The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem ...tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.
Neural Network Acceptability Judgments Warstadt, Alex; Singh, Amanpreet; Bowman, Samuel R.
Transactions of the Association for Computational Linguistics,
11/2019, Letnik:
7
Journal Article
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This paper investigates the ability of artificial neural networks to judge the grammatical acceptability of a sentence, with the goal of testing their linguistic competence. We introduce the Corpus ...of Linguistic Acceptability (CoLA), a set of 10,657 English sentences labeled as grammatical or ungrammatical from published linguistics literature. As baselines, we train several recurrent neural network models on acceptability classification, and find that our models outperform unsupervised models by Lau et al. (2016) on CoLA. Error-analysis on specific grammatical phenomena reveals that both Lau et al.’s models and ours learn systematic generalizations like subject-verb-object order. However, all models we test perform far below human level on a wide range of grammatical constructions.
More adults are undergoing autism assessment due to recent changes in awareness, diagnostic criteria and professional practices. This scoping review aimed to summarise research on autism diagnosis in ...adulthood and identify any gaps for future study. The authors searched for studies involving first-time assessment and diagnosis of autism in adults, which identified 82 studies from 13 countries using various methodologies. Six themes of (1) prevalence, (2) diagnostic pathways and processes, (3) gender, (4) psychosocial characteristics, (5) co-occurring conditions and (6) experiences of diagnosis were identified across the studies. Findings suggest that receiving an autism diagnosis has a significant emotional impact on adults, but accessibility and processes are inconsistent, and formal support services are lacking. More research is needed on autism diagnosis in adults with intellectual disability, consequences of the timing of diagnosis, and support after diagnosis.
Lay abstract
More adults are getting assessed for possible autism. Here, we give an overview on what is already known about autism diagnosis in adulthood and find areas that need more research. We divided results from the studies we found into six topics of (1) rates of autism in different groups; (2) the process of getting an autism diagnosis in adulthood; (3) gender; (4) personality traits, abilities and behaviours of diagnosed adults; (5) mental and physical health conditions that occur together with autism; and (6) how adults think and feel about being assessed and diagnosed. We found that adults often have strong emotions after being diagnosed, the process of getting a diagnosis can be unclear and different for everyone, and not many support services are available for adults. More research on diagnosing adults with intellectual disability, differences between early and late-diagnosed adults, and support after diagnosis would be useful.
Pseudocapacitors harness unique charge-storage mechanisms to enable high-capacity, rapidly cycling devices. Here we describe an organic system composed of perylene diimide and hexaazatrinaphthylene ...exhibiting a specific capacitance of 689 F g
at a rate of 0.5 A g
, stability over 50,000 cycles, and unprecedented performance at rates as high as 75 A g
. We incorporate the material into two-electrode devices for a practical demonstration of its potential in next-generation energy-storage systems. We identify the source of this exceptionally high rate charge storage as surface-mediated pseudocapacitance, through a combination of spectroscopic, computational and electrochemical measurements. By underscoring the importance of molecular contortion and complementary electronic attributes in the selection of molecular components, these results provide a general strategy for the creation of organic high-performance energy-storage materials.
Step counting has long been used as a method of measuring distance. Starting in the mid-1900s, researchers became interested in using steps per day to quantify ambulatory physical activity. This line ...of research gained momentum after 1995, with the introduction of reasonably accurate spring-levered pedometers with digital displays. Since 2010, the use of accelerometer-based “activity trackers” by private citizens has skyrocketed. Steps have several advantages as a metric for assessing physical activity: they are intuitive, easy to measure, objective, and they represent a fundamental unit of human ambulatory activity. However, since they measure a human behavior, they have inherent biological variability; this means that measurements must be made over 3–7 days to attain valid and reliable estimates. There are many different kinds of step counters, designed to be worn on various sites on the body; all of these devices have strengths and limitations. In cross-sectional studies, strong associations between steps per day and health variables have been documented. Currently, at least eight prospective, longitudinal studies using accelerometers are being conducted that may help to establish dose–response relationships between steps/day and health outcomes. Longitudinal interventions using step counters have shown that they can help inactive individuals to increase by 2500 steps per day. Step counting is useful for surveillance, and studies have been conducted in a number of countries around the world. Future challenges include the need to establish testing protocols and accuracy standards, and to decide upon the best placement sites. These challenges should be addressed in order to achieve harmonization between studies, and to accurately quantify dose–response relationships.
Little is known about the biology of the emerging human group c betacoronavirus, Middle East Respiratory Syndrome coronavirus (MERS-CoV). Because coronavirus spike glycoproteins (S) mediate virus ...entry, affect viral host range, and elicit neutralizing antibodies, analyzing the functions of MERS-CoV S protein is a high research priority. MERS-CoV S on lentivirus pseudovirions mediated entry into a variety of cell types including embryo cells from New World Eptesicus fuscus bats. Surprisingly, a polyclonal antibody to the S protein of MHV, a group a murine betacoronavirus, cross-reacted in immunoblots with the S2 domain of group c MERS-CoV spike protein. MERS pseudovirions released from 293T cells contained only uncleaved S, and pseudovirus entry was blocked by lysosomotropic reagents NH4Cl and bafilomycin and inhibitors of cathepsin L. However, when MERS pseudovirions with uncleaved S protein were adsorbed at 4°C to Vero E6 cells, brief trypsin treatment at neutral pH triggered virus entry at the plasma membrane and syncytia formation. When 293T cells producing MERS pseudotypes co-expressed serine proteases TMPRSS-2 or -4, large syncytia formed at neutral pH, and the pseudovirions produced were non-infectious and deficient in S protein. These experiments show that if S protein on MERS pseudovirions is uncleaved, then viruses enter by endocytosis in a cathepsin L-dependent manner, but if MERS-CoV S is cleaved, either during virus maturation by serine proteases or on pseudovirions by trypsin in extracellular fluids, then viruses enter at the plasma membrane at neutral pH and cause massive syncytia formation even in cells that express little or no MERS-CoV receptor. Thus, whether MERS-CoV enters cells within endosomes or at the plasma membrane depends upon the host cell type and tissue, and is determined by the location of host proteases that cleave the viral spike glycoprotein and activate membrane fusion.
•BBB breakdown is a major driving force in dementia pathology.•DCE-MRI is the most advanced method to investigate BBB leakage in the living human and rodent brain.•Many different DCE-MRI techniques ...and imaging processing methods exist.•Detecting subtle BBB breakdown using DCE-MRI can be challenging.
Alzheimer’s disease (AD) and cerebral small vessel disease (cSVD) are the two main causes of dementia with blood–brain barrier (BBB) breakdown being a common contributor. Recent advances in neuroimaging techniques offer new possibilities to understand how the brain functions in health and disease. This includes methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which allows the detection of subtle regional changes in the BBB integrity. The purpose of this work is to provide a review on the recent DCE-MRI findings of subtle BBB leakage focusing on cSVD and AD, including both clinical and pre-clinical studies. Despite being widely used and well-established, we also highlight some of the DCE-MRI challenges and pitfalls faced in the context of dementia inherent to the subtle nature of BBB impairment.
Skeletal muscle fibrosis can be a devastating clinical problem that arises from many causes, including primary skeletal muscle tissue diseases, as seen in the muscular dystrophies, or it can be ...secondary to events that include trauma to muscle or brain injury. The cellular source of activated fibroblasts (myofibroblasts) may include resident fibroblasts, adult muscle stem cells, or inflammatory or perivascular cells, depending on the model studied. Even though it is likely that there is no single source for all myofibroblasts, a common mechanism for the production of fibrosis is via the transforming growth factor-β/phosphorylated Smad3 pathway. This pathway and its downstream targets thus provide loci for antifibrotic therapies, as do methods for blocking the transdifferentiation of progenitors into activated fibroblasts. A structural model for the extracellular collagen network of skeletal muscle is needed so that measurements of collagen content, morphology, and gene expression can be related to mechanical properties. Approaches used to study fibrosis in tissues, such as lung, kidney, and liver, need to be applied to studies of skeletal muscle to identify ways to prevent or even cure the devastating maladies of skeletal muscle.
Tumor metabolism supports the energetic and biosynthetic needs of rapidly proliferating cancer cells and modifies intra- and intercellular signaling to enhance cancer cell invasion, metastasis, and ...immune evasion. Prostate cancer exhibits unique metabolism with high rates of
fatty acid synthesis driven by activation of the androgen receptor (AR). Increasing evidence suggests that activation of this pathway is functionally important to promote prostate cancer aggressiveness. However, the mechanisms by which fatty acid synthesis are beneficial to prostate cancer have not been well defined. In this review, we summarize evidence indicating that fatty acid synthesis drives progression of prostate cancer. We also explore explanations for this phenomenon and discuss future directions for targeting this pathway for patient benefit.
Enzyme-mimicking catalytic nanoparticles, more commonly known as NanoZymes, have been at the forefront for the development of new sensing platforms for the detection of a range of molecules. Although ...solution-based NanoZymes have shown promise in glucose detection, the ability to immobilize NanoZymes on highly absorbent surfaces, particularly on free-standing substrates that can be feasibly exposed and removed from the reaction medium, can offer significant benefits for a range of biosensing and catalysis applications. This work, for the first time, shows the ability of Ag nanoparticles embedded within the 3D matrix of a cotton fabric to act as a free-standing peroxidase-mimic NanoZyme for the rapid detection of glucose in complex biological fluids such as urine. The use of cotton fabric as a template not only allows high number of catalytically active sites to participate in the enzyme-mimic catalytic reaction, the absorbent property of the cotton fibres also helps in rapid absorption of biological molecules such as glucose during the sensing event. This, in turn, brings the target molecule of interest in close proximity of the NanoZyme catalyst enabling accurate detection of glucose in urine. Additionally, the ability to extract the free-standing cotton fabric-supported NanoZyme following the reaction overcomes the issue of potential interference from colloidal nanoparticles during the assay. Based on these unique characteristics, nanostructured silver fabrics offer remarkable promise for the detection of glucose and other biomolecules in complex biological and environmental fluids.
•A simple strategy to incorporate Ag nanoparticles within the 3D matrix of a cotton fabric (Ag@Fabric).•Ag@Fabric as a free-standing NanoZyme showing intrinsic peroxidase-mimic activity which is dependent on the concentration of Ag, pH and temperature.•Use of free-standing Ag@Fabric NanoZyme for the detection of glucose.•Practical applicability of our colorimetric biosensor for accurately quantifying glucose levels in the urine of healthy and diabetes volunteers.
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