bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological targeting of KDM6A and KDM6B, as a novel therapeutic strategy for treating craniosynostosis in Saethre-Chotzen syndrome
Authors: Pribadi Clara , Camp Esther , Cakouros Dimitrios , Anderson Peter , Glackin Carlotta , Gronthos Stan 
Published: December 2020

AbstractBackgroundDuring development, excessive osteogenic differentiation of mesenchymal progenitor cells (MPC) within the cranial sutures can lead to premature suture fusion or craniosynostosis, leading to craniofacial and cognitive issues. Saethre-Chotzen syndrome (SCS) is a common form of craniosynostosis, caused byTWIST-1gene mutations. Currently, the only treatment option for craniosynostosis involves multiple invasive cranial surgeries, which can lead to serious complications.MethodsThe present study utilizedTwist-1haploinsufficient (Twist-1del/+) mice as SCS mouse model to investigate the inhibition of Kdm6a and Kdm6b activity using the pharmacological inhibitor, GSK-J4, on calvarial cell osteogenic potential.ResultsThis study showed that the histone methyltransferaseEZH2, an osteogenesis inhibitor, is downregulated in calvarial cells derived fromTwist-1del/+mice, whereas the counter histone demethylases,Kdm6aandKdm6b, known promoters of osteogenesis, were upregulated. In vitro studies confirmed that siRNA-mediated inhibition ofKdm6aandKdm6bexpression suppressed osteogenic differentiation ofTwist-1del/+calvarial cells. Moreover, pharmacological targeting of Kdm6a and Kdm6b activity, with the inhibitor, GSK-J4, caused a dose-dependent suppression of osteogenic differentiation byTwist-1del/+calvarial cells in vitro and reduced mineralized bone formation inTwist-1del/+calvarial explant cultures. Chromatin immunoprecipitation and Western blot analyses found that GSK-J4 treatment elevated the levels of the Kdm6a and Kdm6b epigenetic target, the repressive mark of tri-methylated lysine 27 on histone 3, on osteogenic genes leading to repression ofRunx2andAlkaline Phosphataseexpression. Pre-clinical in vivo studies showed that local administration of GSK-J4 to the calvaria ofTwist-1del/+mice prevented premature suture fusion and kept the sutures open up to postnatal day 20.ConclusionThe inhibition of Kdm6a and Kdm6b activity by GSK-J4 could be used as a potential non-invasive therapeutic strategy for preventing craniosynostosis in children with SCS.Graphical abstractPharmacological targeting of Kdm6a/b activity can alleviate craniosynostosis in Saethre-Chotzen syndrome. Aberrant osteogenesis by Twist-1 mutant cranial suture mesenchymal progenitor cells occurs via deregulation of epigenetic modifiers Ezh2 and Kdm6a/Kdm6b. Suppression of Kdm6a- and Kdm6b-mediated osteogenesis with GSK-J4 inhibitor can prevent prefusion of cranial sutures.
Neural field models with transmission delays and diffusion
Authors: Spek Len , Kuznetsov Yuri A. , van Gils Stephan A. 
Published: December 2020

AbstractA neural field models the large scale behaviour of large groups of neurons. We extend previous results for these models by including a diffusion term into the neural field, which models direct, electrical connections. We extend known and prove new sun-star calculus results for delay equations to be able to include diffusion and explicitly characterise the essential spectrum. For a certain class of connectivity functions in the neural field model, we are able to compute its spectral properties and the first Lyapunov coefficient of a Hopf bifurcation. By examining a numerical example, we find that the addition of diffusion suppresses non-synchronised steady-states while favouring synchronised oscillatory modes.
18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography
Authors: Bulat Flaviu , Hesse Friederike , Hu De-En , Ros Susana , Willminton-Holmes Connor , Xie Bangwen , Attili Bala , Soloviev Dmitry , Aigbirhio Franklin , Leeper Finian. J. , Brindle Kevin M. , Neves André A. 
Published: December 2020

Abstract
Introduction
Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET.

Methods
A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging.

Results
18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9–58.8% and 11.3–79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023).

Conclusion
The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors.
Systematic review and validity assessment of methods used in discrete choice experiments of primary healthcare professionals
Authors: Merlo Gregory , van Driel Mieke , Hall Lisa 
Published: December 2020

Abstract
Introduction
Discrete choice experiments (DCEs) have been used to measure patient and healthcare professionals preferences in a range of settings internationally. Using DCEs in primary care is valuable for determining how to improve rational shared decision making. The purpose of this systematic review is to assess the validity of the methods used for DCEs assessing the decision making of healthcare professionals in primary care.

Main body
A systematic search was conducted to identify articles with original data from a discrete choice experiment where the population was primary healthcare professionals. All publication dates from database inception to 29th February 2020 were included. A data extraction and validity assessment template based on guidelines was used. After screening, 34 studies met the eligibility criteria and were included in the systematic review. The sample sizes of the DCEs ranged from 10 to 3727. The published DCEs often provided insufficient detail about the process of determining the attributes and levels. The majority of the studies did not involve primary care healthcare professionals outside of the research team in attribute identification and selection. Less than 80% of the DCEs were piloted and few papers investigated internal or external validity.

Conclusions
For findings to translate into improvements in rational shared decision making in primary care DCEs need to be internally and externally valid and the findings need to be able to be communicated to stakeholders in a way that is understandable and relevant.
Botulinum toxin type A alleviates neuropathic pain and suppresses inflammatory cytokines release from microglia by targeting TLR2/MyD88 and SNAP23
Authors: Wang Xuan , Tian Sheng , Wang Hansen , Liu Pan , Zheng Heqing , Wu Lanxiang , Liu Qian , Wu Wei 
Published: December 2020

AbstractBackgroundBotulinum toxin type A (BTX-A) was considered to be a new potential drug for neuropathic pain (NP) treatment.ResultsIn vivo, BTX-A attenuated chronic compression injury (CCI)-induced pain in rats, and reduced production of pro-inflammatory factors. The inhibition of BTX-A to expression and phosphorylation of SNAP23 were partly reversed by TLR2/MyD88 upregulation. In LPS-stimulated microglia, we also found that BTX-A suppressed TLR2, MyD88, p-SNAP23 and SNAP23 expression, and reduced pro-inflammatory factors secretion. Upregulation of TLR2 and MyD88 recued the inhibition of BTX-A to LPS-induced activation of SNAP23. Then, we demonstrated that BTX-A reduced expression of SNAP23 through inhibition of IKKα/β phosphorylation. Besides, the inhibition of BTX-A to LPS-induced upregulation of SNAP23 can be reversed by proteasome inhibitor. NEDD4, an E3 ubiquitin ligase, was proved to be bind with SNAP23. BTX-A reduced expression of SNAP23 via facilitating ubiquitin-mediated degradation of SNAP23.ConclusionOverall, our data demonstrated that BTX-A attenuated NP via reducing the secretion of pro-inflammatory factors from microglia by inhibition of TLR2/MyD88 signaling. BTX-A downregulated expression of SNAP23 via reducing phosphorylation of IKKα/β, and enhancing ubiquitination of SNAP23 by suppressing TLR2/MyD88 signaling.
Treatment of allergic rhinitis during and outside the pollen season using mobile technology. A MASK study
Authors:   the MASK study group, Bédard A. , Basagaña X. , Anto J. M. , Garcia-Aymerich J. , Devillier P. , Arnavielhe S. , Bedbrook A. , Onorato G. L. , Czarlewski W. , Murray R. , Almeida R. , Fonseca J. A. , Correia da Sousa J. , Costa E. , Morais-Almeida M. , Todo-Bom A. , Cecchi L. , De Feo G. , Illario M. , Menditto E. , Monti R. , Stellato C. , Ventura M. T. , Annesi-Maesano I. , Bosse I. , Fontaine J. F. , Pham-Thi N. , Thibaudon M. , Schmid-Grendelmeier P. , Spertini F. , Chavannes N. H. , Fokkens W. J. , Reitsma S. , Dubakiene R. , Emuzyte R. , Kvedariene V. , Valiulis A. , Kuna P. , Samolinski B. , Klimek L. , Mösges R. , Pfaar O. , Shamai S. , Roller-Wirnsberger R. E. , Tomazic P. V. , Ryan D. , Sheikh A. , Haahtela T. , Toppila-Salmi S. , Valovirta E. , Cardona V. , Mullol J. , Valero A. , Makris M. , Papadopoulos N. G. , Prokopakis E. P. , Psarros F. , Bachert C. , Hellings P. W. , Pugin B. , Bindslev-Jensen C. , Eller E. , Kull I. , Melén E. , Wickman M. , De Vries G. , van Eerd M. , Agache I. , Ansotegui I. J. , Bosnic-Anticevich S. , Cruz A. A. , Casale T. , Ivancevich J. C. , Larenas-Linnemann D. E. , Sofiev M. , Wallace D. , Waserman S. , Yorgancioglu A. , Laune D. , Bousquet J. 
Published: December 2020

Abstract
Background
The analysis of mobile health (mHealth) data has generated innovative insights into improving allergic rhinitis control, but additive information is needed. A cross-sectional real-world observational study was undertaken in 17 European countries during and outside the estimated pollen season. The aim was to collect novel information including the phenotypic characteristics of the users.

Methods
The Allergy Diary–MASK-air–mobile phone app, freely available via Google Play and App, was used to collect the data of daily visual analogue scales (VASs) for overall allergic symptoms and medication use. Fluticasone Furoate (FF), Mometasone Furoate (MF), Azelastine Fluticasone Proprionate combination (MPAzeFlu) and eight oral H1-antihistamines were studied. Phenotypic characteristics were recorded at entry. The ARIA severity score was derived from entry data. This was an a priori planned analysis.

Results
9037 users filled in 70,286 days of VAS in 2016, 2017 and 2018. The ARIA severity score was lower outside than during the pollen season. Severity was similar for all treatment groups during the pollen season, and lower in the MPAzeFlu group outside the pollen season. Days with MPAzeFlu had lower VAS levels and a higher frequency of monotherapy than the other treatments during the season. Outside the season, days with MPAzeFlu also had a higher frequency of monotherapy. The number of reported days was significantly higher with MPAzeFlu during and outside the season than with MF, FF or oral H1-antihistamines.

Conclusions
This study shows that the overall efficacy of treatments is similar during and outside the pollen season and indicates that medications are similarly effective during the year.
A novel method in determining a layered periodic structure
Authors: Cui Yanli , Li Xiliang , Qu Fenglong 
Published: December 2020

AbstractThis paper is concerned with the inverse scattering of time-harmonic waves by a penetrable structure. By applying the integral equation method, we establish the uniform $L^{p}_{\alpha }\ (1< p\leq 2)$

L
α
p

(
1
<
p
≤
2
)
estimates for the scattered and transmitted wave fields corresponding to a series of incident point sources. Based on these a priori estimates and a mixed reciprocity relation, we prove that the penetrable structure can be uniquely identified by means of the scattered field measured only above the structure induced by a countably infinite number of quasi-periodic incident plane waves.
The Pohozaev-type inequalities and their applications for a kind of elliptic equation (system)
Authors: Kou Bingyu , An Tianqing , Wang Zeyan 
Published: December 2020

AbstractIn this paper, we first derive a new kind of Pohozaev-type inequalities for p-Laplacian equations in a more general class of non-star-shaped domains, and then we take two examples and their graphs to explain the shape of the new kind of the non-star-shaped domain. At last, we extend the results of Pohozaev-type inequalities to elliptic systems, which are used to derive the nonexistence of positive solutions of this type of systems in the non-star-shaped domains. On this basis, we also discuss the existence of positive solutions of a kind of elliptic systems with double critical growth.
Some Ramanujan-type circular summation formulas
Authors: Ge Ji-Ke , Luo Qiu-Ming 
Published: December 2020

AbstractIn this paper, we give two Ramanujan-type circular summation formulas by applying the way of elliptic functions and the properties of theta functions. As applications, we obtain the corresponding imaginary transformation formulas for Ramanujan-type circular summations and some theta function identities.
High-order compact finite volume scheme for the 2D multi-term time fractional sub-diffusion equation
Authors: Su Baojin , Jiang Ziwen 
Published: December 2020

AbstractBased on anL1 interpolation operator, a new high-order compact finite volume scheme is derived for the 2D multi-term time fractional sub-diffusion equation. It is shown that the difference scheme is unconditionally convergent and stable in$L_{\infty }$L∞-norm. The convergence order is$O(\tau ^{2-\alpha }+h_{1}^{4}+h_{2}^{4})$O(τ2−α+h14+h24), whereτis the temporal step size and$h_{1}$h1is the spatial step size in one direction,$h_{2}$h2is the spatial step size in another direction. Two numerical examples are implemented, testifying to their efficiency and confirming their convergence order.
Existence and uniqueness of solutions for a mixed p-Laplace boundary value problem involving fractional derivatives
Authors: Wang Shuqi , Bai Zhanbing 
Published: December 2020

AbstractIn this article, the existence and uniqueness of solutions for a multi-point fractional boundary value problem involving two different left and right fractional derivatives with p-Laplace operator is studied. A novel approach is used to acquire the desired results, and the core of the method is Banach contraction mapping principle. Finally, an example is given to verify the results.
A new generalization of Mittag-Leffler function via q-calculus
Authors: Nadeem Raghib , Usman Talha , Nisar Kottakkaran Sooppy , Abdeljawad Thabet 
Published: December 2020

AbstractThe present paper deals with a new different generalization of the Mittag-Leffler function through q-calculus. We then investigate its remarkable properties like convergence, recurrence relation, integral representation, q-derivative formula, q-Laplace transformation, and image formula under q-derivative operator. In addition to this, we consider some specific cases to give the utilization of our main results.
Distributed data hiding in multi-cloud storage environment
Authors: Moyou Metcheka Leonel , Ndoundam René 
Published: December 2020

AbstractClassical or traditional steganography aims at hiding a secret in cover media such as text, image, audio, video or even in network protocols. Recent research has improved this approach called distributed steganography by fragmenting the secret message and embedding each secret piece into a distinct cover media. The major interest of this approach is to make the secret message detection extremely difficult. However, these file modifications leave fingerprints which can reveal a secret channel to an attacker. Our contribution is a new steganography paradigm transparent to any attacker and resistant to the detection and the secret extraction. Two properties contribute to achieve these goals: the files do not undergo any modification while the distribution of the secret in the multi-cloud storage environment allows us to hide the existence of the covert channel between the communicating parties. Information’s are usually hidden inside the cover media. In this work, the covert media is a pointer to information. Therefore the file carries the information without being modified and the only way to access it is to have the key. Experiments show interesting comparison results with remarkable security contributions. The work can be seen as a new open direction for further research in the field.
Comparative evaluation of the effect of different growth media on in vitro sensitivity to azithromycin in multi-drug resistant Pseudomonas aeruginosa isolated from cystic fibrosis patients
Authors: Sörensen Michael , Khakimov Bakhodur , Nurjadi Dennis , Boutin Sébastien , Yi Buqing , Dalpke Alexander H. , Eigenbrod Tatjana 
Published: December 2020

AbstractLong-term treatment with azithromycin is a therapeutic option in Cystic Fibrosis (CF) patients chronically infected with P. aeruginosa. It was recently shown that azithromycin has direct antimicrobial activity when P. aeruginosa isolates are tested in Roswell Park Memorial Institute medium supplemented with fetal calf serum (RPMI 1640/FCS) by broth microdilution. We now investigated whether (i) azithromycin might also be active against multidrug resistant (MDR) P. aeruginosa isolated from CF patients and (ii) how in vitro sensitivity assays perform in synthetic cystic fibrosis sputum medium (SCFM), a medium that mimics the particular CF airway environment.
In 17 (59%) out of 29 MDR P. aeruginosa CF isolates MICs for azithromycin ranged between 0.25 and 8 μg/ml and 12 isolates (41%) showed a MIC ≥512 μg/ml when measured in RPMI/FCS. In contrast, MICs were ≥ 256 μg/ml for all P. aeruginosa MDR isolates when tested in either SCFM or in conventional cation-adjusted Mueller Hinton Broth. High MIC values observed in CF adapted medium SCFM for both PAO1 and MDR P. aeruginosa CF isolates, as opposed to findings in RPMI, argue against routine azithromycin MIC testing of CF isolates.
Evaluating the yield of systematic screening for tuberculosis among three priority groups in Ho Chi Minh City, Viet Nam
Authors: Vo Luan Nguyen Quang , Codlin Andrew James , Forse Rachel Jeanette , Nguyen Nga Thuy , Vu Thanh Nguyen , Le Giang Truong , Van Truong Vinh , Do Giang Chau , Dang Ha Minh , Nguyen Lan Huu , Nguyen Hoa Binh , Nguyen Nhung Viet , Levy Jens , Lonnroth Knut , Squire S. Bertel , Caws Maxine 
Published: December 2020

Abstract
Background
In order to end tuberculosis (TB), it is necessary to expand coverage of TB care services, including systematic screening initiatives. However, more evidence is needed for groups among whom systematic screening is only conditionally recommended by the World Health Organization. This study evaluated concurrent screening in multiple target groups using community health workers (CHW).

Methods
In our two-year intervention study lasting from October 2017 to September 2019, CHWs in six districts of Ho Chi Minh City, Viet Nam verbally screened three urban priority groups: (1) household TB contacts; (2) close TB contacts; and (3) residents of urban priority areas without clear documented exposure to TB including hotspots, boarding homes and urban slums. Eligible persons were referred for further screening with chest radiography and follow-on testing with the Xpert MTB/RIF assay. Symptomatic individuals with normal or without radiography results were tested on smear microscopy. We described the TB care cascade and characteristics for each priority group, and calculated yield and number needed to screen. Subsequently, we fitted a mixed-effect logistic regression to identify the association of these target groups and secondary patient covariates with TB treatment initiation.

Results
We verbally screened 321 020 people including 24 232 household contacts, 3182 social and close contacts and 293 606 residents of urban priority areas. This resulted in 1138 persons treated for TB, of whom 85 were household contacts, 39 were close contacts and 1014 belonged to urban priority area residents. The yield of active TB in these groups was 351, 1226 and 345 per 100 000, respectively, corresponding to numbers needed to screen of 285, 82 and 290. The fitted model showed that close contacts [adjusted odds ratio (aOR) = 2.07; 95% CI: 1.38–3.11; P < 0.001] and urban priority area residents (aOR = 2.18; 95% CI: 1.69–2.79; P < 0.001) had a greater risk of active TB than household contacts.

Conclusions
The study detected a large number of unreached persons with TB, but most of them were not among persons in contact with an index patient. Therefore, while programs should continue to optimize screening in contacts, to close the detection gap in high TB burden settings such as Viet Nam, coverage must be expanded to persons without documented exposure such as residents in hotspots, boarding homes and urban slums.