Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of circadian rhythms in Nannochloropsis species using bioluminescence reporter lines

Circadian clocks allow organisms to predict environmental changes caused by the rotation of the Earth. Although circadian rhythms are widespread among different taxa, the core components of circadian oscillators are not conserved and differ between bacteria, plants, animals and fungi. Stramenopiles are a large group of organisms in which circadian rhythms have been only poorly characterized and no clock components have been identified. We have investigated cell division and molecular rhythms in Nannochloropsis species. In the four strains tested, cell division occurred principally during the night period under diel conditions, however, rhythms dampened within 2-3 days after transfer to constant light. We developed firefly luciferase reporters for long-term monitoring of in vivo transcriptional rhythms in two Nannochlropsis species, N. oceanica CCMP1779 and N. salina CCMP537. The reporter lines express free-running bioluminescence rhythms with periods of ~21-31 h that dampen within ~3-4 days under constant light. Using different entrainment regimes, we demonstrate that these rhythms are regulated by a circadian-type oscillator. In addition, the phase of free-running luminescence rhythms can be modulated pharmacologically using a CK1 ε/δ inhibitor, suggesting a role of this kinase in the Nannochloropsis clock. Together with the molecular and genomic tools available for Nannochloropsis species, these reporter lines represent an excellent system for future studies on the molecular mechanisms of stramenopile circadian oscillators. Significance statement Stramenopiles are a large and diverse line of eukaryotes in which circadian rhythms have been only poorly characterized and no clock components have been identified. We have developed bioluminescence reporter lines in Nannochloropsis species and provide evidence for the presence of a circadian oscillator in stramenopiles; these lines will serve as tools for future studies to uncover the molecular mechanisms of circadian oscillations in these species.
A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. ABSTRACT Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.
Influence of nonsynaptic α1 glycine receptors on ethanol consumption and place preference

Alcohol abuse leads to great medical, social, and economic burdens throughout the world. It is believed that the rewarding actions of alcohol are mediated by alterations in the mesolimbic dopaminergic system leading to increased levels of dopamine in the nucleus accumbens (NAc). Little is known about the role that ligand‐gated ion channels (LGICs), such as glycine receptors (GlyRs), have in regulating levels of ethanol intake and place preference. In this study, we used knock‐in (KI) mice that have ethanol‐insensitive α1 GlyRs (KK385/386AA) and a combination of electrophysiological and behavioral approaches to examine how expression of ethanol‐resistant α1 GlyRs in brain neurons might affect binge drinking and conditioned place preference. Data show that tonic α1 GlyR–mediated currents that modulate accumbal excitability were exclusively sensitive to ethanol only in wild‐type (WT) mice. Behavioral studies showed that the KI mice have a higher intake of ethanol upon first exposure to drinking and greater conditioned place preference to ethanol, suggesting that α1 GlyRs in the brain have a protective role against abuse. This study suggests that nonsynaptic α1–containing GlyRs have a role in motivational and early reinforcing effects of ethanol and open a novel opportunity for pharmacotherapy development to treat alcohol use disorders.
JNK inactivation suppresses osteogenic differentiation, but robustly induces osteopontin expression in osteoblasts through the induction of inhibitor of DNA binding 4 (Id4)

Osteoblasts are versatile cells involved in multiple whole‐body processes, including bone formation and immune response. Secretory amounts and patterns of osteoblast‐derived proteins such as osteopontin (OPN) and osteocalcin (OCN) modulate osteoblast function. However, the regulatory mechanism of OPN and OCN expression remains unknown. Here, we demonstrate that p54/p46 c‐jun N‐terminal kinase (JNK) inhibition suppresses matrix mineralization and OCN expression but increases OPN expression in MC3T3‐E1 cells and primary osteoblasts treated with differentiation inducers, including ascorbic acid, bone morphogenic protein‐2, or fibroblast growth factor 2. Preinhibition of JNK before the onset of differentiation increased the number of osteoblasts that highly express OPN but not OCN (OPN‐OBs), indicating that JNK affects OPN secretory phenotype at the early stage of osteogenic differentiation. Additionally, we identified JNK2 isoform as being critically involved in OPN‐OB differentiation. Microarray analysis revealed that OPN‐OBs express characteristic transcription factors, cell surface markers, and cytokines, including glycoprotein hormone α2 and endothelial cell–specific molecule 1. Moreover, we found that inhibitor of DNA binding 4 is an important regulator of OPN‐OB differentiation and that dual‐specificity phosphatase 16, a JNK‐specific phosphatase, functions as an endogenous regulator of OPN‐OB induction. OPN‐OB phenotype was also observed following LPS from Porphyromonas gingivalis stimulation during osteogenic differentiation. Collectively, these results suggest that the JNK‐Id4 signaling axis is crucial in the control of OPN and OCN expression during osteoblastic differentiation. —Kusuyama, J., Amir, M. S. , Albertson, B. G. , Bandow, K. , Ohnishi, T. , Nakamura, T. , Noguchi, K. , Shima, K. , Semba, I. , Matsuguchi, T. JNK inactivation suppresses osteogenic differentiation, but robustly induces osteopontin expression in osteoblasts through the induction of inhibitor of DNA binding 4 (Id4). FASEB J. 33, 7331–7347 (2019). www.fasebj. org
Intake of Meat, Fish, Fruits, and Vegetables and Long-Term Risk of Dementia and Alzheimer's Disease.

BACKGROUND The links between diet and the risk of dementia have never been studied considering the possibility of protopathic bias (i.e., reverse causation). OBJECTIVE We aimed to examine the relationship between consumption frequency of meat, fish, fruits, and vegetables and long-term risk of dementia and Alzheimer's disease (AD), by taking into account this possibility. METHODS We analyzed data of 5,934 volunteers aged 65 and over from the Three-city study who were followed every 2 to 4 years for 12 years. Dietary habits were assessed at inclusion using a brief food frequency questionnaire. The presence of symptoms of dementia was investigated at each follow-up visit. To limit the risk of protopathic bias, a 4-year lag window between exposure and disease assessment was implemented by excluding from the analyses all dementia cases that occurred during the first four years after inclusion. Analyses were performed using a Cox proportional hazard model and were adjusted for socio-demographic, lifestyle, and health factors. RESULTS The average follow-up time was 9.8 years. During this period, 662 cases of dementia, including 466 of AD, were identified. After adjustment, only low meat consumption (≤1 time/week) was associated with an increased risk of dementia and AD compared with regular consumption (≥4 times/week) (HR = 1.58 95% CI = [1.17-2.14], HR = 1.67 95% CI = [1.18-2.37], respectively). No association was found between the consumption of fish, raw fruits, or cooked fruits and vegetables and the risk of dementia or AD. CONCLUSION These findings suggest very low meat consumption increases the long-term risk of dementia and AD, and that a protopathic bias could have impacted finding from previous studies.
QT Assessment in Early Drug Development: The Long and the Short of It

The QT interval occupies a pivotal role in drug development as a surface biomarker of ventricular repolarization. The electrophysiologic substrate for QT prolongation coupled with reports of non-cardiac drugs producing lethal arrhythmias captured worldwide attention from government regulators eventuating in a series of guidance documents that require virtually all new chemical compounds to undergo rigorous preclinical and clinical testing to profile their QT liability. While prolongation or shortening of the QT interval may herald the appearance of serious cardiac arrhythmias, the positive predictive value of an abnormal QT measurement for these arrhythmias is modest, especially in the absence of confounding clinical features or a congenital predisposition that increases the risk of syncope and sudden death. Consequently, there has been a paradigm shift to assess a compound’s cardiac risk of arrhythmias centered on a mechanistic approach to arrhythmogenesis rather than focusing solely on the QT interval. This entails both robust preclinical and clinical assays along with the emergence of concentration QT modeling as a primary analysis tool to determine whether delayed ventricular repolarization is present. The purpose of this review is to provide a comprehensive understanding of the QT interval and highlight its central role in early drug development.
TET1 reprograms the epithelial ovarian cancer epigenome and reveals casein kinase 2α as a therapeutic target

Ten‐eleven translocation methylcytosine dioxygenase‐1, TET1, takes part in active DNA demethylation. However, our understanding of DNA demethylation in cancer biology and its clinical significance remain limited. This study showed that TET1 expression correlated with poor survival in advanced‐stage epithelial ovarian carcinoma (EOC), and with cell migration, anchorage‐independent growth, cancer stemness, and tumorigenicity. In particular, TET1 was highly expressed in serous tubal intraepithelial carcinoma (STIC), a currently accepted type II EOC precursor, and inversely correlated with TP53 mutations. Moreover, TET1 could demethylate the epigenome and activate multiple oncogenic pathways, including an immunomodulation network having casein kinase II subunit alpha (CK2α) as a hub. Patients with TET1highCK2αhigh EOCs had the worst outcomes, and TET1‐expressing EOCs were more sensitive to a CK2 inhibitor, both in vitro and in vivo. Our findings uncover the oncogenic and poor prognostic roles of TET1 in EOC and suggest an unexplored role of epigenetic reprogramming in early ovarian carcinogenesis. Moreover, the immunomodulator CK2α represents a promising new therapeutic target, warranting clinical trials of the tolerable CK2 inhibitor, CX4945, for precision medicine against EOC. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Enabling free‐breathing background suppressed renal pCASL using fat imaging and retrospective motion correction

For free‐breathing renal perfusion imaging using arterial spin labeling (ASL), retrospective image realignment has been found essential to reduce subtraction artifacts and, independently, background suppression has been demonstrated to reduce physiologic noise. However, negative results on ASL precision and accuracy have been reported for the combination of both. In this study, the effect of background suppression ‐level in combination with image registration on free‐breathing renal ASL signal quality, with registration either on ASL‐images themselves or guided by additionally acquired fat‐images, was investigated. The results from free‐breathing acquisitions were compared with the reference paced‐breathing motion compensation strategy.
Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences

The stability and dynamics of cytoskeleton in brain nerve cells are regulated by microtubule associated proteins (MAPs), tau and MAP2. Both proteins are intrinsically disordered and involved in multiple molecular interactions important for normal physiology and pathology of chronic neurodegenerative diseases. Nuclear magnetic resonance and cryo-electron microscopy recently revealed propensities of MAPs to form transient local structures and long-range contacts in the free state, and conformations adopted in complexes with microtubules and filamentous actin, as well as in pathological aggregates. In this paper, we compare the longest, 441-residue brain isoform of tau (tau40), and a 467-residue isoform of MAP2, known as MAP2c. For both molecules, we present transient structural motifs revealed by conformational analysis of experimental data obtained for free soluble forms of the proteins. We show that many of the short sequence motifs that exhibit transient structural features are linked to functional properties, manifested by specific interactions. The transient structural motifs can be therefore classified as molecular recognition elements of tau40 and MAP2c. Their interactions are further regulated by post-translational modifications, in particular phosphorylation. The structure-function analysis also explains differences between biological activities of tau40 and MAP2c.
Supplementation with Hydroxytyrosol and Punicalagin Improves Early Atherosclerosis Markers Involved in the Asymptomatic Phase of Atherosclerosis in the Adult Population: A Randomized, Placebo-Controlled, Crossover Trial

Hydroxytyrosol (HT) and Punicalagin (PC) exert cardioprotective and anti-atherosclerotic effects. This study evaluates the effect of oral supplementation with HT and PC (SAx) on early atherosclerosis markers in middle-aged, seemingly healthy adults. A randomized, double-blinded, placebo-controlled, crossover trial was performed for 20 weeks. There were two treatment sequences (Placebo/SAx, n = 41; SAx/Placebo, n = 43) for which the intervention periods (Placebo and SAx) were 8 weeks long, followed by a 4-week wash out period. The supplement was composed of 9.9 mg of HT and 195 mg of PC, and the placebo was composed of maltodextrin. SAx increased endothelial function (Flow-mediated dilatation [FMD]: 2.36%; p < 0.001) in the endothelial dysfunction subgroup compared to the placebo (2.36 ± 3.9 vs. 0.76 ± 3.5%, p < 0.05). SAx also reduced oxLDL by −28.74 ng/mL (p < 0.05) in subjects with higher levels of oxLDL, which was an improvement compared with the placebo (−28.74 ± 40.2 vs. 25.64 ± 93.8 ng/mL, p < 0.001). The prehypertension and hypertension subgroups exhibited decreased systolic (−15.75 ± 9.9 mmHg; p < 0.001) and diastolic (−6.36 ± 8.7 mmHg; p < 0.001) blood pressure after SAx consumption. Moreover, the systolic prehypertension and hypertension subgroups presented significant differences in systolic blood pressure compared to the placebo (−15.75 ± 9.9 vs. −2.67 ± 12.0 mmHg, p < 0.05). In conclusion, the supplement exerted anti-atherosclerotic effects by improving endothelial function, blood pressure, and levels of circulating oxLDL, especially for persons in whom these parameters were altered.
The impacts of depression and anxiety on quality of life among patients with HIV/AIDS and their spouses: testing dyadic dynamics using the actor-partner interdependence model

ABSTRACT HIV/AIDS not only affects the patients, but also their entire family. This study aimed to assess the impacts of the patients’ and their spouses’ anxiety and depression on their quality of life (QoL) at the dyadic level. A total of 120 serodiscordant husband-wife dyads from the voluntary counselling and testing center in Shiraz, Iran, were involved in this study from February to June 2015. The WHOQOL-BREEF, CESD-10, and Beck Anxiety Inventory instruments were used, respectively, to assess the QoL, depression, and anxiety scores of the participants. The actor-partner interdependence model (APIM) was used to estimate the effects of depression and anxiety of both the people living with HIV/AIDS (PLWHA) and their spouses on their own QoL (actor effect) as well as their partners’ (partner effect). The APIM analysis revealed that both PLWHAs’ and their spouses’ depression and anxiety showed actor effects on their own QoL. Furthermore, spouses’ depression showed a significant partner effect on PLWHAs’ QoL and PLWHAs’ anxiety had significant partner effects on spouses’ QoL. Accordingly, this data can be used to develop targeted interventions aimed at guidance and assistance of PLWHAs and their spouses to find coping strategies that improve their own QoL as well as their partners’.
Temperature-Dependent Resistive Properties of Vanadium Pentoxide/Vanadium Multi-Layer Thin Films for Microbolometer & Antenna-Coupled Microbolometer Applications

In this study, vanadium oxide (VxOy) semiconducting resistive thermometer thin films were developed, and their temperature-dependent resistive behavior was examined. Multilayers of 5-nm-thick vanadium pentoxide (V2O5) and 5-nm-thick vanadium (V) films were alternately sputter-deposited, at room temperature, to form 105-nm-thick VxOy films, which were post-deposition annealed at 300 °C in O2 and N2 atmospheres for 30 and 40 min. The synthesized VxOy thin films were then patterned into resistive thermometer structures, and their resistance versus temperature (R-T) characteristics were measured. Samples annealed in O2 achieved temperature coefficients of resistance (TCRs) of −3.0036 and −2.4964%/K at resistivity values of 0.01477 and 0.00819 Ω·cm, respectively. Samples annealed in N2 achieved TCRs of −3.18 and −1.1181%/K at resistivity values of 0.04718 and 0.002527 Ω·cm, respectively. The developed thermometer thin films had TCR/resistivity properties suitable for microbolometer and antenna-coupled microbolometer applications. The employed multilayer synthesis technique was shown to be effective in tuning the TCR/resistivity properties of the thin films by varying the annealing conditions.
Artemisinin resistance-associated markers in Plasmodium falciparum parasites from the China-Myanmar border: predicted structural stability of K13 propeller variants detected in a low-prevalence area

Background Malaria reduction and future elimination in China is made more difficult by the importation of cases from neighboring endemic countries, particularly Myanmar, Laos, and Vietnam, and increased travel to Africa by Chinese nationals. The increasing prevalence of artemisinin resistant parasites across Southeast Asia highlights the importance of monitoring the parasite importation into China. Artemisinin resistance in the Mekong region is associated with variants of genes encoding the K13 kelch domain protein (pf13k), found in specific genetic backgrounds, including certain alleles of genes encoding the chloroquine resistance transporter (pfcrt) and multidrug resistance transporter PgH1 (pfmdr1). Methods In this study we investigated the prevalence of drug resistance markers in 72 P. falciparum samples from uncomplicated malaria infections in Tengchong and Yingjiang, counties on the Yunnan-Myanmar border. Variants of pf13k, pfcrt and pfmdr1 are described. Results Almost all parasites harboured chloroquine-resistant alleles of pfcrt, whereas pfmdr1 was more diverse. Major mutations in the K13 propeller domain associated with artemisinin resistance in the Mekong region (C580Y, R539T and Y493H) were absent, but F446I and two previously undescribed mutations (V603E and V454I) were identified. Protein structural modelling was carried out in silico on each of these K13 variants, based on recently published crystal structures for the K13 propeller domain. Whereas F446I was predicted to elicit a moderate destabilisation of the propeller structure, the V603E substitution is likely to lead to relatively high protein instability. We plotted these stability estimates, and those for all previously described variants, against published values for in vivo parasitaemia half-life, and found that quadratic regression generates a useful predictive algorithm. Conclusion This study provides a baseline of P. falciparum resistance-associated mutations prevalent at the China-Myanmar border. We also show that protein modelling can be used to generate testable predictions as to the impact of pfk13 mutations on in vivo (and potentially in vitro) artemisinin susceptibility.
Artificial Light at Night Alleviates the Negative Effect of Pb on Freshwater Ecosystems

Artificial light at night (ALAN) is an increasing phenomenon worldwide that can cause a series of biological and ecological effects, yet little is known about its potential interaction with other stressors in aquatic ecosystems. Here, we tested whether the impact of lead (Pb) on litter decomposition was altered by ALAN exposure using an indoor microcosm experiment. The results showed that ALAN exposure alone significantly increased leaf litter decomposition, decreased the lignin content of leaf litter, and altered fungal community composition and structure. The decomposition rate was 51% higher in Pb with ALAN exposure treatments than in Pb without ALAN treatments, resulting in increased microbial biomass, β-glucosidase (β-G) activity, and the enhanced correlation between β-G and litter decomposition rate. These results indicate that the negative effect of Pb on leaf litter decomposition in aquatic ecosystems may be alleviated by ALAN. In addition, ALAN exposure also alters the correlation among fungi associated with leaf litter decomposition. In summary, this study expands our understanding of Pb toxicity on litter decomposition in freshwater ecosystems and highlights the importance of considering ALAN when assessing environmental metal pollutions.