In Vitro Safety Study on the Use of Cold Atmospheric Plasma in the Upper Respiratory Tract.

Cold atmospheric plasma (CAP) devices generate reactive oxygen and nitrogen species, have antimicrobial and antiviral properties, but also affect the molecular and cellular mechanisms of eukaryotic cells. The aim of this study is to investigate CAP treatment in the upper respiratory tract (URT) to reduce the incidence of ventilator-associated bacterial pneumonia (especially superinfections with multi-resistant pathogens) or viral infections (e.g.

Multimeric immunotherapeutic complexes activating natural killer cells towards HIV-1 cure.

Background: Combination antiretroviral therapy (cART) has dramatically extended the life expectancy of people living with HIV-1 and improved their quality of life. There is nevertheless no cure for HIV-1 infection since HIV-1 persists in viral reservoirs of latently infected CD4 T cells. cART does not eradicate HIV-1 reservoirs or restore cytotoxic natural killer (NK) cells which are dramatically reduced by HIV-1 infection, and express the checkpoint inhibitors NKG2A or KIR2DL upregulated after HIV-1 infection.

Non degradation of chitosan and initial degradation of collagen nerve conduits used for protection of nerve coaptations.

Background: Nerve conduits are either used to bridge nerve gaps of up to 3 cm or to protect nerve coaptations. Biodegradable nerve conduits, which are currently commercially available, include Chitosan or collagen-based ones. As histological aspects of their degradation are highly relevant for the progress of neuronal regeneration, the aim of this study was to report the histopathological signs of such nerve conduits, which were removed during revision surgery.

The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4 T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice.

HIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34 hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1β was increased in lymph nodes and bone marrow between day 1 and 3 after HIV-1 infection (mean fold change (FC) of 2.

Molecular Noise in Synaptic Communication.

In synaptic molecular communication (MC), the activation of postsynaptic receptors by neurotransmitter (NTs) is governed by a stochastic reaction-diffusion process. This randomness of synaptic MC contributes to the randomness of the electrochemical downstream signal in the postsynaptic cell, called postsynaptic membrane potential (PSP). Since the randomness of the PSP is relevant for neural computation and learning, characterizing the statistics of the PSP is critical.

Orai1 Boosts SK3 Channel Activation.

The interplay of SK3, a Ca sensitive K ion channel, with Orai1, a Ca ion channel, has been reported to increase cytosolic Ca levels, thereby triggering proliferation of breast and colon cancer cells, although a molecular mechanism has remained elusive to date. We show in the current study, via heterologous protein expression, that Orai1 can enhance SK3 K currents, in addition to constitutively bound calmodulin (CaM). At low cytosolic Ca levels that decrease SK3 K permeation, co-expressed Orai1 potentiates SK3 currents.

Senile plaque calcification of the lamina circumvoluta medullaris in Alzheimer's disease.

Vascular calcification is a common phenomenon in the elderly, predominantly appearing in the basal ganglia and in the lamina circumvoluta medullaris of the hippocampus. Calcifications are not an inherent feature of Alzheimer's disease. On the other hand, a rare presenile type of dementia with symmetrical Fahr-type calcifications and numerous neurofibrillary tangles without senile plaques has been described by Kosaka in 1994 and was termed "diffuse neurofibrillary tangles with calcification" (DNTC).

Saturating Receiver and Receptor Competition in Synaptic DMC: Deterministic and Statistical Signal Models.

Synaptic communication is based on a biological Molecular Communication (MC) system which may serve as a blueprint for the design of synthetic MC systems. However, the physical modeling of synaptic MC is complicated by the possible saturation of the molecular receiver caused by the competition of neurotransmitters (NTs) for postsynaptic receptors. Receiver saturation renders the system behavior nonlinear in the number of released NTs and is commonly neglected in existing analytical models.

CD32CD4 memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice.

CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4 T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time.

CRAC channel opening is determined by a series of Orai1 gating checkpoints in the transmembrane and cytosolic regions.

The initial activation step in the gating of ubiquitously expressed Orai1 calcium (Ca) ion channels represents the activation of the Ca-sensor protein STIM1 upon Ca store depletion of the endoplasmic reticulum. Previous studies using constitutively active Orai1 mutants gave rise to, but did not directly test, the hypothesis that STIM1-mediated Orai1 pore opening is accompanied by a global conformational change of all Orai transmembrane domain (TM) helices within the channel complex. We prove that a local conformational change spreads omnidirectionally within the Orai1 complex.

Twisting gating residues in the Orai pore.

The store-operated calcium channels Orai1-3 form extraordinary long and funnel like pores, in stark contrast to a classical pore loop architecture. A hydrophobic segment centrally located in the Orai pore controls gating. Here, we comment on a recent work that describes decisive binding between three residues that controls the open and closed conformation of Orai channels.

Oxidative Stress-Induced STIM2 Cysteine Modifications Suppress Store-Operated Calcium Entry.

Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood.

Blockage of Store-Operated Ca Influx by Synta66 is Mediated by Direct Inhibition of the Ca Selective Orai1 Pore.

The Ca sensor STIM1 and the Ca channel Orai1 that form the store-operated Ca (SOC) channel complex are key targets for drug development. Selective SOC inhibitors are currently undergoing clinical evaluation for the treatment of auto-immune and inflammatory responses and are also deemed promising anti-neoplastic agents since SOC channels are linked with enhanced cancer cell progression. Here, we describe an investigation of the site of binding of the selective inhibitor Synta66 to the SOC channel Orai1 using docking and molecular dynamics simulations, and live cell recordings.

Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes.

Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca sensor protein that induces permeation of Orai Ca channels upon endoplasmic reticulum Ca-store depletion. A drop in luminal Ca causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure.

Mechanism of conditional partner selectivity in MITF/TFE family transcription factors with a conserved coiled coil stammer motif.

Interrupted dimeric coiled coil segments are found in a broad range of proteins and generally confer selective functional properties such as binding to specific ligands. However, there is only one documented case of a basic-helix-loop-helix leucine zipper transcription factor-microphthalmia-associated transcription factor (MITF)-in which an insertion of a three-residue stammer serves as a determinant of conditional partner selectivity. To unravel the molecular principles of this selectivity, we have analyzed the high-resolution structures of stammer-containing MITF and an engineered stammer-less MITF variant, which comprises an uninterrupted symmetric coiled coil.

Sequential activation of STIM1 links Ca with luminal domain unfolding.

The stromal interaction molecule 1 (STIM1) has two important functions, Ca sensing within the endoplasmic reticulum and activation of the store-operated Ca channel Orai1, enabling plasma-membrane Ca influx. We combined molecular dynamics (MD) simulations with live-cell recordings and determined the sequential Ca-dependent conformations of the luminal STIM1 domain upon activation. Furthermore, we identified the residues within the canonical and noncanonical EF-hand domains that can bind to multiple Ca ions.

A novel STIM1-Orai1 gating interface essential for CRAC channel activation.

Calcium signalling through store-operated calcium (SOC) entry is of crucial importance for T-cell activation and the adaptive immune response. This entry occurs via the prototypic Ca release-activated Ca (CRAC) channel. STIM1, a key molecular component of this process, is located in the membrane of the endoplasmic reticulum (ER) and is initially activated upon Ca store depletion.

TRPC-mediated Ca signaling and control of cellular functions.

Canonical members of the TRP superfamily of ion channels have long been recognized as key elements of Ca handling in a plethora of cell types. The emerging role of TRPC channels in human physiopathology has generated considerable interest in their pharmacological targeting, which requires detailed understanding of their molecular function. Although consent has been reached that receptor-phospholipase C (PLC) pathways and generation of lipid mediators constitute the prominent upstream signaling process that governs channel activity, multimodal sensing features of TRPC complexes have been demonstrated repeatedly.

Magnetic Nanoparticle-Based Molecular Communication in Microfluidic Environments.

The possibility to guide and control magnetic nanoparticles in a non-invasive manner has spawned various applications in biotechnology, such as targeted drug delivery and sensing of biological substances. These applications are facilitated by the engineering of the size, selective chemical reactivity, and general chemical composition of the employed particles. Motivated by their widespread use and favorable properties, in this paper, we provide a theoretical study of the potential benefits of magnetic nanoparticles for the design of molecular communication systems.

Mechanistic insights into the Orai channel by molecular dynamics simulations.

Highly Ca selective channels trigger a large variety of cellular signaling processes in both excitable and non-excitable cells. Among these channels, the Orai channel is unique in its activation mechanism and its structure. It mediates Ca influx into the cytosol with an extremely small unitary conductance over longer time-scales, ranging from minutes up to several hours.