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An array of nanoscale polar domains with varying conductance and that are electrically insulated by domain walls can be induced by the interplay of strain and defects in oxide thin films. Local perturbations in complex oxides, such as domain walls 1 , 2 , strain 3 , 4 and defects 5 , 6 , are of interest because they can modify the conduction or the dielectric and magnetic response, and can even promote phase transitions. Here, we show that the interaction between different types of local perturbations in oxide thin films is an additional source of functionality. Taking SrMnO 3 as a model system, we use nonlinear optics to verify the theoretical prediction that strain induces a polar phase, and apply density functional theory to show that strain simultaneously increases the concentration of oxygen vacancies. These vacancies couple to the polar domain walls, where they establish an electrostatic barrier to electron migration. The result is a state with locally structured room-temperature conductivity consisting of conducting nanosized polar domains encased by insulating domain boundaries, which we resolve using scanning probe microscopy. Our ‘nanocapacitor’ domains can be individually charged, suggesting stable capacitance nanobits with a potential for information storage technology.

Rasmussen's encephalitis is a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. Neuropathological and immunological studies support the notion that Rasmussen's encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. Careful analysis of the association between histopathology and clinical presentation suggests that initial damage to the brain is mediated by T cells and microglia, suggesting a window for treatment if Rasmussen's encephalitis can be diagnosed early. Advances in neuroimaging suggest that progression of the inflammatory process seen with MRI might be a good biomarker in Rasmussen's encephalitis. For many patients, families, and doctors, choosing the right time to move from medical management to surgery is a real therapeutic dilemma. Cerebral hemispherectomy remains the only cure for seizures, but there are inevitable functional compromises. Decisions of whether or when surgery should be undertaken are challenging in the absence of a dense neurological deficit, and vary by institutional experience. Further, the optimum time for surgery, to give the best language and cognitive outcome, is not yet well understood. Immunomodulatory treatments seem to slow rather than halt disease progression in Rasmussen's encephalitis, without changing the eventual outcome.

Uranium-lead geochronology in detrital zircons and provenance analyses in eight boreholes and two surface stratigraphic sections in the northern Andes provide insight into the time of closure of the Central American Seaway. The timing of this closure has been correlated with Plio-Pleistocene global oceanographic, atmospheric, and biotic events. We found that a uniquely Panamanian Eocene detrital zircon fingerprint is pronounced in middle Miocene fluvial and shallow marine strata cropping out in the northern Andes but is absent in underlying lower Miocene and Oligocene strata. We contend that this fingerprint demonstrates a fluvial connection, and therefore the absence of an intervening seaway, between the Panama arc and South America in middle Miocene times; the Central American Seaway had vanished by that time.

Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression.

The amplitude of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) is a common yet highly variable measure of corticospinal excitability. The tradeoff between maximizing the number of trials and minimizing experimental time remains a hurdle. It is therefore important to establish how many trials should be used. The aim of this study is not to provide rule-of-thumb answers that may be valid only in specific experimental conditions, but to offer a more general framework to inform the decision about how many trials to use under different experimental conditions. Specifically, we present a set of equations that show how the number of trials affects single-subject MEP amplitude, population MEP amplitude, hypothesis testing and test–retest reliability, depending on the variability within and between subjects. The equations are derived analytically, validated with Monte Carlo simulations, and representatively applied to experimental data. Our findings show that the minimum number of trials for estimating single-subject MEP amplitude largely depends on the experimental conditions and on the error considered acceptable by the experimenter. Conversely, estimating population MEP amplitude and hypothesis testing are markedly more dependent on the number of subjects than on the number of trials. These tools and results help to clarify the impact of the number of trials in the design and reproducibility of past and future experiments.

In a randomized, sham-controlled trial involving 40 patients, therapeutic lesions on one side in the subthalamic nucleus were produced by focused ultrasound. At 4 months, motor performance was better in the active-treatment group. Twelve patients had neurologic deficits, many of which resolved by 12 months.

The blood-brain-barrier (BBB) helps maintain a tightly regulated microenvironment for optimal central nervous system (CNS) homeostasis and facilitates communications with the peripheral circulation. The brain endothelial cells, lining the brain’s vasculature, maintain close interactions with surrounding brain cells, e.g. astrocytes, pericytes and perivascular macrophages. This function facilitates critical intercellular crosstalk, giving rise to the concept of the neurovascular unit (NVU). The steady and appropriate communication between all components of the NVU is essential for normal CNS homeostasis and function, and dysregulation of one of its constituents can result in disease. Among the different brain regions, and along the vascular tree, the cellular composition of the NVU varies. Therefore, differential cues from the immediate vascular environment can affect BBB phenotype. To support the fluctuating metabolic and functional needs of the underlying neuropil, a specialized vascular heterogeneity is required. This is achieved by variances in barrier function, expression of transporters, receptors, and adhesion molecules. This mini-review will take you on a journey through evolving concepts surrounding the BBB, the NVU and beyond. Exploring classical experiments leading to new approaches will allow us to understand that the BBB is not merely a static separation between the brain and periphery but a closely regulated and interactive entity. We will discuss shifting paradigms, and ultimately aim to address the importance of BBB endothelial heterogeneity with regard to the function of the BBB within the NVU, and touch on its implications for different neuro-pathologies.

There is recent evidence of widespread declines of shovelnose ray populations (Order Rhinopristiformes) in heavily fished regions. These declines, which are likely driven by high demand for their fins in Asian markets, raises concern about their risk of over-exploitation and extinction. Using life-history theory and incorporating uncertainty into a modified Euler-Lotka model, the maximum intrinsic rates of population increase (rmax) were estimated for nine species from four families of Rhinopristiformes, using four different natural mortality estimators. Estimates of mean rmax, across the different natural mortality methods, varied from 0.03 to 0.59 year-1 among the nine species, but generally increased with increasing maximum size. Comparing these estimates to rmax values for other species of chondrichthyans, the species Rhynchobatus australiae, Glaucostegus typus, and Glaucostegus cemiculus were relatively productive, while most species from Rhinobatidae and Trygonorrhinidae had relatively low rmax values. If the demand for their high-value products can be addressed then population recovery for some species is likely possible, but will vary depending on the species.

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson’s disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in β-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2–3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders. Blood brain barrier (BBB) opening is being investigated as a therapeutic approach for neurodegenerative diseases. Here, the authors report the results of a phase I trial to evaluate the feasibility and safety of BBB opening of the right parieto-occipito-temporal cortex in Parkinson´s disease with dementia.

The marine phase of anadromous Atlantic salmon (Salmo salar) is the least known yet one of the most crucial with regards to population persistence. Recently, declines in many salmon populations in eastern Canada have been attributed to changes in the conditions at sea, thus reducing their survival. However, marine survival estimates are difficult to obtain given that many individuals spend multiple winters in the ocean before returning to freshwater to spawn; therefore, multiple parameters need to be estimated. We develop a model that uses an age-structured projection matrix which, coupled with yearly smolt and return abundance estimates, allows us to resample a distribution of matrices weighted by how close the resulting return estimates match the simulated returns, using a sample-importance-resampling algorithm. We test this model by simulating a simple time series of salmon abundances, and generate six different scenarios of varying salmon life histories where we simulate data for one-sea-winter (1SW)-dominated and non-1SW dominated populations, as well as scenarios where the proportion returning as 1SW is stable or highly variable. We find that our model provides reasonable estimates of marine survival for the first year at sea (S1), but highly uncertain estimates of proportion returning as 1SW (Pr) and survival in the second year at sea (S2). Our exploration of variable scenarios suggests the model is able to detect temporal trends in S1 for populations that have a considerable 1SW component in the returns; the ability of the model to detect trends in S1 diminishes as the proportion of two-sea-winter fish increases. Variability in the annual proportion of fish returning as 1SW does not seem to impact model accuracy. Our approach provides an instructive stepping-stone towards a model that can be applied to empirical abundance estimates of Atlantic salmon, and anadromous fishes in general, and therefore improve our knowledge of the marine phase of their life cycles as well as examining spatial and temporal trends in their variability.