bluuebunny/crossref_metadata_2025 huggingface dataset:
Chitooligosaccharide inhibits RANKL‐induced osteoclastogenesis and ligation‐induced periodontitis by suppressing MAPK/ c‐fos/NFATC1 signaling
Authors: Xu Weifeng , Chen Xinwei , Wang Yexin , Fan Baoting , Guo Ke , Yang Chi , Yu Shiqi , Pang Yichuan , Zhang Shanyong
Published: September 2019

Considering the high rate of osteoclast‐related diseases worldwide, research targeting osteoclast formation/function is crucial. In vitro, we demonstrated that chitooligosaccharide (CS) dramatically inhibited osteoclastogenesis as well as osteoclast function dose‐dependently. CS suppressed osteoclast‐specific genes expression during osteoclastogenesis. Furthermore, we found that CS attenuated receptor activator of nuclear factor kappa B ligand (RANKL)‐mediated mitogen‐activated protein kinase (MAPK) pathway involving p38, erk1/2, and jnk, leading to the reduced expression of c‐fos and nuclear factor of activated T cells c1 (NFATc1) during osteoclast differentiation. In vivo, we found CS protected rats from periodontitis‐induced alveolar bone loss by micro‐computerized tomography and histological analysis. Overall, CS inhibited RANKL‐induced osteoclastogenesis and ligature‐induced rat periodontitis model, probably by suppressing the MAPK/c‐fos/NFATc1 signaling pathway. Therefore, CS may be a safe and promising treatment for osteoclast‐related diseases.
Acetaminophen sensitizing erastin‐induced ferroptosis via modulation of Nrf2/heme oxygenase‐1 signaling pathway in non‐small‐cell lung cancer
Authors: Gai Chengcheng , Yu Mengyu , Li Zihaoran , Wang Yonghong , Ding Dejun , Zheng Jie , Lv Shijun , Zhang Weifen , Li Wentong
Published: September 2019

Growing evidence confirms that ferroptosis plays an important role in tumor growth inhibition. However, some non‐small‐cell lung cancer (NSCLC) cell lines are less sensitive to erastin‐induced ferroptotic cell death. Elucidating the mechanism of resistance of cancer cells to erastin‐induced ferroptosis and increasing the sensitivity of cancer cells to erastin need to be addressed. In our experiment, erastin and acetaminophen (APAP) cotreatment inhibited NSCLC cell viability and promoted ferroptosis and apoptosis, accompanied with attenuation of glutathione and ectopic increases in lipid peroxides. Erastin and APAP promoted NSCLC cell death by regulating nucleus translocation of nuclear factor erythroid 2‐related factor 2 (Nrf2); and the ferroptosis induced by erastin and APAP was abrogated by bardoxolone methyl (BM) with less generation of reactive oxygen species and malondialdehyde. As a downstream gene of Nrf2, heme oxygenase‐1 expression decreased significantly with the cotreatment of erastin and APAP, which could be rescued by BM. In vivo experiment showed that the combination of erastin and APAP had a synergic therapeutic effect on xenograft of lung cancer. In short, the present study develops a new effective treatment for NSCLC by synergizing erastin and APAP to induce ferroptosis.
Intact caveolae are required for proper extravillous trophoblast migration and differentiation
Authors: Reppetti Julieta , Reca Alejandra , Seyahian E. Abril  , Medina Yollyseth , Martínez Nora , Szpilbarg Natalia , Damiano Alicia E.
Published: September 2019

Caveolae constitute membrane domains critical for the organization and synchronization of different signaling molecules related to numerous cell processes such as cell migration, invasion, and differentiation. Caveolin‐1 (Cav‐1) is the main integral membrane protein of these domains. Recently, it was found that a normal expression of aquaporin‐3 (AQP3) is required for extravillous trophoblast (EVT) cell migration. Our aim was to investigate the role of caveolae in the migration, invasion, and endovascular differentiation of human EVT cells during placentation and its interaction with AQP3. EVT cells (Swan 71 cell line) were cultured in complete Dulbecco's modified Eagle's medium–nutrient mixture F12 and treated with 5 mM methyl‐β‐cyclodextrin (MβCD) to disrupt caveolae. We found that after MβCD treatment, Cav‐1 protein was undetectable. In this condition, the ability of the cells to migrate was significantly decreased compared with the control cells, while no differences were observed in the number of invading cells and the metalloproteinases activity between control and MβCD‐treated cells. Surprisingly, the disruption of caveolae significantly enhanced EVT endovascular differentiation. On the contrary, the silencing of AQP3, negatively affected tube‐like formation. The theoretical analysis of the primary sequence of AQP3 protein revealed a putative Cav‐1‐binding site. In addition, immunoprecipitation and double immunofluorescence assays showed that AQP3 colocalized with Cav‐1. These results showed that during placentation an intact caveola in EVT cells may be necessary for AQP3 and Cav‐1 interaction and any perturbations might result in serious pregnancy disorders.
Local anesthetics counteract cell proliferation and migration of human triple‐negative breast cancer and melanoma cells
Authors: Castelli Vanessa , Piroli Alba , Marinangeli Franco , d'Angelo Michele , Benedetti Elisabetta , Ippoliti Rodolfo , Zis Panagiotis , Varrassi Giustino , Giordano Antonio , Paladini Antonella , Cimini Annamaria
Published: September 2019

In different retrospective studies, a protective role of regional anesthetics in reducing cancer recurrence after surgery was indicated. Accordingly, it has been previously demonstrated a protective effect of anesthetics in breast cancer cells and in other types of cancer. On the other hand, how anesthetics influence cancer needs in‐depth investigations. For this purpose, two different human cancer cell lines, MDA‐MB‐231, triple‐negative breast cancer, and A375, melanoma, were used in this study. By means of Western blotting and immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labeling analyses, the signal transduction pathways activated by the anesthetics, such as ropivacaine and levobupivacaine, were analyzed. The data obtained demonstrated that both anesthetics are able to counteract cell proliferation by positively modulating cell death signaling and by decreasing cell proliferation and survival pathways.
The effect of learning on heart rate and behavior of European starlings (Sturnus vulgaris)
Authors: Glassman Laura W. , Hagmann  Carl E. , Qadri Muhammad A. , Cook Robert G. , Romero L. Michael
Published: September 2019

Wild‐caught European starlings (Sturnus vulgaris) were exposed to a learning task to determine whether heart rate (HR) and behavior responses to the learning activated the sympathetic nervous system. Birds learned to discriminate between images of opposite convexity (concave and convex) based on shading cues in a closed economy (food only available through task completion). Once learned, the task was changed in three ways: (a) manipulating the angle and shape of the image; (b) altering the availability of the task; and (c) reversing the positive stimulus. HR, used as an index of catecholamine release, was measured during each change to determine whether having to alter previously established behaviors to learn new behaviors elicited a sympathetic response. Starlings decreased their HR during the initial discrimination training and did not alter their HR when presented with modified images or when the positive stimulus was reversed. However, HR increased when the task became unavailable and decreased upon its return, suggesting that preventing task performance was perceived as stressful. Birds also modified their behavior when tasks were changed. The number of trials per minute decreased during the reversal treatment, as did the success rate, suggesting that starlings may try to conserve energy when access to food diminishes. This is also supported by the decrease in perch hops per minute when the task was unavailable and the subsequent increase upon its return. Overall, these results suggest that learning per se does not activate the sympathetic nervous system and, therefore, is not a stressor for wild birds.
Advances in Conservation and Management of the Alligator Gar: A Synthesis of Current Knowledge and Introduction to a Special Section
Authors: Smith N. G. , Daugherty D. J. , Brinkman E. L. , Wegener M. G. , Kreiser B. R. , Ferrara A. M. , Kimmel K. D. , David S. R.
Published: September 2019

Growing appreciation of biodiversity and the role of apex predators, along with the increasing popularity of multispecies and trophy-oriented angling, has elevated the status of gars—in particular, the Alligator Gar Atractosteus spatula—among anglers and biologists alike. As a result, considerable effort has been spent in recent years to gain a working knowledge of the biology and ecology of the species in order to advance science-based management. In January 2019, the Alligator Gar Technical Committee of the Southern Division of the American Fisheries Society hosted a symposium entitled “Advances in the Conservation and Management of North American Gars” to showcase the results of research and management efforts conducted throughout the species’ range. Fishery researchers and managers presented a diversity of works, furthering our understanding of population dynamics, stock assessment, genetics, hatchery practices and stocking, habitat use, and angler desires associated with Alligator Gar fisheries. In our introduction to this special section, we introduce these works and provide a synthesis of the current state of scientific knowledge regarding the Alligator Gar. We hope that this will provide context to the works presented in the symposium and will serve to guide the development of future research that addresses the remaining knowledge gaps concerning the species and its growing fishery.
Ba‐Wei‐Die‐Huang‐Wan (Hachimi‐jio‐gan) can ameliorate ketamine‐induced cystitis by modulating neuroreceptors, inflammatory mediators, and fibrogenesis in a rat model
Authors: Lee Wei‐Chia , Tain You‐Lin , Chuang Yao‐Chi , Tsai Cheng‐Nan , Yu Chun‐Chieh , Su Chia‐Hao
Published: September 2019

Aim

We investigated the effects of Ba‐Wei‐Die‐Huang‐Wan (BWDHW) on ketamine‐induced cystitis (KIC) in a rat model.

Methods

Female Sprague‐Dawley rats were distributed into three groups: control (saline), ketamine (25 mg/kg/day for 28 days), or ketamine (25 mg/kg/day for 28 days) plus BWDHW (90 mg/kg/day, started from day 14). Functional magnetic resonance imaging (fMRI), metabolic cage study, and cystometry were evaluated. Bladder histology was evaluated. Western blots of the bladder proteins were carried out.

Results

Compared with controls, ketamine‐treated rats showed stronger fMRI intensity in the periaqueductal gray area and bladder overactivity in the bladder functional study, but the ketamine/BWDHW‐treated rats did not. Furthermore, ketamine breached the uroplakin III membrane at the apical surface of the urothelium, enhanced substance P spread over the urothelium, induced suburothelial hemorrhage and monocyte/macrophage infiltration, and caused interstitial fibrosis deposition. By contrast, the BWDHW‐treated rats exhibited less substance P spread, lower suburothelial monocyte/macrophage infiltration, and lower interstitial fibrosis deposition. The ketamine group showed significant overexpression of neuroreceptors in the bladder mucosa (the transient receptor potential vanilloid 1 and M2‐ and M3‐muscarinic receptors) and detrusor (M2‐ and M3‐muscarinic receptors); inflammatory mediators in the detrusor (interleukin‐1β [IL‐1β], IL‐6, tumor necrosis factor‐α, nuclear factor‐κB, cyclooxygenase‐2, and intercellular adhesion molecule‐1); and fibrogenesis molecules in the detrusor (transforming growth factor‐β1, collagen I, collagen III, and fibronectin). However, no significant changes were noted between the ketamine/BWDHW and control groups.

Conclusion

BWDHW could exert therapeutic effects by inhibiting the upregulation of neuroreceptors, modulating inflammatory mediators, suppressing fibrogenesis, and ameliorating bladder overactivity in rats with KIC.
Role of Intrinsic Dipoles in the Evaporation‐Driven Assembly of Perovskite Nanocubes into Energy‐Harvesting Composites
Authors: Zablotsky Dmitry , Kuzovkov Vladimir , Kotomin Eugene
Published: September 2019

Efficient ambient energy scavenging exploiting piezoelectric properties of ferroelectric perovskites is an attractive green strategy to power low‐energy devices. In turn, the colloidal processing of the nearly monodisperse and highly crystalline single‐domain nanocubes of BaTiO3 is a promising route to produce oriented, high‐performance thin films for integration into nanostructured‐ferroelectric devices. Controlling the local behavior of nanocrystals is imperative for fabricating highly ordered assemblies, whereas the current picture of nanoscale polarization suggests a potential presence of significant electrodipolar interaction in ferroelectric nanoparticles. However, its role in the condensation of perovskite nanocubes remains unknown. The results of simulated self‐assembly and characterization of osmotically densified ensembles of dipolar nanocubes are reported. It is shown that in fact for solubilized BaTiO3 nanocubes, the polarization screening must be complete without appreciable dipole moment (below a few kBT), whereas stray interactions from incompletely screened surface charges are likely the major sources of disorder in self‐assembled architectures of SrTiO3.
Characterization of the Electronic Properties of Single‐Walled Carbon Nanotubes Filled with an Electron Donor—Rubidium Iodide: Multifrequency Raman and X‐ray Photoelectron Spectroscopy Studies
Authors: Kharlamova Marianna V. , Kramberger Christian , Rudatis Paolo , Yanagi Kazuhiro , Eder Dominik
Published: September 2019

Single‐walled carbon nanotubes (SWCNTs) with a mean diameter of 1.4 nm are filled with rubidium iodide. The filling of nanotubes is proved by high‐resolution scanning transmission electron microscopy. The chemical composition of the filler is confirmed by X‐ray photoelectron spectroscopy (XPS). The electronic properties of the filled SWCNTs are studied by XPS and Raman spectroscopy. The encapsulated salt leads to n‐doping of nanotubes. The detailed multifrequency Raman spectroscopy investigation of the alteration of Raman modes of SWCNTs upon filling is conducted. The doping‐induced changes in the radial breathing mode and G‐band are revealed. It is found that these changes differ for the metallic and semiconducting SWCNTs. The obtained data and revealed trends are expected to be helpful for forthcoming studies to interpret the observed changes in Raman spectra of filled metallic and semiconducting SWCNTs.
Luminescence of Fluorochlorozirconate Glasses Doped with Manganese Ions
Authors: Brekhovskikh Maria N. , Batygov Sergei Kh. , Moiseeva Ljudmila V. , Kirikova Natalia Yu. , Kondratyuk Valentin A. , Oja Marek , Kirm Marco , Zając Marcin , Makhov Vladimir N.
Published: September 2019

A series of fluorochlorozirconate glasses doped with manganese ions is synthesized and investigated as possible red‐emitting phosphors in comparison with conventional green‐emitting fluorozirconate glasses doped with Mn2+. It is found that the replacement of fluorine by chlorine ions results in broadening and a long‐wavelength shift of the manganese luminescence band into the red region (peaked at 615 nm) although the emission spectrum still has some contribution of the green sub‐band. It turns out also that decay kinetics of luminescence from fluorochlorozirconate glasses becomes nonexponential in contrast to single‐exponential decay observed for green luminescence from Mn2+‐doped fluorozirconate glasses. The observation of two emission components in the luminescence spectrum of fluorochlorozirconate glasses is interpreted as being due to the presence of two Mn2+ emission centers in different local environments. The presence of 2+ valence states of manganese ions in both types of glasses is confirmed by recording X‐ray absorption near edge structure (XANES) spectra at Mn L2,3 edge. Substitution of F− by Cl− ions in anion sites neighboring to Mn2+, leads to a significant rearrangement of the local environment of Mn2+ ions, which results in the long‐wavelength shift of Mn2+ emission spectrum.
Electronic States at the Zigzag Edges of Graphene Terraces
Authors: Alattas Maha , Schwingenschlögl Udo
Published: September 2019

Density functional theory is used to study the electronic states at the zigzag edges of graphene terraces, considering bare edges and H, F, Cl, NH2 terminations. In contrast to the H and F terminations, periodic structural reconstructions are observed for the Cl and NH2 terminations due to interaction between the terminating atoms/groups. It is shown that the Cl termination of the edges leads to p‐doping of the terraces, whereas NH2 termination results in n‐doping.
Tubulointerstitial nephritis antigen‐like 1 deficiency alleviates age‐dependent depressed ovulation associated with ovarian collagen deposition in mice
Authors: Akaiwa Masato , Fukui Emiko , Matsumoto Hiromichi
Published: September 2019

Purpose

This study aimed to examine whether the Tinagl1 might be associated with ovulation in aged females and reproductive age‐associated fibrosis in the stroma of the ovary.

Methods

To address the ovulatory ability and quality of ovulated oocytes, we induced ovulation by treatment with equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) followed by in vitro fertilization. We also performed Picrosirius Red (PSR) staining to evaluate ovarian collagen deposition.

Results

As compared to ovulation in 8‐ to 9‐month‐old Tinagl1flox/flox mice, the number of ovulated oocytes from Tinagl1flox/flox mice decreased in an age‐dependent manner in mice more than 10‐11 months old, whereas the ovulated oocyte numbers in Tinagl1−/− mice decreased significantly at 14‐15 months. In vitro fertilization followed by embryo culture demonstrated the normal developmental potential of Tinagl1‐null embryos during the preimplantation period. PSR staining indicated that collagen was found throughout the ovarian stroma in an age‐dependent manner in Tinagl1flox/flox females, whereas those distributions were delayed to 14‐15 months in Tinagl1−/− females. This timing was consistent with the delayed timing of age‐related decline of ovulation in Tinagl1−/− females.

Conclusions

The alleviation of age‐associated depression of ovulation was caused by delayed ovarian collagen deposition in Tinagl1‐null female mice.
Improving Molecular Planarity by Changing Alky Chain Position Enables 12.3% Efficiency All‐Small‐Molecule Organic Solar Cells with Enhanced Carrier Lifetime and Reduced Recombination
Authors: Dong Xiyue , Yang Ke , Tang Hua , Hu Dingqin , Chen Shanshan , Zhang Jun , Kan Zhipeng , Duan Tainan , Hu Chao , Dai Xuexin , Xiao Zeyun , Sun Kuan , Lu Shirong
Published: September 2019

Molecular stacking plays an important role in defining the active layer morphology in all‐small‐molecule organic solar cells (ASM OSCs). However, the precise control of donor/acceptor stacking to afford optimal phase separation remains challenging. Herein, the molecular stacking of a small‐molecule donor is tuned by changing the alky chain position to match a high‐performance small‐molecule nonfullerene acceptor (NFA), Y6. The alky chain engineering not only affects the planarity of the small‐molecule donor, but also the molecular aggregation and the active layer morphology, and thus the photovoltaic performance. Notably, single‐junction ASM OSCs with 12.3% power conversion efficiency (PCE) are achieved. The PCE of 12.3% is among the top efficiencies of single‐junction ASM OSCs reported in the literature to date. The results highlight the importance of fine‐tuning the molecular structure to achieve high‐performance ASM OSCs.
A Nonfullerene Acceptor with Alkylthio‐ and Dimethoxy‐Thiophene‐Groups Yielding High‐Performance Ternary Organic Solar Cells
Authors: Zeng Anping , Pan Mingao , Lin Baojun , Lau Tsz-Ki , Qin Minchao , Li Kun , Ma Wei , Lu Xinhui , Zhan Chuanlang , Yan He
Published: September 2019

Herein, an A–D–A‐type nonfullerene acceptor (named IDTS‐4F) with an alkyl thiophenyl side chain and dimethoxy thiophene bridging unit is reported. The use of an alkyl thiophenyl group is important, as the insertion of sulfur atoms can slightly downshift the highest occupied molecular orbital (HOMO) level of the molecule and allows IDTS‐4F to match with state‐of‐the‐art donor polymer PM6 (or PM7). Compared with conventional nonfullerene acceptors, IT‐4F, the IDTS‐4F molecule, has a smaller optical bandgap and higher lowest unoccupied molecular orbital (LUMO) level, which are beneficial to increase the Voc and Jsc of the devices. Nonfullerene organic solar cell devices are fabricated using IDTS‐4F. Although the binary device based on IDTS‐4F exhibits a lower fill factor (FF, 70%), the ternary device by incorporating 0.2 of IDTS‐4F and 0.8 of IT‐4F (with PM6 as the donor polymer) can simultaneously achieve a higher Voc and Jsc, while maintaining the high FF (77%) of IT‐4F based system. Morphology characterizations indicate the formation of homogeneous film morphology, the large increase in phase purity and crystallinity, and the reduction in domain size upon addition of crystalline IDTS‐4F, while the electron/hole mobilities and recombination losses of the IT‐4F system are both maintained.
Pt Decorated (Au Nanosphere)/(CuSe Ultrathin Nanoplate) Tangential Hybrids for Efficient Photocatalytic Hydrogen Generation via Dual‐Plasmon‐Induced Strong VIS–NIR Light Absorption and Interfacial Electric Field Coupling
Authors: Ma Liang , Yang Da-Jie , Song Xiang-Ping , Li Hai-Xia , Ding Si-Jing , Xiong Lun , Qin Ping-Li , Chen Xiang-Bai
Published: September 2019

The rational regulation of geometry and dimension of plasmonic metal/semiconductor photocatalysts is crucial to optimize their photocatalytic performance by maxing the plasmonic effect. Herein, Au/CuSe/Pt hybrids with a tangential structure and strong dual‐plasmon resonance are prepared, for the first time, through a convenient hydrothermal method, which display a prominent photocatalytic hydrogen generation activity from water splitting. In the ternary nanostructure, a 2D CuSe ultrathin nanoplate is grown along the tangent of Au nanospheres, and Pt nanoparticles are deposited on Au and CuSe. Under visible and near‐infrared (VIS–NIR) light irradiation, the Au/CuSe/Pt hybrids exhibit an outstanding photocatalytic hydrogen generation activity, that is, 7.8 and 9.7 times that of Au/CuSe and Pt/CuSe, respectively. In an Au/CuSe/Pt nanosystem, CuSe and Au are both plasmonic units for light harvesting and near‐field enhancement, and Pt is cocatalyst for hydrogen reaction. Numerical simulations verify that Au and CuSe have strong electric field coupling around their interface, which can improve the abilities of light trapping and charge generation. Moreover, the closely contacted components and tangential architecture of Au/CuSe/Pt hybrids can generate multiple electron‐transfer pathways and abundant surface‐active sites, which arrestingly enhance the utilization of dual‐plasmon‐induced hot electrons and photoexcited charges, thus boosting hydrogen generation.
Immigrants’ mental health service use compared to that of native Finns: a register study
Authors: Kieseppä Valentina , Torniainen-Holm Minna , Jokela Markus , Suvisaari Jaana , Gissler Mika , Markkula Niina , Lehti Venla
Published: September 2019

Purpose

Many aspects related to migration might predispose immigrants to mental health problems. Yet immigrants have been shown to underuse mental health services. The aim of this study was to compare the intensity of psychiatric care, as an indicator of treatment adequacy, between natives and immigrants living in Finland.

Methods

We used nationwide register data that included all the immigrants living in Finland at the end of 2010 (n = 185,605) and their matched controls. Only those who had used mental health services were included in the analyses (n = 14,285). We used multinomial logistic regression to predict the categorized treatment intensity by immigrant status, region and country of origin, length of residence, and other background variables.

Results

Immigrants used mental health services less than Finnish controls and with lower intensity. The length of residence in Finland increased the probability of higher treatment intensity. Immigrants from Eastern Europe, sub-Saharan Africa, the Middle East, and Northern Africa were at the highest risk of receiving low-intensity treatment.

Conclusions

Some immigrant groups seem to persistently receive less psychiatric treatment than Finnish-born controls. Identification of these groups is important and future research is needed to determine the mechanisms behind these patterns.
Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development
Authors: McCluskey Stuart P. , Plisson Christophe , Rabiner Eugenii A. , Howes Oliver
Published: September 2019

Purpose

A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for in-human imaging.

Methods

We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties.

Results and conclusions

Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18F-MK-6240 for tau imaging, 11C-UCB-J for imaging SV2A, 11C-CURB and 11C-MK-3168 for characterisation of fatty acid amide hydrolase, 18F-FIMX for metabotropic glutamate receptor 1, and 18F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete pre-clinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.
Alternative dosing regimens for atezolizumab: an example of model-informed drug development in the postmarketing setting
Authors: Morrissey Kari M. , Marchand Mathilde , Patel Hina , Zhang Rong , Wu Benjamin , Phyllis Chan H. , Mecke Almut , Girish Sandhya , Jin Jin Y. , Winter Helen R. , Bruno René
Published: September 2019

Purpose

To determine the exposure–response (ER) relationships between atezolizumab exposure and efficacy or safety in patients with advanced non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) and to identify alternative dosing regimens.

Methods

ER analyses were conducted using pooled NSCLC and UC data from phase 1 and 3 studies (PCD4989g, OAK, IMvigor211; ClinicalTrials.gov IDs, NCT01375842, NCT02008227, and NCT02302807, respectively). Objective response rate, overall survival, and adverse events were evaluated vs pharmacokinetic (PK) metrics. Population PK-simulated exposures for regimens of 840 mg every 2 weeks (q2w) and 1680 mg every 4 weeks (q4w) were compared with the approved regimen of 1200 mg every 3 weeks (q3w) and the maximum assessed dose (MAD; 20 mg/kg q3w). Phase 3 IMpassion130 (NCT02425891) data were used to validate the PK simulations for 840 mg q2w. Observed safety data were evaluated by exposure and body weight subgroups.

Results

No significant ER relationships were observed for safety or efficacy. Predicted exposures for 840 mg q2w and 1680 mg q4w were comparable to 1200 mg q3w and the MAD and consistent with observed PK data from IMpassion130. Observed safety was similar between patients with a Cmax above and below the predicted Cmax for 1680 mg q4w and between patients in the lowest and upper 3 body weight quartiles.

Conclusion

Atezolizumab regimens of 840 mg q2w and 1680 mg q4w are expected to have comparable efficacy and safety as the approved regimen of 1200 mg q3w, supporting their interchangeable use and offering patients greater flexibility.
Coarse-graining molecular dynamics: stochastic models with non-Gaussian force distributions
Authors: Erban Radek
Published: September 2019

Incorporating atomistic and molecular information into models of cellular behaviour is challenging because of a vast separation of spatial and temporal scales between processes happening at the atomic and cellular levels. Multiscale or multi-resolution methodologies address this difficulty by using molecular dynamics (MD) and coarse-grained models in different parts of the cell. Their applicability depends on the accuracy and properties of the coarse-grained model which approximates the detailed MD description. A family of stochastic coarse-grained (SCG) models, written as relatively low-dimensional systems of nonlinear stochastic differential equations, is presented. The nonlinear SCG model incorporates the non-Gaussian force distribution which is observed in MD simulations and which cannot be described by linear models. It is shown that the nonlinearities can be chosen in such a way that they do not complicate parametrization of the SCG description by detailed MD simulations. The solution of the SCG model is found in terms of gamma functions.
Do anticoagulants affect outcomes of hip fracture surgery? A cross-sectional analysis
Authors: Hoerlyck Caroline , Ong Terence , Gregersen Merete , Damsgaard Else Marie , Borris Lars , Chia Jac Kie , Yap Ying Yi Wendy , Weerasuriya Namal , Sahota Opinder
Published: September 2019

Introduction

The management of patients with a hip fracture is affected by the use of oral anticoagulants. A cross-sectional analysis was undertaken to investigate health outcome differences in those anticoagulated compared to those not anticoagulated.

Methods

Patients aged 50 years and over presenting to a large university hospital with hip fractures were identified from the service registry. Patient characteristics and health outcomes between those not anticoagulated were compared with those anticoagulated (warfarin and direct oral anticoagulants, DOAC).

Results

200/2307 (9%) patients were anticoagulated. 84% were on warfarin, and the rest a DOAC. Compared to those anticoagulated, there was a higher prevalence of dementia (25% vs. 18%, p = 0.02) and a lower prevalence of cardiovascular disease (54% vs. 78%, p < 0.01), atrial fibrillation (10% vs. 82%, p < 0.01), and polypharmacy (55% vs. 76%, p < 0.01). Renal function was lower in the anticoagulated group. Time to operation for those not anticoagulated and anticoagulated was a median (IQR) of 25 (15) and 27 (18) hours. There was no difference in blood transfusion and hospital mortality. Postoperative complications were similar except a higher rate of renal failure (14% vs. 19%, p = 0.04) and heart failure (1% vs. 5%, p < 0.01), and a longer length of stay [median (IQR): 14 (10) vs. 16 (12) days] in the anticoagulated group. This was no longer significant after adjustment of confounders.

Conclusion

There was no statistically significant difference in health outcomes between those anticoagulated and those not after adjusting for patient characteristics. It was feasible to avoid significant delay in hip fracture surgery in those anticoagulated.
The effect of solid solution on the stability of talc and 10-Å phase
Authors: Howe Harriet , Pawley Alison R.
Published: September 2019

Talc and 10-Å phase are hydrous phases that are implicated in fluid processes and rheological behaviour in subduction zones. Natural samples of talc show limited compositional variation away from the MgO–SiO2–H2O (MSH) endmember, with only substitution of Fe2+ for Mg occurring in significant amounts. In experiments at 2 GPa, talc containing 0.48 apfu Fe2+ begins to break down in the divariant field talc + anthophyllite + quartz at ~ 550 °C, a temperature ~ 270 °C lower than in the MSH system. At 4 GPa, Fe-bearing talc breaks down over a wide temperature interval in the divariant field talc + enstatite + coesite. The large decrease in temperature of the beginning of talc breakdown shows that Fe2+ is partitioned strongly into enstatite and anthophyllite with respect to talc. In phase reversal experiments at 6.5 GPa, the beginning of the dehydration of 10-Å phase containing 0.48 apfu Fe2+ was bracketed between 575 °C and 600 °C, a temperature ~ 100 °C lower than the MSH endmember reaction. The relative positions of the talc and 10-Å phase dehydration reactions indicate that the latter is able to accommodate greater Fe substitution, and is, therefore, more stable in Fe-bearing systems. In experiments at 6.2 GPa, 650 °C in the systems MgO–Al2O3–SiO2–H2O (MASH) and Na2O–MgO–Al2O3–SiO2–H2O (NMASH), 10-Å phase was synthesised that contains up to 0.5 apfu Al in the system MASH (compared to 0.8 in the starting material) and up to 0.4 apfu Al + 0.4 apfu Na in the system NMASH (compared to 0.7 of each of Al and Na in the starting material). Further experiments are required to determine if higher Al and Na contents in 10-Å phase are possible. The much higher Al and Na contents than found in talc indicate that, as with Fe, substitution of these elements enlarges the 10-Å phase stability field with respect to talc. In contrast to the effect of Fe, Al and Na also increase the stability of 10-Å phase relative to its thermal breakdown products enstatite + coesite.
GORTS: genetic algorithm based on one-by-one revision of two sides for dynamic travelling salesman problems
Authors: Xu Xiaolong , Yuan Hao , Matthew Peter , Ray Jeffrey , Bagdasar Ovidiu , Trovati Marcello
Published: September 2019

The dynamic travelling salesman problem (DTSP) is a natural extension of the standard travelling salesman problem, and it has attracted significant interest in recent years due to is practical applications. In this article, we propose an efficient solution for DTSP, based on a genetic algorithm (GA), and on the one-by-one revision of two sides (GORTS). More specifically, GORTS combines the global search ability of GA with the fast convergence feature of the method of one-by-one revision of two sides, in order to find the optimal solution in a short time. An experimental platform was designed to evaluate the performance of GORTS with TSPLIB. The experimental results show that the efficiency of GORTS compares favourably against other popular heuristic algorithms for DTSP. In particular, a prototype logistics system based on GORTS for a supermarket with an online map was designed and implemented. It was shown that this can provide optimised goods distribution routes for delivery staff, while considering real-time traffic information.
Dynamic sampling rate algorithm (DSRA) implemented in self-adaptive software architecture: a way to reduce the energy consumption of wireless sensors through event-based sampling
Authors: Algabroun Hatem
Published: September 2019

With the recent digitalization trends in the industry, wireless sensors are, in particular, gaining a growing interest. This is due to the possibility of being installed in inaccessible locations for wired sensors. Although great success has already been achieved in this area, energy limitation remains a major obstacle for further advances. As such, it is important to optimize the sampling with a sufficient rate to catch important information without excessive energy consumption, and one way to achieve sufficient sampling is using adaptive sampling for sensors. As software plays an important role in the techniques of adaptive sampling, a reference framework for software architecture is important in order to facilitate their design, modeling, and implementation. This study proposes a software architecture, named Rainbow, as the reference architecture, also, it develops an algorithm for adaptive sampling. The algorithm was implemented in the Rainbow architecture and tested using two datasets; the results show the proper operation of the architecture as well as the algorithm. In conclusion, the Rainbow software architecture has the potential to be used as a framework for adaptive sampling algorithms, and the developed algorithm allows adaptive sampling based on the changes in the signal.
Service- and practitioner-level variation in non-consensual dropout from child mental health services
Authors: Edbrooke-Childs Julian , Boehnke Jan R. , Zamperoni Victoria , Calderon Ana , Whale Andy
Published: September 2019

Non-attendance of mental health service appointments is an international problem. In the UK, for example, the estimated cost of non-attendance in child mental health services is over £45 million (US dollar 60.94 million) per annum. The objective of this study was to examine whether there were service- and practitioner-level variation in non-consensual dropout in child mental health services. This was an analysis of routinely collected data. Service-level variation (as services covered different geographic areas) and practitioner-level variation were examined in N = 3622 children (mean age 12.70 years; SD 3.62, 57% female, 50% white or white British) seen by 896 practitioners across 39 services. Overall, 35% of the variation in non-consensual dropout was explained at the service level and 15% at the practitioner level. Children were almost four times more likely to drop out depending on which service they attended (median odds ratio = 3.92) and were two-and-a-half times more likely to drop out depending on which practitioner they saw (median odds ratio = 2.53). These levels of variation were not explained by levels of deprivation in areas covered by services or by children’s demographic and case characteristics. The findings of the present research may suggest that, beyond service-level variation, there is also practitioner-level variation in non-consensual dropout in child mental health services.
Phase II study of capecitabine plus oxaliplatin (CapOX) as adjuvant chemotherapy for locally advanced rectal cancer (CORONA II)
Authors: Hattori Norifumi , Nakayama Goro , Uehara Keisuke , Aiba Toshisada , Ishigure Kiyoshi , Sakamoto Eiji , Tojima Yuichiro , Kanda Mitsuro , Kobayashi Daisuke , Tanaka Chie , Yamada Suguru , Koike Masahiko , Fujiwara Michitaka , Nagino Masato , Kodera Yasuhiro
Published: September 2019

Objective

This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer.

Methods

Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1–14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety.

Results

A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57–86%) and 96% (95% CI 80–99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively.

Conclusion

CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.
Moment explosions in the rough Heston model
Authors: Gerhold Stefan , Gerstenecker Christoph , Pinter Arpad
Published: September 2019

We show that the moment explosion time in the rough Heston model, introduced by El Euch and Rosenbaum in 2016, is finite if and only if it is finite for the classical Heston model. Upper and lower bounds for the explosion time are established, as well as an algorithm to compute the explosion time (under some restrictions). We show that the critical moments are finite for all maturities. For negative correlation, we apply our algorithm for the moment explosion time to compute the lower critical moment.
Machine imports, technology adoption, and local spillovers
Authors: Békés Gábor , Harasztosi Péter
Published: September 2019

In developing economies import can be the primary source of adopting new technologies and modern production equipment. Using a uniquely compiled Hungarian firm-level dataset, we investigated whether firms’ decision to import a specific machine is influenced by the local accumulation of experience in that same imported machine. Our results suggested that an additional local importer in the firm’s vicinity increases the probability of importing that particular machine considerably. Distance plays a key mediating role as firms, especially in small cities, learned mostly from neighboring peers. We also found that even within a type of imported machine, the source country of the product matters a great deal. Finally, the extent of spillover effects was found to vary a great deal both with respect to the importing firm as well as the composition of peers. Larger, foreign owned and internationalized firms are the ones that benefit from having importing firms in their vicinity, while small and domestically owned firms could actually be adversely affected by peer effects. Our results could be indicative for policy-makers interested in indirect impact of technology upgrade subsidy programs. We found that such indirect effects do exist. However, they are centered on large to large firm interactions. As smaller sized firms producing for the domestic market do not benefit much from import spillovers, policies aimed at helping such firms may not rely on these indirect effects.
Policy measures to promote mid-summer drainage in paddy fields for a reduction in methane gas emissions: the application of a dynamic, spatial computable general equilibrium model
Authors: Kunimitsu Yoji , Nishimori Motoki
Published: September 2019

Rice production is affected by climate change, while climate change is simultaneously accelerated by methane gas (CH4) emissions from paddy fields. The rice sector must take suitable mitigation measures, such as prolonging mid-summer drainage (MSD) before the rice flowering period. To propose a mitigation policy, this study aims to demonstrate the environmental and economic effects of MSD in Japanese paddy fields by using a dynamic, spatial computable general equilibrium (CGE) model and crop model; the study also considers environmental subsidies with a carbon tax scheme to promote MSD measures. The results demonstrate that climate change under the 8.5 representative concentration pathway (RCP) scenario will reduce rice prices and rice farmers’ nominal income due to bumper harvests until the 2050s. Promoting MSD in paddy fields can prevent a decrease in farmers’ nominal income and effectively reduce CH4 emissions if all farmers adopt this measure. However, some farmers can potentially increase their own yield by avoiding MSD under high rice prices, which would be maintained through other farmers’ participation. A strong motivation exists for some farmers to gain a “free ride,” and an environmental subsidy with a carbon tax can help motivate farmers to adopt MSD. Therefore, the policy mix of prolonging MSD and environmental subsidies can increase all farmers’ incomes by preventing “free rides” and decrease greenhouse gas emissions with a slight decrease in Japan’s GDP.
Hashtag hijacking and crowdsourcing transparency: social media affordances and the governance of farm animal protection
Authors: Rodak Olga
Published: September 2019

The post-war Western world has seen a gradual shift from government to governance, a process that also concerned the issues related to agro-food sustainability, such as food quality, environmental impact, social justice, and farm animal welfare. Scholars believe that social media are a new site that reconfigures relations between various actors involved in the governance of these problems. However, empirical research on this matter remains scarce. This paper fills this gap by examining the case of Februdairy, a Twitter hashtag campaign to promote the British dairy industry, hijacked by animal protection activists. For this case, I employ the relational perspective on technology affordances—as operationalised by Faraj and Azad (in: Leonard et al. (eds), Materiality and organizing. Social interaction in a technological world, Oxford University Press, Oxford, 2012)—to highlight two distinct strategic modes of embracement of social media functionalities by the opposing groups: hashtag hijacking and crowdsourcing transparency. The analysis reveals also that a pre-existing social structure of the agro-food system conditions reconfiguration of social relations by technology in a way that actually strengthens the tendency to govern the issue of farm animal protection with market mechanisms.
Recent large-scale landscape changes, genetic drift and reintroductions characterize the genetic structure of Norwegian wild reindeer
Authors: Kvie Kjersti S. , Heggenes Jan , Bårdsen Bård-Jørgen , Røed Knut H.
Published: September 2019

Landscape changes, such as habitat loss and fragmentation, subdivide wild populations, reduce their size, and limit gene flow. These changes may further lead to depletion of genetic variation within populations as well as accelerating differentiation among populations. As a migratory species requiring large living areas, wild reindeer (Rangifer tarandus) is highly vulnerable to human activity. The number and continued presence of wild reindeer have been significantly reduced due to accelerating anthropogenic habitat modifications, as well as displacement in benefit of domesticated herds of the species. As a basis for future management strategies we assess genetic structure and levels of genetic variation in Norwegian wild reindeer by analysing 12 microsatellite loci and the mitochondrial control region in 21 management units with varying population sizes. Overall, both markers showed highly varying levels of genetic variation, with reduced variation in the smaller and more isolated populations. The microsatellite data indicated a relationship between population size and genetic variation. This relationship was positive and linear until a threshold for population size was reached at approximately 1500 reindeer. We found high levels of differentiation among most populations, indicating low levels of gene flow, but only a weak correlation between geographic and genetic distances. Our results imply that the genetic structure of Norwegian wild reindeer is mainly driven by recent colonization history, population size, as well as human-induced landscape fragmentation, restricting gene flow and leading to high levels of genetic drift. To sustain viable populations, conservation strategies should focus on genetic connectivity between populations.