Multiperiodicity in the newly discovered mid-late Be star V2104 Cygni

We obtained the first long, homogenous time-series of V2104Cyg, consisting of 679 datapoints, with the uvbybeta photometers of Sierra Nevada and San Pedro Martir Observatories with the aim to detect and subsequently interpret the intrinsic frequencies of this previously unstudied variable star, which turned out to be a Be star. We try to figure out its place among the variable B stars on the upper Main Sequence. In order to obtain additional information on physical parameters we collected a few spectra with the ELODIE and FIES instruments. We searched for frequencies in the uvby passbands using 2 different frequency analysis methods and used the S/N>4 criterion to select the significant periodicities. We obtained an estimate of the physical parameters of the underlying B star of spectral type between B5 and B7, by correcting for the presence of a circumstellar disk, using a formalism based on the strenght of the Halpha line emission. We detected 3 independent frequencies with amplitudes below 0.01mag, f1 = 4.7126 c/d, f2 = 2.2342 c/d and f3 = 4.671 c/d, and discovered that V2104Cyg is a Be star. The fast rotation (vsini=290+/-10 km/s, and 27<i<45) hampered the investigation of the associated pulsational parameters l. Nevertheless, the most plausible explanation for the observed variability of this mid-late type Be star is a non-radial pulsation model. This paper is based on observations obtained at the Observatorio Astronomico Nacional San Pedro Martir (Mexico), Observatorio de Sierra Nevada (Spain), Observatoire de Haute Provence (France), and on observations made with the Nordic Optical Telescope, Observatorio Roque de los Muchachos, La Palma, Spain.Comment: 7 pages, 4 figures, A&A accepte

A distinctive requirement for p53 in the genome protective Topoisomerase 2a-dependent G2 arrest in hTERT positive cancer cells

Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention.SignificanceThe identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality

The immunogenicity of ReFacto AF (moroctocog alfa AF-CC) in previously untreated patients with haemophilia A in the United Kingdom

Introduction Factor VIII inhibitor development is currently the most serious complication of the treatment of haemophilia A. Differences in manufacturing and the molecular structure of brands of recombinant factor VIII have led to speculation that concentrates may differ in immunogenicity. This has led to a regulatory focus on the immunogenicity of factor VIII concentrates both before and after licensure. Aim To investigate the immunogenicity of ReFacto AF post licensure in a real‐world setting in previously untreated patients (PUPs) treated exclusively with this product until at least 50 exposure days (EDs). Methods The United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) National Haemophilia Database (NHD) identified a consecutive cohort of patients with severe haemophilia A (<0.01 IU/L) whose first treatment was with ReFacto AF, monitored time to inhibitor development and described associated risk factors. Results One hundred and three boys reached 50 EDs within the study period, of whom 35 developed an inhibitor (P(t ≤ 50) = 0.33, [95% CI: 0.25‐0.43]), of which 15 (P(t ≤ 50) = 0.16, [95% CI: 0.10‐0.25]) were high titre. Inhibitors arose after a median (interquartile range) 11 (7‐16) EDs. Inhibitors were significantly associated with high‐risk mutations and non‐significantly associated with non‐white ethnicity. Inhibitors were negatively associated with a family history of haemophilia A. High‐titre inhibitors were significantly associated with a family history of inhibitors. Conclusion Inhibitor incidence in a single country population of ReFacto AF PUPs was similar to that previously described. Low‐ and high‐titre inhibitors were detected after a similar number of EDs, contrasting with previous data, probably reflecting standardized inhibitor monitoring within the United Kingdom

A high affinity RIM-binding protein/Aplip1 interaction prevents the formation of ectopic axonal active zones

Synaptic vesicles (SVs) fuse at active zones (AZs) covered by a protein scaffold, at Drosophila synapses comprised of ELKS family member Bruchpilot (BRP) and RIM-binding protein (RBP). We here demonstrate axonal co-transport of BRP and RBP using intravital live imaging, with both proteins co- accumulating in axonal aggregates of several transport mutants. RBP, via its C-terminal Src-homology 3 (SH3) domains, binds Aplip1/JIP1, a transport adaptor involved in kinesin-dependent SV transport. We show in atomic detail that RBP C-terminal SH3 domains bind a proline-rich (PxxP) motif of Aplip1/JIP1 with submicromolar affinity. Pointmutating this PxxP motif provoked formation of ectopic AZ-like structures at axonal membranes. Direct interactions between AZ proteins and transport adaptors seem to provide complex avidity and shield synaptic interaction surfaces of pre-assembled scaffold protein transport complexes, thus, favouring physiological synaptic AZ assembly over premature assembly at axonal membranes. - See more at: http://elifesciences.org/content/4/e06935#sthash.oVGZ8cdi.dpu

A Novel, Enriched Population Pharmacokinetic Model for Recombinant Factor VIII-Fc Fusion Protein Concentrate in Hemophilia A Patients

Background The currently published population pharmacokinetic (PK) models used for PK-guided dosing in hemophilia patients are based on clinical trial data and usually not externally validated in clinical practice. The aim of this study was to validate a published model for recombinant factor VIII-Fc fusion protein (rFVIII-Fc) concentrate and to develop an enriched model using independently collected clinical data if required. Methods Clinical data from hemophilia A patients treated with rFVIII-Fc concentrate (Elocta) participating in the United Kingdom Extended Half-Life Outcomes Registry were collected. The predictive performance of the published model was assessed using mean percentage error (bias) and mean absolute percentage error (inaccuracy). An extended population PK model was developed using nonlinear mixed-effects modeling (NONMEM). Results A total of 43 hemophilia A patients (FVIII Conclusion We concluded that the existing rFVIII-Fc population PK model is valid for patients >= 12 years. However, it is not reliable in younger patients. Our alternative model, constructed from real world patient data including children, allows for better description of patients >= 5 years

Closing the gap between science and management of cold-water refuges in rivers and streams

Human activities and climate change threaten coldwater organisms in freshwater eco-systems by causing rivers and streams to warm, increasing the intensity and frequency of warm temperature events, and reducing thermal heterogeneity. Cold-water refuges are discrete patches of relatively cool water that are used by coldwater organisms for thermal relief and short-term survival. Globally, cohesive management approaches are needed that consider interlinked physical, biological, and social factors of cold-water refuges. We review current understanding of cold-water refuges, identify gaps between science and management, and evaluate policies aimed at protecting thermally sensitive species. Existing policies include designating cold-water habitats, restricting fishing during warm periods, and implementing threshold temperature standards or guidelines. However, these policies are rare and uncoordinated across spatial scales and often do not consider input from Indigenous peoples. We propose that cold-water refuges be managed as dis-tinct operational landscape units, which provide a social and ecological context that is relevant at the watershed scale. These operational landscape units provide the founda-tion for an integrated framework that links science and management by (1) mapping and characterizing cold-water refuges to prioritize management and conservation actions, (2) leveraging existing and new policies, (3) improving coordination across jurisdictions, and (4) implementing adaptive management practices across scales. Our findings show that while there are many opportunities for scientific advancement, the current state of the sciences is sufficient to inform policy and management. Our proposed framework pro-vides a path forward for managing and protecting cold-water refuges using existing and new policies to protect coldwater organisms in the face of global change. behavioral thermoregulation, climate change adaptation, lotic ecosystem management, refugia, salmonids, temperature, thermal heterogeneity, thermal refugespublishedVersio

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF &lt;5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants