Proton-transfer spectroscopy beyond the normal-mode scenario

A stochastic theory is developed to predict the spectral signature of proton-transfer processes and is applied to infrared spectra computed from ab initio molecular-dynamics simulations of a single H5O2+ cation. By constraining the oxygen atoms to a fixed distance, this system serves as a tunable model for general proton-transfer processes with variable barrier height. Three spectral contributions at distinct frequencies are identified and analytically predicted: the quasi-harmonic motion around the most probable configuration, amenable to normal-mode analysis, the contribution due to transfer paths when the proton moves over the barrier, and a shoulder for low frequencies stemming from the stochastic transfer-waiting-time distribution; the latter two contributions are not captured by normal-mode analysis but exclusively reported on the proton-transfer kinetics. In accordance with reaction rate theory, the transfer-waiting-contribution frequency depends inversely exponentially on the barrier height, whereas the transfer-path-contribution frequency is rather insensitive to the barrier height

ADAM10 is expressed in human podocytes and found in urinary vesicles of patients with glomerular kidney diseases

<p>Abstract</p> <p>Background</p> <p>The importance of the Notch signaling in the development of glomerular diseases has been recently described. Therefore we analyzed in podocytes the expression and activity of ADAM10, one important component of the Notch signaling complex.</p> <p>Methods</p> <p>By Western blot, immunofluorescence and immunohistochemistry analysis we characterized the expression of ADAM10 in human podocytes, human urine and human renal tissue.</p> <p>Results</p> <p>We present evidence, that differentiated human podocytes possessed increased amounts of mature ADAM10 and released elevated levels of L1 adhesion molecule, one well known substrate of ADAM10. By using specific siRNA and metalloproteinase inhibitors we demonstrate that ADAM10 is involved in the cleavage of L1 in human podocytes. Injury of podocytes enhanced the ADAM10 mediated cleavage of L1. In addition, we detected ADAM10 in urinary podocytes from patients with kidney diseases and in tissue sections of normal human kidney. Finally, we found elevated levels of ADAM10 in urinary vesicles of patients with glomerular kidney diseases.</p> <p>Conclusions</p> <p>The activity of ADAM10 in human podocytes may play an important role in the development of glomerular kidney diseases.</p

Investigation of the use of a sensor bracelet for the presymptomatic detection of changes in physiological parameters related to COVID-19: an interim analysis of a prospective cohort study (COVI-GAPP).

OBJECTIVES We investigated machinelearningbased identification of presymptomatic COVID-19 and detection of infection-related changes in physiology using a wearable device. DESIGN Interim analysis of a prospective cohort study. SETTING, PARTICIPANTS AND INTERVENTIONS Participants from a national cohort study in Liechtenstein were included. Nightly they wore the Ava-bracelet that measured respiratory rate (RR), heart rate (HR), HR variability (HRV), wrist-skin temperature (WST) and skin perfusion. SARS-CoV-2 infection was diagnosed by molecular and/or serological assays. RESULTS A total of 1.5 million hours of physiological data were recorded from 1163 participants (mean age 44±5.5 years). COVID-19 was confirmed in 127 participants of which, 66 (52%) had worn their device from baseline to symptom onset (SO) and were included in this analysis. Multi-level modelling revealed significant changes in five (RR, HR, HRV, HRV ratio and WST) device-measured physiological parameters during the incubation, presymptomatic, symptomatic and recovery periods of COVID-19 compared with baseline. The training set represented an 8-day long instance extracted from day 10 to day 2 before SO. The training set consisted of 40 days measurements from 66 participants. Based on a random split, the test set included 30% of participants and 70% were selected for the training set. The developed long short-term memory (LSTM) based recurrent neural network (RNN) algorithm had a recall (sensitivity) of 0.73 in the training set and 0.68 in the testing set when detecting COVID-19 up to 2 days prior to SO. CONCLUSION Wearable sensor technology can enable COVID-19 detection during the presymptomatic period. Our proposed RNN algorithm identified 68% of COVID-19 positive participants 2 days prior to SO and will be further trained and validated in a randomised, single-blinded, two-period, two-sequence crossover trial. Trial registration number ISRCTN51255782; Pre-results

A Riboswitch-Based Inducible Gene Expression System for Mycobacteria

Research on the human pathogen Mycobacterium tuberculosis (Mtb) would benefit from novel tools for regulated gene expression. Here we describe the characterization and application of a synthetic riboswitch-based system, which comprises a mycobacterial promoter for transcriptional control and a riboswitch for translational control. The system was used to induce and repress heterologous protein overexpression reversibly, to create a conditional gene knockdown, and to control gene expression in a macrophage infection model. Unlike existing systems for controlling gene expression in Mtb, the riboswitch does not require the co-expression of any accessory proteins: all of the regulatory machinery is encoded by a short DNA segment directly upstream of the target gene. The inducible riboswitch platform has the potential to be a powerful general strategy for creating customized gene regulation systems in Mtb

How cell culture conditions affect the microstructure and nanomechanical properties of extracellular matrix formed by immortalized human mesenchymal stem cells: An experimental and modelling study

This paper presents an investigation of how different culture media (i.e. basal and osteogenic media) affect the nanomechanical properties and microstructure of the mineralized matrix produced by the human mesenchymal stem cell line Y201, from both an experimental and theoretical approach. A bone nodule (i.e. mineralized matrix) cultured from basal medium shows a more anisotropic microstructure compared to its counterpart cultured from an osteogenic medium. As confirmed by finite element simulations, this anisotropic microstructure explains the bimodal distribution of the corresponding mechanical properties very well. The overall nanomechanical response of the bone nodule from the osteogenic medium is poorer compared to its counterpart from the basal medium. The bone nodules, from both basal and osteogenic media, have shown reverse aging effects in terms of mechanical properties. These are possibly due to the fact that cell proliferation outcompetes the mineralization process

A melody through life. How humans wander.

Recollection or remembering events while listening to music is mediated not only by the personal relevance of that music, but also by different aspects, such as concentration on the music, influences of the environment, and the momentary state of the human mind. To further clarify this phenomenon, my paper addresses the question: “How does personally relevant music induce certain individual memories, and what other factors are of importance?” By means of an interview, followed by an analysis of that interview, it may be demonstrated that the process of remembering cannot take place under certain circumstances, e.g., in the presence of inhibiting stressors. If there is no concentration and the listener is otherwise preoccupied, true remembrance will be inhibited. It is also possible that the situation in which a trigger is present does not allow for the recollection of autobiographical events. However, this inhibiting process is also necessary, since a lack of inhibition would result in constant remembering, and human minds would not be able to wander at all. It was also shown that the experience of music becomes a cultural experience, and that there is an association of music with extramusical events. For further investigations, research should focus on the situatedness of the recollection, since the recollection changes depending on the present situation in which the music is heard.Recollection or remembering events while listening to music is mediated by not only the personal relevance of that music, but also by different aspects, such as concentration on the music, influences of the environment and the momentary state of the human mind. To further clarify this phenomenon this paper addresses the question “How does personally relevant music induce certain individual memories and what other factors are of importance?” By means of an interview followed by an analysis of that interview it could be demonstrated that the process of remembering cannot take place under certain circumstances, e.g. in the presence of inhibiting stressors. If there is no concentration and the listener is otherwise preoccupied, true remembrance will be inhibited. It is also possible that the situation in which a trigger is present does not allow the recollection of autobiographical events. However, this inhibiting process is also necessary since a lack of inhibition would result in constant remembering and human minds would not be able to wander at all. It was also shown that the experience of music becomes a cultural experience and that there is an association of music with extramusical events

Responsive Contrast Agents: Synthesis and Characterization of a Tunable Series of pH-Sensitive Near-Infrared Pentamethines

The demand for responsive dyes in optical imaging is high to achieve a better signal-to-noise ratio and, more specifically, to visualize acidic compartments of the endocytic pathway. Herein, we present a new synthetic route, with a step-by-step synthesis of water-soluble pH-sensitive cyanine dyes exhibiting p<i>K</i>_a values in the region of physiological pH, as confirmed by absorption and fluorescence spectra. Moreover, modification of p<i>K</i>_a values was achieved by two different substitution patterns, creating tunable pH-sensitive dyes. We demonstrated the functionality of the pH-sensitive dyes and their suitability as contrast agents for cellular uptake studies by preparing dye-labeled cetuximab and transferrin conjugates. Sulfonated head chains increased water solubility and prevented the formation of dimers, even in the context of dye-labeled bioconjugates. Confocal microscopy images of living cells revealed their pH-responsiveness, as specific fluorescence signal enhancements were observed in acidic compartments of the endocytic pathway (endosomes and lysosomes), although the background signal was low in a pH-neutral environment. Using mixtures of conjugates labeled with either a pH-sensitive or non-pH-sensitive dye for the uptake studies, we could follow the receptor binding and distinguish it from the endocytic uptake process of the conjugates in a simultaneous manner. Moreover, we used flow cytometry to quantify the fluorescence and observed a 3-fold signal enhancement for the pH-sensitive dye conjugates over a period of 3 h