bluuebunny/crossref_metadata_2025 huggingface dataset:
Seismic Performance of Full‐Scale Joints Composed by Concrete‐Filled Steel Tube Column and Reinforced Concrete Beam with Steel Plate‐Stud Connections
Authors: Li Zhenbao , Liu Yashuang , Ma Hua , Wang Qianqian , Tang Zhenyun
Published: March 2019

A concrete‐filled steel tube (CFST) column has the advantages of high bearing capacity, high stiffness, and good ductility, while reinforced concrete (RC) structure systems are familiar to engineers. The combinational usage of CFST and RC components is playing an important role in contemporary projects. However, existing CFST column‐RC beam joints are either too complex or have insufficient stiffness at the interface, so their practical engineering application has been limited. In this study, the results of a practical engineering project were used to develop two kinds of CFST column‐RC beam joints that are connected by vertical or U‐shaped steel plates and studs. The seismic performance of full‐scale column‐beam joints with a shear span ratio of 4 was examined when they were subjected to a low‐cyclic reversed loading test. The results showed a plump load‐displacement curve for the CFST column‐RC beam joint connected by steel plates and studs, and the connection performance satisfied the building code. The beam showed a bending failure mode similar to that of traditional RC joints. The failure area was mainly concentrated outside the steel plate, and the plastic hinge moved outward from the ends of the beam. When the calculated cross section was set at the ends of the beam, the bending capacity of joints with the vertical or U‐shaped steel plates and studs increased compared to the RC joint. However, when the calculated cross section was set to the failure area, the capacity was similar to that of the RC joint. The proposed joints showed increases in the energy dissipation, average energy dissipation coefficient, and ductility coefficient compared to the RC joint.
Modification of Jet Structure in High-Multiplicity pp Collisions due to Multiple-Parton Interactions and Observing a Multiplicity-Independent Characteristic Jet Size
Authors: Varga Zoltán , Vértesi Róbert , Barnaföldi Gergely Gábor
Published: March 2019

We study the multiplicity dependence of jet structures in pp collisions using Monte Carlo event generators. We give predictions for multiplicity-differential jet structures and present evidence for a nontrivial jet shape dependence on charged hadron event multiplicity that can be used as a sensitive tool to experimentally differentiate between equally well-preforming simulation tunes. We also propose a way to validate the presence and extent of effects such as multiple-parton interactions (MPI) or color reconnection (CR), based on the detection of nontrivial jet shape modification in high-multiplicity events at high pT. Using multiplicity-dependent jet structure observables in various pT windows might also help understanding the interplay between jet particles and the underlying event (UE). We introduce a multiplicity-independent characteristic jet size measure and use a simplistic model to aid its physical interpretation.
The Differential Expression of Mitochondrial Function-Associated Proteins and Antioxidant Enzymes during Bovine Herpesvirus 1 Infection: A Potential Mechanism for Virus Infection-Induced Oxidative Mitochondrial Dysfunction
Authors: Fu Xiaotian , Jiang Xinyi , Chen Xinye , Zhu Liqian , Zhang Gaiping
Published: March 2019

Reactive oxidative species (ROS) are important inflammatory mediators. Electrons escaping from the mitochondrial electron transport chain (ETC) during oxidative phosphorylation (OXPHOS) in the mitochondrial respiratory chain (RC) complexes contribute to ROS production. The cellular antioxidant enzymes are important for maintaining ROS release at the physiological levels. It has been reported that BoHV-1 infection induces overproduction of ROS and oxidative mitochondrial dysfunction in cell cultures. In this study, we found that chemical interruption of RC complexes by TTFA (an inhibitor of RC complex II), NaN3 (an inhibitor of RC complex IV), and oligomycin A (an inhibitor of ATP synthase) consistently decreased virus productive infection, suggesting that the integral processes of RC complexes are important for the virus replication. The virus infection significantly increased the expression of subunit SDHB (succinate dehydrogenase) and MTCO1 (cytochrome c oxidase subunit I), critical components of RC complexes II and IV, respectively. The expression of antioxidant enzymes including superoxide dismutase 1 (SOD1), SOD2, catalase (CAT), and glutathione peroxidase 4 (GPX4) was differentially affected following the virus infection. The protein TFAM (transcription factor A, mitochondrial) stimulated by either nuclear respiratory factor 1 (NRF1) or NRF2 is a key regulator of mitochondrial biogenesis. Interestingly, the virus infection at the late stage (at 16 h after infection) stimulated TFAM expression but decreased the levels of both NRF1 and NRF2, indicating that virus infection activated TFAM signaling independent of either NRF1 or NRF2. Overall, this study provided evidence that BoHV-1 infection altered the expression of molecules associated with RC complexes, antioxidant enzymes, and mitochondrial biogenesis-related signaling NRF1/NRF2/TFAM, which correlated with the previous report that virus infection induces ROS overproduction and mitochondrial dysfunction.
Postinfectious Acute Glomerulonephritis in Renal Transplantation: An Emergent Aetiology of Renal Allograft Loss
Authors: Molina-Andújar Alícia , Montagud-Marrahí Enrique , Cucchiari David , Ventura-Aguiar Pedro , De Sousa-Amorim Erika , Revuelta Ignacio , Cofan Frederic , Solé Manel , García-Herrera Adriana , Diekmann Fritz , Poch Esteban , Quintana Luis F.
Published: March 2019

Despite the high incidence of posttransplant infections, postinfectious acute glomerulonephritis (PIAGN) in renal allograft is a rare entity, without effective treatment and a bad prognosis. We describe two cases of PIAGN: the first one was developed 2 years after kidney transplantation, secondary to Staphylococcus aureus bacteremia with presence of extracapillary proliferation in biopsy. The patient was treated with methylprednisolone and plasma exchanges without response, remaining dialysis dependent. The second case was reported 5 years after kidney transplantation, secondary to influenza A infection. Kidney biopsy showed an IgA-dominant PIAGN and methylprednisolone boluses were initiated without clinical response, suffering a progressive worsening and loss of kidney graft. Due to the aggressive clinical course of this entity, PIAGN should be considered in the differential diagnosis of acute kidney graft failure in the context of an infection. Elderly patients have a higher risk of more severe acute renal dysfunction, requiring dialysis in a great proportion of cases.
T1 Vertebra Pedicular Osteoid Osteoma: Minimally Invasive Surgical Resection Aided by New Integrated Navigation to 3D Imaging Device
Authors: Prod’homme M. , Cavalié G. , Kerschbaumer G. , Valmary-Degano S. , Boudissa M. , Tonetti J.
Published: March 2019

We hereby describe a minimally invasive resection of a T1 pedicular osteoid osteoma next to the vertebral canal. The patient had an 18-month report of painful radiculopathy. We performed the surgery under 3D imaging guidance using navigation with an all-in-one device. Full procedure irradiation was 1.17 mSv for a 181-picture acquisition. Complete operative time incision to closure was 58 minutes. Despite sparing the vertebral stability without any fixation, the tumor resection was well-margined, thanks to the focused guidance. After surgery, the patient had complete relief of his symptoms at the 6-month follow-up. 3D imaging system coupled to navigation made the procedure safe without consuming time. The single Surgivisio® device allows comfortable 3D minimally invasive spine navigation surgery with the ergonomics of a C-arm.
Covariance Matrix Reconstruction for Direction Finding with Nested Arrays Using Iterative Reweighted Nuclear Norm Minimization
Authors: Tan Weijie , Feng Xi’an
Published: March 2019

In this paper, we address the direction finding problem in the background of unknown nonuniform noise with nested array. A novel gridless direction finding method is proposed via the low-rank covariance matrix approximation, which is based on a reweighted nuclear norm optimization. In the proposed method, we first eliminate the noise variance variable by linear transform and utilize the covariance fitting criteria to determine the regularization parameter for insuring robustness. And then we reconstruct the low-rank covariance matrix by iteratively reweighted nuclear norm optimization that imposes the nonconvex penalty. Finally, we exploit the search-free DoA estimation method to perform the parameter estimation. Numerical simulations are carried out to verify the effectiveness of the proposed method. Moreover, results indicate that the proposed method has more accurate DoA estimation in the nonuniform noise and off-grid cases compared with the state-of-the-art DoA estimation algorithm.
On the Development of an Optimal Structure of Tree Parity Machine for the Establishment of a Cryptographic Key
Authors: Salguero Dorokhin Édgar , Fuertes Walter , Lascano Edison
Published: March 2019

When establishing a cryptographic key between two users, the asymmetric cryptography scheme is generally used to send it through an insecure channel. However, given that the algorithms that use this scheme, such as RSA, have already been compromised, it is imperative to research for new methods of establishing a cryptographic key that provide security when they are sent. To solve this problem, a new branch known as neural cryptography was born, using a modified artificial neural network called Tree Parity Machine or TPM. Its purpose is to establish a private key through an insecure channel. This article proposes the analysis of an optimal structure of a TPM network that allows generating and establishing a private cryptographic key of 512-bit length between two authorized parties. To achieve this, the combinations that make possible to generate a key of that length were determined. In more than 15 million simulations that were executed, we measured synchronization times, the number of steps required, and the number of times in which an attacking TPM network manages to imitate the behaviour of the two networks. The simulations resulted in the optimal combination, minimizing the synchronization time and prioritizing security against the attacking network. Finally, the model was validated by applying a heuristic rule.
Vitamin D Receptor Gene Polymorphism: An Important Predictor of Arthritis Development
Authors: Mukhtar Maryam , Sheikh Nadeem , Suqaina Saira Kainat , Batool Andleeb , Fatima Naz , Mehmood Rabia , Nazir Sabeen
Published: March 2019

Vitamin D is an anti-inflammatory molecule and has a role in prevention of arthritis development. Biologically active form 1, 25(OH)2D3 of vitamin D can only exert its action after binding its definite vitamin D receptor encoded by VDR gene. VDR gene polymorphism leads to dysfunctioning of 1, 25(OH)2D3 ultimately disease onset. The purpose of current study was to evaluate the effect of vitamin D level and VDR gene polymorphism on rheumatoid arthritis and osteoarthritis. Blood samples were collected from case and control after taking written consent. Serum was separated and vitamin D level as determined from each sample by ELISA. DNA was extracted from each blood sample and amplified by using gene specific primers. Genotyping was performed by Sangers sequencing and PCR-RFLP technique. It was found that vitamin D level was not significantly different among patients and controls. The rs10735810, rs1544410, rs7975232, and rs731236 were associated with the onset of arthritis at both allelic and genotypic level (p < 0.01). Nucleotide change on rs10735810 site leads to change of tryptophan with arginine. The frequencies of haplotype CGAT, CGGA, CGGT, CTAA, CTAT, TGAA, TGAT, TGGA, and TTGA were higher in patients and act as risk factors of RA onset, whereas haplotypes CGAT, CGAT, CGGT, CTGA, TGAT, TGGA, TTAA, and TTGA were associated with OA onset. In conclusion, serum vitamin D level may be normal among arthritis patients but polymorphism on VDR gene restricts vitamin D to perform its anti-inflammatory function by altering the 1, 25(OH)2 D3 binding sites.
Spatiotemporal Distribution Characteristics of Mesoscale Convective Systems Producing Short-Duration Heavy Rainfall over the Tianshan Mountain Area
Authors: Li Jiangang , Yang Lianmei , Liu Wen , Jiang Cailian
Published: March 2019

Based on hourly precipitation data and FY-2 satellite infrared (IR) digital satellite imagery collected during the warm season from 2005 to 2015 in the Tianshan Mountains and the adjacent areas in Xinjiang, China, the definition of mesoscale convective systems (MCSs) was revised based on short-duration heavy precipitation processes. The spatiotemporal development of MCSs in terms of the initiation, maturation, dissipation, duration, and movement was statistically analyzed. Most mesoscale systems in the area were dominated by meso-β convective systems (MβCSs), which was in line with the annual heavy precipitation frequency. In meso-α convective systems (MαCSs), persistent elongated convective systems (PECSs) occurred more commonly than mesoscale convective complexes (MCCs). MCSs were common in summer, with the peak frequency of MαCS occurrence in June and the peak frequency of MβCS occurrence mainly in July and August. From the perspective of diurnal variations, MCSs initiated in the late afternoon, developed during the evening, and dissipated before midnight. MCSs in general lasted 6∼9 h between June and July and 9∼11 h in August. The MαCSs lasted approximately 14 h, and the MβCSs lasted from 7 h to 12 h. The development and termination stages of MCSs lasted 3∼6 h and 2∼7 h, respectively. In low-elevation areas and on the windward slope of the mountains, MCSs initiated more easily and more frequently over the northern and western slopes than that over the southern and eastern slopes. The central area of the Junggar basin hosted the development of MCSs, but the distribution of the convective systems at different scales varied. During the termination stage, these mesoscale systems were mainly located at the basin edges. In terms of tracks, most MCSs moved eastward under the influence of the westerlies and the MαCSs moved faster but in a more scattered manner than the MβCSs. Additionally, some unusual tracks appeared because of the effects of the underlying surface topography and environmental wind.
Dynamic Profile of CD4+ T-Cell-Associated Cytokines/Chemokines following Murine Myocardial Infarction/Reperfusion
Authors: Yuan Dongsheng , Tie Jinjun , Xu Zhican , Liu Guanya , Ge Xinyu , Wang Zhulin , Zhang Xumin , Gong Shiyu , Liu Gang , Meng Qingshu , Lin Fang , Liu Zhongmin , Fan Huimin , Zhou Xiaohui
Published: March 2019

CD4+ T-cells play crucial roles in the injured heart. However, the way in which different CD4+ T subtypes function in the myocardial infarction/reperfusion (MI/R) heart is still poorly understood. We aimed to detect the dynamic profile of distinct CD4+ subpopulation-associated cytokines/chemokines by relying on a closed-chest acute murine MI/R model. The protein levels of 26 CD4+ T-cell-associated cytokines/chemokines were detected in the heart tissues and serum of mice at day 7 and day 14 post-MI/R or sham surgery. The mRNA levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α were measured in blood mononuclear cells. The protein levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α increased in both injured heart tissues and serum, while IFN-γ, IL-12P70, IL-2, IL-1β, IL-18, TNF-α, IL-5, IL-9, IL-17A, IL-23, IL-10, eotaxin, MIP-1α, RANTES, MCP-1, and MIP-2 increased only in MI/R heart tissues in the day 7 and day 14 groups compared to the sham group. In serum, the IFN-γ, IL-23, and IL-10 levels were downregulated in the MI/R model at both day 7 and day 14 compared to the sham. Compared with the protein expressions in injured heart tissues at day 7, IFN-γ, IL-12P70, IL-2, IL-18, TNF-α, IL-6, IL-4, IL-5, IL-9, IL-17A, IL-23, IL-27, IL-10, eotaxin, IP-10, RANTES, MCP-1, MCP-3, and GRO-α were reduced, while IL-1β and MIP-2 were elevated at day 14. IL-13 and MIP-1β showed higher levels in the MI/R serum at day 14 than at day 7. mRNA levels of IL-4, IL-6, IL-13, and IL-27 were increased in the day 7 group compared to the sham, while MIP-1β, MCP-3, and GRO-α mRNA levels showed no significant difference between the MI/R and sham groups in blood mononuclear cells. Multiple CD4+ T-cell-associated cytokines/chemokines were upregulated in the MI/R hearts at the chronic stage. These results provided important evidence necessary for developing future immunomodulatory therapies after MI/R.
Investigation of Efficacy Enhancing and Toxicity Reducing Mechanism of Combination of Aconiti Lateralis Radix Praeparata and Paeoniae Radix Alba in Adjuvant-Induced Arthritis Rats by Metabolomics
Authors: Xie Yun-fei , Feng Wu-wen , Liu Mei-chen , Xie Jun , Yu Lei , Gong Xiao-hong , Li Yun-xia , Peng Cheng
Published: March 2019

Combination of Aconiti Lateralis Radix Praeparata (FZ) and Paeoniae Radix Alba (BS) shows a significant effect in rheumatoid arthritis (RA). This study aimed to investigate the efficacy enhancing and toxicity reducing mechanism of combination of them in adjuvant-induced arthritis (AIA) rats by metabolomics. Rats were randomly divided into seven groups, including A (healthy control), B (model control), C1 (therapy group), C2 (efficacy enhancing group), D1 (toxicity group), and D2 (toxicity reducing group), and dexamethasone group was used as positive control. The plasma biochemical indexes showed that therapeutic dose of lipid-soluble alkaloids of FZ could significantly inhibit the concentrations of IL-1β, TNF-α, and IFN-γ in AIA rats, and combination with total glucosides of peony could further reduce the concentration of IL-1β. Then, UPLC-LTQ/Orbitrap MS with untargeted metabolomics was performed to identify the possible metabolites and pathways. Through multivariate data analysis of therapeutic dose groups (A vs. B vs. C1 vs. C2) and multivariate data analysis of toxic dose groups (A vs. B vs. D1 vs. D2), 10 and 7 biomarkers were identified based on biomarker analysis, respectively. After inducing AIA model, the plasma contents of spermidine, vanillylmandelic acid, catechol, and linoleate were increased significantly, and the contents of citric acid, L-tyrosine, L-phenylalanine, leucine, L-tryptophan, and uridine 5'-monophosphate (UMP) were decreased significantly. High dose of lipid-soluble alkaloids of FZ could increase the plasma contents of L-lysine, L-arginine, and deoxycholic acid, while the plasma contents of UMP, carnitine, N-formylanthranilic acid, and adenosine were decreased significantly. The pathway analysis indicated that therapeutic dose of lipid-soluble alkaloids of FZ could regulate energy and amino acid metabolic disorders in AIA rats. However, toxic dose could cause bile acid, fat, amino acid, and energy metabolic disorders. And combination with total glucosides of peony could enhance the therapeutic effects and attenuate the toxicity induced by lipid-soluble alkaloids of FZ.
Numerical Investigation of Distribution Laws of Shear Force in Box Girder Webs
Authors: Xue Xingwei , Zang Chao , Zhou Junlong , Zhang Hai
Published: March 2019

To study the shear force distribution laws of a box girder with a single-box multichamber (SB-MC) configuration for different supporting conditions, numbers of webs, stiffness of end diaphragm, and web thickness values, a box girder with SB-MC was numerically simulated using three-dimensional finite element model. According to the comparison results of web shear force, the concept of η, a shear-increased coefficient for webs, was introduced. The results show that supporting conditions and chambers have a significant impact on the shear-increased coefficient η, and end diaphragm must be set up in the 3D finite element model when calculating η. Nonlinear analysis shows that in the elastic phase, the shear-increased coefficient η basically does not change, but in the cracking stage, the coefficient η of each web changes with the degree of web cracking, and side-webs (S-Webs) reach the ultimate load first. The variation of the web thickness hardly affects the distribution of the shear force, so the method to adjust the web thickness of S-Web was proposed according to the result of shear-increased coefficient η to improve the shear resistance of the box girder.
An HK2 Antisense Oligonucleotide Induces Synthetic Lethality in HK1−HK2+ Multiple Myeloma
Authors: Xu Shili , Zhou Tianyuan , Doh Hanna M. , Trinh K Ryan , Catapang Art , Lee Jason T. , Braas Daniel , Bayley Nicholas A. , Yamada Reiko E. , Vasuthasawat Alex , Sasine Joshua P. , Timmerman John M. , Larson Sarah M. , Kim Youngsoo , MacLeod A. Robert , Morrison Sherie L. , Herschman Harvey R.
Published: March 2019

Although the majority of adult tissues express only hexokinase 1 (HK1) for glycolysis, most cancers express hexokinase 2 (HK2) and many coexpress HK1 and HK2. In contrast to HK1+HK2+ cancers, HK1−HK2+ cancer subsets are sensitive to cytostasis induced by HK2shRNA knockdown and are also sensitive to synthetic lethality in response to the combination of HK2shRNA knockdown, an oxidative phosphorylation (OXPHOS) inhibitor diphenyleneiodonium (DPI), and a fatty acid oxidation (FAO) inhibitor perhexiline (PER). The majority of human multiple myeloma cell lines are HK1−HK2+. Here we describe an antisense oligonucleotide (ASO) directed against human HK2 (HK2-ASO1), which suppressed HK2 expression in human multiple myeloma cell cultures and human multiple myeloma mouse xenograft models. The HK2-ASO1/DPI/PER triple-combination achieved synthetic lethality in multiple myeloma cells in culture and prevented HK1−HK2+ multiple myeloma tumor xenograft progression. DPI was replaceable by the FDA-approved OXPHOS inhibitor metformin (MET), both for synthetic lethality in culture and for inhibition of tumor xenograft progression. In addition, we used an ASO targeting murine HK2 (mHK2-ASO1) to validate the safety of mHK2-ASO1/MET/PER combination therapy in mice bearing murine multiple myeloma tumors. HK2-ASO1 is the first agent that shows selective HK2 inhibition and therapeutic efficacy in cell culture and in animal models, supporting clinical development of this synthetically lethal combination as a therapy for HK1−HK2+ multiple myeloma.

Significance:

A first-in-class HK2 antisense oligonucleotide suppresses HK2 expression in cell culture and in in vivo, presenting an effective, tolerated combination therapy for preventing progression of HK1−HK2+ multiple myeloma tumors.
Hyperspectral Imaging for Resection Margin Assessment during Cancer Surgery
Authors: Kho Esther , de Boer Lisanne L. , Van de Vijver Koen K. , van Duijnhoven Frederieke , Vrancken Peeters Marie-Jeanne T.F.D. , Sterenborg Henricus J.C.M. , Ruers Theo J.M.
Published: March 2019

Purpose:

Complete tumor removal during cancer surgery remains challenging due to the lack of accurate techniques for intraoperative margin assessment. This study evaluates the use of hyperspectral imaging for margin assessment by reporting its use in fresh human breast specimens.

Experimental Design:

Hyperspectral data were first acquired on tissue slices from 18 patients after gross sectioning of the resected breast specimen. This dataset, which contained over 22,000 spectra, was well correlated with histopathology and was used to develop a support vector machine classification algorithm and test the classification performance. In addition, we evaluated hyperspectral imaging in clinical practice by imaging the resection surface of six lumpectomy specimens. With the developed classification algorithm, we determined if hyperspectral imaging could detect malignancies in the resection surface.

Results:

The diagnostic performance of hyperspectral imaging on the tissue slices was high; invasive carcinoma, ductal carcinoma in situ, connective tissue, and adipose tissue were correctly classified as tumor or healthy tissue with accuracies of 93%, 84%, 70%, and 99%, respectively. These accuracies increased with the size of the area, consisting of one tissue type. The entire resection surface was imaged within 10 minutes, and data analysis was performed fast, without the need of an experienced operator. On the resection surface, hyperspectral imaging detected 19 of 20 malignancies that, according to the available histopathology information, were located within 2 mm of the resection surface.

Conclusions:

These findings show the potential of using hyperspectral imaging for margin assessment during breast-conserving surgery to improve surgical outcome.
Adaptation to HIF1α Deletion in Hypoxic Cancer Cells by Upregulation of GLUT14 and Creatine Metabolism
Authors: Valli Alessandro , Morotti Matteo , Zois Christos E. , Albers Patrick K. , Soga Tomoyoshi , Feldinger Katharina , Fischer Roman , Frejno Martin , McIntyre Alan , Bridges Esther , Haider Syed , Buffa Francesca M. , Baban Dilair , Rodriguez Miguel , Yanes Oscar , Whittington Hannah J. , Lake Hannah A. , Zervou Sevasti , Lygate Craig A. , Kessler Benedikt M. , Harris Adrian L.
Published: March 2019

Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It is well recognized to regulate glycolysis and is a target for therapy. However, how tumor cells adapt to grow in the absence of HIF1α is poorly understood and an important concept to understand for developing targeted therapies is the flexibility of the metabolic response to hypoxia via alternative pathways. We analyzed pathways that allow cells to survive hypoxic stress in the absence of HIF1α, using the HCT116 colon cancer cell line with deleted HIF1α versus control. Spheroids were used to provide a 3D model of metabolic gradients. We conducted a metabolomic, transcriptomic, and proteomic analysis and integrated the results. These showed surprisingly that in three-dimensional growth, a key regulatory step of glycolysis is Aldolase A rather than phosphofructokinase. Furthermore, glucose uptake could be maintained in hypoxia through upregulation of GLUT14, not previously recognized in this role. Finally, there was a marked adaptation and change of phosphocreatine energy pathways, which made the cells susceptible to inhibition of creatine metabolism in hypoxic conditions. Overall, our studies show a complex adaptation to hypoxia that can bypass HIF1α, but it is targetable and it provides new insight into the key metabolic pathways involved in cancer growth.

Implications:

Under hypoxia and HIF1 blockade, cancer cells adapt their energy metabolism via upregulation of the GLUT14 glucose transporter and creatine metabolism providing new avenues for drug targeting.
Mice Lacking Fatty Acid-Binding Protein 5 Are Resistant to Listeria monocytogenes
Authors: Rao Deviyani M. , Phan Della T. , Choo Michelle J. , Owen Amie L. , Perraud Anne-Laure , Gally Fabienne
Published: March 2019

To investigate the role of fatty acid-binding protein 5 (FABP5) in infectious diseases, FABP5-deficient mice were challenged with Listeria monocytogenes, a facultative intracellular bacterial pathogen. Interestingly, FABP5-deficient animals were able to clear the infection within 3 days whereas control wild-type (WT) animals showed comparatively higher bacterial burdens in the liver and spleen. Sections of infected tissues showed an increase in inflammatory foci in WT mice compared to FABP5-deficient mice. FABP5-deficient mice had lower circulating inflammatory cytokines and increased inducible nitric oxide synthase production. FABP5-deficient mouse bone marrow-derived macrophages produced higher levels of nitrite anion than their WT counterparts in response to various stimuli. Additionally, in contrast to FABP5–/– mice, transgenic mice overexpressing FABP5 in myeloid cells (LysM-Cre driven) showed decreased survival rates and increased bacterial burden and inflammatory cytokines. Overall, these findings suggest that increased FABP5 levels correlate with a higher L. monocytogenes bacterial burden and elevated subsequent inflammation.
Naringin (4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside) Attenuates β-Cell Dysfunction in Diabetic Rats through Upregulation of PDX-1
Authors: Subramanian Manickam , Thotakura Balaji , Chandra Sekaran Swathi Priyadarshini , Jyothi Ashok kumar , Sundaramurthi Indumathi
Published: March 2019

Background: Pancreatic duodenal homeobox-1 (PDX-1) is a key transcription factor which regulates Insulin gene expression and insulin secretion in adult β-cells and helps to maintain β-cells mass. Naringin, a flavanone, owing to its anti­oxidant property, is reported to have antidiabetic effects. Objectives: The present study tries to evaluate the role of naringin on the β-cell-specific transcription factor PDX-1 in diabetic rats. Methods: Diabetes was induced in male rats using streptozotocin and treated with naringin (100 mg/kg) orally for 4 and 8 weeks. Serum insulin level, Pdx-1 and Insulin gene expression, and PDX-1 protein expression were assessed in the rat pancreas. Histopathological and ultrastructural changes in the islet and β-cells were observed. Results: Naringin prevented leukocytic infiltration in the pancreas of diabetic rats and recouped the β-cells with adequate secretory granules. Naringin-treated diabetic rats showed significantly increased mRNA expression of Pdx-1 and Insulin genes, increased expression of transcription factor PDX-1, and higher serum insulin levels than the diabetic control animals. These changes were more pronounced in the 8-week naringin-treated diabetic animals. Conclusions: Naringin was found to be an effective antidiabetic agent which increased Insulin gene expression and insulin secretion by upregulating the PDX-1 gene and protein expression.
Hypothalamic Obesity: Prologue and Promise
Authors: Abuzzahab M. Jennifer , Roth Christian L. , Shoemaker Ashley H.
Published: March 2019

Hypothalamic obesity (HO) frequently occurs following damage to the medial hypothalamic region, encompassing the arcuate nucleus, the paraventricular nucleus, the ventromedial nucleus, the dorsomedial nucleus, and the dorsal hypothalamic area, which are critically involved in the regulation of satiety and energy balance through neural and humoral connections. HO is most commonly described in the context of craniopharyngioma and its treatment, but it can also occur following other suprasellar tumors, radiation, trauma, or a surgical insult to the hypothalamus. A constellation of loss of satiety and a reduction of the metabolic rate, thermogenesis, and physical activity as well as increased vagal tone and hyperinsulinism with insulin and leptin resistance results in rapid weight gain due to a decreased energy expenditure and increased energy storage in adipose cells. To date, no viable long-term solution for HO has been found, due either to the requirement of intact hypothalamic pathways or to significant side effects. Newer therapeutic modalities focused on the unique pathophysiology of this condition offer potential for successful treatment. In this review, we describe the etiology of HO as well as past/current treatment approaches in the categories of hyperinsulinism, surgical approaches, and targeting energy expenditure/anorectic drugs. We conclude by providing an overview of the clinical trials currently underway.
QUAESTIO DE INFINITO. EL PROBLEMA DE LA TEMPORALIDAD EN LA CARTA 12 A MEYER
Authors: Sibilia Guillermo
Published: March 2019

Na carta 12 de sua correspondência, Spinoza expõe sua concepção do infinito atual. Nesse contexto, ele desenvolve certos aspectos de sua ontologia de imanência, assim como o significado que para ele tem os conceitos de eternidade, duração e tempo. Este texto torna-se então central para qualquer estudioso da questão da temporalidade em Spinoza. Nosso autor distancia-se da perspectiva cartesiana que, na mesma questão, expôs —não sem críticas— nos Princípios da Filosofia do Descartes e nos Pensamentos Metafísicos, ambos publicados em 1663. Neste artigo nós propomos estudar a distinção entre duração e tempo, para sublinhar a perspectiva propriamente spinozista da letra 12, e assim mostrar o significado que para Spinoza tem esses conceitos no contexto de uma discussão científica sobre o infinito atual.
HDAC (Histone Deacetylase) Inhibitor Valproic Acid Attenuates Atrial Remodeling and Delays the Onset of Atrial Fibrillation in Mice
Authors: Scholz Beatrix , Schulte Jan Sebastian , Hamer Sabine , Himmler Kirsten , Pluteanu Florentina , Seidl Matthias Dodo , Stein Juliane , Wardelmann Eva , Hammer Elke , Völker Uwe , Müller Frank Ulrich
Published: March 2019

Background:

A structural, electrical and metabolic atrial remodeling is central in the development of atrial fibrillation (AF) contributing to its initiation and perpetuation. In the heart, HDACs (histone deacetylases) control remodeling associated processes like hypertrophy, fibrosis, and energy metabolism. Here, we analyzed, whether the HDAC class I/IIa inhibitor valproic acid (VPA) is able to attenuate atrial remodeling in CREM-IbΔC-X (cAMP responsive element modulator isoform IbΔC-X) transgenic mice, a mouse model of extensive atrial remodeling with age-dependent progression from spontaneous atrial ectopy to paroxysmal and finally long-lasting AF.

Methods:

VPA was administered for 7 or 25 weeks to transgenic and control mice. Atria were analyzed macroscopically and using widefield and electron microscopy. Action potentials were recorded from atrial cardiomyocytes using patch-clamp technique. ECG recordings documented the onset of AF. A proteome analysis with consecutive pathway mapping identified VPA-mediated proteomic changes and related pathways.

Results:

VPA attenuated many components of atrial remodeling that are present in transgenic mice, animal AF models, and human AF. VPA significantly (
P
<0.05) reduced atrial dilatation, cardiomyocyte enlargement, atrial fibrosis, and the disorganization of myocyte’s ultrastructure. It significantly reduced the occurrence of atrial thrombi, reversed action potential alterations, and finally delayed the onset of AF by 4 to 8 weeks. Increased histone H4-acetylation in atria from VPA-treated transgenic mice verified effective in vivo HDAC inhibition. Cardiomyocyte-specific genetic inactivation of HDAC2 in transgenic mice attenuated the ultrastructural disorganization of myocytes comparable to VPA. Finally, VPA restrained dysregulation of proteins in transgenic mice that are involved in a multitude of AF relevant pathways like oxidative phosphorylation or RhoA (Ras homolog gene family, member A) signaling and disease functions like cardiac fibrosis and apoptosis of muscle cells.

Conclusions:

Our results suggest that VPA, clinically available, well-tolerated, and prescribed to many patients for years, has the therapeutic potential to delay the development of atrial remodeling and the onset of AF in patients at risk.
Long-Term Consumption of Sugar-Sweetened and Artificially Sweetened Beverages and Risk of Mortality in US Adults
Authors: Malik Vasanti S. , Li Yanping , Pan An , De Koning Lawrence , Schernhammer Eva , Willett Walter C. , Hu Frank B.
Published: March 2019

Background:

Whether consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) is associated with risk of mortality is of public health interest.

Methods:

We examined associations between consumption of SSBs and ASBs with risk of total and cause-specific mortality among 37 716 men from the Health Professional’s Follow-up study (from 1986 to 2014) and 80 647 women from the Nurses’ Health study (from 1980 to 2014) who were free from chronic diseases at baseline. Cox proportional hazards regression was used to estimate hazard ratios and 95% confidence intervals.

Results:

We documented 36 436 deaths (7896 cardiovascular disease [CVD] and 12 380 cancer deaths) during 3 415 564 person-years of follow-up. After adjusting for major diet and lifestyle factors, consumption of SSBs was associated with a higher risk of total mortality; pooled hazard ratios (95% confidence intervals) across categories (<1/mo, 1–4/mo, 2–6/week, 1-<2/d, and ≥2/d) were 1.00 (reference), 1.01 (0.98, 1.04), 1.06 (1.03, 1.09), 1.14 (1.09, 1.19), and 1.21 (1.13, 1.28;
P
trend <0.0001). The association was observed for CVD mortality (hazard ratio comparing extreme categories was 1.31 [95% confidence interval, 1.15, 1.50],
P
trend <0.0001) and cancer mortality (1.16 [1.04, 1.29],
P
trend =0.0004). ASBs were associated with total and CVD mortality in the highest intake category only; pooled hazard ratios (95% confidence interval) across categories were 1.00 (reference), 0.96 (0.93, 0.99), 0.97 (0.95, 1.00), 0.98 (0.94, 1.03), and 1.04 (1.02, 1.12;
P
trend = 0.01) for total mortality and 1.00 (reference), 0.93 (0.87, 1.00), 0.95 (0.89, 1.00), 1.02 (0.94, 1.12), and 1.13 (1.02, 1.25;
P
trend = 0.02) for CVD mortality. In cohort-specific analysis, ASBs were associated with mortality in NHS (Nurses’ Health Study) but not in HPFS (Health Professionals Follow-up Study) (
P
interaction, 0.01). ASBs were not associated with cancer mortality in either cohort.

Conclusions:

Consumption of SSBs was positively associated with mortality primarily through CVD mortality and showed a graded association with dose. The positive association between high intake levels of ASBs and total and CVD mortality observed among women requires further confirmation.
Retinoic Acid Is a Negative Regulator of sFLT1 Expression in Decidual Stromal Cells, and Its Levels Are Reduced in Preeclamptic Decidua
Authors: Deepak Venkataraman , Sahu Margaret B. , Yu Jianshi , Jones Jace W. , Kane Maureen A. , Taylor Robert N. , Badell Martina L. , Sidell Neil , Rajakumar Augustine
Published: March 2019

sFLT1 (soluble VEGF [vascular endothelial growth factor] receptor-1) levels are increased in preeclampsia—a pathological condition of pregnancy. The mechanism of sFLT1 overexpression by gestational tissues, particularly the decidua, remains unknown. Mass spectrometry measurement of the active retinoid metabolite, all-trans retinoic acid (RA), showed significantly lower levels of RA in preeclamptic versus normotensive decidua. In this study, we investigated the involvement of RA in regulating decidual sFLT1 expression. When decidual stromal cells (DSCs) isolated from the decidua basalis of normotensive and preeclampsia placentas were treated with BMS493—a pan-RAR (RA nuclear receptor) antagonist—upregulation of sFLT1 expression was observed. Conversely, treatment with RA resulted in downregulation of sFLT1 in normotensive DSCs and preeclampsia DSCs. Unlike treatment with cAMP, which induces decidualization while downregulating sFLT1, RA treatment did not alter DSC expression of prolactin—a marker of decidualization—or FOXO1 (forkhead box protein 01)—a transcription factor required for prolactin upregulation. TFAP2A (transcription factor AP-2-alpha [activating enhancer-binding protein 2 alpha]), a different transcription factor was upregulated in normotensive DSCs but not in preeclampsia DSCs after RA treatment. Collectively, our data show that RA suppresses sFLT1 expression in DSCs independently of cellular decidualization. These findings suggest that reduced decidual RA levels may contribute to preeclampsia pathogenesis by allowing sFLT1 accumulation at the maternal-fetal interface.
Renal Inflammation in DOCA-Salt Hypertension
Authors: Banek Christopher T. , Gauthier Madeline M. , Van Helden Dusty A. , Fink Gregory D. , Osborn John W.
Published: March 2019

Recent reports indicate that, in addition to treating hypertension, renal denervation (RDN) also mitigates renal inflammation. However, because RDN decreases renal perfusion pressure, it is unclear whether these effects are because of the direct effects of RDN on inflammatory signaling or secondary to decreased arterial pressure (AP). Therefore, this study was conducted to elucidate the contribution of renal nerves to renal inflammation in the deoxycorticosterone (DOCA)-salt rat, a model in which RDN decreases AP and abolishes renal inflammation. In Experiment 1, we assessed the temporal changes in renal inflammation by measuring renal cytokines and AP in DOCA-salt rats. Uninephrectomized (1K) adult male Sprague Dawley rats that received surgical RDN or sham (Sham) were administered DOCA (100 mg, SC) and 0.9% saline for 21 days. AP was measured by radiotelemetry, and urinary cytokine excretion was measured repeatedly. In Experiment 2, the contribution of renal nerves in renal inflammation was assessed in a 2-kidney DOCA-salt rat to control for renal perfusion pressure. DOCA-salt treatment was administered after unilateral (U-)RDN. In Experiment 1, DOCA-salt–induced increases in AP and renal inflammation (assessed by urinary cytokines) were attenuated by RDN versus Sham. In Experiment 2, GRO/KC (growth-related oncogene/keratinocyte chemoattractant), MCP (monocyte chemoattractant protein)-1, and macrophage infiltration were lower in the denervated kidney versus the contralateral Sham kidney. No differences in T-cell infiltration were observed. Together, these data support the hypothesis that renal nerves mediate, in part, the development of renal inflammation in the DOCA-salt rat independent of hypertension. The mechanisms and cell-specificity mediating these effects require further investigation.
Association of Atrial Fibrillation With White Matter Disease
Authors: Shao Iris Yuefan , Power Melinda C. , Mosley Thomas , Jack Clifford , Gottesman Rebecca F. , Chen Lin Y. , Norby Faye L. , Soliman Elsayed Z. , Alonso Alvaro
Published: March 2019

Background and Purpose—

Evidence suggests that atrial fibrillation (AF) is associated with increased risk of cognitive decline and dementia, even in the absence of stroke. White matter disease (WMD) is a potential mechanism linking AF to cognitive impairment. In this study, we explored the association between prevalent AF and WMD.

Methods—

We performed a cross-sectional analysis of participants attending the ARIC-NCS (Atherosclerosis Risk in Communities–Neurocognitive Study) in 2011 to 2013 who underwent brain magnetic resonance imaging. AF was ascertained from study visit electrocardiograms or prior hospitalization codes. Extent of WMD was defined by measures of white matter (WM) microstructural integrity and WM hyperintensity volume. Multivariable linear regression models were used to assess the association between AF and WMD.

Results—

Among 1899 participants (mean age, 76 years; 28% black; 60% women), 133 (7%) had prevalent AF. After multivariable adjustment, differences between participants with and without AF were −0.001 (95% CI, −0.006 to 0.004) for global WM fractional anisotropy, 0.031×10
−4
mm
2
/s (95% CI, −0.075 to 0.137) for global WM mean diffusivity, and 0.08 mm
3
(95% CI, −0.14 to 0.30) for WM hyperintensity volume.

Conclusions—

The results suggest that there is no association between prevalent AF and WMD.
Impact of Endovascular Therapy in Patients With Large Ischemic Core
Authors: Kakita Hiroto , Yoshimura Shinichi , Uchida Kazutaka , Sakai Nobuyuki , Yamagami Hiroshi , Morimoto Takeshi ,   RESCUE-Japan Registry 2 Investigators, Doijiri Ryosuke , Enomoto Yukiko , Ezura Masayuki , Fukawa Norihito , Furui Eisuke , Handa Akira , Haraguchi Koichi , Hatano Taketo , Hayase Makoto , Hiyama Nagayasu , Iihara Koji , Ikeda Norio , Imai Keisuke , Ishihara Hideyuki , Itabashi Ryou , Kamiya Yuki , Kanbayashi Chisaku , Kimura Kazumi , Kitagawa Kazuo , Kiura Yoshihiro , Kobayashi Junya , Kojima Takao , Kondo Ryuji , Kuwayama Naoya , Matsumaru Yuji , Matsumoto Keigo , Matsumoto Yoshihisa , Minematsu Kazuo , Morimoto Masafumi , Nii Kohei , Ogasawara Kuniaki , Ohnishi Hiroyuki , Ohta Hajime , Ohta Takahiro , Okada Yasushi , Onda Toshiyuki , Sakaguchi Manabu , Sakamoto Shigeyuki , Sasaki Makoto , Satomi Junichiro , Shibata Masunari , Shindo Atsushi , Takeuchi Masataka , Tanahashi Norio , Toma Naoki , Toyoda Kazunori , Tsumoto Tomoyuki , Tsuruta Wataro , Uchiyama Naoyuki , Yagita Yoshiki , Yamashita Taro , Yamamoto Daisuke , Yamaura Ikuya , Yamazaki Takaaki , Yasuda Hiroaki
Published: March 2019

Background and Purpose—

Endovascular therapy (EVT) is strongly recommended for acute cerebral large vessel occlusion with the Alberta Stroke Program Early CT Score (ASPECTS) ≥6 due to occlusion of the internal carotid artery or M1 segment of the middle cerebral artery. However, the effect of EVT for patients who have ischemic core with ASPECTS ≤5 (0–5) was not established. The purpose of this study was to elucidate the outcomes of EVT for patients with large ischemic core.

Methods—

Based on the data of The Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism Japan Registry 2, patients with internal carotid artery or M1 segment of the middle cerebral artery occlusion and pretreatment ASPECTS 0 to 5 on noncontrast CT or diffusion-weighted image were extracted, and the outcomes by EVT were analyzed. Primary end point was defined as a good functional outcome (modified Rankin Scale score of ≤2) after 90 days.

Result—

Among 2420 registered patients, 504 patients were with internal carotid artery or M1 segment of the middle cerebral artery occlusion and ASPECTS 0 to 5. Among these 504 patients, 172 (34.1 %) were treated with EVT (EVT group) and 332 (65.9 %) without (no-EVT group). In the no-EVT group, elderly patients, females, poor prestroke modified Rankin Scale, high National Institutes of Health Stroke Scale, low ASPECTS, and late admission were significantly more observed. Good functional outcomes were significantly more observed in the EVT group than in the no-EVT group (19.8 % versus 4.2 %;
P
<0.0001; adjusted odds ratio, 2.33; 95% CI, 1.10–4.94). The incidences of symptomatic intracranial hemorrhage within 72 hours did not significantly different between the EVT group and the no-EVT group (3.7 % versus 4.9%;
P
=0.55; adjusted odds ratio, 0.50; 95% CI, 0.14–1.73).

Conclusions—

Although outcomes in this group of patients were usually poor, the data suggested EVT may increase the likelihood of a good functional outcome.
Temporal Dynamics of Shape Processing Differentiate Contributions of Dorsal and Ventral Visual Pathways
Authors: Collins Elliot , Freud Erez , Kainerstorfer Jana M. , Cao Jiaming , Behrmann Marlene
Published: March 2019

Although shape perception is primarily considered a function of the ventral visual pathway, previous research has shown that both dorsal and ventral pathways represent shape information. Here, we examine whether the shape-selective electrophysiological signals observed in dorsal cortex are a product of the connectivity to ventral cortex or are independently computed. We conducted multiple EEG studies in which we manipulated the input parameters of the stimuli so as to bias processing to either the dorsal or ventral visual pathway. Participants viewed displays of common objects with shape information parametrically degraded across five levels. We measured shape sensitivity by regressing the amplitude of the evoked signal against the degree of stimulus scrambling. Experiment 1, which included grayscale versions of the stimuli, served as a benchmark establishing the temporal pattern of shape processing during typical object perception. These stimuli evoked broad and sustained patterns of shape sensitivity beginning as early as 50 msec after stimulus onset. In Experiments 2 and 3, we calibrated the stimuli such that visual information was delivered primarily through parvocellular inputs, which mainly project to the ventral pathway, or through koniocellular inputs, which mainly project to the dorsal pathway. In the second and third experiments, shape sensitivity was observed, but in distinct spatio-temporal configurations from each other and from that elicited by grayscale inputs. Of particular interest, in the koniocellular condition, shape selectivity emerged earlier than in the parvocellular condition. These findings support the conclusion of distinct dorsal pathway computations of object shape, independent from the ventral pathway.