Deactivated State Research Articles

Defibrillation deactivation state and activation status in patients with implantable cardioverter-defibrillators at the end of life

Abstract Background Implantable cardioverter-defibrillators (ICDs) are effective in preventing sudden cardiac death due to lethal arrhythmias. Defibrillation is also known to cause physical and emotional distress to patients, and guidelines on palliative care for cardiovascular disease recommend that when patients with ICDs reach the end of life, the benefits and burdens of ICDs should be fully explained to patients and a policy regarding the cessation of defibrillation discussed. However, there are few reports on the treatment status and defibrillation deactivation in patients with ICDs in the terminal phase. Aim To investigate defibrillation activation and defibrillation deactivation in terminally ill patients with ICDs. Results Death was confirmed in 146 patients in the medical record, and a DNAR policy was decided in 46 patients. The decision to deactivate defibrillation was informed to 24 patients (16%), and 15 patients (10%) were deactivated (11 patients in terminal heart failure and 4 patients in others). Four of the nine patients (6%) who did not deactivate defibrillation had a shock before death.Of the 22 patients (14 cardiovascular deaths and 8 others) who were not explained about the deactivation of defibrillation, 4 had shock activation before death.Of the 24 patients who received explanation about defibrillation deactivation, 6 (25%) had the policy decided by the patient and family, and 18 (75%) had the policy decided by the family because the patient's will could not be confirmed due to deterioration of end-stage condition. Discussion This study showed that defibrillation was deactivated in only 10% of Japanese patients with end-stage ICDs.ICD patients do not always reach the end of life due to heart failure. It is important for physicians, clinical engineers, and device nurses involved in device care to provide information and to confirm the wishes of patients and their families regarding the deactivation of defibrillation so that they can be supported in their decision-making regarding defibrillation no matter under what circumstances they reach the end of life. Conclusion Discussion of ICD deactivation in palliative care is needed to reduce the risk of painful shock and distress at the end of life.

Research Progress in Structure Evolution and Durability Modulation of Ir- and Ru-Based OER Catalysts under Acidic Conditions.

Green hydrogen energy, as one of the most promising energy carriers, plays a crucial role in addressing energy and environmental issues. Oxygen evolution reaction catalysts, as the key to water electrolysis hydrogen production technology, have been subject to durability constraints, preventing large-scale commercial development. Under the high current density and harsh acid-base electrolyte conditions of the water electrolysis reaction, the active metals in the catalysts are easily converted into high-valent soluble species to dissolve, leading to poor structural durability of the catalysts. There is an urgent need to overcome the durability challenges under acidic conditions and develop electrocatalysts with both high catalytic activity and high durability. In this review, the latest research results are analyzed in depth from both thermodynamic and kinetic perspectives. First, a comprehensive summary of the structural deactivation state process of noble metal oxide catalysts is presented. Second, the evolution of the structure of catalysts possessing high durability is discussed. Finally, four new strategies for the preparation of stable catalysts, "electron buffer (ECB) strategy", combination strength control, strain control, and surface coating, are summarized. The challenges and prospects are also elaborated for the future synthesis of more effective Ru/Ir-based catalysts and boost their future application.

Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers.

The complex multistep activation cascade of Ire1 involves changes in the Ire1 conformation and oligomeric state. Ire1 activation enhances ER folding capacity, in part by overexpressing the ER Hsp70 molecular chaperone BiP; in turn, BiP provides tight negative control of Ire1 activation. This study demonstrates that BiP regulates Ire1 activation through a direct interaction with Ire1 oligomers. Particularly, we demonstrated that the binding of Ire1 luminal domain (LD) to unfolded protein substrates not only trigger conformational changes in Ire1-LD that favour the formation of Ire1-LD oligomers but also exposes BiP binding motifs, enabling the molecular chaperone BiP to directly bind to Ire1-LD in an ATP-dependent manner. These transient interactions between BiP and two short motifs in the disordered region of Ire1-LD are reminiscent of interactions between clathrin and another Hsp70, cytoplasmic Hsc70. BiP binding to substrate-bound Ire1-LD oligomers enables unfolded protein substrates and BiP to synergistically and dynamically control Ire1-LD oligomerisation, helping to return Ire1 to its deactivated state when an ER stress response is no longer required.

Dynamic aberrances of substantia nigra-relevant coactivation patterns in first-episode treatment-naïve patients with schizophrenia.

Although dopaminergic disturbances are well-known in schizophrenia, the understanding of dopamine-related brain dynamics remains limited. This study investigates the dynamic coactivation patterns (CAPs) associated with the substantia nigra (SN), a key dopaminergic nucleus, in first-episode treatment-naïve patients with schizophrenia (FES). Resting-state fMRI data were collected from 84 FES and 94 healthy controls (HCs). Frame-wise clustering was implemented to generate CAPs related to SN activation or deactivation. Connectome features of each CAP were derived using an edge-centric method. The occurrence for each CAP and the balance ratio for antagonistic CAPs were calculated and compared between two groups, and correlations between temporal dynamic metrics and symptom burdens were explored. Functional reconfigurations in CAPs exhibited significant differences between the activation and deactivation states of SN. During SN activation, FES more frequently recruited a CAP characterized by activated default network, language network, control network, and the caudate, compared to HCs (F = 8.54, FDR-p = 0.030). Moreover, FES displayed a tilted balance towards a CAP featuring SN-coactivation with the control network, caudate, and thalamus, as opposed to its antagonistic CAP (F = 7.48, FDR-p = 0.030). During SN deactivation, FES exhibited increased recruitment of a CAP with activated visual and dorsal attention networks but decreased recruitment of its opposing CAP (F = 6.58, FDR-p = 0.034). Our results suggest that neuroregulatory dysfunction in dopaminergic pathways involving SN potentially mediates aberrant time-varying functional reorganizations in schizophrenia. This finding enriches the dopamine hypothesis of schizophrenia from the perspective of brain dynamics.

Monocytes as Targets for Immunomodulation by Regional Citrate Anticoagulation.

Immune alterations in end-stage renal patients receiving hemodialysis are complex and predispose patients to infections. Anticoagulation may also play an immunomodulatory role in addition to the accumulation of uremic toxins and the effects of the dialysis procedure. Accordingly, it has been recently shown that the infection rate increases in patients under regional citrate anticoagulation (RCA) compared with systemic heparin anticoagulation (SHA). We hypothesized that RCA affects the immune status of hemodialysis patients by targeting monocytes. In a cohort of 38 end-stage renal patients undergoing hemodialysis, we demonstrated that whole blood monocytes of patients receiving RCA-but not SHA-failed to upregulate surface activation markers, like human leukocyte antigen class II (HLA-DR), after stressful insults, indicating a state of deactivation during and immediately after dialysis. Additionally, RNA sequencing (RNA-seq) data and gene set enrichment analysis of pre-dialysis monocytes evidenced a great and complex difference between the groups given that, in the RCA group, monocytes displayed a dramatic transcriptional change with increased expression of genes related to the cell cycle regulation, cellular metabolism, and cytokine signaling, compatible with the reprogramming of the immune response. Transcriptomic changes in pre-dialysis monocytes signalize the lasting nature of the RCA-related effects, suggesting that monocytes are affected even beyond the dialysis session. Furthermore, these findings demonstrate that RCA-but not SHA-impairs the response of monocytes to activation stimuli and alters the immune status of these patients with potential clinical implications.

Perylene-Mediated Cytoskeletal Dysfunction Remodels Cancer-Associated Fibroblasts to Augment Antitumor Immunotherapy.

Targeted reprogramming of cancer-associated fibroblasts (CAFs) is one of the most essential cancer therapies. However, how to reprogram active CAFs toward deactivated state still remains immense challenge. To tackle this challenge, herein, one perylene N, N'-bis(2-((dimethylammonium)ethylene)-2-(methoxylethyl))-1, 6, 7, 12-tetrachloroperylene-3, 4, 9, 10-tetracarboxylic diimide (PDIC-OC) is prepared, which can trigger endogenous reactive oxygen species (ROS) burst to result in cytoskeletal dysfunction and cell apoptosis so that suppress transforming growth factor β (TGF-β) production. As a result, PDIC-OC can reprogram the activated CAFs and relieve immunosuppressive tumor microenvironment by efficient polarization of M2-typed macrophages into M1-typed ones, downregulation of alpha-smooth muscle actin (α-SMA), alleviation of hypoxic state to promote infiltration of cytotoxic T lymphocytes, and ultimately realizes outstanding antitumor performance on B16F10 tumor-xenografted and lung-metastatic mouse model even at low concentration of 1mg kg-1 body weight. This work thus presents a novel strategy that cytoskeleton dysfunction and cell apoptosis cooperatively suppress the secretion of TGF-β to reprogram CAFs and meanwhile clarifies intrinsic mechanism for perylene-triggered chemo-immunotherapy against hypoxic tumors.

Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action.

Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (NaVs) are responsible for action potential initiation and transmission of pain signals. NaV1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective inhibition of NaV1.8 can ameliorate pain while minimizing effects on other NaV isoforms essential for cardiac, respiratory, and central nervous system physiology. Here we present the pharmacology, interaction site, and mechanism of action of LTGO-33, a novel NaV1.8 small molecule inhibitor. LTGO-33 inhibited NaV1.8 in the nM potency range and exhibited over 600-fold selectivity against human NaV1.1-NaV1.7 and NaV1.9. Unlike prior reported NaV1.8 inhibitors that preferentially interacted with an inactivated state via the pore region, LTGO-33 was state-independent with similar potencies against closed and inactivated channels. LTGO-33 displayed species specificity for primate NaV1.8 over dog and rodent NaV1.8 and inhibited action potential firing in human dorsal root ganglia neurons. Using chimeras combined with mutagenesis, the extracellular cleft of the second voltage-sensing domain was identified as the key site required for channel inhibition. Biophysical mechanism of action studies demonstrated that LTGO-33 inhibition was relieved by membrane depolarization, suggesting the molecule stabilized the deactivated state to prevent channel opening. LTGO-33 equally inhibited wild-type and multiple NaV1.8 variants associated with human pain disorders. These collective results illustrate LTGO-33 inhibition via both a novel interaction site and mechanism of action previously undescribed in NaV1.8 small molecule pharmacologic space. SIGNIFICANCE STATEMENT: NaV1.8 sodium channels primarily expressed in peripheral pain-sensing neurons represent a validated target for the development of novel analgesics. Here we present the selective small molecule NaV1.8 inhibitor LTGO-33 that interdicts a distinct site in a voltage-sensor domain to inhibit channel opening. These results inform the development of new analgesics for pain disorders.

Resting mitochondrial complex I from Drosophila melanogaster adopts a helix-locked state.

Respiratory complex I is a proton-pumping oxidoreductase key to bioenergetic metabolism. Biochemical studies have found a divide in the behavior of complex I in metazoans that aligns with the evolutionary split between Protostomia and Deuterostomia. Complex I from Deuterostomia including mammals can adopt a biochemically defined off-pathway 'deactive' state, whereas complex I from Protostomia cannot. The presence of off-pathway states complicates the interpretation of structural results and has led to considerable mechanistic debate. Here, we report the structure of mitochondrial complex I from the thoracic muscles of the model protostome Drosophila melanogaster. We show that although D. melanogaster complex I (Dm-CI) does not have a NEM-sensitive deactive state, it does show slow activation kinetics indicative of an off-pathway resting state. The resting-state structure of Dm-CI from the thoracic muscle reveals multiple conformations. We identify a helix-locked state in which an N-terminal α-helix on the NDUFS4 subunit wedges between the peripheral and membrane arms. Comparison of the Dm-CI structure and conformational states to those observed in bacteria, yeast, and mammals provides insight into the roles of subunits across organisms, explains why the Dm-CI off-pathway resting state is NEM insensitive, and raises questions regarding current mechanistic models of complex I turnover.

Hydrophobic gating in bundle-crossing ion channels: A case study of TRPV4.

Many transmembrane (TM) ion channels regulate ion permeation by forming bundle crossing of the pore-lining TM helices when deactivated. The resulting physical constriction is generally believed to serve as the “gate” and impose the major free energy barrier to ion permeation. On the other hand, many ion channels have been observed contain inner pores that are highly hydrophobic and can undergo spontaneous dewetting transitions. The resulting “vapor” region can block ion flow even in the absence of physical constriction. However, it is not clear whether such hydrophobic gating mechanism could be involved in channels with bundle-crossing in the deactivated state. Using atomistic simulations, we show that the human TRPV4 (hTRPV4) channel in the bundle-crossing closed state can readily undergoes hydrophobic dewetting transition and forms a vapor region in the lower pore region. Importantly, free energy analysis reveals that the major barrier for ion permeation is not located at the most constricted site, but within the vapor region. Furthermore, a single hydrophilic mutation I715N in the lower pore region significantly increases pore hydration without affecting the physical opening near bundle crossing; yet it largely removes the free energy barrier of ion permeation in hTRPV4, consistent with a previous experimental study showing that I715N leads to a constitutively conductive channel. Therefore, hTRPV4 is a hydrophobic gating channel despite the presence of bundle-crossing in the deactivated state. We anticipate that hydrophobic gating may play a key role in other bundle-crossing ion channels with hydrophobic inner pores.

Using rosetta and alphafold to assess Jingzhaotoxin-III binding to hNav1.5 and hKv2.1.

Ion channels are pore-forming transmembrane proteins regulating ion flux across cell membranes and regulators of the ventricular action potential. The human voltage-gated sodium channel 1.5 (hNav1.5) is predominantly expressed in cardiac myocytes and is solely responsible for the ventricular action potential's initial upstroke phase. A series of mutations in hNav1.5 are classified as Long QT Syndrome subtype 3 (LQT3) and are linked to hNav1.5 gain-of-function, resulting in an enhanced inward current prolonging repolarization. Alternatively, improper hNav1.5 inactivation results in a prolonged, late sodium current during the action potential plateau, causing a similar LQT3 gain-of function phenotype. Current drug therapies for hNav1.5-associated arrhythmia involve combinations of beta-adrenergic blockers and hNav1.5-targeting small-molecules such as flecainide. Alternatively, hNav1.5-targeting peptide toxins have the potential as novel therapeutics and investigational tools for ion channel disorders. One such peptide, Jingzhaotoxin-III (JzTx-III) is a 36-residue peptide that has been found to inhibit hNav1.5 and human voltage-gated potassium channel isoform 2.1 (hKv2.1) but does not inhibit neuronal and skeletal hNav channels. Mutational studies of JzTx-III identified unique residues that modulate hNav1.5 and hKv2.1 activity. We hypothesize that prior single-point mutational data will demonstrate differing sets of binding free energies and peptide-channel contacts for hNav1.5 and hKv2.1. In this study, we used AlphaFold and Rosetta to generate models of hNav1.5 and hKv2.1 in the deactivated state, docked JzTx-III to each channel, and assessed in silico binding free energies of wild-type and single-point mutations. This structural and energetic information can then be used as a guideline for multi-point mutational design to predict improved hNav1.5 binding specificity for further investigation of LQTS and pro-arrhythmic ventricular action potentials.

Self-Centering Rotational Joints for Seismic Resilient Steel Moment Resisting Frame

A novel self-centering rotational joint (SCRJ) was proposed to replace the plastic hinge at the beam end to achieve a seismic resilient frame without diminishing the structural usability. The quasi-static cyclic tests of the SCRJs with different sets of friction components and disc springs were conducted, with the results showing that the precompressive force, stiffness of the compressive force, and slope angle of the right helicoid surfaces can significantly affect the hysteresis behavior. The hysteresis curve of the SCRJ demonstrates a flag shape with four characteristic states: activation state, ultimate state, reversal activation state, and deactivation state. The displacement-based design approach was adopted for the resilient steel moment resisting frame structure with the SCRJs based on which a six-story resilient frame structure was designed with the SCRJs at the beam ends. The nonlinear dynamic analysis shows that the interstory drift ratio and residual interstory drift ratio of the resilient frame structure can meet the design objectives, in which the SCRJs reach the plastic state (caused by geometric nonlinearity) more easily than conventional plastic hinges (caused by material plasticity), resulting in larger deformations, and can effectively dissipate seismic energy and protect the main frame from yielding under the rarely occurring earthquake (ROE) level.

Effect of Active and Passive Function of the Posterosuperior Rotator Cuff on Compensatory Muscle Loads in the Shoulder.

Background:Irreparable posterosuperior rotator cuff (PSRC) tears have been shown to result in shoulder pain and loss of function.Purpose/Hypothesis:The purpose of this study was to determine the effect of the loss of active or passive function of the PSRC on compensatory muscle loads in the deltoid and the remaining rotator cuff. It was hypothesized that both deactivation and resection of the PSRC would result in load increases in the remaining muscles and that resection of the PSRC would result in even higher required compensatory forces than would mere deactivation.Study Design:Controlled laboratory study.Methods:A total of 7 cadaveric shoulders were tested using a biomechanical shoulder simulator with 10 independently controlled actuators for various muscles (anterior, middle, and posterior deltoid; inferior and superior subscapularis; latissimus dorsi; pectoralis major; teres minor; supraspinatus; and infraspinatus) and 3-dimensional motion tracking. The muscle loads representing the latissimus dorsi and pectoralis major were each held constant, and the remaining muscle actuator forces required to abduct the arm in the scapular plane were determined. The actuator forces corresponding with arm elevation from 20° to 65° were compared at 5° increments for 3 testing conditions: (1) intact, active PSRC; (2) intact, deactivated PSRC; and (3) resected PSRC and shoulder capsule.Results:In both the deactivated and resected states, the teres minor showed a significant increase in required muscle forces through nearly the entire tested range of arm elevation compared to the active state. This was also the case for the subscapularis but only at higher elevation angles. The deltoid demonstrated increased muscle forces of at least 1 of its subunits between 25° and 55° of elevation when comparing the deactivated state or resected state to the active state. However, through nearly the entire range of elevation, no statistically significant differences were found between the deactivated and resected states for any of the actuator loads representing muscle forces.Conclusion:The loss of active function of the PSRC led to compensatory loads on the remaining rotator cuff and deltoid, regardless of the passive presence of the PSRC as a supposed subacromial spacer.Clinical Relevance:The findings encourage the exploration of treatment procedures that mimic the active function of the PSRC when the rotator cuff itself is irreparable.

Stimuli-Responsive Anion Transport through Acylhydrazone-Based Synthetic Anionophores.

Photoswitchable acylhydrazone-based synthetic anionophores are reported. Single-crystal X-ray structure and 1H NMR titration studies confirmed the chloride binding in solid and solution states. The ion transport activity of 1a was greatly attenuated through a phototriggered E to Z photoisomerization process, and the photoisomerized deactivated state showed high kinetic stability due to an intramolecular hydrogen bond. Switchable "OFF-ON" transport activity was achieved by the application of light and acid-catalyzed reactivation process.

Co-activation pattern alterations in autism spectrum disorder-A volume-wise hierarchical clustering fMRI study.

IntroductionThere has been a growing effort to characterize the time‐varying functional connectivity of resting state (RS) fMRI brain networks (RSNs). Although voxel‐wise connectivity studies have examined different sliding window lengths, nonsequential volume‐wise approaches have been less common.MethodsInspired by earlier co‐activation pattern (CAP) studies, we applied hierarchical clustering (HC) to classify the image volumes of the RS‐fMRI data on 28 adolescents with autism spectrum disorder (ASD) and their 27 typically developing (TD) controls. We compared the distribution of the ASD and TD groups' volumes in CAPs as well as their voxel‐wise means. For simplification purposes, we conducted a group independent component analysis to extract 14 major RSNs. The RSNs' average z‐scores enabled us to meaningfully regroup the RSNs and estimate the percentage of voxels within each RSN for which there was a significant group difference. These results were jointly interpreted to find global group‐specific patterns.ResultsWe found similar brain state proportions in 58 CAPs (clustering interval from 2 to 30). However, in many CAPs, the voxel‐wise means differed significantly within a matrix of 14 RSNs. The rest‐activated default mode‐positive and default mode‐negative brain state properties vary considerably in both groups over time. This division was seen clearly when the volumes were partitioned into two CAPs and then further examined along the HC dendrogram of the diversifying brain CAPs. The ASD group network activations followed a more heterogeneous distribution and some networks maintained higher baselines; throughout the brain deactivation state, the ASD participants had reduced deactivation in 12/14 networks. During default mode‐negative CAPs, the ASD group showed simultaneous visual network and either dorsal attention or default mode network overactivation.ConclusionNonsequential volume gathering into CAPs and the comparison of voxel‐wise signal changes provide a complementary perspective to connectivity and an alternative to sliding window analysis.

Regulating Catalytic Activity of DNA-Templated Silver Nanoclusters Based on their Differential Interactions with DNA Structures and Stimuli-Responsive Structural Transition.

This work reports exquisite engineering of catalytic activity of DNA-templated silver nanoclusters (DNA-AgNCs) based on unique adsorption phenomena of DNAs on DNA-AgNCs and reversible transition between double and triple-stranded DNAs. Four DNA homopolymers exhibit different inhibition effects on the catalytic activity of DNA-AgNCs, poly adenine (polyA) > poly guanine (polyG) > poly cytosine (polyC) > poly thymine (polyT), demonstrating that polyA strands have the strongest adsorption affinity on DNA-AgNCs. Through the formation of T-A•T triplex DNAs, catalytic activity of DNA-AgNCs is restored from the deactivated state by double or single-stranded DNAs, indicating the participation of N7 groups of adenine bases in binding to DNA-AgNCs and blocking active sites. Accordingly, reversibly regulating catalytic activity of DNA-AgNCs can be realized based on DNA input-stimulated transition between duplex and triplex structures. In the end, two low-cost and facile biosensing methods are presented, which are derived from the activity-switchable platform. It is worthy to anticipate that the DNA-AgNCs with controlled catalytic activity will inspire researchers to devise more functionalized nanocatalysts and contribute to the exploration of intelligent biomedicine in the future.

Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels.

Peptide toxins isolated from venomous creatures, long prized as research tools due to their innate potency for ion channels, are emerging as drugs as well. However, it remains challenging to understand why peptide toxins bind with high potency to ion channels, to identify residues that are key for activity, and to improve their affinities via mutagenesis. We use WaterMap, a molecular dynamics simulation-based method, to gain computational insight into these three questions by calculating the locations and thermodynamic properties of water molecules in the peptide toxin binding sites of five ion channels. These include an acid-sensing ion channel, voltage-gated potassium channel, sodium channel in activated and deactivated states, transient-receptor potential channel, and a nicotinic receptor whose structures were recently determined by crystallography and cryo-electron microscopy (cryo-EM). All channels had water sites in the peptide toxin binding site, and an average of 75% of these sites were stable (low-energy), and 25% were unstable (medium or high energy). For the sodium channel, more unstable water sites were present in the deactivated state structure than the activated. Additionally, for each channel, unstable water sites coincided with the positions of peptide toxin residues that previous mutagenesis experiments had shown were important for activity. Finally, for the sodium channel in the deactivated state, unstable water sites were present in the peptide toxin binding pocket but did not overlap with the peptide toxin, suggesting that future experimental efforts could focus on targeting these sites to optimize potency.

Operating conditions to maximize clean liquid fuels yield by oligomerization of 1-butene on HZSM-5 zeolite catalysts

Abstract The effect of operating conditions has been extensively studied for the selective oligomerization of 1-butene to clean synthetic liquid fuels. HZSM-5 zeolite (SiO2/Al2O3 ratio = 30–280) based catalysts provided with a hierarchical porous structure have been tested in a fixed bed reactor under the following conditions: 175–325 °C; 1.5–40 bar; space time, 0.5–6 gcatalyst·h molC−1. Special attention has been paid to individual and lumped gaseous and liquid product distribution (which have been characterized by gas chromatography, GC × GC/MS and simulated distillation), as well as to catalyst stability, by performing long duration experiments (20 h). An optimum region to maximize both naphtha (C5-11, >40%), and diesel (C12-20, >20%) yields has been established at 250–275 °C and 30 bar for space time values of 2–4 gcatalyst h molC−1. Furthermore, the catalysts have tended to a pseudo-stationary deactivation state after 5 h on stream, where the coke deposited on the spent catalysts is mainly composed of adsorbed bulky oligomers (determined by TPD-N2), with low coke contents ∼1.0–1.5 wt% (determined by TPO).

Low-pressure oligomerization of 1-butene to liquid fuels on HZSM-5 zeolite catalysts: Effect of operating conditions

The capacity of HZSM-5 zeolite (SiO2/Al2O3 ratio=30–280) based catalysts with a hierarchical porous structure has been explored for the oligomerization of 1-butene at low pressure. Catalysts were characterized (structural, physical and acid properties) and tested in a fixed bed reactor under the following conditions: 1.5bar; 175–325°C; space time, 0.5–10gcatalysth(molC)−1; butene partial pressure, 0.375–1.5bar; time on stream, 10h. Results were evaluated with the aim of boosting naphtha (C5-C12=) fraction. A good compromise between conversion (62% in C units contained) and naphtha yield (42%) was achieved by using a HZSM-5 zeolite with SiO2/Al2O3=30 at 275°C and 6gcatalysth(molC)−1, where 23% corresponds to C8-C12= and 19% to C5-C7=, respectively. Furthermore, the hierarchical porous structure facilitated catalysts to tend to a pseudo-stationary deactivation state after 2–3h time on stream, which could be interesting for process scale up.

Deactivation of mitochondrial NADH:ubiquinone oxidoreductase (respiratory complex I): Extrinsically affecting factors

Mitochondrial NADH:ubiquinone oxidoreductase (proton translocating respiratory complex I) serves several essential functions in cell metabolism: it maintains the intramitochondrial NADH/NAD+ ratio, contributes to generation of the proton-motive force, and participates in physiological and/or pathophysiological production of so-called reactive oxygen species. A characteristic feature of complex I is a slow, compared with its catalytic turnover, transformation to its inactive (deactivated) state, a phenomenon operationally called A/D transition. Here we report data on several extrinsic factors affecting deactivation as observed in coupled or uncoupled bovine heart submitochondrial particles. The time course of the strongly temperature-dependent deactivation deviates from first-order kinetics, and this deviation is abolished in the presence of an SH-group-specific reagent. The residual fraction of activity attained upon extensive deactivation shows the same kinetics of NADH oxidation as the fully active enzyme does. The rate of complex I deactivation is only slightly pH dependent within the range of 7.0–8.5 and significantly increases at higher pH. ATP∙(Mg) decreases the rate of complex I deactivation in coupled SMP, and this effect is abolished if the proton-motive force generating ATPase activity of Fo∙F1 is precluded. Taken together, the data show that an equilibrium between the A and D forms of complex I exists. Possible mechanistic aspects of the deactivation process are discussed.

Scorpion toxin inhibits the voltage-gated proton channel using a Zn2+ -like long-range conformational coupling mechanism.

Blocking the voltage-gated proton channel HV 1 is a promising strategy for the treatment of diseases like ischaemia stroke and cancer. However, few HV 1 channel antagonists have been reported. Here, we have identified a novel HV 1 channel antagonist from scorpion venom and have elucidated its action mechanism. HV 1 and NaV channels were heterologously expressed in mammalian cell lines and their currents recorded using whole-cell patch clamp. Site-directed mutagenesis was used to generate mutants. Toxins were recombinantly produced in Escherichia coli. AGAP/W38F-HV 1 interaction was modelled by molecular dynamics simulations. The scorpion toxin AGAP (anti-tumour analgesic peptide) potently inhibited HV 1 currents. One AGAP mutant has reduced NaV channel activity but intact HV 1 activity (AGAP/W38F). AGAP/W38F inhibited HV 1 channel activation by trapping its S4 voltage sensor in a deactivated state and inhibited HV 1 currents with less pH dependence than Zn2+ . Mutation analysis showed that the binding pockets of AGAP/W38F and Zn2+ in HV 1 channel partly overlapped (common sites are His140 and His193). The E153A mutation at the intracellular Coulombic network (ICN) in HV 1 channel markedly reduced AGAP/W38F inhibition, as observed for Zn2+ . Experimental data and MD simulations suggested that AGAP/W38F inhibited HV 1 channel using a Zn2+ -like long-range conformational coupling mechanism. Our results suggest that the Zn2+ binding pocket in HV 1 channel might be a hotspot for modulators and valuable for designing HV 1 channel ligands. Moreover, AGAP/W38F is a useful molecular probe to study HV 1 channel and a lead compound for drug development.