4,386 research outputs found
Brain-age is associated with progression to dementia in memory clinic patients
Background: Biomarkers for the early detection of dementia risk hold promise for better disease monitoring and targeted interventions. However, most biomarker studies, particularly in neuroimaging, have analysed artificially ‘clean’ research groups, free from comorbidities, erroneous referrals, contraindications and from a narrow sociodemographic pool. Such biases mean that neuroimaging samples are often unrepresentative of the target population for dementia risk (e.g., people referred to a memory clinic), limiting the generalisation of these studies to real-world clinical settings. To facilitate better translation from research to the clinic, datasets that are more representative of dementia patient groups are warranted. Methods: We analysed T1-weighted MRI scans from a real-world setting of patients referred to UK memory clinic services (n = 1140; 60.2 % female and mean [SD] age of 70.0[10.8] years) to derive ‘brain-age’. Brain-age is an index of age-related brain health based on quantitative analysis of structural neuroimaging, largely reflecting brain atrophy. Brain-predicted age difference (brain-PAD) was calculated as brain-age minus chronological age. We determined which patients went on to develop dementia between three months and 7.8 years after neuroimaging assessment (n = 476) using linkage to electronic health records. Results: Survival analysis, using Cox regression, indicated a 3 % increased risk of dementia per brain-PAD year (hazard ratio [95 % CI] = 1.03 [1.02,1.04], p < 0.0001), adjusted for baseline age, age2, sex, Mini Mental State Examination (MMSE) score and normalised brain volume. In sensitivity analyses, brain-PAD remained significant when time-to-dementia was at least 3 years (hazard ratio [95 % CI] = 1.06 [1.02, 1.09], p = 0.0006), or when baseline MMSE score ≥ 27 (hazard ratio [95 % CI] = 1.03 [1.01, 1.05], p = 0.0006). Conclusions: Memory clinic patients with older‐appearing brains are more likely to receive a subsequent dementia diagnosis. Potentially, brain-age could aid decision-making during initial memory clinic assessment to improve early detection of dementia. Even when neuroimaging assessment was more than 3 years prior to diagnosis and when cognitive functioning was not clearly impaired, brain-age still proved informative. These real-world results support the use of quantitative neuroimaging biomarkers like brain-age in memory clinics
Burden of visceral leishmaniasis in villages of eastern gedaref state, Sudan: an exhaustive cross-sectional survey.
Since December 2009, Médecins Sans Frontières has diagnosed and treated patients with visceral leishmaniasis (VL) in Tabarak Allah Hospital, eastern Gedaref State, one of the main endemic foci of VL in Sudan. A survey was conducted to estimate the VL incidence in villages around Tabarak Allah
Photocurrent measurements of supercollision cooling in graphene
The cooling of hot electrons in graphene is the critical process underlying
the operation of exciting new graphene-based optoelectronic and plasmonic
devices, but the nature of this cooling is controversial. We extract the hot
electron cooling rate near the Fermi level by using graphene as novel
photothermal thermometer that measures the electron temperature () as it
cools dynamically. We find the photocurrent generated from graphene
junctions is well described by the energy dissipation rate , where the heat capacity is and is the
base lattice temperature. These results are in disagreement with predictions of
electron-phonon emission in a disorder-free graphene system, but in excellent
quantitative agreement with recent predictions of a disorder-enhanced
supercollision (SC) cooling mechanism. We find that the SC model provides a
complete and unified picture of energy loss near the Fermi level over the wide
range of electronic (15 to 3000 K) and lattice (10 to 295 K) temperatures
investigated.Comment: 7pages, 5 figure
Fluctuating selection models and Mcdonald-Kreitman type analyses
It is likely that the strength of selection acting upon a mutation varies through time due to changes in the environment. However, most population genetic theory assumes that the strength of selection remains constant. Here we investigate the consequences of fluctuating selection pressures on the quantification of adaptive evolution using McDonald-Kreitman (MK) style approaches. In agreement with previous work, we show that fluctuating selection can generate evidence of adaptive evolution even when the expected strength of selection on a mutation is zero. However, we also find that the mutations, which contribute to both polymorphism and divergence tend, on average, to be positively selected during their lifetime, under fluctuating selection models. This is because mutations that fluctuate, by chance, to positive selected values, tend to reach higher frequencies in the population than those that fluctuate towards negative values. Hence the evidence of positive adaptive evolution detected under a fluctuating selection model by MK type approaches is genuine since fixed mutations tend to be advantageous on average during their lifetime. Never-the-less we show that methods tend to underestimate the rate of adaptive evolution when selection fluctuates
Wolbachia in the flesh: symbiont intensities in germ-line and somatic tissues challenge the conventional view of Wolbachia transmission routes
Symbionts can substantially affect the evolution and ecology of their hosts. The investigation of the tissue-specific distribution of symbionts (tissue tropism) can provide important insight into host-symbiont interactions. Among other things, it can help to discern the importance of specific transmission routes and potential phenotypic effects. The intracellular bacterial symbiont Wolbachia has been described as the greatest ever panzootic, due to the wide array of arthropods that it infects. Being primarily vertically transmitted, it is expected that the transmission of Wolbachia would be enhanced by focusing infection in the reproductive tissues. In social insect hosts, this tropism would logically extend to reproductive rather than sterile castes, since the latter constitute a dead-end for vertically transmission. Here, we show that Wolbachia are not focused on reproductive tissues of eusocial insects, and that non-reproductive tissues of queens and workers of the ant Acromyrmex echinatior, harbour substantial infections. In particular, the comparatively high intensities of Wolbachia in the haemolymph, fat body, and faeces, suggest potential for horizontal transmission via parasitoids and the faecal-oral route, or a role for Wolbachia modulating the immune response of this host. It may be that somatic tissues and castes are not the evolutionary dead-end for Wolbachia that is commonly thought
Can we continue research in splenectomized dogs? Mycoplasma haemocanis: Old problem - New insight
We report the appearance of a Mycoplasma haemocanis infection in laboratory dogs, which has been reported previously, yet, never before in Europe. Outbreak of the disease was triggered by a splenectomy intended to prepare the dogs for a hemorrhagic shock study. The clinical course of the dogs was dramatic including anorexia and hemolytic anemia. Treatment included allogeneic transfusion, prednisone, and oxytetracycline. Systematic follow-up (n=12, blood smears, antibody testing and specific polymerase chain reaction) gives clear evidence that persistent eradication of M. haemocanis is unlikely. We, therefore, had to abandon the intended shock study. In the absence of effective surveillance and screening for M. haemocanis, the question arises whether it is prudent to continue shock research in splenectomized dogs. Copyright (C) 2004 S. Karger AG, Basel
Photoconductivity of biased graphene
Graphene is a promising candidate for optoelectronic applications such as
photodetectors, terahertz imagers, and plasmonic devices. The origin of
photoresponse in graphene junctions has been studied extensively and is
attributed to either thermoelectric or photovoltaic effects. In addition, hot
carrier transport and carrier multiplication are thought to play an important
role. Here we report the intrinsic photoresponse in biased but otherwise
homogeneous graphene. In this classic photoconductivity experiment, the
thermoelectric effects are insignificant. Instead, the photovoltaic and a
photo-induced bolometric effect dominate the photoresponse due to hot
photocarrier generation and subsequent lattice heating through electron-phonon
cooling channels respectively. The measured photocurrent displays polarity
reversal as it alternates between these two mechanisms in a backgate voltage
sweep. Our analysis yields elevated electron and phonon temperatures, with the
former an order higher than the latter, confirming that hot electrons drive the
photovoltaic response of homogeneous graphene near the Dirac point
Preconditioning of mesenchymal stromal cells with low-intensity ultrasound: influence on chondrogenesis and directed SOX9 signaling pathways
Background: Continuous low-intensity ultrasound (cLIUS) facilitates the chondrogenic differentiation of human mesenchymal stromal cells (MSCs) in the absence of exogenously added transforming growth factor-beta (TGFβ) by upregulating the expression of transcription factor SOX9, a master regulator of chondrogenesis. The present study evaluated the molecular events associated with the signaling pathways impacting SOX9 gene and protein expression under cLIUS.
Methods: Human bone marrow-derived MSCs were exposed to cLIUS stimulation at 14 kPa (5 MHz, 2.5 Vpp) for 5 min. The gene and protein expression of SOX9 was evaluated. The specificity of SOX9 upregulation under cLIUS was determined by treating the MSCs with small molecule inhibitors of select signaling molecules, followed by cLIUS treatment. Signaling events regulating SOX9 expression under cLIUS were analyzed by gene expression, immunofluorescence staining, and western blotting.
Results: cLIUS upregulated the gene expression of SOX9 and enhanced the nuclear localization of SOX9 protein when compared to non-cLIUS-stimulated control. cLIUS was noted to enhance the phosphorylation of the signaling molecule ERK1/2. Inhibition of MEK/ERK1/2 by PD98059 resulted in the effective abrogation of cLIUS-induced SOX9 expression, indicating that cLIUS-induced SOX9 upregulation was dependent on the phosphorylation of ERK1/2. Inhibition of integrin and TRPV4, the upstream cell-surface effectors of ERK1/2, did not inhibit the phosphorylation of ERK1/2 and therefore did not abrogate cLIUS-induced SOX9 expression, thereby suggesting the involvement of other mechanoreceptors. Consequently, the effect of cLIUS on the actin cytoskeleton, a mechanosensitive receptor regulating SOX9, was evaluated. Diffused and disrupted actin fibers observed in MSCs under cLIUS closely resembled actin disruption by treatment with cytoskeletal drug Y27632, which is known to increase the gene expression of SOX9. The upregulation of SOX9 under cLIUS was, therefore, related to cLIUS-induced actin reorganization. SOX9 upregulation induced by actin reorganization was also found to be dependent on the phosphorylation of ERK1/2.
Conclusions: Collectively, preconditioning of MSCs by cLIUS resulted in the nuclear localization of SOX9, phosphorylation of ERK1/2 and disruption of actin filaments, and the expression of SOX9 was dependent on the phosphorylation of ERK1/2 under cLIUS
CD8(+) T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo
Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8+ T cell responses, which can be observed during symptomatic primary
infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged
CD8+ T cell stimulation during IM, EBV enters latency and is under lifelong immune control
in most individuals that experience this disease. We investigated whether changes in T cell
function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive
CD8+ T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during
IM and in mice with reconstituted human immune system components (huNSG mice) that
had been infected with a high dose of EBV. These PD-1 positive CD8+ T cells, however,
retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8+
T cells expanded during EBV infection, including PD-1+
Tim-3+
KLRG1+ cells that express
CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain
BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and
resulted in virus-associated lymphomagenesis. Finally, PD-1+
, Tim-3+
, and KLRG1+ CD8+ T
cell expansion coincided with declining viral loads during low dose EBV infection. These
findings suggest that EBV infection primes PD-1 positive CD8+ T cell populations that rely
on this receptor axis for the efficient immune control of this ubiquitous human tumor virus
- …