We consider the effects of neutralino-stau (
χ−
τ
̃
) coannihilations on the cosmological relic density of the lightest supersymmetric particle (LSP)
χ
̃
in the minimal supersymmetric extension of ...the Standard Model (MSSM), particularly in the constrained MSSM in which universal supergravity inputs at the GUT scale are assumed. For much of the parameter space in these models,
χ
̃
is approximately a
U(1) gaugino
B
̃
, and constraints on the cosmological relic density
Ω
B
̃
h
2
yield an upper bound on
m
B
̃
. We show that in regions of parameter space for which the cosmological bound is nearly saturated, coannihilations of the
B
̃
with the
τ
̃
, the next lightest sparticle, are important and may reduce significantly the
B
̃
relic density. Including also
B
̃
coannihilations with the
e
̃
and
μ
̃
, we find that the upper limit on
m
χ
̃
is increased from about 200 GeV to about 600 GeV in the constrained MSSM, with a similar new upper limit expected in the MSSM.
Raman spectroscopy was applied to nail clippings from 633 postmenopausal British and Irish women, from six clinical sites, of whom 42% had experienced a fragility fracture. The objective was to build ...a prediction algorithm for fracture using data from four sites (known as the calibration set) and test its performance using data from the other two sites (known as the validation set). Results from the validation set showed that a novel algorithm, combining spectroscopy data with clinical data, provided area under the curve (AUC) of 74% compared to an AUC of 60% from a reduced QFracture score (a clinically accepted risk calculator) and 61% from the dual-energy X-ray absorptiometry T-score, which is in current use for the diagnosis of osteoporosis. Raman spectroscopy should be investigated further as a noninvasive tool for the early detection of enhanced risk of fragility fracture.
Membrane rafts are thought to be sphingolipid- and cholesterol-dependent lateral assemblies involved in diverse cellular functions. Their biological roles and even their existence, however, remain ...controversial. Using an original fluorescence correlation spectroscopy strategy that recently enabled us to identify nanoscale membrane organizations in live cells, we report here that highly dynamic nanodomains exist in both the outer and inner leaflets of the plasma membrane. Through specific inhibition of biosynthesis, we show that sphingolipids and cholesterol are essential and act in concert for formation of nanodomains, thus corroborating their raft nature. Moreover, we find that nanodomains play a crucial role in triggering the phosphatidylinositol-3 kinase/Akt signaling pathway, by facilitating Akt recruitment and activation upon phosphatidylinositol-3,4,5-triphosphate accumulation in the plasma membrane. Thus, through direct monitoring and controlled alterations of rafts in living cells, we demonstrate that rafts are critically involved in the activation of a signaling axis that is essential for cell physiology.
Feeding strategies are dependent on multi-modal sensory processing, that integrates visual, chemosensory, and mechanoreceptive cues. In many fish species, local environments and food availability ...dramatically influence the evolution of sensory and morphological traits that underlie feeding. The Mexican cavefish, Astyanax mexicanus, have developed robust changes in sensory-dependent behaviors, but the impact on prey detection and feeding behavior is not known. In the absence of eyes, cavefish have evolved enhanced sensitivity of the lateral line, comprised of mechanosensory organs that sense water flow and detect prey. Here, we identify evolved differences in prey capture behavior of larval cavefish that are dependent on lateral line sensitivity. Under lighted conditions, cavefish strike Artemia prey at a wider angle than surface fish; however, this difference is diminished under dark conditions. In addition, the strike distance is greater in cavefish than surface fish, revealing an ability to capture, and likely detect, prey at greater distances. Experimental ablation of the lateral line disrupts prey capture in cavefish under both light and dark conditions, while it only impacts surface fish under dark conditions. Together, these findings identify an evolutionary shift towards a dependence on the lateral line for prey capture in cavefish, providing a model for investigating how loss of visual cues impacts multi-modal sensory behaviors.
•Surface and cave populations of A. mexicanus differ in the mechanics of prey capture.•The lateral line detects prey vibrations that are critical for capture in the dark.•Cavefish have evolved increase reliance on the lateral-line during prey-capture.
Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice ...donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.
The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first 2 weeks of life display altered behavioral and neuroendocrinological stress ...responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, and amphetamine. However, no studies have yet examined the effects of MS on methamphetamine (METH) SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, we also investigated group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core. Long-Evans pups and dams were separated on postnatal days (PND) 2-14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-h daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.
A growing body of evidence suggests that the accumulation of amyloid-β and tau (HPτ) in the brain of patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) is associated ...with delayed extravascular clearance of metabolic waste. Whether also clearance of intracellular debris is affected in these patients needs to be examined. Hypothetically, defective extra- and intra-cellular clearance of metabolites may be instrumental in the neurodegeneration and dementia characterizing iNPH. This study explores whether iNPH is associated with altered mitochondria phenotype in neurons and astrocytes.
Cortical brain biopsies of 9 reference (REF) individuals and 30 iNPH patients were analyzed for subcellular distribution and morphology of mitochondria using transmission electron microscopy. In neuronal soma of REF and iNPH patients, we identified normal, pathological and clustered mitochondria, mitochondria-endoplasmic reticulum contact sites and autophagic vacuoles. We also differentiated normal and pathological mitochondria in pre- and post-synaptic nerve terminals, as well as in astrocytic endfoot processes towards vessels.
We found a high prevalence of pathological mitochondria in neuronal soma and pre- and post-synaptic terminals, as well as increased mitochondrial clustering, and altered number of mitochondria-endoplasmic reticulum contact sites in iNPH. Non-fused autophagic vacuoles were more abundant in neuronal soma of iNPH patients, suggestive of cellular clearance failure. Moreover, the length of postsynaptic densities was reduced in iNPH, potentially related to reduced synaptic activity. In astrocytic endfoot processes, we also found increased number, area and area fraction of pathological mitochondria in iNPH patients. The proportion of pathological mitochondria correlated significantly with increasing degree of astrogliosis and reduced perivascular expression of aquaporin-4 (AQP4), assessed by light microscopy immunohistochemistry.
Our results provide evidence of mitochondrial pathology and signs of impaired cellular clearance in iNPH patients. The results indicate that iNPH is a neurodegenerative disease with close similarity to Alzheimer's disease.
The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by ...which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T‐cell acute lymphoblastic leukemia (T‐ALL) comparing early progenitor (ETP‐ALL) cell lines whose growth is driven by PIM kinases to more mature T‐ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP‐ALL. Overexpression or knockdown of PIM in these T‐ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T‐ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT‐4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan‐PIM inhibitors (PIM‐i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T‐ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan‐PIM‐i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan‐PIM‐i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.
The present study demonstrates that in T‐ALL and prostate cancer, proviral integration site for Moloney murine leukemia virus (PIM) kinase induction increases long noncoding RNA‐H19 that in turn regulates stem cell genes. In resistant T‐ALL, PIM1/H19 signaling restores partial sensitivity to pan‐PIM inhibitors (PIM‐i). In prostate cancer, elevated PIM1 contributes to androgen deprivation therapy resistance reversed by a combination with PIM‐i. These data suggest a novel and clinically relevant pathway controlled by PIM kinases.
Inherited heterozygous BRCA2 mutations predispose carriers to tissue-specific cancers, but somatic deletion of the wild-type allele is considered essential for carcinogenesis. We find in a murine ...model of familial pancreatic cancer that germline heterozygosity for a pathogenic Brca2 truncation suffices to promote pancreatic ductal adenocarcinomas (PDACs) driven by Kras(G12D), irrespective of Trp53 status. Unexpectedly, tumor cells retain a functional Brca2 allele. Correspondingly, three out of four PDACs from patients inheriting BRCA2(999del5) did not exhibit loss-of-heterozygosity (LOH). Three tumors from these patients displaying LOH were acinar carcinomas, which also developed only in mice with biallelic Brca2 inactivation. We suggest a revised model for tumor suppression by BRCA2 with implications for the therapeutic strategy targeting BRCA2 mutant cancer cells.
Aims. A detailed study of the spectrum and variability of the source HESS J1745-290 in the Galactic Center (GC) region using new data from the H.E.S.S. array of Cherenkov telescopes is presented. ...Flaring activity and quasi periodic oscillations (QPO) of HESS J1745-290 are investigated. Methods. The image analysis is performed with a combination of a semi-analytical shower model and the statistical moment-based Hillas technique. The spectrum and lightcurves of HESS J1745-290 are derived with a likelihood method based on a spectral shape hypothesis. Rayleigh tests and Fourier analysis of the H.E.S.S. GC signal are used to study the periodicity of the source. Results. With a three-fold increase in statistics compared to previous work, a deviation from a simple power law spectrum is detected for the first time. The measured energy spectrum over the three years 2004, 2005 and 2006 of data taking is compatible with both a power law spectrum with an exponential cut-off and a broken power law spectrum. The curvature of the energy spectrum is likely to be intrinsic to the photon source, as opposed to effects of interstellar absorption. The power law spectrum with an exponential cut-off is characterized by a photon index of 2.10 ± 0.04$_{\mathrm{stat}}$ ± 0.10$_{\mathrm{syst}}$ and a cut-off energy at 15.7 ± 3.4$_{\mathrm{stat}}$ ± 2.5$_{\mathrm{syst}}$ TeV. The broken power law spectrum exhibits spectral indices of 2.02 ± 0.08$_{\mathrm{stat}}$ ± 0.10$_{\mathrm{syst}}$ and 2.63 ± 0.14$_{\mathrm{stat}}$ ± 0.10$_{\mathrm{syst}}$ with a break energy at 2.57 ± 0.19$_{\mathrm{stat}}$ ± 0.44$_{\mathrm{syst}}$ TeV. No significant flux variation is found. Increases in the γ-ray flux of HESS J1745-290 by at least a factor of two would be required for a 3σ detection of a flare with time scales of an hour. Investigation of possible QPO activity at periods claimed to be detected in X-rays does not show any periodicities in the H.E.S.S. signal.
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