Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Complete Genome Sequences of Cluster A Mycobacteriophages BobSwaget, Fred313, KADY, Lokk, MyraDee, Stagni, and StepMih

Seven mycobacteriophages from distinct geographical locations were isolated, using Mycobacterium smegmatis mc2155 as the host, and then purified and sequenced. All of the genomes are related to cluster A mycobacteriophages, BobSwaget and Lokk in subcluster A2; Fred313, KADY, Stagni, and StepMih in subcluster A3; and MyraDee in subcluster A18, the first phage to be assigned to that subcluster

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Models of classroom assessment for course-based research experiences

Course-based research pedagogy involves positioning students as contributors to authentic research projects as part of an engaging educational experience that promotes their learning and persistence in science. To develop a model for assessing and grading students engaged in this type of learning experience, the assessment aims and practices of a community of experienced course-based research instructors were collected and analyzed. This approach defines four aims of course-based research assessment—(1) Assessing Laboratory Work and Scientific Thinking; (2) Evaluating Mastery of Concepts, Quantitative Thinking and Skills; (3) Appraising Forms of Scientific Communication; and (4) Metacognition of Learning—along with a set of practices for each aim. These aims and practices of assessment were then integrated with previously developed models of course-based research instruction to reveal an assessment program in which instructors provide extensive feedback to support productive student engagement in research while grading those aspects of research that are necessary for the student to succeed. Assessment conducted in this way delicately balances the need to facilitate students’ ongoing research with the requirement of a final grade without undercutting the important aims of a CRE education

Suppression of the PI3K subunit p85α delays embryoid body development and inhibits cell adhesion

Phosphatidylinositol-3-kinases (PI3Ks) exert a variety of signaling functions in eukaryotes. We suppressed the PI3K regulatory subunit p85α using a small interfering RNA (Pik3r1 siRNA) and examined the effects on embryoid body (EB) development in hanging drop culture. We observed a 150% increase in the volume of the treated EBs within 24 h, compared to the negative controls. Fluorescence Activated Cell Sorting (FACS) assays showed that this increase in volume is not due to increased cellular proliferation. Instead, the increase in volume appears to be due to reduced cellular aggregation and adherence. This is further shown by our observation that 40% of treated EBs form twin instead of single EBs, and that they have a significantly reduced ability to adhere to culture dishes when plated. A time course over the first 96 h reveals that the impaired adherence is transient and explained by an initial 12-hour delay in EB development. Quantitative PCR expression analysis suggests that the adhesion molecule integrin-β1 (ITGB1) is transiently downregulated by the p85α suppression. In conclusion we found that suppressing p85α leads to a delay in forming compact EBs, accompanied by a transient inability of the EBs to undergo normal cell-cell and cell-substrate adhesion.</p

Evaluating length heteroplasmy in the human mitochondrial DNA control region

We present allelic data for three known and one new C-tract in the human mitochondrial DNA (mtDNA) control region, and we measure intergenerational mutation rates at such C-tracts. In detail, in a sample of 1,172 mtDNA sequences, we demonstrate the existence of an instability threshold of eight consecutive cytosines, at and above which the phenomenon of length heteroplasmy arises. To determine mutation rates, we draw on mtDNA sequences in up to four generations of 248 pedigrees for families living in high or low-radiation environmental conditions. The high-radiation sample gives the most conservative (fastest) mutation rate likely to be encountered in any forensic context. We find that the C-tract mutation rate is up to 6% per generation, and we observe an excess of cytosine gains over losses. Case studies and guidelines for evaluating mtDNA heteroplasmy are provided.</p

Developing equine mtDNA profiling for forensic application

Horse mtDNA profiling can be useful in forensic work investigating degraded samples, hair shafts or highly dilute samples. Degraded DNA often does not allow sequencing of fragments longer than 200 nucleotides. In this study we therefore search for the most discriminatory sections within the hypervariable horse mtDNA control region. Among a random sample of 39 horses, 32 different sequences were identified in a stretch of 921 nucleotides. The sequences were assigned to the published mtDNA types A-G, and to a newly labelled minor type H. The random match probability within the analysed samples is 3.61%, and the average pairwise sequence difference is 15 nucleotides. In a "sliding window" analysis of 200-nucleotide sections of the mtDNA control region, we find that the known repetitive central motif divides the mtDNA control region into a highly diverse segment and a markedly less discriminatory segment.</p

Work practices and childhood agricultural injury

Objective: To evaluate whether children\u27s agricultural work practices were associated with agricultural injury and to identify injury and work practice predictors. Design: Analyses were based on nested case-control data collected by the Regional Rural Injury Study-II (RRIS-II) surveillance study in 1999 and 2001 by computer-assisted telephone interviews. Subjects: Cases (n = 425) and controls (n = 1886) were persons younger than 20 years of age from Midwestern agricultural households. Those reporting agricultural injuries became cases; controls (no injury) were selected using incidence density sampling. Main outcome measures: Multivariate logistic regression was used to estimate the risks of injury associated with agricultural work, performing chores earlier than developmentally appropriate, hours worked per week, and number of chores performed. Results: Increased risks of injury were observed for children who performed chores 2-3 years younger than recommended, compared to being age-appropriate (odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.4-4.5); performed any agricultural work (3.9 (2.6-5.6)); performed seven to ten chores per month compared to one chore (2.2 (1.3-3.5)); and worked 11-30 or 31-40 h per week compared to 1-10 h (1.6 (1.2-2.1) and 2.2 (1.3-3.7), respectively). Decreased risks of injury were observed for non-working children compared to children performing what are commonly considered safe levels of agricultural work. Conclusions: This study demonstrated elevated risks of agricultural injury among children who perform developmentally inappropriate chores. Results suggest that the efficacy of age restrictions for preventing the occurrence of childhood agricultural injuries warrants further evaluation