bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation
Authors: Teshima Yasutomo , Kizaki Minako , Kurihara Ryohei , Kano Ryosuke , Harumiya Miki
Published: July 2020

Purpose

To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting.

Patients

The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled.

Results

The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118–300), and median daily dose of trametinib was 2.00 mg/day (1.0–4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence ≥ 5%) were pyrexia (n = 49, 43.75%), hepatic function abnormal (n = 11, 9.82%), rash and blood creatine phosphokinase increased (n = 9 each, 8.04%), and erythema nodosum (n = 6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67–64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached).

Conclusions

No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.
How Humean is Bohumianism?
Authors: Bigaj Tomasz , Vassallo Antonio
Published: July 2020

An important part of the influential Humean doctrine in philosophy is the supervenience principle (sometimes referred to as the principle of separability). This principle asserts that the complete state of the world supervenes on the intrinsic properties of its most fundamental components and their spatiotemporal relations (the so-called Humean mosaic). There are well-known arguments in the literature purporting to show that in quantum mechanics the Humean supervenience principle is violated, due to the existence of entangled states. Recently, however, arguments have been presented to the effect that the supervenience principle can be defended in Bohmian mechanics. The key element of this strategy lies in the observation that according to Bohmian mechanics the fundamental facts about particles are facts about their spatial locations, and moreover, for any proper subsystem of the world its state may non-trivially depend on the spatial configuration of the rest of the universe. Thus quantum-mechanical states of subsystems do not represent their intrinsic properties but rather characterize their relations with the environment. In this paper we point out the worry that this Bohmian strategy—known as Bohumianism—saves the letter but not the spirit of the Humean doctrine of supervenience, since it prima facie violates another seemingly important Humean principle, which we call Strong Supervenience and whose denial implies the existence of necessary connections among distinct individuals. We argue that the best defense for Bohumians is to question the fundamental existence of complex physical systems and their states by treating any reference to them as a convenient description of the underlying collection of Bohmian particles. We consider several pros and cons of this strategy.
The role of ozonized oil and a combination of tobramycin/dexamethasone eye drops in the treatment of viral conjunctivitis: a randomized clinical trial
Authors: Cagini C. , Mariniello M. , Messina M. , Muzi A. , Balducci C. , Moretti A. , Levorato L. , Mencacci A.
Published: July 2020

Purpose

To determine whether topical tobramycin 0.3%/dexamethasone 0.1% plus ozonized oil eye drops reduces clinical signs and infectious viral titers of presumed viral conjunctivitis more than tobramycin/dexamethasone eye drops alone.

Methods

Prospective, single-blind, randomized, parallel-groups trial. Eighty patients with a clinical diagnosis of presumed viral conjunctivitis were randomizedly divided into two treatment groups: a study group and a control group, 40 for each group. Patients in the study group received topical tobramycin 0.3%/dexamethasone 0.1% eye drops, plus ozonized oil eye drops, both four times daily; patients in the control group received only topical tobramycin 0.3%/dexamethasone eye drops four times daily. The treatment was for seven days in both groups. Swabs were taken from the conjunctival fornix for adenovirus PCR analysis on the day of recruitment and at seven days follow-up. Clinical signs were also recorded on the day of recruitment and at follow-up examination: the main outcomes were conjunctival injection and conjunctival chemosis, graded on a 4-point clinical scale, presence or absence of superficial punctate keratitis and subepithelial corneal infiltrates.

Results

No statistically significant difference was reached in adenoviral infection negativization between the two groups, although the study group showed a higher number of PCR negative results at seven days follow-up. PCR real time detected adenoviral infection in 17 of 24 patients on the day of recruitment and it was positive in 4 patients on the seventh day (viral positivity reduction of 76%). In the control group PCR was positive for adenovirus in 18 of 24 patients on the day of recruitment and in 7 patients at seven days follow-up (reduction of 61%). There was statistically significant difference on conjunctival clinical signs between the study and control groups. Significant difference was also found on superficial punctate keratitis resolution between the study and the control group. In the former superficial punctate keratitis was detected in 14 eyes on the first day and in 5 eyes after seven days while in the latter superficial punctate keratitis was found in 124 eyes on the first day and in 6 eyes on the seventh day. No difference was found in subepithelial corneal infiltrates appearance between the two groups.

Conclusions

The use of ozonized-oil containing eye drops in combination with topical tobramycin 0.3%/dexamethasone 0.1% eye drops four times daily seems to reduce the signs of conjunctivitis, and the duration of viral infection, although it does not affect the subepithelial corneal infiltrates appearance.
Susy for Non-Hermitian Hamiltonians, with a View to Coherent States
Authors: Bagarello F.
Published: July 2020

We propose an extended version of supersymmetric quantum mechanics which can be useful if the Hamiltonian of the physical system under investigation is not Hermitian. The method is based on the use of two, in general different, superpotentials. Bi-coherent states of the Gazeau-Klauder type are constructed and their properties are analyzed. Some examples are also discussed, including an application to the Black-Scholes equation, one of the most important equations in Finance.
Emerging Topics in Brexit Debate on Twitter Around the Deadlines
Authors: del Gobbo Emiliano , Fontanella Sara , Sarra Annalina , Fontanella Lara
Published: July 2020

The present study is focused on the online debate relating to the Brexit process, three years and half since the historical referendum that has sanctioned the divide of the United Kingdom from the European Union. In our analysis we consider a corpus of approximately 33 million Brexit related tweets, shared on Twitter for 58 weeks, spanning from 31 December 2019 to 9 February 2020. Due to its great accessibility to data, Twitter constitutes a convenient data source to monitor and evaluate a wide variety of topics. In addition, Twitter’s marked orientation towards news and the dissemination of information makes this microblogging network more connected to politics compared to other platforms. Through static and dynamic topic modelling techniques, we were able to identify the topics that have attracted the most attention from Twitters users and to characterise their temporal evolution. The topics retrieved by the static model highlight the major events of the Brexit process while the dynamic analysis recovered the persistent themes of discussion and debate over the entire period.
Metabolism of synthetic cathinones through the zebrafish water tank model: a promising tool for forensic toxicology laboratories
Authors: Prado Estefany , Matos Rebecca Rodrigues , de Lima Gomes Geovana Maria , de Sá Clarisse Baptista Lima , da Costa Nunes Isabelle Karine , de Souza Anselmo Carina , de Oliveira Adriana Sousa , do Amaral Cohen Luciana Silva , de Siqueira Denilson Soares , de Oliveira Marco Antônio Martins , Ambrosio João Carlos Laboissiere , Costa Gabriela Vanini , de Aquino Neto Francisco Radler , Padilha Monica Costa , Pereira Henrique Marcelo Gualberto
Published: July 2020

Purpose

The aim of this study was to identify in vivo phase I metabolites of five psychoactive substances: N-ethylpentylone, ethylone, methylone, α-PVP and 4-CDC, using the in house developed experimental set-up zebrafish (Danio rerio) water tank (ZWT). High-resolution mass spectrometry allowed for metabolite identification. A pilot study of reference standard collection of N-ethylpentylone from the water tank was conducted.

Methods

ZWT consisted in 8 fish placed in a 200 mL recipient-containing water for a single cathinone. Experiments were performed in triplicate. Water tank samples were collected after 8 h and pretreated through solid-phase extraction. Separation and accurate-mass spectra of metabolites were obtained using liquid chromatography–high resolution tandem mass spectrometry.

Results

Phase I metabolites of α-PVP were identified, which were formed involving ketone reduction, hydroxylation, and 2″-oxo-pyrrolidine formation. The lactam derivative was the major metabolite observed for α-PVP in ZWT. N-Ethylpentylone and ethylone were transformed into phase I metabolites involving reduction, hydroxylation, and dealkylation. 4-CDC was transformed into phase I metabolites, reported for the first time, involving N-dealkylation, N,N-bis-dealkylation and reduction of the ketone group, the last one being the most intense after 8 h of the experiment.

Conclusions

ZWT model indicated to be very useful to study the metabolism of the synthetic cathinones, such as N-ethylpentylone, ethylone, α-PVP and 4-CDC. Methylone seems to be a potent CYP450 inhibitor in zebrafish. More experiments are needed to better evaluate this issue. Finally, this approach was quite simple, straightforward, extremely low cost, and fast for “human-like” metabolic studies of synthetic cathinones.
Ethical and Social Aspects of Neurorobotics
Authors: Aicardi Christine , Akintoye Simisola , Fothergill B. Tyr , Guerrero Manuel , Klinker Gudrun , Knight William , Klüver Lars , Morel Yannick , Morin Fabrice O. , Stahl Bernd Carsten , Ulnicane Inga
Published: July 2020

The interdisciplinary field of neurorobotics looks to neuroscience to overcome the limitations of modern robotics technology, to robotics to advance our understanding of the neural system’s inner workings, and to information technology to develop tools that support those complementary endeavours. The development of these technologies is still at an early stage, which makes them an ideal candidate for proactive and anticipatory ethical reflection. This article explains the current state of neurorobotics development within the Human Brain Project, originating from a close collaboration between the scientific and technical experts who drive neurorobotics innovation, and the humanities and social sciences scholars who provide contextualising and reflective capabilities. This article discusses some of the ethical issues which can reasonably be expected. On this basis, the article explores possible gaps identified within this collaborative, ethical reflection that calls for attention to ensure that the development of neurorobotics is ethically sound and socially acceptable and desirable.
Boundary value problems for Caputo fractional differential equations with nonlocal and fractional integral boundary conditions
Authors: Derbazi Choukri , Hammouche Hadda
Published: July 2020

In this paper, we study the existence and uniqueness of solutions for fractional differential equations with nonlocal and fractional integral boundary conditions. New existence and uniqueness results are established using the Banach contraction principle. Other existence results are obtained using O’Regan fixed point theorem and Burton and Kirk fixed point. In addition, an example is given to demonstrate the application of our main results.
Stress-induced trend: the clustering feature of coal mine disasters and earthquakes in China
Authors: Chen Bo
Published: July 2020

Nearly half of coal mine disasters in China have been found to occur in clusters or to be accompanied by earthquakes nearby, in which all the disaster types are involved. Stress disturbances seem to exist among mining areas and to be responsible for the observed clustering. The earthquakes accompanied by coal mine disasters may be the vital geophysical evidence for tectonic stress disturbances around mining areas. This paper analyzes all the possible causative factors to demonstrate the authenticity and reliability of the observed phenomena. A quantitative study was performed on the degree of clustering, and space–time distribution curves are obtained. Under the threshold of 100 km, 47% of disasters are involved in cluster series and 372 coal mine disasters accompanied by earthquakes. The majority cluster series lasting for 1–2 days correspond well earthquakes nearby, which are speculated to be related to local stress disturbance. While the minority lasting longer than 4 days correspond well with fatal earthquakes, which are speculated to be related to regional stress disturbance. The cluster series possess multiple properties, such as the area, the distance, the related disasters, etc., and compared with the energy and the magnitude of earthquakes, good correspondences are acquired. It indicates that the cluster series of coal mine disasters and earthquakes are linked with fatal earthquakes and may serve as footprints of regional stress disturbance. Speculations relating to the geological model are made, and five disaster-causing models are examined. To earthquake research and disaster prevention, widely scientific significance is suggested.
Arrayed Cobalt Phosphide Electrocatalyst Achieves Low Energy Consumption and Persistent H2 Liberation from Anodic Chemical Conversion
Authors: Zhang Kai , Zhang Gong , Ji Qinghua , Qu Jiuhui , Liu Huijuan
Published: July 2020

Electrochemical reduction of water to hydrogen (H2) offers a promising strategy for production of clean energy, but the design and optimization of electrochemical apparatus present challenges in terms of H2 recovery and energy consumption. Using cobalt phosphide nanoarrays (Co2P/CoP NAs) as a charge mediator, we effectively separated the H2 and O2 evolution of alkaline water electrolysis in time, thereby achieving a membrane-free pathway for H2 purification. The hierarchical array structure and synergistic optimization of the electronic configuration of metallic Co2P and metalloid CoP make the Co2P/CoP NAs high-efficiency bifunctional electrocatalysts for both charge storage and hydrogen evolution. Theoretical investigations revealed that the introduction of Co2P into CoP leads to a moderate hydrogen adsorption free energy and low water dissociation barrier, which are beneficial for boosting HER activity. Meanwhile, Co2P/CoP NAs with high capacitance could maintain a cathodic H2 evolution time of 1500 s at 10 mA cm−2 driven by a low average voltage of 1.38 V. Alternatively, the energy stored in the mediator could be exhausted via coupling with the anodic oxidation of ammonia, whereby only 0.21 V was required to hold the current for 1188 s. This membrane-free architecture demonstrates the potential for developing hydrogen purification technology at low cost.
Restoration at the landscape scale as a means of mitigation and adaptation to climate change
Authors: von Holle Betsy , Yelenik Stephanie , Gornish Elise S.
Published: July 2020

Purpose of Review

Although landscape-scale restoration efforts are gaining traction worldwide, their success is generally unknown. We review landscape-scale restorations to gain insight to whether focal ecological outcomes have been achieved, in the face of changing environmental conditions.

Recent Findings

Only 9% of the 477 articles that resulted from our search were studies of landscape-scale restorations. The majority (73%) of the landscape restorations from our study have occurred since the 1990s, indicating that this type of restoration has gained in popularity in the last 30 years. Furthermore, 67% of these restoration studies occurred in a single country: China. Many scientific studies have addressed the ability of a species to shift ranges with climate change, yet few of the landscape-scale restoration studies used for our study addressed this question. Instead, 87% of the studies focused on ecosystem function, rather than community-level processes, as a result of restoration.

There is a clear need for more research to be undertaken on the ecological outcomes of landscape-scale restorations to understand whether they enable species and communities to shift their ranges or adapt to climate change. Conservation practitioners could utilize our decision matrix as a tool to guide restoration of individual sites within a landscape context, as well as current and future climatic conditions, to guide ecological outcomes of interest. Optimal biodiversity maintenance requires habitat conservation in concert with restoration activities at the landscape scale, and the latter, likely increasingly so in a world of changing climate.
GraphSIF: analyzing flow of payments in a Business-to-Business network to detect supplier impersonation
Authors: Canillas Rémi , Hasan Omar , Sarrat Laurent , Brunie Lionel
Published: July 2020

Supplier Impersonation Fraud (SIF) is a rising issue for Business-to-Business companies. The use of remote and quick digital transactions has made the task of identifying fraudsters more difficult. In this paper, we propose a data-driven fraud detection system whose goal is to provide an accurate estimation of financial transaction legitimacy by using the knowledge contained in the network of transactions created by the interaction of a company with its suppliers. We consider the real dataset collected by SIS-ID for this work.We propose to use a graph-based approach to design an Anomaly Detection System (ADS) based on a Self-Organizing Map (SOM) allowing us to label a suspicious transaction as either legitimate or fraudulent based on its similarity with frequently occurring transactions for a given company. Experiments demonstrate that our approach shows high consistency with expert knowledge on a real-life dataset, while performing faster than the expert system.
Assessment of trace elements natural enrichment in topsoil by some Italian case studies
Authors: Sappa Giuseppe , Barbieri Maurizio , Andrei Francesca
Published: July 2020

Trace elements (for example As, V, Cr, Ni, Cu, Z, Cd and Pb) released by human activity are ubiquitously detected in topsoil. They can be conveyed from the topsoil to the ecosystem, thus affecting human health. Also, trace elements are not sensitive to any process of decomposition in soils and the bioavailability is complicated due to the reactive nature of soil constituent. The goal of this assessment is to present a methodology able to evaluate the topsoil trace elements natural enrichment and distinguish between geogenic phenomena and anthropogenic contributions. This paper presents some Italian case studies in Lombardy and Lazio. The potential pollution risks of trace elements in topsoil were evaluated by geoaccumulation index (Igeo) and enrichment factor. The results show an absence of anthropogenic contamination, highlighting the need to consider the local characteristics (landfills, municipal solid waste plants, industrial areas, quarries, etc.). Moreover, a statistical method (cumulative frequency and normalization method) was presented to determine the geochemical baseline values. In the case of Borgo Montello (Lazio), manganese is used as a relative element due to its high presence in soils. The proposed geochemical baseline values of V, Cr, Co and Ni thorough normalization method were, respectively, 123.07, 82.10, 9.41 and 29.70 mg kg−1, instead by cumulative frequency the results were 78.24, 84.10, 6.67 and 23.70 mg kg−1. This methodology shows a potential validity to define the geochemical baseline values, but it is necessary many data (n ≥ 40) and distributed homogeneously over the study area.
Cepharanthine: a review of the antiviral potential of a Japanese-approved alopecia drug in COVID-19
Authors: Rogosnitzky Moshe , Okediji Paul , Koman Igor
Published: July 2020

Cepharanthine (CEP) is a naturally occurring alkaloid derived from Stephania cepharantha Hayata and demonstrated to have unique anti-inflammatory, antioxidative, immunomodulating, antiparasitic, and antiviral properties. Its therapeutic potential as an antiviral agent has never been more important than in combating COVID-19 caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) virus. Cepharanthine suppresses nuclear factor-kappa B (NF-κB) activation, lipid peroxidation, nitric oxide (NO) production, cytokine production, and expression of cyclooxygenase; all of which are crucial to viral replication and inflammatory response. Against SARS-CoV-2 and homologous viruses, CEP predominantly inhibits viral entry and replication at low doses; and was recently identified as the most potent coronavirus inhibitor among 2406 clinically approved drug repurposing candidates in a preclinical model. This review critically analyzes and consolidates available evidence establishing CEP’s potential therapeutic importance as a drug of choice in managing COVID-19 cases.
Heavy-tailed branching random walks on multidimensional lattices. A moment approach
Authors: Rytova Anastasiya , Yarovaya Elena
Published: July 2020

We study a continuous-time branching random walk (BRW) on the lattice ℤd,d∈ ℕ, with a single source of branching, that is the lattice point where the birth and death of particles can occur. The random walk is assumed to be spatially homogeneous, symmetric and irreducible but, in contrast to the majority of previous investigations, the random walk transition intensitiesa(x,y) decrease as |y−x|−(d+α)for |y−x| → ∞, whereα∈ (0, 2), that leads to an infinite variance of the random walk jumps. The mechanism of the birth and death of particles at the source is governed by a continuous-time Markov branching process. The source intensity is characterized by a certain parameterβ. We calculate the long-time asymptotic behaviour for all integer moments for the number of particles at each lattice point and for the total population size. With respect to the parameterβ, a non-trivial critical pointβc> 0 is found for everyd≥ 1. In particular, ifβ>βcthe evolutionary operator generated a behaviour of the first moment for the number of particles has a positive eigenvalue. The existence of a positive eigenvalue yields an exponential growth intof the particle numbers in the caseβ>βccalledsupercritical. Classification of the BRW treated assubcritical(β<βc) orcritical(β=βc) for the heavy-tailed random walk jumps is more complicated than for a random walk with a finite variance of jumps. We study the asymptotic behaviour of all integer moments of a number of particles at any pointy∈ ℤdand of the particle population on ℤdaccording to the ratiod/α.
The Staging of Ciudad Juárez’s Feminicides: Àlex Rigola and Angélica Liddell Speak for the Victims
Authors: Nicolau Adriana , Iribarren Teresa
Published: July 2020

Tackling violence against women in the theatre is often a controversial matter. To identify the ethical risks that victim representation may entail, we conduct a comparative analysis of two works about Ciudad Juárez’s feminicides staged in Barcelona: 2666 (2007), an adaptation of Roberto Bolaño’s novel directed by Àlex Rigola, and House of Strength (2011) by Angélica Liddell. This article argues that while Rigola reduces victims to mere sexual objects with no narrative of their own, Liddell places the voice and resilience of Mexicans in the foreground and represents their bodies respectfully. Adriana Nicolau is completing her doctoral studies on ‘Feminisms in contemporary Catalan theatre’ at Universitat Oberta de Catalunya (UOC) in Barcelona. Her publications include articles for Feminismo/s. Teresa Iribarren is an assistant professor at UOC, where she is the Director of the Catalan Literature, Publishing, and Society research group. Her current research focuses on narratives of violence and the promotion of human rights in literature.
Why Do Practitioners Want to Connect with Researchers? Evidence from a Field Experiment
Authors: Levine Adam Seth
Published: July 2020

Researchers often want to increase the broader societal impact of their work. One way to do that is to discuss research findings directly with practitioners. Yet, such interactions are voluntary and do not regularly arise, which raises a key demand question: Under what conditions do practitioners want to connect with researchers? This article shows that relational considerations affect these decisions—that is, what practitioners expect the interaction will be like. I partnered with a US-based civic association to conduct a field experiment. I find that group leaders in this association are more likely to speak with researchers after learning that the researchers will (1) efficiently share information during the interaction, and (2) value practitioners’ knowledge. The results provide actionable guidance for how researchers should approach practitioners and also demonstrate one powerful way that social science evidence can inform efforts to bridge research and practice.
Food insecurity and mental health outcomes among homeless adults: a scoping review
Authors: Loftus Elizabeth I , Lachaud James , Hwang Stephen W , Mejia-Lancheros Cilia
Published: July 2020

Objective:

This review summarises and synthesises the existing literature on the relationship between food insecurity (FS) and mental health conditions among adult individuals experiencing homelessness.

Design:

Scoping review. Papers published between 1 January 2008 and 2 November 2018, searched in PubMed, Web of Science, Scopus, PsycINFO, Cochrane Library and CINAHL, using homelessness, food security and mental health keywords.

Setting:

Global evidence.

Participants:

Homeless adults aged 18 years or more.

Results:

Nine articles (eight cross-sectional and one longitudinal) were included in the present review. FS was measured using the Household Food Insecurity Access Scale, the United States Department of Agriculture Household Food Security Survey Module, as well as single-item or constructed measures. Depression and depressive symptoms were the most common mental health conditions studied. Other mental health conditions assessed included alcohol and substance use, emotional disorders, mental health problems symptoms severity and psychiatric hospitalisations. Composite measures such as axis I and II categories and a cluster of severe mental conditions and mental health-related functioning status were also analysed. FS and mental health-related problems were considered as both exposure and outcome variables. The existing evidence suggests a potential association between FS and several mental health conditions, particularly depression, mental health symptoms severity and poor mental health status scores.

Conclusions:

This review suggests the potential association between some mental health conditions and FS among homeless adults. However, there is a need for more longitudinal- and interventional-based studies, in order to understand the nature and directionality of the links between FS and mental health in this population group.
Evaluation of the morphological diversity of tea roses (Rosa x odorata) based on phenotypic traits
Authors: Cheng Bixuan , Yu Chao , Fu Heling , Zhou Lijun , Luo Le , Pan Huitang , Zhang Qixiang
Published: July 2020

Rosa x odorata (sect. Chinenses, Rosaceae) is an important species distributed only in Yunnan Province, China. There is an abundance of wild variation within the species. Using 22 germplasm resources collected from the wild, as well as R. chinensis var. spontanea, R. chinensis ‘Old Blush’ and R. lucidissima, this study involved morphological variation analysis, inter-trait correlation analysis, principal component analysis and clustering analysis based on 16 morphological traits. This study identified a high degree of morphological diversity in R. x odorata germplasm resources and the variation coefficients had a distribution range from 18.00 to 184.04%. The flower colour had the highest degree of variation, while leaflet length/width had the lowest degree of variation. Inter-trait correlation analysis revealed that there was an extremely significant positive correlation between leaflet length and leaflet width. There was also a significant positive correlation between the number of petals and duration of blooming, and the L* and a* values of flower colour were significantly negatively correlated. Principal component analysis screened five principal components with the highest cumulative contribution rate (81.679%) to population variance. Among the 16 morphological traits, style length, sepal width, flower diameter, flower colour, leaflet length and leaflet width were important indices that influenced the morphology of R. x odorata. This study offers guidance for the further development and utilization of R. x odorata germplasm resources.
Utility of a novel high pressure non-compliant balloon for tibial atherosclerotic lesions in Asian patients with chronic limb threatening ischaemia
Authors: Tang Tjun Yip , Lee Shaun Qing Wei , Chan Sze Ling , Yap Charyl Jia Qi , Soon Shereen Xue Yun , Chong Tze Tec , Choke Edward Tieng Chek , Yan Bryan P.Y.
Published: July 2020

Summary: Background: The aim was to evaluate the safety and efficacy of a high pressure, non-compliant balloon in the treatment of infrapopliteal occlusive disease in Asian patients with chronic limb threatening ischaemia (CLTI) from Singapore. Patients and methods: Prospective, multi-centre, single arm, non-randomized study. Immediate technical success, 6-month primary vessel patency (determined by Duplex ultrasonography), limb salvage, one-year clinically driven target lesion re-intervention (TLR) and amputation free survival (AFS) were the efficacy endpoints of interest. Results: 86 patients (63% males, mean age 68.9 ± 9.9 years) were enrolled over a 15-month period. Diabetes mellitus (DM) and end-stage renal failure (ESRF) were present in 94% and 38% of patients respectively. All had some degree of tissue loss at baseline (Rutherford scale 5 and 6 = 91% and 9% respectively). Of the 86 legs, 72% had 3 crural vessel disease and 84% had moderate/severe vessel wall calcification. 90% had > = 1 TASC D tibial lesion. Acute technical success was 89%. One month mortality was 3.5% and one-year freedom from TLR was 91%. 6-month tibial patency was 73%. 54/66 (82%) patients had at least one target treated tibial artery open at 6 months. A lower baseline toe pressure (OR 1.03, 95%CI 1.00–1.05) and elastic recoil post angioplasty (OR 0.20, 95%CI 0.05–0.79) were associated with a worse 6 month tibial patency. One-year AFS was 67%. 47/66 (71%) patients had a clinical improvement of at least one Rutherford class at 6 months and 52/59 (88%) experienced complete wound healing at 12 months. Conclusions: Use of a high pressure non-compliant balloon is safe and efficacious in treating highly complex infra-popliteal atherosclerotic lesions in an otherwise challenging population of CLTI patients with a high incidence of DM and ESRF. It is associated with highly satisfactory acute technical success, 6-month target lesion patency and one-year limb salvage.
Outer Radiation Belt Electron Lifetime Model Based on Combined Van Allen Probes and Cluster VLF Measurements
Authors: Aryan Homayon , Agapitov Oleksiy V. , Artemyev Anton , Mourenas Didier , Balikhin Michael A. , Boynton Richard , Bortnik Jacob
Published: July 2020

The flux of energetic electrons in the outer radiation belt shows a high variability. The interactions of electrons with very low frequency (VLF) chorus waves play a significant role in controlling the flux variation of these particles. Quantifying the effects of these interactions is crucially important for accurately modeling the global dynamics of the outer radiation belt and to provide a comprehensive description of electron flux variations over a wide energy range (from the source population of 30 keV electrons up to the relativistic core population of the outer radiation belt). Here, we use a synthetic chorus wave model based on a combined database compiled from the Van Allen Probes and Cluster spacecraft VLF measurements to develop a comprehensive parametric model of electron lifetimes as a function of L‐shell, electron energy, and geomagnetic activity. The wave model takes into account the wave amplitude dependence on geomagnetic latitude, wave normal angle distribution, and variations of wave frequency with latitude. We provide general analytical formulas to estimate electron lifetimes as a function of L‐shell (for L = 3.0 to L = 6.5), electron energy (from 30 keV to 2 MeV), and geomagnetic activity parameterized by the AE index. The present model lifetimes are compared to previous studies and analytical results and also show a good agreement with measured lifetimes of 30 to 300 keV electrons at geosynchronous orbit.
ARHGAP10, which encodes Rho GTPase-activating protein 10, is a novel gene for schizophrenia risk
Authors: Sekiguchi Mariko , Sobue Akira , Kushima Itaru , Wang Chenyao , Arioka Yuko , Kato Hidekazu , Kodama Akiko , Kubo Hisako , Ito Norimichi , Sawahata Masahito , Hada Kazuhiro , Ikeda Ryosuke , Shinno Mio , Mizukoshi Chikara , Tsujimura Keita , Yoshimi Akira , Ishizuka Kanako , Takasaki Yuto , Kimura Hiroki , Xing Jingrui , Yu Yanjie , Yamamoto Maeri , Okada Takashi , Shishido Emiko , Inada Toshiya , Nakatochi Masahiro , Takano Tetsuya , Kuroda Keisuke , Amano Mutsuki , Aleksic Branko , Yamomoto Takashi , Sakuma Tetsushi , Aida Tomomi , Tanaka Kohichi , Hashimoto Ryota , Arai Makoto , Ikeda Masashi , Iwata Nakao , Shimamura Teppei , Nagai Taku , Nabeshima Toshitaka , Kaibuchi Kozo , Yamada Kiyofumi , Mori Daisuke , Ozaki Norio
Published: July 2020

Schizophrenia (SCZ) is known to be a heritable disorder; however, its multifactorial nature has significantly hampered attempts to establish its pathogenesis. Therefore, in this study, we performed genome-wide copy-number variation (CNV) analysis of 2940 patients with SCZ and 2402 control subjects and identified a statistically significant association between SCZ and exonic CNVs in the ARHGAP10 gene. ARHGAP10 encodes a member of the RhoGAP superfamily of proteins that is involved in small GTPase signaling. This signaling pathway is one of the SCZ-associated pathways and may contribute to neural development and function. However, the ARHGAP10 gene is often confused with ARHGAP21, thus, the significance of ARHGAP10 in the molecular pathology of SCZ, including the expression profile of the ARHGAP10 protein, remains poorly understood. To address this issue, we focused on one patient identified to have both an exonic deletion and a missense variant (p.S490P) in ARHGAP10. The missense variant was found to be located in the RhoGAP domain and was determined to be relevant to the association between ARHGAP10 and the active form of RhoA. We evaluated ARHGAP10 protein expression in the brains of reporter mice and generated a mouse model to mimic the patient case. The model exhibited abnormal emotional behaviors, along with reduced spine density in the medial prefrontal cortex (mPFC). In addition, primary cultured neurons prepared from the mouse model brain exhibited immature neurites in vitro. Furthermore, we established induced pluripotent stem cells (iPSCs) from this patient, and differentiated them into tyrosine hydroxylase (TH)-positive neurons in order to analyze their morphological phenotypes. TH-positive neurons differentiated from the patient-derived iPSCs exhibited severe defects in both neurite length and branch number; these defects were restored by the addition of the Rho-kinase inhibitor, Y-27632. Collectively, our findings suggest that rare ARHGAP10 variants may be genetically and biologically associated with SCZ and indicate that Rho signaling represents a promising drug discovery target for SCZ treatment.
Genome-wide association study of cognitive function in diverse Hispanics/Latinos: results from the Hispanic Community Health Study/Study of Latinos
Authors: Jian Xueqiu , Sofer Tamar , Tarraf Wassim , Bressler Jan , Faul Jessica D. , Zhao Wei , Ratliff Scott M. , Lamar Melissa , Launer Lenore J. , Laurie Cathy C. , Schneiderman Neil , Weir David R. , Wright Clinton B. , Yaffe Kristine , Zeng Donglin , DeCarli Charles , Mosley Thomas H. , Smith Jennifer A. , González Hector M. , Fornage Myriam
Published: July 2020

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K,FRMD4B, theHLAgene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, includingIFT122in the hippocampus for SIS,SNX31in the basal ganglia for B-SEVLT,RPS6KB2in the frontal cortex for WFT, andCSPG5in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.
Applying dimensional psychopathology: transdiagnostic associations among regional homogeneity, leptin and depressive symptoms
Authors: Wei Yan-ge , Duan Jia , Womer Fay Y. , Zhu Yue , Yin Zhiyang , Cui Lingling , Li Chao , Liu Zhuang , Wei Shengnan , Jiang Xiaowei , Zhang Yanbo , Zhang Xizhe , Tang Yanqing , Wang Fei
Published: July 2020

Dimensional psychopathology and its neurobiological underpinnings could provide important insights into major psychiatric disorders, including major depressive disorder, bipolar disorder and schizophrenia. In a dimensional transdiagnostic approach, we examined depressive symptoms and their relationships with regional homogeneity and leptin across major psychiatric disorders. A total of 728 participants (including 403 patients with major psychiatric disorders and 325 age–gender-matched healthy controls) underwent resting-state functional magnetic resonance imaging at a single site. We obtained plasma leptin levels and depressive symptom measures (Hamilton Depression Rating Scale (HAMD)) within 24 h of scanning and compared the regional homogeneity (ReHo), plasma leptin levels and HAMD total score and factor scores between patients and healthy controls. To reveal the potential relationships, we performed correlational and mediational analyses. Patients with major psychiatric disorders had significant lower ReHo in primary sensory and visual association cortices and higher ReHo in the frontal cortex and angular gyrus; plasma leptin levels were also elevated. Furthermore, ReHo alterations, leptin and HAMD factor scores had significant correlations. We also found that leptin mediated the transdiagnostic relationships among ReHo alterations in primary somatosensory and visual association cortices, core depressive symptoms and body mass index. The transdiagnostic associations we demonstrated support the common neuroanatomical substrates and neurobiological mechanisms. Moreover, leptin could be an important association among ReHo, core depressive symptoms and body mass index, suggesting a potential therapeutic target for dimensional depressive symptoms across major psychiatric disorders.
Cancer immunotherapy with γδ T cells: many paths ahead of us
Authors: Kabelitz Dieter , Serrano Ruben , Kouakanou Léonce , Peters Christian , Kalyan Shirin
Published: July 2020

γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.
Oceanographic features and limited dispersal shape the population genetic structure of the vase sponge Ircinia campana in the Greater Caribbean
Authors: Griffiths Sarah M. , Butler Mark J. , Behringer Donald C. , Pérez Thierry , Preziosi Richard F.
Published: July 2020

Understanding population genetic structure can help us to infer dispersal patterns, predict population resilience and design effective management strategies. For sessile species with limited dispersal, this is especially pertinent because genetic diversity and connectivity are key aspects of their resilience to environmental stressors. Here, we describe the population structure ofIrcinia campana, a common Caribbean sponge subject to mass mortalities and disease. Microsatellites were used to genotype 440 individuals from 19 sites throughout the Greater Caribbean. We found strong genetic structure across the region, and significant isolation by distance across the Lesser Antilles, highlighting the influence of limited larval dispersal. We also observed spatial genetic structure patterns congruent with oceanography. This includes evidence of connectivity between sponges in the Florida Keys and the southeast coast of the United States (>700 km away) where the oceanographic environment is dominated by the strong Florida Current. Conversely, the population in southern Belize was strongly differentiated from all other sites, consistent with the presence of dispersal-limiting oceanographic features, including the Gulf of Honduras gyre. At smaller spatial scales (<100 km), sites showed heterogeneous patterns of low-level but significant genetic differentiation (chaotic genetic patchiness), indicative of temporal variability in recruitment or local selective pressures. Genetic diversity was similar across sites, but there was evidence of a genetic bottleneck at one site in Florida where past mass mortalities have occurred. These findings underscore the relationship between regional oceanography and weak larval dispersal in explaining population genetic patterns, and could inform conservation management of the species.
B cell zone reticular cell microenvironments shape CXCL13 gradient formation
Authors: Cosgrove Jason , Novkovic Mario , Albrecht Stefan , Pikor Natalia B. , Zhou Zhaoukun , Onder Lucas , Mörbe Urs , Cupovic Jovana , Miller Helen , Alden Kieran , Thuery Anne , O’Toole Peter , Pinter Rita , Jarrett Simon , Taylor Emily , Venetz Daniel , Heller Manfred , Uguccioni Mariagrazia , Legler Daniel F. , Lacey Charles J. , Coatesworth Andrew , Polak Wojciech G. , Cupedo Tom , Manoury Bénedicte , Thelen Marcus , Stein Jens V. , Wolf Marlene , Leake Mark C. , Timmis Jon , Ludewig Burkhard , Coles Mark C.
Published: July 2020

Through the formation of concentration gradients, morphogens drive graded responses to extracellular signals, thereby fine-tuning cell behaviors in complex tissues. Here we show that the chemokine CXCL13 forms both soluble and immobilized gradients. Specifically, CXCL13+follicular reticular cells form a small-world network of guidance structures, with computer simulations and optimization analysis predicting that immobilized gradients created by this network promote B cell trafficking. Consistent with this prediction, imaging analysis show that CXCL13 binds to extracellular matrix components in situ, constraining its diffusion. CXCL13 solubilization requires the protease cathepsin B that cleaves CXCL13 into a stable product. Mice lacking cathepsin B display aberrant follicular architecture, a phenotype associated with effective B cell homing to but not within lymph nodes. Our data thus suggest that reticular cells of the B cell zone generate microenvironments that shape both immobilized and soluble CXCL13 gradients.