Explore the vast range of titles available.

Damaged Manchester PD detective Aidan Waits investigates the murder of a man with no identifying marks except an unsettling smile, a case that is complicated by all-too-personal attacks.

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource 1 , involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network. Using mouse lines in which subsets of neurons are genetically labelled, the authors provide generalized anatomical rules for connections within and between the cortex and thalamus.

Maintaining DNA integrity is vital for all cells and organisms. Defective DNA repair may contribute to neurological disorders, including Alzheimer’s disease (AD). We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice. Amyloid-β oligomers reduced BRCA1 levels in primary neuronal cultures. In wild-type mice, knocking down neuronal BRCA1 in the dentate gyrus caused increased DNA double-strand breaks, neuronal shrinkage, synaptic plasticity impairments, and learning and memory deficits, but not apoptosis. Low levels of hAPP/Amyloid-β overexpression exacerbated these effects. Physiological neuronal activation increased BRCA1 levels, whereas stimulating predominantly extrasynaptic N -methyl- D -aspartate receptors promoted the proteasomal degradation of BRCA1. We conclude that BRCA1 is regulated by neuronal activity, protects the neuronal genome, and critically supports neuronal integrity and cognitive functions. Pathological accumulation of Aβ depletes neuronal BRCA1, which may contribute to cognitive deficits in AD. DNA repair deficits have been suggested to play a role in Alzheimer’s pathology. Here, the authors report reduced levels of the DNA repair factor BRCA1 in patient brains, and provide evidence that loss of BRCA1 in the dentate gyrus leads to spatial learning and memory deficits in mice.

Knowledge of mesoscopic brain connectivity is important for understanding inter- and intraregion information processing. Models of structural connectivity are typically constructed and analyzed with the assumption that regions are homogeneous. We instead use the Allen Mouse Brain Connectivity Atlas to construct a model of whole-brain connectivity at the scale of 100 μm voxels. The data consist of 428 anterograde tracing experiments in wild type C57BL/6J mice, mapping fluorescently labeled neuronal projections brain-wide. Inferring spatial connectivity with this dataset is underdetermined, since the approximately 2 × 10 source voxels outnumber the number of experiments. To address this issue, we assume that connection patterns and strengths vary smoothly across major brain divisions. We model the connectivity at each voxel as a radial basis kernel-weighted average of the projection patterns of nearby injections. The voxel model outperforms a previous regional model in predicting held-out experiments and compared with a human-curated dataset. This voxel-scale model of the mouse connectome permits researchers to extend their previous analyses of structural connectivity to much higher levels of resolution, and it allows for comparison with functional imaging and other datasets. Anatomical tracing experiments can provide a wealth of information regarding connectivities originating from the injection sites. However, it is difficult to integrate all this information into a comprehensive connectivity model. In this study we construct a high-resolution model of the mouse brain connectome using the assumption that connectivity patterns vary smoothly within brain regions, and we present several extensions of this model. We believe that this higher resolution connectome will be of great use to the community, enabling comparisons with other data modalities, such as functional imaging and gene expression, as well as for theoretical studies.

Background Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer’s disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear. Methods We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau. Results We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca 2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca 2+ influx and excitotoxicity in tau-deficient ( Mapt −/− ) neurons. Reconstituting tau expression in Mapt −/− neurons with mutant forms of tau reveals that the tau-related enhancement of Ca 2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B–containing NMDA receptors, and do not require binding of Fyn to tau’s major interacting PxxP motif or of tau to microtubules. Conclusions Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca 2+ influx.

Access to multi-detector computed tomography (MDCT) scanning for interventional procedures can prove to be logistically challenging as resources are often in different areas within the hospital. At some institutions, interventional radiology suites have moved to the operating room, separate from the diagnostic radiology department. At these institutions, complex interventional procedures requiring both fluoroscopy and MDCT may pose logistical challenges, especially as they pertain to timely patient transfers. Hybrid CT/fluoroscopy suite provides rapid, reliable MDCT assessment of trauma patients before and after emergent surgery, as well as access to the entire spectrum of emergent image-guided interventions in the same suite.

Isolation by distance (IBD) has been a common measure of genetic structure among populations and is based on Euclidean distances among populations. Whereas IBD does not incorporate geographic complexity (e.g. dispersal barriers, corridors) that may better predict genetic structure, a new approach (landscape genetics) joins landscape ecology with population genetics to better model genetic structure. Should IBD be set aside or should it persist as the most simple model in landscape genetics? We evaluated the status of IBD by collecting and analyzing results of 240 IBD data sets among diverse taxa and study systems. IBD typically represented a low proportion of variance in genetic structure (mean r² = 0.22) in part because many studies included relatively few populations (mean = 11). The number of populations studied (N) was asymptotically related to IBD significance; a study with 9 populations has only 50% probability of significance, while one with >23 populations will have 90% probability of significance. Surprisingly, ectothermic animals were significantly (p = 0.0018) more likely to have significant IBD than endotherms, which suggests a metabolic basis underlying gene flow rates. We also observed marginally significant effects on IBD significance for a) taxa in general and b) dispersal modes within actively-dispersing endotherms. Other factors analyzed (genetic markers, genetic distances, habitats, active or passive dispersal, plant growth form) did not significantly affect IBD, likely related to typical N. For multiple reasons we conclude that IBD should continue as the simplest reference standard against which all other, more complex models should be compared in landscape genetics research.

Background: An altered tibial position is still present despite anterior cruciate ligament (ACL) reconstruction. It has been demonstrated that an abnormal tibial position after an ACL injury may play a role in subsequent injuries to the meniscus, which can lead to early cartilage degeneration. Purpose: To determine changes in both the tibial position and the meniscal matrix present before and after ACL reconstruction as well as to evaluate the association between these 2 variables in ACL-injured knees 3 years after reconstruction. Study Design: Cohort study; Level of evidence, 2. Methods: Bilateral knee magnetic resonance imaging (MRI) of 32 patients with unilateral ACL injuries was performed before reconstruction; 13 control participants also underwent MRI. Follow-up MRI was performed up to 3 years after surgery. Tibial position, internal tibial rotation, and T1ρ and T2 values of the menisci were calculated using an in-house MATLAB program. Student t tests and multiple linear regression were used to compare differences between injured, uninjured, and control knees as well as to assess correlations between the tibial position at 3 years and 3-year changes in quantitative MRI meniscal relaxation values. Results: The tibial position of injured knees was more anterior than that of uninjured knees at baseline, 6 months, and 1, 2, and 3 years (P < .05 for all). The T1ρ and T2 values of the menisci of injured knees were greater than those of uninjured and control knees in the posterior lateral and posterior medial horns up to 1 and 2 years after surgery, respectively (P < .05 for all). The tibial position at 3 years was associated with increased T2 values from baseline to 3 years in the posterior medial horn (β = 0.397; P = .031) and anterior medial horn (β = 0.360; P = .040). Conclusion: Results of the current study indicate that there is a persistently altered tibial position after ACL reconstruction. Initial preoperative meniscal abnormalities show prolonged but gradual improvement. Additionally, correlations between the tibial position and changes in the medial meniscal matrix suggest that the tibial position may play a role in the increased susceptibility to medial meniscal tears seen after reconstruction. The development of newer surgical techniques must address a persistently altered tibial position. Quantitative MRI is an effective instrument to evaluate meniscal matrix changes and can serve as an early radiological tool for meniscal injuries.

OBJECTIVES/SPECIFIC AIMS: This study aims to examine the relative impact of aortic arch and carotid artery anatomy on the procedural times and clinical outcomes in patients who have suffered acute ischemic strokes (AIS). Mechanical thrombectomy remains the gold-standard of care for large vessel ischemic stroke. Given that short procedural times are necessary for good clinical outcomes, arterial access is an important technical consideration. It has been recently demonstrated that abnormal carotid artery anatomy can increase endovascular procedure times in this patient population. However, there are no studies examining the impact of aortic arch anatomy on operative times. Additionally, no studies have looked at the impact of aortic arch and carotid artery tortuosity on clinical outcomes in AIS. Thus, we sought to exam the influence of various aortic arch and carotid artery anatomic variables on interventional procedure times and clinical outcomes. METHODS/STUDY POPULATION: We included 56 patients who underwent embolectomy with successful revascularization for acute ischemic stroke in the anterior circulation from a period of 01/2016-05/2018. The average age was 71 (+/− 17 years) with 39% being male. We calculated anatomic variables on the affected side from CT angiograms immediately prior to embolectomy including the medial-to-lateral span, as well as the anterior-to-posterior span, of both the aortic arch and carotid arteries. In addition, the take-off angle of the respective vessel (left common carotid or right brachiocephalic) was calculated. Charts were reviewed for procedural times and epidemiologic information (HTN, HLD, DM, CAD and Afib). Modified Rankin Scale (mRS) was calculated from PT/OT and outpatient neurology notes. Partial correlation coefficients were performed between anatomic variables, temporal variables and outcome variables after adjustment for age, gender and epidemiologic information. RESULTS/ANTICIPATED RESULTS: There was a significant positive correlation between procedure time (time at groin puncture to time at reperfusion) and take-off angle. There were no other significant correlations between anatomic measures and procedure time. In addition, there was as a significant positive correlation between both procedure time and time from last seen normal to reperfusion and delta mRS (the difference between pre-stroke and post-stroke mRS). DISCUSSION/SIGNIFICANCE OF IMPACT: These results suggest that patients with larger take-off angles have an association with longer procedural times and worse outcomes. If these patients can be effectively identified prior to the procedure, operators could feasibly use a non-femoral access method initially to reduce procedure time.

Neurodegenerative tauopathies are hypothesized to propagate via brain networks. This is uncertain because we have lacked precise network resolution of pathology. We therefore developed whole-brain staining methods with anti-p-tau nanobodies and imaged in 3D PS19 tauopathy mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of p-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We discovered a bias towards retrograde network-based propagation of tau. This novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease.