Animal Models of Hemophilia and Related Bleeding Disorders

Animal models of hemophilia and related diseases are important for development of novel treatments and to understand the pathophysiology of bleeding disorders in humans. Testing in animals with the equivalent human disorder provides informed estimates of doses and measures of efficacy, which aids in design of human trials. Many models of hemophilia A, hemophilia B, and von Willebrand disease have been developed from animals with spontaneous mutations (hemophilia A dogs, rats, sheep; hemophilia B dogs; and von Willebrand disease pigs and dogs), or by targeted gene disruption in mice to create hemophilia A, B, or VWD models. Animal models have been used to generate new insights into the pathophysiology of each bleeding disorder and also to perform pre-clinical assessments of standard protein replacement therapies as well as novel gene transfer technology. Both the differences between species and differences in underlying causative mutations must be considered in choosing the best animal for a specific scientific stud

Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII

Animals with hemophilia are models for gene therapy, factor replacement, and inhibitor development in humans. We have actively sought dogs with severe hemophilia A that have novel factor VIII mutations unlike the previously described factor VIII intron 22 inversion. A male Old English Sheepdog with recurrent soft-tissue hemorrhage and hemarthrosis was diagnosed with severe hemophilia A (factor VIII activity less than 1% of normal). We purified genomic DNA from this dog and ruled out the common intron 22 inversion; we then sequenced all 26 exons. Comparing the results with the normal canine factor VIII sequence revealed a C→T transition in exon 12 of the factor VIII gene that created a premature stop codon at amino acid 577 in the A2 domain of the protein. In addition, 2 previously described polymorphisms that do not cause hemophilia were present at amino acids 909 and 1184. The hemophilia mutation creates a new TaqI site that facilitates rapid genotyping of affected offspring by PCR and restriction endonuclease analyses. This mutation is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12. Thus far, despite extensive treatment with factor VIII, this dog has not developed neutralizing antibodies (‘inhibitors’) to the protein. This novel mutation in a dog gives rise to severe hemophilia A analogous to a mutation seen in humans. This model will be useful for studies of the treatment of hemophilia

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months, suggesting that the risk of bleeding decreases with continued therapy. At baseline, von Willebrand factor and factor VIII levels were often high and normalized on treatment. Platelet function measured via the platelet function analyzer (PFA-100™) was impaired in 22 patients at baseline and in an additional 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not. Compared to untreated chronic lymphocytic leukemia patients, response to collagen showed a mild further decrement on ibrutinib, while response to adenosine diphosphate improved. All parameters associated with a significantly increased risk of bleeding-related events were present at baseline, including prolonged epinephrine closure time (HR 2.74, P=0.012), lower levels of von Willebrand factor activity (HR 2.73, P=0.009) and factor VIII (HR 3.73, P=0.0004). In conclusion, both disease and treatment-related factors influence the risk of bleeding. Patients at greater risk for bleeding of grade ≤2 can be identified by clinical laboratory tests and counseled to avoid aspirin, non-steroidal anti-inflammatory drugs and fish oils. ClinicalTrials.gov identifier NCT0150073

Global Oceans, BAMS State of the Climate in 2021, Chapter 3

Patterns of variability in ocean properties are often closely related to large-scale climate pattern indices, and 2021 is no exception. The year 2021 started and ended with La Niña conditions, charmingly dubbed a “double-dip” La Niña. Hence, stronger-than-normal easterly trade winds in the tropical south Pacific drove westward surface current anomalies in the equatorial Pacific; reduced sea surface temperature (SST) and upper ocean heat content in the eastern tropical Pacific; increased sea level, upper ocean heat content, and salinity in the western tropical Pacific; resulted in a rim of anomalously high chlorophyll-a (Chla) on the poleward and westward edges of the anomalously cold SST wedge in the eastern equatorial Pacific; and increased precipitation over the Maritime Continent. The Pacific decadal oscillation remained strongly in a negative phase in 2021, with negative SST and upper ocean heat content anomalies around the eastern and equatorial edges of the North Pacific and positive anomalies in the center associated with low Chla anomalies. The South Pacific exhibited similar patterns. Fresh anomalies in the northeastern Pacific shifted towards the west coast of North America. The Indian Ocean dipole (IOD) was weakly negative in 2021, with small positive SST anomalies in the east and nearly-average anomalies in the west. Nonetheless, upper ocean heat content was anomalously high in the west and lower in the east, with anomalously high freshwater flux and low sea surface salinities (SSS) in the east, and the opposite pattern in the west, as might be expected during a negative phase of that climate index. In the Atlantic, the only substantial cold anomaly in SST and upper ocean heat content persisted east of Greenland in 2021, where SSS was also low, all despite the weak winds and strong surface heat flux anomalies into the ocean expected during a negative phase of the North Atlantic Oscillation. These anomalies held throughout much of 2021. An Atlantic and Benguela Niño were both evident, with above-average SST anomalies in the eastern equatorial Atlantic and the west coast of southern Africa. Over much of the rest of the Atlantic, SSTs, upper ocean heat content, and sea level anomalies were above average. Anthropogenic climate change involves long-term trends, as this year’s chapter sidebars emphasize. The sidebars relate some of the latest IPCC ocean-related assessments (including carbon, the section on which is taking a hiatus from our report this year). This chapter estimates that SST increased at a rate of 0.16–0.19°C decade−1 from 2000 to 2021, 0–2000-m ocean heat content warmed by 0.57–0.73 W m−2 (applied over Earth’s surface area) from 1993 to 2021, and global mean sea level increased at a rate of 3.4 ± 0.4 mm yr−1 from 1993 to 2021. Global mean SST, which is more subject to interannual variations than ocean heat content and sea level, with values typically reduced during La Niña, was ~0.1°C lower in 2021 than in 2020. However, from 2020 to 2021, annual average ocean heat content from 0 to 2000 dbar increased at a rate of ~0.95 W m−2, and global sea level increased by ~4.9 mm. Both were the highest on record in 2021, and with year-on-year increases substantially exceeding their trend rates of recent decades

Sulfide tarnishing of metals

M.S.Miroslav Mare