bluuebunny/crossref_metadata_2025 huggingface dataset:
Inside Back Cover: Multiphoton dynamic imaging of the effect of chronic hepatic diseases on hepatobiliary metabolism in vivo (J. Biophotonics 9/2018)
Authors: Lin Chih‐Ju , Lee Sheng‐Lin , Wang Wei‐Hsiang , Hovhannisyan Vladimir A. , Huang Yao‐De , Lee Hsuan‐Shu , Dong Chen‐Yuan
Published: September 2018

In vivo multiphoton imaging was used to map changes in hepatobiliary metabolism in liver fibrosis (left column) and hepatocellular carcinoma (right column). The top row shows the maps of kinetic rate constant of the uptake and esterase processing while the bottom row shows that of bile canalicular excretion of xenobiotics.

Further details can be found in the article by Chih‐Ju Lin, Sheng‐Lin Lee, Wei‐Hsiang Wang, et al. (e201700338).

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Back Cover: Joint tagging assisted fluctuation nanoscopy enables fast high‐density super‐resolution imaging (J. Biophotonics 9/2018)
Authors: Zeng Zhiping , Ma Jing , Xi Peng , Xu Canhua
Published: September 2018

Based on multicolor quantum dots (QDs) labeling, the joint tagging assisted super‐resolution radial fluctuation (JT‐SRRF) nanoscopy achieves high‐fidelity super‐resolution imaging of subcellular microtubules and fast live‐cell parallel tracking of cholera toxin subunit B (CTB) induced lipid clusters spatially distributed below the optical diffraction limit. This method paves the way for fast high‐density parallel tracking, which is especially beneficial for the investigation of the intensive dynamics in live‐cell applications.

Further details can be found in the article by Zhiping Zeng, Jing Ma, Peng Xi, and Canhua Xu (e201800020).

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Molecular inhibitory mechanism study on the potent inhibitor brigatinib against four crizotinib‐resistant ALK mutations
Authors: Tu Jing , Song Li Ting , Liu Rui Rui , Zhai Hong Lin , Wang Juan , Zhang Xiao Yun
Published: September 2018

As a potent and selective drug, brigatinib exhibits high efficacy against wild‐type and mutant anaplastic lymphoma kinase (ALK) proteins to treat non–small cell lung cancer. In this work, the mechanisms of brigatinib binding to wild type and four mutant ALKs were investigated to gain insight into the dynamic energetic and structural information with respect to the design of novel inhibitors. Comparison between ALK‐brigatinib and ALK‐crizotinib suggests that the scaffold of brigatinib is well anchored to the residue Met1199 of hinge region by two hydrogen bonds, and the residue Lys1150 has the strong electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. These ALK mutations have significant influences on the flexibility of P‐loop region and DFG sequences, but do not impair the hydrogen bonds between brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and Asp1203. Together, the detailed explanation of mechanisms of those mutations with brigatinib further provide several guidelines for the development of more effective ALK inhibitors.
Mesenchymal stem cell and bone marrow mononuclear cell therapy for cardiomyopathy: From bench to bedside
Authors: Dolati Sanam , Yousefi Mehdi , Mahdipour Mahdi , Afrasiabi Rad Abbas , Pishgahi Alireza , Nouri Mohammad , Jodati Ahmad Reza
Published: September 2018

To date, stem cell–based therapies for cardiac diseases have not achieved any significant clinical accomplishment. Globally, numerous patients are currently treated with autologous stem cells. The safety and practicality of this technique have been well‐examined, its disadvantages have been recognized, and many trials have been proposed. Inadequate description of the implemented cell types, a variety of cell‐handling proficiencies, and concerning factors related to autologous stem cells have been known as the central elements restricting the approval of cell‐based therapies. The idea that bone marrow (BM)‐derived cells could be applied to regenerate and cure damage in various organs is the basis for bone marrow mononuclear cell (BMMNC) therapy for heart disease. Mesenchymal stem cells (MSCs) are a part of the BMMNCs; on one hand, they have the capability to differentiate into various tissues, and, on the other, their immunomodulatory effects have been considered and clinically confirmed in different experiments. In this review, we summarize the knowledge obtained by trials in which mesenchymal cell–based therapy has been practiced. Furthermore, we accentuate the developments in the purification and lineage specification of MSCs as well as BMMNCs that have influenced the progress of future stem cell–based therapies with special attention on cardiovascular disease.
Retracted: MicroRNA‐590‐5p functions as a tumor suppressor in breast cancer conferring inhibitory effects on cell migration, invasion, and epithelial–mesenchymal transition by downregulating the Wnt–β‐catenin signaling pathway
Authors: Gao Jin , Yu Shao‐Rong , Yuan Yuan , Zhang Li‐Li , Lu Jian‐Wei , Feng Ji‐Feng , Hu Sai‐Nan
Published: September 2018

Breast cancer remains one of the foremost primary causes of female morbidity and mortality worldwide. During the current study, the effect of miR‐590‐5p and paired‐like homeodomain transcription factor 2 (PITX2) on proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) of human breast cancer via the Wnt–β‐catenin signaling pathway was investigated. Breast cancer–related genes and related signaling pathways were obtained from KEGG database. The PITX2 regulatory microRNA was predicted. To define the contributory role by which miR‐590‐5p influences the progression of breast cancer, the interaction between miR‐590‐5p and PITX2 was explored; the proliferation, invasion, and migration abilities as well as the tumor growth and metastasis in nude mice were detected following the overexpression or silencing of miR‐590‐5p. PITX2 was determined to share a correlation with breast cancer and miR‐590‐5p was selected for further analysis. PITX2, Wnt‐1, β‐catenin, N‐cadherin, and vimentin all displayed higher levels, while miR‐590‐5p and E‐cadherin expression were lower among breast cancer tissues than in the adjacent normal tissue. After overexpression of miR‐590‐5p or si‐PITX2, the expression of E‐cadherin was markedly increased, decreases in the expression of Wnt‐1, β‐catenin, N‐cadherin, and vimentin, as well as inhibited cell proliferation, invasion, migration, metastasis, and EMT were observed. This study provides evidence suggesting that the transfection of overexpressed miR‐590‐5p can act to alleviate the effects of breast cancer demonstrating an ability to inhibit the processes of cell proliferation, migration, and invasion as well as EMT by suppressing the expression of PITX2 and activation of the Wnt–β‐catenin pathway.
PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma cell line CNE‐2 by inducing endoplasmic reticulum stress, downregulating STAT3 signaling, and modulating the MAPK pathway
Authors: Tan Gui‐Xiang , Wang Xin‐Ning , Tang Yun‐Yun , Cen Wan‐Jing , Li Zhen‐Hua , Wang Guo‐Cai , Jiang Jian‐Wei , Wang Xi‐Cheng
Published: September 2018

Paris polyphylla var. yunnanensis, named Chong Lou, is considered an antitumor substance. In this study, we investigated the effect of
PP‐22, a monomer purified from
P. polyphylla var. yunnanensis, on the nasopharyngeal carcinoma cell line CNE‐2 in vitro. The results showed that
PP‐22 could inhibit the proliferation of CNE‐2 cells via the induction of apoptosis, with evidence of the characteristic morphological changes in the apoptosis in the nucleus and an increase in Annexin V‐positive cells. In addition, we found that
PP‐22 could activate the p38 mitogen‐activated protein kinase (MAPK) pathway and that this activation was reversed by SB203580, a specific inhibitor of the p38 MAPK pathway. In contrast,
PP‐22 promoted apoptosis via an intrinsic pathway, including the endoplasmic reticulum stress pathway, in a caspase‐dependent manner. A further study showed that
PP‐22 also induced apoptosis by downregulating the signal transducers and activators of transcription 3 (STAT3) pathway, and the inhibitory effect was also confirmed by STAT3 small interfering RNA. In addition,
PP‐22 could promote autophagy by inhibiting the extracellular regulated protein kinases (ERK) pathway. And autophagy plays a protective role against apoptosis. Together, these data show that
PP‐22 promotes autophagy and apoptosis in the nasopharyngeal carcinoma CNE‐2 cell line.
Methylation of CLEC14A is associated with its expression and lung adenocarcinoma progression
Authors: Su Chongyu , Shi Kang , Cheng Xu , Han Yi , Li Yunsong , Yu Daping , Liu Zhidong
Published: September 2018

Our main objective is probing the effect of methylation of CLEC14A on its expression and lung adenocarcinoma (LUAD) progression. Microarray analysis was utilized to screen out differentially downregulated genes with hypermethylation in LUAD tissues. The
CLEC14A expression level was measured by western blot analysis and qRT‐PCR. Methylation‐specific‐PCR was performed to evaluate methylation status of
CLEC14A. The 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromid (MTT) assay was used to check the relation between
CLEC14A expression and cell proliferation. Cell cycle, cell apoptosis, migration, and invasion were respectively detected by the flow cytometry assay, wound healing assay, and transwell assay. Tumor xenograft models were established for investigating the effect of
CLEC14A on tumor formation.
CLEC14A expression in LUAD tissues was impaired compared with that in adjacent tissues, and
CLEC14A promoter was highly methylated in LUAD. Overexpressing
CLEC14A or inhibiting the methylation level of
CLEC14A in A549 and LTEP‐a‐2 cells impeded the duplication of LUAD cells, promoted apoptosis, attenuated cell migration, and invasion ability, and arrested cell cycle at the G0/G1 phase. Overexpression of
CLEC14A inhibited tumorigenesis of LUAD cells in nude mice. The promoter of
CLEC14A is methylated in LUAD, leading to downregulation of
CLEC14A in LUAD.
CLEC14A acts as an antitumor role in LUAD by suppressing cell proliferation, migration, invasion, promoting cell apoptosis, and reducing tumorigenicity in nude mice. Thus, the inhibition of CLEC14A methylation is a novel strategy for the clinic treatment of LUAD.
KRT1 gene silencing ameliorates myocardial ischemia–reperfusion injury via the activation of the Notch signaling pathway in mouse models
Authors: Fang Hong‐Cheng , Wu Bao‐Quan , Hao Yun‐Ling , Luo Ying , Zhao Hong‐Lei , Zhang Wen‐Ying , Zhang Zhi‐Ling , Liang Jin‐Jie , Liu Wei , Chen Xie‐Hui
Published: September 2018

Myocardial ischemia and reperfusion injury (MIRI) includes major drawbacks, such as excessive formation of free radicals and also overload of calcium, which lead to cell death, tissue scarring, and remodeling. The current study aims to explore whether KRT1 silencing may ameliorate MIRI via the Notch signaling pathway in mouse models. Myocardial tissues were used for the determination of the positive rate of KRT1 protein expression, apoptosis of myocardial cells, creatine kinase (CK) and lactate dehydrogenase (LDH) expression, expression of related biomarkers as well as myocardial infarction area. The transfected myocardial cells were treated with KRT1‐siRNA, Jagged1, and DAPT (inhibitor of Notch‐1 signaling pathway). The expression of KRT1, NICD, Hes1, Bcl‐2, and Bax protein was detected. The MTT assay was applied for cell proliferation and flow cytometry was used for cell apoptosis. Mice with MIRI had a higher positive rate of KRT1 protein expression, apoptosis of myocardial cells, CK and LDH expression, myocardial infarction area, increased expression of MDA, NO, SDH, IL‐1, IL‐6, TNF‐α, CRP, KRT1, Bax protein, CK, and LDH, and decreased expression of SOD, NICD, Hes1, and Bcl‐2. The downregulation of KRT1 led to decreased expression of KRT1 and Bax protein, increased expression of NICD, Hes1, and Bcl‐2, decreased cell apoptosis, and improved cell proliferation. The inhibition of the Notch signaling pathway leads to reduced expression of Bax, increased expression of NICD, Hes1, and Bcl 2, and also decreased cell apoptosis and increased cell proliferation. Our data conclude that KRT1 silencing is able to make MIRI better by activating the Notch signaling pathway in mice.
Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality?
Authors: Marofi Faroogh , Vahedi Ghasem , hasanzadeh Ali , Salarinasab Sadegh , Arzhanga Pishva , Khademi Bahareh , Farshdousti Hagh Majid
Published: September 2018

Recently a growing attention in scientific community has been gathered on potential application of mesenchymal stem cells (MSCs) in various fields of medicine. Owing to the fact that they can be easily isolated from different sources, and simply proliferated in large quantities while keeping their original biological characteristics, they can be successfully used as cell‐based therapeutics. Engineering MSCs and other type of stem cells to be carriers of therapeutic agents is a new tactic in the targeted gene and cell therapy of cancers and degenerative diseases. Various useful properties of MSCs including tropism toward tumor/injury site(s), weakly immunogenic, production of anti‐inflammatory molecules, and safety against normal tissues have made them prone for regenerative medicine, targeted therapy and treating injured tissues, and immunological abnormalities. In this review, we introduce latest advances, methods, and applications of MSCs in gene therapy of various malignant organ disorders. Additionally, we will cover the problems and challenges which researchers have faced with when trying to translate their basic experimental findings in MSCs research to clinically applicable therapeutics.
Cell shape alteration during adipogenesis is associated with coordinated matrix cues
Authors: Mor‐Yossef Moldovan Lisa , Lustig Maayan , Naftaly Alex , Mardamshina Mariya , Geiger Tamar , Gefen Amit , Benayahu Dafna
Published: September 2018

Obesity has become one of the leading pathophysiologic disorders in recent years. Adipose tissue is the main tissue related to obesity and is known to play a role in various physiological complications, including type 2 diabetes. To better understand how the fat tissue develops, we used an in vitro live cell imaging system to quantify the adipogenesis by means of nondestructive digital imaging to monitor the accumulation of intracellular lipid droplets (LDs), a hallmark of adipogenesis, from the macro‐ to the micro‐scale. Analyzing the cells’ shape at the single‐cell level allows to quantify the cells’ shape change from a fibroblast to spherical morphology, indicating the start of adipogenesis. To reveal the molecular alterations, we applied a proteomic approach using high‐resolution mass spectrometry of the proliferation, confluent fibroblasts and of adipocytes. During this process, we noted the reorganization of the cells’ extracellular matrix (ECM) network microenvironment from fibrillary collagen types I, III and V to collagens IV and VI, which affected the cells niche. The changes in ECM are translated for cytoskeleton remodeling according to cell fate‐determining mechanisms. We quantified the cytoskeleton rearrangement of long oriented actin fibers or short cortical and disorganized fibers, associated with LDs accumulation in adipocytes. Developing in vitro models and analytical methods enable us to study differentiation into adipocytes that will advance our understanding regarding the niche conditions that affect adipogenesis. Consequently, this will enable the development of new modalities to prevent obesity and its deleterious outcomes and to develop potential treatments to battle pathophysiology‐related diseases.
Clinicopathological and prognostic value of lncRNA PANDAR expression in solid tumors: Evidence from a systematic review and meta‐analysis
Authors: Mehrad‐Majd Hassan , Akhtari Javad , Haerian Monir‐Sadat , Ravanshad Yalda
Published: September 2018

PANDAR (promoter of CDKN1A antisense DNA damage activated RNA) has been shown to be aberrantly expressed in many types of cancer. Considering conflicting data, the current study was aimed to assess its potential role as a prognostic marker in malignant tumors. A comprehensive literature search of PubMed, Medline, and Web of Science was performed to identify all eligible studies describing the use of PANDAR as a prognostic factor for different types of cancer. Data related to overall survival (OS) and clinicopathologic features were collected and analyzed. The pooled hazard ratio (HR) and odds radio (OR) with a 95% confidence interval (CI) were used to estimate associations. Ten original studies containing 1,231 patients were included. The results showed that in patients with cancer, high PANDAR expression is correlated with lymph node metastasis (LNM; OR = 2.57; 95% CI, 1.76–3.81; p < 0.001), tumor stage (OR = 2.90; 95% CI, 1.25–6.75; p = 0.013), and tumor size (OR = 1.79; 95% CI, 1.11–2.91; p = 0.018). However, sensitivity analysis further demonstrated a significant association between high PANDAR expression and OS, both in multivariate and univariate analysis models (pooled HR 2.01; 95% CI, 1.17–3.44 and pooled HR 2.62; 95% CI, 1.98–3.47, respectively), after omitting one study. These results suggested that PANDAR expression might be indicative of advanced disease and poor prognosis in patients with cancer. Further studies are necessary to determine the value of this risk stratification biomarker in clinical management of patients with cancer.
The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases
Authors: Ranjbar Reza , Shafiee Mojtaba , Hesari AmirReza , Ferns Gordon A. , Ghasemi Faezeh , Avan Amir
Published: September 2018

Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti‐inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin–angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT1) receptor, and direct renin inhibitors, angiotensin‐converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti‐inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.
Comparative study of interruption of signaling pathways in lung epithelial cell by two different Mycobacterium tuberculosis lineages
Authors: Hadifar Shima , Behrouzi Ava , Fateh Abolfazl , Khatami Shohreh , Rahimi Jamnani Fatemeh , Siadat Seyed Davar , Vaziri Farzam
Published: September 2018

Alveolar epithelial cell (AEC) provides a replication niche for Mycobacterium tuberculosis. Based on the role of AEC in
M. tuberculosis pathogenesis and existence of genetic diversity within this bacterium, we investigated interactions between AEC II and two different
M. tuberculosis lineages. We have compared the transcriptome and cytokines/chemokines levels of A549 infected by
M. tuberculosis lineage three and four using qRT‐PCR and ELISA arrays, respectively. We showed different
M. 
tuberculosis strains induced changes in different effectors that involved in TLRs and NF‐κB signaling pathways. We observed different reaction of the studied lineages specifically in pathogenesis, immune evasion mechanism, IL‐12/IFN‐γ axis, and autophagy. Similar behavior was detected in regarding to apoptosis, necroptosis, anti‐inflammatory responses, and canonical inflammasome. Our findings contribute to elucidate more details in pathogenesis, immune evasion strategies, novel target and druggable pathway for therapeutic intervention, and host directed therapy in tuberculosis infection. Also, different
M. 
tuberculosis lineages‐dependent host–pathogen interactions suggested using only one strain for this kind of research will be controversial.
Dose‐Finding Studies Among Orphan Drugs Approved in the EU: A Retrospective Analysis
Authors: Schuller Yvonne , Gispen‐de Wied Christine , Hollak Carla E. M. , Leufkens Hubertus G. M. , Stoyanova‐Beninska Violeta
Published: September 2018

In the development process for new drugs, dose‐finding studies are of major importance. Absence of these studies may lead to failed phase 3 trials and delayed marketing authorization. In our study we investigated to what extent dose‐finding studies are performed in the case of orphan drugs for metabolic and oncologic indications. We identified all orphan drugs that were authorized until August 1, 2017. European Public Assessment Reports were used to extract the final dose used in the summary of product characteristics, involvement of healthy volunteers, study type, end points used, number of patients, number of doses, studies in special populations, and dose used for phase 3 studies. Each drug was checked for major objections and dose changes postmarketing. We included 49 orphan drugs, of which 28 were indicated for metabolic disorders and 21 for oncologic indications. Dose‐finding studies were performed in 32 orphan drugs, and studies in healthy volunteers in 26. The absence of dose‐finding studies was mostly due to the rarity of the disease. In this case the dose was determined based on factors such as animal studies or clinical experience. Dose‐related major objections were raised for 9 orphan drugs. Postmarketing dose‐finding studies were conducted in 18 orphan drugs, but dose changes were applied in only 2 drugs. In conclusion, dose‐finding studies in the case of metabolic and oncologic orphan drugs were conducted in the development programs of two thirds of orphan drugs. Dose‐finding studies performed postmarketing suggest that registered doses are not always optimal. It is thus important to perform more robust dose‐finding studies both pre‐ and postmarketing.
Proposition of a Minimal Effective Dose of Vigabatrin for the Treatment of Infantile Spasms Using Pediatric and Adult Pharmacokinetic Data
Authors: Ounissi Marwa , Rodrigues Christelle , Bienayme Hugues , Duhamel Paul , Pons Gérard , Dulac Olivier , Nabbout Rima , Chiron Catherine , Jullien Vincent
Published: September 2018

Vigabatrin is an antiepileptic drug indicated as monotherapy in infantile spasms. However, the pharmacokinetic profile of this compound in infants and young children is still poorly understood, as is the minimal effective dose, critical information given the risk of exposure‐related retinal toxicity with vigabatrin. A reasonable approach to determining this minimal dose would be to identify the lowest dose providing a low risk of exposure overlap with the 36‐mg/kg dose, which is the highest dose associated with an increased risk for treatment failure, based on randomized dose‐ranging data. A population pharmacokinetic model was consequently developed from 28 children (aged 0.4‐5.7 years) for the active S(+)‐enantiomer, using Monolix software. In parallel, a population model was developed from published adult data and scaled to children using theoretical allometry and maturation of the renal function. A one‐compartment model with zero‐order absorption and first‐order elimination described the pediatric data. Mean population estimates (percentage interindividual variability) for the apparent clearance, apparent distribution volume, and absorption duration were 2.36 L/h (24.5%), 17 L (38%), and 0.682 hours, respectively. Apparent clearance and apparent distribution volume were related to body weight by empirical allometric equations. Monte Carlo simulations evidenced that a daily dose of 80 mg/kg should minimize exposure overlap with the 36‐mg/kg dose. Similar results were obtained for the adult model scaled to children. Consequently, a minimal effective dose of 80 mg/kg/day could be considered for patients with infantile spasms.
Oral immunization with recombinant Lactococcus lactis NZ9000 expressing human papillomavirus type 16 E7 antigen and evaluation of its immune effects in female C57BL/6 mice
Authors: Mohseni Amir Hossein , Razavilar Vadood , Keyvani Hossein , Razavi Mohammad Reza , Khavari‐Nejad Ramazan Ali
Published: September 2018

The ORFs of both native and codon‐optimized E7 genes were successfully fused to SPusp45 signal peptide and expressed by a nisin‐controlled gene expression system in the NZ9000 strains of Lactococcus lactis. Recombinant strains were confirmed by Western blot analysis. To measure immune responses against the E7 antigen, specific‐pathogen‐free C57BL/6 mice were inoculated with L lactis harboring pNZ8123‐rE7 by oral gavage. Then, specific antibodies and cytokines were measured by enzyme‐linked immunosorbent assay and enzyme‐linked immunospot assay, respectively. Oral administration of L lactis strains expressing rE7 elicited the highest levels of E7‐specific antibody and greatest numbers of E7‐specific CD4+ T helper and CD8+ T cell precursors. Our outcomes indicated that the HPV‐16 E7 specific IL‐2‐ and IFN‐γ‐secreting T cells in antigen‐stimulated splenocytes and intestinal mucosal lymphocytes were significantly higher than the control groups. Our data also demonstrated that mice vaccinated with recombinant L lactis were able to generate potent protective effects against challenge with the E7‐expressing tumor cell line (TC‐1). Moreover, L lactis containing pNZ8123‐HPV16‐optiE7 showed strong therapeutic antitumor effects against established tumors in vivo. These findings demonstrate that recombinant L lactis induce both humoral and cellular immune responses in mice and are therefore recommended for therapeutic treatments in humans after oral administration.
Spatial and temporal changes in the frequency and magnitude of intense precipitation events in the southeastern United States
Authors: Skeeter Walker J. , Senkbeil Jason C. , Keellings David J.
Published: September 2018

Intense precipitation events (IPE; 99th percentile) in the southeastern United States from 1950 to 2016 were analysed temporally, spatially, and synoptically. The study area was partitioned into latitudinal and physiographic regions to identify subregions that experienced significant changes in IPE frequency or intensity. Furthermore, the spatial synoptic classification (SSC) was used to ascertain what surface weather types are associated with IPEs. Additionally, in conjunction with the SSC, surface forcing mechanisms for the 30 most extreme subregional IPEs were studied to uncover the surface synoptic conditions responsible for IPEs. Results revealed that IPEs increased in frequency and intensity on an annual basis for the southeastern United States. Seasonal results indicated that IPE frequency only increased in the fall. Subregional results reveal that latitudinally, IPEs became more common in the northern latitudes of the study area, while physiographically, significant increases in IPE frequency were most pronounced in areas inland from the Atlantic Coastal Plain. An increase in the annual number of IPEs associated with moist tropical (MT) days was identified across the study area, but was more prevalent in the central and north central latitudinal regions, and areas inland from the Atlantic Coastal Plain outside of the Appalachian Mountains. This MT increase was possibly caused by more common northwards and inland intrusion of these types of IPEs. While moist moderate (MM) and transitional (TR) days were most commonly associated with IPEs, these weather types did not have significant trends. The surface forcing mechanisms most commonly associated with the strongest IPEs were tropical events, followed by stationary fronts and concentric low‐pressure systems.
Mode‐Locking of All‐Fiber Lasers Operating at Both Anomalous and Normal Dispersion Regimes in the C‐ and L‐Bands Using Thin Film of 2D Perovskite Crystallites
Authors: Hong Seongjin , Lédée Ferdinand , Park Jaedeok , Song Sanggwon , Lee Hyeonwoo , Lee Yong Soo , Kim Byungjoo , Yeom Dong‐Il , Deleporte Emmanuelle , Oh Kyunghwan
Published: September 2018

Two‐dimensional hybrid organic–inorganic perovskites have recently attracted attention in various optoelectronic applications. A novel thin film of 2D perovskite (C6H5C2H4NH3)2PbI4 crystallites is synthesized and its nonlinear optical properties are experimentally investigated within the optical gain of an Erbium‐doped fiber. Utilizing its unique nonlinear optical response, efficient mode‐locking of an all‐fiber Erbium laser is demonstrated at the anomalous dispersion regime in both the C‐ and L‐bands stably generating femtosecond pulse trains, where the thin film of 2D perovskite crystallites function as an in‐line saturable absorber. At this anomalous dispersion regime, self‐started femtosecond pulses are generated whose center wavelength are tuned from 1565.9 nm in C‐band and 1604 nm in L‐band by adjusting the optical gain. Furthermore, by managing the chromatic dispersion of the total fiber laser cavity to reach the normal dispersion regime, a stable dissipative soliton is successfully generated in the C‐band with the spectral bandwidth of 15 nm and pulse duration of 3.2 ps. Detailed material properties of the thin film of 2D perovskite crystallites, their characterization, and fiber laser mode‐locking performance is reported.
A framework for performance characterization of energy‐resolving photon‐counting detectors
Authors: Persson Mats , Rajbhandary Paurakh L. , Pelc Norbert J.
Published: September 2018

Purpose

Photon‐counting, energy‐resolving detectors are subject to intense research interest, and there is a need for a general framework for performance assessment of these detectors. The commonly used linear‐systems theory framework, which measures detector performance in terms of noise‐equivalent quanta (NEQ) and detective quantum efficiency (DQE) is widely used for characterizing conventional x‐ray detectors but does not take energy‐resolving capabilities into account. The purpose of this work is to extend this framework to encompass energy‐resolving photon‐counting detectors and elucidate how the imperfect energy response and other imperfections in real‐world detectors affect imaging performance, both for feature detection and for material quantification tasks.

Method

We generalize NEQ and DQE to matrix‐valued quantities as functions of spatial frequency, and show how these matrices can be calculated from simple Monte Carlo simulations. To demonstrate how the new metrics can be interpreted, we compute them for simplified models of fluorescence and Compton scatter in a photon‐counting detector and for a Monte Carlo model of a CdTe detector with pixels.

Results

Our results show that the ideal‐linear‐observer performance for any detection or material quantification task can be calculated from the proposed generalized NEQ and DQE metrics. We also demonstrate that the proposed NEQ metric is closely related to a generalized version of the Cramér‐Rao lower bound commonly used for assessing material quantification performance. Off‐diagonal elements in the NEQ and DQE matrices are shown to be related to loss of energy information due to imperfect energy resolution. The Monte Carlo model of the CdTe detector predicts a zero‐frequency dose efficiency relative to an ideal detector of 0.86 and 0.65 for detecting water and bone, respectively. When the task instead is to quantify these materials, the corresponding values are 0.34 for water and 0.26 for bone.

Conclusions

We have developed a framework for assessing the performance of photon‐counting energy‐resolving detectors and shown that the matrix‐valued NEQ and DQE metrics contain sufficient information for calculating the dose efficiency for both detection and quantification tasks, the task having any spatial and energy dependence. This framework will be beneficial for the development and optimization of photon‐counting x‐ray detectors.
Theoretical and experimental analysis of photon counting detector CT for proton stopping power prediction
Authors: Taasti Vicki T. , Hansen David C. , Michalak Gregory J. , Deisher Amanda J. , Kruse Jon J. , Muren Ludvig P. , Petersen Jørgen B. B. , McCollough Cynthia H.
Published: September 2018

Purpose

Photon counting detectors (PCDs) are being introduced in advanced x‐ray computed tomography (CT) scanners. From a single PCD‐CT acquisition, multiple images can be reconstructed, each based on only a part of the original x‐ray spectrum. In this study, we investigated whether PCD‐CT can be used to estimate stopping power ratios (SPRs) for proton therapy treatment planning, both by comparing to other SPR methods proposed for single energy CT (SECT) and dual energy CT (DECT) as well as to experimental measurements.

Methods

A previously developed DECT‐based SPR estimation method was adapted to PCD‐CT data, by adjusting the estimation equations to allow for more energy spectra. The method was calibrated directly on noisy data to increase the robustness toward image noise. The new PCD SPR estimation method was tested in theoretical calculations as well as in an experimental setup, using both four and two energy bin PCD‐CT images, and through comparison to two other SPR methods proposed for SECT and DECT. These two methods were also evaluated on PCD‐CT images, full spectrum (one‐bin) or two‐bin images, respectively. In a theoretical framework, we evaluated the effect of patient‐specific tissue variations (density and elemental composition) and image noise on the SPR accuracy; the latter effect was assessed by applying three different noise levels (low, medium, and high noise). SPR estimates derived using real PCD‐CT images were compared to experimentally measured SPRs in nine organic tissue samples, including fat, muscle, and bone tissues.

Results

For the theoretical calculations, the root‐mean‐square error (RMSE) of the SPR estimation was 0.1% for the new PCD method using both two and four energy bins, compared to 0.2% and 0.7% for the DECT‐ and SECT‐based method, respectively. The PCD method was found to be very robust toward CT image noise, with a RMSE of 2.7% when high noise was added to the CT numbers. Introducing tissue variations, the RMSE only increased to 0.5%; even when adding high image noise to the changed tissues, the RMSE stayed within 3.1%. In the experimental measurements, the RMSE over the nine tissue samples was 0.8% when using two energy bins, and 1.0% for the four‐bin images.

Conclusions

In all tested cases, the new PCD method produced similar or better results than the SECT‐ and DECT‐based methods, showing an overall improvement of the SPR accuracy. This study thus demonstrated that PCD‐CT scans will be a qualified candidate for SPR estimations.
MicroRNA‐130a inhibits spermatogenesis by directly targeting androgen receptor in mouse Sertoli cells
Authors: Li Cailing , Yang Bo , Pan Peng , Ma Qian , Wu Yong , Zhang Zeng , Guo Xin , Ye Jing , Gui Yaoting
Published: September 2018

MicroRNAs (miRNAs) have been shown to play a key role in spermatogenesis. However, whether the miRNAs influence androgen/androgen receptor (AR) signaling during spermatogenesis remains unclear. Using a bioinformatic approach, a potential miRNA, miR‐130a, which could bind to Ar‐3′untranslated region directly was identified. The expression pattern of miR‐130a was further characterized by quantitative real‐time polymerase chain reaction. It was found that miR‐130a was abundant in testis and its expression level was negatively correlated with age. Overexpression of miR‐130a could inhibit AR expression both in vitro and in vivo. Moreover, the mice with an intratesticular injection of miR‐130a showed defects in spermatogenesis and increased germ cell apoptosis. Taken together, these results suggest that miR‐130a could negatively regulate AR expression in mouse Sertoli cell, which further cause defects in spermatogenesis.
Gait pattern changes after six‐minute walk test in persons with multiple sclerosis
Authors: Escudero‐Uribe Shahid , Hochsprung Anja , Izquierdo‐Ayuso Guillermo
Published: September 2018

Objective

To examine the effect of induced fatigue on spatiotemporal gait parameters in persons with multiple sclerosis (PwMS) by using 6‐min walk test (6MWT).

Methods

A cross‐sectional study with a control group (25 healthy persons) was performed. Fifty‐six PwMS (37 female) were divided into three groups according to their level of disability, as measured by the expanded disability status scale (EDSS): mild (n = 23, EDSS = 1.0–3.5), moderate (n = 19, EDSS = 4.0–5.5), and severe (n = 12, EDSS = 6.0–6.5). Spatiotemporal gait parameters were measured by the GAITRite electronic walkway before and after 6MWT performance. In addition, to determine the level of fatigue in PwMS, the participants completed the questionnaire modified fatigue impact scale (MFIS) before performing the 6MWT. Statistical analyses were performed to compare intragroup and intergroup differences.

Results

Fatigue level was lower in the mild (37.6 ± 20.5) versus moderate (54.3 ± 17.2) versus severe (53.6 ± 12.9) groups (p < 0.05). Significant differences were found among all the groups in terms of the distance walked during the 6MWT (p = 0.001) and of the spatiotemporal gait parameters: gait velocity (cm/s), cadence (steps/min), and step length (cm) decreased and, on the contrary, step time (sec), stance, and double support time (% gait cycle) increased when EDSS scores were higher (p < 0.05). The percentage of change (%) in the spatiotemporal gait parameters, after 6MWT performance, was statistically significant in the moderate and severe groups: gait velocity (−8.8%, −25.9%) and step length (−6.5%, −13.4%) decreased, whereas step time (3.0%, 15.0%), double support time (8.8%, 19.1%), step time asymmetry (32.1%, 64.0%), and single support asymmetry (60.0%, 74.7%) increased (p < 0.05).

Conclusions

Gait pattern worsen after performing a walking‐induced fatigue test, such as 6MWT, in moderate–severe PwMS (EDSS ≥ 4.0). Identifying these gait alterations will allow physiotherapists to determine specific therapeutic objectives.
Effects of clothianidin‐treated seed on the arthropod community in a mid‐Atlantic no‐till corn agroecosystem
Authors: Disque Heather H , Hamby Kelly A , Dubey Aditi , Taylor Christopher , Dively Galen P
Published: September 2018

BACKGROUND

Nearly all corn seed in the US is coated with neonicotinoid insecticides to protect against soil and foliar arthropod pests. Exposure in the soil and the systemic activity in the plant can pose non‐target risks. We assessed the community‐level effects of clothianidin‐treated seed on the diversity and abundance of arthropod communities in a no‐till corn agroecosystem over a single growing season.

RESULTS

Epigeal and foliage‐dwelling communities were disturbed by the clothianidin seed treatment, with significant negative and positive changes in taxa abundances. Clothianidin reduced the abundance of minute pirate bugs by 66.2%, lady beetles by 44.7%, ants by 43.4%, ground beetle adults and larvae by 31.7%, and rove beetles by 44.1% during the early corn growth stages. Herbivores, particularly thrips, were more negatively affected by clothianidin than other trophic groups. In contrast, some groups, such as collembolans and leafhoppers, exhibited significantly higher abundances in the seed treated plots.

CONCLUSION

Clothianidin primarily influenced arthropod communities during the 4 weeks following planting, with disruptions to major natural enemy taxa, but communities showed trends toward recovery at the later corn stages. While the insecticide suppressed multiple herbivores, none were economically damaging to corn; thus, the pest suppression benefits of clothianidin observed in this study did not justify the non‐target impacts. © 2018 Society of Chemical Industry
Influence of insulators on the propagation characteristics of UHF signals
Authors: Shi Minxia , Han Xutao , Zhang Xuanrui , Zhang Zheming , Li Junhao
Published: September 2018

The partial discharge (PD) in gas‐insulated switchgear (GIS) will stimulate the ultra‐high frequency (UHF) electromagnetic (EM) wave signal of 300 MHz to ∼3 GHz. The PD signal will appear in the resonance, distortion, and attenuation during propagating in GIS due to the complexity of the internal structure of GIS. Thus, it increases the intricacy of detection and evaluation. The Finite difference time domain (FDTD) algorithm has been used in this paper to investigate the influence of the insulator structure parameters on the propagation characteristics of the UHF signal. The results show that the dielectric loss of insulator causes the attenuation of the UHF signal inside and outside GIS, with an increase in the thickness and dielectric constant of the insulator. The shape of the insulator has little influence on the propagation characteristics of the UHF signal within GIS. © 2018 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Performance of semiconductor sequencing platform for non‐invasive prenatal genetic screening for fetal aneuploidy: results from a multicenter prospective cohort study in a clinical setting
Authors: El Khattabi L. Allach , Brun S. , Gueguen P. , Chatron N. , Guichoux E. , Schutz S. , Nectoux J. , Sorlin A. , Quere M. , Boudjarane J. , Tsatsaris V. , Mandelbrot L. , Schluth‐Bolard C. , Dupont J. M. , Rooryck C. ,   the H+ Consortium
Published: September 2018

Objective

To validate and evaluate the performance metrics of the high‐throughput semiconductor sequencing platform, Ion Proton®, in non‐invasive prenatal genetic screening (NIPS) for common fetal aneuploidies in a clinical setting.

Methods

This prospective cohort study included 2505 pregnant women from eight academic genetics laboratories (695 high risk for trisomy 21 (risk ≥ 1/250) pregnancies in a validation study, and 1810 such pregnancies, without ultrasound anomalies, in a real‐life NIPS clinical setting). Outcome was available for all cases in the validation cohort and for 521 in the clinical cohort. Cell‐free DNA from plasma samples was sequenced using the Ion Proton sequencer, and sequencing data were analyzed using the open‐access software, WISECONDOR. Performance metrics for detection of trisomies 21, 18 and 13 were calculated based on either fetal karyotype result or clinical data collected at birth. We also evaluated the failure rate and compared three methods of fetal fraction quantification (RASSF1A assay, and DEFRAG and SANEFALCON software).

Results

Results from both cohorts were consistent and their gestational age was not significantly different so their data were combined to increase the sample size for analysis. Sensitivities and specificities, respectively, were as follows: for trisomy 21, 98.3% (95% CI, 93.5–99.7%) and 99.9% (95% CI, 99.4–100%); for trisomy 18, 96.7% (95% CI, 80.9–99.8%) and 100% (95% CI, 99.6–100%); and for trisomy 13, 94.1% (95% CI, 69.2–99.7%) and 100% (95% CI, 99.6–100%). Our failure rate was 1.2% initially and as low as 0.6% after retesting some of the failed samples. Fetal fraction estimation by the RASSF1A assay was consistent with DEFRAG results, and both were adequate for routine diagnosis.

Conclusions

We describe one of the largest studies evaluating Ion Proton‐based NIPS and the first clinical study reporting pregnancy outcome in a large series of patients. This platform is highly efficient in detecting the three most common trisomies. Our protocol is robust and can be implemented easily in any medical genetics laboratory. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
Attention Speculation and Political Bubbles
Authors: Hendricks Vincent F. , Vestergaard Mads
Published: September 2018

We live in an increasingly mediatized world. Mediatization refers to the tendency of societal institutions to be more and more dependent on the media and adapt themselves to its conventions and to media logic (Hjarvad 2008). In a mediatized society, the media veritably establish the conditions for social interactions and relationships, commerce and marketing, science and debate, and activism and politics. When political activists protest or organize a demonstration in order to send a political message, it is essential to get media coverage. The message must be heard by people and parties other than the activists themselves. There is no point in “Occupying Wall Street” unless documented and disseminated. Mediatization provides social and political actors with a strong incentive to act according to the media’s precepts.
Epilogue: Digital Roads to Totalitarianism
Authors: Hendricks Vincent F. , Vestergaard Mads
Published: September 2018

The digital revolution was meant to emancipate. In the Declaration of the Independence of Cyberspace from 1996, John Berry Barlow declares the new digital reality, Cyberspace, to be an independent new world of freedom and equality without oppression of the old world of nation-states ruled by governments. Barlow compares the digital revolution to the American War of Independence and the pioneers of digitalization to the heroes of the American Revolution: “… those previous lovers of freedom and self-determination who had to reject the authorities of distant, uninformed powers.”
The diagnostic challenge in very‐long chain acyl‐CoA dehydrogenase deficiency (VLCADD)
Authors: Hesse Julia , Braun Carina , Behringer Sidney , Matysiak Uta , Spiekerkoetter Ute , Tucci Sara
Published: September 2018

Very long‐chain acyl‐CoA dehydrogenase deficiency (VLCADD) is the most common defect of mitochondrial β‐oxidation of long‐chain fatty acids. However, the unambiguous diagnosis of true VLCADD patients may be challenging, and a high rate of false positive individuals identified by newborn screening undergo confirmation diagnostics. In this study, we show the outcome of enzyme testing in lymphocytes as a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of the ACADVL gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl‐CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA) <50%. In almost 50% of the samples (209/403) the RA was >50%, one‐third of the individuals (125/403) displayed a RA of 30–50% and 69/403 individuals showed a residual activity of 0–30%. Sequencing of the ACADVL gene revealed that all individuals with activities below 24% were true VLCADD patients, individuals with residual activities between 24 and 27% carried either one or two mutations. Twenty new mutations could be identified and functionally classified based on their effect on enzyme function. Finally, we observed an up‐regulation of MCAD‐activity in many patients. However, this did not correlate with the degree of VLCAD RA. Although the likely clinical phenotype cannot be fully foreseen by genetic and functional tests as it depends on many factors, our data demonstrate the strength of this functional enzyme test in lymphocytes as a quick and reliable method for confirmation diagnostics of VLCADD.