Open State Research Articles

Becoming Matter/Becoming Mother: Wilding in Ali Abbasi’s Border (Gräns)

This paper provides an analysis of Ali Abbasi’s film Border through a feminist new materialist approach that centers what I call “wilding”—a process of worlding that challenges binary and rigid structures of thought that dichotomize existence into fixed categories through the cultivation of bewilderment, a state of openness to not-knowing which requires the unlearning of anthropocentric epistemologies. Paying attention to the etymological roots of the word “matter” (as body, wood, mother/nourishment, and place), the paper shows how the film displaces the dominion of sight with an emphasis on symbiosis that foregrounds the sense of touch

The Role of Open Government in Maintaining Trust in Public Administration

The concept of trust has gained significance in the discourse surrounding traditional public administration, which has been questioned in various respects regarding its relationship with the public. The political, social, and economic changes that have occurred in recent times have led to numerous transformations in the unx”derstanding of public administration. It is crucial to maintain trust in relationships, and this is a topic that has been thoroughly discussed. Trust approaches are evaluated within public administration paradigms in this study. The objective of this research is to assess how government openness impacts citizens’ trust in the government. To measure the influence of open states on public trust, European social research data and data from the open government index, developed by the World Justice Project, were utilised. To investigate whether the countries’ level of open statehood alters trust in public administration, the study initially utilized the Kruskal-Wallis test, followed by the Mann-Whitney U test to identify the variance origin. The findings confirmed the positive impact of open statehood on trust.

Dynamic coupling of fast channel gating with slow ATP-turnover underpins protein transport through the Sec translocon.

The Sec translocon is a highly conserved membrane assembly for polypeptide transport across, or into, lipid bilayers. In bacteria, secretion through the core channel complex-SecYEG in the inner membrane-is powered by the cytosolic ATPase SecA. Here, we use single-molecule fluorescence to interrogate the conformational state of SecYEG throughout the ATP hydrolysis cycle of SecA. We show that the SecYEG channel fluctuations between open and closed states are much faster (~20-fold during translocation) than ATP turnover, and that the nucleotide status of SecA modulates the rates of opening and closure. The SecY variant PrlA4, which exhibits faster transport but unaffected ATPase rates, increases the dwell time in the open state, facilitating pre-protein diffusion through the pore and thereby enhancing translocation efficiency. Thus, rapid SecYEG channel dynamics are allosterically coupled to SecA via modulation of the energy landscape, and play an integral part in protein transport. Loose coupling of ATP-turnover by SecA to the dynamic properties of SecYEG is compatible with a Brownian-rachet mechanism of translocation, rather than strict nucleotide-dependent interconversion between different static states of a power stroke.

Local Anesthetics: Review of Pharmacological Considerations

Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is not so regular, and the negative effects are so low, that providers can overlook a lot of their pharmacotherapeutic principles understandable. The purpose of this continuing education article is important for various local anesthesia formulas in current use. Local anesthetics inhibit nerve conduction by inhibiting the passage of sodium ions through channels or ionophores within neural membranes. Usually these channels are present at rest, during which access to sodium ions is prohibited. When the neuron is excited, the channel adopts an activated or open state, in which sodium ions spread to the cell and begin depolarization. After a sharp change in membrane voltage, the sodium channel adopts an inactive state, at which point the active transport mechanisms return sodium ions outward. After this repolarization, the canal receives a normal state of rest. Valuing these sodium channel States helps explain the privileged sensitivity of local anesthetics for different classes of neuronal fibers

Development of BSCMF system of cathode materials and fabrication of symmetrical cell (BSCMF/GDC/BSCMF) for low temperature solid oxide fuel cell applications

ABSTRACT In the present work, cathode materials of Ba0.5Sr0.5(Co1-xMgx)0.2Fe0.8O3 system (x = 0, 0.2, 0.4, 0.6, 0.8, 1) have been produced and the effect of magnesium (Mg) doping level on cathode performance with Gadolinium doped Cerium (GDC) electrolyte was investigated. The polarisation resistance (RP) for cathode symmetric cells was measured from 600°C to 700°C under open circuit state. At 700 °C, the polarisation resistance of BSCF is 13.96 ohm-cm2 and with the addition of Mg it has decreased to 5.17 ohm-cm2. Further increase in the Mg concentration decreased the polarisation resistance up to 0.34 ohm-cm2, which is the minimum value obtained in the composition BSCMF8. It is observed that charge transfer (CT) is more in the case of Mg-rich compositions. With the increase of magnesium concentration in the cathode, RP value was observed as decreased. This is due to the high oxygen permeation flux behaviour of magnesium, which is in the B-site of the cathode. The coefficient of thermal expansion (CTE) of BSCF is measured to be 22.1 × 10−6/K and decreased to 17.45 × 10−6/K with Mg addition in the composition to BSCMF8, due to the constant oxidation state of Mg by which it suppressed the chemical expansion caused by Co.

CENP-A and CENP-B collaborate to create an open centromeric chromatin state

Centromeres are epigenetically defined via the presence of the histone H3 variant CENP-A. Contacting CENP-A nucleosomes, the constitutive centromere associated network (CCAN) and the kinetochore assemble, connecting the centromere to spindle microtubules during cell division. The DNA-binding centromeric protein CENP-B is involved in maintaining centromere stability and, together with CENP-A, shapes the centromeric chromatin state. The nanoscale organization of centromeric chromatin is not well understood. Here, we use single-molecule fluorescence and cryoelectron microscopy (cryoEM) to show that CENP-A incorporation establishes a dynamic and open chromatin state. The increased dynamics of CENP-A chromatin create an opening for CENP-B DNA access. In turn, bound CENP-B further opens the chromatin fiber structure and induces nucleosomal DNA unwrapping. Finally, removal of CENP-A increases CENP-B mobility in cells. Together, our studies show that the two centromere-specific proteins collaborate to reshape chromatin structure, enabling the binding of centromeric factors and establishing a centromeric chromatin state.

Study of nonlinear dynamic modes of native DNA via mathematical modeling methods

One of the main problems in the nonlinear dynamics of DNA is the identification of physical mechanisms responsible for the mechanical features of its behaviour. The formation and interaction of open states in the DNA structure may be one such mechanism. In this paper we propose a mathematical model of native DNA, which allows us to describe its thermodynamic and kinetic properties taking into account the collective behaviour of the ensemble of open states. The concept of a microscopic open state in DNA and its associated parameter, the displacement vector of nitrogenous bases, are introduced. By averaging the base displacement vectors over the ensemble of states, the thermodynamic variable is determined. According to the statistical model of DNA in the self-consistent field approximation, the structural parameter of the system thermalization is derived. This parameter reflects the statistical self-similarity in the behaviour of the ensemble of open states. Regularities of "criticality" for different ranges of the structural parameter are established and phenomenological representations of the free energy in the framework of the Ginzburg-Landau approach are proposed. Numerical modelling of the dynamics of native DNA is carried out for different ranges of the structural parameter, which has allowed us to establish the types of self-similar solutions and the corresponding open-state collective modes. It is shown that the latter have the nature of finite-amplitude fluctuations in the form of breahters and autosoliton modes, as well as blow-up dissipative structures. The sensitivity of the model to initial conditions is investigated, and the influence of nonlinearity inherent in the model on the modelling results is established. The limitations and prospects of using the approach proposed in this work for mathematical modelling of native DNA are discussed.

Medium viscosity influence on the open states genesis in a DNA molecule

The studies were carried out by the mathematical modeling of DNA mechanical deformations. Numerical calculations done for the interferon alpha 17 gene, which consists of 980 base pairs. It has been established that the genesis and dynamics of open states in the DNA molecule depends on the magnitude of the external influence (torque) and on the viscosity of the environment. In addition, it is shown that the dynamics of open states zones can have a jump-like character with a small change in the magnitude of the torque. When torque is applied to all 980 base pairs of the gene, the following effect is observed: an increase in the viscosity of the medium leads to an increase in the value of the torque necessary for the occurrence of OS and DNA unwinding, i.e. viscosity plays an important stabilizing role in DNA dynamics. Under the influence of a localized torque on different (by the content of A-T and G-C pairs and location) regions of the interferon alpha 17 gene, it was found that the magnitude of the external torque necessary for the occurrence of open states at all calculated values of viscosity depends on the nucleotide composition. The dependence of the torque magnitude required for the open states occurrence on viscosity is observed when the torque is applied to areas close to the gene boundaries. At the same time, the significance of the end effect, which weakens DNA, decreased with increasing viscosity of the medium. Communicated by Ramaswamy H. Sarma

State-independent inhibition of the oncogenic Kv10.1 channel by desethylamiodarone, a comparison with amiodarone

Kv10.1 is a voltage-dependent K channel whose ectopic expression is associated with several human cancers. Additionally, Kv10.1 has structure–function properties which are not yet well understood. We are using drugs of clinical importance in an attempt to gain insight on the relationship between pharmacology and characteristic functional properties of this channel. Herein, we report the interaction of desethylamiodarone (desAd), the active metabolic product of the antiarrhythmic amiodarone with Kv10.1: desAd binds to both closed and open channels, with most inhibition taking place from the open state, with affinity ~ 5 times smaller than that of amiodarone. Current inhibition by desAd and amiodarone is not synergistic. Upon repolarization desAd becomes trapped in Kv10.1 and thereafter dissociates slowly from closed-and-blocked channels. The addition of the Cole-Moore shift plus desAd open-pore-block time courses yields an increasing phase on the steady-state inhibition curve (H∞) at hyperpolarized holding potentials. In contrast to amiodarone, desAd does not inhibit the Kv10.1 Cole-Moore shift, suggesting that a relevant hydrophobic interaction between amiodarone and Kv10.1 participates in the inhibition of the Cole-Moore shift, which is lost with desAd.

Structural and thermodynamic framework for PIEZO1 modulation by small molecules.

Mechanosensitive PIEZO channels constitute potential pharmacological targets for multiple clinical conditions, spurring the search for potent chemical PIEZO modulators. Among them is Yoda1, a widely used synthetic small molecule PIEZO1 activator discovered through cell-based high-throughput screening. Yoda1 is thought to bind to PIEZO1's mechanosensory arm domain, sandwiched between two transmembrane regions near the channel pore. However, how the binding of Yoda1 to this region promotes channel activation remains elusive. Here, we first demonstrate that cross-linking PIEZO1 repeats A and B with disulfide bridges reduces the effects of Yoda1 in a redox-dependent manner, suggesting that Yoda1 acts by perturbing the contact between these repeats. Using molecular dynamics-based absolute binding free energy simulations, we next show that Yoda1 preferentially occupies a deeper, amphipathic binding site with higher affinity in PIEZO1 open state. Using Yoda1's binding poses in open and closed states, relative binding free energy simulations were conducted in the membrane environment, recapitulating structure-activity relationships of known Yoda1 analogs. Through virtual screening of an 8 million-compound library using computed fragment maps of the Yoda1 binding site, we subsequently identified two chemical scaffolds with agonist activity toward PIEZO1. This study supports a pharmacological model in which Yoda1 activates PIEZO1 by wedging repeats A and B, providing a structural and thermodynamic framework for the rational design of PIEZO1 modulators. Beyond PIEZO channels, the three orthogonal computational approaches employed here represent a promising path toward drug discovery in highly heterogeneous membrane protein systems.

Permeant cations modulate pore dynamics and gating of TRPV1 ion channels.

The transient receptor vanilloid 1 (TRPV1) is a non-selective ion channel, which is activated by several chemical ligands and heat. We have previously shown that activation of TRPV1 by different ligands results in single-channel openings with different conductance, suggesting that the selectivity filter is highly dynamic. TRPV1 is weakly voltage dependent; here, we sought to explore whether the permeation of different monovalent ions could influence the voltage dependence of this ion channel. By using single-channel recordings, we show that TRPV1 channels undergo rapid transitions to closed states that are directly connected to the open state, which may result from structural fluctuations of their selectivity filter. Moreover, we demonstrate that the rates of these transitions are influenced by the permeant ion, suggesting that ion permeation regulates the voltage dependence of these channels. Our data could be the basis for more detailed MD simulations exploring the permeation mechanism and how the occupancy of different ions alters the three-dimensional structure of the pore of TRPV1 channels.

The influence of flow, nutrient enrichment and aquatic macrophytes on benthic microalgal dynamics in a perched temporarily closed estuary

This study investigated the benthic microalgal dynamics in a temporarily closed microtidal estuary situated along a degraded stretch of coastline, where estuaries are impacted by development, flow modification, and nutrient pollution. The near natural, perched uMdlotane Estuary experienced regular high flow conditions that maintained the open mouth state for 40% of the study period. Increased nutrient input originated from agricultural-return flow derived from the extensive catchment sugarcane farming (55.9%). No notable temporal differences were recorded for the benthic microalgal biomass (range: 0–41.3 mg m−2). The benthic diatom diversity and evenness indices ranged between 0.6 and 3.1 H′ and 0.2–1 J′, respectively. Higher benthic microalgal biomass (14.9 ± 15.6 mg m−2) coincided with lower diatom diversity (1.3 H’) in the lower reaches. The habitat stability provided by the rooted Stuckenia pectinata facilitated benthic microalgal accumulation, while the absence of sediment disturbance contributed to the decrease in the benthic diatom diversity. The benthic diatom species Cocconeis lineata, Halamphora acutiuscula, and Hantzschia amphioxys largely dominated the community. Temporal differentiation in benthic diatom composition was driven by salinity, water temperature, phosphate, and photic depth changes. The pollution tolerant species Cyclotella atomus increased in abundance (sub-dominant RA = 5%) in response to increased phosphate availability. The presence of nutrient tolerant taxa serves as an early warning of impending environmental deterioration. Implementation of an adaptive management approach supported by monitoring is required to facilitate timely interventions to prevent the loss of ecosystem functionality induced by nutrient enrichment.

Conformational Dynamics of the Most Efficient Carboxylase Contributes to Efficient CO2 Fixation.

Crotonyl-CoA carboxylase/reductase (Ccr) is one of the fastest CO2 fixing enzymes and has become part of efficient artificial CO2-fixation pathways in vitro, paving the way for future applications. The underlying mechanism of its efficiency, however, is not yet completely understood. X-ray structures of different intermediates in the catalytic cycle reveal tetramers in a dimer of dimers configuration with two open and two closed active sites. Upon binding a substrate, this active site changes its conformation from the open state to the closed state. It is challenging to predict how these coupled conformational changes will alter the CO2 binding affinity to the reaction's active site. To determine whether the open or closed conformations of Ccr affect binding of CO2 to the active site, we performed all-atom molecular simulations of the various conformations of Ccr. The open conformation without a substrate showed the highest binding affinity. The CO2 binding sites are located near the catalytic relevant Asn81 and His365 residues and in an optimal position for CO2 fixation. Furthermore, they are unaffected by substrate binding, and CO2 molecules stay in these binding sites for a longer time. Longer times at these reactive binding sites facilitate CO2 fixation through the nucleophilic attack of the reactive enolate in the closed conformation. We previously demonstrated that the Asn81Leu variant cannot fix CO2. Simulations of the Asn81Leu variant explain the loss of activity through the removal of the Asn81 and His365 binding sites. Overall, our findings show that the conformational dynamics of the enzyme controls CO2 binding. Conformational changes in Ccr increase the level of CO2 in the open subunit before the substrate is bound, the active site closes, and the reaction starts. The full catalytic Ccr cycle alternates among CO2 addition, conformational change, and chemical reaction in the four subunits of the tetramer coordinated by communication between the two dimers.

Transient Receptor Potential channels (TRP) in GtoPdb v.2023.3

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [176, 1075]), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative TM domains and assemble as homo- or hetero-tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [730]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books [401, 686, 1158, 256]. The established, or potential, involvement of TRP channels in disease [1129] is reviewed in [448, 685], [688] and [464], together with a special edition of Biochemica et Biophysica Acta on the subject [685]. Additional disease related reviews, for pain [633], stroke [1138], sensation and inflammation [990], itch [130], and airway disease [310, 1054], are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [806]. Most TRP channels are regulated by phosphoinostides such as PtIns(4,5)P2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels (reviewed by [1011, 689, 802]). Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10-30, but does not necessarily imply that the channel's function is to act as a 'hot' or 'cold' sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response. TRPA (ankyrin) familyTRPA1 is the sole mammalian member of this group (reviewed by [293]). TRPA1 activation of sensory neurons contribute to nociception [414, 891, 602]. Pungent chemicals such as mustard oil (AITC), allicin, and cinnamaldehyde activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus [575, 60, 365, 577]. Alkenals with α, β-unsaturated bonds, such as propenal (acrolein), butenal (crotylaldehyde), and 2-pentenal can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases [26, 60]. Covalent modification leads to sustained activation of TRPA1. Chemicals including carvacrol, menthol, and local anesthetics reversibly activate TRPA1 by non-covalent binding [424, 511, 1084, 1083]. TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures [425, 212]. The electron cryo-EM structure of TRPA1 [741] indicates that it is a 6-TM homotetramer. Each subunit of the channel contains two short ‘pore helices’ pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions. TRPC (canonical) familyMembers of the TRPC subfamily (reviewed by [284, 779, 18, 4, 94, 446, 740, 70]) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11-coupled receptors, or receptor tyrosine kinases (reviewed by [766, 955, 1075]). A comprehensive listing of G-protein coupled receptors that activate TRPC channels is given in [4]. Hetero-oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [18] and [447]. TRPC channels have frequently been proposed to act as store-operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores (reviewed by [742, 18, 771, 821, 1124, 157, 726, 64, 158]). However, the weight of the evidence is that they are not directly gated by conventional store-operated mechanisms, as established for Stim-gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by 2-APB and SKF96365 [347, 346]. Activation of TRPC channels by lipids is discussed by [70]. Important progress has been recently made in TRPC pharmacology [806, 619, 436, 102, 852, 191, 291]. TRPC channels regulate a variety of physiological functions and are implicated in many human diseases [295, 71, 886, 1034, 1028, 154, 103, 561, 914, 409]. TRPC1/C4/C5 subgroup TRPC1 alone may not form a functional ion channel [229]. TRPC4/C5 may be distinguished from other TRP channels by their potentiation by micromolar concentrations of La3+. TRPC2 is a pseudogene in humans, but in other mammals appears to be an ion channel localized to microvilli of the vomeronasal organ. It is required for normal sexual behavior in response to pheromones in mice. It may also function in the main olfactory epithelia in mice [1117, 723, 724, 1118, 539, 1171, 1112].TRPC3/C6/C7 subgroup All members are activated by diacylglycerol independent of protein kinase C stimulation [347].TRPM (melastatin) familyMembers of the TRPM subfamily (reviewed by [275, 346, 742, 1154]) fall into the five subgroups outlined below. TRPM1/M3 subgroupIn darkness, glutamate released by the photoreceptors and ON-bipolar cells binds to the metabotropic glutamate receptor 6 , leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [398, 708]. TRPM3 (reviewed by [714]) exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [943]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue [713, 942]. TRPM3 may contribute to the detection of noxious heat [1020]. TRPM2TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells). The direct activators are calcium, adenosine diphosphate ribose (ADPR) [972] and cyclic ADPR (cADPR) [1121]. As for many ion channels, PI(4,5)P2 must also be present [1112]. Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [239]. Recent studies have reported structures of human (hs) TRPM2, which demonstrate two ADPR binding sites in hsTRPM2, one in the N-terminal MHR1/2 domain and the other in the C-terminal NUDT9-H domain. In addition, one Ca2+ binding site in the intracellular S2-S3 loop is revealed and proposed to mediate Ca2+ binding that induces conformational changes leading the ADPR-bound closed channel to open [387, 1030]. Meanwhile, a quadruple-residue motif (979FGQI982) was identified as the ion selectivity filter and a gate to control ion permeation in hsTRPM2 [1123]. TRPM2 is involved in warmth sensation [849], and contributes to several diseases [76]. TRPM2 interacts with extra synaptic NMDA receptors (NMDAR) and enhances NMDAR activity in ischemic stroke [1167]. Activation of TRPM2 in macrophages promotes atherosclerosis [1168, 1150]. Moreover, silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction [1031]. Recent studies have designed various compounds for their potential to selectively inhibit the TRPM2 channel, including ACA derivatives A23, and 2,3-dihydroquinazolin-4(1H)-one derivatives [1140, 1142]. TRPM4/5 subgroupTRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+ [1075]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium-activated cation (CAN) channels [327]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic-mediated inotropy [593]. Mutations are associated with conduction defects [404, 593, 880]. TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [995] and dendritic cell migration [52]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [537] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [513]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [246]. TRPM6/7 subgroupTRPM6 and 7 combine channel and enzymatic activities (‘chanzymes’) [172]. These channels have the unusual property of permeation by divalent (Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at ~0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. PIP2 is required for TRPM6 and TRPM7 activation [811, 1080]. When either gene is deleted in mice, the result is embryonic lethality [413, 1068]. The C-terminal kinase region of TRPM6 and TRPM7 is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones [479, 480]. TRPM7 is responsible for oxidant- induced Zn2+ release from intracellular vesicles [3] and contributes to intestinal mineral absorption essential for postnatal survival [622]. The putative metal transporter proteins CNNM1-4 interact with TRPM7 and regulate TRPM7 channel activity [40, 467]. TRPM8Is a channel activated by cooling and pharmacological agents evoking a ‘cool’ sensation and participates in the thermosensation of cold temperatures [63, 178, 224] reviewed by [1013, 562, 457, 649]. Direct chemical agonists include menthol and icilin[1089]. Besides, linalool can promote ERK phosphorylation in human dermal microvascular endothelial cells, down-regulate intracellular ATP levels, and activate TRPM8 [68]. Recent studies have found that TRPM8 has typical S4-S5 connectomes with clear selective filters and exowell rings [512], and have identified cryo-electron microscopy structures of mouse TRPM8 in closed, intermediate, and open states along the ligand- and PIP2-dependent gated pathways [1114]. Moreover, the last 36 amino acids at the carboxyl terminal of TRPM8 are key protein sequences for TRPM8's temperature-sensitive function [194]. TRPM8 deficiency reduced the expression of S100A9 and increased the expression of HNF4α in the liver of mice, which reduced inflammation and fibrosis progression in mice with liver fibrosis, and helped to alleviate the symptoms of bile duct disease [556]. Channel deficiency also shortens the time of hypersensitivity reactions in migraine mouse models by promoting the recovery of normal sensitivity [12]. A cyclic peptide DeC‐1.2 was designed to inhibit ligand activation of TRPM8 but not cold activation, which can eliminate the side effects of cold dysalgesia in oxaliplatin-treated mice without changing body temperature [9]. Analysis of clinical data shows that TRPM8-specific blockers WS12 can reduce tumor growth in colorectal cancer xenografted mice by reducing transcription and activation of Wnt signaling regulators and β-catenin and its target oncogenes, such as C-Myc and Cyclin D1 [732]. TRPML (mucolipin) familyThe TRPML family [783, 1135, 776, 1087, 190] consists of three mammalian members (TRPML1-3). TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin-1) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome-lysosome hybrid vesicles and lysosomal exocytosis [823]. TRPML2 and TRPML3 show increased channel activity in low luminal sodium and/or increased luminal pH, and are activated by similar small molecules [319, 147, 878]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype (reviewed by [783, 690]). TRPP (polycystin) familyThe TRPP family (reviewed by [216, 214, 300, 1064, 374]) or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [1075]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [345]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero-oligomeric complex with a 1:3 ratio. [906]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels. TRPV (vanilloid) familyMembers of the TRPV family (reviewed by [997]) can broadly be divided into the non-selective cation channels, TRPV1-4 and the more calcium selective channels TRPV5 and TRPV6. TRPV1-V4 subfamilyTRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat (reviewed by [763, 883, 923]). Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co-expressed with TRPV1 [845]. The pharmacology of TRPV1 channels is discussed in detail in [329] and [1018]. TRPV2 is probably not a thermosensor in man [736], but has recently been implicated in innate immunity [547]. Functional TRPV2 expression is described in placental trophoblast cells of mouse [204]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment [127, 530]. TRPV5/V6 subfamily TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia (reviewed by [1060, 205, 651, 270]).TRPV6 is reported to play a key role in calcium transport in the mouse placenta [1059].

HIV-1 Env trimers asymmetrically engage CD4 receptors in membranes

Human immunodeficiency virus 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein (Env) to the cell-surface receptor CD41–4. Although high-resolution structures of Env in a complex with the soluble domains of CD4 have been determined, the binding process is less understood in native membranes5–13. Here we used cryo-electron tomography to monitor Env–CD4 interactions at the membrane–membrane interfaces formed between HIV-1 and CD4-presenting virus-like particles. Env–CD4 complexes organized into clusters and rings, bringing the opposing membranes closer together. Env–CD4 clustering was dependent on capsid maturation. Subtomogram averaging and classification revealed that Env bound to one, two and finally three CD4 molecules, after which Env adopted an open state. Our data indicate that asymmetric HIV-1 Env trimers bound to one and two CD4 molecules are detectable intermediates during virus binding to host cell membranes, which probably has consequences for antibody-mediated immune responses and vaccine immunogen design.

Temperature-Controlled Switchable Photonic Nanojet Generated by Truncated Cylindrical Structure.

We propose a novel micro-nano structure that can realize a photonic nanojet (PNJ) switch by adjusting the temperature, which is composed of a truncated cylinder coated with a thin vanadium dioxide (VO2) film. The influence of temperature on the maximum strength, full width at half maximum (FWHM), working distance, and focal length of the PNJ were studied by finite-difference time-domain (FDTD) method. The results demonstrate that the structure can adjust the open and close state of the PNJ by changing the temperature. A PNJ with varying characteristics can be obtained at both high and low temperatures, and the maximum intensity ratio of the PNJ can reach up to 7.25. This discovery provides a new way of optical manipulation, sensing and detection, microscopy imaging, optoelectronic devices, and other fields.

Extracting thermodynamic properties from van ’t Hoff plots with emphasis on temperature-sensing ion channels

ABSTRACT Transient receptor potential (TRP) ion channels are among the most well-studied classes of temperature-sensing molecules. Yet, the molecular mechanism and thermodynamic basis for the temperature sensitivity of TRP channels remains to this day poorly understood. One hypothesis is that the temperature-sensing mechanism can simply be described by a difference in heat capacity between the closed and open channel states. While such a two-state model may be simplistic it nonetheless has descriptive value, in the sense that it can be used to compare overall temperature sensitivity between different channels and mutants. Here, we introduce a mathematical framework based on the two-state model to reliably extract temperature-dependent thermodynamic potentials and heat capacities from measurements of equilibrium constants at different temperatures. Our framework is implemented in an open-source data analysis package that provides a straightforward way to fit both linear and nonlinear van ’t Hoff plots, thus avoiding some of the previous, potentially erroneous, assumptions when extracting thermodynamic variables from TRP channel electrophysiology data.

The switch of the DNA tetrahedral tweezers controlled by mercury ions

In this paper, the one-pot method is used to make the four DNA strands complement each other to construct the basic framework for DNA tetrahedral tweezers. To regulate the opening and closing of DNA tetrahedral tweezers, DNA strands with a high amount of T-base sequences is partially complementary to the tetrahedral framework. Hg2+ can form T-Hg-T hairpin structures with T-base. When DNA tetrahedral tweezers encounter Hg2+, the T-Hg-T structure is formed to shorten the connecting chain, and the tightening force causes the DNA tweezers to change from an open state to a closed state. Conversely, changes in fluorescence intensity due to the structure change can be used to detect the presence of Hg2+.

Performance calculation for a MEMS switch with «floating» electrode

Switches fabricated using MEMS technology are considered as a promising element base of radio electronics. The main characteristic of a MEMS switch is the ratio of capacitances in the closed and open states. For conventional devices, this ratio is of several units, but it can be significantly increased by implementing original design solutions. The work is devoted to the switch, which is a combination of capacitive and resistive devices. Its working characteristics are considered depending on the substrate properties and contact resistance. The switch provides a capacitance ratio of 27.7 and 46.1 at sapphire and borosilicate glass substrates, while high-resistivity silicon does not allow the value above 7.4. Isolation and insertion loss are of 14.7-19.4 and 0.8-1.1 dB in the frequency range of 4-10 GHz on a sapphire wafer. Acceptable S-parameters are achieved when the contact resistance is not higher than 1 Ohm

Energetic and structural insights behind calcium induced conformational transition in calmodulin.

Calmodulin (CaM) is a key signaling protein that triggers several cellular and physiological processes inside the cell. Upon binding with calcium ion, CaM undergoes large scale conformational transition from a closed state to an open state that facilitates its interaction with various target protein and regulates their activity. This work explores the origin of the energetic and structural variation of the wild type and mutated CaM and explores the molecular origin for the structural differences between them. We first calculated the sequential calcium binding energy to CaM using the PDLD/S-LRA/β approach. This study shows a very good correlation with experimental calcium binding energies. Next we calculated the calcium binding energies to the wild type CaM and several mutated CaM systems which were reported experimentally. On the structural aspect, it has been reported experimentally that certain mutation (Q41L-K75I) in calcium bound CaM leads to complete conformational transition from an open to a closed state. By using equilibrium molecular dynamics simulation, free energy calculation and contact frequency map analysis, we have shown that the formation of a cluster of long-range hydrophobic contacts, initiated by the Q41L-K75I CaM variant is the driving force behind its closing motion. This study unravels the energetics and structural aspects behind calcium ion induced conformational changes in wild type CaM and its variant.