Origin of the success of mGGAs for bandgaps.

One of the well-known limitations of Kohn-Sham density functional theory is the tendency to strongly underestimate bandgaps. Meta-generalized gradient approximations (mGGAs), which include the kinetic energy density in the functional form, have been shown to significantly alleviate this deficiency. In this study, we explore the mechanisms responsible for this improvement from the angle of the underlying local densities. We find that the highest occupied and lowest unoccupied states are distinct in the space of the underlying descriptors. The gap opening is compared to a simple scaling of the local density approximation, and two mechanisms responsible for opening the mGGA gaps are identified. First of all, the relatively large negative derivative of the functional form with respect to reduced kinetic energy tends to elevate the lowest unoccupied state. Second, the curvature of functional, which ensures that it is bounded, tends to lower the highest occupied state. Remarkably, these two mechanisms are found to be transferable over a large and diverse database of compounds.

[The importance and areas of modern supportive and early integrated palliative care in the treatment of brain tumor patients]. / A korszeru szupportív ellátás és az integrált korai palliatív gondozás jelentosége és fontosabb területei agydaganatos betegek kezelése során.

During the care of brain tumor patients, supportive care and palliation are carried out in an individualized manner, accompanied by adequate communication, in a multidisciplinary professional environment. In the case of brain tumor patients, the burden of symptoms resulting from the progression of the disease and the complications of treatments occur in a particularly high proportion. The supportive care of patients in a modern approach covers the targeted treatment of physical and psychosocial problems and also includes integrated palliation. Palliative care is a form of care that can be used in addition to curative therapies, and it is advisable and necessary to introduce it as early as possible among brain tumor patients due to the significant deterioration of the quality of life. Dealing with seriously ill patients on a daily basis is also an emotional burden for the professional staff, and carries the risk of burnout. The support of the staff and family members, as well as the issues of adequate communication, are also part of the scope of the supportive care approach.

Perturbing cortical networks: in vivo electrophysiological consequences of pan-neuronal chemogenetic manipulations using deschloroclozapine.

Introduction: Chemogenetic techniques, specifically the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), have become invaluable tools in neuroscience research. Yet, the understanding of how Gq- and Gicoupled DREADDs alter local field potential (LFP) oscillations in vivo remains incomplete. Methods: This study investigates the in vivo electrophysiological effects of DREADD actuation by deschloroclozapine, on spontaneous firing rate and LFP oscillations recorded from the anterior cingulate cortex in lightly anesthetized male rats. Results: Unexpectedly, in response to the administration of deschloroclozapine, we observed inhibitory effects with pan-neuronal hM3D(Gq) stimulation, and excitatory effects with pan-neuronal hM4D(Gi) stimulation in a significant portion of neurons. These results emphasize the need to account for indirect perturbation effects at the local neuronal network level in vivo, particularly when not all neurons express the chemogenetic receptors uniformly. In the current study, for instance, the majority of cells that were transduced with both hM3D(Gq) and hM4D(Gi) were GABAergic. Moreover, we found that panneuronal cortical chemogenetic modulation can profoundly alter oscillatory neuronal activity, presenting a potential research tool or therapeutic strategy in several neuropsychiatric models and diseases. Discussion: These findings help to optimize the use of chemogenetic techniques in neuroscience research and open new possibilities for novel therapeutic strategies.

Intrinsic anticipatory motives in non-human primate food consumption behavior.

Future-oriented behavior is regarded as a cornerstone of human cognition. One key phenomenon through which future orientation can be studied is the delay of gratification, when consumption of an immediate reward is withstood to achieve a larger reward later. The delays used in animal delay of gratification paradigms are rather short to be considered relevant for studying human-like future orientation. Here, for the first time, we show that rhesus macaques exhibit human-relevant future orientation downregulating their operant food consumption in anticipation of a nutritionally equivalent but more palatable food with an unprecedentedly long delay of approximately 2.5 h. Importantly, this behavior is not a result of conditioning but intrinsic to the animals. Our results show that the cognitive time horizon of primates, when tested in ecologically valid foraging-like experiments, extends much further into the future than previously considered, opening up new avenues for translational biomedical research.

Tissue-resident bacteria in metabolic diseases: emerging evidence and challenges.

Although the impact of the gut microbiome on health and disease is well established, there is controversy regarding the presence of microorganisms such as bacteria and their products in organs and tissues. However, recent contamination-aware findings of tissue-resident microbial signatures provide accumulating evidence in support of bacterial translocation in cardiometabolic disease. The latter provides a distinct paradigm for the link between microbial colonizers of mucosal surfaces and host metabolism. In this Perspective, we re-evaluate the concept of tissue-resident bacteria including their role in metabolic low-grade tissue and systemic inflammation. We examine the limitations and challenges associated with studying low bacterial biomass samples and propose experimental and analytical strategies to overcome these issues. Our Perspective aims to encourage further investigation of the mechanisms linking tissue-resident bacteria to host metabolism and their potentially actionable health implications for prevention and treatment.

Quantifying the Suitability of Biosignals Acquired During Surgery for Multimodal Analysis.

Goal: Recently, large datasets of biosignals acquired during surgery became available. As they offer multiple physiological signals measured in parallel, multimodal analysis - which involves their joint analysis - can be conducted and could provide deeper insights than unimodal analysis based on a single signal. However, it is unclear what percentage of intraoperatively acquired data is suitable for multimodal analysis. Due to the large amount of data, manual inspection and labelling into suitable and unsuitable segments are not feasible. Nevertheless, multimodal analysis is performed successfully in sleep studies since many years as their signals have proven suitable. Hence, this study evaluates the suitability to perform multimodal analysis on a surgery dataset (VitalDB) using a multi-center sleep dataset (SIESTA) as reference. Methods: We applied widely known algorithms entitled "signal quality indicators" to the common biosignals in both datasets, namely electrocardiography, electroencephalography, and respiratory signals split in segments of 10 s duration. As there are no multimodal methods available, we used only unimodal signal quality indicators. In case, all three signals were determined as being adequate by the indicators, we assumed that the whole signal segment was suitable for multimodal analysis. Results: 82% of SIESTA and 72% of VitalDB are suitable for multimodal analysis. Unsuitable signal segments exhibit constant or physiologically unreasonable values. Histogram examination indicated similar signal quality distributions between the datasets, albeit with potential statistical biases due to different measurement setups. Conclusions: The majority of data within VitalDB is suitable for multimodal analysis.

Chemogenetic inhibition of the lateral hypothalamus effectively reduces food intake in rats in a translational proof-of-concept study.

Despite the therapeutic potential of chemogenetics, the method lacks comprehensive preclinical validation, hindering its progression to human clinical trials. We aimed to validate a robust but simple in vivo efficacy assay in rats which could support chemogenetic drug discovery by providing a quick, simple and reliable animal model. Key methodological parameters such as adeno-associated virus (AAV) serotype, actuator drug, dose, and application routes were investigated by measuring the food-intake-reducing effect of chemogenetic inhibition of the lateral hypothalamus (LH) by hM4D(Gi) designer receptor stimulation. Subcutaneous deschloroclozapine in rats transfected with AAV9 resulted in a substantial reduction of food-intake, comparable to the efficacy of exenatide. We estimated that the effect of deschloroclozapine lasts 1-3 h post-administration. AAV5, oral administration of deschloroclozapine, and clozapine-N-oxide were also effective but with slightly less potency. The strongest effect on food-intake occurred within the first 30 min after re-feeding, suggesting this as the optimal experimental endpoint. This study demonstrates that general chemogenetic silencing of the LH can be utilized as an optimal, fast and reliable in vivo experimental model for conducting preclinical proof-of-concept studies in order to validate the in vivo effectiveness of novel chemogenetic treatments. We also hypothesize based on our results that universal LH silencing with existing and human translatable genetic neuroengineering techniques might be a viable strategy to affect food intake and influence obesity.

Blood methylation pattern reflects epigenetic remodelling in adipose tissue after bariatric surgery.

BACKGROUND: Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue. Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood. METHODS: Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals (N = 6 female) with severe obesity pre- and post-surgery. FINDINGS: The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from -11.5 to 10.8%; OVAT: 14,632 DMRs from -13.7 to 12.8%) than in blood (9267 DMRs from -8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery. INTERPRETATION: Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors AT's inflammatory state post-bariatric surgery. FUNDING: The funding sources are listed in the Acknowledgments section.

Investigation of the Tensile Strength of Adhesive-Bonded Steels Using Surface Treatments.

This study explores the tensile strength of adhesive joints in steel, focusing on the influence of heat treatment and diverse surface modifications. Results indicate a notable relationship between annealing temperature and tensile strength, with the most favorable outcomes identified at 90 min and 165 °C. Particularly, surfaces treated through turning, sandblasting, and plasma treatment (type C) consistently outperformed other methods. A standout revelation emerged from the turned, sandblasted, and plasma-treated surface (C), showcasing an exceptional tensile strength of 69.06 MPa. Load-holding tests underscored its resilience under diverse load conditions. Surface analyses, including roughness measurements, wetting characteristics, and Scanning Electron Microscope imaging, provided valuable insights into structural transformations induced by different treatments. Chemical composition examinations unveiled significant alterations post-plasma treatment, impacting surface chemistry and contributing to an outstanding tensile strength of 67.63 MPa. In essence, this research offers a glimpse into the nuanced factors influencing adhesive joint strength in steel. The turned, sandblasted, and plasma-treated surface emerges as a promising avenue, sparking further curiosity into the underlying mechanisms propelling superior tensile strength in adhesive joints.

Cattle manure application for 12 and 17 years enhanced depth distribution of soil organic carbon and X-ray computed tomography-derived pore characteristics.

Long-term fertilizer application in row crops may influence soil pore characteristics, thereby impacting soil aggregation and structure. Therefore, understanding the influences on soil pore characteristics is useful for adopting suitable conservation practices. However, the impact of cattle manure and inorganic fertilizer application at varied rates on soil pore characteristics in the soil profile at a microscale level remains limited. This study quantifies the impacts of manure and inorganic fertilizer amendments under a corn (Zea mays L.)-soybean (Glycine max L.)-spring wheat (Triticum aestivum) rotation system on soil pore characteristics using the X-ray computed tomography (XCT). Treatments included: low manure (LM; 4.4 and 3.3 Mg ha-1), medium manure (MM; 27.4 and 18.7 Mg ha-1), high manure (HM; 54.8 and 37.4 Mg ha-1), medium fertilizer (MF; 136 kg N ha-1, 49 kg P2O5 ha-1, and 91.5 kg K2O ha-1), high fertilizer (HF; 204 kg N ha-1, 73.5 kg P2O5 ha-1, and 137.3 kg K2O ha-1), and control (CK), respectively, at Brookings (initiated in 2008) and Beresford (2003) in South Dakota. Four intact soil cores were collected from each treatment at 0-10, 10-20, 20-30, and 30-40 cm depths. Results showed that the HM treatment increased the SOC by 8-68% compared to the CK and MF at 0-20 cm at the study sites. Both HM and MM treatments increased the macroporosity and mesoporosity in 0-20 cm soil depths at both study sites. Treatment did not always improve soil pore characteristics below 20 cm soil depth. Additionally, a positive correlation was observed between the XCT-derived macroporosity, total number of macropores, and SOC for all the treatments. Therefore, this study encourages the adoption of the XCT technique in quantifying soil pore characteristics and suggests that long-term medium manure application enhances soil structure as compared to an equivalent inorganic fertilizer application.

Pancreatic SABR using peritumoral fiducials, triggered imaging and breath-hold.

Background: We aim to present our linear accelerator-based workflow for pancreatic stereotactic ablative radiotherapy (SABR) in order to address the following issues: intrafractional organ motion management, Cone Beam CT (CBCT) image quality, residual errors with dosimetric consequences, treatment time, and clinical results. Methods: Between 2016 and 2021, 14 patients with locally advanced pancreatic cancer were treated with induction chemotherapy and SABR using volumetric modulated arc therapy (VMAT). Internal target volume (ITV) concept (5), phase-gated (4), or breath hold (5) techniques were used. Treatment was verified by CBCT before and after irradiation, while tumor motion was monitored and controlled by kV triggered imaging and beam hold using peritumoral surgical clips. Beam interruptions and treatment time were recorded. The CBCT image quality was scored and supplemented by an agreement analysis (Krippendorff's-α) of breath-hold CBCT images to determine the position of OARs relative to the planning risk volumes (PRV). Residual errors and their dosimetry impact were also calculated. Progression free (PFS) and overall survival (OS) were assessed by the Kaplan-Meier analysis with acute and late toxicity reporting (CTCAEv4). Results: On average, beams were interrupted once (range: 0-3) per treatment session on triggered imaging. The total median treatment time was 16.7 ± 10.8 min, significantly less for breath-hold vs. phase-gated sessions (18.8 ± 6.2 vs. 26.5 ± 13.4, p < 0.001). The best image quality was achieved by breath hold CBCT. The Krippendorff's-α test showed a strong agreement among five radiation therapists (mean K-α value: 0.8 (97.5%). The mean residual errors were <0.2 cm in each direction resulting in an average difference of <2% in dosimetry for OAR and target volume. Two patients received offline adaptation. The median OS/PFS after induction chemotherapy and SABR was 20/12 months and 15/8 months. No Gr. ≥2 acute/late RT-related toxicity was noted. Conclusion: Linear accelerator based pancreatic SABR with the combination of CBCT and triggered imaging + beam hold is feasible. Peritumoral fiducials improve utility while breath-hold CBCT provides the best image quality at a reasonable treatment time with offline adaptation possibilities. In well-selected cases, it can be an effective alternative in clinics where CBCT/MRI-guided online adaptive workflow is not available.