Editorial

In a globally changing climate and with the alarming loss of biodiversity Comparative Endocrinology becomes ever more relevant as a scientific discipline. The comparative endocrinologist continues to be at the frontline of scientific endeavour trying to understand the myriad complexities of life forms on earth by looking at the regulatory factors that underpin key events in an organisms’ life and ensure maintenance of homeostasis and species survival

Connecting every bit of knowledge: The structure of Wikipedia\u27s First Link Network

Apples, porcupines, and the most obscure Bob Dylan song—is every topic a few clicks from Philosophy? Within Wikipedia, the surprising answer is yes: nearly all paths lead to Philosophy. Wikipedia is the largest, most meticulously indexed collection of human knowledge ever amassed. More than information about a topic, Wikipedia is a web of naturally emerging relationships. By following the first link in each article, we algorithmically construct a directed network of all 4.7 million articles: Wikipedia\u27s First Link Network. Here, we study the English edition of Wikipedia\u27s First Link Network for insight into how the many articles on inventions, places, people, objects, and events are related and organized. By traversing every path, we measure the accumulation of first links, path lengths, groups of path-connected articles, and cycles. We also develop a new method, traversal funnels, to measure the influence each article exerts in shaping the network. Traversal funnels provide a new measure of influence for directed networks without spill-over into cycles, in contrast to traditional network centrality measures. Within Wikipedia\u27s First Link Network, we find scale-free distributions describe path length, accumulation, and influence. Far from dispersed, first links disproportionately accumulate at a few articles—flowing from specific to general and culminating around fundamental notions such as Community, State, and Science. Philosophy directs more paths than any other article by two orders of magnitude. We also observe a gravitation toward topical articles such as Health Care and Fossil Fuel. These findings enrich our view of the connections and structure of Wikipedia\u27s ever growing store of knowledge

Isolation of circulating tumor cells from glioblastoma patients by direct immunomagnetic targeting

Glioblastoma (GBM) is the most common form of primary brain cancer in adults and tissue biopsies for diagnostic purposes are often inaccessible. The postulated idea that brain cancer cells cannot pass the blood-brain barrier to form circulating tumor cells (CTCs) has recently been overthrown and CTCs have been detected in the blood of GBM patients albeit in low numbers. Given the potential of CTCs to be analyzed for GBM biomarkers that may guide therapy decisions it is important to define methods to better isolate these cells. Here, we determined markers for immunomagnetic targeting and isolation of GBM-CTCs and confirmed their utility for CTC isolation from GBM patient blood samples. Further, we identified a new marker to distinguish isolated GBM-CTCs from residual lymphocytes

Isolation of circulating tumor cells from glioblastoma patients by direct immunomagnetic targeting

Glioblastoma (GBM) is the most common form of primary brain cancer in adults and tissue biopsies for diagnostic purposes are often inaccessible. The postulated idea that brain cancer cells cannot pass the blood-brain barrier to form circulating tumor cells (CTCs) has recently been overthrown and CTCs have been detected in the blood of GBM patients albeit in low numbers. Given the potential of CTCs to be analyzed for GBM biomarkers that may guide therapy decisions it is important to define methods to better isolate these cells. Here, we determined markers for immunomagnetic targeting and isolation of GBM-CTCs and confirmed their utility for CTC isolation from GBM patient blood samples. Further, we identified a new marker to distinguish isolated GBM-CTCs from residual lymphocytes

Microevolution of Helicobacter pylori during prolonged infection of single hosts and within families

Our understanding of basic evolutionary processes in bacteria is still very limited. For example, multiple recent dating estimates are based on a universal inter-species molecular clock rate, but that rate was calibrated using estimates of geological dates that are no longer accepted. We therefore estimated the short-term rates of mutation and recombination in Helicobacter pylori by sequencing an average of 39,300 bp in 78 gene fragments from 97 isolates. These isolates included 34 pairs of sequential samples, which were sampled at intervals of 0.25 to 10.2 years. They also included single isolates from 29 individuals (average age: 45 years) from 10 families. The accumulation of sequence diversity increased with time of separation in a clock-like manner in the sequential isolates. We used Approximate Bayesian Computation to estimate the rates of mutation, recombination, mean length of recombination tracts, and average diversity in those tracts. The estimates indicate that the short-term mutation rate is 1.4×10−6 (serial isolates) to 4.5×10−6 (family isolates) per nucleotide per year and that three times as many substitutions are introduced by recombination as by mutation. The long-term mutation rate over millennia is 5–17-fold lower, partly due to the removal of non-synonymous mutations due to purifying selection. Comparisons with the recent literature show that short-term mutation rates vary dramatically in different bacterial species and can span a range of several orders of magnitude

Variability in practices for drinking water vaccination of meat chickens against infectious laryngotracheitis

Context: Drinking water vaccination of young meat chickens with Infectious Laryngotracheitis (ILT) vaccine is problematic. Vaccine failure and adverse vaccine reactions are frequently reported. Variations in the technique of applying ILT vaccines by this mass vaccination method need to be understood to contribute to improving the success of vaccination. Aims: This study aimed to examine variations in the techniques of application of Infectious Laryngotracheitis vaccines via drinking water for young meat chickens. Methods: Drinking water vaccination techniques were observed and recorded across 52 broiler flocks during ILT outbreaks in three geographic areas of Australia. Descriptive statistics for all variables were computed and variations between integrator company procedures were statistically compared. Key results: Despite rigorous standard operating procedures, wide variations were observed in time of water deprivation prior to vaccination (3–15 min), time drinking water was stabilised prior to addition of vaccine and the type of stabiliser product used, time to activate the flock following filling of the water lines with vaccine (10–127 min), time for the vaccine to be consumed (36–226 min) and the volume of drinking water per bird used to provide the vaccine (11–48 mL/bird). Conclusions: Variation in vaccination technique can affect the success of drinking water vaccination against ILT in young meat chickens. Implications: Understanding the importance of the variable factors in vaccine application method can improve the success of water vaccination against ILT

A single dose of ChAdOx1 Chik vaccine induces neutralising antibodies against four chikungunya virus lineages in a phase 1 clinical trial

Chikungunya virus (CHIKV) is a reemerging mosquito-borne virus that causes swift outbreaks. Major concerns are the persistent and disabling polyarthralgia in infected individuals. Here we present the results from a first-in-human trial of the candidate simian adenovirus vectored vaccine ChAdOx1 Chik, expressing the CHIKV full-length structural polyprotein (Capsid, E3, E2, 6k and E1). 24 adult healthy volunteers aged 18–50 years, were recruited in a dose escalation, open-label, nonrandomized and uncontrolled phase 1 trial (registry NCT03590392). Participants received a single intramuscular injection of ChAdOx1 Chik at one of the three preestablished dosages and were followed-up for 6 months. The primary objective was to assess safety and tolerability of ChAdOx1 Chik. The secondary objective was to assess the humoral and cellular immunogenicity. ChAdOx1 Chik was safe at all doses tested with no serious adverse reactions reported. The vast majority of solicited adverse events were mild or moderate, and self-limiting in nature. A single dose induced IgG and Tcell responses against the CHIKV structural antigens. Broadly neutralizing antibodies against the four CHIKV lineages were found in all participants and as early as 2 weeks after vaccination. In summary, ChAdOx1 Chik showed excellent safety, tolerability and 100% PRNT50 seroconversion after a single dose

Epigenetic Characterization of the FMR1 Gene and Aberrant Neurodevelopment in Human Induced Pluripotent Stem Cell Models of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In addition to cognitive deficits, FXS patients exhibit hyperactivity, attention deficits, social difficulties, anxiety, and other autistic-like behaviors. FXS is caused by an expanded CGG trinucleotide repeat in the 5′ untranslated region of the Fragile X Mental Retardation (FMR1) gene leading to epigenetic silencing and loss of expression of the Fragile X Mental Retardation protein (FMRP). Despite the known relationship between FMR1 CGG repeat expansion and FMR1 silencing, the epigenetic modifications observed at the FMR1 locus, and the consequences of the loss of FMRP on human neurodevelopment and neuronal function remain poorly understood. To address these limitations, we report on the generation of induced pluripotent stem cell (iPSC) lines from multiple patients with FXS and the characterization of their differentiation into post-mitotic neurons and glia. We show that clones from reprogrammed FXS patient fibroblast lines exhibit variation with respect to the predominant CGG-repeat length in the FMR1 gene. In two cases, iPSC clones contained predominant CGG-repeat lengths shorter than measured in corresponding input population of fibroblasts. In another instance, reprogramming a mosaic patient having both normal and pre-mutation length CGG repeats resulted in genetically matched iPSC clonal lines differing in FMR1 promoter CpG methylation and FMRP expression. Using this panel of patient-specific, FXS iPSC models, we demonstrate aberrant neuronal differentiation from FXS iPSCs that is directly correlated with epigenetic modification of the FMR1 gene and a loss of FMRP expression. Overall, these findings provide evidence for a key role for FMRP early in human neurodevelopment prior to synaptogenesis and have implications for modeling of FXS using iPSC technology. By revealing disease-associated cellular phenotypes in human neurons, these iPSC models will aid in the discovery of novel therapeutics for FXS and other autism-spectrum disorders sharing common pathophysiology.FRAXA Research FoundationHarvard Stem Cell Institute (seed grant)Stanley Medical Research InstituteNational Institute of Mental Health (U.S.) (grant #R33MH087896

Open‐label, clinical trial extension:Two‐year safety and efficacy results of seladelpar in patients with primary biliary cholangitis

SummaryBackgroundSeladelpar is a potent and selective peroxisome proliferator‐activated receptor‐δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti‐cholestatic, anti‐inflammatory and anti‐pruritic effects.AimsTo evaluate the long‐term safety and efficacy of seladelpar in patients with PBC.MethodsIn an open‐label, international, long‐term extension study, patients with PBC completing seladelpar lead‐in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non‐alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years.ResultsThere were no serious treatment‐related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] &lt;1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.ConclusionsSeladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year. Clinicaltrials.gov: NCT03301506; Clinicaltrialsregister.eu: 2017‐003910‐16.</jats:sec