bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Interplay of the DNA Replication Program and the Intra-S Phase Checkpoint Pathway
Authors: Ciardo Diletta , Goldar Arach , Marheineke Kathrin
Published: January 2019

DNA replication in eukaryotes is achieved by the activation of multiple replication origins which needs to be precisely coordinated in space and time. This spatio-temporal replication program is regulated by many factors to maintain genome stability, which is frequently threatened through stresses of exogenous or endogenous origin. Intra-S phase checkpoints monitor the integrity of DNA synthesis and are activated when replication forks are stalled. Their activation leads to the stabilization of forks, to the delay of the replication program by the inhibition of late firing origins, and the delay of G2/M phase entry. In some cell cycles during early development these mechanisms are less efficient in order to allow rapid cell divisions. In this article, we will review our current knowledge of how the intra-S phase checkpoint regulates the replication program in budding yeast and metazoan models, including early embryos with rapid S phases. We sum up current models on how the checkpoint can inhibit origin firing in some genomic regions, but allow dormant origin activation in other regions. Finally, we discuss how numerical and theoretical models can be used to connect the multiple different actors into a global process and to extract general rules.
Replication of G Quadruplex DNA
Authors: Lerner Leticia Koch , Sale Julian E.
Published: January 2019

A cursory look at any textbook image of DNA replication might suggest that the complex machine that is the replisome runs smoothly along the chromosomal DNA. However, many DNA sequences can adopt non-B form secondary structures and these have the potential to impede progression of the replisome. A picture is emerging in which the maintenance of processive DNA replication requires the action of a significant number of additional proteins beyond the core replisome to resolve secondary structures in the DNA template. By ensuring that DNA synthesis remains closely coupled to DNA unwinding by the replicative helicase, these factors prevent impediments to the replisome from causing genetic and epigenetic instability. This review considers the circumstances in which DNA forms secondary structures, the potential responses of the eukaryotic replisome to these impediments in the light of recent advances in our understanding of its structure and operation and the mechanisms cells deploy to remove secondary structure from the DNA. To illustrate the principles involved, we focus on one of the best understood DNA secondary structures, G quadruplexes (G4s), and on the helicases that promote their resolution.
Genetic Structure and Eco-Geographical Differentiation of Lancea tibetica in the Qinghai-Tibetan Plateau
Authors: Chi Xiaofeng , Zhang Faqi , Gao Qingbo , Xing Rui , Chen Shilong
Published: January 2019

The uplift of the Qinghai-Tibetan Plateau (QTP) had a profound impact on the plant speciation rate and genetic diversity. High genetic diversity ensures that species can survive and adapt in the face of geographical and environmental changes. The Tanggula Mountains, located in the central of the QTP, have unique geographical significance. The aim of this study was to investigate the effect of the Tanggula Mountains as a geographical barrier on plant genetic diversity and structure by using Lancea tibetica. A total of 456 individuals from 31 populations were analyzed using eight pairs of microsatellite makers. The total number of alleles was 55 and the number per locus ranged from 3 to 11 with an average of 6.875. The polymorphism information content (PIC) values ranged from 0.2693 to 0.7761 with an average of 0.4378 indicating that the eight microsatellite makers were efficient for distinguishing genotypes. Furthermore, the observed heterozygosity (Ho), the expected heterozygosity (He), and the Shannon information index (I) were 0.5277, 0.4949, and 0.9394, respectively, which indicated a high level of genetic diversity. We detected high genetic differentiation among all sampling sites and restricted gene flow among populations. Bayesian-based cluster analysis (STRUCTURE), principal coordinates analysis (PCoA), and Neighbor-Joining (NJ) cluster analysis based on microsatellite markers grouped the populations into two clusters: the southern branch and the northern branch. The analysis also detected genetic barriers and restricted gene flow between the two groups separated by the Tanggula Mountains. This study indicates that the geographical isolation of the Tanggula Mountains restricted the genetic connection and the distinct niches on the two sides of the mountains increased the intraspecific divergence of the plants.
Plastic Accumulation in the Sea Surface Microlayer: An Experiment-Based Perspective for Future Studies
Authors: Galgani Luisa , Loiselle Steven A.
Published: January 2019

Plastic particles are ubiquitous in the marine environment. Given their low density, they have the tendency to float on the sea surface, with possible impacts on the sea surface microlayer (SML). The SML is an enriched biofilm of marine organic matter, that plays a key role in biochemical and photochemical processes, as well as controlling gas exchange between the ocean and the atmosphere. Recent studies indicate that plastics can interfere with the microbial cycling of carbon. However, studies on microplastic accumulation in the SML are limited, and their effects on organic matter cycling in the surface ocean are poorly understood. To explore potential dynamics in this key ocean compartment, we ran a controlled experiment with standard microplastics in the surface and bulk water of a marine monoculture. Bacterial abundance, chromophoric dissolved organic matter (CDOM), and oxygen concentrations were measured. The results indicate an accumulation of CDOM in the SML and immediate underlying water when microplastic particles are present, as well as an enhanced oxygen consumption. If extrapolated to a typical marine environment, this indicates that alterations in the quality and reactivity of the organic components of the SML could be expected. This preliminary study shows the need for a more integrated effort to our understanding the impact of microplastics on SML functioning and marine biological processes.
Case Study: Comparative Analysis of Hydrologic Simulations with Areal-Averaging of Moving Rainfall
Authors: Fang Zheng N. , Shultz Michael J. , Wienhold Kevin J. , Zhang Jiaqi , Gao Shang
Published: February 2019

The goal of this investigation is to compare the hydrologic simulations caused by the areal-averaging of dynamic moving rainfall. Two types of synthetic rainfall are developed: spatially varied rainfall (SVR) is the typical input to a distributed model while temporally varied rainfall (TVR) emulates SVR but is spread uniformly over the entire watershed as in the case of a lumped model. This study demonstrates a direct comparison of peak discharge and peak timing generated by synthetic moving storms over idealized rectangular basins and a real watershed. It is found that the difference between the hydrologic responses from SVR and TVR reflects the impact from the areal-averaging of rainfall; the areal-averaging of rainfall for the movement from upstream to downstream over a lumped model can result in underestimated and delayed peak values in comparison to those from a distributed model; the flood peaks from SVR and TVR are found similar when the storm moves from downstream to upstream. The findings of the study suggest that extra cautions are needed for practitioners when evaluating simulated results from distributed and lumped modeling approaches even using the same rainfall information.
Where Do Vapers Buy Their Vaping Supplies? Findings from the International Tobacco Control (ITC) 4 Country Smoking and Vaping Survey
Authors: Braak David C. , Cummings K. Michael , Nahhas Georges J. , Heckman Bryan W. , Borland Ron , Fong Geoffrey T. , Hammond David , Boudreau Christian , McNeill Ann , Levy David T. , Shang Ce
Published: January 2019

Aim: This study examines where vapers purchase their vaping refills in countries having different regulations over such devices, Canada (CA), the United States (US), England (EN), and Australia (AU). Methods: Data were available from 1899 current adult daily and weekly vapers who participated in the 2016 (Wave 1) International Tobacco Control Four Country Smoking and Vaping. The outcome was purchase location of vaping supplies (online, vape shop, other). Adjusted odds ratios and 95% confidence intervals were reported for between country comparisons. Results: Overall, 41.4% of current vapers bought their vaping products from vape shops, 27.5% bought them online, and 31.1% from other retail locations. The vast majority of vapers (91.1%) reported using nicotine-containing e-liquids. In AU, vapers were more likely to buy online vs other locations compared to CA (OR = 6.4, 2.3–17.9), the US (OR = 4.1, 1.54–10.7), and EN (OR = 7.9, 2.9–21.8). In the US, they were more likely to buy from vape shops (OR = 3.3, 1.8–6.2) or online (OR = 1.9, 1.0–3.8) vs other retail locations when compared to those in EN. In CA, vapers were more likely to purchase at vape shops than at other retail locations when compared to vapers in EN (5.9, 3.2–10.9) and the US (1.87, 1.0–3.1). Conclusions: The regulatory environment and enforcement of such regulations appear to influence the location where vapers buy their vaping products. In AU, banning the retail sale of nicotine vaping products has led vapers to rely mainly on online purchasing sources, whereas the lack of enforcement of the same regulation in CA has allowed specialty vape shops to flourish.
A Framework for Rice Heavy Metal Stress Monitoring Based on Phenological Phase Space and Temporal Profile Analysis
Authors: Zou Xinyu , Liu Xiangnan , Liu Mengxue , Liu Meiling , Zhang Biyao
Published: January 2019

Previous studies make it possible to use remote sensing techniques to monitor heavy metal stress of rice synchronously and continuously. However, most studies mainly focus on the analysis of rice’s visual symptoms and physiological functions rather than temporal information during the growth period, which may reflect significant changes of rice under heavy metal stress. In this paper, an enhanced spatial and temporal adaptive reflectance fusion model was used to generate synthetic Landsat time series. A normalized difference water index and an enhanced vegetation index were employed to build phenological phase space. Then, the ratio of the rice growth rate fluctuation (GRFI Ratio) was constructed for discriminating the different heavy metal stress levels on rice. Results suggested that the trajectories of rice growth in phenological phase space can depict the similarities and differences of rice growth under different heavy metal stress levels. The most common phenological parameters in the phase space cannot accurately discriminate the heavy metal stress level. However, the GRFI Ratio that we proposed outperformed in discriminating different levels of heavy metal stress. This study suggests that this framework of detecting the heavy metal pollution in paddy filed based on phenological phase space and temporal profile analysis is promising.
Identification and Prioritization of Environmental Reproductive Hazards: A First Step in Establishing Environmental Perinatal Care
Authors: Teysseire Raphaëlle , Brochard Patrick , Sentilhes Loïc , Delva Fleur
Published: January 2019

In 2015, the International Federation of Gynecology and Obstetrics established the prevention of exposures to environmental reprotoxic substances as a priority for health professionals. However, available information about reproductive hazards is voluminous, dispersed, and complex, and this is a severe limitation for physicians to incorporate the prevention of environmental exposure into standard preventive care. One difficulty frequently cited by physicians is the lack of evidence-based information. The objective of our study was to identify a list of environmental chemical hazards to reproduction. We used lists present in relevant regulations or included in scientific reports or databases to identify reproductive hazards. The reproductive hazards were prioritized according to the strength of evidence concerning their impact on fertility or development of the offspring. We identified 1251 reproductive hazards. Our prioritization approach resulted in a high-priority classification for 462 risk factors belonging to the following eight classes: drugs (n = 206), metals (n = 116), pesticides (n = 38), organic solvents (n = 27), synthesizing and/or processing agents in industrial processes (n = 23), phthalates (n = 13), perfluorinated compounds (n = 13), and other compounds (n = 26). Despite the limitations of this work, the generated lists constitute a useful working basis to put in place innovative environmental preventive measures according to the principle of evidence-based medicine.
Zinc and Cadmium Mapping in the Apical Shoot and Hypocotyl Tissues of Radish by High-Resolution Secondary Ion Mass Spectrometry (NanoSIMS) after Short-Term Exposure to Metal Contamination
Authors: Ondrasek Gabrijel , Clode Peta L. , Kilburn Matt R. , Guagliardo Paul , Romić Davor , Rengel Zed
Published: January 2019

Zinc (as an essential phytonutrient) and cadmium (as a toxic but readily bioavailable nonessential metal for plants) share similar routes for crossing plant biomembranes, although with a substantially different potential for translocation into above-ground tissues. The in situ distribution of these metals in plant cells and tissues (particularly intensively-dividing and fast-growing areas) is poorly understood. In this study, 17-day-old radish (Raphanus sativus L.) plants grown in nutrient solution were subjected to short-term (24 h) equimolar contamination (2.2 µM of each 70Zn and Cd) to investigate their accumulation and distribution in the shoot apex (leaf primordia) and edible fleshy hypocotyl tissues. After 24-h exposure, radish hypocotyl had similar concentration (in µg/g dry weight) of 70Zn (12.1 ± 1.1) and total Cd (12.9 ± 0.8), with relatively limited translocation of both metals to shoots (concentrations lower by 2.5-fold for 70Zn and 4.8-fold for Cd) as determined by inductively-coupled plasma mass spectrometry (ICP-MS). The in situ Zn/Cd distribution maps created by high-resolution secondary ion mass spectrometry (NanoSIMS, Cameca, Gennevilliers, France) imaging corresponded well with the ICP-MS data, confirming a similar pattern and uniform distribution of 70Zn and Cd across the examined areas. Both applied techniques can be powerful tools for quantification (ICP-MS) and localisation and visualisation (NanoSIMS) of some ultra-trace isotopes in the intensively-dividing cells and fast-growing tissues of non-metalophytes even after short-term metal exposure. The results emphasise the importance of the quality of (agro)ecosystem resources (growing media, metal-contaminated soils/waters) in the public health risk, given that, even under low contamination and short-term exposure, some of the most toxic metallic ions (e.g., Cd) can relatively rapidly enter the human food chain.
Identification of Diabetic Patients through Clinical and Para-Clinical Features in Mexico: An Approach Using Deep Neural Networks
Authors: Alcalá-Rmz Vanessa , Zanella-Calzada Laura A. , Galván-Tejada Carlos E. , García-Hernández Alejandra , Cruz Miguel , Valladares-Salgado Adan , Galván-Tejada Jorge I. , Gamboa-Rosales Hamurabi
Published: January 2019

Diabetes is a chronic and noncommunicable but preventable disease that is affecting the Mexican population at worrying levels, being the first place in prevalence worldwide. Early diabetes detection has become important to prevent other health conditions that involve low organ yield until the patient death. Based on this problem, this work proposes the architecture of an Artificial Neural Network (ANN) for the automated classification of healthy patients from diabetics patients. The analysis was performed used a set of 19 para-clinical features to determine the health status of the patients. The developed model was evaluated through a statistical analysis based on the calculation of the loss function, accuracy, area under the curve (AUC) and receiving operating characteristics (ROC) curve. The results obtained present statistically significant values, with accuracy of 0.94 and AUC values of 0.98. Based on these results, it is possible to conclude that the ANN implemented in this work can classify patients with presence of diabetes from controls with significant accuracy, presenting preliminary results for the development of a diagnostic tool that can be supportive for health specialists.
“Back to the Future”: Time for a Renaissance of Public Health Engineering
Authors: Gelting Richard J. , Chapra Steven C. , Nevin Paul E. , Harvey David E. , Gute David M.
Published: January 2019

Public health has always been, and remains, an interdisciplinary field, and engineering was closely aligned with public health for many years. Indeed, the branch of engineering that has been known at various times as sanitary engineering, public health engineering, or environmental engineering was integral to the emergence of public health as a distinct discipline. However, in the United States (U.S.) during the 20th century, the academic preparation and practice of this branch of engineering became largely separated from public health. Various factors contributed to this separation, including an evolution in leadership roles within public health; increasing specialization within public health; and the emerging environmental movement, which led to the creation of the U.S. Environmental Protection Agency (EPA), with its emphasis on the natural environment. In this paper, we consider these factors in turn. We also present a case study example of public health engineering in current practice in the U.S. that has had large-scale positive health impacts through improving water and sanitation services in Native American and Alaska Native communities. We also consider briefly how to educate engineers to work in public health in the modern world, and the benefits and challenges associated with that process. We close by discussing the global implications of public health engineering and the need to re-integrate engineering into public health practice and strengthen the connection between the two fields.
Importance of the Interaction between Heading Date Genes Hd1 and Ghd7 for Controlling Yield Traits in Rice
Authors: Zhang Zhen-Hua , Zhu Yu-Jun , Wang Shi-Lin , Fan Ye-Yang , Zhuang Jie-Yun
Published: January 2019

Appropriate flowering time is crucial for successful grain production, which relies on not only the action of individual heading date genes, but also the gene-by-gene interactions. In this study, influences of interaction between Hd1 and Ghd7 on flowering time and yield traits were analyzed using near isogenic lines derived from a cross between indica rice cultivars ZS97 and MY46. In the non-functional ghd7ZS97 background, the functional Hd1ZS97 allele promoted flowering under both the natural short-day (NSD) conditions and natural long-day (NLD) conditions. In the functional Ghd7MY46 background, Hd1ZS97 remained to promote flowering under NSD conditions, but repressed flowering under NLD conditions. For Ghd7, the functional Ghd7MY46 allele repressed flowering under both conditions, which was enhanced in the functional Hd1ZS97 background under NLD conditions. With delayed flowering, spikelet number and grain weight increased under both conditions, but spikelet fertility and panicle number fluctuated. Rice lines carrying non-functional hd1MY46 and functional Ghd7MY46 alleles had the highest grain yield under both conditions. These results indicate that longer growth duration for a larger use of available temperature and light does not always result in higher grain production. An optimum heading date gene combination needs to be carefully selected for maximizing grain yield in rice.
Autophagy Activation by Crepidiastrum Denticulatum Extract Attenuates Environmental Pollutant-Induced Damage in Dermal Fibroblasts
Authors: Yoon Seok Jeong , Lim Chae Jin , Chung Hwa-Jee , Kim Joo-Hwan , Huh Yang Hoon , Park Keedon , Jeong Sekyoo
Published: January 2019

Pollution-induced skin damage results in oxidative stress; cellular toxicity; inflammation; and, ultimately, premature skin aging. Previous studies suggest that the activation of autophagy can protect oxidation-induced cellular damage and aging-like changes in skin. In order to develop new anti-pollution ingredients, this study screened various kinds of natural extracts to measure their autophagy activation efficacy in cultured dermal fibroblast. The stimulation of autophagy flux by the selected extracts was further confirmed both by the expression of proteins associated with the autophagy signals and by electron microscope. Crepidiastrum denticulatum (CD) extract treated cells showed the highest autophagic vacuole formation in the non-cytotoxic range. The phosphorylation of adenosine monophosphate kinase (AMPK), but not the inhibition of mammalian target of rapamycin (mTOR), was observed by CD-extract treatment. Its anti-pollution effects were further evaluated with model compounds, benzo[a]pyrene (BaP) and cadmium chloride (CdCl2), and a CD extract treatment resulted in both the protection of cytotoxicity and a reduction of proinflammatory cytokines. These results suggest that the autophagy activators can be a new protection regimen for anti-pollution. Therefore, CD extract can be used for anti-inflammatory and anti-pollution cosmetic ingredients.
Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis
Authors: Frese Jenny , Kettwig Matthias , Zappel Hildegard , Hofer Johannes , Gröne Hermann-Josef , Nagel Mato , Sunder-Plassmann Gere , Kain Renate , Neuweiler Jörg , Gross Oliver
Published: January 2019

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.
Reaction with Proteins of a Five-Coordinate Platinum(II) Compound
Authors: Ferraro Giarita , Marzo Tiziano , Cucciolito Maria Elena , Ruffo Francesco , Messori Luigi , Merlino Antonello
Published: January 2019

Stable five-coordinate Pt(II) complexes have been highlighted as a promising and original platform for the development of new cytotoxic drugs. Their interaction with proteins has been scarcely studied. Here, the reactivity of the five-coordinate Pt(II) compound [Pt(I)(Me) (dmphen)(olefin)] (Me = methyl, dmphen = 2,9-dimethyl-1,10-phenanthroline, olefin = dimethylfumarate) with the model proteins hen egg white lysozyme (HEWL) and bovine pancreatic ribonuclease (RNase A) has been investigated by X-ray crystallography and electrospray ionization mass spectrometry. The X-ray structures of the adducts of RNase A and HEWL with [Pt(I)(Me)(dmphen)(olefin)] are not of very high quality, but overall data indicate that, upon reaction with RNase A, the compound coordinates the side chain of His105 upon releasing the iodide ligand, but retains the pentacoordination. On the contrary, upon reaction with HEWL, the trigonal bi-pyramidal Pt geometry is lost, the iodide and the olefin ligands are released, and the metal center coordinates the side chain of His15 probably adopting a nearly square-planar geometry. This work underlines the importance of the combined use of crystallographic and mass spectrometry techniques to characterize, in detail, the protein–metallodrug recognition process. Our findings also suggest that five-coordinate Pt(II) complexes can act either retaining their uncommon structure or functioning as prodrugs, i.e., releasing square-planar platinum complexes as bioactive species.
Identification of a Novel Quinoxaline-Isoselenourea Targeting the STAT3 Pathway as a Potential Melanoma Therapeutic
Authors: Alcolea Verónica , Karelia Deepkamal N. , Pandey Manoj K. , Plano Daniel , Singh Parvesh , Palop Juan Antonio , Amin Shantu , Sanmartín Carmen , Sharma Arun K.
Published: January 2019

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032.
Engineering Translation Components Improve Incorporation of Exotic Amino Acids
Authors: Katoh Takayuki , Suga Hiroaki
Published: January 2019

Methods of genetic code manipulation, such as nonsense codon suppression and genetic code reprogramming, have enabled the incorporation of various nonproteinogenic amino acids into the peptide nascent chain. However, the incorporation efficiency of such amino acids largely varies depending on their structural characteristics. For instance, l-α-amino acids with artificial, bulky side chains are poorer substrates for ribosomal incorporation into the nascent peptide chain, mainly owing to the lower affinity of their aminoacyl-tRNA toward elongation factor-thermo unstable (EF-Tu). Phosphorylated Ser and Tyr are also poorer substrates for the same reason; engineering EF-Tu has turned out to be effective in improving their incorporation efficiencies. On the other hand, exotic amino acids such as d-amino acids and β-amino acids are even poorer substrates owing to their low affinity to EF-Tu and poor compatibility to the ribosome active site. Moreover, their consecutive incorporation is extremely difficult. To solve these problems, the engineering of ribosomes and tRNAs has been executed, leading to successful but limited improvement of their incorporation efficiency. In this review, we comprehensively summarize recent attempts to engineer the translation systems, resulting in a significant improvement of the incorporation of exotic amino acids.
Improved Anticancer Effect of Recombinant Protein izTRAIL Combined with Sorafenib and Peptide iRGD
Authors: Fadeev Roman , Chekanov Alexey , Solovieva Marina , Bezborodova Olga , Nemtsova Elena , Dolgikh Nadezda , Fadeeva Irina , Senotov Anatoly , Kobyakova Margarita , Evstratova Yana , Yakubovskaya Raisa , Akatov Vladimir
Published: January 2019

One of the main problems in oncology is the development of drugs that cause the death of cancer cells without damaging normal cells. Another key problem to be solved is to suppress the drug resistance of cancer cells. The third important issue is to provide effective penetration of drug molecules to cancer cells. TRAIL (TNFα-related apoptosis inducing ligand)/Apo2L is a highly selective anticancer agent. However, the recombinant TRAIL protein having high efficiency against cancer cells in vitro was not effective in clinical trials. Recently we have discovered an acquisition of TRAIL resistance by cancer cells in confluent cultures, which is apparently a manifestation of the general phenomenon of multicellular resistance. The aim of this study was to evaluate whether the anticancer effect of the recombinant protein TRAIL in vivo can be improved by the suppression of multicellular TRAIL-resistance using sorafenib and a tumor-penetrating peptide iRGD, c(CRGDKGPDC). The results testified a great increase in the resistance of human fibrosarcoma HT-1080 cells to izTRAIL both in confluent cultures and in spheroids. Sorafenib administered at nontoxic concentration effectively suppressed confluent- or spheroid-mediated TRAIL-resistance of HT-1080 cells in vitro. Sorafenib combined with iRGD significantly improved the anticancer effect of the recombinant protein izTRAIL in HT-1080 human fibrosarcoma grafts in BALB/c nude mice. Consistent with this finding, multicellular TRAIL-resistance may be a reason of inefficacy of izTRAIL alone in vivo. The anticancer effect of the recombinant protein izTRAIL in vivo may be improved in combination with sorafenib, an inhibitor of multicellular TRAIL resistance and iRGD, the tumor-penetrating peptide.
The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain
Authors: Hossain Mohammad Zakir , Bakri Marina Mohd , Yahya Farhana , Ando Hiroshi , Unno Shumpei , Kitagawa Junichi
Published: January 2019

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.
Pollen Tube and Plant Reproduction
Authors: Cai Giampiero , Del Duca Stefano
Published: January 2019

The pollen tube was a fundamental step forward in the evolution of terrestrial plants; in fact, it allowed plants to liberate themselves from water demand during reproduction [...]
Epigallocatechin Gallate Modulates Muscle Homeostasis in Type 2 Diabetes and Obesity by Targeting Energetic and Redox Pathways: A Narrative Review
Authors: Casanova Ester , Salvadó Josepa , Crescenti Anna , Gibert-Ramos Albert
Published: January 2019

Obesity is associated with the hypertrophy and hyperplasia of adipose tissue, affecting the healthy secretion profile of pro- and anti-inflammatory adipokines. Increased influx of fatty acids and inflammatory adipokines from adipose tissue can induce muscle oxidative stress and inflammation and negatively regulate myocyte metabolism. Muscle has emerged as an important mediator of homeostatic control through the consumption of energy substrates, as well as governing systemic signaling networks. In muscle, obesity is related to decreased glucose uptake, deregulation of lipid metabolism, and mitochondrial dysfunction. This review focuses on the effect of epigallocatechin-gallate (EGCG) on oxidative stress and inflammation, linked to the metabolic dysfunction of skeletal muscle in obesity and their underlying mechanisms. EGCG works by increasing the expression of antioxidant enzymes, by reversing the increase of reactive oxygen species (ROS) production in skeletal muscle and regulating mitochondria-involved autophagy. Moreover, EGCG increases muscle lipid oxidation and stimulates glucose uptake in insulin-resistant skeletal muscle. EGCG acts by modulating cell signaling including the NF-κB, AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase (MAPK) signaling pathways, and through epigenetic mechanisms such as DNA methylation and histone acetylation.
The Effects of Resveratrol in the Treatment of Metabolic Syndrome
Authors: Hou Chih-Yao , Tain You-Lin , Yu Hong-Ren , Huang Li-Tung
Published: January 2019

Resveratrol, also known as 3,5,4′-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This review summarizes the mounting evidence that resveratrol is helpful in treating metabolic syndrome and related disorders. Resveratrol can be provided either early as a reprogramming agent or later as part of treatment. A few of the main mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are outlined. This review also discusses the potential of resveratrol derivatives as a complementary or alternative medicine. In conclusion, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions.
Leathesia difformis Extract Inhibits α-MSH-Induced Melanogenesis in B16F10 Cells via Down-Regulation of CREB Signaling Pathway
Authors: Seo Ga-Young , Ha Yuna , Park Ah-Hyun , Kwon Oh Wook , Kim Youn-Jung
Published: January 2019

Leathesia difformis (L.) Areschoug (L. difformis) is a species of littoral brown algae of the class Phaeophyceae. Only a few studies on the apoptotic, antiviral, and antioxidant properties of L. difformis have been reported, and its inhibitory effect on melanin synthesis has not been studied. The aim of this study was to investigate the anti-melanogenic effect of L. difformis extract on α-melanocyte-stimulating hormone (α-MSH)-induced B16F10 melanocytes and its mechanism of action. L. difformis was extracted using 80% ethanol (LDE) and then fractioned between ethyl acetate (LDE-EA) and water (LDE-A). Our data demonstrated that LDE-EA significantly inhibited melanin level and cellular tyrosinase activity in α-MSH-stimulated B16 cells. In addition, the expression of genes associated with melanin synthesis, such as microphthalmia-associated transcription factor (Mitf), tyrosinase (Tyr), tyrosinase-related protein-1 (Trp-1), dopachrome tautomerase (Dct), and melanocortin 1 receptor (Mc1r) was down-regulated by LDE-EA treatment. Moreover, LDE-EA decreased p-CREB levels, which suggests that the inhibition of the cAMP/PKA/CREB pathways may be involved in the anti-melanogenic effect of LDE-EA. Thus, this study revealed that LDE-EA is an effective inhibitor of hyperpigmentation through inhibition of CREB pathways and may be considered as a potential therapeutic agent for hyperpigmentation disorders.
The Cutaneous Inflammatory Response to Thermal Burn Injury in a Murine Model
Authors: Lateef Zabeen , Stuart Gabriella , Jones Nicola , Mercer Andrew , Fleming Stephen , Wise Lyn
Published: January 2019

Many burn interventions aim to target the inflammatory response as a means of enhancing healing or limiting hypertrophic scarring. Murine models of human burns have been developed, but the inflammatory response to injury in these models has not been well defined. The aim of this study was to profile inflammatory cell populations and gene expression relative to healing and scarring in a murine model of thermal burns. Cutaneous injuries were created on the dorsal region of C57Bl/6 mice using a heated metal rod. Animals were euthanized at selected time points over ten weeks, with the lesions evaluated using macroscopic measurements, histology, immunofluorescent histochemistry and quantitative PCR. The burn method generated a reproducible, partial-thickness injury that healed within two weeks through both contraction and re-epithelialization, in a manner similar to human burns. The injury caused an immediate increase in pro-inflammatory cytokine and chemokine expression, coinciding with an influx of neutrophils, and the disappearance of Langerhans cells and mast cells. This preceded an influx of dendritic cells and macrophages, a quarter of which displayed an inflammatory (M1) phenotype, with both populations peaking at closure. As with human burns, the residual scar increased in size, epidermal and dermal thickness, and mast cell numbers over 10 weeks, but abnormal collagen I-collagen III ratios, fibre organization and macrophage populations resolved 3–4 weeks after closure. Characterisation of the inflammatory response in this promising murine burn model will assist future studies of burn complications and aid in the preclinical testing of new anti-inflammatory and anti-scarring therapies.
Localized Delivery of Pilocarpine to Hypofunctional Salivary Glands through Electrospun Nanofiber Mats: An Ex Vivo and In Vivo Study
Authors: Muthumariappan Sujatha , Ng Wei Cheng , Adine Christabella , Ng Kiaw Kiaw , Davoodi Pooya , Wang Chi-Hwa , Ferreira Joao N.
Published: January 2019

Dry mouth or xerostomia is a frequent medical condition among the polymedicated elderly population. Systemic pilocarpine is included in the first line of pharmacological therapies for xerostomia. However, the efficacy of existing pilocarpine formulations is limited due to its adverse side effects and multiple daily dosages. To overcome these drawbacks, a localized formulation of pilocarpine targeting the salivary glands (SG) was developed in the current study. The proposed formulation consisted of pilocarpine-loaded Poly(lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) nanofiber mats via an electrospinning technique. The nanofiber mats were fully characterized for their size, mesh porosity, drug encapsulation efficiency, and in vitro drug release. Mat biocompatibility and efficacy was evaluated in the SG organ ex vivo, and the expression of proliferation and pro-apoptotic markers at the cellular level was determined. In vivo short-term studies were performed to evaluate the saliva secretion after acute SG treatment with pilocarpine-loaded nanofiber mats, and after systemic pilocarpine for comparison purposes. The outcomes demonstrated that the pilocarpine-loaded mats were uniformly distributed (diameter: 384 ± 124 nm) in a highly porous mesh, and possessed a high encapsulation efficiency (~81%). Drug release studies showed an initial pilocarpine release of 26% (4.5 h), followed by a gradual increase (~46%) over 15 d. Pilocarpine-loaded nanofiber mats supported SG growth with negligible cytotoxicity and normal cellular proliferation and homeostasis. Salivary secretion was significantly increased 4.5 h after intradermal SG treatment with drug-loaded nanofibers in vivo. Overall, this study highlights the strengths of PLGA/PEG nanofiber mats for the localized daily delivery of pilocarpine and reveals its potential for future clinical translation in patients with xerostomia.
Reply: “Comment on: Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases”
Authors: Simonini Marco , Casanova Paola , Citterio Lorena , Messaggio Elisabetta , Lanzani Chiara , Manunta Paolo
Published: January 2019

In his recent letter, Dr [...]
5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells
Authors: Córdova-Rivas Sergio , Fraire-Soto Ixamail , Mercado-Casas Torres Andrea , Servín-González Luis Steven , Granados-López Angelica Judith , López-Hernández Yamilé , Reyes-Estrada Claudia Araceli , Gutiérrez-Hernández Rosalinda , Castañeda-Delgado Julio Enrique , Ramírez-Hernández Leticia , Varela-Silva José Antonio , López Jesús Adrián
Published: January 2019

The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand’s expression and function is studied in cervical cancer. The 3p strand’s function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer.
A Systematic Review of Neuroprotective Strategies in the Management of Hypoglycemia
Authors: Nistor Marius , Schmidt Martin , Graul Isabel , Rakers Florian , Schiffner René
Published: January 2019

Severe hypogylcemia has been found to induce cerebral damage. While a number of illnesses can lead to hypoglycemic episodes, antidiabetic medications prescribed for glycemic control are a common cause. Considering the rising prevalence of diabetes mellitus in the population, we investigated neuroprotective strategies during hypoglycemia in the form of a systematic review in adherence to the PRISMA statement. A review protocol was registered in the PROSPERO database. A systematic literature search of PubMed, Web of Science, and CENTRAL was performed in September 2018. Based on a predefined inclusion protocol, results were screened and evaluated by two researchers. Both animal experiments and human studies were included, and their risk of bias was assessed with SYRCLE’s and the Cochrane risk of bias tools, respectively. Of a total of 16,230 results, 145 were assessed in full-text form: 27 articles adhered to the inclusion criteria and were qualitatively analyzed. The retrieved neuroprotective strategies could be categorized into three subsets: (1) Energy substitution, (2) hypoglycemia unawareness, and (3) other neuroprotective strategies. While on a study level, the individual results appeared promising, more research is required to investigate not only specific neuroprotective strategies against hypoglycemic cerebral damage, but also its underlying pathophysiological mechanisms.
Deducting MicroRNA-Mediated Changes Common in Bronchial Epithelial Cells of Asthma and Chronic Obstructive Pulmonary Disease—A Next-Generation Sequencing-Guided Bioinformatic Approach
Authors: Tsai Ming-Ju , Tsai Yu-Chen , Chang Wei-An , Lin Yi-Shiuan , Tsai Pei-Hsun , Sheu Chau-Chyun , Kuo Po-Lin , Hsu Ya-Ling
Published: January 2019

Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway inflammatory diseases that share some common features, although these diseases are somewhat different in etiologies, clinical features, and treatment policies. The aim of this study is to investigate the common microRNA-mediated changes in bronchial epithelial cells of asthma and COPD. The microRNA profiles in primary bronchial epithelial cells from asthma (AHBE) and COPD (CHBE) patients and healthy subjects (NHBE) were analyzed with next-generation sequencing (NGS) and the significant microRNA changes common in AHBE and CHBE were extracted. The upregulation of hsa-miR-10a-5p and hsa-miR-146a-5p in both AHBE and CHBE was confirmed with quantitative polymerase chain reaction (qPCR). Using bioinformatic methods, we further identified putative targets of these microRNAs, which were downregulated in both AHBE and CHBE: miR-10a-5p might suppress BCL2, FGFR3, FOXO3, PDE4A, PDE4C, and PDE7A; miR-146a-5p might suppress BCL2, INSR, PDE4D, PDE7A, PDE7B, and PDE11A. We further validated significantly decreased expression levels of FOXO3 and PDE7A in AHBE and CHBE than in NHBE with qPCR. Increased serum miR-146a-5p level was also noted in patients with asthma and COPD as compared with normal control subjects. In summary, our study revealed possible mechanisms mediated by miR-10a-5p and miR-146a-5p in the pathogenesis of both asthma and COPD. The findings might provide a scientific basis for developing novel diagnostic and therapeutic strategies.