Suppression of Conductance in a Topological Insulator Nanostep Junction

We investigate quantum transport via surface states in a nanostep junction on the surface of a 3D topological insulator that involves two different side surfaces. We calculate the conductance across the junction within the scattering matrix formalism and find that as the bias voltage is increased, the conductance of the nanostep junction is suppressed by a universal factor of 1/3 compared to the conductance of a similar planar junction based on a single surface of a topological insulator. We also calculate and analyze the Fano factor of the nanostep junction and predict that the Fano factor saturates at 1/5, five times smaller than for a Poisson process

Identification of a novel quinoxaline-isoselenourea targeting the STAT3 pathway as a potential melanoma therapeutic

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032

Staged decline of neuronal function in vivo in an animal model of Alzheimer's disease

The accumulation of amyloid-β in the brain is an essential feature of Alzheimer's disease. However, the impact of amyloid-β-accumulation on neuronal dysfunction on the single cell level in vivo is poorly understood. Here we investigate the progression of amyloid-β load in relation to neuronal dysfunction in the visual system of the APP23×PS45 mouse model of Alzheimer's disease. Using in vivo two-photon calcium imaging in the visual cortex, we demonstrate that a progressive deterioration of neuronal tuning for the orientation of visual stimuli occurs in parallel with the age-dependent increase of the amyloid-β load. Importantly, we find this deterioration only in neurons that are hyperactive during spontaneous activity. This impairment of visual cortical circuit function also correlates with pronounced deficits in visual-pattern discrimination. Together, our results identify distinct stages of decline in sensory cortical performance in vivo as a function of the increased amyloid-β-load

Innovación sanitaria en la gestión del riesgo de caídas de personas mayores en Atención Primaria

[ES] Las caídas son actualmente uno de los problemas de salud más frecuentes y graves en las personas mayores. La gestión sociosanitaria eficiente desde el punto de vista preventivo se destaca como uno de los objetivos principales para afrontar esta problemática. Para dar respuesta a ello, el IBV y el Hospital Universitario de la Ribera, gestionado por Ribera Salud II UTE Ley 18/82, llevan a cabo de forma conjunta una línea de investigación para desarrollar y validar nuevos avances tecnológicos. El proyecto que se presenta a continuación ha servido para conocer la aplicabilidad y utilidad de la herramienta FallSkip en el contexto de la consulta del médico de Atención Primaria. Se han valorado, entre otros aspectos, el tiempo y la facilidad de uso, así como la utilidad de la información proporcionada en la evaluación del riesgo de caídas respecto a los métodos convencionales basados en cuestionarios y escalas clínicas.Folch, B.; Donato, C.; Ruivo, M.; Ruiz, A.; Tapia, A.; Palop, V.; Pitarch Corresa, S.... (2019). Innovación sanitaria en la gestión del riesgo de caídas de personas mayores en Atención Primaria. Revista de Biomecánica (Online). (66). http://hdl.handle.net/10251/128736S6

Effects of in vitro metabolism of a broccoli leachate, glucosinolates and S-methylcysteine sulphoxide on the human faecal microbiome

Purpose: Brassica are an important food source worldwide and are characterised by the presence of compounds called glucosinolates. Studies indicate that the glucosinolate derived bioactive metabolite sulphoraphane can elicit chemoprotective benefits on human cells. Glucosinolates can be metabolised in vivo by members of the human gut microbiome, although the prevalence of this activity is unclear. Brassica and Allium plants also contain S-methylcysteine sulphoxide (SMCSO), that may provide additional health benefits but its metabolism by gut bacteria is not fully understood. Methods: We examined the effects of a broccoli leachate (BL) on the composition and function of human faecal microbiomes of five different participants under in vitro conditions. Bacterial isolates from these communities were then tested for their ability to metabolise glucosinolates and SMCSO. Results: Microbial communities cultured in vitro in BL media were observed to have enhanced growth of lactic acid bacteria, such as lactobacilli, with a corresponding increase in the levels of lactate and short-chain fatty acids. Members of Escherichia isolated from these faecal communities were found to bioconvert glucosinolates and SMCSO to their reduced analogues. Conclusion: This study uses a broccoli leachate to investigate the bacterial-mediated bioconversion of glucosinolates and SMCSO, which may lead to further products with additional health benefits to the host. We believe that this is the first study that shows the reduction of the dietary compound S-methylcysteine sulphoxide by bacteria isolated from human faeces

Orchestrated experience-driven Arc responses are disrupted in a mouse model of Alzheimer's disease

Experience-induced expression of immediate-early gene Arc/Arg3.1 is known to play a pivotal role in the consolidation of memory. Here we use in-vivo longitudinal multiphoton imaging to show orchestrated activity-dependent expression of Arc in the mouse extrastriate visual cortex in response to a structured visual stimulation. In wild-type mice, the amplitude of the Arc response in individual neurons strongly predicts the probability of reactivation by a subsequent presentation of the same stimulus. In a mouse model of Alzheimer’s disease, this association is markedly disrupted in the cortex specifically near senile plaques. Neurons in the vicinity of plaques are less likely to respond but, paradoxically, there is stronger response in those few neurons around plaques that do respond. To the extent that the orchestrated pattern of Arc expression reflects nervous system responses to, and physiological consolidation of, behavioral experience, the disruption in Arc patterns reveals plaque-associated interference with neural network integration

Computational Study of Hippocampal-Septal Theta Rhythm Changes Due to Beta-Amyloid-Altered Ionic Channels

Electroencephagraphy (EEG) of many dementia patients has been characterized by an increase in low frequency field potential oscillations. One of the characteristics of early stage Alzheimer’s disease (AD) is an increase in theta band power (4–7 Hz). However, the mechanism(s) underlying the changes in theta oscillations are still unclear. To address this issue, we investigate the theta band power changes associated with β-Amyloid (Aβ) peptide (one of the main markers of AD) using a computational model, and by mediating the toxicity of hippocampal pyramidal neurons. We use an established biophysical hippocampal CA1-medial septum network model to evaluate four ionic channels in pyramidal neurons, which were demonstrated to be affected by Aβ. They are the L-type Ca2+ channel, delayed rectifying K+ channel, A-type fast-inactivating K+ channel and large-conductance Ca2+-activated K+ channel. Our simulation results demonstrate that only the Aβ inhibited A-type fast-inactivating K+ channel can induce an increase in hippocampo-septal theta band power, while the other channels do not affect theta rhythm. We further deduce that this increased theta band power is due to enhanced synchrony of the pyramidal neurons. Our research may elucidate potential biomarkers and therapeutics for AD. Further investigation will be helpful for better understanding of AD-induced theta rhythm abnormalities and associated cognitive deficits

Gamma frequency entrainment attenuates amyloid load and modifies microglia

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)[subscript 1-40] and Aβ [subscript 1-42] isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ[subscript 1-40] and Aβ[subscript 1-42] levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.National Institutes of Health (U.S.) (Grant 1R01EY023173)National Institutes of Health (U.S.) (Grant 1DP1NS087724)National Institutes of Health (U.S.) (Grant RF1AG047661)National Institutes of Health (U.S.) (Grant ROIGM104948

Crucial role of calbindin-D28k in the pathogenesis of Alzheimer's disease mouse model

Calbindin-D28k (CB), one of the major calcium-binding and buffering proteins, has a critical role in preventing a neuronal death as well as maintaining calcium homeostasis. Although marked reductions of CB expression have been observed in the brains of mice and humans with Alzheimer disease (AD), it is unknown whether these changes contribute to AD-related dysfunction. To determine the pathogenic importance of CB depletions in AD models, we crossed 5 familial AD mutations (5XFAD; Tg) mice with CB knock-out (CBKO) mice and generated a novel line CBKO·5XFAD (CBKOTg) mice. We first identified the change of signaling pathways and differentially expressed proteins globally by removing CB in Tg mice using mass spectrometry and antibody microarray. Immunohistochemistry showed that CBKOTg mice had significant neuronal loss in the subiculum area without changing the magnitude (number) of amyloid β-peptide (Aβ) plaques deposition and elicited significant apoptotic features and mitochondrial dysfunction compared with Tg mice. Moreover, CBKOTg mice reduced levels of phosphorylated mitogen-activated protein kinase (extracellular signal-regulated kinase) 1/2 and cAMP response element-binding protein at Ser-133 and synaptic molecules such as N-methyl-D-aspartate receptor 1 (NMDA receptor 1), NMDA receptor 2A, PSD-95 and synaptophysin in the subiculum compared with Tg mice. Importantly, this is the first experimental evidence that removal of CB from amyloid precursor protein/presenilin transgenic mice aggravates AD pathogenesis, suggesting that CB has a critical role in AD pathogenesis