Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.

p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate

Recent translational research: stem cells as the roots of breast cancer

Common phenotypes of cancer and stem cells suggest that breast cancers arise from stem cells. Breast epithelial cells with stem cell phenotypes have been shown to be more susceptible to immortalization and neoplastic transformation. Breast tumor stem cells with CD44(+)/CD24(-/low)Lineage(- )markers have been isolated. The role of these cells in tumor progression and clinical outcome is not clear. The relationship between breast stem cell and tumor stem cell may be elucidated by further studies of carcinogenesis of nonadherent mammosphere cells with stem cell features and by derivation of CD44(+)/CD24(-/low )cells from an adherent breast epithelial stem cell type

Use of a Cholera Rapid Diagnostic Test during a Mass Vaccination Campaign in Response to an Epidemic in Guinea, 2012

During the 2012 cholera outbreak in the Republic of Guinea, the Ministry of Health, supported by Médecins Sans Frontières - Operational Center Geneva, used the oral cholera vaccine Shanchol as a part of the emergency response. The rapid diagnostic test (RDT) Crystal VC, widely used during outbreaks, detects lipopolysaccharide antigens of Vibrio cholerae O1 and O139, both included in Shanchol. In the context of reactive use of a whole-cell cholera vaccine in a region where cholera cases have been reported, it is essential to know what proportion of vaccinated individuals would be reactive to the RDT and for how long after vaccination

Probing Nucleation Mechanism of Self-Catalyzed InN Nanostructures

The nucleation and evolution of InN nanowires in a self-catalyzed growth process have been investigated to probe the microscopic growth mechanism of the self-catalysis and a model is proposed for high pressure growth window at ~760 Torr. In the initial stage of the growth, amorphous InNx microparticles of cone shape in liquid phase form with assistance of an InNx wetting layer on the substrate. InN crystallites form inside the cone and serve as the seeds for one-dimensional growth along the favorable [0001] orientation, resulting in single-crystalline InN nanowire bundles protruding out from the cones. An amorphous InNx sheath around the faucet tip serves as the interface between growing InN nanowires and the incoming vapors of indium and nitrogen and supports continuous growth of InN nanowires in a similar way to the oxide sheath in the oxide-assisted growth of other semiconductor nanowires. Other InN 1D nanostructures, such as belts and tubes, can be obtained by varying the InN crystallites nucleation and initiation process

Exotendons for assistance of human locomotion

BACKGROUND: Powered robotic exoskeletons for assistance of human locomotion are currently under development for military and medical applications. The energy requirements for such devices are excessive, and this has become a major obstacle for practical applications. Legged locomotion in many animals, however, is very energy efficient. We propose that poly-articular elastic mechanisms are a major contributor to the economy of locomotion in such specialized animals. Consequently, it should be possible to design unpowered assistive devices that make effective use of similar mechanisms. METHODS: A passive assistive technology is presented, based on long elastic cords attached to an exoskeleton and guided by pulleys placed at the joints. A general optimization procedure is described for finding the best geometrical arrangement of such "exotendons" for assisting a specific movement. Optimality is defined either as minimal residual joint moment or as minimal residual joint power. Four specific exotendon systems with increasing complexity are considered. Representative human gait data were used to optimize each of these four systems to achieve maximal assistance for normal walking. RESULTS: The most complex exotendon system, with twelve pulleys per limb, was able to reduce the joint moments required for normal walking by 71% and joint power by 74%. A simpler system, with only three pulleys per limb, could reduce joint moments by 46% and joint power by 47%. CONCLUSION: It is concluded that unpowered passive elastic devices can substantially reduce the muscle forces and the metabolic energy needed for walking, without requiring a change in movement. When optimally designed, such devices may allow independent locomotion in patients with large deficits in muscle function

Enhanced virtual microscopy for collaborative education

<p>Abstract</p> <p>Background</p> <p>Curricular reform efforts and a desire to use novel educational strategies that foster student collaboration are challenging the traditional microscope-based teaching of histology. Computer-based histology teaching tools and Virtual Microscopes (VM), computer-based digital slide viewers, have been shown to be effective and efficient educational strategies. We developed an open-source VM system based on the Google Maps engine to transform our histology education and introduce new teaching methods. This VM allows students and faculty to collaboratively create content, annotate slides with markers, and it is enhanced with social networking features to give the community of learners more control over the system.</p> <p>Results</p> <p>We currently have 1,037 slides in our VM system comprised of 39,386,941 individual JPEG files that take up 349 gigabytes of server storage space. Of those slides 682 are for general teaching and available to our students and the public; the remaining 355 slides are used for practical exams and have restricted access. The system has seen extensive use with 289,352 unique slide views to date. Students viewed an average of 56.3 slides per month during the histology course and accessed the system at all hours of the day. Of the 621 annotations added to 126 slides 26.2% were added by faculty and 73.8% by students. The use of the VM system reduced the amount of time faculty spent administering the course by 210 hours, but did not reduce the number of laboratory sessions or the number of required faculty. Laboratory sessions were reduced from three hours to two hours each due to the efficiencies in the workflow of the VM system.</p> <p>Conclusions</p> <p>Our virtual microscope system has been an effective solution to the challenges facing traditional histopathology laboratories and the novel needs of our revised curriculum. The web-based system allowed us to empower learners to have greater control over their content, as well as the ability to work together in collaborative groups. The VM system saved faculty time and there was no significant difference in student performance on an identical practical exam before and after its adoption. We have made the source code of our VM freely available and encourage use of the publically available slides on our website.</p

Attention wins over sensory attenuation in a sound detection task

'Sensory attenuation', i.e., reduced neural responses to self-induced compared to externally generated stimuli, is a well-established phenomenon. However, very few studies directly compared sensory attenuation with attention effect, which leads to increased neural responses. In this study, we brought sensory attenuation and attention together in a behavioural auditory detection task, where both effects were quantitatively measured and compared. The classic auditory attention effect of facilitating detection performance was replicated. When attention and sensory attenuation were both present, attentional facilitation decreased but remained significant. The results are discussed in the light of current theories of sensory attenuation

Neurophysiological modeling of bladder afferent activity in the rat overactive bladder model

The overactive bladder (OAB) is a syndrome-based urinary dysfunction characterized by “urgency, with or without urge incontinence, usually with frequency and nocturia”. Earlier we developed a mathematical model of bladder nerve activity during voiding in anesthetized rats and found that the nerve activity in the relaxation phase of voiding contractions was all afferent. In the present study, we applied this mathematical model to an acetic acid (AA) rat model of bladder overactivity to study the sensitivity of afferent fibers in intact nerves to bladder pressure and volume changes. The afferent activity in the filling phase and the slope, i.e., the sensitivity of the afferent fibers to pressure changes in the post-void relaxation phase, were found to be significantly higher in AA than in saline measurements, while the offset (nerve activity at pressure ~0) and maximum pressure were comparable. We have thus shown, for the first time, that the sensitivity of afferent fibers in the OAB can be studied without cutting nerves or preparation of single fibers. We conclude that bladder overactivity induced by AA in rats is neurogenic in origin and is caused by increased sensitivity of afferent sensors in the bladder wall

How predictive is the MMSE for cognitive performance after stroke?

Cognitive deficits are commonly observed in stroke patients. Neuropsychological testing is time-consuming and not easy to administer after hospital discharge. Standardised screening measures are desirable. The Mini-Mental State Examination (MMSE) is the test most widely applied to screen for cognitive deficits. Despite its broad use, its predictive characteristics after stroke have not been exhaustively investigated. The aim of this study was to determine whether the MMSE is able to adequately screen for cognitive impairment and dementia after stroke and whether or not the MMSE can predict further deterioration or recovery in cognitive function over time. To this end, we studied 194 first-ever stroke patients without pre-stroke cognitive deterioration who underwent MMSEs and neuropsychological test batteries at 1, 6, 12, and 24 months after stroke. The MMSE score 1 month after stroke predicted cognitive functioning at later follow-up visits. It could not predict deterioration or improvement in cognitive functioning over time. The cut-off score in the screening for 1 cognitive disturbed domain was 27/28 with a sensitivity of 0.72. The cut-off score in the screening for at least 4 impaired domains and dementia were 26/27 and 23/24 with a sensitivity of 0.82 and 0.96, respectively. The results indicated that the MMSE has modest qualities in screening for mild cognitive disturbances and is adequate in screening for moderate cognitive deficits or dementia in stroke patients 1 month after stroke. Poor performance on the MMSE is predictive for cognitive impairment in the long term. However, it cannot be used to predict further cognitive deterioration or improvement over time