Stellar Orbit Constraints on Neutralino Annihilation at the Galactic Center

Dark matter annihilation has been proposed to explain the TeV gamma rays observed from the Galactic Center. We study constraints on this hypothesis coming from the mass profile around the Galactic Center measured by observing stellar dynamics. We show that for current particle models, the constraints on the dark matter density profile from measurements of mass by infrared observations are comparable to the constraints from the measurements of the TeV source extension.Comment: replaced with accepted version, improved presentation, some figures corrected, results unchange

The Role of Racial Identity and Implicit Racial Bias in Self-Reported Racial Discrimination: Implications for Depression Among African American Men

Racial discrimination is conceptualized as a psychosocial stressor that has negative implications for mental health. However, factors related to racial identity may influence whether negative experiences are interpreted as instances of racial discrimination and subsequently reported as such in survey instruments, particularly given the ambiguous nature of contemporary racism. Along these lines, dimensions of racial identity may moderate associations between racial discrimination and mental health outcomes. This study examined relationships between racial discrimination, racial identity, implicit racial bias, and depressive symptoms among African American men between 30 and 50 years of age (n = 95). Higher racial centrality was associated with greater reports of racial discrimination, while greater implicit anti-Black bias was associated with lower reports of racial discrimination. In models predicting elevated depressive symptoms, holding greater implicit anti-Black bias in tandem with reporting lower racial discrimination was associated with the highest risk. Results suggest that unconscious as well as conscious processes related to racial identity are important to consider in measuring racial discrimination, and should be integrated in studies of racial discrimination and mental health

Geometric origin of mechanical properties of granular materials

Some remarkable generic properties, related to isostaticity and potential energy minimization, of equilibrium configurations of assemblies of rigid, frictionless grains are studied. Isostaticity -the uniqueness of the forces, once the list of contacts is known- is established in a quite general context, and the important distinction between isostatic problems under given external loads and isostatic (rigid) structures is presented. Complete rigidity is only guaranteed, on stability grounds, in the case of spherical cohesionless grains. Otherwise, the network of contacts might deform elastically in response to load increments, even though grains are rigid. This sets an uuper bound on the contact coordination number. The approximation of small displacements (ASD) allows to draw analogies with other model systems studied in statistical mechanics, such as minimum paths on a lattice. It also entails the uniqueness of the equilibrium state (the list of contacts itself is geometrically determined) for cohesionless grains, and thus the absence of plastic dissipation. Plasticity and hysteresis are due to the lack of such uniqueness and may stem, apart from intergranular friction, from small, but finite, rearrangements, in which the system jumps between two distinct potential energy minima, or from bounded tensile contact forces. The response to load increments is discussed. On the basis of past numerical studies, we argue that, if the ASD is valid, the macroscopic displacement field is the solution to an elliptic boundary value problem (akin to the Stokes problem).Comment: RevTex, 40 pages, 26 figures. Close to published paper. Misprints and minor errors correcte

A new technique for mandibular osteotomy

Sagittal split osteotomy (SSO) is a surgical technique largely employed for mandibular mobilizations in orthognatic procedures. However, the traditional design of buccal osteotomy, located at the junction of mandibular ramus and body, may prevent more extensive sliding between the bone segments, particularly on the advance, laterality and verticality of the mandibular body. The author proposes a new technical and conceptual solution, in which osteotomy is performed in a more distal region, next to the mental formamen. Technically, the area of contact between medullary-cancellous bone surfaces is increased, resulting in larger sliding rates among bone segments; it also facilitates the use of rigid fixation systems, with miniplates and monocortical screws. Conceptually, it interferes with the resistance arm of the mandible, seen as an interpotent lever of the third gender

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient

Snail1 induces epithelial-to-mesenchymal transition and tumor initiating stem cell characteristics

<p>Abstract</p> <p>Background</p> <p>Tumor initiating stem-like cells (TISCs) are a subset of neoplastic cells that possess distinct survival mechanisms and self-renewal characteristics crucial for tumor maintenance and propagation. The induction of epithelial-mesenchymal-transition (EMT) by TGFβ has been recently linked to the acquisition of TISC characteristics in breast cancer. In HCC, a TISC and EMT phenotype correlates with a worse prognosis. In this work, our aim is to elucidate the underlying mechanism by which cells acquire tumor initiating characteristics after EMT.</p> <p>Methods</p> <p>Gene and protein expression assays and Nanog-promoter luciferase reporter were utilized in epithelial and mesenchymal phenotype liver cancer cell lines. EMT was analyzed with migration/invasion assays. TISC characteristics were analyzed with tumor-sphere self-renewal and chemotherapy resistance assays. <it>In vivo </it>tumor assay was performed to investigate the role of Snail1 in tumor initiation.</p> <p>Conclusion</p> <p>TGFβ induced EMT in epithelial cells through the up-regulation of Snail1 in Smad-dependent signaling. Mesenchymal liver cancer post-EMT demonstrates TISC characteristics such as tumor-sphere formation but are not resistant to cytotoxic therapy. The inhibition of <it>Snail1 </it>in mesenchymal cells results in decreased <it>Nanog </it>promoter luciferase activity and loss of self-renewal characteristics <it>in vitro</it>. These changes confirm the direct role of Snail1 in some TISC traits. <it>In vivo</it>, the down-regulation of <it>Snail1 </it>reduced tumor growth but was not sufficient to eliminate tumor initiation. In summary, TGFβ induces EMT and TISC characteristics through Snail1 and Nanog up-regulation. In mesenchymal cells post-EMT, Snail1 directly regulates <it>Nanog </it>expression, and loss of Snail1 regulates tumor growth without affecting tumor initiation.</p

Universal WBC reduction

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75583/1/j.1537-2995.2000.40060751.x.pd

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV1 or FVC levels between treatment arms or time points. Diffusion capacity (TLCO) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated

Prostate Cancer Cell Lines under Hypoxia Exhibit Greater Stem-Like Properties

Hypoxia is an important environmental change in many cancers. Hypoxic niches can be occupied by cancer stem/progenitor-like cells that are associated with tumor progression and resistance to radiotherapy and chemotherapy. However, it has not yet been fully elucidated how hypoxia influences the stem-like properties of prostate cancer cells. In this report, we investigated the effects of hypoxia on human prostate cancer cell lines, PC-3 and DU145. In comparison to normoxia (20% O2), 7% O2 induced higher expressions of HIF-1α and HIF-2α, which were associated with upregulation of Oct3/4 and Nanog; 1% O2 induced even greater levels of these factors. The upregulated NANOG mRNA expression in hypoxia was confirmed to be predominantly retrogene NANOGP8. Similar growth rates were observed for cells cultivated under hypoxic and normoxic conditions for 48 hours; however, the colony formation assay revealed that 48 hours of hypoxic pretreatment resulted in the formation of more colonies. Treatment with 1% O2 also extended the G0/G1 stage, resulting in more side population cells, and induced CD44 and ABCG2 expressions. Hypoxia also increased the number of cells positive for ABCG2 expression, which were predominantly found to be CD44bright cells. Correspondingly, the sorted CD44bright cells expressed higher levels of ABCG2, Oct3/4, and Nanog than CD44dim cells, and hypoxic pretreatment significantly increased the expressions of these factors. CD44bright cells under normoxia formed significantly more colonies and spheres compared with the CD44dim cells, and hypoxic pretreatment even increased this effect. Our data indicate that prostate cancer cells under hypoxia possess greater stem-like properties