Miracle-dz/UniFAR-FTUs huggingface dataset:
Profiling lasmiditan as a treatment option for migraine

ABSTRACT Introduction: In recent years, research into acute migraine treatment has aimed to develop molecules capable of inhibiting trigeminal pathways, mediated by agonism to 5-HT1F receptors in order to avoid the vasoconstrictive action due to the stimulation of 5-HT 1B/1D receptors. A novel migraine drug class, called ‘neurally acting anti-migraine agents’, has been developed for the management of acute migraine attacks. Lasmiditan is the only compound of this drug class that has been evaluated in Phase III clinical trials. Areas covered: This review discusses lasmiditan including its pharmacokinetics, pharmacodynamics, efficacy and safety profile. Original research and review articles, relative to the period 2010–2019, were included in the reviewed literature. Expert opinion: The most recent phase III trials have demonstrated the efficacy of lasmiditan for acute migraine treatment, even if compared only with placebo. Nevertheless, the low rate of cardiovascular side effects with lasmiditan might offer a potential therapeutic option for migraine patients with cardiovascular disorders. With the lack of data on lasmiditan’s pharmacokinetic features, several phase I clinical trials are still ongoing in order to evaluate half-life, metabolism, excretion and the potential production of active metabolites. Possible pharmacodynamic interaction with drugs acting on central nervous system should be evaluated in future studies.
A Novel Upstream Regulator of Trichome Development Inhibitors

Much like the spikes that deter birds from sitting on fences, trichomes (hair-like projections on the leaf surface) are the epidermis’ first line of defense, discouraging insects and other pests ([Levin, 1973][1]). In addition to their role protecting the plant, trichomes are an excellent marker
Whole Genome Sequencing of Aggregatibacter actinomycetemcomitans Cultured from Blood Stream Infections Reveals Three Major Phylogenetic Groups Including a Novel Lineage Expressing Serotype a Membrane O Polysaccharide

Twenty-nine strains of Aggregatibacter actinomycetemcomitans cultured from blood stream infections in Denmark were characterised. Serotyping was unremarkable, with almost equal proportions of the three major types plus a single serotype e strain. Whole genome sequencing positioned the serotype e strain outside the species boundary; moreover, one of the serotype a strains was unrelated to other strains of the major serotypes and to deposited sequences in the public databases. We identified five additional strains of this type in our collections. The particularity of the group was corroborated by phylogenetic analysis of concatenated core genes present in all strains of the species, and by uneven distribution of accessory genes only present in a subset of strains. Currently, the most accurate depiction of A. actinomycetemcomitans is a division into three lineages that differ in genomic content and competence for transformation. The clinical relevance of the different lineages is not known, and even strains excluded from the species sensu stricto can cause serious human infections. Serotyping is insufficient for characterisation, and serotypes a and e are not confined to specific lineages.
Machine learning approach to literature mining for the genetics of complex diseases

Abstract To generate a parsimonious gene set for understanding the mechanisms underlying complex diseases, we reasoned it was necessary to combine the curation of public literature, review of experimental databases and interpolation of pathway-associated genes. Using this strategy, we previously built the following two databases for reproductive disorders: The Database for Preterm Birth (dbPTB) and The Database for Preeclampsia (dbPEC). The completeness and accuracy of these databases is essential for supporting our understanding of these complex conditions. Given the exponential increase in biomedical literature, it is becoming increasingly difficult to manually maintain these databases. Using our curated databases as reference data sets, we implemented a machine learning-based approach to optimize article selection for manual curation. We used logistic regression, random forests and neural networks as our machine learning algorithms to classify articles. We examined features derived from abstract text, annotations and metadata that we hypothesized would best classify articles with genetically relevant content associated to the disorder of interest. Combinations of these features were used build the classifiers and the performance of these feature sets were compared to a standard ‘Bag-of-Words’. Several combinations of these genetic based feature sets outperformed ‘Bag-of-Words’ at a threshold such that 95% of the curated gene set obtained from the original manual curation of all articles were extracted from the articles classified by machine learning as ‘considered’. The performance was superior in terms of the reduction of required manual curation and two measures of the harmonic mean of precision and recall. The reduction in workload ranged from 0.814 to 0.846 for the dbPTB and 0.301 to 0.371 for the dbPEC. Additionally, a database of metadata and annotations is generated which allows for rapid query of individual features. Our results demonstrate that machine learning algorithms can identify articles with relevant data for databases of genes associated with complex diseases.
Unexpected quenching effect on new particle formation from the atmospheric reaction of methanol with SO3

Significance New particle formation (NPF) is an important global phenomenon, contributing nearly half of the cloud condensation nuclei in nature. Today, NPF is believed to be mainly promoted by low-volatile species formed in atmosphere. Herein, we show that in certain cases, the formation of low-volatile species could undermine NPF. Specifically, we identify previously unreported catalytic reactions between alcohols and SO3 which yield low-volatile organic sulfates. Rather than being a promoter to NPF, the low-volatile organic sulfates can compete for consuming SO3, thereby disfavoring H2SO4 formation. Such unexpected quenching effects on NPF are most likely to occur in dry and polluted regions with abundant alcohols, illustrating the importance in understanding the interplay between nucleation precursor formation and subsequent NPF. Despite the high abundance in the atmosphere, alcohols in general and methanol in particular are believed to play a small role in atmospheric new particle formation (NPF) largely due to the weak binding abilities of alcohols with the major nucleation precursors, e.g., sulfuric acid (SA) and dimethylamine (DMA). Herein, we identify a catalytic reaction that was previously overlooked, namely, the reaction between methanol and SO3, catalyzed by SA, DMA, or water. We found that alcohols can have unexpected quenching effects on the NPF process, particularly in dry and highly polluted regions with high concentrations of alcohols. Specifically, the catalytic reaction between methanol and SO3 can convert methanol into a less-volatile species––methyl hydrogen sulfate (MHS). The latter was initially thought to be a good nucleation agent for NPF. However, our simulation results suggest that the formation of MHS consumes an appreciable amount of atmospheric SO3, disfavoring further reactions of SO3 with H2O. Indeed, we found that MHS formation can cause a reduction of SA concentration up to 87%, whereas the nucleation ability of MHS toward new particles is not as good as that of SA. Hence, a high abundance of methanol in the atmosphere can lower the particle nucleation rate by as much as two orders of magnitude. Such a quenching effect suggests that the recently identified catalytic reactions between alcohols and SO3 need to be considered in atmospheric modeling in order to predict SA concentration from SO2, while also account for their potentially negative effect on NPF.
Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells

RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.
Cytokine Network and Sexual HIV Transmission in Men Who Have Sex With Men.

BACKGROUND Seminal HIV transmission from men to their partners remains the main driver of HIV epidemics worldwide. Semen is not merely a carrier of virus but provides an immunological milieu that affects HIV transmission. METHODS We collected blood and semen from people with HIV (PWH) whose epidemiologically-linked sexual partners became HIV infected or did not acquire HIV. Viral transmission was confirmed by phylogenetic linkage (HIV pol). We measured the concentration of 34 cytokines/chemokines by Luminex in blood and semen of 21 source partners who transmit ('transmitters') and 22 who did not transmit HIV ('non-transmitters') to their sexual partners. Differences between cytokine profiles in transmitters versus non-transmitters were analyzed using the multivariate statistical technique Partial Least Square-Discriminant Analysis. RESULTS The cytokine profile in seminal, but not in the peripheral blood, was significantly different between men who have sex wirth men (MSM) who transmitted and those who did not transmit HIV to their sexual partners (E=19.77, p<0.01). This difference persisted after excluding people with undetectable HIV RNA levels in non-transmitters. CONCLUSIONS Seminal cytokine profiles correlated with transmission or non-transmission of HIV from the infected MSM to their partners, independently from seminal viral load. Seminal cytokine spectra might be a contributing determinant of sexual HIV transmission thus providing new directions for the development of strategies aiming at preventing HIV transmission.
Elevated temperature and CO2 cause differential growth stimulation and drought survival responses in eucalypt species from contrasting habitats.

Climate change scenarios predict increasing atmospheric CO2 concentrations ([CO2]), temperatures and droughts in tropical regions. Individually, the effects of these climate factors on plants are well established, whereas experiments on the interactive effects of a combination of factors are rare. Moreover, how these environmental factors will affect tree species along a wet to dry gradient (e.g., along tropical forest-savanna transitions) remains to be investigated. We hypothesized that under the simulated environmental conditions, plant growth, physiological performance and survivorship would vary in a manner consistent with the species' positions of origin along this gradient. In a glasshouse experiment, we raised seedlings of three Eucalyptus species, each occurring naturally in a wet forest, savanna and forest-savanna ecotone, respectively. We evaluated the effect of drought, elevated temperature (4 °C above ambient glasshouse temperature of 22 °C) and elevated temperature in combination with elevated [CO2] (400 ppm [CO2] above ambient of 400 ppm), on seedling growth, survivorship and physiological responses (photosynthesis, stomatal conductance and water-use efficiency). Elevated temperature under ambient [CO2] had little effect on growth, biomass and plant performance of well-watered seedlings, but hastened mortality in drought-affected seedlings, affecting the forest and ecotone more strongly than the savanna species. In contrast, elevated [CO2] in combination with elevated temperatures delayed the appearance of drought stress symptoms and enhanced survivorship in drought-affected seedlings, with the savanna species surviving the longest, followed by the ecotone and forest species. Elevated [CO2] in combination with elevated temperatures also enhanced growth and biomass and photosynthesis in well-watered seedlings of all species, but modified shoot:root biomass partitioning and stomatal conductance differentially across species. Our study highlights the need for a better understand of the interactive effects of elevated [CO2], temperature and drought on plants and the potential to upscale these insights for understanding biome changes.
Anthocyanins Potentially Contribute to Defense against Alzheimer’s Disease

Anthocyanins (ANTs) are plant pigments that belong to a flavanol class of polyphenols and have diverse pharmacological properties. These compounds are primarily found in fruits and vegetables, with an average daily intake of 180 mgd−1 of these compounds in the developed world. ANTs are potent antioxidants that might regulate the free radical-mediated generation of amyloid peptides (Abeta-amyloids) in the brain, which causes Alzheimer’s disease (AD). This study presents a literature review of ANTs from different berries and their potential therapeutic value, with particular emphasis on neurodegenerative AD, which owing to oxidative stress. This review also highlights reactive oxygen species (ROS) generation through energy metabolism, nitrogen reactive species, the role of transition metals in generating ROS, and the radical-quenching mechanisms of natural antioxidants, including ANTs. The current status of the bioavailability, solubility, and structure activity relationship of ANTs is discussed herein.
Aptamers: A Review of Their Chemical Properties and Modifications for Therapeutic Application

Aptamers are short, single-stranded oligonucleotides that bind to specific target molecules. The shape-forming feature of single-stranded oligonucleotides provides high affinity and excellent specificity toward targets. Hence, aptamers can be used as analogs of antibodies. In December 2004, the US Food and Drug Administration approved the first aptamer-based therapeutic, pegaptanib (Macugen), targeting vascular endothelial growth factor, for the treatment of age-related macular degeneration. Since then, however, no aptamer medication for public health has appeared. During these relatively silent years, many trials and improvements of aptamer therapeutics have been performed, opening multiple novel directions for the therapeutic application of aptamers. This review summarizes the basic characteristics of aptamers and the chemical modifications available for aptamer therapeutics.
Cancer Cell Membrane-Coated Nanoparticles for Cancer Management

Cancer is a global health problem in need of transformative treatment solutions for improved patient outcomes. Many conventional treatments prove ineffective and produce undesirable side effects because they are incapable of targeting only cancer cells within tumors and metastases post administration. There is a desperate need for targeted therapies that can maximize treatment success and minimize toxicity. Nanoparticles (NPs) with tunable physicochemical properties have potential to meet the need for high precision cancer therapies. At the forefront of nanomedicine is biomimetic nanotechnology, which hides NPs from the immune system and provides superior targeting capabilities by cloaking NPs in cell-derived membranes. Cancer cell membranes expressing “markers of self” and “self-recognition molecules” can be removed from cancer cells and wrapped around a variety of NPs, providing homotypic targeting and circumventing the challenge of synthetically replicating natural cell surfaces. Compared to unwrapped NPs, cancer cell membrane-wrapped NPs (CCNPs) provide reduced accumulation in healthy tissues and higher accumulation in tumors and metastases. The unique biointerfacing capabilities of CCNPs enable their use as targeted nanovehicles for enhanced drug delivery, localized phototherapy, intensified imaging, or more potent immunotherapy. This review summarizes the state-of-the-art in CCNP technology and provides insight to the path forward for clinical implementation.
CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3β/cyclinD1 signal pathway in Myeloma Bone Disease

Myeloma‐related bone disease (MBD) is a common complication of multiple myeloma (MM), which can both decrease life quality and influence the prognosis of the patients. We have found that CCN1 stimulated proliferation and differentiation of osteoblasts in MM in vitro and in vivo, while its mechanism still remains unknown.
Histone H2A phosphorylation recruits topoisomerase IIα to centromeres to safeguard genomic stability

Chromosome segregation in mitosis requires the removal of catenation between sister chromatids. Timely decatenation of sister DNAs at mitotic centromeres by topoisomerase IIα (TOP2A) is crucial to maintain genomic stability. The chromatin factors that recruit TOP2A to centromeres during mitosis remain unknown. Here, we show that histone H2A Thr‐120 phosphorylation (H2ApT120), a modification generated by the mitotic kinase Bub1, is necessary and sufficient for the centromeric localization of TOP2A. Phosphorylation at residue‐120 enhances histone H2A binding to TOP2A in vitro. The C‐gate and the extreme C‐terminal region are important for H2ApT120‐dependent localization of TOP2A at centromeres. Preventing H2ApT120‐mediated accumulation of TOP2A at mitotic centromeres interferes with sister chromatid disjunction, as evidenced by increased frequency of anaphase ultra‐fine bridges (UFBs) that contain catenated DNA. Tethering TOP2A to centromeres bypasses the requirement for H2ApT120 in suppressing anaphase UFBs. These results demonstrate that H2ApT120 acts as a landmark that recruits TOP2A to mitotic centromeres to decatenate sister DNAs. Our study reveals a fundamental role for histone phosphorylation in resolving centromere DNA entanglements and safeguarding genomic stability during mitosis.
Oriented Cell Alignment Induced by a Nanostructured Titanium Surface Enhances Expression of Cell Differentiation Markers

A key factor for dental implant success is a good sealing between the implant surface and both soft (gum) and hard (bone) tissues. Surface nanotopography can modulate cell response through mechanotransduction. The main objective of this research was the development of nanostructured titanium (Ti) surfaces that promote both soft and hard tissue integration with potential application in dental implants. Nanostructured Ti surfaces were developed by electrochemical anodization—nanopores (NPs) and nanonets (NNs)—and characterized by atomic force microscopy, scanning electronic microscopy, and contact angle analysis. In addition, nanoparticle release and apoptosis activation were analyzed on cell culture. NP surfaces showed nanoparticle release, which increased in vitro cell apoptosis. Primary human gingival fibroblasts (hGFs) and human bone marrow mesenchymal stem cells (hBM-MSCs) were used to test cell adhesion, cytotoxicity, metabolic activity, and differentiation markers. Finally, cell orientation on the different surfaces was analyzed using a phalloidin staining. NN surfaces induced an oriented alignment of both cell types, leading in turn to an improved expression of differentiation markers. Our results suggest that NN structuration of Ti surfaces has great potential to be used for dental implant abutments to improve both soft and hard tissue integration.
Aquaculture Feeds Can Be Outlaws for Eutrophication When Hidden in Rice Fields? A Case Study in Qianjiang, China

Water eutrophication caused by agricultural production has become one of the most important factors that impede sustainable rural environmental governance in China. As a result, the Chinese central and local governments want to reduce the use of nitrogen and phosphorus fertilizer and gain socioeconomical profit simultaneously by promoting crayfish and rice integrated system (CRIS) in the rural areas with abundant water resources. In this article, we investigated whether CRIS in Qianjiang, Hubei, the origin place of the system in China, contributes to fulfilling the governments’ expectations. We found that CRIS efficaciously cuts the fertilizer rate in rice production and boosts farmers’ incomes because crayfish has a demand for water quality and holds a large internal market requirement. However, higher profit encourages farmers to expand crayfish production and thus discourages the initiatives in rice production. The area of the ditch for crayfish production expands ceaselessly and exceeds the limit of regulation of CRIS. As a result, the CRIS in the areas has emerged as a practice of aquaculture but in farmland. This is a regulatory gap. The input–output analysis of CRIS by material balance method can also reveal that excessive feed for crayfish has become a new source of agricultural pollution. Beyond that, due to the changed irrigation system and increased water exchange frequency of CRIS, the pollution has transformed from passive distribution to active, which will increase the risk of water eutrophication on a large area.