Miracle-dz/UniFAR-FTUs huggingface dataset:
Interest of Homodialkyl Neamine Derivatives against Resistant P. aeruginosa, E. coli, and β-Lactamases-Producing Bacteria—Effect of Alkyl Chain Length on the Interaction with LPS

Development of novel therapeutics to treat antibiotic-resistant infections, especially those caused by ESKAPE pathogens, is urgent. One of the most critical pathogens is P. aeruginosa, which is able to develop a large number of factors associated with antibiotic resistance, including high level of impermeability. Gram-negative bacteria are protected from the environment by an asymmetric Outer Membrane primarily composed of lipopolysaccharides (LPS) at the outer leaflet and phospholipids in the inner leaflet. Based on a large hemi-synthesis program focusing on amphiphilic aminoglycoside derivatives, we extend the antimicrobial activity of 3′,6-dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine on clinical P. aeruginosa, ESBL, and carbapenemase strains. We also investigated the capacity of 3′,6-homodialkyl neamine derivatives carrying different alkyl chains (C7–C11) to interact with LPS and alter membrane permeability. 3′,6-Dinonyl neamine and its branched isomer, 3′,6-di(dimethyloctyl) neamine showed low MICs on clinical P. aeruginosa, ESBL, and carbapenemase strains with no MIC increase for long-duration incubation. In contrast from what was observed for membrane permeability, length of alkyl chains was critical for the capacity of 3′,6-homodialkyl neamine derivatives to bind to LPS. We demonstrated the high antibacterial potential of the amphiphilic neamine derivatives in the fight against ESKAPE pathogens and pointed out some particular characteristics making the 3′,6-dinonyl- and 3′,6-di(dimethyloctyl)-neamine derivatives the best candidates for further development.
WNT-5a and SOST Levels in Gingival Crevicular Fluid Depend on the Inflammatory and Osteoclastogenic Activities of Periodontal Tissues

Background and Objectives: Wnt signaling leads to stimulation of osteoblasts and it reduces osteoclastogenesis and bone resorption via the regulation of the osteprotegrin and receptor activator of nuclear factor kappa-Β ligan (RANKL). Wnt signaling pathways are regulated by their physiological antagonists such as sclerostin (SOST) as well as WNT-5a. The aim of this study was to determine the total amount of Sclerostin and WNT-5a in the gingival crevicular fluid (GCF) in sites with a continuum from a healthy to diseased periodontium. Materials and Methods: In this cross-sectional study, a total of 20 patients with generalized periodontitis, 10 subjects with gingivitis as well as 14 individuals with a healthy periodontium were recruited upon clinical and radiographic periodontal examination. In patients diagnosed with periodontitis, GCF samples were collected from periodontitis, gingivitis and healthy sites, while gingivitis patients provided samples from gingivitis and healthy sites. In healthy patients, only healthy sites were sampled. Protein total amount of SOST and WNT-5a were quantified by sandwich enzyme-linked immunosorbent assay (ELISA). Results: A total of 108 GCF samples were collected from a total of 44 individuals. When all periodontitis (n = 51), gingivitis (n = 12) and healthy (n = 45) sites were analyzed regardless of the patient diagnosis, periodontitis sites demonstrated significantly elevated WNT-5a total amounts (p = 0.03) when compared to gingivitis sites. Gingivitis sites demonstrated a trend of more total SOST (p = 0.09) when compared to periodontitis and healthy sites. Within each patient diagnostic category, sites showed similar SOST and WNT-5a total amounts (p > 0.05). Conclusions: WNT-5a levels in GCF depend on the stage of periodontitis sites. SOST trended higher in the GCF of gingivitis sites but similar in chronic periodontitis and healthy sites. WNT-5a and SOST play a crucial role in periodontal tissue remodeling and depend on the inflammatory and osteoclastogenic activities.
Phenolic Content, Main Flavonoids, and Antioxidant Capacity of Instant Sweet Tea (Lithocarpus litseifolius [Hance] Chun) Prepared with Different Raw Materials and Drying Methods

This study aims to investigate the effects of raw materials and drying methods on the phytochemical and antioxidant capacities of instant sweet tea powder. Four raw materials of sweet tea leave powders (STUT) were extracted and dried with two methods (freeze-drying and spray-drying). The antioxidant capacity, total phenolic content (TPC), total flavonoid content (TFC), and phlorizin and trilobatin contents of obtained instant sweet tea powders were compared. In addition, the single-factor experiments coupled with response surface methodology were used to study the influences of solvent-to-sample ratio, extraction temperature, extraction time, and their interactions on instant sweet tea yield. Results showed that the optimal conditions for extraction were the solvent-to-sample ratio of 19:1 mL/g, extraction temperature of 88 °C, and extraction time of 30 min. The TPC, TFC, antioxidant capacities, and phloridzin and trilobatin contents of instant sweet teas were higher than those of STUT, and the TPC and TFC of freeze-dried instant sweet teas were higher than those of spray-dried instant sweet teas. Significant correlations were found among TPC, TFC, and antioxidant capacities (p < 0.01). The freeze-dried instant sweet tea produced by young leaves (prepared by oven-drying) showed the highest TPC, TFC, and antioxidant capacities, compared with other raw materials and drying methods.
Sleep Disorders in Pediatric Migraine: A Questionnaire-Based Study

There is a high comorbidity between migraine and sleep disorders (SD), with a mutual dependence between sleep and headache. This study aimed to analyze the relationship between headache features (migraine frequency and severity, migraine equivalents, use and efficacy of treatments) and sleep in pediatric migraine. Parents of children and adolescents with migraine completed the Children’s Sleep Habits Questionnaire (CSHQ) and the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) and answered questions about headache characteristics. The presence of SD was defined according to CSHQ score. SD were detected in 72.9% of 140 subjects, but only 5.0% already received a diagnosis. Patients with SD presented statistically significant higher headache frequency (p = 0.031) and higher prevalence of migraine equivalents (p = 0.007). A higher CSHQ total score was associated with higher frequency of severe attacks (p = 0.012) and lower acute drug efficacy (p = 0.003). Significant positive correlations of sleep onset delay, sleep duration and nightwakings subscales with migraine frequency emerged. Our findings indicate that SD are highly prevalent in pediatric migraine and frequently associated with a higher headache severity and lower response to acute therapy, but often remain underdiagnosed. Improving sleep quality could help to reduce migraine intensity and disability and vice versa.
Plant Variety Protection: Current Practices and Insights

Breeders persistently supply farmers with the best varieties in order to exceed consumer demand through plant-breeding processes that are resource-intensive. In order to motivate continuous innovation in variety development, a system needs to provide incentives for plant breeders to develop superior varieties, for example, exclusive ownership to produce and market those varieties. The most common system is the acquisition of intellectual property protection through plant variety protection, also known as the breeder’s right. Most countries have adopted the system established by the International Union for the Protection of New Varieties of Plants (UPOV). To be granted plant variety protection, the variety should prove to be unique by meeting three requirements: distinctness, uniformity, and stability. This review summarizes (1) the plant variety protection via UPOV convention, (2) technical methods for distinctness, uniformity, and stability testing via phenotype, molecular markers, and sequencing as well as their challenges and potentiality, and (3) additional discussions in essentially derived variety, value for cultivation and use testing, and open source seed initiative.
Prognostic Value of Procalcitonin, C-Reactive Protein, and Lactate Levels in Emergency Evaluation of Cancer Patients with Suspected Infection

Simple Summary Cancer patients are at increased risk of infections and related complications, including sepsis. We developed a scoring system for mortality prediction based on readily available clinical and laboratory data, including the quick sequential organ failure assessment (qSOFA) score, cancer subtype, and several laboratory markers (procalcitonin, C-reactive protein, lactate dehydrogenase, and albumin) that can be used in emergency departments for cancer patients with suspected infection. The prediction score, which stratifies patients into four different risk groups (from low risk to very high risk), achieved excellent performance in predicting 14-day mortality, with an area under the receiver operating characteristic curve value of 0.88 (95% confidence interval 0.85–0.91). The score was also effective in predicting intensive care unit admission and 30-day mortality. Abstract Cancer patients have increased risk of infections, and often present to emergency departments with infection-related problems where physicians must make decisions based on a snapshot of the patient’s condition. Although C-reactive protein, procalcitonin, and lactate are popular biomarkers of sepsis, their use in guiding emergency care of cancer patients with infections is unclear. Using these biomarkers, we created a prediction model for short-term mortality in cancer patients with suspected infection. We retrospectively analyzed all consecutive patients who visited the emergency department of MD Anderson Cancer Center between 1 April 2018 and 30 April 2019. A clinical decision model was developed using multiple logistic regression for various clinical and laboratory biomarkers; coefficients were used to generate a prediction score stratifying patients into four groups according to their 14-day mortality risk. The prediction score had an area under the receiver operating characteristic curve value of 0.88 (95% confidence interval 0.85–0.91) in predicting 14-day mortality. The prediction score also accurately predicted intensive care unit admission and 30-day mortality. Our simple new scoring system for mortality prediction, based on readily available clinical and laboratory data, including procalcitonin, C-reactive protein, and lactate, can be used in emergency departments for cancer patients with suspected infection.
CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation

Simple Summary Overexpressed ErbB2/HER2 receptor drives up to a quarter of breast cancers. One aspect of ErbB2 biology that is poorly understood is how it reaches the cell surface following biosynthesis in the endoplasmic reticulum (ER). Here, the authors show that the CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) protein targets the newly synthesized ErbB2 for ubiquitin/proteasome-dependent degradation in the ER and Golgi, identifying a novel mechanism that negatively regulates cell surface expression of ErbB2. These findings provide one explanation for frequent loss of CHIP expression is ErbB2-overexpressing breast cancers. The authors further show that ErbB2-overexpressing breast cancer cells with low CHIP expression exhibit higher ER stress inducibility, and ER stress-inducing anticancer drug Bortezomib synergizes with ErbB2-targeted humanized antibody Trastuzumab to inhibit cancer cell proliferation. These new insights suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents. Abstract Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.
Experimental Approaches for Testing the Hypothesis of the Emergence of Life at Submarine Alkaline Vents

Since the pioneering experimental work performed by Urey and Miller around 70 years ago, several experimental works have been developed for approaching the question of the origin of life based on very few well-constructed hypotheses. In recent years, attention has been drawn to the so-called alkaline hydrothermal vents model (AHV model) for the emergence of life. Since the first works, perspectives from complexity sciences, bioenergetics and thermodynamics have been incorporated into the model. Consequently, a high number of experimental works from the model using several tools have been developed. In this review, we present the key concepts that provide a background for the AHV model and then analyze the experimental approaches that were motivated by it. Experimental tools based on hydrothermal reactors, microfluidics and chemical gardens were used for simulating the environments of early AHVs on the Hadean Earth (~4.0 Ga). In addition, it is noteworthy that several works used techniques from electrochemistry to investigate phenomena in the vent–ocean interface for early AHVs. Their results provided important parameters and details that are used for the evaluation of the plausibility of the AHV model, and for the enhancement of it.
Associations of Vitamin D Levels with Physical Fitness and Motor Performance; A Cross-Sectional Study in Youth Soccer Players from Southern Croatia

Simple Summary Vitamin D is a fat-soluble prohormone crucial for bone mineralization, muscle contractility, and neurological conductivity. It is theorized that Vitamin D plays an important role in sport performances, especially in young athletes. In this study we examined the associations of levels of 25-hydroxyvitamin D (25(OH)D) with physical fitness and motor-performance achievements in youth soccer players from Southern Croatia. Participants were tested on physical fitness, motor performance and vitamin D at the end of the winter period, when levels of vitamin D are known to be lowest due to low exposure to sunlight. Results showed that deficiency of 25(OH)D was widespread among youth soccer players living in Southern Croatia. Low 25(OH)D levels were associated with lower results in fitness tests (i.e., tests of energetic capacities), but there was no correlation between 25(OH)D levels and the results in motor performance tests (i.e., skill tests). Our results support the theory of the association between vitamin D and energetic capacities of athletes, but there is no evidence on association between vitamin D and skill-based capacities. Abstract Vitamin D level is known to be a factor potentially influencing physical fitness, but few studies have examined this phenomenon among youth athletes. We aimed to evaluate the associations of vitamin D levels (as measured by 25-hydroxyvitamin D concentrations—25(OH)D) with various physical fitness and motor performance tests in youth football (soccer) players. This cross-sectional study included a total of 52 youth soccer players (15.98 ± 2.26 years old) from Southern Croatia. The participants were evaluated at the end of the winter period and data were collected of anthropometric measures (body mass and body height), vitamin D status (25(OH)D levels), physical fitness tests (sprints of 10 and 20 m, 20 yards test, the countermovement jump, the reactive strength index (RSI)) and motor performance tests (the soccer-specific CODS, the soccer-specific agility, and static balance). Among the studied players, 54% had 25(OH)D insufficiency/deficiency, showing a lack of 25(OH)D is widespread even in youth athletes living at a southern latitude. The 25(OH)D level was correlated with sprint 20 m, 20 yards tests, and RSI, showing a greater role of 25(OH)D in physical fitness tests where energetic capacity is essential than in sport-related motor performance tests where skills are crucial. Our results support the idea that vitamin D can play a determinant role in physical fitness tests with a clear physiological component, but is not crucial in motor performance tests related to specific sports where skills are a key component. Future studies should investigate the effects of vitamin D supplementation on the performance in physical fitness and motor performance tests among youth athletes.
Harnessing the Nucleolar DNA Damage Response in Cancer Therapy

The nucleoli are subdomains of the nucleus that form around actively transcribed ribosomal RNA (rRNA) genes. They serve as the site of rRNA synthesis and processing, and ribosome assembly. There are 400–600 copies of rRNA genes (rDNA) in human cells and their highly repetitive and transcribed nature poses a challenge for DNA repair and replication machineries. It is only in the last 7 years that the DNA damage response and processes of DNA repair at the rDNA repeats have been recognized to be unique and distinct from the classic response to DNA damage in the nucleoplasm. In the last decade, the nucleolus has also emerged as a central hub for coordinating responses to stress via sequestering tumor suppressors, DNA repair and cell cycle factors until they are required for their functional role in the nucleoplasm. In this review, we focus on features of the rDNA repeats that make them highly vulnerable to DNA damage and the mechanisms by which rDNA damage is repaired. We highlight the molecular consequences of rDNA damage including activation of the nucleolar DNA damage response, which is emerging as a unique response that can be exploited in anti-cancer therapy. In this review, we focus on CX-5461, a novel inhibitor of Pol I transcription that induces the nucleolar DNA damage response and is showing increasing promise in clinical investigations.
Novel Severe Hemophilia A Mouse Model with Factor VIII Intron 22 Inversion

Simple Summary Recently, innovative gene therapy has been developing toward functional restoration by gain of function or gene correction. Hemophilia is a representative genetic disorder with many human patients and is considered a candidate disease for gene therapy. The most frequent severe hemophilia A is caused by inversion mediated structural variation of the human F8 gene. Nevertheless, a mouse model with F8 intron 22 inversion is not developed yet. This study presents a novel hemophilia A mouse model with 319 kb inversion and severe coagulation disorder and could be utilized in future gene correction preclinical trials. Abstract Hemophilia A (HA) is an X-linked recessive blood coagulation disorder, and approximately 50% of severe HA patients are caused by F8 intron 22 inversion (F8I22I). However, the F8I22I mouse model has not been developed despite being a necessary model to challenge pre-clinical study. A mouse model similar to human F8I22I was developed through consequent inversion by CRISPR/Cas9-based dual double-stranded breakage (DSB) formation, and clinical symptoms of severe hemophilia were confirmed. The F8I22I mouse showed inversion of a 391 kb segment and truncation of mRNA transcription at the F8 gene. Furthermore, the F8I22I mouse showed a deficiency of FVIII activity (10.9 vs. 0 ng/mL in WT and F8I22I, p < 0.0001) and severe coagulation disorder phenotype in the activated partial thromboplastin time (38 vs. 480 s, p < 0.0001), in vivo bleeding test (blood loss/body weight; 0.4 vs. 2.1%, p < 0.0001), and calibrated automated thrombogram assays (Thrombin generation peak, 183 vs. 21.5 nM, p = 0.0012). Moreover, histological changes related to spontaneous bleeding were observed in the liver, spleen, and lungs. We present a novel HA mouse model mimicking human F8I22I. With a structural similarity with human F8I22I, the F8I22I mouse model will be applicable to the evaluation of general hemophilia drugs and the development of gene-editing-based therapy research.
Unraveling the cooperative synergy of zero-dimensional graphene quantum dots and metal nanocrystals enabled by layer-by-layer assembly

Recent years have witnessed a cornucopia of synthetic methods for fabricating carbon–metal nanocomposites. Nonetheless, achieving a cooperative synergy of zero-dimensional carbon nanomaterials and metal nanocrystals is still uncommon. To this end, we performed a controllable structural design comprising customizable alternating layers of active and functional zero-dimensional nanomaterials, which were intimately assembled together. This unique highly-ordered multilayer configuration was afforded by a judicious layer-by-layer (LbL) assembly strategy, enabling the rational and tunable construction of a series of well-defined metal/graphene quantum dots (M/GQDs)n (M = Au, Ag, Pt) multilayers. This strategy allows the direct assembly of customized units of positively-charged graphene quantum dots (GQDs) and negatively-charged metal nanocrystals (NCs), which were integrated in an alternating stacked fashion under a pronounced electrostatic attractive interaction. Moreover, these multilayer thin films demonstrate remarkably efficient and versatile catalytic performance toward the selective organic transformation of aromatic nitro compounds, electrocatalytic methanol oxidation and photoelectrochemical water splitting under simulated solar light irradiation under ambient conditions, attributed to the cooperative synergy of the metal NC and GQD building blocks. More significantly, the catalytic performances of the (M/GQDs)n (M = Au, Ag, Pt) multilayer thin films are tunable via the assembly cycle and sequence, as well as by selecting different metal NC types. This work highlights the significance of the customizable design of GQDs–metal-based systems for various advanced chemical-to-energy conversion applications.