Regional diversity in the murine cortical vascular network is revealed by synchrotron X-ray tomography and is amplified with age

Cortical bone is permeated by a system of pores, occupied by the blood supply and osteocytes. With ageing, bone mass reduction and disruption of the microstructure are associated with reduced vascular supply. Insight into the regulation of the blood supply to the bone could enhance the understanding of bone strength determinants and fracture healing. Using synchrotron radiation-based computed tomography, the distribution of vascular canals and osteocyte lacunae was assessed in murine cortical bone and the influence of age on these parameters was investigated. The tibiofibular junction from 15-week- and 10-month-old female C57BL/6J mice were imaged post-mortem. Vascular canals and three-dimensional spatial relationships between osteocyte lacunae and bone surfaces were computed for both age groups. At 15 weeks, the posterior region of the tibiofibular junction had a higher vascular canal volume density than the anterior, lateral and medial regions. Intracortical vascular networks in anterior and posterior regions were also different, with connectedness in the posterior higher than the anterior at 15 weeks. By 10 months, cortices were thinner, with cortical area fraction and vascular density reduced, but only in the posterior cortex. This provided the first evidence of age-related effects on murine bone porosity due to the location of the intracortical vasculature. Targeting the vasculature to modulate bone porosity could provide an effective way to treat degenerative bone diseases, such as osteoporosis

Experimental and numerical validation of active flaps for wind turbine blades

An industrial active flap concept for wind turbine rotor blades is validated numerically by means of CFD, as well as experimentally in a wind tunnel environment. This paper presents the numerical and experimental results, as well as a discussion regarding the testing of airfoils equipped with active flaps with a highly loaded aft portion. A conceptual implementation for an offshore wind turbine and the potential for load reduction is shown by means of aeroelastic calculations. The work presented herein is conducted within the frame of the Induflap2 project and is partially funded by the Danish funding board EUDP

The Overall Coefficient of the Two-loop Superstring Amplitude Using Pure Spinors

Using the results recently obtained for computing integrals over (non-minimal) pure spinor superspace, we compute the coefficient of the massless two-loop four-point amplitude from first principles. Contrasting with the mathematical difficulties in the RNS formalism where unknown normalizations of chiral determinant formulae force the two-loop coefficient to be determined only indirectly through factorization, the computation in the pure spinor formalism can be smoothly carried out.Comment: 29 pages, harvmac TeX. v2: add reference

Testing Yukawa-unified SUSY during year 1 of LHC: the role of multiple b-jets, dileptons and missing E_T

We examine the prospects for testing SO(10) Yukawa-unified supersymmetric models during the first year of LHC running at \sqrt{s}= 7 TeV, assuming integrated luminosity values of 0.1 to 1 fb^-1. We consider two cases: the Higgs splitting (HS) and the D-term splitting (DR3) models. Each generically predicts light gluinos and heavy squarks, with an inverted scalar mass hierarchy. We hence expect large rates for gluino pair production followed by decays to final states with large b-jet multiplicity. For 0.2 fb^-1 of integrated luminosity, we find a 5 sigma discovery reach of m(gluino) ~ 400 GeV even if missing transverse energy, E_T^miss, is not a viable cut variable, by examining the multi-b-jet final state. A corroborating signal should stand out in the opposite-sign (OS) dimuon channel in the case of the HS model; the DR3 model will require higher integrated luminosity to yield a signal in the OS dimuon channel. This region may also be probed by the Tevatron with 5-10 fb^-1 of data, if a corresponding search in the multi-b+ E_T^miss channel is performed. With higher integrated luminosities of ~1 fb^-1, using E_T^miss plus a large multiplicity of b-jets, LHC should be able to discover Yukawa-unified SUSY with m(gluino) up to about 630 GeV. Thus, the year 1 LHC reach for Yukawa-unified SUSY should be enough to either claim a discovery of the gluino, or to very nearly rule out this class of models, since higher values of m(gluino) lead to rather poor Yukawa unification.Comment: 32 pages including 31 EPS figure

Tailoring the atomic structure of graphene nanoribbons by STM lithography

The practical realization of nano-scale electronics faces two major challenges: the precise engineering of the building blocks and their assembly into functional circuits. In spite of the exceptional electronic properties of carbon nanotubes only basic demonstration-devices have been realized by time-consuming processes. This is mainly due to the lack of selective growth and reliable assembly processes for nanotubes. However, graphene offers an attractive alternative. Here we report the patterning of graphene nanoribbons (GNRs) and bent junctions with nanometer precision, well-defined widths and predetermined crystallographic orientations allowing us to fully engineer their electronic structure using scanning tunneling microscope (STM) lithography. The atomic structure and electronic properties of the ribbons have been investigated by STM and tunneling spectroscopy measurements. Opening of confinement gaps up to 0.5 eV, allowing room temperature operation of GNR-based devices, is reported. This method avoids the difficulties of assembling nano-scale components and allows the realization of complete integrated circuits, operating as room temperature ballistic electronic devices.Comment: 8 pages text, 5 figures, Nature Nanotechnology, in pres

Life-threatening acute acalculous cholecystitis in a patient with renal cell carcinoma treated by sunitinib: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sunitinib, an oral multitargeted tyrosine kinase inhibitor, is widely used in the treatment of renal cell carcinoma and gastrointestinal stromal tumor and has had a variety of adverse events. However, sunitinib-related acute cholecystitis has been reported in only two patients with gastrointestinal stromal tumor and renal cell carcinoma (clear cell subtype).</p> <p>Case presentation</p> <p>A 75-year-old Japanese woman with a right sided abdominal swelling was referred to our hospital. Computed tomography (CT) showed a hypervascular bulky tumor in her right kidney, suggesting right renal cell carcinoma in clinical T4N0M0. Although sunitinib therapy was started as neoadjuvant chemotherapy, during the fourth week of the first cycle, she developed acute acalculous cholecystitis and disseminated intravascular coagulation associated with sunitinib. Sunitinib therapy was discontinued immediately and she recovered after subsequent treatment with antibiotics and gabexate mesilate followed by percutaneous cholecystostomy. Cholecystectomy and right radical nephrectomy were performed and pathological examination showed that her renal tumor was a chromophobe renal cell carcinoma (pT2) with necrosis. Inflammation and ischemia were observed in the gallbladder wall, which was compatible with acute acalculous cholecystitis. There has been no evidence of disease recurrence for more than six months.</p> <p>Conclusion</p> <p>We described the third case of sunitinib-related acute cholecystitis in a patient with chromophobe renal cell carcinoma. Attention is required to sunitinib-related acute cholecystitis which, while uncommon, could be life-threatening.</p

Mitochondrial clearance by the STK38 kinase supports oncogenic Ras-induced cell transformation.

Oncogenic Ras signalling occurs frequently in many human cancers. However, no effective targeted therapies are currently available to treat patients suffering from Ras-driven tumours. Therefore, it is imperative to identify downstream effectors of Ras signalling that potentially represent promising new therapeutic options. Particularly, considering that autophagy inhibition can impair the survival of Ras-transformed cells in tissue culture and mouse models, an understanding of factors regulating the balance between autophagy and apoptosis in Ras-transformed human cells is needed. Here, we report critical roles of the STK38 protein kinase in oncogenic Ras transformation. STK38 knockdown impaired anoikis resistance, anchorage-independent soft agar growth, and in vivo xenograft growth of Ras-transformed human cells. Mechanistically, STK38 supports Ras-driven transformation through promoting detachment-induced autophagy. Even more importantly, upon cell detachment STK38 is required to sustain the removal of damaged mitochondria by mitophagy, a selective autophagic process, to prevent excessive mitochondrial reactive oxygen species production that can negatively affect cancer cell survival. Significantly, knockdown of PINK1 or Parkin, two positive regulators of mitophagy, also impaired anoikis resistance and anchorage-independent growth of Ras-transformed human cells, while knockdown of USP30, a negative regulator of PINK1/Parkin-mediated mitophagy, restored anchorage-independent growth of STK38-depleted Ras-transformed human cells. Therefore, our findings collectively reveal novel molecular players that determine whether Ras-transformed human cells die or survive upon cell detachment, which potentially could be exploited for the development of novel strategies to target Ras-transformed cells

May measurement month 2018: an analysis of blood pressure screening in the Philippines.

Building on the gains of May Measurement Month 2017 (MMM17), the Philippine Society of Hypertension once again took part in MMM18 to raise awareness of high blood pressure (BP) in the country and to harness opportunistic BP screening in detecting unaware hypertensive individuals and referring them for treatment. We followed the standard MMM18 protocol designed by the International Society of Hypertension, utilizing convenience sampling with volunteer investigators, taking three sitting BP measurements of volunteer adults (≥18 years). Basic data on demographic, lifestyle, and environmental factors were also taken. We analysed 177 176 screened individuals from the Philippines. Of these, 29.1% (51 527) had also participated in MMM17, whereas 68.8% (121 893) were new screenees; and 14.2% (25 232) had their BP taken for the first time ever. After multiple imputation, 39.0% (69 126) were hypertensive. Of these, 50.3% (34 795) were aware they were hypertensive. 49.9% (34 491) were on antihypertensive medication, 58.0% (20 010) of whom had controlled BP <140/90 mmHg. Only 28.9% of all participants with hypertension had controlled BP. Systolic BPs and diastolic BPs were significantly higher in the overweight and obese, in those receiving antihypertensive medications, in patients with diabetes, and significantly lower in pregnant women. MMM18 has again shown that opportunistic BP screening, harnessing volunteers, is a pragmatic public health measure to improve awareness and treatment rates of raised BP

Analysis of host responses to Mycobacterium tuberculosis antigens in a multi-site study of subjects with different TB and HIV infection states in sub-Saharan Africa.

BACKGROUND: Tuberculosis (TB) remains a global health threat with 9 million new cases and 1.4 million deaths per year. In order to develop a protective vaccine, we need to define the antigens expressed by Mycobacterium tuberculosis (Mtb), which are relevant to protective immunity in high-endemic areas. METHODS: We analysed responses to 23 Mtb antigens in a total of 1247 subjects with different HIV and TB status across 5 geographically diverse sites in Africa (South Africa, The Gambia, Ethiopia, Malawi and Uganda). We used a 7-day whole blood assay followed by IFN-γ ELISA on the supernatants. Antigens included PPD, ESAT-6 and Ag85B (dominant antigens) together with novel resuscitation-promoting factors (rpf), reactivation proteins, latency (Mtb DosR regulon-encoded) antigens, starvation-induced antigens and secreted antigens. RESULTS: There was variation between sites in responses to the antigens, presumably due to underlying genetic and environmental differences. When results from all sites were combined, HIV- subjects with active TB showed significantly lower responses compared to both TST(-) and TST(+) contacts to latency antigens (Rv0569, Rv1733, Rv1735, Rv1737) and the rpf Rv0867; whilst responses to ESAT-6/CFP-10 fusion protein (EC), PPD, Rv2029, TB10.3, and TB10.4 were significantly higher in TST(+) contacts (LTBI) compared to TB and TST(-) contacts fewer differences were seen in subjects with HIV co-infection, with responses to the mitogen PHA significantly lower in subjects with active TB compared to those with LTBI and no difference with any antigen. CONCLUSIONS: Our multi-site study design for testing novel Mtb antigens revealed promising antigens for future vaccine development. The IFN-γ ELISA is a cheap and useful tool for screening potential antigenicity in subjects with different ethnic backgrounds and across a spectrum of TB and HIV infection states. Analysis of cytokines other than IFN-γ is currently on-going to determine correlates of protection, which may be useful for vaccine efficacy trials

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development