Neighboring Catalytic Sites Are Essential for Electrochemical Dechlorination of 2-Chlorophenol.

The electrocatalytic reduction process is a promising technology for decomposing chlorinated organic pollutants in water but is limited by the lack of low-cost catalysts that can achieve high activity and selectivity. In studying electrochemical dechlorination of 2-chlorophenol (2-CP) in aqueous media, we find that cobalt phthalocyanine molecules supported on carbon nanotubes (CoPc/CNT), which is a highly effective electrocatalyst for breaking the aliphatic C-Cl bonds in 1,2-dichloroethane (DCA) and trichloroethylene (TCE), are completely inactive for reducing the aromatic C-Cl bond in 2-CP. Detailed mechanistic investigation, including volcano plot correlation between dechlorination rate and atomic hydrogen adsorption energy on various transition metal surfaces, kinetic measurements, in situ Raman spectroscopy, and density functional theory calculations, reveals that the reduction of the aromatic C-Cl bond in 2-CP goes through a hydrodechlorination mechanism featuring a bimolecular reaction between adsorbed atomic hydrogen and 2-CP on the catalyst surface, which requires neighboring catalytic sites, whereas the aliphatic C-Cl bonds in DCA and TCE are cleaved by direct electron transfer from the catalyst, which can occur on isolated single sites. This investigation leads to the discovery of metallic Co as a highly selective and active electrocatalyst for 2-CP dechlorination. This work provides new insights into the fundamental chemistry and catalyst design of electrochemical dechlorination reactions for wastewater treatment.

Knockout of syntaxin-4 in 3T3-L1 adipocytes reveals new insight into GLUT4 trafficking and adiponectin secretion.

Adipocytes are key to metabolic regulation, exhibiting insulin-stimulated glucose transport that is underpinned by the insulin-stimulated delivery of glucose transporter type 4 (SLC2A4, also known and hereafter referred to as GLUT4)-containing vesicles to the plasma membrane where they dock and fuse, and increase cell surface GLUT4 levels. Adipocytokines, such as adiponectin, are secreted via a similar mechanism. We used genome editing to knock out syntaxin-4, a protein reported to mediate fusion between GLUT4-containing vesicles and the plasma membrane in 3T3-L1 adipocytes. Syntaxin-4 knockout reduced insulin-stimulated glucose transport and adiponectin secretion by ∼50% and reduced GLUT4 levels. Ectopic expression of haemagglutinin (HA)-tagged GLUT4 conjugated to GFP showed that syntaxin-4-knockout cells retain significant GLUT4 translocation capacity, demonstrating that syntaxin-4 is dispensable for insulin-stimulated GLUT4 translocation. Analysis of recycling kinetics revealed only a modest reduction in the exocytic rate of GLUT4 in knockout cells, and little effect on endocytosis. These analyses demonstrate that syntaxin-4 is not always rate limiting for GLUT4 delivery to the cell surface. In sum, we show that syntaxin-4 knockout results in reduced insulin-stimulated glucose transport, depletion of cellular GLUT4 levels and inhibition of adiponectin secretion but has only modest effects on the translocation capacity of the cells. This article has an associated First Person interview with Hannah L. Black and Rachel Livingstone, joint first authors of the paper.

Solar-Driven CO2 Conversion via Optimized Photothermal Catalysis in a Lotus Pod Structure.

Photothermal CO2 reduction is one of the most promising routes to efficiently utilize solar energy for fuel production at high rates. However, this reaction is currently limited by underdeveloped catalysts with low photothermal conversion efficiency, insufficient exposure of active sites, low active material loading, and high material cost. Herein, we report a potassium-modified carbon-supported cobalt (K+ -Co-C) catalyst mimicking the structure of a lotus pod that addresses these challenges. As a result of the designed lotus-pod structure which features an efficient photothermal C substrate with hierarchical pores, an intimate Co/C interface with covalent bonding, and exposed Co catalytic sites with optimized CO binding strength, the K+ -Co-C catalyst shows a record-high photothermal CO2 hydrogenation rate of 758 mmol gcat -1 h-1 (2871 mmol gCo -1 h-1 ) with a 99.8 % selectivity for CO, three orders of magnitude higher than typical photochemical CO2 reduction reactions. We further demonstrate with this catalyst effective CO2 conversion under natural sunlight one hour before sunset during the winter season, putting forward an important step towards practical solar fuel production.

Synergizing Electron and Heat Flows in Photocatalyst for Direct Conversion of Captured CO2.

We report a ternary hybrid photocatalyst architecture with tailored interfaces that boost the utilization of solar energy for photochemical CO2 reduction by synergizing electron and heat flows in the photocatalyst. The photocatalyst comprises cobalt phthalocyanine (CoPc) molecules assembled on multiwalled carbon nanotubes (CNTs) that are decorated with nearly monodispersed cadmium sulfide quantum dots (CdS QDs). The CdS QDs absorb visible light and generate electron-hole pairs. The CNTs rapidly transfer the photogenerated electrons from CdS to CoPc. The CoPc molecules then selectively reduce CO2 to CO. The interfacial dynamics and catalytic behavior are clearly revealed by time-resolved and in situ vibrational spectroscopies. In addition to serving as electron highways, the black body property of the CNT component can create local photothermal heating to activate amine-captured CO2 , namely carbamates, for direct photochemical conversion without additional energy input.

Aqueous Photoelectrochemical CO2 Reduction to CO and Methanol over a Silicon Photocathode Functionalized with a Cobalt Phthalocyanine Molecular Catalyst.

We report a precious-metal-free molecular catalyst-based photocathode that is active for aqueous CO2 reduction to CO and methanol. The photoelectrode is composed of cobalt phthalocyanine molecules anchored on graphene oxide which is integrated via a (3-aminopropyl)triethoxysilane linker to p-type silicon protected by a thin film of titanium dioxide. The photocathode reduces CO2 to CO with high selectivity at potentials as mild as 0 V versus the reversible hydrogen electrode (vs RHE). Methanol production is observed at an onset potential of -0.36 V vs RHE, and reaches a peak turnover frequency of 0.18 s-1 . To date, this is the only molecular catalyst-based photoelectrode that is active for the six-electron reduction of CO2 to methanol. This work puts forth a strategy for interfacing molecular catalysts to p-type semiconductors and demonstrates state-of-the-art performance for photoelectrochemical CO2 reduction to CO and methanol.

Electrochemical CO2 Reduction in the Presence of Impurities: Influences and Mitigation Strategies.

The electrochemical conversion of waste CO2 into useful fuels and chemical products is a promising approach to reduce CO2 emissions; however, several challenges still remain to be addressed. Thus far, most CO2 reduction studies use pure CO2 as the gas reactant, but CO2 emissions typically contain a number of gas impurities, such as nitrogen oxides, oxygen gas, and sulfur oxides. Gas impurities in CO2 can pose a significant obstacle for efficient CO2 electrolysis because they can influence the reaction and catalyst. This Minireview highlights early examples of CO2 reduction studies using mixed-gas feeds, explores strategies to sustain CO2 reduction in the presence of gas impurities, and discusses their implications for future progress in this emerging field.

Timing, duration, and differential susceptibility to early life adversities and cardiovascular disease risk across the lifespan: Implications for future research.

Early life adversities (ELA), include experiences such as child maltreatment, household dysfunction, bullying, exposure to crime, discrimination, bias, and victimization, and are recognized as social determinants of cardiovascular disease (CVD). Strong evidence shows exposure to ELA directly impacts cardiometabolic risk in adulthood and emerging evidence suggests there may be continuity in ELA's prediction of cardiometabolic risk over the life course. Extant research has primarily relied on a cumulative risk framework to evaluate the relationship between ELA and CVD. In this framework, risk is considered a function of the number of risk factors or adversities that an individual was exposed to across developmental periods. The cumulative risk exposure approach treats developmental periods and types of risk as equivalent and interchangeable. Moreover, cumulative risk models do not lend themselves to investigating the chronicity of adverse exposures or consider individual variation in susceptibility, differential contexts, or adaptive resilience processes, which may modify the impact of ELA on CVD risk. To date, however, alternative models have received comparatively little consideration. Overall, this paper will highlight existing gaps and offer recommendations to address these gaps that would extend our knowledge of the relationship between ELA and CVD development. We focus specifically on the roles of: 1) susceptibility and resilience, 2) timing and developmental context; and 3) variation in risk exposure. We propose to expand current conceptual models to incorporate these factors to better guide research that examines ELA and CVD risk across the life course.

Secukinumab maintains superiority over ustekinumab in clearing skin and improving quality of life in patients with moderate to severe plaque psoriasis: 52-week results from a double-blind phase 3b trial (CLARITY).

BACKGROUND: Secukinumab demonstrated superior efficacy over ustekinumab in the treatment of moderate to severe plaque psoriasis over 16 weeks in the CLARITY study and over 52 weeks in the CLEAR study. OBJECTIVE: To compare the efficacy and safety of secukinumab vs. ustekinumab over 52 weeks in CLARITY. METHODS: Analysis of 52-week data from CLARITY (NCT02826603), a phase 3b study in which patients were randomized to receive secukinumab 300 mg (n = 550) or ustekinumab 45/90 mg (n = 552) per label. RESULTS: At week 52, secukinumab was superior to ustekinumab in the proportion of patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (73.2% vs. 59.8%; odds ratio [OR], 1.84 [95% CI, 1.41-2.41]; P < 0.0001), Investigator's Global Assessment modified 2011 responses of clear (0) or almost clear (1) skin (76.0% vs. 60.2%; OR, 2.12 [95% CI, 1.61-2.79]; P < 0.0001) and Dermatology Life Quality Index response of no effect (0/1) (69.9% vs. 61.2%; P = 0.0028). Proportions of patients with any adverse events were comparable between treatment arms. CONCLUSIONS: This second head-to-head study confirmed the superior efficacy of secukinumab over ustekinumab in skin clearance and quality of life through 52 weeks, with safety comparable to that reported in previous trials. Clinicaltrials.gov identifier: NCT02826603.

Alopecia areata is characterized by expansion of circulating Th2/Tc2/Th22, within the skin-homing and systemic T-cell populations.

BACKGROUND: Characterizing blood profile of alopecia areata (AA) is important not only for treatment advancements, but also for possibly identifying peripheral biomarkers that will eliminate the need for scalp biopsies. We aimed to compare frequencies of skin homing (CLA+ ) vs systemic (CLA- ) "polar" CD4+ and CD8+ and activated T-cell subsets in AA vs atopic dermatitis (AD) and control blood. METHODS: Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+ and CD8+ T cells. Inducible co-stimulator molecule (ICOS) and HLA-DR were used to define mid- and long-term T-cell activation. We compared peripheral blood from 32 moderate-to-severe AA adults with 43 moderate-to-severe AD patients and 30 age-matched controls. RESULTS: AA patients had increased CLA+ /CLA- Th2 (P < .007), CLA+ Tc2 (P = .04), and CLA+ Th22 (P < .05) frequencies than controls. Except of CLA- Tc1 cells (P = .03), IFN-γ levels were mostly similar between AA, AD, and controls (P > .1). ICOS and HLA-DR activation were significantly higher in AA than controls (P < .05). T regulatory cells were significantly decreased in AA patients than controls (P < .01) and were correlated with activated CD8+ T cells and with multiple cytokine subsets (P < .05). While Th2 and Tc2 clustered with disease severity, IFN-γ producing cells were linked with AA duration. CONCLUSIONS: Alopecia areata is accompanied by Th2/Tc2 activation in skin-homing and systemic subsets, correlating with disease severity, while IFN-γ is linked to disease chronicity. These data hint for a possible role of diverse T-cells subsets in disease pathogenesis and emphasize the systemic nature of AA supporting the need for systemic therapeutic strategies in severe patients.

Use of a gelling fibre dressing in complex surgical or chronic wounds: a case series.

OBJECTIVE: To evaluate the safety and performance of a gelling fibre dressing, with respect to wound exudate management, maceration and periwound skin conditions. METHOD: Complex (non-healing) surgical or chronic wounds healing by secondary intention were treated with a gelling fibre dressing (Biosorb, Acelity) as part of a prospective, two-centre case series product evaluation study. Dressing performance was evaluated at each change, and weekly for up to four weeks or until the wound healed, if this was in less than four weeks. The main outcome measure was dressing performance, wound bed and periwound skin condition. RESULTS: A total of 15 patients, aged 26-87 years, were enrolled; 10 patients (66.7%) presented with chronic wounds including venous leg ulcers (VLUs), arterial leg ulcer, one mixed leg ulcer, pressure ulcer (PU), and diabetic foot ulcers (DFUs). The remaining wounds (33.3%) were postsurgical complex wounds healing by secondary intention, located in the upper leg, foot, abdomen, and sacrum. Mean wound area was 22.6±36.6cm2 (range: 1.3-144.0cm2). Treated wounds showed complete granulation in eight (53.0%) wounds, 75% granulation coverage in two (13.3%) wounds, 50% coverage in three (20.3%), and 25% coverage in two (13.3%) wounds. Patients evaluated the dressing effectiveness as 'excellent' or 'very good' in 45% of cases, 'moderate' in 45%, and 'poor' in 10% of cases. Results of Visual Analogue Scale (VAS) showed 70% of patients rated their pain as 'low' and 30% as 'moderate' at dressing removal. Clinicians' evaluation of dressing ability to absorb and retain wound exudate was rated 'excellent' or 'very good' in 80% of cases, and moderate in 20% and poor in 10% of cases. Overall, clinicians' impression of the dressing performance was reported as 'excellent' or 'very good' in 80% of cases and 'moderate' in 20% of cases. No patient had to be removed from the study due to adverse events directly related to the dressing or its performance. CONCLUSION: These clinical findings suggest the new gelling fibre dressing to be safe and effective in wound treatment of complex (non-healing) surgical or chronic wounds, to manage exudate effectively, and to optimise the conditions of wounds healing by secondary intention.

Neuromuscular electrostimulation on lower limb wounds.

The geko™ is a disposable neuromuscular electrostimulation (NMES) device intended to increase blood circulation and promote wound healing in a range of lower limb conditions. The purpose of this case series was to evaluate the therapeutic effect of the geko device on wound healing outcomes over an 8-week period. Thirty patients with non-healing wounds (≥ 12-week duration) of either venous leg ulceration (VLU), mixed leg ulceration (MLU) or diabetic foot ulceration aetiology were recruited from a local outpatient wound clinic in the South Wales area. Over the 8 weeks 2 participants (8%) achieved complete re-epithelialisation between baseline and endpoint. Mean wound surface area decreased (7.6 cm2) and there was an increase of 21% in the mean percentage of granulation tissue in the wound bed. Pain levels reduced in 52% of patients who completed the study, but the extent of oedema reduction was difficult to establish given that 76% of the cohort were treated with a form of compression as part of standard care. The findings support the use of the therapy in patients with painful VLUs and MLUs, but further research needs to be conducted to establish the generalisability of the findings to the wider population of patients living with chronic wounds of differing aetiology in the lower limb.

Alternative routes to the cell surface underpin insulin-regulated membrane trafficking of GLUT4.

Insulin-stimulated delivery of glucose transporters (GLUT4, also known as SLC2A4) from specialized intracellular GLUT4 storage vesicles (GSVs) to the surface of fat and muscle cells is central to whole-body glucose regulation. This translocation and subsequent internalization of GLUT4 back into intracellular stores transits through numerous small membrane-bound compartments (internal GLUT4-containing vesicles; IGVs) including GSVs, but the function of these different compartments is not clear. Cellugyrin (also known as synaptogyrin-2) and sortilin define distinct populations of IGV; sortilin-positive IGVs represent GSVs, but the function of cellugyrin-containing IGVs is unknown. Here, we demonstrate a role for cellugyrin in intracellular sequestration of GLUT4 in HeLa cells and have used a proximity ligation assay to follow changes in pairwise associations between cellugyrin, sortilin, GLUT4 and membrane trafficking machinery following insulin-stimulation of 3T3-L1 adipoctyes. Our data suggest that insulin stimulates traffic from cellugyrin-containing to sortilin-containing membranes, and that cellugyrin-containing IGVs provide an insulin-sensitive reservoir to replenish GSVs following insulin-stimulated exocytosis of GLUT4. Furthermore, our data support the existence of a pathway from cellugyrin-containing membranes to the surface of 3T3-L1 adipocytes that bypasses GSVs under basal conditions, and that insulin diverts traffic away from this into GSVs.

SNARE phosphorylation: a control mechanism for insulin-stimulated glucose transport and other regulated exocytic events.

Trafficking within eukaryotic cells is a complex and highly regulated process; events such as recycling of plasma membrane receptors, formation of multivesicular bodies, regulated release of hormones and delivery of proteins to membranes all require directionality and specificity. The underpinning processes, including cargo selection, membrane fusion, trafficking flow and timing, are controlled by a variety of molecular mechanisms and engage multiple families of lipids and proteins. Here, we will focus on control of trafficking processes via the action of the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) family of proteins, in particular their regulation by phosphorylation. We will describe how these proteins are controlled in a range of regulated trafficking events, with particular emphasis on the insulin-stimulated delivery of glucose transporters to the surface of adipose and muscle cells. Here, we focus on a few examples of SNARE phosphorylation which exemplify distinct ways in which SNARE machinery phosphorylation may regulate membrane fusion.

Arabidopsis Sec1/Munc18 protein SEC11 is a competitive and dynamic modulator of SNARE binding and SYP121-dependent vesicle traffic.

The Arabidopsis thaliana Qa-SNARE SYP121 (=SYR1/PEN1) drives vesicle traffic at the plasma membrane of cells throughout the vegetative plant. It facilitates responses to drought, to the water stress hormone abscisic acid, and to pathogen attack, and it is essential for recovery from so-called programmed stomatal closure. How SYP121-mediated traffic is regulated is largely unknown, although it is thought to depend on formation of a fusion-competent SNARE core complex with the cognate partners VAMP721 and SNAP33. Like SYP121, the Arabidopsis Sec1/Munc18 protein SEC11 (=KEULE) is expressed throughout the vegetative plant. We find that SEC11 binds directly with SYP121 both in vitro and in vivo to affect secretory traffic. Binding occurs through two distinct modes, one requiring only SEC11 and SYP121 and the second dependent on assembly of a complex with VAMP721 and SNAP33. SEC11 competes dynamically for SYP121 binding with SNAP33 and VAMP721, and this competition is predicated by SEC11 association with the N terminus of SYP121. These and additional data are consistent with a model in which SYP121-mediated vesicle fusion is regulated by an unusual "handshaking" mechanism of concerted SEC11 debinding and rebinding. They also implicate one or more factors that alter or disrupt SEC11 association with the SYP121 N terminus as an early step initiating SNARE complex formation.

Endosomal sorting of GLUT4 and Gap1 is conserved between yeast and insulin-sensitive cells.

The insulin-regulated trafficking of the facilitative glucose transporter GLUT4 in human fat and muscle cells and the nitrogen-regulated trafficking of the general amino acid permease Gap1 in the yeast Saccharomyces cerevisiae share several common features: Both Gap1 and GLUT4 are nutrient transporters that are mobilised to the cell surface from an intracellular store in response to an environmental cue; both are polytopic membrane proteins harbouring amino acid targeting motifs in their C-terminal tails that are required for their regulated trafficking; ubiquitylation of both Gap1 and GLUT4 plays an important role in their regulated trafficking, as do the ubiquitin-binding GGA (Golgi-localised, γ-ear-containing, ARF-binding) adaptor proteins. Here, we find that when expressed heterologously in yeast, human GLUT4 is subject to nitrogen-regulated trafficking in an ubiquitin-dependent manner similar to Gap1. In addition, by expressing a GLUT4/Gap1 chimeric protein in adipocytes we show that the carboxy-tail of Gap1 directs intracellular sequestration and insulin-regulated trafficking in adipocytes. These findings demonstrate that the trafficking signals and their cognate molecular regulatory machinery that mediate regulated exocytosis of membrane proteins are conserved across evolution.

The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.

Severe congenital neutropenia as well as primary myelofibrosis are rare in infancy. Elucidation of the underlying mechanism is important because it extends our understanding of the more common adult forms of these disorders. Using homozygosity mapping followed by exome sequencing, we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia, which was refractory to granulocyte CSF, from defective platelet aggregation and myelofibrosis. The mutation segregated in the families, was not present in controls, affected a highly conserved codon, and apparently destabilized the Vps45 protein, which was reduced in the patients' leukocytes. Introduction of the corresponding mutation into yeast resulted in reduced cellular levels of Vps45 and also of the cognate syntaxin Tlg2, which is required for membrane traffic through the endosomal system. A defect in the endosomal-lysosomal pathway, the homologous system in humans, was suggested by the absence of lysosomes in the patients' fibroblasts and by the depletion of α granules in their platelets. Importantly, accelerated apoptosis was observed in the patients' neutrophils and bone marrow. This is the first report of a Vps45-related disease in humans, manifesting by neutropenia, thrombasthenia, myelofibrosis, and progressive bone marrow failure.

Studies of the regulated assembly of SNARE complexes in adipocytes.

Insulin plays a fundamental role in whole-body glucose homeostasis. Central to this is the hormone's ability to rapidly stimulate the rate of glucose transport into adipocytes and muscle cells [1]. Upon binding its receptor, insulin stimulates an intracellular signalling cascade that culminates in redistribution of glucose transporter proteins, specifically the GLUT4 isoform, from intracellular stores to the plasma membrane, a process termed 'translocation' [1,2]. This is an example of regulated membrane trafficking [3], a process that also underpins other aspects of physiology in a number of specialized cell types, for example neurotransmission in brain/neurons and release of hormone-containing vesicles from specialized secretory cells such as those found in pancreatic islets. These processes invoke a number of intriguing biological questions as follows. How is the machinery involved in these membrane trafficking events mobilized in response to a stimulus? How do the signalling pathways that detect the external stimulus interface with the trafficking machinery? Recent studies of insulin-stimulated GLUT4 translocation offer insight into such questions. In the present paper, we have reviewed these studies and draw parallels with other regulated trafficking systems.

Application of the PAPERS Grading Criteria Within a Rapid Evidence Review to Determine the Psychometric and Pragmatic Properties of Patient Empowerment Tools.

Self-management of long-term conditions requires health professionals to understand and develop capabilities that empower the population they serve. A rapid evidence review was undertaken to assess the current evidence based on the psychometric properties of patient empowerment tools. MEDLINE was searched, and data were extracted for each publication and scored using a modified Psychometric and Pragmatic Evidence Rating Scale (PAPERS) evidence rating scale. The results were grouped into the following domains: (a) health literacy; (b) patient activation; (c) long-term conditions; (d) self-management needs and behaviors. A full-text review of 65 publications led to the inclusion of 29 primary studies. The highest scoring tools were selected with respect to performance for each domain: (a) Newest Vital Sign and the Brief Health Literacy Screen; (b) Consumer Health Activation Index and PAM-13; (c) LTCQ and LTCQ8; and (d) SEMCD and Patient Enablement Instrument. PAPERS was a useful tool in determining the generalizability, validity, and reliability of these patient empowerment tools. However, further research is required to establish whether an individual's health literacy status influences patient empowerment tool outcomes.

Dissecting cell death pathways in fed-batch bioreactors.

Chinese hamster ovary (CHO) cells are widely used for production of biologics including therapeutic monoclonal antibodies. Cell death in CHO cells is a significant factor in biopharmaceutical production, impacting both product yield and quality. Apoptosis has previously been described as the major form of cell death occurring in CHO cells in bioreactors. However, these studies were undertaken when less was known about non-apoptotic cell death pathways. Here, we report the occurrence of non-apoptotic cell death in an industrial antibody-producing CHO cell line during fed-batch culture. Under standard conditions, crucial markers of apoptosis were not observed despite a decrease in viability towards the end of the culture; only by increasing stress within the system did we observe caspase activation indicative of apoptosis. In contrast, markers of parthanatos and ferroptosis were observed during standard fed-batch culture, indicating that these non-apoptotic cell death pathways contribute to viability loss under these conditions. These findings pave the way for targeting non-conventional cell death pathways to improve viability and biologic production in CHO cells.