The Jacobi orientation and the two-variable elliptic genus

We explain the relationship between the sigma orientation and Witten genus on the one hand and the two-variable elliptic genus on the other. We show that if E is an elliptic spectrum, then the Theorem of the Cube implies the existence of canonical SU-orientation of the associated spectrum of Jacobi forms. In the case of the elliptic spectrum associated to the Tate curve, this gives the two-variable elliptic genus. We also show that the two-variable genus arises as an instance of the circle-equivariant sigma orientation.Comment: Revised to better exhibit complex orientation of MSU^(CP^\infty_{-infty}

Elastomeric pump infusion failures caused by inadequate Luer lock connector engagement to needleless connectors

Needleless connectors are used widely across all types of vascular access devices and provide safe, needleless administration of intravenous fluids and medications. An analysis of patients from an outpatient parenteral antimicrobial therapy program is presented in which elastomeric pumps had failed to flow due to incomplete tightening of Luer lock needleless connections. An alert was issued to community nursing staff responsible for daily elastomeric pump changes to ensure that needleless connectors were properly checked for full tightening. The frequency of failure of flow events before and after the alert was reviewed. Force and torque profiles required to activate the internal mechanism of connectors were measured in the 4 most frequently used needleless connectors in the outpatient parenteral antimicrobial therapy program. The degree of torque and force required to activate the different needleless connectors varied and was identified as a factor contributing to inadequate connection with the elastomeric pump and consequent failure of flow. Repeated feedback to nursing staff over the study period about the force and torque required for needleless connector flow activation resulted in a highly significant decrease in the rate of failure of flow events per elastomeric pump from a rate of 0.0147 events per elastomeric pump per year in the last 3 months of 2018 to 0.0003 in the first 6 months of 2020 (difference = 0.0144 [CI, 0.0097-0.02]; P < .0001)

Vacuum polarization on the brane

We compute the renormalized expectation value of the square of a massless, conformally coupled, quantum scalar field on the brane of a higher-dimensional black hole. Working in the AADD brane-world scenario, the extra dimensions are flat and we assume that the compactification radius is large compared with the size of the black hole. The four-dimensional on-brane metric corresponds to a slice through a higher-dimensional Schwarzschild-Tangherlini black hole geometry and depends on the number of bulk space-time dimensions. The quantum scalar field is in a thermal state at the Hawking temperature. An exact, closed-form expression is derived for the renormalized expectation value of the square of the quantum scalar field on the event horizon of the black hole. Outside the event horizon, this renormalized expectation value is computed numerically. The answer depends on the number of bulk space-time dimensions, with a magnitude which increases rapidly as the number of bulk space-time dimensions increases

Canine Prostate Cancer Cell Line (Probasco) Produces Osteoblastic Metastases In Vivo

In 2012, over 240,000 men were diagnosed with prostate cancer and over 28,000 died from the disease. Animal models of prostate cancer are vital to understanding its pathogenesis and developing therapeutics. Canine models in particular are useful due to their similarities to late-stage, castration-resistant human disease with osteoblastic bone metastases. This study established and characterized a novel canine prostate cancer cell line that will contribute to the understanding of prostate cancer pathogenesis

A holistic and comprensive data approach validates the distribution of the critically endangered flapper skate (Dipturus intermedius)

Morphological similarities between skates of the genus Dipturus in the north-eastern Atlantic and mediterranean have resulted in longstanding confusion, misidentification and misreporting. Current evidence indicates that the common skate is best explained as two species, the flapper skate (Dipturus intermedius) and the common blue skate (D. batis). However, some management and conservation initiatives developed prior to the separation continue to refer to common skate (as ‘D. batis’). This taxonomic uncertainty can lead to errors in estimating population viability, distribution range, and impact on fisheries management and conservation status. Here, we demonstrate how a concerted taxonomic approach, using molecular data and a combination of survey, angler and fisheries data, in addition to expert witness statements, can be used to build a higher resolution picture of the current distribution of D. intermedius. Collated data indicate that flapper skate has a more constrained distribution compared to the perceived distribution of the ‘common skate’, with most observations recorded from Norway and the western and northern seaboards of Ireland and Scotland, with occasional specimens from Portugal and the Azores. Overall, the revised spatial distribution of D. intermedius has significantly reduced the extant range of the species, indicating a possibly fragmented distribution range.acceptedVersio

FLT3 mutations in canine acute lymphocytic leukemia

<p>Abstract</p> <p>Background</p> <p>FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit <it>FLT3 </it>ITD mutations.</p> <p>Methods</p> <p>We molecularly characterized <it>FLT3 </it>mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via <it>in vitro </it>proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting.</p> <p>Results</p> <p>The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have <it>FLT3 </it>ITD mutations and <it>FLT3 </it>mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the <it>FLT3 </it>mutation. Finally, western blots were used to confirm the conserved downstream mediators of <it>FLT3 </it>activating mutations.</p> <p>Conclusions</p> <p>These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias.</p

Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B

Background: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. Results: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. Conclusions: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease

Genome-wide association study identifies 30 loci associated with bipolar disorder.

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P &lt; 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P &lt; 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder

Genome-Wide Analysis of Neuroblastomas using High-Density Single Nucleotide Polymorphism Arrays

BACKGROUND: Neuroblastomas are characterized by chromosomal alterations with biological and clinical significance. We analyzed paired blood and primary tumor samples from 22 children with high-risk neuroblastoma for loss of heterozygosity (LOH) and DNA copy number change using the Affymetrix 10K single nucleotide polymorphism (SNP) array. FINDINGS: Multiple areas of LOH and copy number gain were seen. The most commonly observed area of LOH was on chromosome arm 11q (15/22 samples; 68%). Chromosome 11q LOH was highly associated with occurrence of chromosome 3p LOH: 9 of the 15 samples with 11q LOH had concomitant 3p LOH (P = 0.016). Chromosome 1p LOH was seen in one-third of cases. LOH events on chromosomes 11q and 1p were generally accompanied by copy number loss, indicating hemizygous deletion within these regions. The one exception was on chromosome 11p, where LOH in all four cases was accompanied by normal copy number or diploidy, implying uniparental disomy. Gain of copy number was most frequently observed on chromosome arm 17q (21/22 samples; 95%) and was associated with allelic imbalance in six samples. Amplification of MYCN was also noted, and also amplification of a second gene, ALK, in a single case. CONCLUSIONS: This analysis demonstrates the power of SNP arrays for high-resolution determination of LOH and DNA copy number change in neuroblastoma, a tumor in which specific allelic changes drive clinical outcome and selection of therapy

Macrophage Activation and Differentiation Signals Regulate Schlafen-4 Gene Expression: Evidence for Schlafen-4 as a Modulator of Myelopoiesis

Background: The ten mouse and six human members of the Schlafen (Slfn) gene family all contain an AAA domain. Little is known of their function, but previous studies suggest roles in immune cell development. In this report, we assessed Slfn regulation and function in macrophages, which are key cellular regulators of innate immunity