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Electron spins in silicon quantum dots provide a promising route towards realizing the large number of coupled qubits required for a useful quantum processor1–7. For the implementation of quantum algorithms and error detection8–10, qubit measurements are ideally performed in a single shot, which is presently achieved using on-chip charge sensors, capacitively coupled to the quantum dots11. However, as the number of qubits is increased, this approach becomes impractical due to the footprint and complexity of the charge sensors, combined with the required proximity to the quantum dots12. Alternatively, the spin state can be measured directly by detecting the complex impedance of spin-dependent electron tunnelling between quantum dots13–15. This can be achieved using radiofrequency reflectometry on a single gate electrode defining the quantum dot itself15–19, significantly reducing the gate count and architectural complexity, but thus far it has not been possible to achieve single-shot spin readout using this technique. Here, we detect single electron tunnelling in a double quantum dot and demonstrate that gate-based sensing can be used to read out the electron spin state in a single shot, with an average readout fidelity of 73%. The result demonstrates a key step towards the readout of many spin qubits in parallel, using a compact gate design that will be needed for a large-scale semiconductor quantum processor.Instead of using capacitively coupled charge sensors, which imply additional complexity in the device architecture, radiofrequency reflectometry on the gate defining the quantum dot can read out the spin state of a double quantum dot in a single shot.

Large-scale automated systems such as manufacturing systems, transportation systems, the Smart Grid and many others are continuously becoming larger, more distributed, more complex, and more intelligent. There is a growing expectation that their software controller will make real-time intelligent decisions, at all levels of the control hierarchy that make up the enterprise. The need is changing for distributed intelligent controllers that are scalable to arbitrarily large systems. In this paper, we first present the model explosion problem. This problem arises when every controller in the control hierarchy is to have a unique simulation model of its unique control domain to use in its decision-making process. That is, the modeling effort needed to provide intelligence to all controllers in the control hierarchy grows exponentially with the number of controllers in the hierarchy using current modeling technology. Since each controller is in a unique location within the control hierarchy, each will need to have its simulation model custom made for its unique control domain, leading to the scalability issue that we refer to as the model explosion problem. Next, a new modeling paradigm that solves the scalability issue resulting from the model explosion problem is presented, where the simulation models are automatically generated by recycling the models used for control. If the controller models are created using the presented modeling paradigm, then these same models can be used for simulation with no modification or the need to understand the control logic. Furthermore, gathering the state from the physical system being controlled to initialize the simulation models in a real-time control application becomes a trivial operation of simply coping data from one software model to its identical copy, without the need to interpret the meaning of the data. Finally, an example of a hierarchical controller to control a small physical model of a manufacturing plant is presented. We show how we automatically generated all the simulation models in the control hierarchy without any modification and with minimal effort, and used them to make intelligent decisions in real time.

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

A diverse heterogeneity of microglial cells was previously described in Alzheimer’s disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aβ) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aβ plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized; however, less is known about the effects of MIA exposure on embryo development. To address this gap, we performed high-resolution ex vivo MRI to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late-exposed offspring. We further examined the putative neuroanatomical underpinnings of MIA timing in the hippocampus using electron microscopy and identified differential effects due to MIA timing. An increase in apoptotic cell density was observed in the GD9-exposed offspring, while an increase in the density of neurons and glia with ultrastructural features reflective of increased neuroinflammation and oxidative stress was observed in GD17-exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA timing on the earliest stages of neurodevelopment.

We examine the fluid flow forced by precession of a rotating cylindrical container using numerical simulations and experimental flow measurements with ultrasonic Doppler velocimetry. The analysis is based on the decomposition of the flow field into contributions with distinct azimuthal symmetry or analytically known inertial modes and the corresponding calculation of their amplitudes. We show that the predominant fraction of the kinetic energy of the precession-driven fluid flow is contained only within a few large-scale modes. The most striking observation shown by simulations and experiments is the transition from a flow dominated by large-scale structures to a more turbulent behaviour with the small-scale fluctuations becoming increasingly important. At a fixed rotation frequency (parametrized by the Reynolds number, $Re$) this transition occurs when a critical precession ratio is exceeded and consists of a two-stage collapse of the directly driven flow going along with a massive modification of the azimuthal circulation (the zonal flow) and the appearance of an axisymmetric double-roll mode limited to a narrow range of precession ratios. A similar behaviour is found in experiments which make it possible to follow the transition up to Reynolds numbers of $Re\\approx 2\\times 10^6$. We find that the critical precession ratio decreases with rotation, initially showing a particular scaling ${\\propto }Re^{-({1}/{5})}$ but developing an asymptotic behaviour for $Re\\gtrsim 10^5$ which might be explained by the onset of turbulence in boundary layers.

Background In newborns with hypoxic-ischemic encephalopathy (HIE), the correlation between neonatal neuroimaging and the degree of neurodevelopmental impairment (NDI) is unclear. Methods Infants with HIE enrolled in a randomized controlled trial underwent neonatal MRI/MR spectroscopy (MRS) using a harmonized protocol at 4–6 days of age. The severity of brain injury was measured with a validated scoring system. Using proportional odds regression, we calculated adjusted odds ratios (aOR) for the associations between MRI/MRS measures of injury and primary ordinal outcome (i.e., normal, mild NDI, moderate NDI, severe NDI, or death) at age 2 years. Results Of 451 infants with MRI/MRS at a median age of 5 days (IQR 4.5–5.8), outcomes were normal (51%); mild (12%), moderate (14%), severe NDI (13%); or death (9%). MRI injury score (aOR 1.06, 95% CI 1.05, 1.07), severe brain injury (aOR 39.6, 95% CI 16.4, 95.6), and MRS lactate/n-acetylaspartate (NAA) ratio (aOR 1.6, 95% CI 1.4,1.8) were associated with worse primary outcomes. Infants with mild/moderate MRI brain injury had similar BSID-III cognitive, language, and motor scores as infants with no injury. Conclusion In the absence of severe injury, brain MRI/MRS does not accurately discriminate the degree of NDI. Given diagnostic uncertainty, families need to be counseled regarding a range of possible neurodevelopmental outcomes. Impact Half of all infants with hypoxic-ischemic encephalopathy (HIE) enrolled in a large clinical trial either died or had neurodevelopmental impairment at age 2 years despite receiving therapeutic hypothermia. Severe brain injury and a global pattern of brain injury on MRI were both strongly associated with death or neurodevelopmental impairment. Infants with mild or moderate brain injury had similar mean BSID-III cognitive, language, and motor scores as infants with no brain injury on MRI. Given the prognostic uncertainty of brain MRI among infants with less severe degrees of brain injury, families should be counseled regarding a range of possible neurodevelopmental outcomes.

As the resident macrophages of the brain and spinal cord, microglia are crucial for the phagocytosis of infectious agents, apoptotic cells and synapses. During brain injury or infection, bone-marrow derived macrophages invade neural tissue, making it difficult to distinguish between invading macrophages and resident microglia. In addition to circulation-derived monocytes, other non-microglial central nervous system (CNS) macrophage subtypes include border-associated meningeal, perivascular and choroid plexus macrophages. Using immunofluorescent labeling, flow cytometry and Cre-dependent ribosomal immunoprecipitations, we describe P2ry12-CreER , a new tool for the genetic targeting of microglia. We use this new tool to track microglia during embryonic development and in the context of ischemic injury and neuroinflammation. Because of the specificity and robustness of microglial recombination with P2ry12-CreER , we believe that this new mouse line will be particularly useful for future studies of microglial function in development and disease.

Western blotting is a standard laboratory method used to detect proteins and assess their expression levels. Unfortunately, poor western blot image display practices and a lack of detailed methods reporting can limit a reader’s ability to evaluate or reproduce western blot results. While several groups have studied the prevalence of image manipulation or provided recommendations for improving western blotting, data on the prevalence of common publication practices are scarce. We systematically examined 551 articles published in the top 25% of journals in neurosciences ( n = 151) and cell biology ( n = 400) that contained western blot images, focusing on practices that may omit important information. Our data show that most published western blots are cropped and blot source data are not made available to readers in the supplement. Publishing blots with visible molecular weight markers is rare, and many blots additionally lack molecular weight labels. Western blot methods sections often lack information on the amount of protein loaded on the gel, blocking steps, and antibody labeling protocol. Important antibody identifiers like company or supplier, catalog number, or RRID were omitted frequently for primary antibodies and regularly for secondary antibodies. We present detailed descriptions and visual examples to help scientists, peer reviewers, and editors to publish more informative western blot figures and methods. Additional resources include a toolbox to help scientists produce more reproducible western blot data, teaching slides in English and Spanish, and an antibody reporting template.

Background Maternal nutrition is critical for proper fetal development. While increased nutrient intake is essential during pregnancy, an excessive consumption of certain nutrients, like fat, can lead to long-lasting detrimental consequences on the offspring. Animal work investigating the consequences of maternal high-fat diet (mHFD) revealed in the offspring a maternal immune activation (MIA) phenotype associated with increased inflammatory signals. This inflammation was proposed as one of the mechanisms causing neuronal circuit dysfunction, notably in the hippocampus, by altering the brain-resident macrophages—microglia. However, the understanding of mechanisms linking inflammation and microglial activities to pathological brain development remains limited. We hypothesized that mHFD-induced inflammation could prime microglia by altering their specific gene expression signature, population density, and/or functions. Methods We used an integrative approach combining molecular (i.e., multiplex-ELISA, rt-qPCR) and cellular (i.e., histochemistry, electron microscopy) techniques to investigate the effects of mHFD (saturated and unsaturated fats) vs control diet on inflammatory priming, as well as microglial transcriptomic signature, density, distribution, morphology, and ultrastructure in mice. These analyses were performed on the mothers and/or their adolescent offspring at postnatal day 30. Results Our study revealed that mHFD results in MIA defined by increased circulating levels of interleukin (IL)-6 in the mothers. This phenotype was associated with an exacerbated inflammatory response to peripheral lipopolysaccharide in mHFD-exposed offspring of both sexes. Microglial morphology was also altered, and there were increased microglial interactions with astrocytes in the hippocampus CA1 of mHFD-exposed male offspring, as well as decreased microglia-associated extracellular space pockets in the same region of mHFD-exposed offspring of the two sexes. A decreased mRNA expression of the inflammatory-regulating cytokine Tgfb1 and microglial receptors Tmem119 , Trem2 , and Cx3cr1 was additionally measured in the hippocampus of mHFD-exposed offspring, especially in males . Conclusions Here, we described how dietary habits during pregnancy and nurturing, particularly the consumption of an enriched fat diet, can influence peripheral immune priming in the offspring. We also found that microglia are affected in terms of gene expression signature, morphology, and interactions with the hippocampal parenchyma, in a partially sexually dimorphic manner, which may contribute to the adverse neurodevelopmental outcomes on the offspring.