bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole-genome fingerprint of the DNA methylome during chemically induced differentiation of the human AML cell line HL-60/S4
Authors: Antwi Enoch Boasiako , Olins Ada , Teif Vladimir B. , Bieg Matthias , Bauer Tobias , Gu Zuguang , Brors Benedikt , Eils Roland , Olins Donald , Ishaque Naveed
Published: January 2020

Epigenomic regulation plays a vital role in cell differentiation. The leukemic HL-60/S4 promyelocytic cell can be easily differentiated from its undifferentiated promyelocyte state into neutrophil- and macrophage-like cell states. In this study, we present the underlying genome and epigenome architecture of HL-60/S4 through its differentiation.

We performed whole genome bisulphite sequencing of HL-60/S4 cells and their differentiated counterparts. With the support of karyotyping, we show that HL-60/S4 maintains a stable genome throughout differentiation. Analysis of differential CpG methylation reveals that most methylation changes occur in the macrophage-like state. Differential methylation of promoters was associated with immune related terms. Key immune genes, CEBPA, GFI1, MAFB and GATA1 showed differential expression and methylation. However, we observed strongest enrichment of methylation changes in enhancers and CTCF binding sites, implying that methylation plays a major role in large scale transcriptional reprogramming and chromatin reorganisation during differentiation. Correlation of differential expression and distal methylation with support from chromatin capture experiments allowed us to identify putative proximal and long-range enhancers for a number of immune cell differentiation genes, including CEBPA and CCNF. Integrating expression data, we present a model of HL-60/S4 differentiation in relation to the wider scope of myeloid differentiation.
Polyphyllin II inhibits liver cancer cell proliferation, migration and invasion through downregulated cofilin activity and the AKT/NF-κB pathway
Authors: Pang Dejiang , Yang Chengcheng , Li Chao , Zou Yuanfeng , Feng Bin , Li Lixia , Liu Wentao , Luo Qihui , Chen Zhengli , Huang Chao
Published: January 2020

The morbidity and mortality of primary liver cancer is one of the highest amongst all cancers. Deficiency of effective treatment and characteristics of cancer metastasis are believed to be responsible for this situation, thus a great demand is required for new agent development. Polyphyllin II (PP2), an important steroidal saponin extracted from Rhizoma Paris, has emerged as a potential anti-cancer agent, but the effects of PP2 in liver cancers and its underlying mechanisms remain unexplored. In our study, we found that PP2 could remarkably suppress the proliferation of two liver cancer cell lines, HepG2 and BEL7402, resulting in significant cell death. Besides, low doses of PP2 have displayed properties that inhibit cellular motility and invasion of liver cancer cells. In addition, we have found that PP2-mediated cofilin activity suppression was implicated in the inhibition of liver cancer cell motility. Decreased expression of two major hydrolytic enzymes (MMP2/MMP9), through the AKT/NF-κB signaling pathway may also be also responsible for this process. Rescue experiments done with either non-phosphorylatable mutant cofilin-1 (S3A) transfection or an activator of the AKT pathway significantly reversed the inhibition effects of PP2 on liver cancer cells. Taken together, we report a potential agent for liver cancer treatment and reveal its underlying mechanisms.
Loss of Crb2b-lf leads to anterior segment defects in old zebrafish
Authors: Kujawski Satu , Crespo Cátia , Luz Marta , Yuan Michaela , Winkler Sylke , Knust Elisabeth
Published: January 2020

Defects in the retina or the anterior segment of the eye lead to compromised vision and affect millions of people. Understanding how these ocular structures develop and are maintained is therefore of paramount importance. The maintenance of proper vision depends, among others, on the function of genes controlling apico-basal polarity. In fact, mutations in polarity genes are linked to retinal degeneration in several species, including human. Here we describe a novel zebrafish crb2b allele (crb2be40), which specifically affects the crb2b long isoform. crb2be40 mutants are viable and display normal ocular development. However, old crb2be40 mutant fish develop multiple defects in structures of the anterior segment, which includes the cornea, the iris and the lens. Phenotypes are characterised by smaller pupils due to expansion of the iris and tissues of the iridocorneal angle, an increased number of corneal stromal keratocytes, an abnormal corneal endothelium and an expanded lens capsule. These findings illustrate a novel role for crb2b in the maintenance of the anterior segment and hence add an important function to this polarity regulator, which may be conserved in other vertebrates, including humans.
FAM172A inhibits EMT in pancreatic cancer via ERK-MAPK signaling
Authors: Chen Ying , Liu Peihui , Shen Di , Liu Han , Xu Lepeng , Wang Jian , Shen Daguang , Sun He , Wu Hongkui
Published: January 2020

Background FAM172A, as a newly discovered gene, is little known in cancer development, especially in pancreatic cancer (PC).

Methods We investigated the potential role and molecular mechanism of FAM172A in epithelial to mesenchymal transition (EMT) in both human clinical samples and PC cells.

Results FAM172A was downregulated in human PC tissues compared with that in adjacent pancreas by IHC and qRT-PCR. FAM172A expression was negatively associated with tumor size (P=0.015), T stage (P=0.006), lymph nodes metastase (P=0.028) and the worse prognosis of PC patients (P=0.004). Meanwhile, a positive relationship between FAM172A and E-cadherin (E-cad) (r=0.381, P=0.002) was observed in clinical samples which contributed to the better prognosis of PC patients (P=0.014). FAM172A silencing induced EMT in both AsPC-1 and BxPC-3 cells, including inducing the increase of Vimentin, MMP9 and pERK and the decrease of E-cad and β-catenin expression, stimulating EMT-like cell morphology and enhancing cell invasion and migration in PC cells. However, MEK1 inhibitor PD98059 reversed FAM172A silencing-enhanced EMT in PC cells.

Conclusion FAM172A inhibits EMT of PC cells via ERK-MAPK signaling.
The absence of SOX2 in the anterior foregut alters the esophagus into trachea and bronchi in both epithelial and mesenchymal components
Authors: Teramoto Machiko , Sugawara Ryo , Minegishi Katsura , Uchikawa Masanori , Takemoto Tatsuya , Kuroiwa Atsushi , Ishii Yasuo , Kondoh Hisato
Published: January 2020

In the anterior foregut (AFG) of mouse embryos, the transcription factor SOX2 is expressed in the epithelia of the esophagus and proximal branches of respiratory organs comprising the trachea and bronchi, whereas NKX2.1 is expressed only in the epithelia of respiratory organs. Previous studies using hypomorphic Sox2 alleles have indicated that reduced SOX2 expression causes the esophageal epithelium to display some respiratory organ characteristics. In the present study, we produced mouse embryos with AFG-specific SOX2 deficiency. In the absence of SOX2 expression, a single NKX2.1-expressing epithelial tube connected the pharynx and the stomach, and a pair of bronchi developed in the middle of the tube. Expression patterns of NKX2.1 and SOX9 revealed that the anterior and posterior halves of SOX2-deficient AFG epithelial tubes assumed the characteristics of the trachea and bronchus, respectively. In addition, we found that mesenchymal tissues surrounding the SOX2-deficient NKX2.1-expressing epithelial tube changed to those surrounding the trachea and bronchi in the anterior and posterior halves, as indicated by the arrangement of smooth muscle cells and SOX9-expressing cells and by the expression of Wnt4 (esophagus specific), Tbx4 (respiratory organ specific), and Hoxb6 (distal bronchus specific). The impact of mesenchyme-derived signaling on the early stage of AFG epithelial specification has been indicated. Our study demonstrated an opposite trend where epithelial tissue specification causes concordant changes in mesenchymal tissues, indicating a reciprocity of epithelial-mesenchymal interactions.
Dendrites with specialized glial attachments develop by retrograde extension using SAX-7 and GRDN-1
Authors: Cebul Elizabeth R. , McLachlan Ian G. , Heiman Maxwell G.
Published: January 2020

Dendrites develop elaborate morphologies in concert with surrounding glia, but the molecules that coordinate dendrite and glial morphogenesis are mostly unknown. C. elegans offers a powerful model for identifying such factors. Previous work in this system examined dendrites and glia that develop within epithelia, similar to mammalian sense organs. Here, we focus on the neurons BAG and URX, which are not part of an epithelium but instead form membranous attachments to a single glial cell at the nose, reminiscent of dendrite-glia contacts in the mammalian brain. We show that these dendrites develop by retrograde extension, in which the nascent dendrite endings anchor to the presumptive nose and then extend by stretch during embryo elongation. Using forward genetic screens, we find that dendrite development requires the adhesion protein SAX-7/L1CAM and the cytoplasmic protein GRDN-1/CCDC88C to anchor dendrite endings at the nose. SAX-7 acts in neurons and glia, while GRDN-1 acts in glia to non-autonomously promote dendrite extension. Thus, this work shows how glial factors can help to shape dendrites, and identifies a novel molecular mechanism for dendrite growth by retrograde extension.
Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation
Authors: Romagnoli Mathilde , Bresson Laura , Di-Cicco Amandine , Pérez-Lanzón María , Legoix Patricia , Baulande Sylvain , de la Grange Pierre , De Arcangelis Adèle , Georges-Labouesse Elisabeth , Sonnenberg Arnoud , Deugnier Marie-Ange , Glukhova Marina A. , Faraldo Marisa M.
Published: January 2020

Integrin dimers α3/β1, α6/β1 and α6/β4 are the mammary epithelial cell receptors for laminins, which are major components of the mammary basement membrane. The roles of specific basement membrane components and their integrin receptors in the regulation of functional gland development have not been analyzed in detail. To investigate the functions of laminin-binding integrins, we obtained mutant mice with mammary luminal cell-specific deficiencies of the α3 and α6 integrin chains generated by the Cre-Lox approach. During pregnancy, mutant mice displayed decreased luminal progenitor activity and retarded lobulo-alveolar development. Mammary glands appeared functional at the onset of lactation in mutant mice, however myoepithelial cell morphology was markedly altered, suggesting cellular compensation mechanisms involving cytoskeleton reorganization. Notably, lactation was not sustained in mutant females, and the glands underwent precocious involution. Inactivation of the p53 gene rescued the growth defects but did not restore lactogenesis in mutant mice. These results suggest that the p53 pathway is involved in the control of mammary cell proliferation and survival downstream of laminin-binding integrins and underline an essential role of cell interactions with laminin for lactogenic differentiation.
Notch signalling regulates epibranchial placode patterning and segregation
Authors: Wang Li , Xie Junjie , Zhang Haoran , Tsang Long Hin , Tsang Sze Lan , Braune Eike-Benjamin , Lendahl Urban , Sham Mai Har
Published: January 2020

Epibranchial placodes are the geniculate, petrosal and nodose placodes which generate parts of cranial nerves VII, IX and X, respectively. How the three spatially separated placodes are derived from the common posterior placodal area is poorly understood. Here, we reveal that the broad posterior placode area is first patterned into a Vgll2+/Irx5+ rostral domain and a Sox2+/Fgf3+/Etv5+ caudal domain relative to the first pharyngeal cleft. This initial rostral and caudal patterning is then sequentially repeated along each pharyngeal cleft for each epibranchial placode. The caudal domains give rise to the neuronal and non-neuronal cells in the placode, while the rostral domains are previously unrecognized structures, serving as spacers between the final placodes. Notch signalling regulates the balance between the rostral and caudal domains: high levels of Notch signalling expand the caudal domain at the expense of the rostral domain, whereas loss of Notch signalling produces the converse phenotype. Collectively, these data unravel a new patterning principle for the early phases of epibranchial placode development and a role for Notch signalling in orchestrating epibranchial placode segregation and differentiation.
Different modes of Notch activation and strength regulation in the spermathecal secretory lineage
Authors: Shen Wei , Sun Jianjun
Published: January 2020

The strength of Notch signaling contributes to pleiotropic actions of Notch; however, we do not yet have a full understanding of the molecular regulation of Notch-signaling strength. We have investigated the mode of Notch activation in binary fate specification in the Drosophila spermathecal linage, where Notch is asymmetrically activated across three divisions to specify different cell fates. Using clonal analysis, we show that Delta (Dl) serves as the ligand for Notch in the first and second divisions. Dl and Serrate (Ser) function redundantly in the third division. Compared with the third division, cell-fate decision in the second division requires a lower level of Suppressor of Hairless protein, and, consequently, a lower level of Notch signaling. Several Notch endosomal trafficking regulators differentially regulate Notch signaling between the second and third divisions. Here, we demonstrate that cell differentiation in spermathecae involves different Notch-activation modes, Notch-signaling strengths and Notch-trafficking regulations. Thus, the Drosophila spermathecal lineage is an exciting model for probing the molecular mechanisms that modulate the Notch signaling pathway.
The myeloid lineage is required for the emergence of a regeneration-permissive environment following Xenopus tail amputation
Authors: Aztekin Can , Hiscock Tom W. , Butler Richard , De Jesús Andino Francisco , Robert Jacques , Gurdon John B. , Jullien Jerome
Published: January 2020

Regeneration-competent vertebrates are considered to suppress inflammation faster than non-regenerating ones. Hence, understanding the cellular mechanisms affected by immune cells and inflammation can help develop strategies to promote tissue repair and regeneration. Here, we took advantage of naturally occurring tail regeneration-competent and -incompetent developmental stages of Xenopus tadpoles. We first establish the essential role of the myeloid lineage for tail regeneration in the regeneration-competent tadpoles. We then reveal that upon tail amputation there is a myeloid lineage-dependent change in amputation-induced apoptosis levels, which in turn promotes tissue remodelling, and ultimately leads to the relocalization of the regeneration-organizing cells responsible for progenitor proliferation. These cellular mechanisms failed to be executed in regeneration-incompetent tadpoles. We demonstrate that regeneration incompetency is characterized by inflammatory myeloid cells whereas regeneration competency is associated with reparative myeloid cells. Moreover, treatment of regeneration-incompetent tadpoles with immune-suppressing drugs restores myeloid lineage-controlled cellular mechanisms. Collectively, our work reveals the effects of differential activation of the myeloid lineage on the creation of a regeneration-permissive environment and could be further exploited to devise strategies for regenerative medicine purposes.
Interspecific variation in hypoxia tolerance and hypoxia acclimation responses in killifish from the family Fundulidae
Authors: Borowiec Brittney G. , Hoffman Ryan D. , Hess Chelsea D. , Galvez Fernando , Scott Graham R.
Published: January 2020

Hypoxia is a pervasive stressor in aquatic environments, and both phenotypic plasticity and evolutionary adaptation could shape the ability to cope with hypoxia. We investigated evolved variation in hypoxia tolerance and the hypoxia acclimation response across fundulid killifishes that naturally experience different patterns of hypoxia exposure. We compared resting O2 consumption rate (MO2), and various indices of hypoxia tolerance (critical O2 tension [Pcrit], regulation index [RI], O2 tension [PO2] at loss of equilibrium [PLOE], and time to LOE [tLOE] at 0.6 kPa O2) in Fundulus confluentus, F. diaphanus, F. heteroclitus, F. rathbuni, Lucania goodei, and L. parva. We examined the effects of chronic (28 d) exposure to constant hypoxia (2 kPa) or nocturnal intermittent hypoxia (12 h normoxia: 12 h hypoxia) in a subset of species. Some species exhibited a two-breakpoint model in MO2 caused by early, modest declines in MO2 in moderate hypoxia. We found that hypoxia tolerance varied appreciably across species: F. confluentus was the most tolerant (lowest PLOE and Pcrit, longest tLOE), whereas F. rathbuni and F. diaphanus were the least tolerant. However, there was not a consistent pattern of interspecific variation for different indices of hypoxia tolerance, with or without taking phylogenetic relatedness into account, likely because these different indices are underlaid by partially distinct mechanisms. Hypoxia acclimation generally improved hypoxia tolerance, but the magnitude of plasticity and responsiveness to different hypoxia patterns varied interspecifically. Our results therefore suggest that hypoxia tolerance is a complex trait that is best appreciated by considering multiple indices of tolerance.
The impact of a high-fat diet in mice is dependent on duration and age, and differs between muscles
Authors: Messa G. A. M. , Piasecki M. , Hurst J. , Hill C. , Tallis J. , Degens H.
Published: January 2020

Prolonged high-fat diets (HFD) can cause intramyocellular lipids (IMCL) accumulation that may negatively affect muscle function. We investigated the duration of a HFD required to instigate these changes, and whether effects are muscle-specific and aggravated in older age. Muscle morphology was determined in the soleus, extensor digitorum longus (EDL) and diaphragm muscles from female CD-1 mice divided into 5 groups: young fed a HFD for 8 weeks (YS-HFD, n=16), young fed a HFD for 16 weeks (YL-HFD, n=28) and young control (Y-CON, n=28). The young animals were 20 weeks old at the end of the experiment. Sixty 70-week-old female CD-1 mice received either a normal diet (O-CON, n=30) or a HFD for 9 weeks (OS-HFD, n=30). Body mass, body mass index and IMCL content increased in old OS-HFD (p≤0.003). In the young mice, this increase was seen in YL-HFD and not YS-HFD (p≤0.006). The soleus and diaphragm fibre cross-sectional area (FCSA) in YL-HFD was larger compared to Y-CON (p≤0.004) while old mice had a larger soleus FCSA compared to CON after only 9 weeks on a HFD (p<0.001). The FCSA of the EDL muscle did not differ significantly between groups. Oxidative capacity of fibres increased in young only, irrespective of HFD duration (p<0.001). High-fat diet-induced morphological changes occur earlier in the old animals when compared to young, and adaptations to HFD are muscle-specific with the EDL being least responsive.
Modification of Neuromuscular Junction Protein Expression by Exercise and Doxorubicin
Authors: HUERTAS ANDRES MOR , MORTON AARON B. , HINKEY J. MATTHEW , ICHINOSEKI-SEKINE NORIKO , SMUDER ASHLEY J.
Published: January 2020

Purpose

Doxorubicin (DOX) is a highly effective antitumor agent widely used in cancer treatment. However, it is well established that DOX induces muscular atrophy and impairs force production. Although no therapeutic interventions exist to combat DOX-induced muscle weakness, endurance exercise training has been shown to reduce skeletal muscle damage caused by DOX administration. Numerous studies have attempted to identify molecular mechanisms responsible for exercise-induced protection against DOX myotoxicity. Nevertheless, the mechanisms by which endurance exercise protects against DOX-induced muscle weakness remain elusive. In this regard, impairments to the neuromuscular junction (NMJ) are associated with muscle wasting, and studies indicate that physical exercise can rescue NMJ fragmentation. Therefore, we tested the hypothesis that exercise protects against DOX-induced myopathy by preventing detrimental changes to key proteins responsible for maintenance of the NMJ.

Methods

Female Sprague–Dawley rats were assigned to sedentary or exercise-trained groups. Exercise training consisted of a 5-d treadmill habituation period followed by 10 d of running (60 min·d−1, 30 m·min−1, 0% grade). After the last training bout, exercise-trained and sedentary animals were paired with either placebo (saline) or DOX (20 mg·kg−1 i.p.) treatment. Two days after drug treatment, the soleus muscle was excised for subsequent analyses.

Results

Our results indicate that endurance exercise training prevents soleus muscle atrophy and contractile dysfunction in DOX-treated animals. These adaptations were associated with the increased expression of the following neurotrophic factors: brain-derived neurotrophic factor, glial cell line–derived neurotrophic factor, nerve growth factor, and neurotrophin-3. In addition, exercise enhanced the expression of receptor-associated protein of the synapse and the acetylcholine receptor (AChR) subunits AChRβ, AChRδ, and AChRγ in DOX-treated animals.

Conclusion

Therefore, upregulating neurotrophic factor and NMJ protein expression may be an effective strategy to prevent DOX-induced skeletal muscle dysfunction.
Cumulative Metrics of Tendon Load and Damage Vary Discordantly with Running Speed
Authors: FIRMINGER COLIN R. , ASMUSSEN MICHAEL J. , CIGOJA SASA , FLETCHER JARED R. , NIGG BENNO M. , EDWARDS W. BRENT
Published: January 2020

Purpose

Cumulative load has become a popular metric in running biomechanics research to account for potential spatiotemporal changes associated with different locomotion strategies. This study investigated how incorporating mechanical fatigue principles into Achilles tendon cumulative load measurements affected their relationship with running speed.

Methods

Achilles tendon forces and strains were estimated from a dynamometry/ultrasound session followed by a motion capture session, where participants ran at three speeds. Three cumulative measures of increasing complexity were calculated using Achilles tendon force/strain: 1) cumulative load, defined as the product of the stance phase time integral of Achilles tendon force/strain and the stride count for 1 km of running; 2) cumulative damage, which accounted for the nonlinear relationship between load magnitude and fatigue life by exponentially weighting the time integral of Achilles tendon force/strain before multiplication with stride count; and (3) the probability of fatigue failure, which expanded upon the cumulative damage measure of Achilles tendon strain by fitting a probabilistic Weibull model to existing fatigue life data to account for the inherent variability that exists in the fatigue life of biological samples.

Results

Cumulative load measures significantly decreased with running speed, whereas the cumulative damage and probabilistic measures either increased or did not change significantly with running speed.

Conclusions

The choice of cumulative metric has an important influence on the interpretation of overuse injury risk with changes in running speed. Although cumulative load metrics certainly provide meaningful information about the load experienced over a given distance, they do not account for the tissue damage incurred by such load. Cumulative load metrics should therefore be interpreted with caution when making inferences to overuse injury risk.
Salt effect on thermodynamics and kinetics of a single RNA base pair
Authors: Wang Yujie , Liu Taigang , Yu Ting , Tan Zhi-Jie , Zhang Wenbing
Published: January 2020

Due to the polyanionic nature of RNAs, the structural folding of RNAs are sensitive to solution salt conditions, while there is still lack of a deep understanding of the salt effect on the thermodynamics and kinetics of RNAs at a single base-pair level. In this work, the thermodynamic and the kinetic parameters for the base-pair AU closing/opening at different salt concentrations were calculated by 3-µsec all-atom molecular dynamics (MD) simulations at different temperatures. It was found that for the base-pair formation, the enthalpy change ΔH is nearly independent of salt concentration, while the entropy change ΔS exhibits a linear dependence on the logarithm of salt concentration, verifying the empirical assumption based on thermodynamic experiments. Our analyses revealed that such salt concentration dependence of the entropy change mainly results from the dependence of ion translational entropy change for the base pair closing/opening on salt concentration. Furthermore, the closing rate increases with the increasing of salt concentration, while the opening rate is nearly independent of salt concentration. Additionally, our analyses revealed that the free energy surface for describing the base-pair opening and closing dynamics becomes more rugged with the decrease of salt concentration.
Efficacy and safety of microbiota transfer therapy for the management of autism spectrum disorder in children: a systematic review
Authors: Estrella Porter Pablo Daniel , Guzmán Freire Luis Eduardo , Adatty Molina Joseth Paulina , Burneo Raza María Verónica , Carrión Celi Henry Alejandro , Espinosa Borja Isabel María , Falconí Páez Andrea Carolina , Gudiño Vega Andrés Sebastián , Jaramillo Cartwright María José , Oña Vargas Sebastián Xavier , Puga Martínez Sebastián Eduardo , Guillemot Jonathan R
Published: January 2020

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with an unclear etiologic mechanism. Following suggestions in the literature of a close relation between the gut microbiota and the central nervous system development, neuroimmune and neuroendocrine systems, new theories and strategies of the management of ASD in children focus on the brain-gut axis via microbiota transfer therapy. Despite the regular appearance in the news, the level of evidence supporting this intervention is unclear and to this date, no systematic review on this issue has been published.

Methods: We conducted a systematic literature review of the efficacy and safety of microbiota transfer therapy for the management of ASD in children. MEDLINE via PubMed, LILACS IBECS via BVS, EMBASE via Ovid, Scopus and Cochrane Library were searched on 19th April 2018.

Results: One single study published in 2017 was identified. The intervention group included 18 patients and showed significant clinical improvements in the gastrointestinal and ASD-related symptoms. The clinical procedure was reported as safe and well-tolerated with some transitory adverse effects.

Conclusions: The causality and correlation of the intervention and the expected outcomes cannot be assumed with current evidence. In addition, recommendations about the effectiveness or safety of microbiota transfer therapy in children with ASD cannot be currently issued. Randomized controlled trials and clinical protocols for the intervention are needed.
In silico study on RNA structures of intronic mutations of beta-globin gene
Authors: Sumantri Nur Imaniati , Lischer Kenny , Wijayanti Dian Rachma , Abuzairi Tomy
Published: January 2020

Background: Mutation of the beta-globin gene (HBB) interferes with primary mRNA transcription, leading to beta-thalassemia disease. The IVS1nt1 and IVS1nt5 mutations were reported as two of the most prevalent intronic mutations associated with beta-thalassemia major. These mutations may affect the mRNA structure of the human beta-globin (HBB) gene. However, the mechanism by which variation in HBB alters the mRNA structure remains unclear. The objective of this study was to unveil the secondary and tertiary conformation difference of the mutants compared to the wildtype using in silico analysis.

Methods: The sequence of HBB was obtained from Ensemble database and mutated manually at nucleotides 143 (IVS1nt1G>T) and 147 (IVS1nt5G>C). The RNA secondary and tertiary structure were performed by ViennaRNA Web Services and RNA Composer, respectively.

Results and Discussion: The results revealed the unique folding characteristics of each mutations for the secondary and tertiary structures. Based on the structure, unwanted folding occurred in the IVS1nt1G>T and IVS1nt5G>C mRNA structures compared to the wild-type structure. This finding was supported by the results of centroid-based analysis and RNA structure analysis, indicating that the larger loops in IVS1nt1 and IVS1nt5 result in an unstable structure. Our study found that intronic mutations affect the mRNA structure of HBB by altering its folding mechanism.
The FRAXA and FRAXE allele repeat size of boys from the Avon Longitudinal Study of Parents and Children (ALSPAC)
Authors: Clark Rosie , Gregory Steven , Ring Susan , Jacobs Patricia , Ennis Sarah , Murray Anna , Ellis Genette , Golding Jean , Northstone Kate , Pembrey Marcus
Published: January 2020

The FRAXA and FRAXE alleles of the FMR1 and FMR2 genes located on the X chromosome contain varying numbers of trinucleotide repeats. Large numbers of repeats at FRAXA (full mutations) manifest as Fragile X syndrome, associated with mental impairment that affects males more severely. In this paper, we present the dataset of frequencies of FRAXA and FRAXE repeat size extracted from DNA samples collected from boys enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). DNA data were extracted from samples collected in ALSPAC clinics from several types of samples: cord blood, venepuncture blood taken at 43 months, 61 months, seven years or nine years. The DNA was amplified at FRAXA and FRAXE using fluorescent PCR in the Wessex Regional Genetics Laboratory, Salisbury District Hospital. The mean repeat size for FRAXA is 28.92 (S.D. 5.44), the median 30 and the range 8 to 68. There were particularly high numbers of boys with repeat sizes of 20 (10.67%) and 23 (7.35%). The mean repeat size for FRAXE is 17.41 (S.D. 3.94), with median of 16 and range of 0 to 61. There is a relatively high degree of variation of the FRAXA repeat size particularly and we suggest the extensive data available from the ALSPAC study opens up areas of research into understanding phenotypes associated with relatively unexplored repeat sizes. This could be particularly interesting for the lower repeat sizes occurring with high frequency at FRAXA in this population. As the data can be linked to exposures and phenotypes, it will provide a resource for researchers worldwide.
DINAMICS OF THE MAIN EFFICIENCY INDICATORS OF THE ONCOLOGIC PROFILE BED FUND OF THE ROUND-THE-CLOCK AND DAILY STAY HOSPITALS IN THE RUSSIAN FEDERATION AND ITS REGIONS
Authors: Bant'eva M. , Manoshkina E. , Kuznecova V.
Published: January 2020

The incidence of malignant neoplasms in Russia is growing and in 2018 amounted to 425.4 cases per 100000 population, what is 23.1% higher than the level of 2008, this requires optimization of the provision of both outpatient and inpatient medical care to this contingent. The main efficiency indicators of the oncologic profile bed fund of both round-the-clock and daily stay hospitals in the Russian Federation, in dynamics for 2010-2018 years are analyzed in the article.
DYNAMICS OF THE MAIN INDICATORS OF HOSPITAL BEDS CARDIOLOGICAL HOUR AND DAY OF STAY IN THE RUSSIAN FEDERATION
Authors: Manoshkina E. , Bant'eva M. , Kuznecova V.
Published: January 2020

. For the period 2010-2018, the number of cardiac macroglobulinov stay in the Russian Federation decreased from 55477 before 49578 (10.6%),polysilazane hospitalizations for cardiac beds (from 9.3 to 10.8 per 1,000 population – 16.1%),decreased provision of cardiological beds (from 3.88 to 3.38 per 1000 population – by 12.9%), the average length of stay for cardiac bed (from 13.1 to 9.1 tnado – by 26.0%) and average employment cardiology bed per year (from 340 to 327 days – 3.8%). Mortality in cardiac beds in the Russian Federation decreased from 1.96% in 2010 to 1.89% in 2018 (by 3.6%).The provision of places for the Russian population in day hospitals of cardiological profile of organizations providing medical care in inpatient conditions increased by 19.6% (from 0.12 per 10,000 population in 2010 to 0.14 in 2018), and in day hospitals of organizations providing medical care in outpatient conditions decreased by 11.5% (from 0.15 per 10,000 population in 2014 up to 0.14 in 2018).In the Russian Federation, during the observation period, the level of hospitalizations in day hospitals of organizations providing medical care in inpatient conditions increased by 43.6%, and the GVA of the cardiological profile of organizations providing medical care in outpatient conditions increased by 5.2%. The dynamics of indicators of the bed Fund of cardiology profile in recent years indicates the process of inpatient replacement, which is undoubtedly one of the ways to improve the efficiency of using health resources.
BED FUND OF THE RUSSIAN FEDERATION: DYNAMICS OF ITS MAIN INDICATORS
Authors: Bant'eva M. , Manoshkina E. , Mel'nikov Yuriy
Published: January 2020

Despite the fact that the process of structural and functional optimization of the hospital bed fund is currently underway, the basis for the provision of medical care remains the assistance provided in around the clock and day time hospitals, which is the most costly because it requires the constant involvement of a large amount of staff, material, technical, financial and other types of resources. The main indicators of the bed fund in around the clock and daily stay hospitals in the Russian Federation, Federal District and regions in dynamics for 2010-2018, as well as mortality in around the clock hospitals, are analyzed using descriptive statistics. In the Russian Federation from 2010 to 2018 the absolute number of hospitals decreased from 5705 to 4323 (by 24.2%), both due to the reduction in the number of hospital beds and in connection with the unification of medical organizations. At the same time, the number of round-the-clock beds decreased from 1250120 to 1044875 (by 16.4%); provision with hospital beds decreased (from 87.5 to 71.1 per 10,000 population - by 18.7%), the average treatment duration (from 12.6 days to 10.7 - by 15.1%) and, unfortunately, average bed occupancy per year (from 325 to 313 days - by 3.7%). In 2018, the extreme values of the indicator of hospitalization rate for 24-hour hospital beds in the regions of the Russian Federation differ 1.8 times, provision with hospital beds - 2.9 times, average bed occupancy per year - 1.2 times, average treatment duration - 1 8 times. The established differences may indicate an imbalance in the ongoing structural transformations. The overall mortality rate in the Russian Federation increased: from 1.5% in 2010 to 1.9% in 2018 (by 28.4%), a similar trend was observed in all regions. The provision of beds in day care hospitals increased from 15.4 per 10,000 in 2010 to 17.0 in 2018 (10.7%). Multidirectional tendencies are noted, both towards increasing and decreasing the number of places in day hospitals, both in the Federal Districts as a whole and in individual regions. The extreme values of the indicator of the provision of places for day care hospitals in the regions of the Russian Federation differ by 30 times, what reflects the disproportionate organization of a network of day care hospitals in the country's regions. During the observation period in the Russian Federation, the level of hospitalization in round-the-clock hospitals decreased from 222.0 to 203.5 per 1000 population (by 8.3%), while the level of hospitalizations in day care hospitals steadily increased from 26.4 to 35.0 per 1,000 (32.8%), what indicates the implementation of the expected hospital-replacing function of day care in the country as a whole. The issue of further structural and functional optimization of the hospital bed fund of the country remains relevant.
Synthetical Methods to Express Semantic Restrictions of Volition in Display Discourse
Authors: Milovanova M. , Meyvey Chzhao
Published: January 2020

The article presents the status of emoji in modern communication, synthetical methods to express semantic restrictions of volition, and the subjective value expressed by them in display text.
Specificity of Expression of Peyorative Evaluation in Massmedia Discourse of Fashion (On the Material of Telecasts “Fashionable Sentence” and “Take It off Immediately”)
Authors: Gaputina V.
Published: January 2020

The article reveals the specific features of the expression of pejorative evaluation in the media discourse of fashion, aimed at a wide mass audience, using tv-shows in the genre of make-over-show “Fashionable sentence” and “Take it off immediately”. The analysis of lexical units containing negative valuation meanings in the denotative component of meaning (general valuation and private valuation), as well as contextually determined lexemes acquiring negative coloring in the context of discourse of fashion, is presented. The author of the article comes to the conclusion that the explicit and implicit evaluative characteristics with a peer-to-peer component used by the leading programs — professionals in the field of fashion, realize the maximum impact on the mind and behavior of the addressee and the formation of the values necessary for the addressee in relation to appearance.
Novel Target Discovery of Existing Therapies: Path to Personalized Cancer Therapy
Authors: Bertsimas Dimitris , Zhuo Ying Daisy
Published: January 2020

Discovering new drugs involves tremendous effort and financial resources, often at a significant risk of failed trials. Identifying new targets of existing drugs provides a promising direction, especially for molecular targeted cancer therapies. This paper presents a novel, machine learning, and optimization-based method that identifies potential targets of existing drugs to expand the treatable patient population. The method has the following advantages: (1) It is based on clinical and genomic data from a large national cancer hospital; (2) it incorporates state-of-the-art knowledge of cancer molecular biology and signaling pathways; and (3) it models patient heterogeneity explicitly outside genomics. The output is an ordered list of therapy–target pairs that our algorithm identifies as highly promising to be further tested. The results are highly accurate when validated against known mechanisms of action for existing drugs, where relationships such as pertuzumab–ERBB2, cetuximab–EGFR, and erlotinib–EGFR were independently identified. We found similar results in the external The Cancer Genome Atlas data set. The findings suggest that a data-driven optimization approach to precision cancer medicine may lead to breakthroughs in the drug-discovery process and recommend effective personalized cancer treatments given patient-specific genomic and phenotypic information.
Managing Online Content to Build a Follower Base: Model and Applications
Authors: Caro Felipe , Martínez-de-Albéniz Victor
Published: January 2020

Content providers manage their production by regulating the pace at which content is created and released. They have two types of consumers: existing ones, or followers; and new visitors who may become followers. To maximize their effectiveness, providers must consider the direct, short-term effect of content and also its indirect, long-term effect on the retention and expansion of their follower base. We develop a simple model to study the dynamics of building up a follower base and then combine that model with stochastic dynamic programming to optimize the content provider’s profit. We find that optimal content policies exhibit trajectories whereby both content and followers increase until reaching a steady state at which revenues equal marginal costs. It is therefore preferable to start slow and then accelerate only after successful content has increased the follower base; thus past success makes the content provider work harder. We apply our model to bloggers by analyzing the traffic from new and returning visitors to several blogs. We find that optimized posting activity yields significantly higher profits than does a steady or seasonal content strategy. Our model contributes to the growing literature on data-driven optimization and prescriptive analytics, specifically for content management.
Higher Minimum Quality Standards and Redistributive Effects on Consumer Welfare
Authors: Kotschedoff Marco J. W. , Pachali Max J.
Published: January 2020

We empirically examine the redistributive effects of higher minimum quality standards on consumer welfare. More specifically, we study the impact of the European Union's ban on battery eggs, the previous minimum quality standard, on household egg purchases and evaluate its redistributive effect on consumer welfare.
Swing Pricing for Mutual Funds: Breaking the Feedback Loop Between Fire Sales and Fund Redemptions
Authors: Capponi Agostino , Glasserman Paul , Weber Marko
Published: January 2020

We develop a model of the feedback between mutual fund outflows and asset illiquidity. Following a market shock, alert investors anticipate the impact on a fund’s net asset value (NAV) of other investors’ redemptions and exit first at favorable prices. This first-mover advantage may lead to fund failure through a cycle of falling prices and increasing redemptions. Our analysis shows that (i) the first-mover advantage introduces a nonlinear dependence between a market shock and the aggregate impact of redemptions on the fund’s NAV; (ii) as a consequence, there is a critical magnitude of the shock beyond which redemptions brings down the fund; (iii) properly designed swing pricing transfers liquidation costs from the fund to redeeming investors and, by removing the nonlinearity stemming from the first-mover advantage, it reduces these costs and prevents fund failure. Achieving these objectives requires a larger swing factor at larger levels of outflows. The swing factor for one fund may also depend on policies followed by other funds.

This paper was accepted by David Simchi-Levi, finance.
Contagion in Derivatives Markets
Authors: Paddrik Mark , Rajan Sriram , Young H. Peyton
Published: January 2020

A major credit shock can induce large intraday variation margin payments between counterparties in derivatives markets, which may force some participants to default on their payments. These payment shortfalls become amplified as they cascade through the network of exposures. Using detailed Depository Trust & Clearing Corporation data, we model the full network of exposures, shock-induced payments, initial margin collected, and liquidity buffers for about 900 firms operating in the U.S. credit default swaps market. We estimate the total amount of contagion, the marginal contribution of each firm to contagion, and the number of defaulting firms for a systemic shock to credit spreads. A novel feature of the model is that it allows for a range of behavioral responses to balance sheet stress, including delayed or partial payments. The model provides a framework for analyzing the relative effectiveness of different policy options, such as increasing margin requirements or mandating greater liquidity reserves.

This paper was accepted by Karl Diether, finance.
EDUCAÇÃO DO CORPO NO ENSINO FUNDAMENTAL: REFLEXÕES A PARTIR DO COTIDIANO DE UMA ESCOLA PÚBLICA
Authors: Bargas Danielle Angelo , Ayoub Eliana , Assaritti Dolores Setuval , Scarazzatto Juliana , Assis Marília Del Ponte de
Published: January 2020

Este artigo resulta de uma pesquisa qualitativa com objetivo de refletir sobre a educação do corpo nos espaços-tempos do cotidiano escolar. Por meio de uma pesquisa de campo em uma escola estadual da cidade de Campinas/SP, buscamos compreender como as crianças experimentam um minucioso processo de educação, que se faz também e fundamentalmente, no corpo e pelo corpo. Observarmos que a educação do corpo faz parte de um processo que sempre esteve presente na escola, com práticas que ensinam, sobretudo, a controlar as manifestações corporais e a gestualidade das crianças. Entretanto, trata-se de um processo amplo, no qual também identificamos que nas brechas do cotidiano há espaços em que o controle escapa e tanto professores como crianças vivem outras relações no contexto escolar.
LINGUAGEM, CORPO E EDUCAÇÃO: UMA CRIANÇA EM BUSCA DA PRÓPRIA FALA
Authors: De Almeida Faria Arnete
Published: January 2020

Este relato busca refletir sobre o acompanhamento fonoaudiológico clínico de uma criança com importantes dificuldades no desenvolvimento da fala e da cognição social e encaminhada pela escola. Aos saberes da Fonoaudiologia foram conjugados os da TransPsicomotricidade Educacional, que se baseia no Pensamento Complexo e sua reforma de paradigmas, na Transdisciplinaridade e nos Sete Saberes Necessários à Educação do Futuro, de Edgar Morin. Foi lançado um olhar para além do sintoma de linguagem na criação de uma clínica singular como um sistema aberto, poliocular, com a prática corporal livre-expressiva, o brincar, a reflexão crítica e a autonomia capazes de gerar a intersubjetividade, possibilitando a imprevisibilidade e a cocriatividade de duas mentes (paciente e terapeuta) em díade.
A DANÇA NA PRÁTICA PEDAGÓGICA COM CRIANÇAS: OLHARES E REFLEXÕES DE UMA PROFESSORA EM FORMAÇÃO
Authors: Camargo Daiana , Galvão Patricia Taborda
Published: January 2020

As reflexões apresentadas neste texto abordam a dança na prática pedagógica na Educação Infantil, a partir do olhar de uma acadêmica de Pedagogia e bailarina. A vivência com a dança possibilitou indagações e inquietações que instigaram a pesquisa.  Escritos da área da dança, da educação física, da pedagogia e da arte nos amparam a tratar a dança na escola. Para compreendermos aspectos da dança na prática pedagógica, o estudo contou com a participação de professoras de Educação Infantil e profissionais da área da dança. É possível apontar a desvinculação da dança de outros conteúdos (ou temas) da prática pedagógica, a relação dança/desenvolvimento motor em detrimento de uma perspectiva mais ampla, expressiva, lúdica e cultural e a ausência de reflexão e/ou fundamentação sobre corpo e o movimento. Ressaltamos a necessidade de que a dança, e toda a sua dimensão cultural e lúdica, possa integrar os espaços de formação de professores de crianças, aqui em específico a Pedagogia, para que possamos questionar, refletir os sentidos e possibilidades do corpo em movimento, para que outras propostas possam ser desenvolvidas a partir da dança nos espaços educativos, com maior sentido e significado.
BELEZA ABAYOMI: EXPERIÊNCIA PEDAGÓGICA ENVOLVENDO ESTÉTICA E IDENTIDADE
Authors: Silva Doralice Palma
Published: January 2020

Este trabalho visa apresentar um relato de experiência acerca da influência e reflexos da estética negra no processo de formação identitária da criança. Considerando-se que ao longo da história o que se aprendeu sobre a formação identitária da população brasileira, em sua perspectiva social, cultural e estética se constituiu à luz de um padrão europeu, seja na literatura, nos currículos escolares, nos livros didáticos, nas mídias, entre outros, cabe compreender que refletir sobre a beleza negra no nosso país é romper com uma série de padrões pré-estabelecidos e consolidados há muitos anos. Sendo assim, trazer a mulher negra para a pauta de atividades da escola, como foi possível com projeto “Julho das Pretas” na escola onde atuo profissionalmente é oportunidade para pensar em autoafirmação, já que no ambiente escolar é possível encontrar um público composto, muitas vezes, majoritariamente por mulheres negras, professoras e alunas, que ainda estão em processo de construção e aceitação de sua identidade cultural e estética. Nesse contexto, o desfile de Beleza Abayomi se transformou no grande momento de demonstração e apreciação da beleza negra.