Bioactivity of Phenanthrenes from Juncus acutus on Selenastrum capricornutum

Twenty-five 9,10-dihydrophenanthrenes, four phenanthrenes, a dihydrodibenzoxepin, and a pyrene, isolated from the wetland plant Juncus acutus, were tested to detect their effects on the green alga Selenastrum capricornutum. Nine of the compounds were isolated and identified for the first time. Most of the compounds caused inhibition of algal growth. The 9,10-dihydrophenanthrenes 1, 5, 21, and 22 were the most active.     

A new contact model for the discrete element method simulation of $$\hbox {TiO}_2$$ nanoparticle films under mechanical load

We develop a novel coarse-grained contact model for Discrete Element Method simulations of \(\hbox {TiO}_2\) nanoparticle films subjected to mechanical stress. All model elements and parameters are derived in a self-consistent and physically sound way from all-atom Molecular Dynamics simulations of interacting particles and surfaces. In particular, the nature of atomic-scale friction and dissipation effects is taken into account by explicit modelling of the surface features and water adsorbate layers that strongly mediate the particle-particle interactions. The quantitative accuracy of the coarse-grained model is validated against all-atom simulations of \(\hbox {TiO}_2\) nanoparticle agglomerates under tensile stress. Moreover, its predictive power is demonstrated with calculations of force-displacement curves of entire nanoparticle films probed with force spectroscopy. The simulation results are compared with Atomic Force Microscopy and Transmission Electron Microscopy experiments.     

I2-Imidazoline Ligand CR4056 Improves Memory,Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.     

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation. The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT–angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.     

Evaluating the performance of machine learning methods and variable selection methods for predicting difficult-to-measure traits in Holstein dairy cattle using milk infrared spectral data

Fourier-transform infrared (FTIR) spectroscopy is a powerful high-throughput phenotyping tool for predicting traits that are expensive and difficult to measure in dairy cattle. Calibration equations are often developed using standard methods, such as partial least squares (PLS) regression. Methods that employ penalization, rank-reduction, and variable selection, as well as being able to model the nonlinear relations between phenotype and FTIR, might offer improvements in predictive ability and model robustness. This study aimed to compare the predictive ability of 2 machine learning methods, namely random forest (RF) and gradient boosting machine (GBM), and penalized regression against PLS regression for predicting 3 phenotypes differing in terms of biological meaning and relationships with milk composition (i.e., phenotypes measurable directly and not directly in milk, reflecting different biological processes which can be captured using milk spectra) in Holstein-Friesian cattle under 2 cross-validation scenarios. The data set comprised phenotypic information from 471 Holstein-Friesian cows, and 3 target phenotypes were evaluated: (1) body condition score (BCS), (2) blood β-hydroxybutyrate (BHB, mmol/L), and (3) κ-casein expressed as a percentage of nitrogen (κ-CN, % N). The data set was split considering 2 cross-validation scenarios: samples-out random in which the population was randomly split into 10-folds (8-folds for training and 1-fold for validation and testing); and herd/date-out in which the population was randomly assigned to training (70% herd), validation (10%), and testing (20% herd) based on the herd and date in which the samples were collected. The random grid search was performed using the training subset for the hyperparameter optimization and the validation set was used for the generalization of prediction error. The trained model was then used to assess the final prediction in the testing subset. The grid search for penalized regression evidenced that the elastic net (EN) was the best regularization with increase in predictive ability of 5%. The performance of PLS (standard model) was compared against 2 machine learning techniques and penalized regression using 2 cross-validation scenarios. Machine learning methods showed a greater predictive ability for BCS (0.63 for GBM and 0.61 for RF), BHB (0.80 for GBM and 0.79 for RF), and κ-CN (0.81 for GBM and 0.80 for RF) in samples-out cross-validation. Considering a herd/date-out cross-validation these values were 0.58 (GBM and RF) for BCS, 0.73 (GBM and RF) for BHB, and 0.77 (GBM and RF) for κ-CN. The GBM model tended to outperform other methods in predictive ability around 4%, 1%, and 7% for EN, RF, and PLS, respectively. The prediction accuracies of the GBM and RF models were similar, and differed statistically from the PLS model in samples-out random cross-validation. Although, machine learning techniques outperformed PLS in herd/date-out cross-validation, no significant differences were observed in terms of predictive ability due to the large standard deviation observed for predictions. Overall, GBM achieved the highest accuracy of FTIR-based prediction of the different phenotypic traits across the cross-validation scenarios. These results indicate that GBM is a promising method for obtaining more accurate FTIR-based predictions for different phenotypes in dairy cattle.     

A theoretical model of the relationship between the <Emphasis Type="Italic">h</Emphasis>-index and other simple citation indicators

In this study, we quantitatively compared the impact of mission-oriented research grants and curiosity-driven grants on the diversity of research subjects in Japan. First, we examined data for Japanese principal investigators receiving research funding between 2000 and 2010 in the field of nanotechnology and materials science, and identified groups of researchers whose publication performance was positively affected by the mission-oriented grant, CREST. We then compared the effect of CREST with that of the curiosity-driven grant, KAKENHI. The analysis uses both propensity score matching and difference in differences (PSM-DID) methodologies. Our results show that for participants in the CREST program there was an increase in number of publications of more than 10% per year, for periods of both 5 and 3 years after the funding ended, even though the observed average effect on citation was not statistically significant. Second, we evaluated the diversity of research subjects through analysis of the distribution of the classification codes applied to articles published between 1996 and 2013, utilizing the J-Global database, which has the finest granularity of category among existing bibliographic scientific publication databases. Research subjects were better conserved under the mission-oriented program than the curiosity-driven one, a finding contrary to predictions of conventional theory. We also found that under mission-oriented funding, there was an increase in diversity in the sense of marginal utility. These findings should be of use in the “diversity-aware” design of programs for the funding of fundamental research.     

Revisitation of Formaldehyde Aniline Condensation. I High Yield Synthesis of 1,3,5-Triphenylhexahydro-symtriazine and its X-Ray Crystal Structure Determination

A rapid and efficient preparation of 1,3,5-triphenylhexahydro-sym-triazine ( 10 ) using paraformaldehyde is reported. The trimeric nature of the compound and its structure in solid state, where a biaxial chair conformation is favoured, are conclusively shown by X-ray diffraction analysis. A recent report on a preparation of 1,3-diphenyl-1,3-diazetidine is invalidated.     

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ_1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.     

Comparison of Automated Ribotyping,spa Typing,and MLST in 108 Clinical Isolates of Staphylococcus aureus from Orthopedic Infections

108 isolates of Staphylococcus aureus, belonging to six large ribogroups according to the automated Ribo-Printer^® system, were studied with two highly used molecular methods for epidemiological studies, namely multi-locus sequence typing (MLST) and spa typing, followed by BURP and eBURST v3 analysis for clustering spa types and sequence (ST) types. The aim was to evaluate whether automated ribotyping could be considered a useful screening tool for identifying S. aureus genetic lineages with respect to spa typing and MLST. Clarifying the relationship of riboprinting with these typing methods and establishing whether ribogroups fit single clonal complexes were two main objectives. Further information on the genetic profile of the isolates was obtained from agr typing and the search for the mecA, tst genes, and the IS256 insertion sequence. Automated ribotyping has been shown to predict spa clonal complexes and MLST clonal complexes. The high cost and lower discriminatory power of automated ribotyping compared to spa and MSLT typing could be an obstacle to fine genotyping analyzes, especially when high discriminatory power is required. On the other hand, numerous advantages such as automation, ease and speed of execution, stability, typeability and reproducibility make ribotyping a reliable method to be juxtaposed to gold standard methods.