First Passage Time Densities in Non-Markovian Models with Subthreshold Oscillations

Motivated by the dynamics of resonant neurons we consider a differentiable, non-Markovian random process $x(t)$ and particularly the time after which it will reach a certain level $x_b$. The probability density of this first passage time is expressed as infinite series of integrals over joint probability densities of $x$ and its velocity $\dot{x}$. Approximating higher order terms of this series through the lower order ones leads to closed expressions in the cases of vanishing and moderate correlations between subsequent crossings of $x_b$. For a linear oscillator driven by white or coloured Gaussian noise, which models a resonant neuron, we show that these approximations reproduce the complex structures of the first passage time densities characteristic for the underdamped dynamics, where Markovian approximations (giving monotonous first passage time distribution) fail

Detection and quantification of Aβ−3–40 (APP669‐711) in cerebrospinal fluid

Neurochemical biomarkers can support the diagnosis of Alzheimer’s disease and may facilitate clinical trials. In blood plasma, the ratio of the amyloid-β (Aβ) peptides Aβ−3– 40/Aβ1–42 can predict cerebral amyloid-β pathology with high accuracy (Nakamura et al., 2018). Whether or not Aβ−3–40 (aka. amyloid precursor protein (APP) 669– 711) is also present in cerebrospinal fluid (CSF) is not clear. Here, we investigated whether Aβ−3–40 can be detected in CSF and to what extent the CSF Aβ−3–40/Aβ42 ratio is able to differentiate between individuals with or without amyloid-β positron emission tomography (PET) evidence of brain amyloid. The occurrence of Aβ−3–40 in human CSF was assessed by immunoprecipitation followed by mass spectrometry. For quantifying the CSF concentrations of Aβ−3–40 in 23 amyloid PET- negative and 17 amyloid PET- positive subjects, we applied a sandwich-type immunoassay. Our findings provide clear evidence of the presence of Aβ−3–40 and Aβ−3–38 in human CSF. While there was no statistically significant difference in the CSF concentration of Aβ−3–40 between the two diagnostic groups, the CSF Aβ−3–40/Aβ42 ratio was increased in the amyloid PET- positive individuals. We conclude that Aβ−3– 40 appears to be a regular constituent of CSF and may potentially serve to accentuate the selec- tive decrease in CSF Aβ42 in Alzheimer's disease

Towards a target label-free suboptimum oligonucleotide displacement-based detection system

A novel method for the future development of label-free DNA sensors is proposed here. The approach is based on the displacement of a labelled suboptimum mutated oligonucleotide hybridised with the immobilised biotin-capture probe. The target fully complementary to the biotin-capture probe can displace the labelled oligonucleotide causing a subsequent decrease of the signal that verifies the presence of the target. The decrease of signal was demonstrated to be proportional to the target concentration. A study of the hybridisation of mutated and complementary labelled oligonucleotides with an immobilised biotin-capture probe was carried out. Different kinetic and thermodynamic behaviour was observed for heterogeneous hybridisation of biotin-capture probe with complementary or suboptimum oligonucleotides. The displacement method evaluated colourimetrically achieved the objective of decreasing the response time from 1 h for direct hybridisation of 19-mer oligonucleotides in the direct enzyme-linked oligonucleotide assay (ELONA) to 5 min in the case of displacement detection in the micromolar concentration range

New Clathrin-Based Nanoplatforms for Magnetic Resonance Imaging

Background: Magnetic Resonance Imaging (MRI) has high spatial resolution, but low sensitivity for visualization of molecular targets in the central nervous system (CNS). Our goal was to develop a new MRI method with the potential for non-invasive molecular brain imaging. We herein introduce new bio-nanotechnology approaches for designing CNS contrast media based on the ubiquitous clathrin cell protein. Methodology/Principal Findings: The first approach utilizes three-legged clathrin triskelia modified to carry 81 gadolinium chelates. The second approach uses clathrin cages self-assembled from triskelia and designed to carry 432 gadolinium chelates. Clathrin triskelia and cages were characterized by size, structure, protein concentration, and chelate and gadolinium contents. Relaxivity was evaluated at 0.47 T. A series of studies were conducted to ascertain whether fluorescent-tagged clathrin nanoplatforms could cross the blood brain barriers (BBB) unaided following intranasal, intravenous, and intraperitoneal routes of administration. Clathrin nanoparticles can be constituted as triskelia (18.5 nm in size), and as cages assembled from them (55 nm). The mean chelate: clathrin heavy chain molar ratio was 27.0464.8: 1 fo

TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the SARS-coronavirus spike-protein

The type II transmembrane serine proteases TMPRSS2 and HAT can cleave and activate the spike protein (S) of the severe acute respiratory syndrome coronavirus (SARS-CoV) for membrane fusion. In addition, these proteases cleave the viral receptor, the carboxypeptidase angiotensin-converting enzyme 2 (ACE2), and it was proposed that ACE2 cleavage augments viral infectivity. However, no mechanistic insights into this process were obtained and the relevance of ACE2 cleavage for SARS-CoV S protein (SARS-S) activation has not been determined. Here, we show that arginine and lysine residues within ACE2 amino acids 697 to 716 are essential for cleavage by TMPRSS2 and HAT and that ACE2 processing is required for augmentation of SARS-S-driven entry by these proteases. In contrast, ACE2 cleavage was dispensable for activation of the viral S protein. Expression of TMPRSS2 increased cellular uptake of soluble SARS-S, suggesting that protease-dependent augmentation of viral entry might be due to increased uptake of virions into target cells. Finally, TMPRSS2 was found to compete with the metalloprotease ADAM17 for ACE2 processing, but only cleavage by TMPRSS2 resulted in augmented SARS-S-driven entry. Collectively, our results in conjunction with those of previous studies indicate that TMPRSS2 and potentially related proteases promote SARS-CoV entry by two separate mechanisms: ACE2 cleavage, which might promote viral uptake, and SARS-S cleavage, which activates the S protein for membrane fusion. These observations have interesting implications for the development of novel therapeutics. In addition, they should spur efforts to determine whether receptor cleavage promotes entry of other coronaviruses, which use peptidases as entry receptors

TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the SARS-coronavirus spike-protein

This article is about an experiment in participatory pedagogy, in which the researcher involved 24 Nigerian University students of French in determining the content of a 6-week Grammar Course in French. The objective of the study was to ensure content relevance in content development in order to guarantee and sustain learners' interest in Grammar learning tasks. The content development exercises comprised 3 phases, namely the collation of raw data of students’ interest inventory, conducting the needs analysis of interesting areas and breaking these areas into teachable modules. The teachable modules that evolved out of the process of co-construction formed the basis for teaching that ensued. The modules are presented in this paper, while a later paper will be evaluated the students' performance at the end of the programme, thereby making a case for the adoption of learner participation in content development.مقاله حاضر تجربه ای از آموزش مشارکتی است که محقق 24 دانشجوی رشته زبان فرانسه از دانشگاه نیجریه را برای بررسی محتوای درس دستور‌زبان فرانسوی 6 هفته درگیر ساخت. هدف از این مطالعه اطمینان از ارتباط محتوا با توسعه محتوا، به منظور تضمین و جلب نظر فراگیران در حین فراگیری دستور زبان بود. تمرینات توسعه محتوا دارای 3 بخش است: تلفیق داده های اولیه با فهرست مورد نظر فراگیران، انجام تجزیه- تحلیل و نیاز سنجی حیطه مورد علاقه و تقسیم حیطه ها به بخش های قابل تدریس. موارد قابل تدریس با مشارکت فراگیران به دست آمدند و اساس پایه های اصلی تدریس شدند. بخش ها در این مقاله و ارزیابی کارآمدی این برنامه در مقاله بعدی که از فراگیران در پایان این دوره بدست آمده ارائه خواهد شد که می‌تواند به عنوان یک نمونه پژوهش در تولید محتوا مشارکتی مورد استفاده قرار گیرد

A Library of Protein Cage Architectures as Nanomaterials

Virus capsids and other structurally related cage-like proteins such as ferritins, dps, and heat shock proteins have three distinct surfaces (inside, outside, interface) that can be exploited to generate nanomaterials with multiple functionality by design. Protein cages are biological in origin and each cage exhibits extremely homogeneous size distribution. This homogeneity can be used to attain a high degree of homogeneity of the templated material and its associated property. A series of protein cages exhibiting diversity in size, functionality, and chemical and thermal stabilities can be utilized for materials synthesis under a variety of conditions. Since synthetic approaches to materials science often use harsh temperature and pH, it is an advantage to utilize protein cages from extreme environments. In this chapter, we review recent studies on discovering novel protein cages from harsh natural environments such as the acidic thermal hot springs at Yellowstone National Park (YNP) and on utilizing protein cages as nano-scale platforms for developing nanomaterials with wide range of applications from electronics to biomedicine.close433