bluuebunny/crossref_metadata_2025 huggingface dataset:
Regioselective Synthesis of 4,5‐Dihydro‐6H‐oxepino[3,2‐c]chromene‐2,6(3H)‐diones through Palladium‐Catalyzed Intramolecular Alkoxycarbonylation of 3‐Allyl‐4‐hydroxycoumarins
Authors: Sosa D. Oliver , Almaraz Karla , Amézquita‐Valencia Manuel
Published: June 2019

Seven‐membered ring lactones fused to coumarin scaffolds were obtained via a palladium‐catalyzed regioselective intramolecular alkoxycarbonylation under a CO atmosphere. Cyclocarbonylation of 3‐allyl‐4‐hydroxycoumarin derivatives was accessed in the absence of hydrogen gas, acidic conditions, or any other additives. The results of the control experiments revealed the importance of pKa of the substrate for initiating the reaction.
Cobalt‐Catalysed C–C Bond Formation and [2+2+2] Annulation of 1,3‐Dicarbonyls to Terminal Alkynes
Authors: Verma Girijesh Kumar , Rawat Manish , Rawat Diwan S.
Published: June 2019

A highly regioselective [Cp*Co(CO)I2]‐catalyzed addition of 1,3‐diketones to terminal alkynes at room temperature has been achieved using Cu(OTf)2 as a co‐catalyst. The reaction of 1,3‐diketones substituted at active methylene carbon with phenyl acetylenes having an electron‐withdrawing group or a bulky group results in the formation of the 2‐alkenylated 1,3‐dicarbonyl product, but phenyl acetylenes with electron donating group led to the formation of tetrahydronaphthalene and terphenyl.
Iron and Phenol Co‐Catalysis for Rapid Synthesis of Nitriles under Mild Conditions
Authors: Meng Hong , Gao Sen , Luo Meiming , Zeng Xiaoming
Published: June 2019

A mild, scalable, high yielding, and rapid route to access diverse nitriles from aldehyde oxime esters enabled by iron(III) and phenol co‐catalysis has been developed. The reaction was performed at room temperature to give nitriles in excellent yield within minutes. Mechanistic studies show that the reaction may proceed through a radical process in which benzoyl aldehyde oxime is not only a substrate, but also an ancillary ligand to support iron salt in the promotion of the transformation.
Reinforcement learning algorithm for 5G indoor device‐to‐device communications
Authors: Sreedevi A.G. , Rama Rao T.
Published: June 2019

Fifth generation (5G), the next generation telecommunications will be striking the markets in near future. Device‐to‐device (D2D) communication would be a part of 5G to serve communication needs for billions of connected devices to support high data rate ultrareliable low latency communications. Indoor 5G will be relying on distributed small cell solutions and D2D along with machine‐to‐machine connections. Machine learning is one of the most promising tools for providing the best set of solutions to learn the influential scenarios and certain parameters of the communication networks. This research proposes reinforcement‐learning‐based latency controlled D2D connectivity (RL‐LCDC) algorithm and its Q‐learning approach in an indoor D2D communication network for strong 5G connectivity with minimum latency. The proposed approach, RL‐LCDC efficiently discovers the neighbors, decides the D2D link, and adaptively controls the communication range for maximum network connectivity. The results show that RL‐LCDC optimizes the connectivity with lower end‐to‐end delay and better energy efficiency with efficient convergence time when compared with other conventional schemes.
Reply to the comments by Pillai, S. P., George, B. G., Ray, J. S., and Kale, V. S., (GJ‐19‐0112) on Paper: “Depositional history and provenance of cratonic “Purana” basins in southern India: A multipronged geochronology approach to the Proterozoic Kaladgi and Bhima basins” by Joy et al., 2018
Authors: Joy Sojen , Patranabis‐Deb Sarbani , Saha Dilip , Jelsma Hielke , Maas Roland , Söderlund Ulf , Tappe Sebastian , van der Linde Gert , Banerjee Amlan , Krishnan Unni
Published: June 2019

We thank Patil Pillai et al. for preparing a critique on our article (Joy et al., 2018). Patil Pillai et al. contest the analytical procedure utilized for the carbonates and “geological information” documented in our research article and raise concerns on our conclusions. We hereby provide our reply to each of their comments.
Fully coupled free‐surface flow and sediment transport modelling of flash floods in a desert stream in the Mojave Desert, California
Authors: Khosronejad Ali , Kang Seokkoo , Flora Kevin
Published: June 2019

For most of the year, a dry‐bed desert wash is void of water flow. Intensive rain events, however, could trigger significant flash floods that bring about highly complicated hydrodynamics and morphodynamics processes within a desert stream. We present a fully coupled three‐phase flow model of air, water, and sediment to simulate numerically the propagation of a flash flood in a field‐scale fluvial desert stream, the so‐called Tex Wash located in the Mojave Desert, California, United States. The turbulent flow of the flash flood is computed using the three‐dimensional unsteady Reynolds‐averaged Navier–Stokes equations closed with the shear stress transport k − ω model. The free surface of the flash flood at the interface of air and water phases is computed with the level‐set method, which enables instantaneous tracking of the water surface as the flash flood propagates over the dry bed of the desert stream. The evolution of the desert fluvial stream's morphology, due to the action of the propagating flash flood on the mobile bed, is calculated using a Eulerian morphodynamics model based on the curvilinear immersed boundary method. The capabilities of the proposed numerical framework are demonstrated by applying it to simulate a flash flood event in a 0.65‐km‐long reach of the Tex Wash, the intricate channel morphology of which is obtained using light imaging detection and ranging technology. The simulated region of the stream includes a number of bridge foundations. The simulation results of the model for the flash flood event revealed the formation of a highly complex flow field and scour patterns within the stream. Moreover, our simulation results showed that most scour processes take place during the steady phase of the flash flood, that is, after the flash flood fills the stream. The transient phase of the flash flood is rather short and contributes to a very limited amount of erosion within the desert stream.
Estimation of the Value of Aquatic Ecosystem Services in the Coastal Area of Jiangsu Province, China
Authors: Yao Hong , Liu Huan , Ni Tianhua
Published: June 2019

Aquatic ecosystems contribute to human welfare in complex nonmarketed ways. The value of aquatic ecological services was estimated in the coastal area of Jiangsu Province, China. We used the contingent valuation method (CVM) values, including the willingness-to-pay (WTP) of households for water quality improvement and the willingness-to-accept (WTA) compensation of households for freshwater deterioration. Valid questionnaires (n = 10 814) were collected in all towns of the area (n = 367). The WTA/WTP ratios ranged from 1 to 200, the average of which was 17.7 and the median was 7.5. A multivariate linear logarithmic model was introduced to characterize the influence of demographic variables on WTP and WTA values. Residents' age, years of residency, education levels, and environmental awareness positively affected the WTA/WTP ratios. The summing of the values of aquatic ecological services in each town was ¥9.4 billion. This estimation may represent the minimum value for aquatic ecosystem services in the study area; nevertheless, this study illustrates how experience, personal wealth, and environmental awareness may influence perceptions of the value of environmental benefits and may influence policy decisions.
DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility
Authors: Pardini Barbara , Corrado Alda , Paolicchi Elisa , Cugliari Giovanni , Berndt Sonja I. , Bezieau Stephane , Bien Stephanie A. , Brenner Hermann , Caan Bette J. , Campbell Peter T. , Casey Graham , Chan Andrew T. , Chang‐Claude Jenny , Cotterchio Michelle , Gala Manish , Gallinger Steven J. , Haile Robert W. , Harrison Tabitha A. , Hayes Richard B. , Hoffmeister Michael , Hopper John L. , Hsu Li , Huyghe Jeroen , Jenkins Mark A. , Le Marchand Loic , Lin Yi , Lindor Noralane M. , Nan Hongmei , Newcomb Polly A. , Ogino Shuji , Potter John D. , Schoen Robert E. , Slattery Martha L. , White Emily , Vodickova Ludmila , Vymetalkova Veronika , Vodicka Pavel , Gemignani Federica , Peters Ulrike , Naccarati Alessio , Landi Stefano
Published: June 2019

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.
In vitro toxicity screening of magnetite nanoparticles by applying mesenchymal stem cells derived from human umbilical cord lining
Authors: Coccini Teresa , De Simone Uliana , Roccio Marianna , Croce Stefania , Lenta Elisa , Zecca Marco , Spinillo Arsenio , Avanzini Maria Antonietta
Published: June 2019

Despite the growing interest in nanoparticles (NPs), their toxicity has not yet been defined and the development of new strategies and predictive models are required. Human stem cells (SCs) offer a promising and innovative cell‐based model. Among SCs, mesenchymal SCs (MSCs) derived from cord lining membrane (CL) may represent a new species‐specific tool for establishing efficient platforms for primary screening and toxicity/safety testing of NPs. Superparamagnetic iron oxide NPs, including magnetite (Fe3O4NPs), have aroused great public health and scientific concerns despite their extensive uses. In this study, CL‐MSCs were characterized and applied for in vitro toxicity screening of Fe3O4NPs. Cytotoxicity, internalization/uptake, differentiation and proliferative capacity were evaluated after exposure to different Fe3O4NP concentrations. Data were compared with those obtained from bone marrow (BM)‐MSCs. We observed, at early passages (P3), that: (1) cytotoxicity occurred at 10 μg/mL in CL‐MSCs and 100 μg/mL in BM‐MSCs (no differences in toxicity, between CL‐ and BM‐MSCs, were observed at higher dosage, 100‐300 μg/mL); (2) cell density decrease and monolayer features loss were affected at ≥50 μg/mL in CL‐MSCs only; and (3) NP uptake was concentration‐dependent in both MSCs. After 100 μg/mL Fe3O4NP exposures, the capacity of proliferation was decreased (P5‐P9) in CL‐MSCs without morphology alteration. Moreover, a progressive decrease of intracellular Fe3O4NPs was observed over culture time. Antigen surface expression and multilineage differentiation were not influenced. These findings suggest that CL‐MSCs could be used as a reliable cell‐based model for Fe3O4NP toxicity screening evaluation and support the use of this approach for improving the confidence degree on the safety of NPs to predict health outcomes.
Impaired Gastric Hormone Regulation of Osteoblasts and Lysyl Oxidase Drives Bone Disease in Diabetes Mellitus
Authors: Daley Eileen J , Pajevic Paola Divieti , Roy Sayon , Trackman Philip C
Published: June 2019

Diabetic bone disease is a complication of type I and type II diabetes, both of which are increasing in the United States and elsewhere. Increased hip and foot fracture rates do not correlate well with changes in bone mineral density (BMD), whereas studies support the importance of collagen structure to bone strength. Extracellular lysyl oxidase (LOX) catalyzes the oxidative deamination of hydroxylysine and lysine residues in collagens resulting in aldehydes that subsequently form critically important biosynthetic crosslinks that stabilize functional collagens. Although LOX‐dependent biosynthetic crosslinks in bone collagen are deficient in diabetic bone, the expression and regulation of bone LOXs in diabetes have not been comprehensively studied. Here, we found that LOX is profoundly downregulated in bone in diabetes. Moreover, we have identified a novel metabolic regulatory relationship that is dysregulated in diabetes using mouse models. Data indicate that the incretin (gastric hormone) known as glucose‐dependent insulinotropic polypeptide (GIP) that is anabolic to osteoblasts strongly upregulates LOX, and that this regulation is disrupted in the streptozotocin‐induced model of diabetes in mice. In vivo and in vitro studies support that diabetes results in elevated circulating peripheral dopamine, likely also derived from the gut, and is responsible for blocking GIP signaling and LOX levels in osteoblasts. Moreover, peripheral administration of the dopamine D2 receptor antagonist amisulpride to diabetic mice restored trabecular bone structure to near normal and partially reversed downregulation of LOX. Taken together our data identifies a novel metabolic relationship between the gut‐derived hormone GIP and bone‐derived LOX, and points to the importance of LOX dysregulation in the pathology of diabetic bone disease. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
Association of Bone Density Monitoring in Routine Clinical Practice With Anti-Osteoporosis Medication Use and Incident Fractures: A Matched Cohort Study
Authors: Leslie William D , Morin Suzanne N , Martineau Patrick , Bryanton Mark , Lix Lisa M
Published: June 2019

Routine bone mineral density (BMD) monitoring of individuals during the initial 5 years of anti-osteoporosis treatment is controversial. Using a registry-based cohort from the Province of Manitoba, Canada, we compared anti-osteoporosis medication use and fracture outcomes in women with versus without BMD monitoring receiving anti-osteoporosis medication. We identified 4559 women aged 40 years and older receiving anti-osteoporosis therapy with serial BMD testing (monitoring) within 5 years (mean interval 3.2 years) and 4559 propensity score–matched women without BMD monitoring. We assessed anti-osteoporosis medication use over 5 years from a population-based retail pharmacy database. Incident fractures to 10 years from health services data. During median 10 years observation, 1225 (13.4%) women developed major osteoporotic fracture, including 382 (4.2%) with hip fractures. Monitored women had significantly better fracture-free survival for major osteoporotic fracture (p = 0.040; 10-year cumulative risk 1.9% lower, 95% confidence interval [CI] 0.3–3.6%) and hip fracture ( p = 0.001; 10-year cumulative risk 1.8% lower, 95% CI 0.7–2.8%) compared with women who were not monitored. Hazard ratios (HRs) were significantly lower in monitored versus not monitored women for major osteoporotic fracture (HR = 0.89, 95% CI 0.80–0.98) and hip fracture (HR = 0.74, 95% CI 0.63–0.87). Days of medication use, medication persistence ratio, and treatment switching over 5 years were greater in monitored versus not monitored women. At the end of 5 years, more women in the monitored group persisted on treatment and more switched treatment, with switching behavior associated with an observed interval reduction in BMD. In conclusion, our findings suggest a possible role for BMD monitoring after initiating anti-osteoporosis therapy in the routine clinical practice setting. © 2019 American Society for Bone and Mineral Research.
AgsA response to cadmium and copper effects at different temperatures in Escherichia coli
Authors: Lv Yanchun , Ezemaduka Anastasia N. , Wang Yunbiao , Xu Jingbo , Li Xiujun
Published: June 2019

Small heat shock proteins (sHsps), present from prokaryotes to eukaryotes, are a highly conserved molecular chaperone family. They play a crucial role in protecting organisms against cellular insults from single or multiple environmental stressors including heavy metal exposure, heat or cold shock, oxidative stress, desiccation, etc. Here, the toxicity of cadmium and copper, and their ability to modify the cellular growth rate at different temperatures in Escherichia coli cells were tested. Also, the response mechanism of the sHSP aggregation‐suppressing protein (AgsA) in such multiple stress conditions was investigated. The results showed that the half effect concentration (EC50) of cadmium in AgsA‐transformed E. coli cells at 37°C, 42°C, and 50°C were 11.106, 29.50, and 4.35 mg/L, respectively, and that of the control cells lacking AgsA were 5.05, 0.93, and 0.18 mg/L, respectively, while the half effect concentration (EC50) of copper in AgsA‐transformed E. coli cells at 37°C, 42°C, and 50°C were 27.3, 3.40, and 1.28 mg/L, respectively, and that of the control cells lacking AgsA were 27.7, 5.93, and 0.134 mg/L, respectively. The toxicities of cadmium and copper at different temperatures as observed by their modification of the cellular growth rate and inhibitory effects were in a dose‐dependent manner. Additionally, biochemical characterization of AgsA protein in cells subjected to cadmium and copper stresses at different temperatures implicated suppressed aggregation of cellular proteins in AgsA‐transformed E. coli cells. Altogether, our data implicate the AgsA protein as a sensitive protein‐based biomarker for metal‐induced toxicity monitoring.
Long noncoding RNA MEG3 plays a promoting role in the proliferation, invasion, and angiogenesis of lung adenocarcinoma cells through the AKT pathway
Authors: Li Hui , Wang Jue , Lv Shuang , Zhang Ying , Zhang Cuiying , Lige Baya , Dan Su , Sun Yanyan
Published: June 2019

The role of long noncoding RNA maternally expressed gene 3 (MEG3) in lung adenocarcinoma has not been explored entirely. In this study, it was demonstrated that the expression of MEG3 was enhanced in lung adenocarcinoma tissues from TCGA database and some specific cell lines, while the survival analysis showed that patients with higher MEG3 levels had lower survival probabilities, which suggested that MEG3 might serve as a lung adenocarcinoma promoter. In addition, the results suggested that the overexpression of MEG3 could promote the proliferation and invasion of lung adenocarcinoma cells. Furthermore, increased MEG3 expression could result in a notable increase in angiogenesis‐related factors as well as in the capillary tube formation of endothelial cells, which indicates that the overexpression of MEG3 could promote the angiogenesis of lung adenocarcinoma. From a mechanistic perspective, the results obtained revealed that the upregulation of MEG3 could stimulate the AKT signaling pathway and consequently lead to the biological behaviors mentioned above. In summary, all the results obtained from this study indicated that MEG3 plays a promoting role in the tumorigenesis and angiogenesis of lung adenocarcinoma, which deserves special attention when considered as a potential therapeutic target for lung adenocarcinoma.
DNA hypomethylation promotes invasion and metastasis of gastric cancer cells by regulating the binding of SP1 to the CDCA3 promoter
Authors: Yu Jiawei , Hua Ruheng , Zhang Yan , Tao Ran , Wang Quhui , Ni Qingfeng
Published: June 2019

Background

Cell division cycle associated protein‐3 (CDCA3) has been reported frequently upregulated in various cancers. It has been progressively realized that changed DNA methylations occur in diverse carcinomas. However, the concrete involvement of CDCA3 and DNA methylation in gastric cancer (GC) still needs to be further elucidated.

Methods

In this study, quantitative reverse‐transcription polymerase chain reaction (PCR) was utilized to determine the relative expressions of CDCA3 in GC and normal tissue samples. The methylation condition of CDCA3 was determined by bisulfite‐sequencing PCR (BSP) and methylation‐specific PCR (MSP). A chromatin immunoprecipitation (ChIP) assay and luciferase activity assay was used for the interaction between transcription factors and promoters and binding site determination, respectively. The effects of knockdown or overexpression of specificity protein 1 (SP1) or CDCA3 on GC cells in vitro were further assessed via wound healing assay, colony formation assay, and matrigel invasion assay.

Results

In comparison to paired normal tissues, CDCA3 expressions were significantly increased in the GC tissues. The CDCA3 expression was regulated by DNA methylation, with the CpG island hypomethylation responsible for CDCA3 upregulation of GC. ChIP assays verified that the activity of SP1 binding to the CDCA3 promoter was dramatically increased. When the CDCA3 expression was downregulated in MKN45 cells by knockdown SP1, the proliferation ability, healing ability, and invasive ability were significantly suppressed.

Conclusion

The process by which SP1 bound to the nearest promoter region was expedited in GC cells, by which DNA was hypomethylated and CDCA3 expression was promoted. The effect on cell proliferation and invasion by CDCA3 was under the regulation of SP1 and also affected by hypomethylation of DNA.
High‐mobility group box 2 promoted proliferation of cervical cancer cells by activating AKT signaling pathway
Authors: Zhang Pengnan , Lu Yuan , Gao Shujun
Published: June 2019

Cervical cancer is one of the leading killers for female worldwide. Nevertheless, the less knowledge of molecular mechanism for cervical cancer limited the improvement of treatment effects. High‐mobility group box 2 (HMGB2) belongs to the HMGB family, which could play diverse roles in cell proliferation. This work mainly aimed to study the functions of HMGB2 on cervical cancer cells proliferation. HMGB2 was highly expressed in cervical cancer tissue. The results of real‐time polymerase chain reaction and Western blot analysis showed that HMGB2 was expressed in all the five cervical cancer cells (HeLa, CaSki, SiHa, C‐33A, and C4‐1 cells). In addition, HMGB2 overexpression obviously improved cell viability and promoted cell cycle progression, which suggested that HMGB2 could promote proliferation of cervical cancer cells. Moreover, HMGB2 overexpression increased the level of p‐AKT and reduced the levels of p21 and p27. However, HMGB2 downregulation had contrary influences on cell proliferation, cell cycle distribution and the levels of p‐AKT, p21, and p27. Notably, LY294002, as an inhibitor of AKT signaling pathway, could significantly weaken the effects of HMGB2 overexpression, which indicated that HMGB2 might promote cell proliferation by activating AKT signaling pathway. Therefore, HMGB2 was hopeful to be a candidate as a new biomarker and therapy target for cervical cancer.
Absent in melanoma 2 suppresses epithelial‐mesenchymal transition via Akt and inflammasome pathways in human colorectal cancer cells
Authors: Yang Yunjia , Zhang Minda , Jin Chenyu , Ding Yang , Yang Mengdi , Wang Rui , Zhou Yunjiang , Zhou Yang , Li Tao , Wang Keke , Hu Rong
Published: June 2019

Absent in melanoma 2 (AIM2) is a critical component in natural immunity system and is closely related to cancer initiation and development. It has been shown that AIM2 inhibited colorectal cancer (CRC) development and cell proliferation. It remains unresolved how AIM2 acts on CRC metastasis. In this study, we assessed migration, invasion ability, and epithelial‐mesenchymal transition (EMT) program upon AIM2 overexpression or knockdown in human CRC cells. Transwell assay demonstrated that upregulation of AIM2 reduced cell migration and invasion. Epithelial marker E‐cadherin was augmented and mesenchymal markers vimentin, as well as Snail, were examined decreased by Western blot, real‐time polymerase chain reaction, and immunofluorescence. Correspondingly, knockdown of AIM2 led to a reverse consequence. In addition, AIM2 regulated Akt phosphorylation and effects of AIM2 on cell invasion and EMT were recovered after administration of Akt inhibitor, suggesting that AIM2 suppressed EMT dependent on Akt pathway. In addition, caspase‐1 inhibitor exposure indicated that AIM2 abrogated EMT through the inflammasome pathway as well. In summary, AIM2 suppressed EMT via Akt and inflammasome pathways in human CRC cells.
Bin1 antibody lowers the expression of phosphorylated Tau in Alzheimer's disease
Authors: Thomas Sunil , Hoxha Kevther , Tran Allison , Prendergast George C.
Published: June 2019

Alzheimer's disease (AD) is an irreversible, progressive brain disorder responsible for memory loss leading to the inability to carry out the simplest tasks. AD is one of the leading causes of death in the United States. As yet there are no effective medications to treat this debilitating disease. In recent years, a human gene called bridging integrator 1 (BIN1) has emerged as one of the most important genes in affecting the incidence of sporadic AD. Bin1 can directly bind to Tau and mediates late onset AD risk by modulating Tau pathology. Recently our group found Bin1 antibody could exert drug‐like properties in an animal model of ulcerative colitis. We hypothesized that the Bin1 monoclonal antibody (mAb) could be used in the treatment of AD by lowering the levels of Tau in cell culture and animal models. Cell culture studies confirmed that the Bin1 mAb (99D) could lower the levels of phosphorylated Tau (pTau). Multiple mechanisms aided by endosomal proteins and Fc gamma receptors are involved in the uptake of Bin1 mAb into cells. In Tau expressing cell culture, the Bin1 mAb induces the proteasome machinery leading to ubiquitination of molecules thereby preventing cell stress. In vivo studies demonstrated that treatment of P301S mice expressing Tau with the Bin1 mAb survived longer than the untreated mice. Our data confirm that Bin1 mAb lowers the levels of pTau and could be a drug candidate in the treatment of AD.
Insights into the molecular regulatory network of pathomechanisms in osteochondroma
Authors: Yang Congyi , Zhang Ruiqian , Lin Hui , Wang Hongmei
Published: June 2019

Osteochondroma is a benign autosomal dominant hereditary disease characterized by abnormal proliferation of cartilage in the long bone. It is divided into solitary osteochondroma and hereditary multiple exostoses (HMEs). The exostosin‐1 (EXT‐1) and exostosin‐2 (EXT‐2) gene mutations are well‐defined molecular mechanisms in the pathogenesis of HME. EXT‐1 and EXT‐2 encode glycosyltransferases that are necessary for the synthesis of heparin sulfate. Accumulating evidence suggests that mutations in the EXT family induce changes in isolated hypogonadotropic hypogonadism‐parathyroid hormone‐related protein, bone morphogenetic protein, and fibroblast growth factor signaling pathways. Studies have also found that a large number of microRNAs (miRNAs) are abnormally expressed in osteochondroma tissues, and some of them also participate in several major signaling pathways. The regulation of miRNA expression could be another breakthrough in the treatment of osteochondroma. Although the pathogenesis of osteochondroma is very complicated, significant progress has been made in recent years. It is hoped that the pathogenesis of osteochondroma will be clearly understood and the most effective methods for the prevention and treatment of osteochondroma will be determined. This review provides an update on the recent progress in the interpretation of the underlying molecular mechanisms of osteochondroma.
Estimation of ABCB1 concentration in plasma membrane
Authors: Mlejnek Petr , Kosztyu Petr , Dolezel Petr , Kimura Yasuhisa , Cizkova Katerina , Ruzickova Eliska
Published: June 2019

The interaction between ABCB1 transporter and its substrates takes place in cell membranes but the available data precludes quantitative analysis of the interaction between transporter and substrate molecules. Further, the amount of transporter is usually expressed as a number of ABCB1 molecules per cell. In contrast, the substrate concentration in cell membranes is estimated by determination of substrate‐lipid partition coefficient, as examples. In this study, we demonstrate an approach, which enables us to estimate the concentration of ABCB1 molecules within plasma membranes. For this purpose, human leukemia K562 cells with varying expression levels of ABCB1 were used: drug selected K562/Dox and K562/HHT cells with very high transporter expression, and K562/DoxDR2, K562/DoxDR1, and K562/DoxDR05 cells with gradually decreased expression of ABCB1 derived from K562/Dox cells using RNA interference technology. First, we determined the absolute amount of ABCB1 in cell lysates using immunoblotting and recombinant ABCB1 as a standard. We then determined the relative portion of transporter residing in the plasma membrane using immunohistochemistry in nonpermeabilized and permeabilized cells. These results enabled us to estimate the concentration of ABCB1 in the plasma membrane in resistant cells. The ABCB1 concentrations in the plasma membrane of drug selected K562/Dox and K562/HHT cells containing the highest amount of transporter reached millimolar levels. Concentrations of ABCB1 in the plasma membrane of resistant K562/DoxDR2, K562/DoxDR1, and K562/DoxDR05 cells with lower transporter expression were proportionally decreased.
Prioritization of SNPs in y+LAT‐1 culpable of Lysinuric protein intolerance and their mutational impacts using protein‐protein docking and molecular dynamics simulation studies
Authors: Gopalakrishnan Chandrasekhar , Al‐Subaie Abeer Mohammed , N Nagasundaram , Yeh Hui‐Yuan , Tayubi Iftikhar Alam , Kamaraj Balu
Published: June 2019

Lysinuric protein intolerance (LPI) is a rare, yet inimical, genetic disorder characterized by the paucity of essential dibasic amino acids in the cells. Amino acid transporter y+LAT‐1 interacts with 4F2 cell‐surface antigen heavy chain to transport the required dibasic amino acids. Mutation in y+LAT‐1 is rumored to cause LPI. However, the underlying pathological mechanism is unknown, and, in this analysis, we investigate the impact of point mutation in y+LAT‐1's interaction with 4F2 cell‐surface antigen heavy chain in causing LPI. Using an efficient and extensive computational pipeline, we have isolated M50K and L334R single‐nucleotide polymorphisms to be the most deleterious mutations in y+LAT‐1s. Docking of mutant y+LAT‐1 with 4F2 cell‐surface antigen heavy chain showed decreased interaction compared with native y+LAT‐1. Further, molecular dynamic simulation analysis reveals that the protein molecules increase in size, become more flexible, and alter their secondary structure upon mutation. We believe that these conformational changes because of mutation could be the reason for decreased interaction with 4F2 cell‐surface antigen heavy chain causing LPI. Our analysis gives pathological insights about LPI and helps researchers to better understand the disease mechanism and develop an effective treatment strategy.
C allele of ‐786 T>C polymorphism in the promoter region of endothelial nitric oxide synthase is responsible for endothelial dysfunction in the patients with rheumatoid arthritis
Authors: Luo Yanli , Wang Yang , Luo Wanjun
Published: June 2019

Background

This study aimed to explore the roles of endothelial nitric oxide synthase (eNOS) in the control of metastasis of infection with endothelial dysfunction, as well as the roles of ‐786T>C polymorphism in eNOS promoter in the control of metastasis of endothelial function.

Method

In‐silicon analysis and luciferase assay were used to identify the location of ‐786>C on the promoter of eNOS. Subsequently, real‐time PCR and Western‐blot were used to determine the expression level of eNOS. Ultrasound examination was used to detect baseline brachial artery diameter and flow‐mediated dilation of patients in different treat groups.

Results

‐786T>C was located on the promoter of eNOS, and the luciferase activity of cells transfected with ‐786‐C allele was much higher than empty vector, while even higher subsequent to transfection of ‐786‐T allele. In addition, the result of ultrasound examination showed that the baseline brachial artery diameter was comparable between patients genotyped as TT, TC and CC, while the flow‐mediated dilation of patients genotyped as TC was much higher compared with CC group, and the flow‐mediated dilation of patients genotyped as TT even higher than TC group. We found eNOS messenger RNA and protein with TT genotype was significantly higher compared with other genotypes. And the production of NO was remarkably higher in TT groups compared with TC and CC, while the production of NO in TC and CC groups were similar.

Conclusion

These findings indicated that down‐expression of ‐786T>C located on the promoter of eNOS is associated with an increased risk of endothelial dysfunction.
School‐wide implementation of positive behavioral interventions and supports in an alternative school setting: A case study
Authors: Griffiths Amy‐Jane , Diamond Elena Lilles , Alsip James , Furlong Michael , Morrison Gale , Do Bich
Published: June 2019

Aims

The purpose of this 1‐year case study was to identify how School‐Wide Positive Behavioral Interventions and Supports (SW‐PBIS) can be adapted to meet the needs of students in alternative schools and to evaluate the early impact of SW‐PBIS on discipline outcomes.

Methods

Suggestions for adaptations are provided at each stage of the intervention process with a focus on buy‐in, training, data collection, and resource allocation.

Results

Data from this case study included information about key components of the implementation process as well as initial outcomes. Process data revealed the importance of stakeholder buy‐in, training opportunities, and potential adaptations to the framework. Outcome data from the first year of implementation indicated that the number of incident reports did not significantly differ from the baseline; however, there was a reduction in defiance‐related behaviors and an increase in on‐task behaviors.

Conclusion

This study contributes to the determination of the efficacy of SW‐PBIS in a historically more punitive environment. Given the initial positive response and lessons learned, it is believed that, with the support of additional Tier 2 and Tier 3 interventions, SW‐PBIS may be an appropriate framework to support students in alternative schools.
Integrated analysis of clinical significance and functional involvement of microRNAs in hepatocellular carcinoma
Authors: Qin Li , Huang Jian , Wang Guodong , Huang Jinxin , Wu Xintian , Li Jinzhuan , Yi Weili , Qin Fuhui , Huang Dongning
Published: June 2019

Hepatocellular carcinoma (HCC) is one of the most common lethal cancers worldwide. To explore the potential prognosis‐associated microRNAs (miRNAs) for HCC patients, we performed integrated analyses on the miRNA expression profiles from The Cancer Genome Atlas project. Genome‐wide overall survival (OS)‐ and progression‐free survival (PFS)‐associated miRNA screening were performed by multivariate Cox proportional hazards regression analyses. A five‐miRNA expression signature (miR‐148a, miR‐3677‐3p, miR‐744*, miR‐210, and miR‐3613‐5p) was identified as an indicator for HCC OS (p < .0001; hazard ratio [HR] = 2.631). In addition, a seven‐miRNA expression signature (miR‐127‐5p, miR‐146a, miR‐152, miR‐193a‐3p, miR‐331‐5p, miR‐500a*, and miR‐550a*) was identified as a predictor for HCC PFS (p < .0001; HR = 2.608). This systematic analysis suggested that both the OS‐ and PFS‐associated signatures have better performance in HCC survival prediction than the conventional clinicopathological parameters. Further functional enrichment analysis of the corresponding genes targeted by these signature miRNAs revealed their biological significance in the PI3K‐Akt signaling pathway. In conclusion, our present study identified a five‐miRNA OS‐associated signature and a seven‐miRNA PFS‐associated signature as HCC prognostic biomarkers with potential clinical significance, which could enable the development of novel targeted therapeutic strategies for HCC treatment.
Retracted: MicroRNA‐132 protects H9c2 cells against oxygen and glucose deprivation‐evoked injury by targeting FOXO3A
Authors: Zhang Jingze , Xu Haiming , Gong Licheng , Liu Long
Published: June 2019

Myocardial ischemia/reperfusion injury (MIRI) is a clinically familiar disease, which possesses a great negative impact on human health. But, the effective treatment is still absent. MicroRNAs (miRNAs) have been testified to play a momentous role in MIRI. The purpose of the study aimed to probe the functions of miR‐132 in oxygen and glucose deprivation (OGD)‐evoked injury in H9c2 cells. miR‐132 expression in H9c2 cells accompanied by OGD disposition was evaluated via real‐time quantitative polymerase chain reaction. After miR‐132 mimic and inhibitor transfections, the impacts of miR‐132 on OGD‐affected H9c2 cell viability, apoptosis, cell cycle, and the interrelated factors were appraised by exploiting cell counting kit‐8, flow cytometry, and western blot analysis. FOXO3A expression was estimated in above‐transfected cells, meanwhile, the correlation between miR‐132 and FOXO3A was probed by dual‐luciferase report assay. Ultimately, above mentioned cell processes were reassessed in H9c2 cells after preprocessing OGD administration and transfection with si‐FOXO3A and si‐NC plasmids. We got that OGD disposition obviously enhanced miR‐132 expression in H9c2 cells. Overexpressed miR‐132 evidently reversed OGD‐evoked cell viability repression and apoptosis induction in H9c2 cells. In addition, overexpressed miR‐132 mitigated OGD‐evoked G0/G1 cell arrest by mediating p21, p27, and cyclin D1 expression. Repression of FOXO3A was observed in miR‐132 mimic‐transfected cells, which was also predicated as a direct gene of miR‐132. We discovered that silenced FOXO3A alleviated OGD‐evoked cell injury in H9c2 cells via facilitating cell viability, hindering apoptosis and restraining cell arrest at G0/G1 phase. In conclusion, these investigations corroborated that miR‐132 exhibited the protective impacts on H9c2 cells against OGD‐evoked injury via targeting FOXO3A.
Intelligent microscopic approach for identification and recognition of citrus deformities
Authors: Safdar Arooj , Khan Muhammad A. , Shah Jamal H. , Sharif Muhammad , Saba Tanzila , Rehman Amjad , Javed Kashif , Khan Junaid A.
Published: June 2019

Plant diseases are accountable for economic losses in an agricultural country. The manual process of plant diseases diagnosis is a key challenge from last one decade; therefore, researchers in this area introduced automated systems. In this research work, automated system is proposed for citrus fruit diseases recognition using computer vision technique. The proposed method incorporates five fundamental steps such as preprocessing, disease segmentation, feature extraction and reduction, fusion, and classification. The noise is being removed followed by a contrast stretching procedure in the very first phase. Later, watershed method is applied to excerpt the infectious regions. The shape, texture, and color features are subsequently computed from these infection regions. In the fourth step, reduced features are fused using serial‐based approach followed by a final step of classification using multiclass support vector machine. For dimensionality reduction, principal component analysis is utilized, which is a statistical procedure that enforces an orthogonal transformation on a set of observations. Three different image data sets (Citrus Image Gallery, Plant Village, and self‐collected) are combined in this research to achieving a classification accuracy of 95.5%. From the stats, it is quite clear that our proposed method outperforms several existing methods with greater precision and accuracy.
The evolution of evolution
Authors: Bonner John T.
Published: June 2019

In the past, most biologists, myself included, did not think of evolution as changing over time. The wonders of natural selection were always at hand and went into operation once there was life. However, with a little reflection it becomes obvious that evolution has changed—there has been an evolution of evolution. Evolution can be separated into four phases, or eras, that may or may not overlap. Thefirst erastarts with the evolution of life on earth, which led to single cells that multiply asexually. Thesecond eratakes advantage of the invention of sexual reproduction as evolution could now gallop forward because of a richer fare of diverse offspring for natural selection. Thethird erabegins with the introduction of multicellularity. In thefourth erathere is a radical innovation: the nervous system that arises animals by standard Darwinian selection. This has allowed major rapid changes to proceed, such as language that led to all the rapid progress we call civilization; a true revolution, and one that does not depend on the slow genetic changes of all other standard gene‐controlled evolutionary steps.
Importance of localization of insulinomas: a systematic analysis
Authors: Burghardt Lilian , Meier Juris J. , Uhl Waldemar , Kahle‐Stefan Melanie , Schmidt Wolfgang E. , Nauck Michael A.
Published: June 2019

Background

Procedures suitable for preoperative localization of insulinomas are widely used but it is unclear whether they determine surgical success. We wanted to clarify whether preoperative localization or intraoperative ultrasound determines the success of surgically identifying and removing insulinomas.

Methods

We performed a systematic literature search (PubMed) yielding 100 publications with patient‐level data on preoperative localization procedures, intraoperative ultrasound, success of surgical identification and removal or single, benign insulinomas (published until 31 December 2016). The consequences of successful preoperative localization and intraoperative ultrasound for surgical identification and removal of an insulinoma could be analyzed for 863 and 529 patients with single benign insulinomas, respectively. Sensitivities of commonly employed methods to localize biochemically proven insulinomas were calculated for single benign (1,153 patients), multiple benign, and malignant insulinomas, also in relation to diameter and intra‐pancreatic location.

Results

The success of surgery (identification and removal of single benign insulinomas) in patients with a biochemically proven insulinoma was high (approximately 98%) even in the absence of preoperative localization. However, successful preoperative localization or intraoperative ultrasonography slightly, but significantly, increased the probability of surgically identifying/removing single benign insulinomas (by 1.4% and 2.0%, P = 0.012 and 0.0032, respectively). Diagnostic sensitivities of localization procedures varied widely, with GLP‐1 receptor scintigraphy achieving the highest sensitivity despite its non‐invasive nature.

Conclusion

The probability of surgically identifying and removing a single, benign insulinoma is high even in the absence of successful preoperative localization or intraoperative ultrasound. However, both approaches slightly, but significantly, improve the outcome to near 100%.
Experience and outcomes in living donor liver procurement using the water jet scalpel
Authors: Hamaoka Michinori , Kobayashi Tsuyoshi , Kuroda Shintaro , Okimoto Sho , Honmyo Naruhiko , Yamaguchi Megumi , Yamamoto Masateru , Ohdan Hideki
Published: June 2019

Background

The aim of the present study was to clarify treatment outcomes of living donor liver procurement using the water jet scalpel (WJS).

Methods

This single‐center, retrospective cohort study included 40 living donors who underwent liver procurement from January 2014 to December 2018. One living donor who underwent posterior segmentectomy was excluded. Clinical data and outcomes after surgery for 20 WJS donors and 19 Cavitron Ultrasonic Surgical Aspirator (CUSA) donors were compared.

Results

Preoperative and excised graft data did not differ significantly between the WJS and CUSA groups. Operation time (P = 0.025) and parenchymal transection time (P = 0.007) were significantly shorter in the WJS group. There was no difference between the groups in terms of short‐term outcomes after surgery. Multivariate analysis revealed that WJS offered significant advantages over CUSA in terms of shortening parenchymal transection time (P = 0.017).

Conclusion

Living donor liver procurement using WJS contributes to shortening of parenchymal transection time while maintaining the same level of safety as when using CUSA.
Acute cellular rejection in hepatitis C recipients following liver transplantation in the era of direct‐acting antivirals: chronological analysis of the United Network for Organ Sharing database
Authors: Tanaka Tomohiro , Voigt Michael D.
Published: June 2019

Introduction

Interferon (IFN) treatment for liver transplant (LT) recipients with hepatitis C virus (HCV) increases acute cellular rejection (ACR) and worsens graft and patient survival. It is unknown if direct‐acting antivirals (DAAs) affect rejection rates or post‐transplant survival.

Method

The United Network for Organ Sharing STAR files of December 2017 (n = 25,916) were analyzed.

Results

Compared with non‐HCV‐LT, HCV‐LT survival was worse in the IFN‐era (2007–2008) and IFN+DAA‐era (2011), but not in the DAA‐era (2014–2015). ACR6m rate has been less frequent in newer eras and was lower in HCV‐LT than in non‐HCV‐LT in both the DAA‐era (6.9% vs. 9.3%, P < 0.001) and in the IFN+DAA‐era (8.8% vs. 11.8%, P = 0.001), but not in the IFN‐era (10.8% vs. 11.0%, P = 0.39). HCV‐LT recipients who had ACR6m had worse 2‐year survival than those without ACR6m, in the IFN‐era (80.0% vs. 88.4%, P < 0.0001) and in the IFN+DAA‐era (81.4% vs. 89.2%, P < 0.01) but not in the DAA‐era (90.4% vs. 93.2%, P = 0.085). Cox proportional hazard model identified ACR6m as independent risk factor for mortality in HCV‐LT in the IFN‐era (HR = 1.88, P ≤ 0.001) and in the IFN+DAA‐era (HR = 1.84, P = 0.005), but not in the DAA‐era (P = n.s.).

Conclusions

Two‐year survival of HCV‐LT recipients were significantly better in the DAA‐era; these were associated with reduced rate and impact of ACR6m.