout mice kept in a clean barriered environment have reduced retinal pathology

Age-related macular degeneration (AMD) is the largest cause of visual loss in those over 60 years in the West and is a condition increasing in prevalence. Many diseases result from genetic/environmental interactions and 50% of AMD cases have an association with polymorphisms of the complement system including complement factor H. Here we explore interactions between genetic predisposition and environmental conditions in triggering retinal pathology in two groups of aged complement factor H knock out (Cfh−/−) mice. Mice were maintained over 9 months in either a conventional open environment or a barriered pathogen free environment. Open environment Cfh−/− mice had significant increases in subretinal macrophage numbers, inflammatory and stress responses and reduced photoreceptor numbers over mice kept in a pathogen free environment. Hence, environmental factors can drive retinal disease in these mice when linked to complement deficits impairing immune function. Both groups of mice had similar levels of retinal amyloid beta accumulation. Consequently there is no direct link between this and inflammation in Cfh−/− mice

Comparison of KRAS Mutation Assessment in Tumor DNA and Circulating Free DNA in Plasma and Serum Samples

Testing for mutations in the KRAS oncogene for patients with metastatic colorectal cancer (mCRC) is generally performed using DNA from formalin-fixed paraffin-embedded tumor tissue; however, access to specimens can be limited and analysis challenging. This study assessed the identification of KRAS mutations in circulating free DNA (cfDNA) using a commercially available KRAS polymerase chain reaction (PCR) kit. Matched plasma, serum and tumor samples were available from 71 patients with mCRC who had received prior therapy but whose disease progressed following therapy. Yields of cfDNA from plasma and serum samples were comparable. Analyses were successful in 70/71 plasma-extracted samples (specificity: 97%, sensitivity: 31%) and 67/71 serum- extracted samples (specificity: 100%, sensitivity: 25%). This study demonstrates that KRAS mutations can be detected in cfDNA using a commercially available KRAS PCR kit, confirming cfDNA as a potential alternative source of tumor DNA in a diagnostic setting if access to archival tumor specimens is limited

Aged complement factor H knockout mice kept in a clean barriered environment have reduced retinal pathology

Age-related macular degeneration (AMD) is the largest cause of visual loss in those over 60 years in the West and is a condition increasing in prevalence. Many diseases result from genetic/environmental interactions and 50% of AMD cases have an association with polymorphisms of the complement system including complement factor H. Here we explore interactions between genetic predisposition and environmental conditions in triggering retinal pathology in two groups of aged complement factor H knock out (Cfh−/−) mice. Mice were maintained over 9 months in either a conventional open environment or a barriered pathogen free environment. Open environment Cfh−/− mice had significant increases in subretinal macrophage numbers, inflammatory and stress responses and reduced photoreceptor numbers over mice kept in a pathogen free environment. Hence, environmental factors can drive retinal disease in these mice when linked to complement deficits impairing immune function. Both groups of mice had similar levels of retinal amyloid beta accumulation. Consequently there is no direct link between this and inflammation in Cfh−/− mice

Pancreatic hormones and amino acid levels following liver transplantation

Glucose intolerance, hyperinsulinemia, peripheral insulin resistance and hyperglucagonemia are common in patients with advanced liver disease. These abnormalities in the plasma levels of the pancreatic hormones, insulin and glucagon have been thought to be responsible, at least in part, for the abnormal plasma ratio of branched‐chain amino acids to aromatic amino acids. To evaluate this issue, plasma levels of glucose, insulin, glucagon, C‐peptide and the branched‐chain and aromatic amino acids were measured before and serially after orthotopic liver transplantation in 9 humans and 5 dogs. The abnormal plasma amino acid levels rapidly improved and achieved normal levels following orthotopic liver transplantation. Insulin levels also became normal following orthotopic liver transplantation, despite enhanced insulin secretion documented by an even further increased level of C‐peptide. In contrast, the baseline abnormal plasma glucagon levels which are commonly seen in cirrhotics became even more abnormal following orthotopic liver transplantation. Despite this progressive increase in the abnormally elevated plasma glucagon levels, plasma amino acid levels, both branched‐chain and aromatic, became normal. These data demonstrate that before and after orthotopic liver transplantation, there is: (i) no relationship between the changes in plasma levels of glucagon and changes observed in the plasma level of amino acids; and (ii) plasma insulin and amino acid levels change in the same direction. In addition, these changes in plasma insulin and amino acid levels following orthotopic liver transplantation occur despite enhanced secretion of insulin evidenced by the progressive increase in plasma levels of C‐peptide. Copyright © 1987 American Association for the Study of Liver Disease

Acquiring and processing verb argument structure : distributional learning in a miniature language

Adult knowledge of a language involves correctly balancing lexically-based and more language-general patterns. For example, verb argument structures may sometimes readily generalize to new verbs, yet with particular verbs may resist generalization. From the perspective of acquisition, this creates significant learnability problems, with some researchers claiming a crucial role for verb semantics in the determination of when generalization may and may not occur. Similarly, there has been debate regarding how verb-specific and more generalized constraints interact in sentence processing and on the role of semantics in this process. The current work explores these issues using artificial language learning. In three experiments using languages without semantic cues to verb distribution, we demonstrate that learners can acquire both verb-specific and verb-general patterns, based on distributional information in the linguistic input regarding each of the verbs as well as across the language as a whole. As with natural languages, these factors are shown to affect production, judgments and real-time processing. We demonstrate that learners apply a rational procedure in determining their usage of these different input statistics and conclude by suggesting that a Bayesian perspective on statistical learning may be an appropriate framework for capturing our findings

Glutamatergic Neurons in Rodent Models Respond to Nanoscale Particulate Urban Air Pollutants in Vivo and in Vitro

Background: Inhalation of airborne particulate matter (PM) derived from urban traffic is associated with pathology in the arteries, heart, and lung; effects on brain are also indicated but are less documented

Harmonic biases in child learners: In support of language universals

A fundamental question for cognitive science concerns the ways in which languages are shaped by the biases of language learners. Recent research using laboratory language learning paradigms, primarily with adults, has shown that structures or rules that are common in the languages of the world are learned or processed more easily than patterns that are rare or unattested. Here we target child learners, investigating a set of biases for word order learning in the noun phrase studied by Culbertson, Smolensky & Legendre (2012) in college-age adults. We provide the first evidence that child learners exhibit a preference for typologically common harmonic word order patterns—those which preserve the order of the head with respect to its complements—validating the psychological reality of a principle formalized in many different linguistic theories. We also discuss important differences between child and adult learners in terms of both the strength and content of the biases at play during language learning. In particular, the bias favoring harmonic patterns is markedly stronger in children than adults, and children (unlike adults) acquire adjective ordering more readily than numeral ordering. The results point to the importance of investigating learning biases across development in order to understand how these biases may shape the history and structure of natural languages

Risk estimation of distant metastasis in node-negative, estrogen receptor-positive breast cancer patients using an RT-PCR based prognostic expression signature

<p>Abstract</p> <p>Background</p> <p>Given the large number of genes purported to be prognostic for breast cancer, it would be optimal if the genes identified are not confounded by the continuously changing systemic therapies. The aim of this study was to discover and validate a breast cancer prognostic expression signature for distant metastasis in untreated, early stage, lymph node-negative (N-) estrogen receptor-positive (ER+) patients with extensive follow-up times.</p> <p>Methods</p> <p>197 genes previously associated with metastasis and ER status were profiled from 142 untreated breast cancer subjects. A "metastasis score" (MS) representing fourteen differentially expressed genes was developed and evaluated for its association with distant-metastasis-free survival (DMFS). Categorical risk classification was established from the continuous MS and further evaluated on an independent set of 279 untreated subjects. A third set of 45 subjects was tested to determine the prognostic performance of the MS in tamoxifen-treated women.</p> <p>Results</p> <p>A 14-gene signature was found to be significantly associated (p < 0.05) with distant metastasis in a training set and subsequently in an independent validation set. In the validation set, the hazard ratios (HR) of the high risk compared to low risk groups were 4.02 (95% CI 1.91–8.44) for the endpoint of DMFS and 1.97 (95% CI 1.28 to 3.04) for overall survival after adjustment for age, tumor size and grade. The low and high MS risk groups had 10-year estimates (95% CI) of 96% (90–99%) and 72% (64–78%) respectively, for DMFS and 91% (84–95%) and 68% (61–75%), respectively for overall survival. Performance characteristics of the signature in the two sets were similar. Ki-67 labeling index (LI) was predictive for recurrent disease in the training set, but lost significance after adjustment for the expression signature. In a study of tamoxifen-treated patients, the HR for DMFS in high compared to low risk groups was 3.61 (95% CI 0.86–15.14).</p> <p>Conclusion</p> <p>The 14-gene signature is significantly associated with risk of distant metastasis. The signature has a predominance of proliferation genes which have prognostic significance above that of Ki-67 LI and may aid in prioritizing future mechanistic studies and therapeutic interventions.</p

PulseNet International survey on the implementation of whole genome sequencing in low and middle-income countries for foodborne disease surveillance

PulseNet International (PNI) is a global network of 88 countries who work together through their regional and national public health laboratories to track foodborne disease around the world. The vision of PNI is to implement globally standardized surveillance using whole genome sequencing (WGS) for real-time identification and subtyping of foodborne pathogens to strengthen preparedness and response and lower the burden of disease. Several countries in North America and Europe have experienced significant benefits in disease mitigation after implementing WGS. To broaden the routine use of WGS around the world, challenges and barriers must be overcome. We conducted this study to determine the challenges and barriers countries are encountering in their attempts to implement WGS and to identify how PNI can provide support to improve and become a better integrated system overall. A survey was designed with a set of qualitative questions to capture the status, challenges, barriers, and successes of countries in the implementation of WGS and was administered to laboratories in Africa, Asia-Pacific, Latin America and the Caribbean, and Middle East. One-third of respondents do not use WGS, and only 8% reported using WGS for routine, real-time surveillance. The main barriers for implementation of WGS were lack of funding, gaps in expertise, and training, especially for data analysis and interpretation. Features of an ideal system to facilitate implementation and global surveillance were identified as an all-in-one software that is free, accessible, standardized and validated. This survey highlights the minimal use of WGS for foodborne disease surveillance outside the United States, Canada, and Europe to date. Although funding remains a major barrier to WGS-based surveillance, critical gaps in expertise and availability of tools must be overcome. Opportunities to seek sustainable funding, provide training, and identify solutions for a globally standardized surveillance platform will accelerate implementation of WGS worldwide.Cooperative Agreement number NU60OE000104, funded by the Centers for Disease Control and Prevention.https://home.liebertpub.com/publications/foodborne-pathogens-and-disease/108hj2023Medical Microbiolog