Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacological disruption of the Notch transcription factor complex

Significance The Notch signaling cascade is deregulated by oncogenic lesions in human cancers and has therefore become an attractive therapeutic target. Inhibitory monoclonal antibodies and small-molecule γ-secretase inhibitors have been developed to target the pathway at the most proximal point of the cascade. Major hurdles to the therapeutic application of these Notch inhibitors have been prevalent dose-limiting toxicities in the intestine. Here we report identification and preclinical validation of a small molecule (CB-103) that inhibits the pathway at the level of the Notch transcription complex without causing intestinal toxicity. Its properties and mechanism of action provide CB-103 with a more favorable therapeutic index than other types of Notch targeting agents, a feature that is currently being tested in cancer patients. Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance, and resistance to cancer therapy. Several strategies, such as monoclonal antibodies against Notch ligands and receptors, as well as small-molecule γ-secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Here, we report the discovery of an orally active small-molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T cell acute lymphoblastic leukemia and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest and apoptosis, thereby impairing proliferation, including in GSI-resistant human tumor cell lines with chromosomal translocations and rearrangements in Notch genes. CB-103 produces Notch loss-of-function phenotypes in flies and mice and inhibits the growth of human breast cancer and leukemia xenografts, notably without causing the dose-limiting intestinal toxicity associated with other Notch inhibitors. Thus, we describe a pharmacological strategy that interferes with Notch signaling by disrupting the Notch transcription complex and shows therapeutic potential for treating Notch-driven cancers.
Response of Trichogramma sp. nr. sibericum (Hymenoptera: Trichogrammatidae) to age and density of its natural hosts, the eggs of Rhopobota naevana (Lepidoptera: Tortricidae)

Responses of an indigenous Trichogramma sp. nr. sibericum (Hymenoptera: Trichogrammatidae) to the age and density of eggs of the blackheaded fireworm. Rhopobota naevana (Hubner) (Lepidoptera: Tortricidae) were determined in the laboratory. The parasitoid wasp showed a significant (P 0.05) in percentages of parasitized eggs, however, were found among groups of eggs below 7-day-old. At host egg densities below 20 per wasp, the number of eggs parasitized significantly (P < 0.05) increased with egg density, and tended to stabilize at densities above 30. The rate of parasitism decreased significantly (P < 0.05) with increased host egg density. Superparasitization occurred at densities of 5-10 host eggs, but was rarely observed at densities above 20 eggs. The mean number of progeny per wasp significantly (P < 0.05) increased with host density, whereas the clutch size (the number of parasitoid offspring per parasitized host) significantly (P < 0.05) decreased with an increase in host density.
Comparison of Endoscopic and Ultrasonographic Measurements of the Subglottic Airway in Children

Objective To compare measurements of the pediatric subglottis obtained by surgeon-performed ultrasound and endoscopy. Study Design Prospective observational comparison-of-methods study. Setting Tertiary care pediatric hospital. Subjects and Methods Thirty-one patients who underwent direct laryngoscopy from May 2017 to July 2018 were recruited. Transcervical ultrasound was used to visualize the vocal folds, subglottis, and cervical trachea. The anterior-posterior (AP) and transverse (TV) diameter of the subglottic space were measured endoscopically and via ultrasound by 2 independent evaluators. Measurements were compared for correlation, bias, and agreement. A clinically acceptable bias for subglottic diameter was assumed to be 0.5 mm or less. Results The median age of enrolled patients was 2.6 years (range, 4 months–13.3 years). Endoscopic subglottic AP and TV measurements ranged from 3.33 mm to 14.81 mm and from 4.44 mm to 11.65 mm, respectively, while ultrasonographic AP and TV measurements ranged from 4.57 mm to 9.85 mm and from 3.77 mm to 8.96 mm. Pearson coefficient showed strong a correlation for both endoscopic and ultrasound AP (R = 0.8081, P < .0001) and TV (R = 0.8796, P < .001) measurements of the subglottis. Bland-Altman plots revealed a bias (average discrepancy) for AP measurements of 0.22 mm and 0.11 mm for TV measurements. Conclusion Endoscopic and ultrasonography measurements of the pediatric subglottic airway were strongly correlated. The discrepancy between AP and TV measurements was less than 0.5 mm. Ultrasound of the subglottis may be an alternative to endoscopic assessment of the airway for measurement of the subglottic airway in children in select cases.
Are Sugar-Reduced and Whole Grain Infant Cereals Sensorially Accepted at Weaning? A Randomized Controlled Cross-Over Trial

The way infants are fed during the complementary period can have a significant impact on infants’ health and development. Infant cereals play an important role in complementary feeding in many countries. In spite of well documented benefits of a low sugar and high whole grain diet, commercial infant cereals are often refined and contain a high amount of sugars. The aim of the present study was to compare the sensory acceptability, gastrointestinal tolerance and bowel habits of two commercially available infant cereals in Spain with varying sugar and whole grain contents in infants at weaning. Forty-six healthy infants (mean age = 5.2 ± 0.4 months) received one of the two infant cereals containing either 0% whole grain flour and a high sugar content produced by starch hydrolysis (24 g/100 g) (Cereal A) or 50% whole grain flour and a medium-sugar content produced by hydrolysis (12 g/100 g) (Cereal B) in a randomized, triple blind, cross-over controlled trial. Both types of infant cereals were consumed for seven weeks. The cross-over was carried out after seven weeks. Sensory acceptability, anthropometry, gastrointestinal tolerance and adverse events were measured, and results evaluated using a linear regression model. No significant differences were observed between groups in any of the main variables analyzed. Importantly, the long-term health implications of our findings represent a wake-up call for the food industry to reduce or even eliminate simple sugars in infant cereals and for regulatory bodies and professional organizations to recommend whole grain infant cereals.
Equilibrium folding intermediates of a greek key β-barrel protein

Protein S is a calcium-binding protein comprising two Greek key b-barrel domains. We have used NMR and optical spectroscopies to show that, in the absence of calcium, the N-terminal domain of protein S forms two equilibrium folding intermediates that are in slow exchange. The intermediates arise from differential calcium-dependent folding of subdomains which are not contiguous along the polypeptide chain. The structures of these intermediates are incompatible with several previously proposed folding mechanisms for Greek key b-barrel domains. We propose a different mechanism that involves multiple nucleation sites for folding and sequential acquisition of native long-range interactions. # 1998 Academic Press Limited
Mediterranean Diet: Lipids, Inflammation, and Malaria Infection

The Mediterranean diet (MedDiet) consists of consumption of vegetables and healthy oils and have beneficial effects on metabolic and inflammatory diseases. Our goal here is to discuss the role of fatty acid content in MedDiet, mostly omega-3, omega-6, and omega-9 on malaria. Malaria affects millions of people around the globe. The parasite Plasmodium causes the disease. The metabolic and inflammatory alterations in the severe forms have damaging consequences to the host. The lipid content in the MedDiet holds anti-inflammatory and pro-resolutive features in the host and have detrimental effects on the Plasmodium. The lipids from the diet impact the balance of pro- and anti-inflammation, thus, lipids intake from the diet is critical to parasite elimination and host tissue damage caused by an immune response. Herein, we go into the cellular and molecular mechanisms and targets of the MedDiet fatty acids in the host and the parasite, reviewing potential benefits of the MedDiet, on inflammation, malaria infection progression, and clinical outcome.
Prey Selection by Myotis myotis (Vespertilionidae) in a Mediterranean Region

Seasonal variations in the diet composition and prey selection by Myotis myotis were studied in a Mediterranean region dominated by open stone oak woodlands, olive groves, and cereal steppes. The diet and food abundance were determined by faecal analysis and pitfall trapping, respectively. Overall, the diet (expressed as % frequency) was dominated by carabid beetles (Carabidae, 52%), crickets (Gryllidae, 43%), and spiders (Arachnida, 34%). Food was far more abundant in the spring than in the summer and autumn. The dietary composition varied significantly throughout the year. In the spring, it was dominated by carabids and crickets, and in the summer by spiders. These were then replaced by carabids, which became the most frequently eaten prey in autumn. The spring-summer switch to spiders coincided with a marked drop in food abundance. Some of the temporal variations in bats' diet can be explained by parallel changes in prey abundance. In comparison to central European populations, our Mediterranean colony of M. myotis consumed much more crickets and spiders, which was balanced with a lower use of carabid beetles. Prey selection was tested using logistic regression models. The results suggest that, although carabids are the most consumed, crickets are preferred. Spiders seem to represent mostly a complement preyed upon at times of lower food abundance. It is not clear if the preference for crickets is simply due to their great conspicuousness, or to the choice based on energetic rewards or taste. Overall, our results are consistent with the predictions of the optimal foraging theory.
Additional toxins for feral pig (Sus scrofa) control: identifying and testing Achilles' heels

A literature review was conducted in order to identify unique weaknesses in the physiology or metabolism of pigs that could be targeted with specific chemicals (i.e. an ‘Achilles’ heel’ search). A promising weakness identified was the species’ susceptibility to methaemoglobin-forming compounds, most likely related to their uniquely low levels of methaemoglobin reductase. Further examination revealed that sodium nitrite is a cost-effective, readily available methaemoglobin-forming compound that is highly toxic to domestic pigs, which has caused numerous accidental poisonings. Pen trials on pigs showed that sodium nitrite delivered by gavage (>90 mg kg-1) and freely consumed in bait (>400 mg kg-1) caused rapid and lethal rises in methaemoglobin. Sodium nitrite appeared to be more humane than currently used toxins, with deaths following bait consumption being considerably quicker and with fewer symptoms (within 80 min of clinical signs beginning; clinical signs including infrequent vomiting, lethargy, ataxia and dyspnoea). The review also identified a second deficiency in the metabolism of pigs, namely high sensitivity to selective inhibition of cytochrome P450 liver enzymes. This leads to potentially lethal interactions between various drugs, such as two antibiotics, monensin and tiamulin. A pen trial confirmed that the antibiotic combination in a single gavage dose was reliably and rapidly lethal to pigs. However, its utility as a pig toxin is low, because it was unpalatable to pigs when delivered in bait and appeared to cause pain and suffering (leading to the early termination of pen trials). The findings presented here demonstrate the potential of sodium nitrite as an additional feral pig toxin.
Kratom Use in the United States: A Diverse and Complex Profile.

Schimmel et al. (1) evaluated the prevalence and substance-abuse profile of kratom users through the Non-Medical Use of Prescription Drugs (NMURx) Program, part of the Research Abuse, Diversion, and Addiction-Related Surveillance (RADARS) system. The study compared Drug Abuse Screening Test (DAST-10) scores of kratom users with non-users, finding users significantly more often in the substantial/severe category and suggesting that kratom users are therefore more likely to suffer from adverse substance-use problems (1). Unfortunately, these findings may be misinterpreted to infer a cause-effect relationship between kratom use and substance-use disorders or to support the suggestion that kratom may increase the risk of drug abuse. Such conclusions are decidedly inconsistent with prior studies on kratom users, who report using kratom to mitigate drug-dependence and reduce the frequent use and severe problems associated with classical opioids and other common drugs of
Herbal Extracts with Antifungal Activity Against Candida albicans: A Systematic Review.

BACKGROUND In the era of antimicrobial resistance, fungal pathogens are not an exception. Several strategies, including antimicrobial stewardship programs and high throughput screening of new drugs are being implemented. Several recent studies have demonstrated effectiveness of plant compounds with antifungal activity. OBJECTIVE In this systematic review we examine the use of natural compounds as a possible avenue to fight fungal infections produced by Candida albicans, the most common human fungal pathogen. METHOD Electronic literature searches were conducted through PubMed/MEDLINE, Cochrane, and Science Direct limited to the 5 years. A total of 131 articles were included with 186 plants extracts evaluated. RESULTS Although the majority of the natural extracts exhibited antifungal activities against C. albicans (both in vivo and in vitro), the strongest antifungal activity was obtained from Lawsonia inermis, Pelargonium graveolens, Camellia sinensis, Mentha piperita, and Citrus latifolia. CONCLUSION The main components with proven antifungal activities were phenolic compounds such as gallic acid, thymol, and flavonoids (specially catechin), polyphenols such as tannins, terpenoids and saponins. The incorporation of nanotechnology enhances greatly the antifungal properties of these natural compounds. Further research is needed to fully characterize the composition of all herbal extracts with antifungal activity as well as the mechanisms of action of the active compounds.
Improving Bilingual Lexicon Induction with Unsupervised Post-Processing of Monolingual Word Vector Spaces

Work on projection-based induction of cross-lingual word embedding spaces (CLWEs) predominantly focuses on the improvement of the projection (i.e., mapping) mechanisms. In this work, in contrast, we show that a simple method for post-processing monolingual embedding spaces facilitates learning of the cross-lingual alignment and, in turn, substantially improves bilingual lexicon induction (BLI). The post-processing method we examine is grounded in the generalisation of first- and second-order monolingual similarities to the nth-order similarity. By post-processing monolingual spaces before the cross-lingual alignment, the method can be coupled with any projection-based method for inducing CLWE spaces. We demonstrate the effectiveness of this simple monolingual post-processing across a set of 15 typologically diverse languages (i.e., 15*14 BLI setups), and in combination with two different projection methods.
Bioclickable and mussel adhesive peptide mimics for engineering vascular stent surfaces

Significance An ideal metal vascular stent has multiple properties for successful reendothelialization. These properties include 1) inhibiting thrombosis by preventing platelet activation/adhesion, 2) suppressing smooth muscle cell migration/proliferation, and 3) accelerating endothelial cell migration/proliferation. With an easy-to-perform, two-step surface bioengineering approach, the multifunctionalized stents reported here contain two vasoactive moieties (i.e., the nitric-oxide-generating organoselenium and the endothelial progenitor cell-targeting peptide) to satisfy all requirements. The surface engineering strategy presented here can be translated into clinical coatings for cardiovascular stents and will benefit enormously and globally the cardiovascular disease patients; it will, moreover, offer insights to engineering surfaces of blood-contacting devices. Thrombogenic reaction, aggressive smooth muscle cell (SMC) proliferation, and sluggish endothelial cell (EC) migration onto bioinert metal vascular stents make poststenting reendothelialization a dilemma. Here, we report an easy to perform, biomimetic surface engineering strategy for multiple functionalization of metal vascular stents. We first design and graft a clickable mussel-inspired peptide onto the stent surface via mussel-inspired adhesion. Then, two vasoactive moieties [i.e., the nitric-oxide (NO)-generating organoselenium (SeCA) and the endothelial progenitor cell (EPC)-targeting peptide (TPS)] are clicked onto the grafted surfaces via bioorthogonal conjugation. We optimize the blood and vascular cell compatibilities of the grafted surfaces through changing the SeCA/TPS feeding ratios. At the optimal ratio of 2:2, the surface-engineered stents demonstrate superior inhibition of thrombosis and SMC migration and proliferation, promotion of EPC recruitment, adhesion, and proliferation, as well as prevention of in-stent restenosis (ISR). Overall, our biomimetic surface engineering strategy represents a promising solution to address clinical complications of cardiovascular stents and other blood-contacting metal materials.
Antiangiogenic Targets for Glioblastoma Therapy from a Pre-Clinical Approach, Using Nanoformulations

Glioblastoma (GBM) is the most aggressive tumor type whose resistance to conventional treatment is mediated, in part, by the angiogenic process. New treatments involving the application of nanoformulations composed of encapsulated drugs coupled to peptide motifs that direct drugs to specific targets triggered in angiogenesis have been developed to reach and modulate different phases of this process. We performed a systematic review with the search criterion (Glioblastoma OR Glioma) AND (Therapy OR Therapeutic) AND (Nanoparticle) AND (Antiangiogenic OR Angiogenesis OR Anti-angiogenic) in Pubmed, Scopus, and Cochrane databases, in which 312 articles were identified; of these, only 27 articles were included after selection and analysis of eligibility according to the inclusion and exclusion criteria. The data of the articles were analyzed in five contexts: the characteristics of the tumor cells; the animal models used to induce GBM for antiangiogenic treatment; the composition of nanoformulations and their physical and chemical characteristics; the therapeutic anti-angiogenic process; and methods for assessing the effects on antiangiogenic markers caused by therapies. The articles included in the review were heterogeneous and varied in practically all aspects related to nanoformulations and models. However, there was slight variance in the antiangiogenic effect analysis. CD31 was extensively used as a marker, which does not provide a view of the effects on the most diverse aspects involved in angiogenesis. Therefore, the present review highlighted the need for standardization between the different approaches of antiangiogenic therapy for the GBM model that allows a more effective meta-analysis and that helps in future translational studies.
High variability in spawner-recruit data hampers learning

Variability is a formidable opponent of experimental management aimed at detecting spawner-recruit (SR) effects in a short time frame. I fitted Ricker SR models to 214 different SR data sets and found that high residual error variability was common. For each of these data sets, in an a priori power analysis, I estimated the power of experi - ments that used the change in Ricker a as the treatment effect and a temporal reference alone (no subpopulation refer- ences). Power was calculated using both bootstrap resampling and the usual normal theory methods. The analysis revealed that large residual variability severely limits the power to detect large changes in recruits per spawner ( R/S). At the median level of error variability, achieving the design criteria of = 0.05 and power = 0.8 required an experi- ment that doubled R/S to last about 20 years (assuming an equal number of treatment and control years). Several ap- proaches to countering large error variability are discussed along with their limitations. Resume : La variabilite pose un defi considerable dans le montage d'experiences qui visent a detecter les effets des geniteurs-recrues (SR) sur une courte echelle de temps. J'ai ajuste les modeles SR de Ricker a 214 series de donnees differentes de SR et j'ai regulierement trouve une grande variabilite dans les erreurs residuelles. Pour chacune de ces series de donnees, j'ai, a l'aide d'une analyse de puissance a priori, estime la puissance des experiences qui utilisaient le changement du parametre a de Ricker comme effet du traitement et une seule reference temporelle (sans reference a la sous-population). La puissance a ete calculee a la fois par le re-echantillonnage par bootstrap et les methodes theori- ques normales. L'analyse a revele que la grande variabilite des residus limite considerablement la capacite de detecter d'importants changements dans le nombre de recrues par geniteur (R/S). Au niveau median de variabilite de l'erreur, pour obtenir comme criteres du plan d'experience un de 0,05 et une puissance de 0,8, il faut une experience qui double R/S pour une duree d'environ 20 ans (en assumant un nombre egal de traitements et d'annees-temoins). On trouvera une discussion sur les diverses strategies possibles pour parer a la grande variabilite dans l'erreur et les limites de chacune. (Traduit par la Redaction) Hinrichsen 776
Nuclear Egress Complexes of HCMV and Other Herpesviruses: Solving the Puzzle of Sequence Coevolution, Conserved Structures and Subfamily-Spanning Binding Properties

Herpesviruses uniquely express two essential nuclear egress-regulating proteins forming a heterodimeric nuclear egress complex (core NEC). These core NECs serve as hexameric lattice-structured platforms for capsid docking and recruit viral and cellular NEC-associated factors that jointly exert nuclear lamina as well as membrane-rearranging functions (multicomponent NEC). The regulation of nuclear egress has been profoundly analyzed for murine and human cytomegaloviruses (CMVs) on a mechanistic basis, followed by the description of core NEC crystal structures, first for HCMV, then HSV-1, PRV and EBV. Interestingly, the highly conserved structural domains of these proteins stand in contrast to a very limited sequence conservation of the key amino acids within core NEC-binding interfaces. Even more surprising, although a high functional consistency was found when regarding the basic role of NECs in nuclear egress, a clear specification was identified regarding the limited, subfamily-spanning binding properties of core NEC pairs and NEC multicomponent proteins. This review summarizes the evolving picture of the relationship between sequence coevolution, structural conservation and properties of NEC interaction, comparing HCMV to α-, β- and γ-herpesviruses. Since NECs represent substantially important elements of herpesviral replication that are considered as drug-accessible targets, their putative translational use for antiviral strategies is discussed.