The Biology of Bone Metastasis

Bone metastasis, or the development of secondary tumors within the bone of cancer patients, is a debilitating and incurable disease. Despite its morbidity, the biology of bone metastasis represents one of the most complex and intriguing of all oncogenic processes. This complexity derives from the intricately organized bone microenvironment in which the various stages of hematopoiesis, osteogenesis, and osteolysis are jointly regulated but spatially restricted. Disseminated tumor cells (DTCs) from various common malignancies such as breast, prostate, lung, and kidney cancers or myeloma are uniquely primed to subvert these endogenous bone stromal elements to grow into pathological osteolytic or osteoblastic lesions. This colonization process can be separated into three key steps: seeding, dormancy, and outgrowth. Targeting the processes of dormancy and initial outgrowth offers the most therapeutic promise. Here, we discuss the concepts of the bone metastasis niche, from controlling tumor-cell survival to growth into clinically detectable disease

Charge of a quasiparticle in a superconductor

Non-linear charge transport in SIS Josephson junctions has a unique signature in the shuttled charge quantum between the two superconductors. In the zero-bias limit Cooper pairs, each with twice the electron charge, carry the Josephson current. An applied bias $V_{SD}$ leads to multiple Andreev reflections (MAR), which in the limit of weak tunneling probability should lead to integer multiples of the electron charge $ne$ traversing the junction, with $n$ integer larger than $2{\Delta}/eV_{SD}$ and ${\Delta}$ the superconducting order parameter. Exceptionally, just above the gap, $eV_{SD}>2{\Delta}$, with Andreev reflections suppressed, one would expect the current to be carried by partitioned quasiparticles; each with energy dependent charge, being a superposition of an electron and a hole. Employing shot noise measurements in an SIS junction induced in an InAs nanowire (with noise proportional to the partitioned charge), we first observed quantization of the partitioned charge $q=e^*/e=n$, with $n=1-4$; thus reaffirming the validity of our charge interpretation. Concentrating next on the bias region $eV_{SD}{\approx}2{\Delta}$, we found a reproducible and clear dip in the extracted charge to $q{\approx}0.6$, which, after excluding other possibilities, we attribute to the partitioned quasiparticle charge. Such dip is supported by numerical simulations of our SIS structure

Land access, livelihoods, and dietary diversity in a fragile setting in northern Uganda

Food systems in fragile contexts are hardly investigated. We examined the crop value chain activities, agriculture income, coping strategy, and food consumption score (FCS) among South Sudan refugees (n = 394; refugee HH) and Uganda host communities (n = 420; host HH) living on the northern border of Uganda. Secondary data analysis was conducted using baseline data collected from an NGO-supported project. Linear regression analysis was conducted to test the association between the type of crop for growing and selling, agriculture income, coping strategy, and FCS in the refugee HH and host HH, separately. The mean number of growing and selling crops was 2.7 (SD 1.7) and 0.6 (1.0) in the refugee HH and 3.6 (1.4) and 1.3 (1.1) in the host HH. Overall food insecurity and FCS was poor in both refugee and host HH. Larger land access was associated with diverse crop production and crop selling in both groups (p < 0.05). The greater number of crop types grown was marginally associated with FCS in host HH only (β = 1.00; p = 0.05). Selling more types of crops was associated with agriculture income in both groups (p < 0.05) and was not related to rCSI in either group, but marginally associated with FCS among only host HH (β = 0.84; p = 0.04). An inequitable food system existed between the host community and South Sudan refugees residing on the northern border of Uganda. The findings suggest that diversifying crops for selling and enhancing marketing channels could aid both host and refugee communities in establishing resilient food systems

Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia

© The Author 2014. Published by Oxford University Press This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications.The study was supported by NIH grants NS077777, EY012245 and AG025532 to G.A.C., and USDA-ARS Intramural Projects 5306-51530-019-00D and 1 U24 DK097154-01 to J.W.N. Funding to pay the Open Access publication charges for this article was provided by the NIH

Melt Property Variation In GeSe2-As2Se3-PbSe Glass Ceramics For Infrared Gradient Refractive Index (GRIN) Applications

Melt size-dependent physical property variation is examined in a multicomponent GeSe2-As2Se3-PbSe chalcogenide glass developed for gradient refractive index applications. The impact of melting conditions on small (40 g) prototype laboratory-scale melts extended to commercially relevant melt sizes (1.325 kg) have been studied and the role of thermal history variation on physical and optical property evolution in parent glass, the glass\u27 crystallization behavior and post heat-treated glass ceramics, is quantified. As-melted glass morphology, optical homogeneity and heat treatment-induced microstructure following a fixed, two-step nucleation and growth protocol exhibit marked variation with melt size. These attributes are shown to impact crystallization behavior (growth rates, resulting crystalline phase formation) and induced effective refractive index change, neff, in the resulting optical nanocomposite. The magnitude of these changes is discussed based on thermal history related melt conditions

Standardization of Epidemiological Surveillance of Group A Streptococcal Impetigo

Impetigo is a highly contagious bacterial infection of the superficial layer of skin. Impetigo is caused by group A Streptococcus (Strep A) and Staphylococcus aureus, alone or in combination, with the former predominating in many tropical climates. Strep A impetigo occurs mainly in early childhood, and the burden varies worldwide. It is an acute, self-limited disease, but many children experience frequent recurrences that make it a chronic illness in some endemic settings. We present a standardized surveillance protocol including case definitions for impetigo including both active (purulent, crusted) and resolving (flat, dry) phases and discuss the current tests used to detect Strep A among persons with impetigo. Case classifications that can be applied are detailed, including differentiating between incident (new) and prevalent (existing) cases of Strep A impetigo. The type of surveillance methodology depends on the burden of impetigo in the community. Active surveillance and laboratory confirmation is the preferred method for case detection, particularly in endemic settings. Participant eligibility, surveillance population and additional considerations for surveillance of impetigo, including examination of lesions, use of photographs to document lesions, and staff training requirements (including cultural awareness), are addressed. Finally, the core elements of case report forms for impetigo are presented and guidance for recording the course and severity of impetigo provided

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp3 papain-like protease

The COVID-19 pandemic has emerged as the biggest life-threatening disease of this century. Whilst vaccination should provide a long-term solution, this is pitted against the constant threat of mutations in the virus rendering the current vaccines less effective. Consequently, small molecule antiviral agents would be extremely useful to complement the vaccination program. The causative agent of COVID-19 is a novel coronavirus, SARS-CoV-2, which encodes at least nine enzymatic activities that all have drug targeting potential. The papain-like protease (PLpro) contained in the nsp3 protein generates viral non-structural proteins from a polyprotein precursor, and cleaves ubiquitin and ISG protein conjugates. Here we describe the expression and purification of PLpro. We developed a protease assay that was used to screen a custom compound library from which we identified dihydrotanshinone I and Ro 08-2750 as compounds that inhibit PLpro in protease and isopeptidase assays and also inhibit viral replication in cell culture-based assays

Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of Nsp5 main protease

The coronavirus 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread around the world with unprecedented health and socio-economic effects for the global population. While different vaccines are now being made available, very few antiviral drugs have been approved. The main viral protease (nsp5) of SARS-CoV-2 provides an excellent target for antivirals, due to its essential and conserved function in the viral replication cycle. We have expressed, purified and developed assays for nsp5 protease activity. We screened the nsp5 protease against a custom chemical library of over 5000 characterised pharmaceuticals. We identified calpain inhibitor I and three different peptidyl fluoromethylketones (FMK) as inhibitors of nsp5 activity in vitro, with IC(50) values in the low micromolar range. By altering the sequence of our peptidomimetic FMK inhibitors to better mimic the substrate sequence of nsp5, we generated an inhibitor with a subnanomolar IC(50). Calpain inhibitor I inhibited viral infection in monkey-derived Vero E6 cells, with an EC(50) in the low micromolar range. The most potent and commercially available peptidyl-FMK compound inhibited viral growth in Vero E6 cells to some extent, while our custom peptidyl FMK inhibitor offered a marked antiviral improvement