Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Multidimensional signals and analytic flexibility: Estimating degrees of freedom in human speech analyses

Recent empirical studies have highlighted the large degree of analytic flexibility in data analysis which can lead to substantially different conclusions based on the same data set. Thus, researchers have expressed their concerns that these researcher degrees of freedom might facilitate bias and can lead to claims that do not stand the test of time. Even greater flexibility is to be expected in fields in which the primary data lend themselves to a variety of possible operationalizations. The multidimensional, temporally extended nature of speech constitutes an ideal testing ground for assessing the variability in analytic approaches, which derives not only from aspects of statistical modeling, but also from decisions regarding the quantification of the measured behavior. In the present study, we gave the same speech production data set to 46 teams of researchers and asked them to answer the same research question, resulting insubstantial variability in reported effect sizes and their interpretation. Using Bayesian meta-analytic tools, we further find little to no evidence that the observed variability can be explained by analysts’ prior beliefs, expertise or the perceived quality of their analyses. In light of this idiosyncratic variability, we recommend that researchers more transparently share details of their analysis, strengthen the link between theoretical construct and quantitative system and calibrate their (un)certainty in their conclusions

Spinal Motor Circuit Synaptic Plasticity after Peripheral Nerve Injury Depends on Microglia Activation and a CCR2 Mechanism

Peripheral nerve injury results in persistent motor deficits, even after the nerve regenerates and muscles are reinnervated. This lack of functional recovery is partly explained by brain and spinal cord circuit alterations triggered by the injury, but the mechanisms are generally unknown. One example ofthis plasticityisthe die-backinthe spinal cord ventral horn ofthe projections of proprioceptive axons mediating the stretch reflex (Ia afferents). Consequently, Ia information about muscle length and dynamics is lost from ventral spinal circuits, degrading motor performance after nerve regeneration. Simultaneously, there is activation of microglia around the central projections of peripherally injured Ia afferents, suggesting a possible causal relationship between neuroinflammation and Ia axon removal. Therefore, we used mice (both sexes) that allow visualization of microglia (CX3CR1-GFP) and infiltrating peripheral myeloid cells (CCR2-RFP) and related changes in these cells to Ia synaptic losses (identified by VGLUT1 content) on retrogradely labeled motoneurons. Microgliosis around axotomized motoneurons starts and peaks within 2 weeks after nervetransection. Thereafter,this region becomes infiltrated by CCR2 cells, and VGLUT1 synapses are lost in parallel. Immunohistochemistry,flow cytometry, and genetic lineage tracing showed that infiltrating CCR2 cells include T cells, dendritic cells, and monocytes, the latter differentiating into tissue macrophages. VGLUT1 synapses were rescued after attenuating the ventral microglial reaction by removal of colony stimulating factor 1 from motoneurons or in CCR2 global KOs. Thus, both activation of ventral microglia and a CCR2-dependent mechanism are necessary for removal of VGLUT1 synapses and alterations in Ia-circuit function following nerve injuries

Spinal Motor Circuit Synaptic Plasticity after Peripheral Nerve Injury Depends on Microglia Activation and a CCR2 Mechanism

Peripheral nerve injury results in persistent motor deficits, even after the nerve regenerates and muscles are reinnervated. This lack of functional recovery is partly explained by brain and spinal cord circuit alterations triggered by the injury, but the mechanisms are generally unknown. One example ofthis plasticityisthe die-backinthe spinal cord ventral horn ofthe projections of proprioceptive axons mediating the stretch reflex (Ia afferents). Consequently, Ia information about muscle length and dynamics is lost from ventral spinal circuits, degrading motor performance after nerve regeneration. Simultaneously, there is activation of microglia around the central projections of peripherally injured Ia afferents, suggesting a possible causal relationship between neuroinflammation and Ia axon removal. Therefore, we used mice (both sexes) that allow visualization of microglia (CX3CR1-GFP) and infiltrating peripheral myeloid cells (CCR2-RFP) and related changes in these cells to Ia synaptic losses (identified by VGLUT1 content) on retrogradely labeled motoneurons. Microgliosis around axotomized motoneurons starts and peaks within 2 weeks after nervetransection. Thereafter,this region becomes infiltrated by CCR2 cells, and VGLUT1 synapses are lost in parallel. Immunohistochemistry,flow cytometry, and genetic lineage tracing showed that infiltrating CCR2 cells include T cells, dendritic cells, and monocytes, the latter differentiating into tissue macrophages. VGLUT1 synapses were rescued after attenuating the ventral microglial reaction by removal of colony stimulating factor 1 from motoneurons or in CCR2 global KOs. Thus, both activation of ventral microglia and a CCR2-dependent mechanism are necessary for removal of VGLUT1 synapses and alterations in Ia-circuit function following nerve injuries

Limits to gauge coupling in the dark sector set by the non-observation of instanton-induced decay of Super-Heavy Dark Matter in the Pierre Auger Observatory data

We investigate instanton-induced decay processes of super-heavy dark matter particles $X$ produced during the inflationary epoch. Using data collected at the Pierre Auger Observatory we derive a bound on the reduced coupling constant of gauge interactions in the dark sector: $\alpha_X^{\rm eff} \lesssim 0.09$, for $10^{10} < M_X/{\rm GeV} < 10^{16}$. We show that this upper limit on $\alpha_X^{\rm eff}$ is complementary to that obtained from the non-observation of tensor modes in the cosmic microwave background

Limits to gauge coupling in the dark sector set by the non-observation of instanton-induced decay of Super-Heavy Dark Matter in the Pierre Auger Observatory data

We investigate instanton-induced decay processes of super-heavy dark matter particles $X$ produced during the inflationary epoch. Using data collected at the Pierre Auger Observatory we derive a bound on the reduced coupling constant of gauge interactions in the dark sector: $\alpha_X^{\rm eff} \lesssim 0.09$, for $10^{10} < M_X/{\rm GeV} < 10^{16}$. We show that this upper limit on $\alpha_X^{\rm eff}$ is complementary to that obtained from the non-observation of tensor modes in the cosmic microwave background

Limits to gauge coupling in the dark sector set by the non-observation of instanton-induced decay of Super-Heavy Dark Matter in the Pierre Auger Observatory data

We investigate instanton-induced decay processes of super-heavy dark matter particles $X$ produced during the inflationary epoch. Using data collected at the Pierre Auger Observatory we derive a bound on the reduced coupling constant of gauge interactions in the dark sector: $\alpha_X^{\rm eff} \lesssim 0.09$, for $10^{10} < M_X/{\rm GeV} < 10^{16}$. We show that this upper limit on $\alpha_X^{\rm eff}$ is complementary to that obtained from the non-observation of tensor modes in the cosmic microwave background

Limits to gauge coupling in the dark sector set by the non-observation of instanton-induced decay of Super-Heavy Dark Matter in the Pierre Auger Observatory data

We investigate instanton-induced decay processes of super-heavy dark matter particles $X$ produced during the inflationary epoch. Using data collected at the Pierre Auger Observatory we derive a bound on the reduced coupling constant of gauge interactions in the dark sector: $\alpha_X^{\rm eff} \lesssim 0.09$, for $10^{10} < M_X/{\rm GeV} < 10^{16}$. We show that this upper limit on $\alpha_X^{\rm eff}$ is complementary to that obtained from the non-observation of tensor modes in the cosmic microwave background