Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of Levodopa Medication on Human Brain Connectome in Parkinson's Disease—A Combined Graph Theory and EEG Study

Background. Levodopa-based drugs are widely used for mitigating the complications induced by Parkinson’s disease (PD). Despite the positive effects, several issues regarding the way that levodopa changes brain activities have remained unclear. Methods. A combined strategy using EEG data and graph theory was used for investigating how levodopa changed connectome and processing hubs of the brain during resting-state. Obtained results were subjected to ANOVA test and multiple-comparison post-hoc correction procedure. Results. Outcomes showed that graph topology was not significantly different between PD and healthy groups during the eyes-closed condition, while in the eyes-open condition, statistically significant differences were found. The main effect of levodopa medication was observed for gamma-band activity in which levodopa changed the brain connectome toward a star-like topology. Considering the beta subband of EEG data, graph leaf number increased following levodopa medication in PD patients. Enhanced brain connectivity in the gamma band and reduced beta band connections in the basal ganglia were also observed after levodopa medication. Furthermore, source localization using dipole fitting showed that levodopa suppressed the activity of collateral trigone. Conclusion. Our combined EEG and graph analysis showed that levodopa medication changed the brain connectome, especially in the high-frequency range of brain electrical activities (beta and gamma).
Draft Genome Sequences of 23 Tenacibaculum Isolates from Farmed Norwegian Lumpfish, Cyclopterus lumpus

Draft genome sequences of 23 Tenacibaculum sp. strains that were isolated from Cyclopterus lumpus (lumpfish) were investigated to elucidate possible routes of transmission between Salmo salar (Atlantic salmon) and lumpfish. ABSTRACT Draft genome sequences of 23 Tenacibaculum sp. strains that were isolated from Cyclopterus lumpus (lumpfish) were investigated to elucidate possible routes of transmission between Salmo salar (Atlantic salmon) and lumpfish.
Infection with intestinal helminth (Hymenolepis diminuta) impacts exploratory behavior and cognitive processes in rats by changing the central level of neurotransmitters

Parasites may significantly affect the functioning of the host organism including immune response and gut-brain-axis ultimately leading to alteration of the host behavior. The impact of intestinal worms on the host central nervous system (CNS) remains unexplored. The aim of this study was to evaluate the effect of intestinal infection by the tapeworm Hymenolepis diminuta on behavior and functions of the CNS in rats. The 3 months old animals were infected, and the effects on anxiety, exploration, sensorimotor skills and learning processes were assessed at 18 months in Open Field (OF), Novel Object Recognition (NOR) and the Water Maze (WM) tests. After completing the behavioral studies, both infected and non-infected rats were sacrificed, and the collected tissues were subjected to biochemical analysis. The levels of neurotransmitters, their metabolites and amino acids in selected structures of the CNS were determined by HPLC. In addition, the gene expression profile of the pro- and anti-inflammatory cytokines (TNF-α, IL-1β, IL-6 and IL-10) was evaluated by Real-Time PCR to determine the immune response within the CNS to the tapeworm infection. The parasites caused significant changes in exploratory behavior, most notably, a reduction of velocity and total distance moved in the OF test; the infected rats exhibited decreased frequency in the central zone, which may indicate a higher level of anxiety. Additionally, parasite infestation improved spatial memory, assessed in the WM test, and recognition of new objects. These changes are related to the identified reduction in noradrenaline level in the CNS structures and less pronounced changes in striatal serotonergic neurotransmission. H. diminuta infestation was also found to cause a significant reduction of hippocampal expression of IL-6. Our results provide new data for further research on brain function during parasitic infections especially in relation to helminths and diseases in which noradrenergic system may play an important role.
Thalamocortical axons control the cytoarchitecture of neocortical layers by area-specific supply of VGF

Neuronal abundance and thickness of each cortical layer are specific to each area, but how this fundamental feature arises during development remains poorly understood. While some of area-specific features are controlled by intrinsic cues such as morphogens and transcription factors, the exact influence and mechanisms of action by cues extrinsic to the cortex, in particular the thalamic axons, have not been fully established. Here, we identify a thalamus-derived factor, VGF, which is indispensable for thalamocortical axons to maintain the proper amount of layer 4 neurons in the mouse sensory cortices. This process is prerequisite for further maturation of the primary somatosensory area, such as barrel field formation instructed by a neuronal activity-dependent mechanism. Our results provide an actual case in which highly site-specific axon projection confers further regional complexity upon the target field through locally secreting signaling molecules from axon terminals.
Design and Analysis of an SPR Sensor Based on Antimonene and Platinum for the Detection of Formalin

Detection of formalin to prevent food adulteration, especially in tropical countries, is of primary concern for public health issues. Life-threatening diseases such as leukaemia and lymphoma occur due to the regular consumption of formalin with food. Traditionally, spectrophotometry and chromatography-based sensors have been employed to detect formalin, which have limitations related to their ability to achieve high sensitivity, selectivity, and fast response. In this paper, a surface plasmon resonance (SPR) sensor for improved sensing of formalin is proposed. The Kretschmann configured SPR sensor probe is designed using silver (Ag), platinum (Pt), antimonene, and chitosan, which increases the sensitivity and selectivity. The maximum sensitivity achieved for the proposed SPR sensor is 206.86 °/RIU. The distribution of the electric field (Ey) component of the electric field is also evaluated to analyze the field enhancement at different layer interfaces and to calculate the penetration depth (176.75 nm).
SARS‐CoV‐2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease

Abstract Background/Aims In this observational study, we explored the humoral and cellular immune response to SARS‐CoV‐2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). Methods Anti‐SARS‐CoV‐2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID‐19 vaccination. The spike‐specific T‐cell response was assessed using an activation‐induced marker assay (AIM) in a subset of individuals. Results Previous SARS‐CoV‐2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike‐specific T‐cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike‐specific T‐cell response. Conclusion Patients with AIH show an increased SARS‐CoV‐2 infection rate as well as an impaired B‐ and T‐cell response to SARS‐CoV‐2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.
Inclisiran inhibits oxidized low-density lipoprotein-induced foam cell formation in Raw264.7 macrophages via activating the PPARγ pathway

Abstract Proprotein convertase subtilisin kexin type 9 (PCSK9) is a well-known proprotein convertase that influences foam cell formation and modulates atherosclerosis. Inclisiran is a novel chemosynthetic small interfering RNA that inhibits PCSK9 synthesis. This study aimed to explore the effect of inclisiran on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation in Raw264.7 macrophages and to investigate the underlying mechanisms. Raw264.7 cells were treated with ox-LDL to induce the formation of macrophage-derived foam cells. Oil Red O staining and high-performance liquid chromatography were performed to detect lipid accumulation and cholesterol levels. Dil-ox-LDL uptake assay, CCK-8, RT-qPCR, and Western blotting analysis were performed to examine ox-LDL uptake, cell viability, and expression of scavenger receptor-related factors. Inclisiran reduced lipid accumulation in ox-LDL-treated macrophages in a dose-dependent manner. Inclisiran significantly inhibited the levels of total cholesterol, free cholesterol, and cholesterol ester in the supernatant of Raw264.7 cells. Inclisiran reduced ox-LDL uptake and increased Raw264.7 cell viability. Meanwhile, inclisiran downregulated the expression of SR-A, LOX-1, and CD36 and upregulated SR-BI, ApoE, and ABCA1. Furthermore, inclisiran increased PPARγ activity and decreased NF-κB activity. An inhibitor of PPARγ (T0070907) reversed the beneficial effects of inclisiran on ox-LDL uptake, NF-κB inactivation, and cytokine expression. In conclusion, these data suggested that inclisiran inhibited the formation of macrophage-derived foam cells by activating the PPARγ pathway. Highlights Inclisiran reduces lipid accumulation in Raw264.7 cells; Inclisiran reduces ox-LDL uptake and increases Raw264.7 cell viability; Inclisiran inhibits foam cell formation by activating the PPARγ pathway.
ProBiS-Dock: A Hybrid Multitemplate Homology Flexible Docking Algorithm Enabled by Protein Binding Site Comparison

The protein data bank (PDB) is a rich source of protein ligand structures, but ligands are not explicitly used in current docking algorithms. We have developed ProBiS-Dock, a docking algorithm complementary to the ProBiS-Dock Database (J. Chem. Inf. Model. 2021, 61, 4097-4107) that treats small molecules and proteins as fully flexible entities and allows conformational changes in both after ligand binding. A new scoring function is described that consists of a binding site-specific scoring function (ProBiS-Score) and a general statistical scoring function. ProBiS-Dock enables rapid docking of small molecules to proteins and has been successfully validated in silico against standard benchmarks. It enables rapid search for new active ligands by leveraging existing knowledge in the PDB. The potential of the software for drug development has been confirmed in vitro by the discovery of new inhibitors of human indoleamine 2,3-dioxygenase 1, an enzyme that is an attractive target for cancer therapy and catalyzes the first rate-determining step of l-tryptophan metabolism via the kynurenine pathway. The software is freely available to academic users at http://insilab.org/probisdock.
Two lanostane triterpenoids with α-glucosidase inhibitory activity from the fruiting bodies of Ganoderma weberianum

Abstract A new oxygenated lanostane-type triterpenoid, 20S,24S-epoxy-lanosta-7,9(11)-dien-3β,15α,25R,26-tetraol (1), together with three known compounds (2–4) were isolated from the fruiting bodies of Ganoderma weberianum. Extensive NMR spectrometry and HRESIMS analysis, as well as NMR and ECD calculations elucidated the structure of the new compound. 27-nor-3β-hydroxylanosta-7,9(11),23E-trien-25-one (2) showed superior α-glucosidase inhibitory activity with IC50 value of 122.1 μM to that of positive control acarbose (304.6 μM). Graphical Abstract
CD24 is a surrogate for ‘immune‐cold’ phenotype in aggressive large B‐cell lymphoma

The tumor microenvironment (TME) is a critical regulator of the development of malignant lymphoma. Therapeutics targeting the TME, especially immune checkpoint molecules, are changing the treatment strategy for lymphoma. However, the overall response to these therapeutics for diffuse large B‐cell lymphoma (DLBCL) is modest and new targets of immunotherapy are needed. To find critical immune checkpoint molecules for DLBCL, we explored the prognostic impact of immune checkpoint molecules and their ligands using publicly available datasets of gene expression profiles. In silico analysis of three independent datasets (GSE117556, GSE10846, and GSE181063) revealed that DLBCL expressing CD24 had a poor prognosis and had a high frequency of MYC aberrations. Moreover, gene set enrichment analysis showed that the ‘MYC‐targets‐hallmark’ (false discovery rate [FDR] = 0.024) and ‘inflammatory‐response‐hallmark’ (FDR = 0.001) were enriched in CD24‐high and CD24‐low DLBCL, respectively. In addition, the expression of cell‐specific markers of various immune cells was higher in CD24‐low DLBCL than in CD24‐high DLBCL. CIBERSORT analysis of the datasets showed fewer macrophages in CD24‐high DLBCL than in CD24‐low DLBCL. Additionally, immunohistochemical analysis of 335 cases of DLBCL showed that few TME cells were found in CD24‐high DLBCL, although statistical differences were not observed. These data indicate that CD24 expression suppresses immune cell components of the TME in DLBCL, suggesting that CD24 may be a target for cancer immunotherapy in aggressive large B‐cell lymphoma.
Peritoneal dialysis adequacy: a paradigm shift

For the past 30 years, nephrologists have focused on a single minimal threshold of Kt/Vurea to determine the adequacy of peritoneal dialysis (PD). To date, there is no evidence that shows Kt/Vurea to be a good surrogate measure of uremic symptom control or nutritional state in patients on PD. Volume of distribution (Vurea) generally is considered equivalent to total body water (TBW). Yet, accurate determination of TBW is difficult. The most recent International Society for Peritoneal Dialysis practice recommendations on prescribing high-quality PD emphasized incorporation of multiple measures rather than the single value of Kt/Vurea. These measures include shared decision-making between the patient and the care team and assessment of health-related quality of life, burden of uremic symptoms, presence of residual kidney function, volume status, and biochemical measures including serum potassium and bicarbonate levels. In some cases, PD prescriptions can be tailored to the patient priorities and goals of care, such as in frail and pediatric patients. Overall, there has been a paradigm shift in providing high-quality care to PD patients. Instead of focusing on small solute clearance in the form of Kt/Vurea, nephrologists are encouraged to use a more comprehensive assessment of the patient as a whole.
Twenty-first century hydroclimate: A continually changing baseline, with more frequent extremes

Significance Twenty-first century trends in hydroclimate are so large that future average conditions will, in most cases, fall into the range of what we would today consider extreme drought or pluvial states. Using large climate model ensembles, we remove the background trend and find that the risk of droughts and pluvials relative to that (changing) baseline is fairly similar to the 20th century risk. By continually adapting to long-term background changes, these risks could therefore perhaps be minimized. However, increases in the frequency of extremely wet and dry years are still present even after removing the trend, indicating that sustainably managing hydroclimate-driven risks in a warmer world will face increasingly difficult challenges.
Evaluating Benefits, Costs, and Social Value as Predictors of Gratitude

Although much is known about cooperation, the internal decision rules that regulate motivations to initiate and maintain cooperative relationships have not been thoroughly explored. Here, we focus on how acts of benefit delivery and perceptions of social value inform gratitude, an emotion that promotes cooperation. We evaluated alternate information-processing models to determine which inputs and internal representations best account for the intensity with which people report experiencing gratitude. Across two experiments (Ns = 257 and 208), we tested 10 models that consider multiple variables: the magnitude of benefits conferred on beneficiaries, the magnitude of costs incurred by benefactors, beneficiaries’ perception of how much benefactors value their welfare, and beneficiaries’ value for the welfare of their benefactors. Across both studies, only beneficiaries’ change in social valuation for their benefactors consistently predicted gratitude. Results point to the need for further research and contribute to the growing literature linking cooperation, social emotions, and social valuation.
Methylation of tumour suppressor genes in benign and malignant salivary gland tumours: a systematic review and meta-analysis

ABSTRACT The aim of the present systematic review was to critically analyse the relationship between tumour suppressor genes (TSGs) promoter methylation, a potent mechanism of gene silencing, and the development of salivary gland tumours, as well as the possible effect on clinical/histological characteristics. Review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (registration ID CRD42020218511). A comprehensive search of Web of Science, Scopus, PubMed, and Cochrane Central Register of Controlled Trials was performed utilizing relevant key terms, supplemented by a search of grey literature. Newcastle-Ottawa Quality Assessment Scale (NOQAS) was used for the quality assessment of included studies. Sixteen cross-sectional and 12 case-control studies were included in the review, predominantly dealing with methylation in TSGs related to DNA repair, cell cycle, and cell growth regulation and differentiation. Quantitative synthesis could be performed on P16 (inhibitor of cyclin-dependent kinase 4a), RASSF1A (Ras association domain family 1 isoform A) and MGMT (O6-methylguanine DNA methyltransferase) genes only. It showed that P16 and RASSF1A genes were more frequently methylated in salivary gland tumours compared to controls (P = .0002 and P < .0001, respectively), while no significant difference was observed for MGMT. Additionally, P16 did not appear to be related to malignant transformation of pleomorphic adenomas (P = .330). In conclusion, TSG methylation is involved in salivary gland tumour pathogenesis and several genes might play a considerable role. Further studies are needed for a better understanding of complex epigenetic deregulation during salivary gland tumour development and progression.
Improving protein–ligand docking and screening accuracies by incorporating a scoring function correction term

Abstract Scoring functions are important components in molecular docking for structure-based drug discovery. Traditional scoring functions, generally empirical- or force field-based, are robust and have proven to be useful for identifying hits and lead optimizations. Although multiple highly accurate deep learning- or machine learning-based scoring functions have been developed, their direct applications for docking and screening are limited. We describe a novel strategy to develop a reliable protein–ligand scoring function by augmenting the traditional scoring function Vina score using a correction term (OnionNet-SFCT). The correction term is developed based on an AdaBoost random forest model, utilizing multiple layers of contacts formed between protein residues and ligand atoms. In addition to the Vina score, the model considerably enhances the AutoDock Vina prediction abilities for docking and screening tasks based on different benchmarks (such as cross-docking dataset, CASF-2016, DUD-E and DUD-AD). Furthermore, our model could be combined with multiple docking applications to increase pose selection accuracies and screening abilities, indicating its wide usage for structure-based drug discoveries. Furthermore, in a reverse practice, the combined scoring strategy successfully identified multiple known receptors of a plant hormone. To summarize, the results show that the combination of data-driven model (OnionNet-SFCT) and empirical scoring function (Vina score) is a good scoring strategy that could be useful for structure-based drug discoveries and potentially target fishing in future.
Application of physiologically based pharmacokinetic modelling for the prediction of drug–drug interactions involving anlotinib as a perpetrator of cytochrome P450 enzymes

Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non‐small cell lung cancer in China. Drug–drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co‐administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens.