bluuebunny/crossref_metadata_2025 huggingface dataset:
An EM‐type approach for classification of bivariate MALDI‐MS data and identification of high fertility markers
Authors: Garcia N. L. , Rodrigues‐Motta M. , Belaz K. R. A. , Tata A. , França M. R. , Binelli M. , Eberlin M. N.
Published: November 2018

Dairy cows are responsible for a fair amount of gas emissions in the atmosphere (mainly methane, ammonia, and carbon dioxide), as well as waste outputs. Therefore, identifying high‐fertility breeding cows and increasing fertility rates can diminish pollution and help minimize the effect of global warming and improve the environmental impact of the farming system. As a step to achieve this goal, changes in the lipid composition of the bovine uterus exposed to greater (LF‐LCL group) or lower (SF‐SCL group) concentrations of progesterone during postovulation were investigated by matrix‐assisted laser desorption ionization mass spectrometry. Two measurements were made for each cow, and after preprocessing the data, the measurements available to analysis consist of relative intensities at significant 76 mass‐to‐charge ratio (m/z) values identifying specific ions in the spectra. Due to the small sample size, seven cows in the LF‐LCL group and 10 cows in the SF‐SCL group, the usual methods could not discriminate between groups. A model‐based approach was therefore proposed, and due to the discrete nature of the data, a truncated mixture of bivariate beta distributions was fitted to the data using an expectation–maximization algorithm. However, unlike the usual approach for mixture density estimation problems, to each 76 m/z value, we assign an unobserved label shared by all cows in the same group. The role of these labels is similar to the frailty effect in survival models in which all cows in a given group would share some random effect due to group effect. These labels will be used to identify m/z values, which could potentially account for different fertility rates.
The species dilemma and its potential impact on enforcing wildlife trade laws
Authors: Jacobs Rachel L. , Baker Barry W.
Published: November 2018

The varied answers to the question “What is a species?” provoke more than lively debates in academic circles. They pose practical problems for law enforcement. Commercial wildlife trade threatens many primate species and is regulated through such laws and international agreements as the U.S. Endangered Species Act and the Convention on International Trade in Endangered Species of Wild Fauna and Flora. Enforcing legislation relies on the ability to identify when violations occur. Species‐defining characters may not be preserved in wildlife trade items. For example, pelage patterns and behavioral characters (e.g., vocalizations) are absent from skulls. Accordingly, identifying victims of illegal trade can be difficult, which hinders enforcement. Moreover, identifying new species and “splitting” of currently recognized species can result in enforcement lags and regulatory loopholes. Although such negative consequences should not hinder scientific advancement, we suggest that they be considered by primate taxonomists and provide recommendations to prevent unintended conservation consequences.
Contrarians or momentum chasers? Individual investors’ behavior when trading exchange‐traded funds
Authors: Da Dalt Carlo , Feldman David , Garvey Gerald , Westerholm Peter Joakim
Published: November 2018

Conducting the first study of momentum impact on households’ exchange‐traded fund (ETF) trading behavior, we find that Finnish households are less contrarian when trading benchmark index ETFs than when trading common stocks. Also, their propensity to chase recent positive momentum is higher when purchasing ETFs than when purchasing stocks. As expected, results are stronger for ETF purchases than sales. Our findings are consistent with hypotheses that households are less overconfident trading index ETFs than common stocks, that contrarian behavior is more often rational when trading stocks than when trading ETFs, and that households trade ETFs for the long run.
Geochronology and geochemistry of the Tongcheng ultrapotassic hypabyssal intrusions at the south‐western margin of the Ordos Block, China: Constraints on the geodynamic processes beneath the North China Craton
Authors: Xu Huan , Luo Jin‐hai , Ren Zhan‐li , Chen Guan‐xu , Li Yi‐fei , You Jia
Published: November 2018

The Tongcheng ultrapotassic rocks intrude in Mesoproterozoic limestones in Chongxin County, Gansu Province, China, at the south‐western margin of the Ordos Block. They are characterized by high K2O and Al2O3 but low SiO2, FeOT, MgO, and CaO. The ultrapotassic rocks are relatively depleted in Nb, Ta, Ti, Zr, and Hf and enriched in the large‐ion lithophile elements Rb, Ba, and Th. Zircons from the ultrapotassic rocks yield an Early Cretaceous U–Pb age of 120 Ma. The slightly enriched whole‐rock Sr and Nd isotopic compositions ((87Sr/86Sr)i = 0.705–0.706; εNd = −4.9 to −5.2) indicate an enriched lithospheric mantle source. Combined with regional tectonic data, the Tongcheng ultrapotassic rocks were generated in an extensional environment, which were caused by the upwelling of asthenospheric mantle. Subduction of the palaeo‐Pacific Plate in Early Cretaceous resulted in large‐scale lithospheric thinning in the eastern North China Craton (NCC), which may have also occurred in the western part of the NCC, but the scale of thinning was smaller compared with that of the eastern NCC.
Geochronology and geochemistry ofca. 2.48 Ga granitoid gneisses from theYudongzi Complexin the north‐westernYangtze Block,China
Authors: Hui Bo , Dong Yunpeng , Zhang Feifei , Sun Shengsi , Liu Xiaoming , Cheng Chao , He Dengfeng
Published: November 2018

The Early Precambrian magmatism in the Archean–Palaeoproterozoic basement Yudongzi Complex is critical for understanding the early crustal formation and evolutionary history of the Yangtze Block in the South China Craton. In this paper, combined zircon UPb geochronological, zircon Hf isotopic, and whole‐rock geochemical studies are carried out on the granitoid gneisses from the Yudongzi Complex, north‐western Yangtze Block. The magmatic zircons from the granitoid gneiss yield a UPb upper intercept age of 2,477±18 Ma, interpreted as the crystallization age of the granitoid gneiss. The granitoid gneiss samples are characterized by high Al2O3contents, moderate to high Sr/Y, (La/Yb)Nand Na2O/K2O ratios, no obvious Eu and Sr anomalies, and depleted Nb, Ta, and Ti values that are similar to those of Archean trondhjemite–tonalite–granodiorite (TTG) suites, indicating that the investigated rocks belonging to TTG‐series rocks. They display pronounced enriched‐LREE patterns with high La/Yb values and relatively high Zr/Sm and Eu/Eu* but low Nb/Ta and Dy/Yb ratios, implying that these rocks were formed by partial melting within amphibolite‐facies conditions with mainly residual amphibole, garnet, and accessory rutile in the magma source. These rocks also display apparently low MgO, Mg#, Ni, and Cr contents, suggesting derivation from partial melting of thickened ancient lower crust. Zircon εHf(t) values from the granitoid gneiss sample vary from −10.1 to −6.9 with TDM2ofca. 3.59–3.40 Ga, what demonstrates their crustal source nature as well. Thus, taking all these factors together, we propose that theca. 2.48 Ga granitoid gneisses in the Yudongzi Complex might have been produced by partial melting of ancient crust material under amphibolite‐facies conditions, with primarily residual assemblages of amphibole, garnet, and attached rutile. Taking together our new data and such from previous studies, the Yangtze Block has been probably involved into a significant reworking of ancient crust event during the Early Palaeoproterozoic time.
Characteristics and formation mechanism of seafloor domes on the north‐eastern continental slope of the South China Sea
Authors: Wu Tingting , Wei Jiangong , Liu Shengxuan , Guan Yongxian , Zhang Ruwei , Su Ming , Wang Hongbin , Zhang Wei , Meng Dajiang , Liu Bin
Published: November 2018

Multibeam echo‐sounding and seismic data were obtained during three geophysical surveys by Guangzhou Marine Geological Survey (GMGS) on the north‐eastern slope of the South China Sea (SCS). Nineteen seafloor domes and numerous elongated pockmarks were distinguished in the study area. The seafloor domes vary on number of summits, shape, and spatial interrelation, based on which they were classified into four types which are single‐summit, double‐summits, elongated, and connected. Bottom simulating reflectors and blanking zone underneath were observed in the seismic profiles, indicating the potential existence of gas hydrate and free gas. Multiple faults and diapirs exist beneath the seafloor domes and pockmarks, which were inferred to provide efficient pathways for fluid migrating from deep subsurface. The seafloor domes exhibits high backscatter feature, which is potentially associated with the seep‐related gas hydrate and authigenic carbonate in the shallow sediment. It is speculated that fault and diapir activity, fault sliding caused by region extension and the interaction between neighbour domes control and affect the activity and formation of the domes. However, further investigations, including geological sampling and seafloor observation, are still needed to confirm whether they are mud volcanoes.
Lipid transporter Spns2 promotes microglia pro‐inflammatory activation in response to amyloid‐beta peptide
Authors: Zhong Liansheng , Jiang Xue , Zhu Zhihui , Qin Haiyan , Dinkins Michael B. , Kong Ji‐Na , Leanhart Silvia , Wang Rebecca , Elsherbini Ahmed , Bieberich Erhard , Zhao Yujie , Wang Guanghu
Published: November 2018

Accumulating evidence indicates that neuroinflammation contributes to the pathogenesis and exacerbation of neurodegenerative disorders, such as Alzheimer's disease (AD). Sphingosine‐1‐phosphate (S1P) is a pleiotropic bioactive lipid that regulates many pathophysiological processes including inflammation. We present evidence here that the spinster homolog 2 (Spns2), a S1P transporter, promotes microglia pro‐inflammatory activation in vitro and in vivo. Spns2 knockout (Spns2KO) in primary cultured microglia resulted in significantly reduced levels of pro‐inflammatory cytokines induced by lipopolysaccharide (LPS) and amyloid‐beta peptide 1–42 oligomers (Aβ42) when compared with littermate controls. Fingolimod (FTY720), a S1P receptor 1 (S1PR1) functional antagonist and FDA approved drug for relapsing–remitting multiple sclerosis, partially blunted Aβ42‐induced pro‐inflammatory cytokine generation, suggesting that Spns2 promotes microglia pro‐inflammatory activation through S1P‐signaling. Spns2KO significantly reduced Aβ42‐induced nuclear factor kappa B (NFκB) activity. S1P increased, while FTY720 dampened, Aβ42‐induced NFκB activity, suggesting that Spns2 activates microglia inflammation through, at least partially, NFκB pathway. Spns2KO mouse brains showed significantly reduced Aβ42‐induced microglia activation/accumulation and reduced levels of pro‐inflammatory cytokines when compared with age‐matched controls. More interestingly, Spns2KO ameliorated Aβ42‐induced working memory deficit detected by Y‐Maze. In summary, these results suggest that Spns2 promotes pro‐inflammatory polarization of microglia and may play a crucial role in AD pathogenesis.
Cognitive deficits in mice lacking Nsun5, a cytosine‐5 RNA methyltransferase, with impairment of oligodendrocyte precursor cells
Authors: Zhang Tingting , Chen Peipei , Li Wei , Sha Sha , Wang Ya , Yuan Zihao , Shen Bin , Chen Ling
Published: November 2018

Williams‐Beuren syndrome (WBS) is a microdeletion disorder with cognitive phenotype. NSUN5 gene, which encodes a cytosine‐5 RNA methyltransferase, is located in WBS deletion locus. To investigate the influence of NSUN5 deletion on cognitive behaviors, we produced single‐gene Nsun5 knockout (Nsun5‐KO) mice. Here, we report that adult Nsun5‐KO mice showed spatial cognitive deficits. Size of the brain and hippocampal structures and the number of CA1 or CA3 pyramidal cells in Nsun5‐KO mice did not differ from WT mice. Basal properties of Schaffer collateral‐CA1 synaptic transmission in Nsun5‐KO mice were unchanged, but NMDA receptor (NMDAr)‐dependent long‐term potentiation (LTP) was not induced. The NMDA‐evoked current in CA1 pyramidal cells was reduced in Nsun5‐KO mice without the changes in expression and phosphorylation of NMDAr subunits NR2A and NR2B. Although the protein level of AMPA receptor subunit GluR2 was attenuated in Nsun5‐KO mice, the AMPA‐evoked current was not altered. Hippocampal immuno‐staining showed the selective expression of Nsun5 in NG2 or PDGFRα labeled oligodendrocyte precursor cells (OPCs), but not in pyramidal cells or astrocytes. Analysis of RT‐PCR determined the Nsun5 expression in purified populations of OPCs rather than neurons or astrocytes. The Nsun5 deficiency led to decreases in the number and neurite outgrowth of OPCs in the hippocampal CA1 and DG, with the decline in NG2 expression and OPCs proliferation. These findings indicate that the Nsun5 deletion suppresses NMDAr activity in neuronal cells probably through the disrupted development and function of OPCs, leading to deficits in NMDAr‐dependent LTP and spatial cognitive abilities.
Differential roles of epigenetic regulators in the survival and differentiation of oligodendrocyte precursor cells
Authors: Egawa Naohiro , Shindo Akihiro , Hikawa Rie , Kinoshita Hisanori , Liang Anna C. , Itoh Kanako , Lok Josephine , Maki Takakuni , Takahashi Ryosuke , Lo Eng H. , Arai Ken
Published: November 2018

During development or after brain injury, oligodendrocyte precursor cells (OPCs) differentiate into oligodendrocytes to supplement the number of oligodendrocytes. Although mechanisms of OPC differentiation have been extensively examined, the role of epigenetic regulators, such as histone deacetylases (HDACs) and DNA methyltransferase enzymes (DNMTs), in this process is still mostly unknown. Here, we report the differential roles of epigenetic regulators in OPC differentiation. We prepared primary OPC cultures from neonatal rat cortex. Our cultured OPCs expressed substantial amounts of mRNA for HDAC1, HDAC2, DNMT1, and DNMT3a. mRNA levels of HDAC1 and HDAC2 were both decreased by the time OPCs differentiated into myelin‐basic‐protein expressing oligodendrocytes. However, DNMT1 or DNMT3a mRNA level gradually decreased or increased during the differentiation step, respectively. We then knocked down those regulators in cultured OPCs with siRNA technique before starting OPC differentiation. While HDAC1 knockdown suppressed OPC differentiation, HDAC2 knockdown promoted OPC differentiation. DNMT1 knockdown also suppressed OPC differentiation, but unlike HDAC1/2, DNMT1‐deficient cells showed cell damage during the later phase of OPC differentiation. On the other hand, when OPCs were transfected with siRNA for DNMT3a, the number of OPCs was decreased, indicating that DNMT3a may participate in OPC survival/proliferation. Taken together, these data demonstrate that each epigenetic regulator has different phase‐specific roles in OPC survival and differentiation.
Effectiveness and safety of reduced‐dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis
Authors: Henricks Linda M. , van Merendonk Lisanne N. , Meulendijks Didier , Deenen Maarten J. , Beijnen Jos H. , de Boer Anthonius , Cats Annemieke , Schellens Jan H.M.
Published: November 2018

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine‐associated toxicity. Upfront DPYD*2A genotype‐based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype‐guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair‐analysis was performed in which for each DPYD*2A carrier a matched DPYD*2A wild‐type patient was identified. Overall survival and progression‐free survival were compared between the matched groups. The frequency of severe (grade ≥ 3) treatment‐related toxicity was compared to 1] a cohort of 1606 wild‐type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, p = 0.47) nor progression‐free survival (median 14 months versus 10 months, p = 0.54). Risk of severe fluoropyrimidine‐related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild‐type patients (23%, p = 0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (p < 0.001). Our study is the first to show that DPYD*2A genotype‐guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine‐based chemotherapy, while resulting in significantly improved patient safety.
Interaction between genetic ancestry and common breast cancer susceptibility variants in Colombian women
Authors: Torres Diana , Lorenzo Bermejo Justo , Garcia Mesa Karen , Gilbert Michael , Briceño Ignacio , Pohl‐Zeidler Svenja , González Silos Rosa , Boekstegers Felix , Plass Christoph , Hamann Ute
Published: November 2018

Latino women show lower incidences of breast cancer (BC) than non‐Hispanic whites. Large‐scale genetic association studies have identified variants robustly associated with BC risk in European women. We examine here the relevance of these variants to Colombian BC and possible interactions with genetic ancestry. Native American, European and African proportions were estimated for 1022 Colombian BC cases and 1023 controls. Logistic regression was applied to assess the association between 78 variants and BC risk and interactions between the variants and ancestry proportions. We constructed a multifactorial risk score combining established BC risk factors, associated risk variants and individual ancestry proportions. Each 1% increase in the Native American proportion translated into a 2.2% lower BC risk (95% CI: 1.4–2.9). Thirteen variants were associated with BC in Colombian women, with allele frequencies and risk effects partially different from European women. Ancestry proportions moderated the risk effects of two variants. The ability of Native American proportions to separate Colombian cases and controls (area‐under‐the‐curve (AUC) = 0.61) was similar to the discriminative ability of family history of BC in first‐degree female relatives (AUC = 0.58) or the combined effect of all 13 associated risk variants (AUC = 0.57). Our findings demonstrate ample potential for individualized BC prevention in Hispanic women taking advantage of individual Native American proportions, information on established susceptibility factors and recently identified common risk variants.
Erroneous blood pressure readings in a patient with Multiple Hereditary Exostoses
Authors: Stein Mark , Mungekar Sagar S.
Published: November 2018

A 15 year old male with Multiple Hereditary Exostoses (MHE) developed what appeared to be profound hypotension shortly after induction of anaesthesia. All other clinical parameters, including skin color, breath sounds, heart rate, peripheral pulses, oxygen saturation and end‐tidal carbon dioxide were normal. When the cuff of the automated blood pressure device was removed and reapplied elsewhere, the blood pressure reading was normal. Examination of the original location of the cuff revealed an exostosis on the medial aspect of the proximal humerus, which had prevented the automated blood pressure device from detecting the pulsation of the artery. Had a preoperative examination of the limb been done, it may have resulted in using a different location for blood pressure monitoring, and prevented the erroneous readings. Additional issues of concern to the anaesthetist in patients with Multiple Hereditary Exostoses are discussed.
One‐lung ventilation in a patient with sickle cell disease
Authors: Francis Katharine , Collins Jonathan , Pigott David
Published: November 2018

We describe the safe management of a patient with sickle cell disease requiring one‐lung ventilation for video‐assisted thoracoscopic thymectomy. Though this technique is associated with a risk of hypoxaemia and, therefore, sickle crisis, our technique resulted in minimal disruption to haemoglobin oxygen saturations and no immediate rise in the sickle haemoglobin fraction. We have found no previous reports of the management of sickle cell disease patients presenting for surgery requiring one‐lung ventilation.
Managing Glanzmann's thrombasthenia in a developing country
Authors: Seenappa Vinayak Pujari , Mungasuvalli Nagaraj Channappa , Abloodu Manjunath Chikkapillappa , Iyer Sadasivan Shanker , Shenoy Bala Krishna
Published: November 2018

Glanzmann's thrombasthenia is a rare inherited bleeding disorder. Patients usually present with easy bruising, epistaxis and prolonged bleeding from minor trauma or procedures. Platelet transfusions are the standard therapy but recombinant activated factor VII has also been used for the treatment of bleeding episodes. We report the successful management of a patient with Glanzmann's thrombasthenia with complex cardiac pathology who presented with a massive gastrointestinal bleed requiring emergency laparotomy. We review the current options for management and highlight the problems faced by the anaesthestist in developing countries due to poor socio‐economic status of patients.
Acute stridor in a child following central venous catheterisation
Authors: Alibhai Moiz , Palmer Vanessa , Kelgeri Nivedita , Ravi Radha
Published: November 2018

A 4 month‐old male infant underwent cannulation of the right internal jugular vein as part of anaesthetic management for elective surgery. Postoperatively he developed acute stridor requiring re‐intubation via a rigid bronchoscope. Examination of airway structures showed gross distortion of the peri‐laryngeal structures. We believe that this airway complication occured as a result of fluid and drug extravasation from the central venous catheter.
Delayed fixation of a fractured neck of femur due to the use of dabigatran
Authors: Turnbull Chris , Levy Nicholas , Parsons Samuel
Published: November 2018

An 82‐year‐old lady was receiving dabigatran for the prevention of stroke in atrial fibrillation. Dabigatran is a new oral anticoagulant. Following a fall, she suffered a fractured neck of femur and acute‐on‐chronic renal impairment. The profound anticoagulation and delayed clearance of dabigatran led to a significant delay in operative intervention. The challenges posed by patients on such anticoagulants requiring emergency surgery are explored.
Urgent Caesarean section in a patient with a late presenting suspected phaeochromocytoma
Authors: Bartakke Ashish , Ricketts Peter , Thompson Rebekah
Published: November 2018

We report the anaesthetic management of a woman who presented at term with a suspected phaeochromocytoma necessitating urgent Caesarean section. Subsequent histological diagnosis confirmed diffuse adrenal medullary hyperplasia. There is little evidence or consensus regarding the optimal anaesthetic technique for caesarean section in patients with raised catecholamines. Both general [1, 2] and regional [3, 4] anaesthetic techniques have been described. We consider the benefits and drawbacks of both.
Cervical vertebral hyperostosis and difficult direct laryngoscopy in a patient for primary thyroplasty
Authors: Turnbull James , Hughes Owain , Rubin John , Patel Anil
Published: November 2018

Diffuse idiopathic skeletal hyperostosis is a disease typified by calcification of ligamentous structures, predominantly in the spine. In the cervical spine, large congruous osteophyte formation anterior to the vertebral bodies can cause significant changes to airway anatomy. Difficult facemask ventilation, direct laryngoscopy and LMA positioning have all been reported. Primary thyroplasty involves medialisation of an immobile vocal cord in order to improve voice production. An unobstructed view of the vocal cords is important to aid implant insertion but can complicate airway management. We present the case of an elderly patient undergoing primary thyroplasty with cervical vertebral hyperostosis, dysphagia, immobile vocal cord and difficult direct laryngoscopy. This case highlights the intricacies involved when anaesthetising a patient for complex vocal cord surgery with abnormal airway anatomy.
Wolff‐Parkinson‐White Syndrome and pheochromocytoma
Authors: Mungasuvalli Nagaraj Channappa , Bevinaguddaiah Yatish , Seenappa Vinayak Pujari , Chikkapillappa Manjunath Abloodu
Published: November 2018

Wolff‐Parkinson‐White syndrome is a cardiac conduction disorder. Management of a patient with WPW syndrome can be compounded when it is associated with pheochromocytoma. We describe the successful perioperative management of a rare case of pheochromocytoma associated with WPW syndrome. We reduced the potential risk of WPW syndrome associated arrythmias by ablation of the aberrant conduction tract prior to surgery.
Focus assessed transthoracic echocardiography and epidural anaesthesia for perioperative management of severe aortic stenosis
Authors: Cortegiani Andrea , Russotto Vincenzo , Cocorullo Giorgia , Genovese Giulia , Raineri Santi Maurizio , Giarratano Antonino
Published: November 2018

We report the case of an 84‐year‐old woman with severe aortic stenosis scheduled for an urgent right hemicolectomy for bleeding. We describe the use of epidural blockade for intra‐operative anaesthesia and postoperative analgesia and focus assessed transthoracic echocardiography as a perioperative haemodynamic monitoring tool. This helped us to evaluate intra‐operative haemodynamic disturbances, optimise preload and to exclude new‐onset segmental cardiac wall motion abnormalities due to myocardial ischaemia.
Kounis syndrome: ST elevation and anaphylaxis
Authors: Gallie Heather
Published: November 2018

We present a case of sudden, dramatic ST elevation followed by profound hypotension at induction of anaesthesia. This was subsequently confirmed as anaphylaxis with acute coronary involvement (Kounis syndrome) by tryptase and troponin assays. This case illustrates the variable presentation of anaphylaxis, the limitations of our current understanding of this condition and the importance of clinical judgment in balancing the management of two pathologies.
In vitro genotoxicity assessment of an oxidized dextrin‐based hydrogel for biomedical applications
Authors: Pereira Isabel , Fraga Sónia , Silva Susana , Teixeira João Paulo , Gama Miguel
Published: November 2018

Hydrogels are three‐dimensional, crosslinked networks of hydrophilic polymers swollen with a large amount of water or biological fluids, without dissolving. Dextrin, a low‐molecular‐weight carbohydrate composed by glucose residues, has been used to develop an injectable hydrogel for biomedical applications. Dextrin was first oxidized to introduce aldehyde groups, which then reticulate with adipic acid dihydrazide, forming the dextrin‐based hydrogel (HG). The HG and its components were tested for cyto‐ and genotoxicity according to the International Standard ISO 10993‐3 on the biological evaluation of medical devices. To assess genotoxicity, a battery of in vitro genotoxicity tests employing both eukaryotic and prokaryotic models was performed: comet assay, cytokinesis‐block micronucleus assay and Ames test. Our data revealed that the HG (IC50 = 2.8 mg/mL) and oxidized dextrin by itself (IC50 = 1.2 mg/mL) caused a concentration‐dependent decrease in cellular viability of human lymphoblastoid TK6 cells after 24 hours of exposure to the test agents. However, these concentrations are unlikely to be reached in vivo. In addition, no significant increase in the DNA and chromosomal damage of TK6 cells exposed to non‐cytotoxic concentrations of the HG and its isolated components was detected. Furthermore, neither the HG nor its metabolites exerted a mutagenic effect in different of Salmonella typhimurium strains and in an Escherichia coli mix. Our data demonstrated the genocompatibility of the HG (up to 3.5 mg/mL) for biomedical applications. To our best acknowledge, this is the first report with a detailed genotoxicity assessment of an aldehyde‐modified polysaccharide/adipic acid dihydrazide hydrogel.
In vivo monitoring blood‐brain barrier permeability using spectral imaging through optical clearing skull window
Authors: Feng Wei , Zhang Chao , Yu Tingting , Semyachkina‐Glushkovskaya Oxana , Zhu Dan
Published: November 2018

The blood‐brain barrier (BBB) plays a key role in the health of the central nervous system. Opening the BBB is very important for drug delivery to brain tissues to enhance the therapeutic effect on brain diseases. It is necessary to in vivo monitor the BBB permeability for assessing drug release with high resolution; however, an effective method is lacking. In this work, we developed a new method that combined spectral imaging with an optical clearing skull window to in vivo dynamically monitor BBB opening caused by 5‐aminolevulinic acid (5‐ALA)‐mediated photodynamic therapy (PDT), in which the Evans blue dye (EBd) acted as an indicator of the BBB permeability. Using this method, we effectively monitored the cerebrovascular EBd leakage process. Moreover, the analysis of changes in the vascular and extravascular EBd concentrations demonstrated that the PDT‐induced BBB opening exhibited spatiotemporal differences in the cortex. This spectral imaging method based on the optical clearing skull window provides a low‐cost and simply operated tool for in vivo monitoring BBB opening process. This has a high potential for the visualization of drug delivery to the central nervous system. Thus, it is of tremendous significance in brain disease therapy. Monitoring the changes in PDT‐induced BBB permeability by evaluating the EBd concentration using an optical clearing skull window. (A) Entire brains and coronal sections following treatment of PDT with/without an optical clearing skull window after injection of EBd. (B) Typical EBd distribution maps before and after laser irradiation captured by the spectral imaging method. (Colorbar represents the EBd concentration).
LncRNA MALAT1 promotes oxidized low‐density lipoprotein‐induced autophagy in HUVECs by inhibiting the PI3K/AKT pathway
Authors: Li Shu , Pan Xudong , Yang Shaonan , Ma Aijun , Yin Shuangshuang , Dong Yi , Pei Haotian , Bi Xinran , Li Wei
Published: November 2018

Emerging evidence suggests that long noncoding RNAs (lncRNAs) are involved in many biological processes, such as cell growth, differentiation, apoptosis, and autophagy. Metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1), highly expressed in endothelial cells, is well conserved and implicated in endothelial cell migration and proliferation. However, whether MALAT1 participates in oxidized low‐density lipoprotein (ox‐LDL)‐induced autophagy regulation in human umbilical vein endothelial cells (HUVECs) remains unknown. In this study, we observed that autophagy was upregulated and MALAT1 expression was markedly increased in HUVECs treated with ox‐LDL. The ox‐LDL‐induced autophagy of HUVECs is significantly associated with the PI3K/AKT pathway. Furthermore, we found that MALAT1 overexpression inhibited PI3K, Akt and p70S6K phosphorylation and downregulated RHEB expression, simultaneously increasing ox‐LDL‐induced autophagy. MALAT1 silencing caused higher phosphorylated PI3K, Akt and p70S6K levels, upregulated RHEB expression and markedly suppressed autophagy. These results indicated that lncRNA MALAT1 promotes ox‐LDL‐induced autophagy in HUVECs partly through the PI3K/AKT signaling pathway.
LincRNA‐p21 enhances the sensitivity of radiotherapy for gastric cancer by targeting the β‐catenin signaling pathway
Authors: Chen Lijun , Yuan Dongfang , Yang Yichen , Ren Minzhu
Published: November 2018

Long noncoding RNAs (lncRNAs) are a large and diverse class of transcribed RNA molecules with a length of more than 200 nucleotides that modulate the gene expression at the posttranscriptional or transcriptional level. LncRNAs played crucial roles in many biological processes, such as cell proliferation, metastasis, and migraton. In this study, we evaluated the role of lincRNA‐p21 in the gastric cancer (GC). We demonstrated that the expression level of lincRNA‐p21 was downregulated in the GC tissues and cell lines. Moreover, ectopic expression of lincRNA‐p21 suppressed the GC cell growth, cell cycle, and migration. Furthermore, we demonstrated that the X‐ray increased the expression level of lincRNA‐p21 in both the HCG‐27 and SGC7901 cells and elevated expression of lincRNA‐p21 increased the radiotherapy sensitivity of the GC cell. In addition, we showed that ectopic expression of lincRNA‐p21 suppressed the β‐catenin and c‐myc expression. Overexpression of lincRNA‐p21 inhibited the GC cell proliferation and increased the radiosensitivity of GC cells by regulating the β‐catenin signaling pathway. These data suggested that lincRNA‐p21 acted as a tumor suppressor gene in the development of GC.
miR‐203 accelerates apoptosis and inflammation induced by LPS via targeting NFIL3 in cardiomyocytes
Authors: Li Yang , Liu Xiping , Du Aolin , Zhu Xiaolong , Yu Bo
Published: November 2018

Myocarditis is an inflammatory disease of the myocardium. MicroRNA‐203 (miR‐203) is involved in various physiological and pathological processes. In this work, we aimed to explore the roles and potential mechanisms of miR‐203 in myocarditis in vitro. Cardiomyocyte H9c2 was subjected to 10 μg/mL lipopolysaccharide (LPS) for 24 hours. Real‐time polymerase chain reaction analysis revealed that LPS upregulated miR‐203 expression in H9c2 cells. Cell counting kit‐8 (CCK‐8) and lactate dehydrogenase (LDH) assays demonstrated that inhibition of miR‐203 reduced cell injury induced by LPS. The cell apoptosis rate, caspase 3 activity, caspase 3/7 activities, and the expression of cleaved‐caspase 3 (c‐caspase 3) were declined upon miR‐203 depletion. In addition, miR‐203 silencing attenuated the expression and production of inflammatory cytokines (tumor necrosis factor‐α, interleukin [IL]‐6, and IL‐8). On the contrary, overexpression of miR‐203 showed the opposite trend in cell apoptosis and inflammation. Luciferase reporter assay confirmed that miR‐203 could bind with the nuclear factor interleukin‐3 (NFIL3) 3′‐untranslated regions (3′‐UTR), and miR‐203 regulated the expression of NFIL3 negatively. Moreover, NFIL3 silencing partly abolished the myocardial protective functions of miR‐203 inhibitor. Herein, we suggest that miR‐203 promoted cell apoptosis and inflammation induced by LPS via targeting NFIL3.
Pyrazinamide resistance and mutations L19R, R140H, and E144K in Pyrazinamidase of Mycobacterium tuberculosis
Authors: Khan Muhammad Tahir , Junaid Muhammad , Mao Xueying , Wang Yanjie , Hussain Abid , Malik Shaukat Iqbal , Wei Dong‐Qing
Published: November 2018

Pyrazinamide (PZA) is an important component of first‐line antituberculosis drugs activated by Mycobacterium tuberculosis pyrazinamidase (PZase) into its active form pyrazinoic acid. Mutations in the
pncA gene have been recognized as the major cause of PZA resistance. We detected some novel mutations, Leucine19Arginine (L19R), Arginine140Histidine (R140H), and Glutamic acid144 Lysine (E144K), in the
pncA gene of PZA‐resistant isolates in our wet lab PZA drug susceptibility testing and sequencing. As the molecular mechanism of resistance of these variants has not been reported earlier, we have performed multiple analyses to unveil different mechanisms of resistance because of PZase mutations L19R, R140H, and E144K. The mutants and native PZase structures were subjected to comprehensive computational molecular dynamics (MD) simulations at 100 nanoseconds in apo and drug‐bound form. Mutants and native PZase binding pocket were compared to observe the consequence of mutations on the binding pocket size. Hydrogen bonding, Gibbs free energy, and natural ligand Fe
+2 effect were also analyzed between native and mutants. A significant variation between native and mutant PZase structure activity was observed. The native PZase protein docking score was found to be the maximum, showing strong binding affinity in comparison with mutants. MD simulations explored the effect of the variants on the biological function of PZase. Hydrogen bonding, metal ion Fe
+2 deviation, and fluctuation also seemed to be affected because of the mutations L19R, R140H, and E144K. The variants L19R, R140H, and E144K play a significant role in PZA resistance, altering the overall activity of native PZase, including metal ion Fe
+2 displacement and free energy. This study offers valuable evidence for better management of drug‐resistant tuberculosis.
USP28 contributes to the proliferation and metastasis of gastric cancer
Authors: Zhao Li‐Juan , Zhang Ting , Feng Xue‐Jian , Chang Jiao , Suo Feng‐Zhi , Ma Jin‐Lian , Liu Ying‐Jun , Liu Ying , Zheng Yi‐Chao , Liu Hong‐Min
Published: November 2018

USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0.01), and its overexpression was related to the degree of differentiation and metastases. Inhibiting USP28 expression in vitro suppressed the proliferation and invasion of gastric cancer cells by downregulating lysine specific demethylase 1. On the basis of our data, it can be concluded that USP28 may be a novel therapeutic target for gastric cancer.
Resveratrol improves ex vivo expansion of CB‐CD34+ cells via downregulating intracellular reactive oxygen species level
Authors: Tang Chaochun , Zhang Weiwei , Cai Haibo , Ye Zhaoyang , Zhang Xu , Tan Wensong
Published: November 2018

Intracellular reactive oxygen species (ROS) play important roles in the ex vivo expansion of hematopoietic stem and progenitor cells (HSPCs). In this study, the effects of resveratrol (RES), on the ex vivo expansion of HSPCs were investigated by analyzing CD34+ cells expansion and biological functions, with the objective to optimize ex vivo culture conditions for CD34
+ cells. Among the five tested doses (0, 0.1, 1, 10, 20, and 50 μM), 10 μM RES was demonstrated to be the most favorable for ex vivo CD34
+ cells expansion. In the primary cultures, 10 μM RES favored higher expansion folds of CD34
+ cells, CD34
+CD38
− cells, and colony‐forming units (CFUs) (
P < 0.05). It was found that the percentages of primitive HSPCs (CD34
+CD38
−CD45R
−CD49f
+CD90
+ cells) in 10 μM RES cultures were higher than those without RES. Further, in the secondary cultures, expanded CD34
+ cells derived from primary cultures with 10 μM RES exhibited significantly higher total cells and CD34
+ cells expansion (
P < 0.05). In the semisolid cultures, the frequency of CFU‐GM and total CFUs of 10 μM RES group were both higher than those of without RES group, demonstrating that CD34
+ cells expanded with 10 μM RES possessed better biological function. Furthermore, the addition of 10 μM RES downregulated the intracellular ROS level via strengthening the scavenging capability of ROS, and meanwhile reducing the percentages of apoptotic cells in cultures. Collectively, RES could stimulate the ex vivo expansion of CD34
+ cells, preserved more primitive HSPCs and maintain better biological function by alleviating intracellular ROS level and cell apoptosis in cultures.
KDM4B promotes gastric cancer metastasis by regulating miR‐125b‐mediated activation of Wnt signaling
Authors: Jing Jia‐Chen , Feng Zhen , Chen Zhong‐Hua , Ji Bei‐Na , Hong Jing , Tang Nan , Yu Jin Ling , Wang Shao‐Ying
Published: November 2018

Emerging evidence has demonstrated that the aberrant expression of histone‐modifying enzymes such as histone demethylases contributes to gastric carcinogenesis and progression. The role of KDM4B in cancer progression has been gradually revealed. However, the underlying mechanisms regulating gastric cancer metastasis of KDM4B remain unclear. In the present study we determined KDM4B expression in gastric cancer and its biologic function in vitro and in vivo. We found that KDM4B expression was significantly increased in most gastric cancer tissues compared with the adjacent normal tissues. Upregulated expression of KDM4B in human gastric cancer was correlated with poor prognosis. In vitro, KDM4B overexpression in AGS cells promoted cell invasion, whereas knockdown of KDM4B inhibited cell invasion. Furthermore, KDM4B overexpression also promoted tumor metastasis in vivo. Mechanistically, KDM4B upregulated miR‐125b expression and activated Wnt signaling pathway. More important, miR‐125b partially mediated KDM4B‐induced activation of Wnt signaling. Finally, we demonstrated that KDM4B promoted gastric cancer cell invasion in vitro and cancer metastasis in vivo, at least in part, by upregulating miR‐125b expression. These data provided novel insights on the role of KDM4B‐driven gastric cancer metastasis and indicated that KDM4B may be served as a potential target for gastric cancer.
Silencing of long noncoding RNA MEG3 enhances cerebral protection of dexmedetomidine against hypoxic‐ischemic brain damage in neonatal mice by binding to miR‐129‐5p
Authors: Zhou Xiu‐Min , Liu Jie , Wang Ying , Zhang Man‐He
Published: November 2018

Hypoxic‐ischemic brain damage (HIBD) is a leading cause of neonatal acute mortality and chronic nervous system injury. Recently, it has been found that long noncoding RNAs (lncRNAs) play a significant role in the neurodevelopment and etiopathogenesis of HIBD. Here, the researchers aimed to determine the role of lncRNA maternally expressed gene (MEG3) in the therapeutic effect of dexmedetomidine (DEX) in neonatal mice with HIBD through the regulation of microRNA‐129‐5p (miR‐129‐5p). HIBD models were established in C57/BL6 neonatal mice. Subsequently, the target relationship between MEG3 and miR‐129‐5p was predicted and verified. The neonatal mice were injected with DEX, ad‐shMEG3, and mimics and inhibitors of miR‐129‐5p to identify roles of MEG3 and miR‐129‐5p in therapeutic effects of DEX on neuronal apoptosis and injury, cerebral atrophy, and learning and memory ability of neonatal mice with HIBD. MEG3 directly targeted and inhibited the expression of miR‐129‐5p. Silencing of MEG3 or upregulation of miR‐129‐5p effectively promoted the therapeutic effect of DEX on neonatal mice with HIBD. Silencing of MEG3 or upregulation of miR‐129‐5p reduced the neuronal apoptosis rate and degree of cerebral atrophy, and also enhanced the learning and memory ability of HIBD neonatal mice. Collectively, the key findings obtained from the present study support the notion that MEG3 silencing enhances the therapeutic effect of DEX on neonatal mice with HIBD by binding to miR‐129‐5p.
Overexpression of miR‐98 attenuates neuropathic pain development via targeting STAT3 in CCI rat models
Authors: Zhong Liang , Fu Kui , Xiao Weimin , Wang Fang , Shen Lu‐Lu
Published: November 2018

MicroRNA (miRNA) are significant regulators of neuropathic pain development and neuroinflammation can contribute a lot to the progression of neuropathic pain. Recently, miR‐98 has been reported to be involved in various diseases. However, little is known about the role of miR‐98 in neuropathic pain development and neuroinflammation. Therefore, our study was aimed to investigate the function of miR‐98 in neuropathic pain via establishing a rat model using chronic constriction injury (CCI) of the sciatic nerve. Here, we observed that miR‐98 was downregulated in CCI rat models. Overexpression of miR‐9 was able to inhibit neuropathic pain progression. Recently, STAT3 has been reported to serve a key role in various processes, including inflammation. Interestingly, our study indicated that STAT3 was dramatically upregulated and activated in CCI rats. By using informatics analysis, STAT3 was predicted as a direct target of miR‐98 and the direct correlation was confirmed. Then, miR‐98 was overexpressed in CCI rats and it was found that miR‐98 was able to repress neuropathic pain development via inhibiting the neuroinflammation. As displayed, interleukin 6 (IL‐6), IL‐1β, and tumor necrosis factor‐α (TNF‐α) expression was obviously induced in CCI rats, while miR‐98 reduced their protein levels. Finally, we found that overexpression of STAT3 reversed the inhibitory effect of miR‐98 on neuropathic pain development. Taken these together, we reported that overexpression of miR‐98 attenuated neuropathic pain development via targeting STAT3 in CCI rat models.
MicroRNA‐9 inhibits retinal neovascularization in rats with diabetic retinopathy by targeting vascular endothelial growth factor A
Authors: Liu Wen‐Lan
Published: November 2018

Diabetic retinopathy (DR) is a leading cause of adult visual impairment and loss. This study aims to explore the effects of microRNA‐9 (miR‐9) on retinal neovascularization during DR by targeting the vascular endothelial growth factor A (VEGFA). DR rat models were successfully established. Retinal microvascular endothelial cells (RMECs) of DR rats were isolated and treated with miR‐9 mimic, miR‐9 inhibitor or small interfering RNA (siRNA)‐VEGFA. The expressions of miR‐9, VEGFA, and cluster of differentiation 31 (CD31) of the rats’ tissues and cells were examined. The targeting relationship between miR‐9 and VEGFA was testified. The tubule formation, the cell proliferation and the periodic distribution and apoptosis were evaluated after transfection. In the retinal tissues of DR rats, miR‐9 expression decreased while the expression of VEGFA and CD31 increased. Notably, miR‐9 targeted and inhibited VEGFA expression. In response to the treatment of miR‐9 mimic and siRNA‐VEGFA, a reduction was identified in CD31 expression, tubule formation, and proliferation of RMECs and cell ratio in the S phase, but an increase was observed in apoptosis rate of RMECs. The treatment of miR‐9 inhibitor reversed the manifestations. Our study demonstrated that miR‐9 could inhibit retinal neovascularization of DR and tubule formation, and promote apoptosis in RMECs by targeting VEGFA.