bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of secondary ions related to plant tissue using least absolute shrinkage and selection operator
Authors: Ito Masaru , Kuga Yukari , Yamagishi Takayuki , Fujita Miya , Aoyagi Satoka
Published: April 2020

With regard to life sciences, it is important to understand biological functions such as metabolic reactions at the cellular level. Time-of-flight secondary ion mass spectrometry (TOF-SIMS) that can provide chemical mappings at 100 nm lateral resolutions is useful for obtaining three-dimensional maps of biological molecules in cells and tissues. TOF-SIMS spectra generally contain several hundred to several thousand secondary ion peaks that provide detailed chemical information. In order to manage such a large number of peaks, data analysis methods such as multivariate analysis techniques have been applied to TOF-SIMS data of complex samples. However, the interpretation of the data analysis results is sometimes still difficult, especially for biological samples. In this study, TOF-SIMS data of resin-embedded plant samples were analyzed using one of the sparse modeling methods, least absolute shrinkage and selection operator (LASSO), to directly select secondary ions related to biological structures such as cell walls and nuclei. The same sample was measured by optical microscopy and the same measurement area as TOF-SIMS was extracted in order to prepare a target image for LASSO. The same area of the TOF-SIMS and microscope data were fused to evaluate the influence of the image fusion on the TOF-SIMS spectrum information using principal component analysis. Specifically, the authors examined onion mycorrhizal root colonized with Gigaspora margarita (an arbuscular mycorrhizal fungus). The results showed that by employing this approach using LASSO, important secondary ions from biological samples were effectively selected and could be clearly distinguished from the embedding resin.
Sound from rotors in non-uniform flow
Authors: Carley Michael
Published: April 2020

An analysis is presented for the evaluation of the acoustic field of a rotating source in a non-uniform potential flow. Other than the restriction to low flow Mach numbers, the method is exact and general. The variation in radiation properties with source position is handled by representation as a Fourier series in source angle, giving rise to an asymmetrically varying acoustic field evaluated by summation of the series. The method is used to develop an exact solution for the model problem of a rotor operating near a cylinder in cross-flow and sample calculations demonstrate the accuracy of the technique when compared to full numerical evaluation. The calculations show changes of greater than one decibel in the acoustic field due to flow non-uniformity at a flow Mach number of 0.15, a typical speed for propeller aircraft at take-off.
Widespread receptor-driven modulation in peripheral olfactory coding
Authors: Xu Lu , Li Wenze , Voleti Venkatakaushik , Zou Dong-Jing , Hillman Elizabeth M. C. , Firestein Stuart
Published: April 2020

The perception of complex scents

It is generally assumed that olfactory receptors faithfully report information to the brain in the form of a linear, additive code. However, under realistic conditions, the olfactory system handles a far more complex input, usually mixtures of odors. Xu
et al.
found that when we smell scents, the nasal olfactory sensory neurons relay a more complex pattern of signals to the brain than previously thought. The responses of individual neurons within the peripheral olfactory epithelium were either amplified or attenuated by the presence of other odors, which could explain the common perception of one odor in a mixture dominating over others. This effect occurs within the peripheral sensory organ's receptors and not within the brain.

Science
, this issue p.
eaaz5390
A parapithecid stem anthropoid of African origin in the Paleogene of South America
Authors: Seiffert Erik R. , Tejedor Marcelo F. , Fleagle John G. , Novo Nelson M. , Cornejo Fanny M. , Bond Mariano , de Vries Dorien , Campbell Kenneth E.
Published: April 2020

A South American anthropoid

Although there are many primate lineages in the Old World, it is thought that the New World is home to just one group, the platyrrhine monkeys, which appear to have colonized the region during the Eocene. Seiffert
et al.
describe a new primate species on the basis of fossil molars found in the Peruvian Amazon that appears to belong to the Parapithecidae, a group of stem anthropoid primates best known from northern Africa (see the Perspective by Godinot). The fossils appear to be from a well-differentiated lineage, suggesting that this species had been evolving within South America for some time. It is likely that the ancestors of this new species arrived via a transatlantic rafting event when sea levels dropped at the Eocene–Oligocene transition ∼32 to 35 million years ago.

Science
, this issue p.
194
; see also p.
136
Congenital intradural melanoma surrounding the spinal cord of a nine‐day‐old Saanen goat
Authors: Sinnott Devinn M , Woolard Kevin D , Heller Meera , Affolter Verena K
Published: April 2020

A nine‐day‐old Saanen kid presented for progressive hind limb paresis since birth. Euthanasia was elected, and on postmortem examination a large, pigmented mass was present in the vertebral canal surrounding the lumbosacral and caudal thoracic spinal cord. Histopathology revealed a homogeneous population of round to spindle neoplastic cells containing finely granular pigment consistent with a melanoma. This diagnosis was further supported by a Fontana‐Masson stain and immunohistochemistry for PNL2, MelanA and SOX10. The tumour presumably arose from melanocytes or melanocytic precursors within the meninges of the lumbosacral spinal cord. No evidence of neoplasia was seen elsewhere in the body; therefore, the meningeal melanoma likely represents the primary tumour. Goats develop neoplasms less frequently than other species, and reports of congenital tumours in goats are rare.
Performance of RC Precast Continuous Beams Incorporating New Strategy for Design and Allocating Connections
Authors: Zhou Yingwu , He Wenlong , Hu Biao , Hu Zhiheng
Published: April 2020

The performance of joint connections has always been the key to precast assembly structures. This paper proposes a new type of joint connection that is made by means of pre-embedded steel plates and connected by bolts or welding without any wet work. Located outside the beam-column joint, the connection is arranged around the inflection point of the beam where the bending moment is small. Three precast beams of different cross-sections and a set of cast-in-place concrete contrast beams were prepared and loaded by the anti-symmetric static loading method. The results show that the joint connection changes the failure mode of the specimens, transfers the failure section from the weak point to the non-weak point, and improves the bearing capacity of the specimens. With the increase of the cross-section area of the embedded steel plate at the joint, the bearing capacity and the ductility of the specimens increase. The energy consumption capacity of the precast specimen is significantly higher than that of the ordinary cast-in-place concrete specimen. Since the joint has not been destroyed, the component can be replaced when other parts of the specimen are destroyed.
Continuous Measurement of Interactions with the Physical World with a Wrist-Worn Backscatter Reader
Authors: Kiaghadi Ali , Hu Pan , Gummeson Jeremy , Rostaminia Soha , Ganesan Deepak
Published: April 2020

Recent years have seen exciting developments in the use of RFID tags as sensors to enable a range of applications including home automation, health and wellness, and augmented reality. However, widespread use of RFIDs as sensors requires significant instrumentation to deploy tethered readers, which limits usability in mobile settings. Our solution is WearID, a low-power wrist-worn backscatter reader that bridges this gap and allows ubiquitous sensing of interaction with tagged objects. Our end-to-end design includes innovations in hardware architecture to reduce power consumption and deal with wrist attenuation and blockage, as well as signal processing architecture to reliably detect grasping, touching, and other hand-based interactions. We show via exhaustive characterization that WearID is roughly 6× more power efficient than state-of-art commercial readers, provides 3D coverage of 30 to 50 cm around the wrist despite body blockage, and can be used to reliably detect hand-based interactions. We also open source the design of WearID with the hope that this can enable a range of new and unexplored applications of wearables.
Deep Generative Modeling for Scene Synthesis via Hybrid Representations
Authors: Zhang Zaiwei , Yang Zhenpei , Ma Chongyang , Luo Linjie , Huth Alexander , Vouga Etienne , Huang Qixing
Published: April 2020

We present a deep generative scene modeling technique for indoor environments. Our goal is to train a generative model using a feed-forward neural network that maps a prior distribution (e.g., a normal distribution) to the distribution of primary objects in indoor scenes. We introduce a 3D object arrangement representation that models the locations and orientations of objects, based on their size and shape attributes. Moreover, our scene representation is applicable for 3D objects with different multiplicities (repetition counts), selected from a database. We show a principled way to train this model by combining discriminative losses for both a 3D object arrangement representation and a 2D image-based representation. We demonstrate the effectiveness of our scene representation and the network training method on benchmark datasets. We also show the applications of this generative model in scene interpolation and scene completion.
Review—Resistive-Type Hydrogen Sensors Based on Zinc Oxide Nanostructures
Authors: Ren Qiang , Cao Yan-Qiang , Arulraj Daniel , Liu Chang , Wu Di , Li Wei-Ming , Li Ai-Dong
Published: April 2020

Hydrogen gas (H2) is used as an alternative renewable and eco-friendly energy source to replace the fossil fuel. However due to its explosive risks in air, the H2 production, storage and transportation are greatly limited. Hence, H2 sensor with quick response, highly sensitive and selective detection is of importance. Recently, zinc oxide (ZnO) as n-type semiconductor has attracted much attention in the field of H2 detection because of its easy synthesis, chemical/thermal stability and extremely abundant nanostructures. The recent advances in resistive-type H2 gas sensors based on ZnO nanostructures are reviewed in this paper. According to zero-dimension, one-dimension, and two-dimension, the H2 sensing properties and related mechanism of various kinds of pristine ZnO nanostructures-based sensors, such as nanowires, nanotubes, and nanofibers are summarized and compared. Furthermore, this paper focuses on strategies to improve the performance of H2 sensors (sensitivity, response speed, operation temperature, and limit of detection) by the surface modification, metal doping, formation of composite, and post-treatment of ZnO nanomaterials. Especially, the selectivity of ZnO nanosturctures-based H2 sensors to H2 in the presence of interfering gases is highlighted and the related enhancement approaches are discussed. Finally, the outlook and challenges on the ZnO nanostructures-based H2 sensors are addressed as well.
A Polymer-Rich Quaternary Composite Solid Electrolyte for Lithium Batteries
Authors: Al-Salih Hilal , Huang Allan , Yim Chae-Ho , Freytag Annica I. , Goward Gillian R. , Baranova Elena , Abu-Lebdeh Yaser
Published: April 2020

All-solid-state batteries continue to grow as an alternative to replace the traditional liquid-based ones not only because they provide increased safety but also higher power and energy densities. However, current solid-state electrolytes are either ceramics that are brittle but highly conducting (e.g. Li0.33La0.55TiO3, LLTO) or polymer electrolytes that are poorly conducting but form flexible films with desired mechanical properties (e.g. Poly(ethylene oxide):Lithium bis(trifluoromethanesulfonyl)imide, PEO:LiTFSI). In this work, we have developed quaternary composite solid-state electrolytes (CSEs) to combine the benefits of the two types along with Succinonitrile (SN) as a solid plasticizer. CSEs with different compositions have been fully characterized over the whole compositional range. Guided by neural network simulation results it has been found that a polymer-rich CSE film gives the optimal ionic conductivity (>10−3 S cm−1 at 55 °C) and mechanical properties (Tensile strength of 16.1 MPa; Elongation-at-break of 2360%). Our solid-state coin-type cell which employs our in-house made cathode shows good cycling performance at C/20 and 55 °C maintaining specific discharge capacity at 143.2 mAh g−1 after 30 cycles. This new approach of formulating quaternary CSEs is proven to give the best combination of properties and should be universal and be applied to other CSEs with different chemistry.
Impact of the Microporous Layer on Gas Diffusion Layers with Patterned Wettability II: Operando Performance and Water Distribution Analysis by Neutron Imaging
Authors: Manzi-Orezzoli Victoria , Siegwart Muriel , Scheuble Dirk , Schmidt Thomas J. , Boillat Pierre
Published: April 2020

We present the operando performance of modified gas diffusion media (GDM) in polymer electrolyte fuel cells (PEFCs) complemented by neutron imaging and pulsed gas analysis, following our previous publication on synthesis and water distribution of modified GDMs. We tested different types of hydrophobic GDMs: a commercial GDM, a GDM with highly porous microporous layer (MPL) and other with crack-free MPL and contrasted them to modified GDM. The modified materials consists on gas diffusion layers (GDL) with patterns of hydrophilic and hydrophobic regions and with different crack-free MPLs. To enhance the GDL patterned wettability efficiency “weak spots” such as a patterned wettability MPL or micro-holes punched into the MPL aligned with the pattern of the GDL were incorporated into the samples and their performance was contrasted to a GDL with patterned wettability and hydrophobic MPL. The experiments show that the GDMs with crack-free MPLs (with or without patterned wettability GDLs) have a higher cell performance and lower mass transport losses than the other fully hydrophobic GDM. No significant performance difference could be established due to the incorporation of modifications to the GDM.
Yupingfeng Granule Improves Th2‐Biased Immune State in Microenvironment of Hepatocellular Carcinoma through TSLP‐DC‐OX40L Pathway
Authors: Yao Fei , Yuan Qin , Song Xiudao , Zhou Liang , Liang Guoqiang , Jiang Guorong , Zhang Lurong
Published: April 2020

The tumor immunological microenvironment in hepatocellular carcinoma (HCC) is the T‐helper (Th) 2 dominant inhibition state. Improving the immunosuppressive tumor microenvironment represents an important strategy for HCC treatment. TSLP‐OX40L pathway is a target to improve Th2 immunosuppression. Yupingfeng granule (YPF) is clinically used to effectively improve the immune status of HCC. In this study, YPF increased the percentage of mature dendritic cells (DCs) and decreased levels of TSLP, TSLPR, and OX40L in tumor and adjacent tissues of the orthotopic‐HCC mice model. This occurs together with the decreased levels of Th2 cytokines and increased levels of Th1 cytokines and Th1/Th2 ratio. In vitro experiment showed that YPF not only increased the percentage of mature DCs and stimulated IL‐12 secretion in DCs but also reduced the positive rate of OX40L expression, decreased the proportion of CD4+ IL‐13+ T cells, increased levels of Th1 cytokines, and decreased levels of Th2 cytokines from TSLP‐treated DCs. In summary, these findings demonstrated that YPF promoted the maturation of DCs, decreased OX40L in TSLP‐induced DCs, and improved the immunosuppressive state of Th2 in HCC microenvironment. Our results suggest that the mechanism underlying the improving effect of YPF on the immunosuppression is related to the DC‐mediated TSLP‐OX40L pathway.
Chinese Herbal Medicine Dingji Fumai Decoction for Ventricular Premature Contraction: A Real‐World Trial
Authors: Liang Bo , Zou Fei-Hu , Fu Ling , Liao Hui-Ling
Published: April 2020

Background. Chinese herbal medicine Dingji Fumai Decoction (DFD) is widely clinically used for ventricular premature contraction (VPC). This real‐word trial was designed to assess the safety and effectiveness of DFD for VPC. Methods. This was a double‐blinded, randomized placebo‐controlled trial. Patients with VPC were randomized (1 : 1) to treatment with DFD combined with metoprolol (DFD arm) or metoprolol combined with placebo (MET arm). A primary end point was a composite of clinical symptoms and signs determined by the traditionalChinese medicine syndrome score and the number of VPC determined by the Holter examination. Second outcomes were adverse events, medication compliance, and laboratory examination. Results. 144 patients were randomized to DFD arm (76 patients) or MET arm (68 patients), and 136 cases (71 in DFD arm and 65 in MET arm) finally completed this trial. After a 12‐week follow‐up, DFD arm significantly decreased traditional Chinese medicine syndrome score and the number of VPC compared with MET arm (P = 0.003 and 0.034, respectively). There was no adverse drug effect and patient medication compliance was good. Conclusions. Superiority with DFD arm for VPC was demonstrated over MET arm for both the safety and effectiveness end points.
Identification of Hub Genes Related to Carcinogenesis and Prognosis in Colorectal Cancer Based on Integrated Bioinformatics
Authors: Gong Benjiao , Kao Yanlei , Zhang Chenglin , Sun Fudong , Gong Zhaohua , Chen Jian
Published: April 2020

The high mortality of colorectal cancer (CRC) patients and the limitations of conventional tumor-node-metastasis (TNM) stage emphasized the necessity of exploring hub genes closely related to carcinogenesis and prognosis in CRC. The study is aimed at identifying hub genes associated with carcinogenesis and prognosis for CRC. We identified and validated 212 differentially expressed genes (DEGs) from six Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. We investigated functional enrichment analysis for DEGs. The protein-protein interaction (PPI) network was constructed, and hub modules and genes in CRC carcinogenesis were extracted. A prognostic signature was developed and validated based on Cox proportional hazards regression analysis. The DEGs mainly regulated biological processes covering response to stimulus, metabolic process, and affected molecular functions containing protein binding and catalytic activity. The DEGs played important roles in CRC-related pathways involving in preneoplastic lesions, carcinogenesis, metastasis, and poor prognosis. Hub genes closely related to CRC carcinogenesis were extracted including six genes in model 1 (CXCL1, CXCL3, CXCL8, CXCL11, NMU, and PPBP) and two genes and Metallothioneins (MTs) in model 2 (SLC26A3 and SLC30A10). Among them, CXCL8 was also related to prognosis. An eight-gene signature was proposed comprising AMH, WBSCR28, SFTA2, MYH2, POU4F1, SIX4, PGPEP1L, and PAX5. The study identified hub genes in CRC carcinogenesis and proposed an eight-gene signature with good reproducibility and robustness at the molecular level for CRC, which might provide directive significance for treatment selection and survival prediction.
Incidental Finding of Nocardia: A Case Series from a Tertiary Care Centre in Uttarakhand
Authors: Mohanty Aroop , Meena Suneeta , Kumar Subodh Pandey , Gupta Puneet Kumar , Kaistha Neelam , Gupta Pratima , Jha Mithilesh Kumar , Rekha Sasi
Published: April 2020

Nocardiosis is a rare bacterial infection that may lead to a severe disease. These infections are rare among normal population and are showing an increasing trend worldwide attributable to the increase in the immunosuppressed population. Most of these patients present with nonspecific clinical features such as fever, productive cough, and exertional dyspnoea as seen in our series of patients which makes it difficult to be diagnosed. Pulmonary nocardiosis is rarely clinically suspected and often diagnosed very late in the course of disease resulting in high mortality. A similar observation was made in one of our cases where the patient was being treated on the lines of pneumonia, and in the end she was diagnosed with pulmonary nocardiosis. In view of the limited literature available, we report here a case series of pulmonary nocardiosis in immunosuppressed patients diagnosed incidentally by fungal KOH mount. The most common conditions causing immunosuppression were type II DM, COPD, and pulmonary tuberculosis.
Shear Strength Prediction Model of FRP Bar-Reinforced Concrete Beams without Stirrups
Authors: Gao Danying , Zhang Changhui
Published: April 2020

The shear strength prediction model for fiber-reinforced polymer (FRP) bar-reinforced concrete beams without stirrups in ACI440.1R-2015 does not consider the “size effect” and the effect of shear span-to-depth ratio and predicts the zero-shear strength for concrete members without longitudinal reinforcement. A modified shear strength prediction model for FRP bar-reinforced concrete beams without stirrups was presented in this paper. The proposed model takes into account the effect of concrete strength, size of the beam, shear span-to-depth ratio, reinforcement ratio, and modulus of elasticity of the longitudinal reinforcement and the “size effect.” The superiority of the proposed model has been evaluated by comparing the calculated shear strength of FRP bar-reinforced concrete beams without stirrups by the proposed model with the experimental results and calculated values by the models in design codes, respectively. It confirmed that the shear strength of FRP bar-reinforced concrete beams without stirrups by the proposed model was in better agreement with the experimental results.
Chaotic Dynamics and Chaos Control of Hassell-Type Recruitment Population Model
Authors: Feng Guo
Published: April 2020

For certain parameters, the mapping of a Hassell-type recruitment population model has a chaotic attractor. The control parameter is disturbed slightly with time by the improvement OGY method. When the mapping point wanders to the neighborhood of the periodic point, the control parameter is perturbed. The chaotic motion is controlled on the stable periodic period-1 point and period-2 orbits, and the influence of different control parameter ranges on the control average time is analyzed. When the selected regulator poles are different, the number of iterations used to control chaotic motion on a stable periodic orbit is different. Numerical simulations are presented to illustrate our results with the theoretical analysis and show the effect of the control method.
Efficacy and Safety of Jueyin Granules for Patients with Mild‐to‐Moderate Psoriasis Vulgaris: Protocol for a Multicenter Randomized Placebo‐Controlled Trial
Authors: Li Su , Zhang Cang , Zhang Hong-Ya , Zhou Meng , Wang Si-Nong , Xu Rong , Zhou Dong-Mei , Ji Yun-Run , Lv Jing-Jing , Yin Qing-Feng , Wang Rui-Ping , Li Wei , Liu Yan-Ping , Wang Jian-Feng , Li Bin , Li Xin
Published: April 2020

Introduction. The etiology and pathogenesis of psoriasis are complex. Blood‐heat syndrome is the core pathogenesis of psoriasis. Based on theories of Chinese medicine (CM), heat‐clearing and blood‐cooling (HCBC) are the primary treatment. Very few studies have investigated the pharmacological mechanism of the CM HCBC method for treating psoriasis. This multicenter randomized controlled trial will focus on treating psoriasis blood‐heat syndrome with the HCBC method using Jueyin granules (JYKL). This will be an objective and standardized evaluation of the efficacy, safety, and reproducibility of the HCBC method to obtain objective evidence meeting international standards that aim to establish a clinical standard suitable for the popular application of CM for treating psoriasis. Methods and Analysis. A five‐center randomized double‐blind placebo‐controlled clinical design will be used in this study. At least 196 participants will be randomly assigned to receive either JYKL or placebo treatment approximately 30 minutes after meals in the morning and evening (one sachet per time, twice daily for 8 consecutive weeks). The study duration will be 17 weeks, including 1 week of screening, 8 weeks of intervention, and 8 weeks of follow‐up. The patients will be evaluated every 2 weeks, and the measures will be compared with baseline values. The primary outcome measure will be the psoriasis lesion area severity index. We will also observe the recurrence rate, body surface area, physician global assessment, dermatology life quality index, quality of life index, visual analogue scale score, CM symptom score, combined drug use, and adverse events. This trial is registered with NCT03961230.
Circulating Exosomal SOCS2‐AS1 Acts as a Novel Biomarker in Predicting the Diagnosis of Coronary Artery Disease
Authors: Liang Caihong , Zhang Lulu , Lian Xiaoqing , Zhu Tiantian , Zhang Yuqing , Gu Ning
Published: April 2020

Background and Aims. Critical roles of circulating exosomal long noncoding RNAs (lncRNAs) have been implicated in multiple diseases. However, little is known about their roles in coronary artery disease (CAD). The aim of the present study was to investigate the relationships between circulating exosomal lncRNAs and CAD and identify the aberrantly expressed disease‐related lncRNAs as biomarkers in diagnosing CAD. Methods. The aberrantly expressed lncRNAs in plasma exosomes from CAD patients and controls were identified by microarray analysis and verified by quantitative real‐time PCR (qRT‐PCR). Then, the correlation between the expression level of candidate biomarker and clinic features in CAD patients, mild coronary artery stenosis (mCAS) patients, and controls was analyzed. Finally, we used the receiver operating characteristic (ROC) curve to examine the diagnosis value of candidate biomarkers. Results. The downregulated SOCS2‐AS1 was determined by microarray analysis and verified by qRT‐PCR in plasma from CAD patients in contrast to controls. The SOCS2‐AS1 expression level in plasma exosomes was negatively correlated with PLT and Lpa. Moreover, CAD patients with elevated levels of plasma exosome‐encapsulated SOCS2‐AS1 were susceptible to multicoronary artery lesions. Additionally, the area under ROC (AUC) of SOCS2‐AS1 was 0.704 (95% CI = 0.607–0.801, P < 0.001) for diagnosis of CAD. Conclusions. Plasma exosome‐encapsulated SOCS2‐AS1 was an independent protective factor against CAD and could be potentially used as a novel biomarker for the diagnosis of CAD.
A Case of Cardiac Tamponade in a Patient with Metastatic Renal Cell Carcinoma on Pazopanib Treatment
Authors: Sarathy Vinu , Jayappa Sriniivas Belagutty , Waran Thianesh , Naik Radheshyam
Published: April 2020

Asymptomatic minimal pericardial effusion may be frequently found in patients with hypothyroidism. Cardiac tamponade secondary to hypothyroidism is rarely referenced in medical literature. Hypothyroidism as an adverse effect of pazopanib (tyrosine kinase inhibitor) treatment leading to cardiac tamponade is an even rarer occurrence. Here, we report an unusual case of a 71-year-old male, with a case of renal cell carcinoma on pazopanib treatment presenting with shortness of breath who was found to have hypothyroidism with a large pericardial effusion leading to cardiac tamponade. The patient did not have any prior reports of thyroid-stimulating hormone (TSH) or thyroid hormone levels at presentation. No such case of cardiac tamponade due to hypothyroidism as an adverse effect of pazopanib tablet treatment has been reported to our knowledge.
A Humanized Lym-1 CAR with Novel DAP10/DAP12 Signaling Domains Demonstrates Reduced Tonic Signaling and Increased Antitumor Activity in B-Cell Lymphoma Models
Authors: Zheng Long , Ren Luqing , Kouhi Aida , Khawli Leslie A. , Hu Peisheng , Kaslow Harvey R. , Epstein Alan L.
Published: April 2020

Purpose:

The murine Lym-1 mAb targets a discontinuous epitope (Lym-1 epitope) on several subtypes of HLA-DR, which is upregulated in a majority of human B-cell lymphomas and leukemias. Unlike CD19, the Lym-1 epitope does not downregulate upon crosslinking, which may provide an advantage as a target for CAR T-cell therapy. Lym-1 CAR T cells with a conventional 4-1BB and CD3ζ (BB3z) signaling domain exhibited impaired ex vivo expansion. This study aimed to identify the underlying mechanisms and develop strategies to overcome this effect.

Experimental Design:

A functional humanized Lym-1 antibody (huLym-1-B) was identified and its scFv form was used for CAR design. To overcome observed impaired expansion in vitro, a huLym-1-B CAR using DAP10 and DAP12 (DAP) signaling domains was evaluated for ex vivo expansion and in vivo function.

Results:

Impaired expansion in huLym-1-B-BB3z CAR T cells was shown to be due to ligand-dependent suboptimal CAR signaling caused by interaction of the CAR binding domain and the surface of human T cells. Using the novel DAP signaling domain construct, the effects of suboptimal CAR signaling were overcome to produce huLym-1-B CAR T cells with improved expansion ex vivo and function in vivo. In addition, the Lym-1 epitope does not significantly downregulate in response to huLym-1-B-DAP CAR T cells both ex vivo and in vivo.

Conclusions:

DAP intracellular domains can serve as signaling motifs for CAR, and this new construct enables nonimpaired production of huLym-1-B CAR T cells with potent in vivo antitumor efficacy.
Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer
Authors: Tsujikawa Takahiro , Crocenzi Todd , Durham Jennifer N. , Sugar Elizabeth A. , Wu Annie A. , Onners Beth , Nauroth Julie M. , Anders Robert A. , Fertig Elana J. , Laheru Daniel A. , Reiss Kim , Vonderheide Robert H. , Ko Andrew H. , Tempero Margaret A. , Fisher George A. , Considine Michael , Danilova Ludmila , Brockstedt Dirk G. , Coussens Lisa M. , Jaffee Elizabeth M. , Le Dung T.
Published: April 2020

Purpose:

Two studies in previously treated metastatic pancreatic cancer have been completed combining GVAX pancreas vaccine (GM-CSF–secreting allogeneic pancreatic tumor cells) with cyclophosphamide (Cy) and CRS-207 (live, attenuated Listeria monocytogenes–expressing mesothelin). In the current study, we compared Cy/GVAX followed by CRS-207 with (Arm A) or without nivolumab (Arm B).

Patients and Methods:

Patients with pancreatic adenocarcinoma who received one prior therapy for metastatic disease and RECIST measurable disease were randomized 1:1 to receive treatment on Arm A or Arm B. The primary objective was to compare overall survival (OS) between the arms. Additional objectives included assessment of progression-free survival, safety, tumor responses, CA19-9 responses, and immunologic correlates.

Results:

Ninety-three patients were treated (Arm A, 51; Arm B, 42). The median OS in Arms A and B were 5.9 [95% confidence interval (CI), 4.7–8.6] and 6.1 (95% CI, 3.5–7.0) months, respectively, with an HR of 0.86 (95% CI, 0.55–1.34). Objective responses were seen in 3 patients using immune-related response criteria (4%, 2/51, Arm A; 2%, 1/42, Arm B). The grade ≥3 related adverse event rate, whereas higher in Arm A (35.3% vs. 11.9%) was manageable. Changes in the microenvironment, including increase in CD8+ T cells and a decrease in CD68+ myeloid cells, were observed in long-term survivors in Arm A only.

Conclusions:

Although the study did not meet its primary endpoint of improvement in OS of Arm A over Arm B, the OS was comparable with standard therapy. Objective responses and immunologic changes in the tumor microenvironment were evident.
Surgical Indication for Advanced Gallbladder Cancer Considering the Optimal Preoperative Carbohydrate Antigen 19-9 Cutoff Value
Authors: Yamamoto Yusuke , Sugiura Teiichi , Okamura Yukiyasu , Ito Takaaki , Ashida Ryo , Ohgi Katsuhisa , Uesaka Katsuhiko
Published: April 2020

Background: Selecting patients who will benefit from resection among those with advanced gallbladder cancer (GBCa) having poor prognostic factors is difficult. Methods: One hundred twenty-one patients who underwent resection for stage II–IV GBCa and 19 unresected patients (unresectable group) were enrolled. The clinical impact of carbohydrate antigen 19-9 (CA19-9) and advanced surgical procedures for GBCa was evaluated. Results: The optimal CA19-9 cutoff value (based on the greatest difference in overall survival) was 250 U/mL. CA19-9 ≥250 U/mL was found to be an independent prognostic factor. Patients with CA19-9 <250 U/mL who developed jaundice (median survival time [MST], 49.1 months) or who required major hepatectomy (MST, 21.5 months) or pancreatoduodenectomy (PD; MST, 50.3 months) had a better prognosis than those with CA19-9 ≥250 U/mL who developed jaundice (MST, 16.1 months; p = 0.061) or who required major hepatectomy (MST, 9.2 months; p = 0.066) or PD (MST, 8.6 months; p = 0.025); their prognosis was comparable to that of the unresectable group (jaundice: p = 0.145, major hepatectomy: p = 0.292, PD: p = 0.756). Conclusions: Even if GBCa patients develop jaundice or require major hepatectomy, or combined PD, resection can be considered for those with CA19-9 <250 U/mL. However, surgical indication should be carefully determined in patients with CA19-9 ≥250 U/mL.
Transposable DNA Elements in Amazonian Fish: From Genome Enlargement to Genetic Adaptation to Stressful Environments
Authors: da Silva Francijara A. , Corrêa Guimarães Erika M. , Carvalho Natália D.M. , Ferreira Alex M.V. , Schneider Carlos H. , Carvalho-Zilse Gislene A. , Feldberg Eliana , Gross Maria C.
Published: April 2020

Transposable elements have driven genome evolution and plasticity in many ways across a range of organisms. Different types of biotic and abiotic stresses can stimulate the expression or transposition of these mobile elements. Here, we cytogenetically analyzed natural fish populations of the same species living under different environmental conditions to test the influence and organization of transposable elements in their genome. Differential behavior was observed for the markers Rex 1, Rex 3, and Rex 6 in the chromosomes of individuals of the same species but coming from different environments (polluted and unpolluted). An increase in the number of Rex transposable elements in the chromosomes and their influence on the genome of populations living in a polluted environment indicates that they must be under constant adaptive evolution.
Treatment With Treprostinil and Metformin Normalizes Hyperglycemia and Improves Cardiac Function in Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction
Authors: Wang Longfei , Halliday Gunner , Huot Joshua R. , Satoh Taijyu , Baust Jeffrey J. , Fisher Amanda , Cook Todd , Hu Jian , Avolio Theodore , Goncharov Dmitry A. , Bai Yang , Vanderpool Rebecca R. , Considine Robert V. , Bonetto Andrea , Tan Jiangning , Bachman Timothy N. , Sebastiani Andrea , McTiernan Charles F. , Mora Ana L. , Machado Roberto F. , Goncharova Elena A. , Gladwin Mark T. , Lai Yen-Chun
Published: April 2020

Objective:

Pulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF.

Approach and Results:

Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.

Conclusions:

Our data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.
Endothelial Scaffolding Protein ENH (Enigma Homolog Protein) Promotes PHLPP2 (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase 2)-Mediated Dephosphorylation of AKT1 and eNOS (Endothelial NO Synthase) Promoting Vascular Remodeling
Authors: Huang Jiaqi , Cai Changhong , Zheng Tianyu , Wu Xinyan , Wang Dongfei , Zhang Kaijie , Xu Bocheng , Yan Ruochen , Gong Hui , Zhang Jie , Shi Yueli , Xu Zhiyong , Zhang Xue , Zhang Xuemin , Shang Tao , Zhou Jianhong , Guo Xiaogang , Zeng Chunlai , Lai En Yin , Xiao Changchun , Chen Ju , Wan Shu , Liu Wen-Hsien , Ke Yuehai , Cheng Hongqiang
Published: April 2020

Objective:

A decrease in nitric oxide, leading to vascular smooth muscle cell proliferation, is a common pathological feature of vascular proliferative diseases. Nitric oxide synthesis by eNOS (endothelial nitric oxide synthase) is precisely regulated by protein kinases including AKT1. ENH (enigma homolog protein) is a scaffolding protein for multiple protein kinases, but whether it regulates eNOS activation and vascular remodeling remains unknown.

Approach and Results:

ENH was upregulated in injured mouse arteries and human atherosclerotic plaques and was associated with coronary artery disease. Neointima formation in carotid arteries, induced by ligation or wire injury, was greatly decreased in endothelium-specific ENH-knockout mice. Vascular ligation reduced AKT and eNOS phosphorylation and nitric oxide production in the endothelium of control but not ENH-knockout mice. ENH was found to interact with AKT1 and its phosphatase PHLPP2 (pleckstrin homology domain and leucine-rich repeat protein phosphatase 2). AKT and eNOS activation were prolonged in VEGF (vascular endothelial growth factor)-induced ENH- or PHLPP2-deficient endothelial cells. Inhibitors of either AKT or eNOS effectively restored ligation-induced neointima formation in ENH-knockout mice. Moreover, endothelium-specific PHLPP2-knockout mice displayed reduced ligation-induced neointima formation. Finally, PHLPP2 was increased in the endothelia of human atherosclerotic plaques and blood cells from patients with coronary artery disease.

Conclusions:

ENH forms a complex with AKT1 and its phosphatase PHLPP2 to negatively regulate AKT1 activation in the artery endothelium. AKT1 deactivation, a decrease in nitric oxide generation, and subsequent neointima formation induced by vascular injury are mediated by ENH and PHLPP2. ENH and PHLPP2 are thus new proatherosclerotic factors that could be therapeutically targeted.
Engineering Life: A Review of Synthetic Biology
Authors: Hanczyc Martin M.
Published: April 2020

Synthetic biology is a field of scientific research that applies engineering principles to living organisms and living systems. It is a field that is increasing in scope with respect to organisms engineered, practical outcomes, and systems integration. There is a commercial dimension as well, where living organisms are engineered as green technologies that could offer alternatives to industrial standards in the pharmaceutical and petroleum-based chemical industries. This review attempts to provide an introduction to this field as well as a consideration of important contributions that exemplify how synthetic biology may be commensurate or even disproportionate with the complexity of living systems. The engineerability of living systems remains a difficult task, yet advancements are reported at an ever-increasing pace.
Exchange Coupling and Its Applications in Magnetic Data Storage
Authors: Li Kebin , Wu Yihong , Guo Zaibing , Zheng Yuankai , Han Guchang , Qiu Jinjun , Luo Ping , An Lihua , Zhou Tiejun
Published: April 2020

The continuing scaling of magnetic recording is facing more and more scientific and technological challenges because both the read sensor and recording bit are approaching sub-50 nm regime with the ever increasing areal density in hard disk drives. One of the key and indispensable elements
for both high-sensitivity sensors and high-density media is the exchange bias between a ferromagnetic and an antiferromagnetic layer or the exchange coupling between two ferromagnets via a non-magnetic spacer. In the nanometer regime, the exchange coupling between ferromagnet and antiferromagnet
or two ferromagnets through a conductive spacer is governed by the intergrain exchange interaction which has its origin in electron spins. Interlayer exchange coupling in multilayer or trilayer essentially originates from the quantum confinement effect. In this paper, we first review the physical
origin and various theoretical models of the two types of exchange couplings, followed by a review of the applications of the exchange bias and interlayer exchange coupling in data storage with emphasis on the advanced read sensor and advanced media including perpendicular media and patterned
media.
Magnetic Random Access Memory (MRAM)
Authors: Zheng Yuankai , Wu Yihong , Li Kebin , Qiu Jinjun , Han Guchang , Guo Zaibing , Luo Ping , An Lihua , Liu Zhiyong , Wang Li , Tan Seng Ghee , Zong Baoyu , Liu Bo
Published: April 2020

The high density and high speed nonvolatile MTJ MRAMs are reviewed from perspective of the reading and writing operation. The reading operation of the MRAM with different sensing schemes and cell array structures is discussed, in particular the reference resistance generating schemes
which are introduced to maximize the cell efficiency and reading reliability. The high density, low cost cross-point cell layout structures are analyzed systematically. The writing operation modes ranging from the half-select, toggle mode, guided SAF direct writing, thermally assisted writing,
to the spin transfer switching are investigated both theoretically and experimentally. The thermal factor always plays an important role in determine not only the thermal stability but also the reading and writing reliability.
FePt Nanocluster Films for High-Density Magnetic Recording
Authors: Xu Y. F. , Yan M. L. , Sellmyer D. J.
Published: April 2020

High anisotropy L10 ordered FePt thin films are considered to have high potential for use as high areal density recording media, beyond 1 Tera bit/in2. In this paper, we review recent results on the synthesis and magnetic properties of L10 FePt nanocomposite
films. Several fabrication methods have been developed to produce high-anisotropy FePt films: epitaxial and non-epitaxial growth of (001)-oriented FePt:X (X = Au, Ag, Cu, C, etc.) composite films that might be used for perpendicular media; monodispersed FePt nanocluster-assembled films grown
with a gas-aggregation technique and having uniform cluster size and narrow size distribution; self-assembled FePt particles prepared with chemical synthesis by reduction/decomposition techniques, etc. The magnetic properties are controllable through variations in the nanocluster properties
and nanostructure. FePt and related films show promise for development as heat-assisted magnetic recording media at extremely high areal densities. The self-assembled FePt arrays show potential for approaching the ultimate goal of single-grain-per-bit patterned media.
Cracking the EMDR code: Recruitment of sensory, memory and emotional networks during bilateral alternating auditory stimulation
Authors: Rousseau Pierre-François , Boukezzi Sarah , Garcia René , Chaminade Thierry , Khalfa Stéphanie
Published: April 2020

Introduction:

The inability to extinguish a conditioned fear is thought to be at the core of post-traumatic stress disorder. Eye movement desensitization and reprocessing therapy has been efficacious for post-traumatic stress disorder, but the brain mechanisms underlying the effect are still unknown. The core effect of eye movement desensitization and reprocessing therapy seems to rely on the simultaneous association of bilateral alternating stimulation and the recall of the traumatic memory. To shed light on how eye movement desensitization and reprocessing therapy functions, we aimed to highlight the structures activated by bilateral alternating stimulation during fear extinction and its recall.

Methods:

We included 38 healthy participants in this study. Participants were examined twice in functional magnetic resonance imaging, over 2 consecutive days. On the first day, they performed two fear conditioning and extinction procedures, one with and one without the bilateral alternating stimulation during the fear extinction learning phase in a counter-balanced order across the participants. On the second day, participants completed the fear extinction recall procedure, in the same order as the previous day. Statistical significance of maps was set at p < 0.05 after correction for family-wise error at the cluster level.

Results:

The analysis revealed significant activation with versus without bilateral alternating stimulation at the early extinction in the bilateral auditory areas, the right precuneus, and the left medial frontal gyrus. The same pattern was found in the early recall on the second day. The connectivity analysis found a significant increase in connectivity during bilateral alternating stimulation versus without bilateral alternating stimulation in the early extinction and recall between the two superior temporal gyri, the precuneus, the middle frontal gyrus and a set of structures involved in multisensory integration, executive control, emotional processing, salience and memory.

Conclusion:

We show for the first time that in the eye movement desensitization and reprocessing therapy the bilateral alternating stimulation is not a simple sensory signal and can activate large emotional neural networks.