Inhibition of Aurora Kinase B activity disrupts development and differentiation of salivary glands

Little is known about the key molecules that regulate cell division during organogenesis. Here we determine the role of the cell cycle promoter aurora kinase B (AURKB) during development, using embryonic salivary glands (E-SGs) as a model. AURKB is a serine/threonine kinase that regulates key events in mitosis, which makes it an attractive target for tailored anticancer therapy. Many reports have elaborated on the role of AURKB in neoplasia and cancer; however, no previous study has shown its role during organ development. Our previous experiments have highlighted the essential requirement for AURKB during adult exocrine regeneration. To investigate if AURKB is similarly required for progression during embryonic development, we pharmacologically inhibited AURKB in developing submandibular glands (SMGs) at embryonic day (E)13.5 and E16.5, using the highly potent and selective drug Barasertib. Inhibition of AURKB interfered with the expansion of the embryonic buds. Interestingly, this effect on SMG development was also seen when the mature explants (E16.5) were incubated for 24 h with another cell cycle inhibitor Aphidicolin. Barasertib prompted apoptosis, DNA damage and senescence, the markers of which (cleaved caspase 3, γH2AX, SA-βgal and p21, respectively), were predominantly seen in the developing buds. In addition to a reduction in cell cycling and proliferation of the epithelial cells in response to AURKB inhibition, Barasertib treatment led to an excessive generation of reactive oxygen species (ROS) that resulted in downregulation of the acinar differentiation marker Mist1. Importantly, inhibition of ROS was able to rescue this loss of identity, with Mist1 expression maintained despite loss of AURKB. Together, these data identify AURKB as a key molecule in supporting embryonic development and differentiation, while inhibiting senescence-inducing signals during organogenesis

\u27Vitamin D and cognition in older adults\u27: updated international recommendations.

BACKGROUND: Hypovitaminosis D, a condition that is highly prevalent in older adults aged 65 years and above, is associated with brain changes and dementia. Given the rapidly accumulating and complex contribution of the literature in the field of vitamin D and cognition, clear guidance is needed for researchers and clinicians. METHODS: International experts met at an invitational summit on \u27Vitamin D and Cognition in Older Adults\u27. Based on previous reports and expert opinion, the task force focused on key questions relating to the role of vitamin D in Alzheimer\u27s disease and related disorders. Each question was discussed and voted using a Delphi-like approach. RESULTS: The experts reached an agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults and may alter the clinical presentation as a consequence of related comorbidities; however, at present, vitamin D level should not be used as a diagnostic or prognostic biomarker of Alzheimer\u27s disease due to lack of specificity and insufficient evidence. This population should be screened for hypovitaminosis D because of its high prevalence and should receive supplementation, if necessary; but this advice was not specific to cognition. During the debate, the possibility of \u27critical periods\u27 during which vitamin D may have its greatest impact on the brain was addressed; whether hypovitaminosis D influences cognition actively through deleterious effects and/or passively by loss of neuroprotection was also considered. CONCLUSIONS: The international task force agreed on five overarching principles related to vitamin D and cognition in older adults. Several areas of uncertainty remain, and it will be necessary to revise the proposed recommendations as new findings become available

Magnetic Fluffy Dark Matter

We explore extensions of inelastic Dark Matter and Magnetic inelastic Dark Matter where the WIMP can scatter to a tower of heavier states. We assume a WIMP mass $m_\chi \sim \mathcal{O}(1-100)$ GeV and a constant splitting between successive states $\delta \sim\mathcal{O}(1 - 100)$ keV. For the spin-independent scattering scenario we find that the direct experiments CDMS and XENON strongly constrain most of the DAMA/LIBRA preferred parameter space, while for WIMPs that interact with nuclei via their magnetic moment a region of parameter space corresponding to $m_{\chi}\sim 11$ GeV and $\delta < 15$ keV is allowed by all the present direct detection constraints.Comment: 16 pages, 6 figures, added comments about magnetic moment form factor to Sec 3.1.2 and results to Sec 3.2.2, final version to be published in JHE

Intervention planning and modification of the BUMP intervention: a digital intervention for the early detection of raised blood pressure in pregnancy

Background: Hypertensive disorders in pregnancy, particularly pre-eclampsia, pose a substantial health risk for both maternal and foetal outcomes. The BUMP (Blood Pressure Self-Monitoring in Pregnancy) interventions are being tested in a trial. They aim to facilitate the early detection of raised blood pressure through self-monitoring. This article outlines how the self-monitoring interventions in the BUMP trial were developed and modified using the person-based approach to promote engagement and adherence. Methods: Key behavioural challenges associated with blood pressure self-monitoring in pregnancy were identified through synthesising qualitative pilot data and existing evidence, which informed guiding principles for the development process. Social cognitive theory was identified as an appropriate theoretical framework. A testable logic model was developed to illustrate the hypothesised processes of change associated with the intervention. Iterative qualitative feedback from women and staff informed modifications to the participant materials. Results: The evidence synthesis suggested women face challenges integrating self-monitoring into their lives and that adherence is challenging at certain time points in pregnancy (for example, starting maternity leave). Intervention modification included strategies to address adherence but also focussed on modifying outcome expectancies, by providing messages explaining pre-eclampsia and outlining the potential benefits of self-monitoring. Conclusions: With an in-depth understanding of the target population, several methods and approaches to plan and develop interventions specifically relevant to pregnant women were successfully integrated, to address barriers to behaviour change while ensuring they are easy to engage with, persuasive and acceptable

Transformations between 2MASS, SDSS and BVRI photometric systems: bridging the near infrared and optical

We present colour transformations for the conversion of the {\em 2MASS} photometric system to the Johnson-Cousins $UBVRI$ system and further into the {\em SDSS} $ugriz$ system. We have taken {\em SDSS} $gri$ magnitudes of stars measured with the 2.5-m telescope from $SDSS$ Data Release 5 (DR5), and $BVRI$ and $JHK_{s}$ magnitudes from Stetson's catalogue and \citet{Cu03}, respectively. We matched thousands of stars in the three photometric systems by their coordinates and obtained a homogeneous sample of 825 stars by the following constraints, which are not used in previous transformations: 1) the data are de-reddened, 2) giants are omitted, and 3) the sample stars selected are of the highest quality. We give metallicity, population type, and transformations dependent on two colours. The transformations provide absolute magnitude and distance determinations which can be used in space density evaluations at short distances where some or all of the {\em SDSS} $ugriz$ magnitudes are saturated. The combination of these densities with those evaluated at larger distances using {\em SDSS} $ugriz$ photometry will supply accurate Galactic model parameters, particularly the local space densities for each population.Comment: 11 pages, including 10 figures and 7 tables, accepted for publication in MNRA

Assessement of tensile strength of graphites by the iosipescu coupon test

Polycrystalline graphites are widely used in the metallurgical, nuclear and aerospace industries. Graphites are particulated composites manufactured with a mixture of coke with pitch, and changes in relative proportions of these materials cause modifications in their mechanical properties. Uniaxial tension tests must be avoided for mechanical characterization in this kind of brittle material, due to difficulties in making the relatively long specimens and premature damages caused during testing set-up. On other types of tests, e.g. bending tests, the specimens are submitted to combined stress states (normal and transverse shear stresses). The Iosipescu shear test, is performed in a beam with two 90° opposite notches machined at the mid-length of the specimens, by applying two forces couples, so that a pure and uniform shear stress state is generated at the cross section between the two notches. When a material is isotropic and brittle, a failure at 45° in relation to the beam long axis can take place, i.e., the tensile normal stress acts parallel to the lateral surface of the notches, controls the failure and the result of the shear test is numerically equivalent to the tensile strength. This work has evaluated a graphite of the type used in rocket nozzles by the Iosipescu test and the resulted stress, ~11 MPa, was found to be equal to the tensile strength. Thus, the tensile strength can be evaluated just by a single and simple experiment, thus avoiding complicated machining of specimen and testing set-up

Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity

Mosaicism for combined tetrasomy of chromosomes 8 and 18 in a dysmorphic child: A result of failed tetraploidy correction?

<p>Abstract</p> <p>Background</p> <p>Mosaic whole-chromosome tetrasomy has not previously been described as a cause of fetal malformations.</p> <p>Case presentation</p> <p>In a markedly dysmorphic child with heart malformations and developmental delay, CGH analysis of newborn blood DNA suggested a 50% dose increase of chromosomes 8 and 18, despite a normal standard karyotype investigation. Subsequent FISH analysis revealed leukocytes with four chromosomes 8 and four chromosomes 18. The child's phenotype had resemblance to both mosaic trisomy 8 and mosaic trisomy 18. The double tetrasomy was caused by mitotic malsegregation of all four chromatids of both chromosome pairs. A possible origin of such an error is incomplete correction of a tetraploid state resulting from failed cytokinesis or mitotic slippage during early embryonic development.</p> <p>Conclusion</p> <p>This unique case suggests that embryonic cells may have a mechanism for tetraploidy correction that involves mitotic pairing of homologous chromosomes.</p

Physics and Applications of Laser Diode Chaos

An overview of chaos in laser diodes is provided which surveys experimental achievements in the area and explains the theory behind the phenomenon. The fundamental physics underpinning this behaviour and also the opportunities for harnessing laser diode chaos for potential applications are discussed. The availability and ease of operation of laser diodes, in a wide range of configurations, make them a convenient test-bed for exploring basic aspects of nonlinear and chaotic dynamics. It also makes them attractive for practical tasks, such as chaos-based secure communications and random number generation. Avenues for future research and development of chaotic laser diodes are also identified.Comment: Published in Nature Photonic