julilili42/papers huggingface dataset:
Evaluation of the drug-drug interaction potential of the novel hepatitis B and D virus entry inhibitor bulevirtide at OATP1B in healthy volunteers
2023-04-06

Introduction: Bulevirtide is a first-in-class antiviral drug to treat chronic hepatitis B/D. We investigated the drug-drug interaction potential and pharmacokinetics of high-dose subcutaneous bulevirtide (5 mg twice daily) with organic anion transporting polypeptide 1B1 (OATP1B1) and cytochrome P450 (CYP) 3A4. Methods: This was a single-center, open-label, fixed-sequence drug-drug interaction trial in 19 healthy volunteers. Before and at bulevirtide steady state, participants ingested a single 40 mg dose of pravastatin. A midazolam microdose was applied to quantify CYP3A4 activity. Results: At bulevirtide steady state, pravastatin area under the concentration-time curve (AUC 0–∞ ) increased 1.32-fold (90% CI 1.08-1.61). The 5 mg bulevirtide twice-daily treatment resulted in a mean AUC 0-12 of 1210 h*ng/ml (95% CI 1040-1408) and remained essentially unchanged under the influence of pravastatin. CYP3A4 activity did not change to a clinically relevant extent. As expected, total bile acids increased substantially (35-fold) compared to baseline during bulevirtide treatment. All study medication was well tolerated. Discussion: The study demonstrated that high-dose bulevirtide inhibited OATP1B-mediated hepatic uptake of the marker substrate pravastatin but the extent is considered clinically not relevant. Changes in CYP3A4 activity were also not clinically relevant. In conclusion, this study suggests that OATP1B substrate drugs as well as CYP3A4 substrates may safely be used without dose adjustment in patients treated with bulevirtide. However, in patients using high statin doses and where concomitant factors potentially further increase statin exposure, caution may be required when using bulevirtide.
In plantaexploitation of leaf apoplastic compounds: a window of opportunity for spatiotemporal studies of apoplastic metabolites, hormones and physiology
2023-04-06

Abstract Processes in the leaf apoplast are relevant for development, cell wall rheological properties, plant nutrition, sink-source portioning, microbe-host plant-interactions or intercellular information exchange and signaling and are therefore regulated or influenced by the composition of the leaf apoplastic solute. In contrast to the traditional methods for the extraction of apoplastic solutes that are more or less destructive, we propose a new method that allows extraction of leaf apoplastic solutes (i) non-invasively and, thus, (ii) over time. Moreover, the method has (iii) a high spatial resolution that allows identification of solute-microdomains in the leaf apoplast. The method was established for Arabidopsis thaliana and Vicia faba leaves but should also be applicable to other plants species with similar leaf morphologies. It is based on the infiltration of an aqueous extraction solution into the apoplast followed by its recovery seconds later, both through the stomata. By this, the apoplast (and its solutes) of an identical leaf can be sampled on successive days with negligible symplastic contamination. A spatiotemporal mapping of leaf apoplastic ion and metabolite patterns within the identical leaf opens a window of opportunity for understanding apoplast biology. As for example, the existence of apoplastic abscisic acid gradients within a leaf in response to salinity was witnessed in this study, as was the unsuspected accumulation of kaempferol glycosides in the leaf apoplast. The presented method is relevant for plant developmental biologists, phytopathologists, plant physiologists, plant nutritionists and others that need to integrate apoplast biology into their research approaches.
Cognitive Stress Regulation in Schizophrenia Patients and Healthy Individuals: Brain and Behavior
2023-04-06

Stress is an important factor in the development, triggering, and maintenance of psychotic symptoms. Still, little is known about the neural correlates of cognitively regulating stressful events in schizophrenia. The current study aimed at investigating the cognitive down-regulation of negative, stressful reactions during a neuroimaging psychosocial stress paradigm (non-regulated stress versus cognitively regulated stress). In a randomized, repeated-measures within-subject design, we assessed subjective reactions and neural activation in schizophrenia patients (SZP) and matched healthy controls in a neuroimaging psychosocial stress paradigm. In general, SZP exhibited an increased anticipation of stress compared to controls (p = 0.020). During non-regulated stress, SZP showed increased negative affect (p = 0.033) and stronger activation of the left parietal operculum/posterior insula (p &lt; 0.001) and right inferior frontal gyrus/anterior insula (p = 0.005) than controls. Contrarily, stress regulation compared to non-regulated stress led to increased subjective reactions in controls (p = 0.003) but less deactivation in SZP in the ventral anterior cingulate cortex (p = 0.027). Our data demonstrate stronger reactions to and anticipation of stress in patients and difficulties with cognitive stress regulation in both groups. Considering the strong association between mental health and stress, the investigation of cognitive regulation in individuals vulnerable to stress, including SZP, has crucial implications for improving stress intervention trainings.
Back to Direct Style: Typed and Tight
2023-04-06

Translating programs into continuation-passing style is a well-studied tool to explicitly deal with the control structure of programs. This is useful, for example, for compilation. In a typed setting, there also is a logical interpretation of such a translation as an embedding of classical logic into intuitionistic logic. A naturally arising question is whether there is an inverse translation back to direct style. The answer to this question depends on how the continuation-passing translation is defined and on the domain of the inverse translation. In general, translating programs from continuation-passing style back to direct style requires the use of control operators to account for the use of continuations in non-trivial ways. We present two languages, one in direct style and one in continuation-passing style. Both languages are typed and equipped with an abstract machine semantics. Moreover, both languages allow for non-trivial control flow. We further present a translation to continuation-passing style and a translation back to direct style. We show that both translations are type-preserving and also preserve semantics in a very precise way giving an operational correspondence between the two languages. Moreover, we show that the compositions of the translations are well-behaved. In particular, they are syntactic one-sided inverses on the full language and full syntactic inverses when restricted to trivial control flow.
“Look straight ahead”—A new test to diagnose spatial neglect by computed tomography
2023-04-06

Spatial neglect is the dominant behavioral disorder after right hemisphere brain lesions. Reliabel diagnosis by formal neuropsychological testing is often achieved only later during hospitalization, leading to delays in targeted therapies. We propose a way to diagnose spatial neglect right at admission. We measured the conjugated eye deviation (CED) on the initial computed tomography (CT) scans, in combination with the verbal instruction “Please look straight ahead” during the scan. The command was implemented in the scanner program and automatically played before a cranial CT started. This prospective study included a total 46 consecutive subjects (16 patients with first ever right brain damage and no spatial neglect, 12 patients with first ever right brain damage and spatial neglect, and 18 healthy controls). The right brain damaged groups were submitted to paper pencil tests to access the diagnosis of a spatial neglect after radiological confirmation of the brain damage during the initial phase of their hospitalisation. This procedure allowed us to define a cut-off value of 14.1 degrees of CED to the ipsilesional side to differentiate right hemispheric stroke patients with versus without spatial neglect with a confidence interval of 99%. This simple addition to a radiological routine procedure provides a new tool to help diagnose spatial neglect at the earliest stage possible and thus offers the possibility of providing patients with optimized rehabilitative therapy from a very early stage on.
Evaluation of a 12-week app-guided exercise intervention in patients with knee osteoarthritis (re.flex): a study protocol for a randomized controlled trial.
2023-04-06

Abstract Background The current health care demonstrates an insufficient provision and utilization of physical exercises that are recommended as first-line treatment in clinical guidelines for patients with knee osteoarthritis. Mobile health (m-health) technologies offer new opportunities to guide and monitor home-based exercise programs by using mobile devices and inertial sensors in combination with a digital application (app). This study evaluates patients benefit using the specific digital health application re.flex for patients with knee osteoarthritis (OA). Methods This monocentric, two-arm, randomized controlled parallel-group trial evaluates the effectiveness of the app- and sensor-guided exercise program re.flex for patients with moderate to severe knee OA. We aim to recruit 200 participants via newspaper, newsletter and information events. Participants will be randomly allocated to the intervention group (IG) and the control group (C) in a 1:1 ratio. Participants of C do not receive any study intervention or instruction for any change to their previous health care utilization. IG comprises a 12-week home training program with three sessions per week in addition to regular care. Exercises are guided and monitored by use of the training app (re.flex) and two accelerometers that are attached proximally and distally to the affected knee joint. Pre- and post-measurements will take place at baseline (t0) and after 12 weeks (t1). Primary outcomes will be osteoarthritis-specific pain and physical function measured with the Knee Osteoarthritis Outcome Score (KOOS) subscales Pain and Function in daily living (ADL). Secondary, further self-reported health outcomes, a performance measurement, app logfiles and safety will be assessed. Discussion M-health interventions can be used independently from time and location and allow most patients to get access to this kind of exercise guidance. As such, re.flex can bridge part of the gap between recommendations for strengthening exercises in patients with knee OA and the insufficient actual care situation. This randomized controlled trial is designed to provide conclusions on the effectiveness of the health application re.flex for the population under study and will give further insight into adherence rates and the safety of its use. Trial registration The trial was registered on 20/01/2023 at www.drks.de (ID: DRKS00030932).
Super-resolution STED imaging in the inner and outer whole-mount mouse retina
2023-04-06

Since its invention, super-resolution microscopy has become a popular tool for advanced imaging of biological structures, allowing visualisation of subcellular structures at a spatial scale below the diffraction limit. Thus, it is not surprising that recently, different super-resolution techniques are being applied in neuroscience, e.g. to resolve the clustering of neurotransmitter receptors and protein complex composition in presynaptic terminals. Still, the vast majority of these experiments were carried out either in cell cultures or very thin tissue sections, while there are only a few examples of super-resolution imaging in deeper layers (30 - 50 μm) of biological samples. In that context, the mammalian whole-mount retina has rarely been studied with super-resolution microscopy. Here, we aimed at establishing a stimulated-emission-depletion (STED) microscopy protocol for imaging whole-mount retina. To this end, we developed sample preparation including horizontal slicing of retinal tissue, an immunolabeling protocol with STED-compatible fluorophores and optimised the image acquisition settings. We labelled subcellular structures in somata, dendrites, and axons of retinal ganglion cells in the inner mouse retina. By measuring the full width at half maximum of the thinnest filamentous structures in our preparation, we achieved a resolution enhancement of two or higher compared to conventional confocal images. When combined with horizontal slicing of the retina, these settings allowed visualisation of putative GABAergic horizontal cell synapses in the outer retina. Taken together, we successfully established a STED protocol for reliable super-resolution imaging in the whole-mount mouse retina at depths between 30 and 50 μm, which enables investigating, for instance, protein complex composition and cytoskeletal ultrastructure at retinal synapses in health and disease.
Microbiome Metabolome Integration Platform (MMIP): a web-based platform for microbiome and metabolome data integration and feature identification
2023-04-06

Abstract A microbial community maintains its ecological dynamics via metabolite crosstalk. Hence knowledge of the metabolome, alongside its populace, would help us understand the functionality of a community and also predict how it will change in atypical conditions. Methods that employ low-cost metagenomic sequencing data can predict the metabolic potential of a community, that is, its ability to produce or utilize specific metabolites. These, in turn, can potentially serve as markers of biochemical pathways that are associated with different communities. We developed MMIP (Microbiome Metabolome Integration Platform), a web-based analytical and predictive tool that can be used to compare the taxonomic content, diversity variation and the metabolic potential between two sets of microbial communities from targeted amplicon sequencing data. MMIP is capable of highlighting statistically significant taxonomic, enzymatic and metabolic attributes as well as learning-based features associated with one group in comparison with another. Further MMIP can predict linkages among species or groups of microbes in the community, specific enzyme profiles, compounds or metabolites associated with such a group of organisms. With MMIP, we aim to provide a user-friendly, online web-server for performing key microbiome-associated analyses of targeted amplicon sequencing data, predicting metabolite signature, and using learning-based linkage analysis, without the need for initial metabolomic analysis, and thereby helping in hypothesis generation.
Application of Effect-Based Methods to Water Quality Monitoring: Answering Frequently Asked Questions by Water Quality Managers, Regulators, and Policy Makers
2023-04-07

Effect-based methods (EBM) have great potential for water quality monitoring as they can detect the mixture effects of all active known and unknown chemicals in a sample, which cannot be addressed by chemical analysis alone. To date, EBM have primarily been applied in a research context, with a lower level of uptake by the water sector and regulators. This is partly due to concerns regarding the reliability and interpretation of EBM. Using evidence from the peer-reviewed literature, this work aims to answer frequently asked questions about EBM. The questions were identified through consultation with the water industry and regulators and cover topics related to the basis for using EBM, practical considerations regarding reliability, sampling for EBM and quality control, and what to do with the information provided by EBM. The information provided in this work aims to give confidence to regulators and the water sector to stimulate the application of EBM for water quality monitoring.
The receptor kinase FERONIA regulates phosphatidylserine localization at the cell surface to modulate ROP signaling
2023-04-07

Cells maintain a constant dialog between the extracellular matrix and their plasma membrane to fine tune signal transduction processes. We found that the receptor kinase FERONIA (FER), which is a proposed cell wall sensor, modulates phosphatidylserine plasma membrane accumulation and nano-organization, a key regulator of Rho GTPase signaling in Arabidopsis. We demonstrate that FER is required for both Rho-of-Plant 6 (ROP6) nano-partitioning at the membrane and downstream production of reactive oxygen species upon hyperosmotic stimulus. Genetic and pharmacological rescue experiments indicate that phosphatidylserine is required for a subset of, but not all, FER functions. Furthermore, application of FER ligand shows that its signaling controls both phosphatidylserine membrane localization and nanodomains formation, which, in turn, tunes ROP6 signaling. Together, we propose that a cell wall–sensing pathway controls via the regulation of membrane phospholipid content, the nano-organization of the plasma membrane, which is an essential cell acclimation to environmental perturbations.
Disturbances in fear extinction learning after mild traumatic brain injury in mice are accompanied by alterations in dendritic plasticity in the medial prefrontal cortex and basolateral nucleus of the amygdala
2023-04-07

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) have emerged as the signature injuries of the U.S. veterans who served in Iraq and Afghanistan, and frequently co-occur in both military and civilian populations. To better understand how fear learning and underlying neural systems might be altered after mTBI, we examined the acquisition of cued fear conditioning and its extinction along with brain morphology and dendritic plasticity in a mouse model of mTBI. To induce mTBI in adult male C57BL/6J mice, a lateral fluid percussive injury (LFP 1.7) was produced using a fluid pulse of 1.7 atmosphere force to the right parietal lobe. Behavior in LFP 1.7 mice was compared to behavior in mice from two separate control groups: mice subjected to craniotomy without LFP injury (Sham) and mice that did not undergo surgery (Unoperated). Following behavioral testing, neural endpoints (dendritic structural plasticity and neuronal volume) were assessed in the basolateral nucleus of the amygdala (BLA), which plays a critical sensory role in fear learning, and medial prefrontal cortex (mPFC), responsible for executive functions and inhibition of fear behaviors. No gross motor abnormalities or increased anxiety-like behaviors were observed in LFP or Sham mice after surgery compared to Unoperated mice. We found that all mice acquired fear behavior, assessed as conditioned freezing to auditory cue in a single session of 6 trials, and acquisition was similar across treatment groups. Using a linear mixed effects analysis, we showed that fear behavior decreased overall over 6 days of extinction training with no effect of treatment group across extinction days. However, a significant interaction was demonstrated between the treatment groups during within-session freezing behavior (5 trials per day) during extinction training. Specifically, freezing behavior increased across within-session extinction trials in LFP 1.7 mice, whereas freezing behavior in control groups did not change on extinction test days, reflecting a dissociation between within-trial and between-trial fear extinction. Additionally, LFP mice demonstrated bilateral increases in dendritic spine density in the BLA and decreases in dendritic complexity in the PFC. The translational implications are that individuals with TBI undergoing fear extinction therapy may demonstrate within-session aberrant learning that could be targeted for more effective treatment interventions.
Change in Metabolomic Profile Associated with an Average Increase in Plain Water Intake of >+1 L/Day, Sustained Over 4 Weeks, in Healthy Young Men with Initial Total Water Intake Below 2 L/Day
2023-04-07

Background/Aims: Cells adapt to chronic extracellular hypotonicity by altering metabolism. Corresponding effects of sustained hypotonic exposure at the whole-person level remain to be confirmed and characterized in clinical and population-based studies. This analysis aimed to 1) describe changes in urine and serum metabolomic profiles associated with four weeks of sustained &gt;+1 L/d drinking water in healthy, normal weight, young men, 2) identify metabolic pathways potentially impacted by chronic hypotonicity, and 3) explore if effects of chronic hypotonicity differ by type of specimen and/or acute hydration condition. Materials: Untargeted metabolomic assays were completed for specimen stored from Week 1 and Week 6 of the Adapt Study for four men (20-25 years) who changed hydration classification during that period. Each week, first-morning urine was collected after overnight food and water restriction, and urine (t+60 min) and serum (t+90 min) were collected after a 750 mL bolus of drinking water. Metaboanalyst 5.0 was used to compare metabolomic profiles. Results: In association with four weeks of &gt;+1 L/d drinking water, urine osmolality decreased below 800 mOsm/kg H2O and saliva osmolality decreased below 100 mOsm/kg H2O. Between Week 1 and Week 6, 325 of 562 metabolic features in serum changed by 2-fold or more relative to creatinine. Based on hypergeometric test p-value &lt;0.05 or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway impact factor &gt;0.2, the sustained &gt;+1 L/d of drinking water was associated with concurrent changes in carbohydrate, protein, lipid, and micronutrient metabolism, a metabolomic pattern of carbohydrate oxidation via the tricarboxylic acid (TCA) cycle, instead of glycolysis to lactate, and a reduction of chronic disease risk factors in Week 6. Similar metabolic pathways appeared potentially impacted in urine, but the directions of impact differed by specimen type. Conclusion: In healthy, normal weight, young men with initial total water intake below 2 L/d, sustained &gt;+1 L/d drinking water was associated with profound changes in serum and urine metabolomic profile, which suggested normalization of an aestivation-like metabolic pattern and a switch away from a Warburg-like pattern. Further research is warranted to pursue whole-body effects of chronic hypotonicity that reflect cell-level effects and potential beneficial effects of drinking water on chronic disease risk.
Photogenerated Carrier-Assisted Electrocatalysts for Efficient Water Splitting
2023-04-08

Electrocatalysts are the core component of electrocatalytic water splitting for improving its overall energy conversion efficiency and reducing the energy input. At present, the design of efficient electrocatalysts mainly focuses on optimizing their electronic structure and local reaction microenvironment to improve the adsorption of reaction intermediates. Although many effective strategies (such as heteroatom doping, vacancy, heterojunction construction, strain engineering, and phase transformation) have been developed, the improvement in catalytic activity has been very limited. Hence, the development of innovative strategies to enhance the optimization of photoelectroactivity is desirable. Inspired by the strategy of applying a potential field to reduce carrier radiation recombination in traditional photoelectrocatalysis, photogenerated carrier-assisted electrocatalysis, based on the synergy effect of light and electric energy, provides a new strategy to enhance the intrinsic activity of water splitting. The essence of the photo-assisted strategy can be attributed to the injection of hot carriers and photogenerated electron–hole pairs or the accelerated reaction kinetics caused by local temperature rises. The photogenerated carrier-assisted strategy has received wide attention due to its simplicity and efficiency. In this review, we focus on the recent advances in photogenerated carrier-assisted strategies (PCAS) for enhancing the performance of HER, OER, and overall water splitting. The possible mechanisms are addressed and the basic composition and latest progress in photo-assisted electrocatalysts using PCAS are summarized. Finally, the challenges and development prospects of PCAS will be detailed.