Miracle-dz/UniFAR-FTUs huggingface dataset:
The Tukey trend test: Multiplicity adjustment using multiple marginal models

In dose–response analysis, it is a challenge to choose appropriate linear or curvilinear shapes when considering multiple, differently scaled endpoints. It has been proposed to fit several marginal regression models that try sets of different transformations of the dose levels as explanatory variables for each endpoint. However, the multiple testing problem underlying this approach, involving correlated parameter estimates for the dose effect between and within endpoints, could only be adjusted heuristically. An asymptotic correction for multiple testing can be derived from the score functions of the marginal regression models. Based on a multivariate t‐distribution, the correction provides a one‐step adjustment of p‐values that accounts for the correlation between estimates from different marginal models. The advantages of the proposed methodology are demonstrated through three example datasets, involving generalized linear models with differently scaled endpoints, differing covariates, and a mixed effect model and through simulation results. The methodology is implemented in an R package.
Dose-Response Relationship between Endurance Training Prescription Variables and Increases in Aerobic Performance of Healthy and Unhealthy Middle and Very Old Individuals Aged 70 Years and Older: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: The objectives of this systematic review and meta-analysis were to quantify the effectiveness of endurance training (ET) on aerobic performance (i.e., peak oxygen uptake (VO2peak)) in healthy and unhealthy middle and very old adults aged 70 years and older, and to provide dose–response relationships of training prescription variables (in terms of frequency, and volume). Methods: Several scholarly databases (i.e., PubMed/MEDLINE, SpringerLink, ScienceDirect Journals, and Taylor & Francis Online—Journals) were searched, identifying randomized controlled studies that investigated the effectiveness of ET on VO2peak in older adults. Standardized mean differences (SMD) were calculated. Results: In terms of changes differences between experimental and control group, ET produced significant large effects on VO2peak performance (SMD = 2.64 (95%CI 0.97–4.31)). The moderator analysis revealed that “health status” variable moderated ET effect onVO2peak performance. More specifically, ET produced larger SMD magnitudes on VO2peak performance in healthy compared with unhealthy individuals. With regard to the dose–response relationships, findings from the meta-regression showed that none of the included training prescription variables predicted ET effects on VO2peak performance. Conclusions: ET is an effective mean for improving aerobic performance in healthy older adults when compared with their unhealthy counterparts.
IceBear: an intuitive and versatile web application for research-data tracking from crystallization experiment to PDB deposition

The IceBear web application for monitoring and recording the results of crystallization experiments is introduced. This software includes tools for interacting directly with the ISPyB synchrotron database: metadata from shipped crystals can be uploaded directly to ISPyB, and for each sample a link to the synchrotron ISPyB diffraction information becomes available in IceBear.
Camptothecin and Topotecan, Inhibitors of Transcription Factor Fli‐1 and Topoisomerase, Markedly Ameliorate Lupus Nephritis in (NZB × NZW)F1 Mice and Reduce the Production of Inflammatory Mediators in Human Renal Cells

To examine the therapeutic effects of camptothecin (CPT) and topotecan (TPT), inhibitors of transcription factor Fli‐1 and topoisomerase, on lupus nephritis in (NZB × NZW)F1 (NZBWF1) mice, and to examine the effects of CPT and TPT on inflammatory mediators in human renal cells.
Divergence in Coding Sequence and Expression of Different Functional Categories of Immune Genes between Two Wild Rodent Species

Abstract Differences in immune function between species could be a result of interspecific divergence in coding sequence and/or expression of immune genes. Here, we investigate how the degree of divergence in coding sequence and expression differs between functional categories of immune genes, and if differences between categories occur independently of other factors (expression level, pleiotropy). To this end, we compared spleen transcriptomes of wild-caught yellow-necked mice and bank voles. Immune genes expressed in the spleen were divided into four categories depending on the function of the encoded protein: pattern recognition receptors (PRR); signal transduction proteins; transcription factors; and cyto- and chemokines and their receptors. Genes encoding PRR and cyto-/chemokines had higher sequence divergence than genes encoding signal transduction proteins and transcription factors, even when controlling for potentially confounding factors. Genes encoding PRR also had higher expression divergence than genes encoding signal transduction proteins and transcription factors. There was a positive correlation between expression divergence and coding sequence divergence, in particular for PRR genes. We propose that this is a result of that divergence in PRR coding sequence leads to divergence in PRR expression through positive feedback of PRR ligand binding on PRR expression. When controlling for sequence divergence, expression divergence of PRR genes did not differ from other categories. Taken together, the results indicate that coding sequence divergence of PRR genes is a major cause of differences in immune function between species.
The Heterogeneous Landscape and Early Evolution of Pathogen-Associated CpG Dinucleotides in SARS-CoV-2

Abstract COVID-19 can lead to acute respiratory syndrome, which can be due to dysregulated immune signaling. We analyze the distribution of CpG dinucleotides, a pathogen-associated molecular pattern, in the SARS-CoV-2 genome. We characterize CpG content by a CpG force that accounts for statistical constraints acting on the genome at the nucleotidic and amino acid levels. The CpG force, as the CpG content, is overall low compared with other pathogenic betacoronaviruses; however, it widely fluctuates along the genome, with a particularly low value, comparable with the circulating seasonal HKU1, in the spike coding region and a greater value, comparable with SARS and MERS, in the highly expressed nucleocapside coding region (N ORF), whose transcripts are relatively abundant in the cytoplasm of infected cells and present in the 3′UTRs of all subgenomic RNA. This dual nature of CpG content could confer to SARS-CoV-2 the ability to avoid triggering pattern recognition receptors upon entry, while eliciting a stronger response during replication. We then investigate the evolution of synonymous mutations since the outbreak of the COVID-19 pandemic, finding a signature of CpG loss in regions with a greater CpG force. Sequence motifs preceding the CpG-loss-associated loci in the N ORF match recently identified binding patterns of the zinc finger antiviral protein. Using a model of the viral gene evolution under human host pressure, we find that synonymous mutations seem driven in the SARS-CoV-2 genome, and particularly in the N ORF, by the viral codon bias, the transition–transversion bias, and the pressure to lower CpG content.
Immobilization of commercial hydrolytic enzymes on poly (acrylonitrile) nanofibers for anti-biofilm activity

BACKGROUND: Chemical methods used to control biofilm formation in filtration systems are not always effective. Two commercially available proteases and an amylase were immobilized onto polymer nanofibers that are used in the production of filtration membranes. RESULTS: The enzymes were immobilized onto poly acrylonitrile nanofibers that were chemically activated by imidoesterification to allow the covalent immobilization of enzymes. The immobilized enzymes retained above 80% of the specific activity of the free enzymes. For each of the immobilized enzymes, just below 30% of initial activity was retained after 10 repeated cycles of use. No biofilm formation was observed on nanofibers that were coated with the enzymes, where biofilms formed on non-coated nanofibers. CONCLUSION: When considering the combined advantages of this effective immobilization process, the robustness of the enzymes used in this study, and the results of this study indicating activity against biofilms, a valuable addition has been made to filtration membrane technology. © 2012 Society of Chemical Industry
Drosophila telomere capping protein HOAP interacts with DSB sensor proteins Mre11 and Nbs

In eukaryotes, specific DNA‐protein structures called telomeres exist at linear chromosome ends. Telomere stability is maintained by a specific capping protein complex. This capping complex is essential for the inhibition of the DNA damage response (DDR) at telomeres and contributes to genome integrity. In Drosophila, the central factors of telomere capping complex are HOAP and HipHop. Furthermore, a DDR protein complex Mre11‐Rad50‐Nbs (MRN) is known to be important for the telomere association of HOAP and HipHop. However, whether MRN interacts with HOAP and HipHop, and the telomere recognition mechanisms of HOAP and HipHop are poorly understood. Here, we show that Nbs interacts with Mre11 and transports the Mre11‐Rad50 complex from the cytoplasm to the nucleus. In addition, we report that HOAP interacts with both Mre11 and Nbs. The N‐terminal region of HOAP is essential for its co‐localization with HipHop. Finally, we reveal that Nbs interacts with the N‐terminal region of HOAP.
Microvascular flow alterations in critically ill COVID-19 patients: A prospective study.

BACKGROUND Data on microcirculatory pattern of COVID-19 critically ill patients are scarce. The objective was to compare sublingual microcirculation parameters of critically ill patients according to the severity of the disease. METHODS The study is a single-center prospective study with critically ill COVID-19 patients admitted in ICU. Sublingual microcirculation was assessed by IDF microscopy within 48 hours of ICU admission. Microcirculatory flow index (MFI), proportion of perfused vessel (PPV), total vessel density (TVD), De Backer score (DBS), perfused vessel density (PVD) and heterogeneity index (HI) were assessed. Patients were divided in 2 groups (severe and critical) according to the World health organization definition. FINDINGS From 19th of March to 7th of April 2020, 43 patients were included. Fourteen patients (33%) were in the severe group and twenty-nine patients (67%) in the critical group. Patients in the critical group were all mechanically ventilated. The critical group had significantly higher values of MFI, DBS and PVD in comparison to severe group (respectively, PaCO2: 49 [44-45] vs 36 [33-37] mmHg; p<0,0001, MFI: 2.8 ± 0.2 vs 2.5 ± 0.3; p = 0.001, DBS: 12.7 ± 2.6 vs 10.8 ± 2.0 vessels mm-2; p = 0.033, PVD: 12.5 ± 3.0 vs 10.1 ± 2.4 mm.mm-2; p = 0.020). PPV, HI and TVD were similar between groups Correlation was found between microcirculatory parameters and PaCO2 levels. CONCLUSION Critical COVID-19 patients under mechanical ventilation seem to have higher red blood cell velocity than severe non-ventilated patients.
Green Silver and Gold Nanoparticles: Biological Synthesis Approaches and Potentials for Biomedical Applications

The nanomaterial industry generates gigantic quantities of metal-based nanomaterials for various technological and biomedical applications; however, concomitantly, it places a massive burden on the environment by utilizing toxic chemicals for the production process and leaving hazardous waste materials behind. Moreover, the employed, often unpleasant chemicals can affect the biocompatibility of the generated particles and severely restrict their application possibilities. On these grounds, green synthetic approaches have emerged, offering eco-friendly, sustainable, nature-derived alternative production methods, thus attenuating the ecological footprint of the nanomaterial industry. In the last decade, a plethora of biological materials has been tested to probe their suitability for nanomaterial synthesis. Although most of these approaches were successful, a large body of evidence indicates that the green material or entity used for the production would substantially define the physical and chemical properties and as a consequence, the biological activities of the obtained nanomaterials. The present review provides a comprehensive collection of the most recent green methodologies, surveys the major nanoparticle characterization techniques and screens the effects triggered by the obtained nanomaterials in various living systems to give an impression on the biomedical potential of green synthesized silver and gold nanoparticles.
Maca Root (Lepidium meyenii) Extract Increases the Expression of MMP-1 and Stimulates Migration of Triple-Negative Breast Cancer Cells

Abstract Maca root (Lepidium meyenii) extract is a worldwide consumed food supplement for sexual dysfunctions, increasing sperm production and its motility, and alleviating menopausal symptoms. Once maca root has a role in cell proliferation and motility, and its consumption may increase along with age, mainly in menopausal women, we aimed to investigate the plant effects on triple-negative breast cancer (TNBC) cell lines. Standardized maca root powdered extract showed significant cytotoxic activity in both MDA-MB-231 and Hs578T cells, and the IC50s were 2000 μg/ml and 3000 μg/ml, respectively. Both cell lines showed an increase in migratory capacity. Using bioinformatics tools, we established genes involved in the metastatic process, CAV1, LAMA4, and MMP-1, and the mRNAs expression was assessed by qPCR. Comparing the treated cells to the negative control, CAV1 presented a decreased expression by 2-fold in MDA-MB-231. LAMA4 presented a decrease by 4-fold in Hs578T cells. MMP-1 showed substantially increase mRNA expression in MDA-MB-231 by 86-fold and in Hs578T by 5-fold. To the best of our knowledge, this is the first study indicating that the human consumption of maca may be dangerous due to the upregulation in MMP-1 expression and the increase in TNBC migrated cells.
Reverse Lymph Node Mapping Using Indocyanine Green Lymphography: A Step Forward in Minimizing Donor-Site Morbidity in Vascularized Lymph Node Transfer

Background: Reverse lymphatic mapping before harvesting a lymph node flap is crucial to avoid donor-site lymphedema; however, the technique is complex and unavailable in many centers. The authors introduce radioisotope-free reverse lymphatic mapping using indocyanine green and Patent Blue dye. Methods: The authors conducted a prospective study in patients undergoing free vascularized groin lymph node transfer for postmastectomy upper extremity lymphedema. The day before surgery, 0.2 ml of technetium-99 was injected into the first and second web spaces of the ipsilateral foot. The following day, once the patient was anesthetized, indocyanine green was injected into the same web spaces of the same foot and Patent Blue dye was injected just proximal to the upper margin of the skin paddle of the lymph node flap. The main lymph nodes draining the limb were localized using indocyanine green lymphography and gamma probe. Results: Thirty-nine patients underwent vascularized groin lymph node transfer with or without deep inferior epigastric artery perforator flap breast reconstruction. Navigation of the main lower extremity draining inguinal lymph nodes using the gamma probe and indocyanine green lymphography was identical in all patients. The blue-stained lymphatics in the skin paddle drained to the superficial proximal inguinal lymph node and were targeted for transfer. No donor-site lymphedema was reported, and lymphatic drainage of the lower extremity was preserved in all cases. Conclusions: Reverse lymphatic mapping using indocyanine green lymphography provides identical results to those using technetium-99 isotope scanning. However, indocyanine green is preferable in terms of safety and reproducibility and also avoids the complexity and hazards of radioisotope mapping. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
Predictive Modeling of Surface Wear in Mechanical Contacts under Lubricated and Non-Lubricated Conditions

The surface wear in mechanical contacts under running conditions is always a challenge to quantify. However, the inevitable relationship between the airborne noise and the surface wear can be used to predict the latter with good accuracy. In this paper, a predictive model has been derived to quantify surface wear by using airborne noise signals collected at a microphone. The noise was generated from a pin on disc setup on different dry and lubricated conditions. The collected signals were analyzed, and spectral features estimated from the measurements and regression models implemented in order to achieve an average wear prediction accuracy of within 1mm3.
Developing and Validating Clinical Questionnaires.

Coinciding with the development and revision of conceptual models of psychopathology, there has been a proliferation in the number of self-report clinical questionnaires and studies evaluating their psychometric properties. Unfortunately, many clinical measures are constructed and evaluated using suboptimal methods. This review provides current guidelines for the conceptualization, development, and psychometric validation of clinical questionnaires using latent variable methods. A two-stage exploratory-confirmatory framework is provided. The exploratory stage includes item selection and revision, initial structural evaluation, and preliminary tests of concurrent validity (e.g., convergent and discriminant). The confirmatory stage involves replicating factor structure using a more restrictive model, identifying areas of model strain, conducting additional tests of concurrent and predictive validity, and evaluating measurement invariance. Recommendations are provided for (a) item generation, (b) how to use different types of exploratory and confirmatory factor models to determine structure, and (c) evaluating reliability and validity using a latent variable measurement model approach. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 17 is May 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Caffeic Acid Enhances the Anti-Leukemic Effect of Imatinib on Chronic Myeloid Leukemia Cells and Triggers Apoptosis in Cells Sensitive and Resistant to Imatinib

Among the phenolic acids tested on the K562 cell line, a model of chronic myeloid leukemia (CML), caffeic acid (CA) was biologically active on sensitive and imatinib (IM)-resistant cells at micro-molar concentration, either in terms of reduction of cell proliferation or triggering of apoptosis. The CA treatment provoked mitochondrial membrane depolarization, genomic DNA fragmentation and phosphatidylserine exposure, hallmarks of apoptosis. Cell cycle analysis following the treatment with comparable cytotoxic concentrations of IM or CA showed marked differences in the distribution profiles. The reduction of cell proliferation by CA administration was associated with increased expression of two cell cycle repressor genes, CDKN1A and CHES1, while IM at a cytotoxic concentration increased the CHES1 but not the CDKN1A expression. In addition, CA treatment affected the proliferation and triggered the apoptosis in IM-resistant cells. Taken together, these data suggested that CA induced the anti-proliferative effect and triggered apoptosis of CML cells by a different mechanism than IM. Finally, the combined administration of IM and CA at suboptimal concentrations evidenced a synergy of action in determining the anti-proliferative effect and triggering apoptosis. The ability of CA to potentiate the anti-leukemic effect of IM highlighted the nutraceutical potential of CA in CML.
Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia

l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20–100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID. SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID.