Chronic Lymphocytic Leukemia B Cells Can Undergo Somatic Hypermutation and Intraclonal Immunoglobulin VHDJH Gene Diversification

Chronic lymphocytic leukemia (CLL) arises from the clonal expansion of a CD5+ B lymphocyte that is thought not to undergo intraclonal diversification. Using VHDJH cDNA single strand conformation polymorphism analyses, we detected intraclonal mobility variants in 11 of 18 CLL cases. cDNA sequence analyses indicated that these variants represented unique point-mutations (1–35/patient). In nine cases, these mutations were unique to individual submembers of the CLL clone, although in two cases they occurred in a large percentage of the clonal submembers and genealogical trees could be identified. The diversification process responsible for these changes led to single nucleotide changes that favored transitions over transversions, but did not target A nucleotides and did not have the replacement/silent nucleotide change characteristics of antigen-selected B cells. Intraclonal diversification did not correlate with the original mutational load of an individual CLL case in that diversification was as frequent in CLL cells with little or no somatic mutations as in those with considerable mutations. Finally, CLL B cells that did not exhibit intraclonal diversification in vivo could be induced to mutate their VHDJH genes in vitro after stimulation. These data indicate that a somatic mutation mechanism remains functional in CLL cells and could play a role in the evolution of the clone

Network approach to internet bandwidth distributions

This study examines the communications networks formed by direct international Internet links, weighted by bandwidth capacity, each year over the 2002–2011 period. Specifically, we analyze changes in bandwidth distributions at country, regional, and continental levels during the period and identify network communities at these different levels. We apply an urn-based model developed with country-level data to bandwidth distributions at regional and continental levels. While the 2011 global Internet network closely resembles that of 2002, the network has become more tightly interconnected over time, and the high international bandwidth regions of Northern Europe, Northern America, and Western Europe have seen a modest decline in their share of total global bandwidth. As a consequence, international bandwidth concentration is showing a slow decline. Relative connectedness as measured by percentage of bandwidth staying within UN geographic regions is decreasing, whereas the percentage remaining within the continent has been fairly constant during the analysis period. All of this must be understood in the context of enormous total international bandwidth growth between 2002 and 2011 at all levels of analysis

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Tube production by extrusion of thermoplastic containing discontinuous fibres - using die with specified dimensions, resulting in improved burst strength

Tubes (pipes) made from fibre-reinforced thermoplastic materials are manufactured by a method for extruding the thermoplastic material into a die having a diverging terminal zone, the terminal zone of which includes a diverging annular flow space which has a ratio As/Ae between the exit area and the inlet area of at least 1.2 and a ratio between the length l of the annular exit space of the diverging zone and the width e of the cross-section of the said annular space less than 5, the extrusion being carried out in the presence of a liquid lubricant which is not compatible with the said thermoplastic material at the extrusion temperatures, the said lubricant being present in the region of the outer wall and in the region of the inner wall of the said flow space. The tubes (pipes) manufactured by this method have an especially high burst strength and an improved surface state

Extrusion of tubes of fiber-reinforced thermoplastics

Fibre-reinforced tubes made of a thermoplastics material are manufactured using a method of extruding thermoplastics material in a drawplate with a diverging end zone, the end zone of which has a diverging annular flow space which has a ratio A.sub.s /A.sub.e between the exit area and entry area of at least 1.2, and a ratio between the length 1 of the lower edge of the annular exit space of the diverging zone and the width e of the straight section of said annular space which is less than 5; the extrusion operation being carried out in the presence of a liquid lubricant which is incompatible with said thermoplastics material at extrusion temperatures, said lubricant being present at the level of the external wall and at the level of the internal wall of said flow space. Tubes which are manufactured by way of this method are particularly resistant to a high degree of bursting and have an improved surface quality

Analyses of the FranceCoag cohort support differences in immunogenicity among one plasma-derived and two recombinant factor VIII brands in boys with severe hemophilia A

International audienceA round one third of boys with severe hemophilia A develop inhibitors (neutralizing antibodies) against their therapeutic factor VIII product. This adverse effect may result in more lifethreatening bleeding, disability, impaired quality of life, and costly care. We compared the incidence of inhibitors in boys treated with the three factor VIII products most used in France: one plasma-derived (Factane) and two recombinant products (Advate and Kogenate Bayer). A previously untreated cohort of patients was created in 1994 to investigate risk factors for inhibitor development. We selected boys with severe hemophilia A (factor VIII < 1 IU/dL) first treated with one of the three factor VIII products studied. Details of product infusions, inhibitor assays and main fixed and time-varying inhibitor risk factors were recorded for the first 75 exposure days. Three outcomes (all inhibitors, high-titer inhibitors and subsequently treated inhibitors) were analyzed by univariate and multivariate Cox models. We studied 395 boys first treated between 2001 and 2016 (131, 137, and 127 with Factane, Advate, and Kogenate Bayer, respectively). Clinically significant inhibitors were diagnosed in 121 patients (70 high-titer). The incidence of high-titer inhibitors was significantly associated with the factor VIII product received (P= 0.005): the cumulative incidence at 75 exposure days was 12.7% (95% CI: 7.7-20.6) with Factane, 20.4% (95% CI: 14.0-29.1) with Advate, and 31.6% (95% CI: 23.5-41.7) with Kogenate Bayer. The low inhibitor incidence observed with Factane is concordant with recent findings from the SIPPET randomized trial. These consistent results from observational and experimental studies should lead to improved care for previously untreated patients and cost savings for healthcare systems worldwide