The InAs/InAsSb (Gallium-free) type-II strained-layer superlattice (T2SLS) has emerged in the last decade as a viable infrared detector material with a continuously adjustable band gap capable of ...accommodating detector cutoff wavelengths ranging from 4 to 15 µm and beyond. When coupled with the unipolar barrier infrared detector architecture, the InAs/InAsSb T2SLS mid-wavelength infrared (MWIR) focal plane array (FPA) has demonstrated a significantly higher operating temperature than InSb FPA, a major incumbent technology. In this brief review paper, we describe the emergence of the InAs/InAsSb T2SLS infrared photodetector technology, point out its advantages and disadvantages, and survey its recent development.
B cells are central to the pathology of ANCA-associated vasculitis (AAV), a disease characterized by autoantibodies and effectively treated by rituximab. In addition to promoting inflammation, a ...subset of B cells act to suppress harmful autoimmune responses (Breg). The balance of effector and regulatory B cell subsets in AAV is not known. This study was conducted to assess the relative frequency of these subsets during different states of disease activity.
B memory (Bmem), naive (Bnaive) and regulatory (Breg) subsets were defined by their relative expression of CD24 and CD38. Function was assessed by cytokine production and suppressive action on CD4(+) Th1 activation evaluated in a co-culture system.
Compared with healthy controls, the frequency of Breg (CD24(hi)CD38(hi)) was significantly reduced during disease remission in both proteinase 3 (PR3)- and MPO-ANCA patients and during acute disease in PR3-ANCA patients, while the frequency of memory cells (CD24(hi)CD38(lo)) was reduced during active disease and restored during remission. Breg cell frequency showed a positive correlation, while Bmem had an inverse correlation with IL-10 production in vitro. B and T cell co-cultures revealed that memory and naive B cell subsets augmented Th1 activation in vitro, which was prevented by Breg, and this pattern did not differ between remission AAV patients and controls.
In remission there is a numerical, but not functional, deficiency in Breg and preservation of Bmem associated with reduced IL-10 production and increased Th1 activation in vitro. This imbalance may contribute to the high rate of relapse observed in AAV, especially in PR3-ANCA patients.
The RAS signaling pathway is a pivotal developmental pathway that controls many fundamental biological processes including cell proliferation, differentiation, movement and apoptosis. Drosophila ...Seven-IN-Absentia (SINA) is a ubiquitin E3 ligase that is the most downstream signaling "gatekeeper" whose biological activity is essential for proper RAS signal transduction. Vertebrate SINA homologs (SIAHs) share a high degree of amino acid identity with that of Drosophila SINA. SINA/SIAH is the most conserved signaling component in the canonical EGFR/RAS/RAF/MAPK signal transduction pathway.
Vertebrate SIAH1, 2, and 3 are the three orthologs to invertebrate SINA protein. SINA and SIAH1 orthologs are found in all major taxa of metazoans. These proteins have four conserved functional domains, known as RING (Really Interesting New Gene), SZF (SIAH-type zinc finger), SBS (substrate binding site) and DIMER (Dimerization). In addition to the siah1 gene, most vertebrates encode two additional siah genes (siah2 and siah3) in their genomes. Vertebrate SIAH2 has a highly divergent and extended N-terminal sequence, while its RING, SZF, SBS and DIMER domains maintain high amino acid identity/similarity to that of SIAH1. But unlike vertebrate SIAH1 and SIAH2, SIAH3 lacks a functional RING domain, suggesting that SIAH3 may be an inactive E3 ligase. The SIAH3 subtree exhibits a high degree of amino acid divergence when compared to the SIAH1 and SIAH2 subtrees. We find that SIAH1 and SIAH2 are expressed in all human epithelial cell lines examined thus far, while SIAH3 is only expressed in a limited subset of cancer cell lines.
Through phylogenetic analyses of metazoan SINA and SIAH E3 ligases, we identified many invariant and divergent amino acid residues, as well as the evolutionarily conserved functional motifs in this medically relevant gene family. Our phylomedicinal study of this unique metazoan SINA/SIAH protein family has provided invaluable evolution-based support towards future effort to design logical, potent, and durable anti-SIAH-based anticancer strategies against oncogenic K-RAS-driven metastatic human cancers. Thus, this method of evolutionary study should be of interest in cancer biology.
Objectives To determine a role for antineutrophil cytoplasmic antibody (ANCA)-activated neutrophils in promoting B cell survival through the release of B lymphocyte stimulator (BLyS). Methods ...Neutrophil BLyS expression was measured by flow cytometry. Concentrations of BLyS in cell supernatants and donor serum samples were measured by ELISA. Cell survival assays were carried out using an L3055 cell line and viability measured by flow cytometry. Results Tumour necrosis factor α and formyl-Met-Leu-Phe (fMLP) treatment of non-primed neutrophils and treatment of primed neutrophils with anti-PR3 ANCA IgG resulted in a significant increase in surface expression of BLyS within 30 min which returned to basal levels by 2 h. Supernatants from ANCA-stimulated neutrophils were shown to contain increased levels of BLyS and to promote the survival of the centroblast cell line L3055. Serum BLyS concentrations are increased in patients with active ANCA-associated systemic vasculitis and these levels are increased further following 1–3 months of treatment with rituximab. Conclusions ANCA specifically causes the release of BLyS from activated neutrophils which can support B cell survival in vitro. The presence of serum BLyS in active disease and its increase following B cell depletion suggest it is an important factor in disease pathogenesis and may facilitate disease relapse.
Juvenile systemic lupus erythematosus (JSLE) is characterised by onset before 18 years of age and more severe disease phenotype, increased morbidity and mortality compared to adult-onset SLE. ...Management strategies in JSLE rely heavily on evidence derived from adult-onset SLE studies; therefore, identifying biomarkers associated with the disease pathogenesis and reflecting particularities of JSLE clinical phenotype holds promise for better patient management and improved outcomes. This narrative review summarises the evidence related to various traditional and novel biomarkers that have shown a promising role in identifying and predicting specific organ involvement in JSLE and appraises the evidence regarding their clinical utility, focusing in particular on renal biomarkers, while also emphasising the research into cardiovascular, haematological, neurological, skin and joint disease-related JSLE biomarkers, as well as genetic biomarkers with potential clinical applications.
Aortic stenosis is one of the most common forms of acquired valvular heart disease. The development of symptoms, namely syncope, angina, or heart failure, in patients with severe aortic stenosis ...predicts a high likelihood of mortality. Aortic valve replacement is the current standard of care. In truly asymptomatic patients, the risk of sudden death is perceived to be low; therefore many advocate conservative management of these patients until symptoms develop. Emerging data suggest that certain markers may identify subsets of asymptomatic patients who are at a high risk of cardiac events. This review critically appraises the growing plethora of adverse prognostic markers that have been identified and evaluates how these parameters may influence clinical practice and potentially identify patients in whom early surgical intervention is warranted.
We cross match the GALEX and Kepler surveys to create a unique dataset with both ultraviolet (UV) measurements and highly precise photometric variability measurements in the visible light spectrum. ...As stellar activity is driven by magnetic field modulations, we have used UV emission from the magnetically heated gas in the stellar atmosphere to serve as our proxy for the more well-known stellar activity indicator, R super(l) sub(H K). The R super(l) sub(H K) approximations were in turn used to estimate the level of asttophysical noise expected in radial velocity (RV) measurements and these were then searched for correlations with photometric variability. We find significant scatter in our attempts to estimate RV noise for magnetically active stars, which we attribute to variations in the phase and strength of the stellar magnetic cycle that drives the activity of these targets. However, for stars we deem to be magnetically quiet, we do find a clear correlation between photometric variability and estimated levels of RV noise (with variability up to ~ 10 m s super(-1)). We conclude that for these quiet stars, we can use photometric measurements as a proxy to estimate the RV noise expected. As a result, the procedure outlined in this paper may help select targets best-suited for RV follow-up necessary for planet confirmation.
•Mammary collagen gene expression, composition, and structure vary by reproductive state.•Peak collagen deposition occurs after weaning, during mammary gland involution.•Involution-collagen shares ...similarities with tumor-associated collagen.•Cases of postpartum breast cancer show elevated tumor-associated collagen gene signatures, implicating involution.
Mammographically-detected breast density impacts breast cancer risk and progression, and fibrillar collagen is a key component of breast density. However, physiologic factors influencing collagen production in the breast are poorly understood. In female rats, we analyzed gene expression of the most abundantly expressed mammary collagens and collagen-associated proteins across a pregnancy, lactation, and weaning cycle. We identified a triphasic pattern of collagen gene regulation and evidence for reproductive state-dependent composition. An initial phase of collagen deposition occurred during pregnancy, followed by an active phase of collagen suppression during lactation. The third phase of collagen regulation occurred during weaning-induced mammary gland involution, which was characterized by increased collagen deposition. Concomitant changes in collagen protein abundance were confirmed by Masson's trichrome staining, second harmonic generation (SHG) imaging, and mass spectrometry. We observed similar reproductive-state dependent collagen patterns in human breast tissue obtained from premenopausal women. SHG analysis also revealed structural variation in collagen across a reproductive cycle, with higher packing density and more collagen fibers arranged perpendicular to the mammary epithelium in the involuting rat mammary gland compared to nulliparous and lactating glands. Involution was also characterized by high expression of the collagen cross-linking enzyme lysyl oxidase, which was associated with increased levels of cross-linked collagen. Breast cancer relevance is suggested, as we found that breast cancer diagnosed in recently postpartum women displayed gene expression signatures consistent with increased collagen deposition and crosslinking compared to breast cancers diagnosed in age-matched nulliparous women. Using publicly available data sets, we found this involution-like, collagen gene signature correlated with poor progression-free survival in breast cancer patients overall and in younger women. In sum, these findings of physiologic collagen regulation in the normal mammary gland may provide insight into normal breast function, the etiology of breast density, and inform breast cancer risk and outcomes.
We report periods for 33 members of Blanco 1 as measured from Kilodegree Extremely Little Telescope-South light curves, the first reported rotation periods for this benchmark zero-age-main-sequence ...open cluster. The distribution of these stars spans from late-A or early-F dwarfs tomid-K with periods ranging from less than a day to ~8 days. The rotation period distribution has a morphology similar to the coeval Pleiades cluster, suggesting the universal nature of stellar rotation distributions. Employing two different gyrochronology methods, we find an age of 146 super(+13) sub(-14) Myr for the cluster. We find the Skumanich-like spin-down rate sufficiently describes the rotation evolution of stars hotter than the Sun; however, we find cooler stars rotating faster than predicted by a Skumanich law, suggesting a mass dependence in the efficiency of stellar angular momentum loss rate. Finally, we compare the Blanco 1 and Pleiades rotation period distributions to available nonlinear angular momentum evolution models.
IMPORTANCE: In women 45 years or younger, breast cancer diagnosis after childbirth increases the risk for metastasis and death, yet limited data exist to define this window of risk and associated ...prognostic factors. OBJECTIVE: To assess the window of elevated risk for metastasis following a postpartum breast cancer (PPBC) diagnosis and whether clinical prognostic factors are associated with the increased risk. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study conducted using cases from the Colorado Young Women’s Breast Cancer Cohort diagnosed between January 1, 1981, and December 31, 2014, included 701 women 45 years or younger with stage I to III invasive breast cancer for whom parity data, including time of last childbirth, were available. Data analysis was conducted from July 1 to September 30, 2017. This study involved a tertiary care academic hospital–based breast center and its regional affiliates with cases from the greater Rocky Mountain region. EXPOSURES: Primary exposures were prior childbirth or no childbirth, time between most recent childbirth and breast cancer diagnosis, and time between breast cancer diagnosis and metastasis. MAIN OUTCOMES AND MEASURES: The primary outcome was distant metastasis–free survival. RESULTS: A total of 701 women 45 years or younger from the greater Rocky Mountain states region were included in the analysis; mean (SD) age at diagnosis was 37.9 (5.1) years. Breast cancer diagnosis within 10 years after parturition was associated with elevated risk for metastasis, particularly in women with stage I or II disease. In addition, women with PPBC diagnosed within 10 years of a completed pregnancy that was estrogen receptor–positive showed distant metastasis–free survival similar to that of nulliparous patients with estrogen receptor–negative cancer, and women with estrogen receptor–negative PPBC had further reduced metastasis-free survival. Moreover, women with PPBC had increased lymphovascular invasion and lymph node involvement. In addition, tumor-associated Ki67 positivity identified 129 patients with luminal B cancer in the cohort that, independent of parity status, had poorer prognosis compared with patients with luminal A cancer, although it did not reach statistical significance. CONCLUSIONS AND RELEVANCE: Diagnosis of PPBC within 10 years post partum appears to be associated with an increased risk for metastasis. This increased risk was highest in stages I and II cancer at diagnosis and present in both patients with estrogen receptor–positive and estrogen receptor–negative cancer, persisting in estrogen receptor–positive cases for up to 15 years after diagnosis. Postpartum breast cancer diagnoses were not associated with increased Ki67 index but were associated with increased lymphovascular invasion and lymph node involvement compared with breast cancer in nulliparous patients.
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