Germline variation at 8q24 and prostate cancer risk in men of European ancestry

Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 × 10−15), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95%CI = 3.62–4.40) greater risk compared to the population average. These 12 variants account for ~25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification

Short-term Memory Representation Of A Complex And Non-familiar Environment After Brief Exposure

The processes in the brain which enable humans to navigate independently through complex environments have been related to functionally identified neural structures involved in long-term memory representation. This study investigates the role of short-term memory representation, activated through brief exposure to the spatial layout of an unfamiliar complex environment. The effects of short-term memory processes on navigation performances of men and women were investigated. After two minutes of either 2D map or direct viewing (learning phase), individuals navigated from memory in Google Street View (test phase). Subjective ratings of psychological stress were recorded after testing. Satisfactory, and significantly better navigation performances compared with 2D map exposure, were found for both men and women after direct viewing. A significant effect of the sex factor was observed after 2D map exposure, where women produced the weakest performances, and the highest psychological stress ratings.We conclude that short-term memory representations of acomplex and novel spatial layout enable successful navigation, depending on the type of visual information made available through prior exposure. Direct visual experience is encoded more effectively by the brain than abstract map experience, especially by women, under the conditions investigated here

ACTIVATION OF MUSCARINIC CHOLINERGIC RECEPTORS STIMULATES INOSITOL PHOSPHATES SYNTHESIS IN THE DEVELOPING AVIAN COCHLEAR DUCT

International audienceWe previously reported that the inositol phosphates (IPs) synthesis is induced by muscarinic agonists in the rat cochlea and that this stimulation is maximal at postnatal day 12. This peak response is concomitant with the onset of the efferent synaptogenesis at the outer hair cell level. Whether the correlation between this neuronal plasticity and the enhanced IPs formation is unique to the rat or a general feature of the developing vertebrate cochlea is not known. To examine this question, we measured, in the presence of LiCI, the accumulation of (3H)-IPs induced by carbachol, in the developing chick cochlear duct during a period ranging from embryonic day (E) 8 to post-hatching day (P) 20. Carbachol (1 mM) causes a significant increase of IPs formation relative to basal values at all ages. This IPs accumulation is maximal at E8 (1854% of the basal level), then, rapidly decreases until P13 when it reaches a steady-state level of 294% of the basal level. Strikingly, this gradual decline in IPs formation is interrupted between El5 and El9, by a transient increase in IPs synthesis. This rise peaks at El6 with a stimulation value of 757% of the control level. This maximal stimulation is inhibited by atropine in a dose-dependent manner, as is the case at E9, suggesting the involvement of muscarinic receptors. Interestingly, the occurrence of the peak response is concomitant with the plastic events associated with the maturation of the efferent innervation of the cochlear duct. Thus, these results suggest that there may be a correlation between cochlear plasticity and enhanced IPs synthesis, which is not species-specific. The possible significance of the overall decrease in IPs formation, occurring during embryonic development , is discussed. The degradation of membrane phosphatidylinositol 4,5 biphosphate, by the enzyme phospholi-pase C, leads to the formation of diacylglycerol and inositol phosphates (IPs). Among these metabolites, diacylglycerol and inositol 1,4,5-trisphosphate are considered as second messengers. 4 The former directly activates the protein kinase C enzymes; the latter elicits a massive release of calcium from intracellular stores. This transduction system has been found to be driven by specific agonist-activated receptors such as muscarinic cholinergic receptors. 7 We previously reported that this transduction system is stimulated, in the rat cochlea, by muscarinic cholinergic agonists probably, via the activation of a M3 muscarinic receptor, s During the postnatal development of the mammalian cochlea, the muscarinic agonist-induced IPs formation is characterized by a peak around postnatal day 12. 3 This peak coincides with a time period during which plastic events lead to the setting up of the mature efferent innervation of the outer hair cells of the organ of Corti. I1 These efferent terminals are thought to be cholinergic. 6 Thus, it is conceivable that the IPs metabolism may play a role in cochlear neural plasticity. Whether this concomitance, between the increased IPs synthesis and the efferent synaptogenesis, is an overall developmental process in the vertebrate inner ear or is a specific feature of the rat cochlea remains to be investigated. To address this question, we studied the pattern of the phosphoinositide breakdown during the development of the chick basiler papilla. Although phylogenetically remote, the avian basilar papilla and the mammalian organ of Corti share some morphological homologies. They both possess, for instance, two types of hair cells lying on a basilar membrane and covered by a tector-ial membrane. The sensory hair cells are innervated, in both classes, by four different types of fibres, two of them belonging to the efferent systems and the other two to the efferent systems. II'16'23'25 Finally, physiological evidence, supporting the possibility of the presence of muscarinic receptors in the chick auditory organ, as this is the case in the rat cochlea, 3,8 i

Wayfinding through an unfamiliar environment.

International audienceStrategies for finding one's way through an unfamiliar environment may be helped by 2D maps, 3D virtual environments, or other navigation aids. The relative effectiveness of aids was investigated. Experiments were conducted in a large, park-like environment. 24 participants (12 men, 12 women; age range = 22-50 years; M=32, SD = 7.4) were divided into three groups of four individuals, who explored a 2D map of a given route prior to navigation, received a silent guided tour by means of an interactive virtual representation, or acquired direct experience of the real route through a silent guided tour. Participants then had to find the same route again on their own. 12 observers were given a "simple" route with only one critical turn, and the other 12 a "complex" route with six critical turns. Compared to three people familiar with the routes, among the naive participants, those who had a direct experience prior to navigation all found their way again on the simple and complex routes. Those who had explored the interactive virtual environment were unable to find their way on the complex route. The relative scale representation in the virtual environment may have given incorrect impressions of relative distances between objects along the itinerary, rendering important landmark information useless

Physiology, pharmacology and plasticity at the inner hair cell synaptic complex.

This report summarizes recent neuropharmacological data at the IHC afferent/efferent synaptic complex: the type of Glu receptors and transporter involved and the modulation of this fast synaptic transmission by the lateral efferents. Neuropharmacological data were obtained by coupling the recording of cochlear potentials and single unit of the auditory nerve with intra-cochlear applications of drugs (multi-barrel pipette). We also describe the IHC afferent/efferent functioning in pathological conditions. After acoustic trauma or ischemia, acute disruption of IHC-auditory dendrite synapses are seen. However, a re-growth of the nerve fibres and a re-afferentation of the IHC were completely done 5 days after injury. During this synaptic repair, multiple presynaptic bodies were commonly found, either linked to the membrane or "floating" in ectopic positions. In the meantime, the lateral efferents directly contact the IHCs. The demonstration that NMDA receptors blockade delayed the re-growth of neurites suggests a neurotrophic role of NMDA receptors in pathological conditions

Vers une étude quantitative du pluralisme et de la redondance de l'informationjournalistique sur Internet

National audienceVers une étude quantitative du pluralisme et de la redondance de l’information journalistique sur Interne

Coxsackie adenovirus receptor and alpha nu beta3/alpha nu beta5 integrins in adenovirus gene transfer of rat cochlea.

International audienceThis study was designed to determine whether Coxsackie adenovirus receptor (CAR) and alpha nu beta3/alpha nu beta5 integrin co-receptors are involved in adenovirus gene transfer in the rat cochlea. We find that CAR and integrin co-receptors are expressed in every cell subtype transduced by the adenoviral vector Ad5 DeltaE1-E3/cytomegalovirus/green fluorescent protein (GFP) on cochlear slices in vitro. The spiral ganglion neurons, which do not express CAR, were not transduced by the virus. Blocking these receptors by monoclonal antibodies decreased transgene expression, whereas disrupting tight junctions with ethylenediaminetetraacetic acid led to an increased transgene expression. However, sensory hair cells and strial cells also expressing CAR and alpha nu integrins were not transduced by the vector. GFP expression was also studied in vivo. Perilymphatic perfusion of adenovirus in vivo did not affect hearing and only cells lining the perilymphatic spaces were transduced. Endolymphatic perfusion resulted in low-frequency hearing loss and although some cells of the organ of Corti were efficiently transduced, the sensory and the strial cells were not. Transduced sensory and strial cells were occasionally observed in cochleas after single shot of adenovirus. Pretreatment with anti-CAR and anti-alpha nu antibodies decreases GFP expression in vivo, suggesting that the CAR/alpha nu integrin pathway is involved in adenovirus transduction in the cochlea

Oxidative stress, inflammation, and autophagic stress as the key mechanisms of premature age-related hearing loss in SAMP8 mouse cochlea

Contact : [email protected] audienceAIMS: In our aging society, age-related hearing loss (ARHL) or presbycusis is increasingly important. Here, we study the mechanism of ARHL using the senescence-accelerated mouse prone 8 (SAMP8) which is a useful model to probe the effects of aging on biological processes. RESULTS: We found that the SAMP8 strain displays premature hearing loss and cochlear degeneration recapitulating the processes observed in human presbycusis (i.e., strial, sensory, and neural degeneration). The molecular mechanisms associated with premature ARHL in SAMP8 mice involve oxidative stress, altered levels of antioxidant enzymes, and decreased activity of Complexes I, II, and IV, which in turn lead to chronic inflammation and triggering of apoptotic cell death pathways. In addition, spiral ganglion neurons (SGNs) also undergo autophagic stress and accumulated lipofuscin. INNOVATION and CONCLUSION: Our results provide evidence that targeting oxidative stress, chronic inflammation, or apoptotic pathways may have therapeutic potential. Modulation of autophagy may be another strategy. The fact that autophagic stress and protein aggregation occurred specifically in SGNs also offers promising perspectives for the prevention of neural presbycusis

Artificial intelligence to improve cytology performances in bladder carcinoma detection: results of the VisioCyt test

International audienceObjectiveTo explore the utility of artificial intelligence (AI) using the VisioCyt® test (VitaDX International, Rennes, France) to improve diagnosis of bladder carcinoma using voided urine cytology.Patients and MethodsA national prospective multicentre trial (14 centres) was conducted on 1360 patients, divided in two groups. The first group included bladder carcinoma diagnosis with different histological grades and stages, and the second group included control patients based on negative cystoscopy and cytology results. The first step of this VISIOCYT1 trial focussed on algorithm development and the second step on validating this algorithm. A total of 598 patients were included in this first step, 449 patients with bladder tumours (219 high-grade and 230 low-grade) and 149 as negative controls. The VisioCyt test was compared to voided urine cytology performed by experienced uro-pathologists from each centre.ResultsOverall sensitivity was highly improved by the VisioCyt test compared to cytology (84.9% vs 43%). For high-grade tumours the VisioCyt test sensitivity was 92.6% vs 61.1% for the uro-pathologists. Regarding low-grade tumours, VisioCyt test sensitivity was 77% vs 26.3% for the uro-pathologists.ConclusionIn comparison to routine cytology, the results of the first phase of the VISIOCYT1 trial show very clear progress in terms of sensitivity, which is particularly visible and interesting for low-grade tumours. If the validation cohort confirms these results, it could lead to the VisioCyt test being considered as a very useful aid for pathologists. Moreover, as this test is in fact software based on AI, it should become more and more efficient as more data are collected