bluuebunny/crossref_metadata_2025 huggingface dataset:
Transforming Growth Factor-beta signaling in αβ thymocytes promotes negative selection
Authors: McCarron Mark J. , Irla Magali , Sergé Arnauld , Soudja Saidi M’Homa , Marie Julien C.
Published: December 2019

In the thymus, the T lymphocyte repertoire is purged of a substantial portion of highly self-reactive cells. This negative selection process relies on the strength of TCR-signaling in response to self-peptide-MHC complexes, both in the cortex and medulla regions. However, whether cytokine-signaling contributes to negative selection remains unclear. Here, we report that, in the absence of Transforming Growth Factor beta (TGF-β) signaling in thymocytes, negative selection is significantly impaired. Highly autoreactive thymocytes first escape cortical negative selection and acquire a Th1-like-phenotype. They express high levels of CXCR3, aberrantly accumulate at the cortico-medullary junction and subsequently fail to sustain AIRE expression in the medulla, escaping medullary negative selection. Highly autoreactive thymocytes undergo an atypical maturation program, substantially accumulate in the periphery and induce multiple organ-autoimmune-lesions. Thus, these findings reveal TGF-β in thymocytes as crucial for negative selection with implications for understanding T cell self-tolerance mechanisms.
Design principles of ion selective nanostructured membranes for the extraction of lithium ions
Authors: Razmjou Amir , Asadnia Mohsen , Hosseini Ehsan , Habibnejad Korayem Asghar , Chen Vicki
Published: December 2019

It is predicted that the continuously increasing demand for the energy-critical element of lithium will soon exceed its availability, rendering it a geopolitically significant resource. The present work critically reviews recent reports on Li+ selective membranes. Particular emphasis has been placed on the basic principles of the materials’ design for the development of membranes with nanochannels and nanopores with Li+ selectivity. Fundamental and practical challenges, as well as prospects for the targeted design of Li+ ion-selective membranes are also presented, with the goal of inspiring future critical research efforts in this scientifically and strategically important field.
Enhancing plasticity in central networks improves motor and sensory recovery after nerve damage
Authors: Meyers Eric C. , Kasliwal Nimit , Solorzano Bleyda R. , Lai Elaine , Bendale Geetanjali , Berry Abigail , Ganzer Patrick D. , Romero-Ortega Mario , Rennaker Robert L. , Kilgard Michael P. , Hays Seth A.
Published: December 2019

Nerve damage can cause chronic, debilitating problems including loss of motor control and paresthesia, and generates maladaptive neuroplasticity as central networks attempt to compensate for the loss of peripheral connectivity. However, it remains unclear if this is a critical feature responsible for the expression of symptoms. Here, we use brief bursts of closed-loop vagus nerve stimulation (CL-VNS) delivered during rehabilitation to reverse the aberrant central plasticity resulting from forelimb nerve transection. CL-VNS therapy drives extensive synaptic reorganization in central networks paralleled by improved sensorimotor recovery without any observable changes in the nerve or muscle. Depleting cortical acetylcholine blocks the plasticity-enhancing effects of CL-VNS and consequently eliminates recovery, indicating a critical role for brain circuits in recovery. These findings demonstrate that manipulations to enhance central plasticity can improve sensorimotor recovery and define CL-VNS as a readily translatable therapy to restore function after nerve damage.
Delay in recovery of the Antarctic ozone hole from unexpected CFC-11 emissions
Authors: Dhomse S. S. , Feng W. , Montzka S. A. , Hossaini R. , Keeble J. , Pyle J. A. , Daniel J. S. , Chipperfield M. P.
Published: December 2019

The Antarctic ozone hole is decreasing in size but this recovery will be affected by atmospheric variability and any unexpected changes in chlorinated source gas emissions. Here, using model simulations, we show that the ozone hole will largely cease to occur by 2065 given compliance with the Montreal Protocol. If the unusual meteorology of 2002 is repeated, an ozone-hole-free-year could occur as soon as the early 2020s by some metrics. The recently discovered increase in CFC-11 emissions of ~ 13 Gg yr−1 may delay recovery. So far the impact on ozone is small, but if these emissions indicate production for foam use much more CFC-11 may be leaked in the future. Assuming such production over 10 years, disappearance of the ozone hole will be delayed by a few years, although there are significant uncertainties. Continued, substantial future CFC-11 emissions of 67 Gg yr−1 would delay Antarctic ozone recovery by well over a decade.
Helix 8 is the essential structural motif of mechanosensitive GPCRs
Authors: Erdogmus Serap , Storch Ursula , Danner Laura , Becker Jasmin , Winter Michaela , Ziegler Nicole , Wirth Angela , Offermanns Stefan , Hoffmann Carsten , Gudermann Thomas , Mederos y Schnitzler Michael
Published: December 2019

G-protein coupled receptors (GPCRs) are versatile cellular sensors for chemical stimuli, but also serve as mechanosensors involved in various (patho)physiological settings like vascular regulation, cardiac hypertrophy and preeclampsia. However, the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here we show that mechanosensitive histamine H1 receptors (H1Rs) are endothelial sensors of fluid shear stress and contribute to flow-induced vasodilation. At the molecular level, we observe that H1Rs undergo stimulus-specific patterns of conformational changes suggesting that mechanical forces and agonists induce distinct active receptor conformations. GPCRs lacking C-terminal helix 8 (H8) are not mechanosensitive, and transfer of H8 to non-responsive GPCRs confers, while removal of H8 precludes, mechanosensitivity. Moreover, disrupting H8 structural integrity by amino acid exchanges impairs mechanosensitivity. Altogether, H8 is the essential structural motif endowing GPCRs with mechanosensitivity. These findings provide a mechanistic basis for a better understanding of the roles of mechanosensitive GPCRs in (patho)physiology.
Natural selection favoring more transmissible HIV detected in United States molecular transmission network
Authors: Wertheim Joel O. , Oster Alexandra M. , Switzer William M. , Zhang Chenhua , Panneer Nivedha , Campbell Ellsworth , Saduvala Neeraja , Johnson Jeffrey A. , Heneine Walid
Published: December 2019

HIV molecular epidemiology can identify clusters of individuals with elevated rates of HIV transmission. These variable transmission rates are primarily driven by host risk behavior; however, the effect of viral traits on variable transmission rates is poorly understood. Viral load, the concentration of HIV in blood, is a heritable viral trait that influences HIV infectiousness and disease progression. Here, we reconstruct HIV genetic transmission clusters using data from the United States National HIV Surveillance System and report that viruses in clusters, inferred to be frequently transmitted, have higher viral loads at diagnosis. Further, viral load is higher in people in larger clusters and with increased network connectivity, suggesting that HIV in the United States is experiencing natural selection to be more infectious and virulent. We also observe a concurrent increase in viral load at diagnosis over the last decade. This evolutionary trajectory may be slowed by prevention strategies prioritized toward rapidly growing transmission clusters.
Biointerfacial self-assembly generates lipid membrane coated bacteria for enhanced oral delivery and treatment
Authors: Cao Zhenping , Wang Xinyue , Pang Yan , Cheng Shanshan , Liu Jinyao
Published: December 2019

The gut microbiota represents a huge community of microorganisms that play essential roles in immune modulation and homeostasis maintenance. Microbiota transplantation is an important approach to prevent and treat disease as it can inhibit pathogen colonization and positively modulate bacterial composition. However, the development of oral bacterial therapeutics has been restricted by low bioavailability and limited retention in the gastrointestinal tract. Here, we report a simple yet highly efficient method to coat gut microbes via biointerfacial supramolecular self-assembly. Coating can be performed within 15 min by simply vortexing with biocompatible lipids. Bacteria coated with an extra self-assembled lipid membrane exhibit significantly improved survival against environmental assaults and almost unchanged viability and bioactivity. We demonstrate their enhanced efficacies in oral delivery and treatment using two murine models of colitis. We suggest that biointerfacial supramolecular self-assembly may provide a unique platform to generate advanced bacterial therapeutics for the treatment of various diseases.
Microbial Fe(III) reduction as a potential iron source from Holocene sediments beneath Larsen Ice Shelf
Authors: Jung Jaewoo , Yoo Kyu-Cheul , Rosenheim Brad E. , Conway Tim M. , Lee Jae Il , Yoon Ho Il , Hwang Chung Yeon , Yang Kiho , Subt Christina , Kim Jinwook
Published: December 2019

Recent recession of the Larsen Ice Shelf C has revealed microbial alterations of illite in marine sediments, a process typically thought to occur during low-grade metamorphism. In situ breakdown of illite provides a previously-unobserved pathway for the release of dissolved Fe2+ to porewaters, thus enhancing clay-rich Antarctic sub-ice shelf sediments as an important source of Fe to Fe-limited surface Southern Ocean waters during ice shelf retreat after the Last Glacial Maximum. When sediments are underneath the ice shelf, Fe2+ from microbial reductive dissolution of illite/Fe-oxides may be exported to the water column. However, the initiation of an oxygenated, bioturbated sediment under receding ice shelves may oxidize Fe within surface porewaters, decreasing dissolved Fe2+ export to the ocean. Thus, we identify another ice-sheet feedback intimately tied to iron biogeochemistry during climate transitions. Further constraints on the geographical extent of this process will impact our understanding of iron-carbon feedbacks during major deglaciations.
Ultrastable Au nanoparticles on titania through an encapsulation strategy under oxidative atmosphere
Authors: Liu Shaofeng , Xu Wei , Niu Yiming , Zhang Bingsen , Zheng Lirong , Liu Wei , Li Lin , Wang Junhu
Published: December 2019

Supported gold catalysts play a crucial role in the chemical industry; however, their poor on-stream stability because of the sintering of the gold nanoparticles restricts their practical application. The strong metal-support interaction (SMSI), an important concept in heterogeneous catalysis, may be applied to construct the structure of catalysts and, hence, improve their reactivity and stability. Here we report an ultrastable Au nanocatalyst after calcination at 800 °C, in which Au nanoparticles are encapsulated by a permeable TiOx thin layer induced by melamine under oxidative atmosphere. Owning to the formed TiOx overlayer, the resulting Au catalyst is resistant to sintering and exhibits excellent activity and stability for catalytic CO oxidation. Furthermore, this special strategy can be extended to colloidal Au nanoparticles supported on TiO2 and commercial gold catalyst denoted as RR2Ti, providing a universal way to engineer and develop highly stable supported Au catalysts with tunable activity.
Differential expression of circulating exosomal microRNAs in refractory intracranial atherosclerosis associated with antiangiogenesis
Authors: Jiang Hao , Toscano Juan F. , Song Shlee S. , Schlick Konrad H. , Dumitrascu Oana M. , Pan Jianwei , Lyden Patrick D. , Saver Jeffrey L. , Gonzalez Nestor R.
Published: December 2019

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence. We aimed to investigate the role of circulating exosomal microRNAs (e-miRNAs) in recurrent ischemic events in ICAD. Consecutive patients with severe ICAD undergoing intensive medical management (IMM) were prospectively enrolled. Those with recurrent ischemic events despite IMM during 6-month follow up were algorithmically matched to IMM responders. Baseline blood e-miRNA expression levels of the matched patients were measured using next generation sequencing. A total of 122 e-miRNAs were isolated from blood samples of 10 non-responders and 11 responders. Thirteen e-miRNAs predicted IMM failure with 90% sensitivity and 100% specificity. Ingenuity pathway analysis (IPA) determined 10 of the 13 e-miRNAs were significantly associated with angiogenesis-related biological functions (p < 0.025) and angiogenic factors that have been associated with recurrent ischemic events in ICAD. These e-miRNAs included miR-122-5p, miR-192-5p, miR-27b-3p, miR-16-5p, miR-486-5p, miR-30c-5p, miR-10b-5p, miR-10a-5p, miR-101-3p, and miR-24-3p. As predicted by IPA, the specific expression profiles of these 10 e-miRNAs in non-responders had a net result of inhibition of the angiogenesis-related functions and up expression of the antiangiogenic factors. This study revealed distinct expression profiles of circulating e-miRNAs in refractory ICAD, suggesting an antiangiogenic mechanism underlying IMM failure.
OutCyte: a novel tool for predicting unconventional protein secretion
Authors: Zhao Linlin , Poschmann Gereon , Waldera-Lupa Daniel , Rafiee Nima , Kollmann Markus , Stühler Kai
Published: December 2019

The prediction of protein localization, such as in the extracellular space, from high-throughput data is essential for functional downstream inference. It is well accepted that some secreted proteins go through the classic endoplasmic reticulum-Golgi pathway with the guidance of a signal peptide. However, a large number of proteins have been found to reach the extracellular space by following unconventional secretory pathways. There remains a demand for reliable prediction of unconventional protein secretion (UPS). Here, we present OutCyte, a fast and accurate tool for the prediction of UPS, which for the first time has been built upon experimentally determined UPS proteins. OutCyte mediates the prediction of protein secretion in two steps: first, proteins with N-terminal signals are accurately filtered out; second, proteins without N-terminal signals are classified as UPS or intracellular proteins based on physicochemical features directly generated from their amino acid sequences. We are convinced that OutCyte will play a relevant role in the annotation of experimental data and will therefore contribute to further characterization of the extracellular nature of proteins by considering the commonly neglected UPS proteins.

OutCyte has been implemented as a web server atwww.outcyte.com.
Hand, foot and lip representations in primary sensorimotor cortex: a high-density electroencephalography study
Authors: Zhao Mingqi , Marino Marco , Samogin Jessica , Swinnen Stephan P. , Mantini Dante
Published: December 2019

The primary sensorimotor cortex plays a major role in the execution of movements of the contralateral side of the body. The topographic representation of different body parts within this brain region is commonly investigated through functional magnetic resonance imaging (fMRI). However, fMRI does not provide direct information about neuronal activity. In this study, we used high-density electroencephalography (hdEEG) to map the representations of hand, foot, and lip movements in the primary sensorimotor cortex, and to study their neural signatures. Specifically, we assessed the event-related desynchronization (ERD) in the cortical space. We found that the performance of hand, foot, and lip movements elicited an ERD in beta and gamma frequency bands. The primary regions showing significant beta- and gamma-band ERD for hand and foot movements, respectively, were consistent with previously reported using fMRI. We observed relatively weaker ERD for lip movements, which may be explained by the fact that less fine movement control was required. Overall, our study demonstrated that ERD based on hdEEG data can support the study of motor-related neural processes, with relatively high spatial resolution. An interesting avenue may be the use of hdEEG for deeper investigations into the pathophysiology of neuromotor disorders.
Novel multimodal MRI and MicroCT imaging approach to quantify angiogenesis and 3D vascular architecture of biomaterials
Authors: Woloszyk Anna , Wolint Petra , Becker Anton S. , Boss Andreas , Fath Weston , Tian Yinghua , Hoerstrup Simon P. , Buschmann Johanna , Emmert Maximilian Y.
Published: December 2019

Quantitative assessment of functional perfusion capacity and vessel architecture is critical when validating biomaterials for regenerative medicine purposes and requires high-tech analytical methods. Here, combining two clinically relevant imaging techniques, (magnetic resonance imaging; MRI and microcomputed tomography; MicroCT) and using the chorioallantoic membrane (CAM) assay, we present and validate a novel functional and morphological three-dimensional (3D) analysis strategy to study neovascularization in biomaterials relevant for bone regeneration. Using our new pump-assisted approach, the two scaffolds, Optimaix (laminar structure mimicking entities of the diaphysis) and DegraPol (highly porous resembling spongy bone), were shown to directly affect the architecture of the ingrowing neovasculature. Perfusion capacity (MRI) and total vessel volume (MicroCT) strongly correlated for both biomaterials, suggesting that our approach allows for a comprehensive evaluation of the vascularization pattern and efficiency of biomaterials. Being compliant with the 3R-principles (replacement, reduction and refinement), the well-established and easy-to-handle CAM model offers many advantages such as low costs, immune-incompetence and short experimental times with high-grade read-outs when compared to conventional animal models. Therefore, combined with our imaging-guided approach it represents a powerful tool to study angiogenesis in biomaterials.
UNI-EM: An Environment for Deep Neural Network-Based Automated Segmentation of Neuronal Electron Microscopic Images
Authors: Urakubo Hidetoshi , Bullmann Torsten , Kubota Yoshiyuki , Oba Shigeyuki , Ishii Shin
Published: December 2019

Recently, there has been rapid expansion in the field of micro-connectomics, which targets the three-dimensional (3D) reconstruction of neuronal networks from stacks of two-dimensional (2D) electron microscopy (EM) images. The spatial scale of the 3D reconstruction increases rapidly owing to deep convolutional neural networks (CNNs) that enable automated image segmentation. Several research teams have developed their own software pipelines for CNN-based segmentation. However, the complexity of such pipelines makes their use difficult even for computer experts and impossible for non-experts. In this study, we developed a new software program, called UNI-EM, for 2D and 3D CNN-based segmentation. UNI-EM is a software collection for CNN-based EM image segmentation, including ground truth generation, training, inference, postprocessing, proofreading, and visualization. UNI-EM incorporates a set of 2D CNNs, i.e., U-Net, ResNet, HighwayNet, and DenseNet. We further wrapped flood-filling networks (FFNs) as a representative 3D CNN-based neuron segmentation algorithm. The 2D- and 3D-CNNs are known to demonstrate state-of-the-art level segmentation performance. We then provided two example workflows: mitochondria segmentation using a 2D CNN and neuron segmentation using FFNs. By following these example workflows, users can benefit from CNN-based segmentation without possessing knowledge of Python programming or CNN frameworks.
Phytoseiid predatory mites can disperse entomopathogenic fungi to prey patches
Authors: Lin Gongyu , Guertin Claude , Di Paolo Sean-Anthony , Todorova Silvia , Brodeur Jacques
Published: December 2019

Recent studies have shown that predatory mites used as biocontrol agents can be loaded with entomopathogenic fungal conidia to increase infection rates in pest populations. Under laboratory conditions, we determined the capacity of two phytoseiid mites,Amblyseius swirskiiandNeoseiulus cucumeristo deliver the entomopathogenic fungusBeauveria bassianato their prey,Frankliniella occidentalis. Predatory mites were loaded with conidia and released on plants that had been previously infested with first instar prey clustered on a bean leaf. We examined each plant section to characterize the spatial distribution of each interacting organism. Our results showed thatA. swirskiidelivered high numbers of conidia to thrips infested leaves, thereby increasing the proportion of thrips that came into contact with the fungus. The effect was larger when thrips infestation occurred on young leaves than on old leaves.Neoseiulus cucumerisdelivered less conidia to the thrips infested leaves. These patterns result from differences in foraging activity between predatory mite species.Amblyseius swirskiistayed longer on plants, especially within thrips colonies, and had a stronger suppressing effect on thrips thanN. cucumeris. Our study suggests that loading certain predatory mite species with fungal conidia can increase their capacity to suppress thrips populations by combining predation and dispersing pathogens.
Performance of deep learning-based algorithm for detection of ileocolic intussusception on abdominal radiographs of young children
Authors: Kim Sungwon , Yoon Haesung , Lee Mi-Jung , Kim Myung-Joon , Han Kyunghwa , Yoon Ja Kyung , Kim Hyung Cheol , Shin Jaeseung , Shin Hyun Joo
Published: December 2019

The purpose of this study was to develop and test the performance of a deep learning-based algorithm to detect ileocolic intussusception using abdominal radiographs of young children. For the training set, children (≤5 years old) who underwent abdominal radiograph and ultrasonography (US) for suspicion of intussusception from March 2005 to December 2017 were retrospectively included and divided into control and intussusception groups according to the US results. A YOLOv3-based algorithm was developed to recognize the rectangular area of the right abdomen and to diagnose intussusception. For the validation set, children (≤5 years old) who underwent both radiograph and US from January to August 2018 with the suspicion of intussusception were included. Diagnostic performances of an algorithm and radiologists were compared. Total 681 children including 242 children in intussusception group were included in the training set and 75 children including 25 children in intussusception group were included in the validation set. The sensitivity of the algorithm was higher compared with that of the radiologists (0.76 vs. 0.46, p = 0.013), while specificity was not different between the algorithm and the radiologists (0.96 vs. 0.92, p = 0.32). Deep learning-based algorithm can aid screening of intussusception using abdominal radiography in young children.
AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice
Authors: Zhu Yongjun , Cui Hongwang , Lv Jie , Liang Haiqin , Zheng Yanping , Wang Shanzhi , Wang Min , Wang Huanan , Ye Feng
Published: December 2019

Abnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.
An improved method for studying mouse diaphragm function
Authors: Hakim Chady H. , Lessa Thais B. , Jenkins Gregory J. , Yang Nora N. , Ambrosio Carlos E. , Duan Dongsheng
Published: December 2019

Dysfunction in the contractile properties of the diaphragm muscle contributes to the morbidity and mortality in many neuromuscular and respiratory diseases. Methods that can accurately quantify diaphragm function in mouse models are essential for preclinical studies. Diaphragm function is usually measured using the diaphragm strip. Two methods have been used to attach the diaphragm strip to the force transducer. The suture method is easy to adopt but it cannot maintain the physiological orientation of the muscle fibers. Hence, results may not accurately reflect diaphragm contractility. The clamp method can better maintain diaphragm muscle fiber orientation but is used less often because detailed information on clamp fabrication and application has never been published. Importantly, a side-by-side comparison of the two methods is lacking. To address these questions, we engineered diaphragm clamps using mechanically highly durable material. Here, we present a detailed and ready-to-use protocol on the design and manufacture of diaphragm clamps. Also, we present a step by step protocol on how to mount the diaphragm strip to the clamp and then to the muscle force measurement system. We compared the diaphragm force from the same mouse with both suture and clamp methods. We found the clamp method yielded a significantly higher muscle force. Finally, we validated the utility of the clamp method in the mdx model of Duchenne muscular dystrophy. In summary, the clamp method described in this paper yields reliable and consistent diaphragm force data. This method will be useful to any laboratory interested in performing mouse diaphragm function assay.
The application of Box-Behnken-Design in the optimization of HPLC separation of fluoroquinolones
Authors: Czyrski Andrzej , Sznura Justyna
Published: December 2019

Box-Behnken Design is a useful tool for the optimization of the chromatographic analysis. The goal of this study was to select the most significant factors that influenced the following parameters of the chromatographic separation: retention time, relative retention time, symmetry of the peaks, tailing factor, a number of theoretical plates, Foley – Dorsey parameter, resolution factor, peak width at half height. The results underwent the ANOVA test to find the statistically significant variables and interactions between them. The level of significance was for p < 0.05. The polynomial equations described quantitatively the statistically significant parameters and the interactions between them. The statistical analysis indicated both the best conditions for the separation of the compounds and the variables that were most influential for peaks’ parameters. The four-factor analysis performed for LEVO and MOXI indicated that ACN, TEA and pH are the most significant factors that influence the separation. The analysis for the pair CIPRO and LEVO required six factors. The statistical analysis proved that the most significant factors are ACN, MeOH and TEA. In the separation of these two compounds on the HPLC column, the interaction ACN × MeOH was also significant.
RRAD expression in gastric and colorectal cancer with peritoneal carcinomatosis
Authors: Kim Hee Kyung , Lee Inkyoung , Kim Seung Tae , Lee Jeeyun , Kim Kyoung-Mee , Park Joon Oh , Kang Won Ki
Published: December 2019

The role of Ras-related associated with diabetes (RRAD) in gastric cancer (GC) or colorectal cancer (CRC) has not been investigated. We aimed to investigate the biological and clinical roles of RRAD in GC and CRC and to assess RRAD as a therapeutic target. A total of 31 cancer cell lines (17 GC cell lines, 14 CRC cell lines), 59 patient-derived cells (PDCs from 48 GC patients and 11 CRC patients), and 84 matched pairs of primary cancer tissue and non-tumor tissue were used to evaluate the role of RRAD in vitro and in vivo. RRAD expression was frequently increased in GC and CRC cell lines, and siRNA/shRNA-mediated RRAD inhibition induced significant decline of tumor cell proliferation both in vitro and in vivo. A synergistic effect of RRAD inhibition was generated by combined treatment with chemotherapy. Notably, RRAD expression was markedly increased in PDCs, and RRAD inhibition suppressed PDC proliferation. RRAD inhibition also resulted in reduced cell invasion, decreased expression of EMT markers, and decreased angiogenesis and levels of associated proteins including VEGF and ANGP2. Our study suggests that RRAD could be a novel therapeutic target for treatment of GC and CRC, especially in patients with peritoneal seeding.
Coupled Charge Transfer Dynamics and Photoluminescence Quenching in Monolayer MoS2 Decorated with WS2 Quantum Dots
Authors: Mawlong Larionette P. L. , Bora Abhilasha , Giri P. K.
Published: December 2019

Herein, we have investigated the tunability of the photoluminescence (PL) of the monolayer MoS2 (1L-MoS2) by decorating it with WS2 quantum dots (WS2 QD). The direct bandgap 1L-MoS2 and WS2 QDs are grown by chemical vapor deposition and liquid exfoliation methods, respectively. The room temperature PL spectrum of bare 1L-MoS2 is systematically quenched with its decoration with WS2 QDs at different concentrations. A decrease in the work function of 1L-MoS2 with the decoration of WS2 QDs was established from the Kelvin probe force microscopy analysis. A detailed quantitative analysis using the four-energy level model involving coupled charge transfer was employed to explain the redshift and the systematic decrease in the intensity of the PL peak in 1L-MoS2/WS2 QD heterostructure. The modulation of the PL in the heterostructure is attributed to the increase in the formation of negative trions through the charge transfer from WS2 QD to the 1L-MoS2 and thus making the 1L-MoS2 heavily n-type doped, with increase in the electron density by ~1.5 × 1013 cm−2. This study establishes the contribution of defects in the coupled charge transfer dynamics in 1L-MoS2, and it lays out a convenient strategy to manipulate the optical and electrical properties of 1L-MoS2 for various optoelectronic applications.
Efficiency of Iterative Metal Artifact Reduction Algorithm (iMAR) Applied to Brain Volume Perfusion CT in the Follow-up of Patients after Coiling or Clipping of Ruptured Brain Aneurysms
Authors: Hakim Arsany , Pastore-Wapp Manuela , Vulcu Sonja , Dobrocky Tomas , Z’Graggen Werner J. , Wagner Franca
Published: December 2019

Metal artifacts resulting from coiling or clipping of a brain aneurysm degrade image quality and reduce diagnostic usefulness of computed tomography perfusion CTP. Our aim was to assess the diagnostic value of the iterative metal artifact reduction algorithm (iMAR) in CTP studies after coiling or clipping of ruptured intracranial aneurysms. Fifty-eight CTP exams performed in 32 patients were analysed. iMAR was applied to the source images from the CT scanner. Perfusion maps were generated from datasets both with and without iMAR, and both datasets were compared qualitatively and quantitatively. Qualitative analysis included evaluation of intensity of artifacts, image quality, presence of new artifacts, and the reader’s confidence in their diagnosis as well as diagnostic impression. Quantitative analysis included evaluation of tissue attenuation curves, evaluation of region of interest (ROI)-based measurement of perfusion values at levels that do and do not contain metal, compared to previously published reference ranges of perfusion values. Our results showed that application of iMAR reduced artifacts and significantly improved image quality. New artifacts were observed adjacent to metallic implants, but did not limit the evaluation of other regions. After correction for artifact readers’ confidence in their diagnosis increased from 41.3% to 87.9%, and the diagnostic impression changed in 31% of the exams. No difference between tissue attenuation curves was found. For slices without metal, no difference was noted between values measured before and after iMAR, and the total number of ROIs in the reference range of perfusion values was unchanged. At the level of the metal implant, 89.85% of ROIs obtained before using iMAR showed calculation errors. After using iMAR, only 1.7% showed errors. Before iMAR 3.1% of values were in the reference range, whereas after iMAR this increased to 33.1%. In conclusion, our results show that iMAR is an excellent tool for reducing artifacts in CTP. It is therefore recommended for use in clinical practice, particularly when severe artifacts are present, or when hypoperfusion is suspected at the level of the coil or clip. After the application of iMAR, the perfusion values at the level of the metal can be better calculated, but may not lie within the reference range; therefore, quantitative analysis at the level of artifacts is not advisable.
Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo
Authors: Morera-Herreras Teresa , Gioanni Yves , Perez Sylvie , Vignoud Gaetan , Venance Laurent
Published: December 2019

Behavioural experience, such as environmental enrichment (EE), induces long-term effects on learning and memory. Learning can be assessed with the Hebbian paradigm, such as spike-timing-dependent plasticity (STDP), which relies on the timing of neuronal activity on either side of the synapse. Although EE is known to control neuronal excitability and consequently spike timing, whether EE shapes STDP remains unknown. Here, using in vivo long-duration intracellular recordings at the corticostriatal synapses we show that EE promotes asymmetric anti-Hebbian STDP, i.e. spike-timing-dependent-potentiation (tLTP) for post-pre pairings and spike-timing-dependent-depression (tLTD) for pre-post pairings, whereas animals grown in standard housing show mainly tLTD and a high failure rate of plasticity. Indeed, in adult rats grown in standard conditions, we observed unidirectional plasticity (mainly symmetric anti-Hebbian tLTD) within a large temporal window (~200 ms). However, rats grown for two months in EE displayed a bidirectional STDP (tLTP and tLTD depending on spike timing) in a more restricted temporal window (~100 ms) with low failure rate of plasticity. We also found that the effects of EE on STDP characteristics are influenced by the anaesthesia status: the deeper the anaesthesia, the higher the absence of plasticity. These findings establish a central role for EE and the anaesthetic regime in shaping in vivo, a synaptic Hebbian learning rule such as STDP.
Type 2 diabetes-associated single nucleotide polymorphism in Sorcs1 gene results in alternative processing of the Sorcs1 protein in INS1 β-cells
Authors: Yau Belinda , Blood Zachary , An Yousun , Su Zhiduan , Kebede Melkam A.
Published: December 2019

A threonine-to-Isoleucine (Thr52Ile) mutation within the pro-domain of the Sorcs1 gene was positionally cloned as the gene underlying a quantitative trait locus that affects fasting insulin levels in mice. In humans, genome-wide association studies and linkage studies have shown that SORCS1 is associated with diabetes and all of diabetes complications. We have recently shown that deletion of Sorcs1 in mice made obese with the leptinob mutation results in diabetes and an insulin granule stability defect. This present study investigates the functional consequence of the Sorcs1 Thr52Ile mutation in the rat INS1 β-cell line expressing either the wildtype or mutant Sorcs1 allele. We find that Sorcs1 Thr52Ile mutation is associated with increased basal insulin secretion, reduced glucose-stimulated insulin secretion and decreased insulin content in INS1 cells. Moreover, expression of Thr52Ile causes differential processing of the Sorcs1 protein resulting in the formation of an additional 90 kDa mutant form of the protein. The mutant form of the protein is localised to the ER, retains its pro-domain, and concurrently reduces expression of the functional mature 130 kDa Sorcs1 protein. These findings provide a mechanistic clue to why this specific allelic variation in Sorcs1 was associated with reduced insulin levels and type 2 diabetes.
Prediction of malignant glioma grades using contrast-enhanced T1-weighted and T2-weighted magnetic resonance images based on a radiomic analysis
Authors: Nakamoto Takahiro , Takahashi Wataru , Haga Akihiro , Takahashi Satoshi , Kiryu Shigeru , Nawa Kanabu , Ohta Takeshi , Ozaki Sho , Nozawa Yuki , Tanaka Shota , Mukasa Akitake , Nakagawa Keiichi
Published: December 2019

We conducted a feasibility study to predict malignant glioma grades via radiomic analysis using contrast-enhanced T1-weighted magnetic resonance images (CE-T1WIs) and T2-weighted magnetic resonance images (T2WIs). We proposed a framework and applied it to CE-T1WIs and T2WIs (with tumor region data) acquired preoperatively from 157 patients with malignant glioma (grade III: 55, grade IV: 102) as the primary dataset and 67 patients with malignant glioma (grade III: 22, grade IV: 45) as the validation dataset. Radiomic features such as size/shape, intensity, histogram, and texture features were extracted from the tumor regions on the CE-T1WIs and T2WIs. The Wilcoxon–Mann–Whitney (WMW) test and least absolute shrinkage and selection operator logistic regression (LASSO-LR) were employed to select the radiomic features. Various machine learning (ML) algorithms were used to construct prediction models for the malignant glioma grades using the selected radiomic features. Leave-one-out cross-validation (LOOCV) was implemented to evaluate the performance of the prediction models in the primary dataset. The selected radiomic features for all folds in the LOOCV of the primary dataset were used to perform an independent validation. As evaluation indices, accuracies, sensitivities, specificities, and values for the area under receiver operating characteristic curve (or simply the area under the curve (AUC)) for all prediction models were calculated. The mean AUC value for all prediction models constructed by the ML algorithms in the LOOCV of the primary dataset was 0.902 ± 0.024 (95% CI (confidence interval), 0.873–0.932). In the independent validation, the mean AUC value for all prediction models was 0.747 ± 0.034 (95% CI, 0.705–0.790). The results of this study suggest that the malignant glioma grades could be sufficiently and easily predicted by preparing the CE-T1WIs, T2WIs, and tumor delineations for each patient. Our proposed framework may be an effective tool for preoperatively grading malignant gliomas.
A Flow Induced Autoimmune Response and Accelerated Senescence of Red Blood Cells in Cardiovascular Devices
Authors: Buerck James P. , Burke Dustin K. , Schmidtke David W. , Snyder Trevor A. , Papavassiliou Dimitrios , O’Rear Edgar A.
Published: December 2019

Red blood cells (RBCs) passing through heart pumps, prosthetic heart valves and other cardiovascular devices undergo early senescence attributed to non-physiologic forces. We hypothesized that mechanical trauma accelerates aging by deformation of membrane proteins to cause binding of naturally occurring IgG. RBCs isolated from blood of healthy volunteers were exposed to high shear stress in a viscometer or microfluidics channel to mimic mechanical trauma and then incubated with autologous plasma. Increased binding of IgG was observed indicating forces caused conformational changes in a membrane protein exposing an epitope(s), probably the senescent cell antigen of band 3. The binding of immunoglobulin suggests it plays a role in the premature sequestration and phagocytosis of RBCs in the spleen. Measurement of IgG holds promise as a marker foreshadowing complications in cardiovascular patients and as a means to improve the design of medical devices in which RBCs are susceptible to sublethal trauma.
SHBG141–161 Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and β-Langerhans cell lines
Authors: De Toni Luca , Guidolin Diego , De Filippis Vincenzo , Peterle Daniele , Rocca Maria Santa , Di Nisio Andrea , De Rocco Ponce Maurizio , Foresta Carlo
Published: December 2019

GPRC6A is acknowledged as a major regulator of energy metabolism and male fertility through the action of undercarboxylated osteocalcin (ucOCN), representing a possible therapeutic target. We recently showed that the sex hormone-binding globulin (SHBG) binds to GPRC6A through the likely involvement of the 141–161 domain. To confirm this model, here we investigated the possible binding and agonist activity of SHBG(141–161) domain-peptide (SHBG141–161) on GPRC6A. The binding of SHBG141–161 to GPRC6A and downstream dissociation from Gαi(GDP) protein was computationally modelled. SHBG141–161 was obtained by solid-phase synthesis, characterized by circular dichroism (CD) and the receptor binding was assessed by displacement of ucOCN on HEK-293 cells transfected with GPRC6A gene. Agonist activity of SHBG141–161 was assessed on Leydig MA-10 and Langerhans β-TC6 cell lines through the GPRC6A-mediated release of testosterone (T) and insulin. SHBG141–161 was predicted to bind to GPRC6A and to reduce the affinity for Gαi(GDP) at computational level. Conformational properties and binding to GPRC6A of the synthetic SHBG141–161 were confirmed by CD and displacement experiments. SHBG141–161 stimulated cell secretion of T and insulin, with dose dependency from 10−13 to 10−11M for T release (respectively P = 0,041 10−13M; P = 0,032 10−12M; P = 0,008 10−11M vs basal) and for 10−12 to 10−10M for insulin (respectively P = 0,041 10−12M; P = 0,007 10−11M; P = 0,047 10−10M; P = 0,045 vs basal). Blockade with anti GPRC6A IgG abolished the response to SHBG141-161, suggesting agonist specificity. SHBG141–161 showed stimulating activity on GPRC6A, representing a template peptide with possible therapeutic use for metabolic and endocrine disorders.
The effect of exercise on intramyocellular acetylcarnitine (AcCtn) concentration in adult growth hormone deficiency (GHD)
Authors: Meienberg Fabian , Loher Hannah , Bucher Julie , Jenni Stefan , Krüsi Marion , Kreis Roland , Boesch Chris , Betz Matthias Johannes , Christ Emanuel
Published: December 2019

To cover increasing energy demands during exercise, tricarboxylic cycle (TCA) flux in skeletal muscle is markedly increased, resulting in the increased formation of intramyocellular acetylcarnitine (AcCtn). We hypothesized that reduced substrate availability within the exercising muscle, reflected by a diminished increase of intramyocellular AcCtn concentration during exercise, might be an underlying mechanism for the impaired exercise performance observed in adult patients with growth hormone deficiency (GHD). We aimed at assessing the effect of 2 hours of moderately intense exercise on intramyocellular AcCtn concentrations, measured by proton magnetic resonance spectroscopy (1H-MRS), in seven adults with GHD compared to seven matched control subjects (CS). Compared to baseline levels AcCtn concentrations significantly increased after 2 hours of exercise, and significantly decreased over the following 24 hours (ANOVA p for effect of time = 0.0023 for all study participants; p = 0.067 for GHD only, p = 0.045 for CS only). AcCtn concentrations at baseline, as well as changes in AcCtn concentrations over time were similar between GHD patients and CS (ANOVA p for group effect = 0.45). There was no interaction between group and time (p = 0.53). Our study suggests that during moderately intense exercise the availability of energy substrate within the exercising muscle is not significantly different in GHD patients compared to CS.
Electrophysiological correlates of the flexible allocation of visual working memory resources
Authors: Salahub Christine , Lockhart Holly A. , Dube Blaire , Al-Aidroos Naseem , Emrich Stephen M.
Published: December 2019

Visual working memory is a brief, capacity-limited store of visual information that is involved in a large number of cognitive functions. To guide one’s behavior effectively, one must efficiently allocate these limited memory resources across memory items. Previous research has suggested that items are either stored in memory or completely blocked from memory access. However, recent behavioral work proposes that memory resources can be flexibly split across items based on their level of task importance. Here, we investigated the electrophysiological correlates of flexible resource allocation by manipulating the distribution of resources amongst systematically lateralized memory items. We examined the contralateral delay activity (CDA), a waveform typically associated with the number of items held in memory. Across three experiments, we found that, in addition to memory load, the CDA flexibly tracks memory resource allocation. This allocation occurred as early as attentional selection, as indicated by the N2pc. Additionally, CDA amplitude was better-described when fit with a continuous model predicted by load and resources together than when fit with either alone. Our findings show that electrophysiological markers of attentional selection and memory maintenance not only track memory load, but also the proportion of memory resources those items receive.
Dystrophin and calcium current are decreased in cardiomyocytes expressing Cre enzyme driven by αMHC but not TNT promoter
Authors: Gillet Ludovic , Guichard Sabrina , Essers Maria C. , Rougier Jean-Sébastien , Abriel Hugues
Published: December 2019

The Cre/lox system is a potent technology to control gene expression in mouse tissues. However, cardiac-specific Cre recombinase expression alone can lead to cardiac alterations when no loxP sites are present, which is not well understood. Many loxP-like sites have been identified in the mouse genome that might be Cre sensitive. One of them is located in the Dmd gene encoding dystrophin, a protein important for the function and stabilization of voltage-gated calcium (Cav1.2) and sodium (Nav1.5) channels, respectively. Here, we investigate whether Cre affects dystrophin expression and function in hearts without loxP sites in the genome. In mice expressing Cre under the alpha-myosin heavy chain (MHC-Cre) or Troponin T (TNT-Cre) promoter, we investigated dystrophin expression, Nav1.5 expression, and Cav1.2 function. Compared to age-matched MHC-Cre− mice, dystrophin protein level was significantly decreased in hearts from MHC-Cre+ mice of more than 12-weeks-old. Quantitative RT-PCR revealed decreased mRNA levels of Dmd gene. Unexpectedly, calcium current (ICaL), but not Nav1.5 protein expression was altered in those mice. Surprisingly, in hearts from 12-week-old and older TNT-Cre+ mice, neither ICaL nor dystrophin and Nav1.5 protein content were altered compared to TNT-Cre−. Cre recombinase unpredictably affects cardiac phenotype, and Cre-expressing mouse models should be carefully investigated before experimental use.