The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

Characterizing Ion-Polymer Interactions in Aqueous Environment with Electric Fields.

Polymers make the basis of highly tunable materials that could be designed and optimized for metal recovery from aqueous environments. While experimental studies show that this approach has potential, it suffers from a limited knowledge of the detailed molecular interaction between polymers and target metal ions. Here, we propose to calculate intrinsic electric fields from polarizable force field molecular dynamics simulations to characterize the driving force behind Eu3+ motion in the presence of poly(ethylenimine methylenephosphonate), a specifically designed metal chelating polymer. Focusing on the metal chelation initiation step (i.e., before binding), we can rationalize the role of each molecule on ion dynamics by projecting these electric fields along the direction of ion motion. We find that the polymer functional groups act indirectly, and the polymer-metal ion interaction is actually mediated by water. This result is consistent with the experimental observation that metal sequestration by these polymers is entropically driven. This study suggests that electric field calculations can help the design of metal chelating polymers, for example, by seeking to optimize polymer-solvent interactions rather than polymer-ion interactions.

Enzyme-Triggered Chemodynamic Therapy via a Peptide-H2 S Donor Conjugate with Complexed Fe2.

Inducing high levels of reactive oxygen species (ROS) inside tumor cells is a cancer therapy method termed chemodynamic therapy (CDT). Relying on delivery of Fenton reaction promoters such as Fe2+ , CDT takes advantage of overproduced ROS in the tumor microenvironment. We developed a peptide-H2 S donor conjugate, complexed with Fe2+ , termed AAN-PTC-Fe2+ . The AAN tripeptide was specifically cleaved by legumain, an enzyme overexpressed in glioma cells, to release carbonyl sulfide (COS). Hydrolysis of COS by carbonic anhydrase formed H2 S, an inhibitor of catalase, an enzyme that detoxifies H2 O2 . Fe2+ and H2 S together increased intracellular ROS levels and decreased viability in C6 glioma cells compared with controls lacking either Fe2+ , the AAN sequence, or the ability to generate H2 S. AAN-PTC-Fe2+ performed better than temezolimide while exhibiting no cytotoxicity toward H9C2 cardiomyocytes. This study provides an H2 S-amplified, enzyme-responsive platform for synergistic cancer treatment.

Exploring the role of polymer hydrophobicity in polymer-metal binding thermodynamics.

Metal-chelating polymers play a key role in rare-earth element (REE) extraction and separation processes. Often, these processes occur in aqueous solution, but the interactions among water, polymer, and REE are largely under-investigated in these applications. To probe these interactions, we synthesized a series of poly(amino acid acrylamide)s with systematically varied hydrophobicity around a consistent chelating group (carboxylate). We then measured the ΔH of Eu3+ chelation as a function of temperature across the polymer series using isothermal titration calorimetry (ITC) to give the change in heat capacity (ΔCP). We observed an order of magnitude variation in ΔCP (39-471 J mol1 K-1) with changes in the hydrophobicity of the polymer. Atomistic simulations of the polymer-metal-water interactions revealed greater Eu3+ and polymer desolvation when binding to the more hydrophobic polymers. These combined experimental and computational results demonstrate that metal binding in aqueous solution can be modulated not only by directly modifying the chelating groups, but also by altering the molecular environment around the chelating site, thus suggesting a new design principle for developing increasingly effective metal-chelating materials.

SARS-CoV-2 in dialysis patients and the impact of vaccination.

BACKGROUND: In centre haemodialysis (ICHD) patients have been identified as high risk of contracting Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection due to frequent healthcare contact and poor innate and adaptive immunity. Our ICHD patients were offered immunisation from January 2021. We aimed to assess outcomes following SARS-CoV-2 infection and report on the effect of vaccination in our ICHD patients. METHODS: Demographics, SARS-CoV-2 status, hospitalisation, mortality and vaccination status were analysed. From 11th March 2020 to 31st March 2021, 662 ICHD patients were included in the study and these patients were then followed up until 31st August 2021. RESULTS: SARS-CoV-2 infection occurred in 28.4% with 51.1% of them requiring hospitalisation in contrast to community infection rates of 13.9% and hospitalisation of 9.0%. 28-day mortality was 19.2% in comparison to 1.9% of the community. Mortality increased to 34.0% over the study period. Mortality over the study period was 1.8 times in infected patients (HR 1.81 (1.32-2.49) P < 0.001) despite adjustment for age, gender and ethnicity. 91.3% of ICHD patients have now received both doses of SARS-CoV-2 vaccinations. CONCLUSIONS: ICHD patients are at increased risk of acquiring SARS-CoV-2, with increased rates of hospitalisation and mortality. The increased mortality extends well beyond the 28 days post-infection and persists in those who have recovered. Peaks and troughs in infection rates mirrored community trends. Preliminary data indicates that the SARS-CoV-2 vaccination provides protection to ICHD patients, with ICHD case rates now comparable to that of the local population.

[DGPPN pilot study on the implementation of the S3 guideline "Prevention of coercion: prevention and therapy of aggressive behavior in adults"]. / DGPPN-Pilotstudie zur Implementierung der S3-Leitlinie "Verhinderung von Zwang: Prävention und Therapie aggressiven Verhaltens bei Erwachsenen".

OBJECTIVE: To investigate whether implementation recommendations derived from the German guidelines "Prevention of coercion" can be implemented on acute psychiatric wards by means of implementation consultants into ward work and if this contributes to an increased level of adherence to guideline intervention recommendations approved by the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde)? MATERIAL AND METHODS: Two medical or nursing experts advised ward teams on the implementation of three individually selected recommendations from the guidelines in a structured consulting process over 6 months. The degree of implementation of the recommendations was assessed before and after the intervention by the ward teams together with the implementation consultants using a tool developed for this purpose (PreVCo rating tool). RESULTS: A total of five wards responsible for compulsorily admitted patients took part in the pilot study; three of them completed the intervention. On all three wards, implementation of the guideline recommendations improved for both selected and unselected recommendations. The strategy of using implementation consultants as well as the application of the PreVCo rating tool were well accepted and considered feasible by both the treatment teams and the implementation consultants. CONCLUSION: This pilot study showed that an implementation of recommendations on psychiatric wards derived from the German guidelines "Prevention of coercion" supported by implementation consultants is feasible, well acceptable among treatment teams and can lead to positive changes. The sample of five wards with diverse patient profiles was convincing. The efficacy in terms of reduction of coercive measures is currently being investigated in a randomized controlled trial on 55 psychiatric wards in different parts of Germany, with an intervention based on this pilot study.

Effect of Copolymer Structure on Rare-Earth-Element Chelation Thermodynamics.

Rare-earth elements (REEs) are crucial to modern technology, leading to a high demand for materials capable of REE extraction and purification. Metal-chelating polymers (e.g., polycarboxylic acids, polyamines, and others) are particularly useful in these applications due to their synthetic accessibility and high selectivity. Copolymers with varied mole fractions of acrylic acid and methyl acrylate are synthesized and isothermal titration calorimetry (ITC) to measure the thermodynamics of REE binding for each material is used. Across a series of copolymer compositions, entropically driven binding thermodynamics (∆G, ∆H, and ∆S) that appear to be independent of χAcrylic Acid  are found. ITC stoichiometry data reveal that each copolymer requires between four and five repeat units to bind each REE. These data suggest that alterations in the copolymer structure do not affect the overall binding thermodynamics of REEs to these copolymers.

Primary dementia care based on the individual needs of the patient: study protocol of the cluster randomized controlled trial, DemStepCare.

BACKGROUND: Most people with dementia (PwD) are cared for at home, with general practitioners (GPs) playing a key part in the treatment. However, primary dementia care suffers from a number of shortcomings: Often, diagnoses are made too late and therapies by GPs do not follow the guidelines. In cases of acute crises, PwD are too often admitted to hospital with adverse effects on the further course of the disease. The aim of this study is to implement and evaluate a new GP-based, complex dementia care model, DemStepCare. DemStepCare aims to ensure demand-oriented, stepped care for PwD and their caregivers. METHODS/DESIGN: In a cluster randomized controlled trial, the care of PwD receiving a complex intervention, where the GP is supported by a multi-professional team, is compared to (slightly expanded) usual care. GPs are clustered by GP practice, with 120 GP practices participating in total. GP practices are randomized to an intervention or a control group. 800 PwD are to be included per group. Recruitment takes place in Rhineland-Palatinate, Germany. In addition, a second control group with at least 800 PwD will be formed using aggregated routine data from German health insurance companies. The intervention comprises the training of GPs, case management including repeated risk assessment of the patients' care situation, the demand-oriented service of an outpatient clinic, an electronic case record, external medication analyses and a link to regional support services. The primary aims of the intervention are to positively influence the quality of life for PwD, to reduce the caregivers' burden, and to reduce the days spent in hospital. Secondary endpoints address medication adequacy and GPs' attitudes and sensitivity towards dementia, among others. DISCUSSION: The GP-based dementia care model DemStepCare is intended to combine a number of promising interventions to provide a complex, stepped intervention that follows the individual needs of PwD and their caregivers. Its effectiveness and feasibility will be assessed in a formative and a summative evaluation. TRIAL REGISTRATION: German Register of Clinical Trials (Deutsches Register Klinischer Studien, DRKS), DRKS00023560 . Registered 13 November 2020 - Retrospectively registered. HTML&TRIAL_ID=DRKS00023560.

Isothermal titration calorimetry: practical approaches and current applications in soft matter.

Isothermal Titration Calorimetry (ITC) elucidates the thermodynamic profile (ΔH, ΔS, ΔG, Ka, and stoichiometry) of binding and dissociation reactions in solution. While ITC has primarily been used to investigate the thermodynamics of interactions between biological macromolecules and small molecules, it has become increasingly common for measuring binding interactions between synthetic polymers and small molecules, ions, or nanoparticles. This tutorial review describes applications of ITC in studying synthetic macromolecules and provides experimental guidelines for performing ITC experiments. We also highlight specific examples of using ITC to study soft matter, then discuss the limitations and the future of ITC in this field.

Normal-phase versus reversed-phase thin-layer chromatography (TLC) to monitor oxidized phosphatidylcholines by TLC/mass spectrometry.

RATIONALE: Normal-phase thin-layer chromatography (NP-TLC) is an established method for the separation of all major phospholipid classes according to the different polarities of the head groups. In contrast, reversed-phase (RP)-TLC is much less frequently used for this purpose. This study aimed to compare the NP and the RP approach regarding their separation potential of phospholipid oxidation products. METHODS: Commercially available 1-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC) (PC 16:0/18:1) and 1-palmitoyl-2-linoleoyl-sn-phosphatidylcholine (PLPC) (PC 16:0/18:2) were oxidized by NaMnO4 . Oxidation products were subsequently separated by NP- and RP-TLC and analyzed by electrospray ionization mass spectrometry. RESULTS: In comparison with NP-TLC, RP-TLC was clearly superior regarding the separation of oxidation products of phospholipids. RP-TLC enabled the separation not only of primary oxidation products of POPC such as alcohols and ketones but also of secondary oxidation products. Furthermore some oxidation products, such as aldehydes, were only detectable by ESI after RP-TLC but not after NP-TLC. CONCLUSIONS: RP-TLC is the method of choice to characterize oxidized PL such as oxidized phosphatidylcholines.

High-resolution neutron depolarization microscopy of the ferromagnetic transitions in Ni3Al and HgCr2Se4 under pressure.

We performed neutron imaging of ferromagnetic transitions in Ni3Al and HgCr2Se4 crystals. These neutron depolarization measurements revealed bulk magnetic inhomogeneities in the ferromagnetic transition temperature with spatial resolution of about 100 µm. To obtain such spatial resolution, we employed a novel neutron microscope equipped with Wolter mirrors as a neutron image-forming lens and a focusing neutron guide as a neutron condenser lens. The images of Ni3Al show that the sample does not homogeneously go through the ferromagnetic transition; the improved resolution allowed us to identify a distribution of small grains with slightly off-stoichiometric composition. Additionally, neutron depolarization imaging experiments on the chrome spinel, HgCr2Se4, under pressures up to 15 kbar highlight the advantages of the new technique especially for small samples or sample environments with restricted sample space. The improved spatial resolution enables one to observe domain formation in the sample while decreasing the acquisition time despite having a bulky pressure cell in the beam.

Spatial Representativeness Error in the Ground-Level Observation Networks for Black Carbon Radiation Absorption.

There is high uncertainty in the direct radiative forcing of black carbon (BC), an aerosol that strongly absorbs solar radiation. The observation-constrained estimate, which is several times larger than the bottom-up estimate, is influenced by the spatial representativeness error due to the mesoscale inhomogeneity of the aerosol fields and the relatively low resolution of global chemistry-transport models. Here we evaluated the spatial representativeness error for two widely used observational networks (AErosol RObotic NETwork and Global Atmosphere Watch) by downscaling the geospatial grid in a global model of BC aerosol absorption optical depth to 0.1° × 0.1°. Comparing the models at a spatial resolution of 2° × 2° with BC aerosol absorption at AErosol RObotic NETwork sites (which are commonly located near emission hot spots) tends to cause a global spatial representativeness error of 30%, as a positive bias for the current top-down estimate of global BC direct radiative forcing. By contrast, the global spatial representativeness error will be 7% for the Global Atmosphere Watch network, because the sites are located in such a way that there are almost an equal number of sites with positive or negative representativeness error.

[Low-Intensity Cognitive Behavioral Therapy (LI-CBT) - An Introduction in Concepts and Framework]. / Low-Intensity Cognitive Behavioral Therapy (LI-CBT) ­ Eine Einführung in Konzepte und Rahmenbedingungen.

Low-intensity cognitive behavioural therapy (LI-CBT) depicts interventions that aim at increasing access to evidence-based psychological therapies. This is achieved by (1) reducing the amount of time in which the practitioner is in contact with individual patients, (2) using practitioners that have been specifically trained to deliver low intensity interventions and without any prior formal health professional qualifications and (3) use of interventions with varying intensity. Stepped care and collaborative care constitute the organizational frame to deliver low-intensity interventions. Whereas large-scale research and health service projects abroad are focussing on LI-CBT, research in German is lagging far behind. Particularly in the light of the growing demands and utilization of mental health care as well as governmental claims to develop and evaluate new forms of providing mental health services, LI-CBT represents a promising approach.

The temporal window of ecological adaptation in postglacial lakes: a comparison of head morphology, trophic position and habitat use in Norwegian threespine stickleback populations.

BACKGROUND: Studying how trophic traits and niche use are related in natural populations is important in order to understand adaptation and specialization. Here, we describe trophic trait diversity in twenty-five Norwegian freshwater threespine stickleback populations and their putative marine ancestor, and relate trait differences to postglacial lake age. By studying lakes of different ages, depths and distance to the sea we examine key environmental variables that may predict adaptation in trophic position and habitat use. We measured trophic traits including geometric landmarks that integrated variation in head shape as well as gillraker length and number. Trophic position (Tpos) and niche use (α) were estimated from stable isotopes (δ(13)C, δ(15)N). A comparison of head shape was also made with two North American benthic-limnetic species pairs. RESULTS: We found that head shape differed between marine and freshwater sticklebacks, with marine sticklebacks having more upturned mouths, smaller eyes, larger opercula and deeper heads. Size-adjusted gillraker lengths were larger in marine than in freshwater stickleback. Norwegian sticklebacks were compared on the same head shape axis as the one differentiating the benthic-limnetic North American threespine stickleback species pairs. Here, Norwegian freshwater sticklebacks with a more "limnetic head shape" had more and longer gillrakers than sticklebacks with "benthic head shape". The "limnetic morph" was positively associated with deeper lakes. Populations differed in α (mean ± sd: 0.76 ± 0.29) and Tpos (3.47 ± 0.27), where α increased with gillraker length. Larger fish had a higher Tpos than smaller fish. Compared to the ecologically divergent stickleback species pairs and solitary lake populations in North America, Norwegian freshwater sticklebacks had similar range in Tpos and α values, but much less trait divergences. CONCLUSIONS: Our results showed trait divergences between threespine stickleback in marine and freshwater environments. Freshwater populations diverged in trophic ecology and trophic traits, but trophic ecology was not related to the elapsed time in freshwater. Norwegian sticklebacks used the same niches as the ecologically divergent North American stickleback species pairs. However, as trophic trait divergences were smaller, and not strongly associated with the ecological niche, ecological adaptations along the benthic-limnetic axis were less developed in Norwegian sticklebacks.

Evaluation of absolute form measurements using a tilted-wave interferometer.

Tilted-wave interferometry is a promising measurement technique for the highly accurate measurement of aspheres and freeform surfaces. However, the interferometric fringe evaluation of the sub-apertures causes unknown patch offsets, which currently prevent this measurement technique from providing absolute measurements. Simple strategies, such as constructing differences of optical path length differences (OPDs) or ignoring the piston parameter, can diminish the accuracy resulting from the absolute form measurement. Additional information is needed instead; in this paper, the required accuracy of such information is explored in virtual experiments. Our simulation study reveals that, when one absolute OPD is known within a range of 500 nm, the accuracy of the final measurement result is significantly enhanced.

Increase in African dust flux at the onset of commercial agriculture in the Sahel region.

The Sahara Desert is the largest source of mineral dust in the world. Emissions of African dust increased sharply in the early 1970s (ref. 2), a change that has been attributed mainly to drought in the Sahara/Sahel region caused by changes in the global distribution of sea surface temperature. The human contribution to land degradation and dust mobilization in this region remains poorly understood, owing to the paucity of data that would allow the identification of long-term trends in desertification. Direct measurements of airborne African dust concentrations only became available in the mid-1960s from a station on Barbados and subsequently from satellite imagery since the late 1970s: they do not cover the onset of commercial agriculture in the Sahel region approximately 170 years ago. Here we construct a 3,200-year record of dust deposition off northwest Africa by investigating the chemistry and grain-size distribution of terrigenous sediments deposited at a marine site located directly under the West African dust plume. With the help of our dust record and a proxy record for West African precipitation we find that, on the century scale, dust deposition is related to precipitation in tropical West Africa until the seventeenth century. At the beginning of the nineteenth century, a sharp increase in dust deposition parallels the advent of commercial agriculture in the Sahel region. Our findings suggest that human-induced dust emissions from the Sahel region have contributed to the atmospheric dust load for about 200 years.

Is adherence therapy an effective adjunct treatment for patients with schizophrenia spectrum disorders? A systematic review and meta-analysis.

BACKGROUND: Poor adherence to medication in schizophrenia spectrum disorders leads to inadequate symptom control. Adherence therapy (AT) is an intervention that seeks to reduce patients' psychiatric symptoms by enhancing treatment adherence. We aimed to systematically review the trial evidence of the effectiveness of AT on improving clinical outcomes in these patients. METHOD: Systematic review and meta-analysis of published RCTs. We included studies testing AT as an adjunct intervention against treatment as usual or a comparator intervention in the general adult psychiatric population. The primary outcome of interest was improvement in psychiatric symptoms. RESULTS: We included six studies testing AT in schizophrenia spectrum disorders published since 2006. A meta-analysis showed AT significantly reduced psychiatric symptoms compared to usual treatment over a follow-up period of less than 1 year. We found no significant effects of AT on patients' adherence and adherence attitudes. CONCLUSIONS: AT is an effective adjunctive treatment for people with schizophrenia spectrum disorders. PROSPERO: CRD42015016779.

Application of Ionic Liquids in Pot-in-Pot Reactions.

Pot-in-pot reactions are designed such that two reaction media (solvents, catalysts and reagents) are isolated from each other by a polymeric membrane similar to matryoshka dolls (Russian nesting dolls). The first reaction is allowed to progress to completion before triggering the second reaction in which all necessary solvents, reactants, or catalysts are placed except for the starting reagent for the target reaction. With the appropriate trigger, in most cases unidirectional flux, the product of the first reaction is introduced to the second medium allowing a second transformation in the same glass reaction pot--albeit separated by a polymeric membrane. The basis of these reaction systems is the controlled selective flux of one reagent over the other components of the first reaction while maintaining steady-state catalyst concentration in the first "pot". The use of ionic liquids as tools to control chemical potential across the polymeric membranes making the first pot is discussed based on standard diffusion models--Fickian and Payne's models. Besides chemical potential, use of ionic liquids as delivery agent for a small amount of a solvent that slightly swells the polymeric membrane, hence increasing flux, is highlighted. This review highlights the critical role ionic liquids play in site-isolation of multiple catalyzed reactions in a standard pot-in-pot reaction.

Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik-Fields Reaction.

Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer-Irani reaction installs the phosphonic acid groups on well-defined, RAFT-generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three-component Kabachnik-Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers.

Results of the HepZero study comparing heparin-grafted membrane and standard care show that heparin-grafted dialyzer is safe and easy to use for heparin-free dialysis.

Heparin is used to prevent clotting during hemodialysis, but heparin-free hemodialysis is sometimes needed to decrease the risk of bleeding. The HepZero study is a randomized, multicenter international controlled open-label trial comparing no-heparin hemodialysis strategies designed to assess non-inferiority of a heparin grafted dialyzer (NCT01318486). A total of 251 maintenance hemodialysis patients at increased risk of hemorrhage were randomly allocated for up to three heparin-free hemodialysis sessions using a heparin-grafted dialyzer or the center standard-of-care consisting of regular saline flushes or pre-dilution. The first heparin-free hemodialysis session was considered successful when there was neither complete occlusion of air traps or dialyzer, nor additional saline flushes, changes of dialyzer or bloodlines, or premature termination. The current standard-of-care resulted in high failure rates (50%). The success rate in the heparin-grafted membrane arm was significantly higher than in the control group (68.5% versus 50.4%), which was consistent for both standard-of-care modalities. The absolute difference between the heparin-grafted membrane and the controls was 18.2%, with a lower bound of the 90% confidence interval equal to plus 7.9%. The hypothesis of the non-inferiority at the minus 15% level was accepted, although superiority at the plus 15% level was not reached. Thus, use of a heparin-grafted membrane is a safe, helpful, and easy-to-use method for heparin-free hemodialysis in patients at increased risk of hemorrhage.