bluuebunny/crossref_metadata_2025 huggingface dataset:
SCY-078, a Novel Fungicidal Agent, Demonstrates Distribution to Tissues Associated with Fungal Infections during Mass Balance Studies with Intravenous and Oral [
14
C]SCY-078 in Albino and Pigmented Rats
Authors: Wring Stephen , Borroto-Esoda Katyna , Solon Eric , Angulo David
Published: November 2018

SCY-078, a fungicidal β-1,3-glucan synthesis inhibitor administered as intravenous or oral [
14
C]SCY-078 to rats, was distributed primarily into tissues associated with invasive fungal disease (kidney, lung, liver, spleen, bone marrow, muscle, vaginal tissue, and skin) to levels exceeding those in plasma. Oral fraction absorbed was ∼40%.
Direct Interaction between the Two Z Ring Membrane Anchors FtsA and ZipA
Authors: Vega Daniel E. , Margolin William
Published: November 2018

To divide, most bacteria first construct a protein machine at the plane of division and then recruit the machinery that will synthesize the division septum. In
Escherichia coli
, this first stage involves the assembly of FtsZ polymers at midcell, which directly bind to membrane-associated proteins FtsA and ZipA to form a discontinuous ring structure. Although FtsZ directly binds both FtsA and ZipA, it is unclear why FtsZ requires two separate membrane tethers. Here, we uncover a new direct interaction between the tethers, which involves a helix within FtsA that is adjacent to its ATP binding pocket. Our findings imply that in addition to their known roles as FtsZ membrane anchors, FtsA and ZipA may regulate each other’s structure and function.
The Core and Holoenzyme Forms of RNA Polymerase from
Mycobacterium smegmatis
Authors: Kouba Tomáš , Pospíšil Jiří , Hnilicová Jarmila , Šanderová Hana , Barvík Ivan , Krásný Libor
Published: November 2018

We describe here three-dimensional structures of core and holoenzyme forms of mycobacterial RNA polymerase (RNAP) solved by cryo-electron microscopy. These structures fill the thus-far-empty spots in the gallery of the pivotal forms of mycobacterial RNAP and illuminate the extent of conformational dynamics of this enzyme. The presented findings may facilitate future designs of antimycobacterial drugs targeting RNAP.
Novel Mutations in nsP2 Abolish Chikungunya Virus-Induced Transcriptional Shutoff and Make the Virus Less Cytopathic without Affecting Its Replication Rates
Authors: Akhrymuk Ivan , Lukash Tetyana , Frolov Ilya , Frolova Elena I.
Published: November 2018

Chikungunya virus is an important human pathogen which now circulates in both the Old and New Worlds. As in the case of other Old World alphaviruses, CHIKV nsP2 not only has enzymatic functions in viral RNA replication but also is a critical inhibitor of the antiviral response and one of the determinants of CHIKV pathogenesis. In this study, we have applied a new strategy to select a variety of CHIKV nsP2 mutants that no longer exhibited transcription-inhibitory functions. The designed CHIKV variants became potent type I interferon inducers and acquired a less cytopathic phenotype. Importantly, they demonstrated the same replication rates as the parental CHIKV. Mutations in the same identified peptide of nsP2 proteins derived from other Old World alphaviruses also abolished their nuclear functions. Such mutations can be further exploited for development of new attenuated alphaviruses.
Tetrasodium EDTA Is Effective at Eradicating Biofilms Formed by Clinically Relevant Microorganisms from Patients’ Central Venous Catheters
Authors: Liu Fangning , Hansra Satyender , Crockford Gordon , Köster Wolfgang , Allan Brenda J. , Blondeau Joseph M. , Lainesse Chantal , White Aaron P.
Published: November 2018

The colonization of catheters by microorganisms often precludes their long-term use, which can be a problem for human patients that have few body sites available for new catheters. The colonizing organisms often form biofilms, and increasingly these organisms are resistant to multiple antibiotics, making them difficult to treat. In this article, we have taken microorganisms that are associated with biofilm formation in catheters from two Canadian hospitals and tested them with tetrasodium EDTA, a new antimicrobial catheter lock solution. Tetrasodium EDTA was effective at eliminating Gram-positive, Gram-negative, and fungal species and represents a promising alternative to antibiotic treatment with less chance of the organisms developing resistance. We expect that our results will be of interest to researchers and clinicians and will lead to improved patient care.
Independent Mechanisms for Acquired Salt Tolerance versus Growth Resumption Induced by Mild Ethanol Pretreatment in
Saccharomyces cerevisiae
Authors: McDaniel Elizabeth A. , Stuecker Tara N. , Veluvolu Manasa , Gasch Audrey P. , Lewis Jeffrey A.
Published: November 2018

Microbes in nature frequently experience “boom or bust” cycles of environmental stress. Thus, microbes that can anticipate the onset of stress would have an advantage. One way that microbes anticipate future stress is through acquired stress resistance, where cells exposed to a mild dose of one stress gain the ability to survive an otherwise lethal dose of a subsequent stress. In the budding yeast
Saccharomyces cerevisiae
, certain stressors can cross protect against high salt concentrations, though the mechanisms governing this acquired stress resistance are not well understood. In this study, we took advantage of wild yeast strains to understand the mechanism underlying ethanol-induced cross protection against high salt concentrations. We found that mild ethanol stress allows cells to resume growth on high salt, which involves a novel role for a well-studied salt transporter. Overall, this discovery highlights how leveraging natural variation can provide new insights into well-studied stress defense mechanisms.
csrB
Gene Duplication Drives the Evolution of Redundant Regulatory Pathways Controlling Expression of the Major Toxic Secreted Metalloproteases in
Vibrio tasmaniensis
LGP32
Authors: Nguyen An Ngoc , Disconzi Elena , Charrière Guillaume M. , Destoumieux-Garzón Delphine , Bouloc Philippe , Le Roux Frédérique , Jacq Annick
Published: November 2018

The conserved CsrB sRNAs are an example of sibling sRNAs, i.e., sRNAs which are present in multiple copies in genomes. This report illustrates how new copies arise through gene duplication events and highlights two evolutionary advantages of having such multiple copies: differential regulation of the multiple copies allows integration of different input signals into the regulatory network of which they are parts, and the high redundancy that they provide confers a strong robustness to the system.
Visual rating assessment of cerebral atrophy and its relationship with cognitive function in chronic obstructive pulmonary disease
Authors: Savage Charlotte Claire , Dixey Piers Henry Anderson , Pennington Catherine , Dodd James W
Published: November 2018

Introduction

Widespread white matter damage and cognitive impairment have been demonstrated in chronic obstructive pulmonary disease (COPD). However, it remains unclear if brain atrophy is a global phenomenon or if specific subregions are differentially affected. The aims of this study are, first, to test a simple, validated visual analogue grading technique. Second, we hypothesised that frontal regions of the brains of patients with COPD will show greater signs of atrophy compared with control subjects. Third, any localised regions of atrophy would correlate with components of cognitive performance. Finally, the severity of cerebral atrophy would be associated with measures of respiratory disease severity.

Methods

We used a simple, validated visual analogue grading technique to assess the degree of regional atrophy in multiple brain regions from cerebral MR images in patients with stable non-hypoxaemic COPD (n=25) and age-matched control subjects (n=25). We also explored correlations between regional brain atrophy with demographics, cognitive performance measures and disease severity. Measures of cognitive performance focused on executive function, working memory, verbal memory, overall memory and processing speed. Measures of disease severity include lung function, gas exchange, health status and breathlessness questionnaires.

Results

The visual grading scale found that patients with COPD had significantly greater frontal atrophy than control subjects (p=0.02), independent of smoking history, comorbid depression or anxiety. Cognitive function was significantly worse in the COPD group for executive function (p<0.001), working memory (p=0.02), verbal memory (p=0.03) and processing speed (p=0.001). Group differences in atrophy did not appear to account for differences in cognitive function. We were unable to identify meaningful correlations between regional atrophy and disease severity or cognitive function.

Conclusion

Further work is needed to identify causative mechanisms behind unexplained structural brain changes in COPD.
Clinical response beyond the Systemic Lupus Erythematosus Responder Index: post-hoc analysis of the BLISS-SC study
Authors: van Vollenhoven Ronald F , Stohl William , Furie Richard A , Fox Norma Lynn , Groark James G , Bass Damon , Kurtinecz Milena , Pobiner Bonnie F , Eastman William J , Gonzalez‑Rivera Tania , Gordon David
Published: November 2018

Objective

The Systemic Lupus Erythematosus (SLE) Responder Index (SRI), developed as a primary outcome measure for use in clinical trials, captures improvement in SLE disease activity without concomitant worsening in disease manifestations. This study investigated the relationships between the SRI and clinical/laboratory correlates of SRI response in patients with SLE.

Methods

This was a post-hoc analysis of the phase III, double-blind, placebo-controlled study of subcutaneous BeLimumab in Subjects with Systemic lupus erythematosus - SubCutaneous (BLISS-SC). Patients were randomised to weekly belimumab 200 mg subcutaneously or placebo, plus standard SLE therapy. Changes from baseline to week 52 in clinical and laboratory parameters were compared among SRI responders and non-responders, irrespective of the treatment received.

Results

SRI responders (n=475) had significantly better (p<0.0001) outcomes compared with non-responders (n=358), including (by definition) higher proportions achieving ≥4-point improvement in Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (100.0% vs 2.0%), no worsening in British Isles Lupus Assessment Group (BILAG; 0 new BILAG A or ≤1 new BILAG B score; 100.0 % vs 50.3%) and no worsening (<0.3-point increase) in Physician’s Global Assessment score (100.0% vs 49.7%). Among patients receiving >7.5  mg/day corticosteroids at baseline, significantly more SRI responders had reductions in prednisone dose to ≤7.5 mg/day than non-responders. SRI responders reported lower flare rates and improvements in serological markers and Functional Assessment of Chronic Illness Therapy-Fatigue score than non-responders.

Conclusion

SRI response is associated with improvements in clinical and laboratory measures, strengthening its value as a clinically meaningful primary endpoint in clinical trials.
Pharmaceuticals and modern statecraft in South Africa: the cases of opium, thalidomide and contraception.
Authors: Parle Julie , Hodes Rebecca , Waetjen Thembisa
Published: November 2018

This article provides a history of three pharmaceuticals in the making of modern South Africa. Borrowing and adapting Arthur Daemmrich’s term ‘pharmacopolitics’, we examine how forms of pharmaceutical governance became integral to the creation and institutional practices of this state. Through case studies of three medicaments: opium (late 19th to early 20th century), thalidomide (late 1950s to early 1960s) and contraception (1970s to 2010s), we explore the intertwining of pharmaceutical regulation, provision and consumption. Our focus is on the modernist imperative towards the rationalisation of pharmaceutical oversight, as an extension of the state’s bureaucratic and ideological objectives, and, importantly, as its obligation. We also explore adaptive and illicit uses of medicines, both by purveyors of pharmaceuticals, and among consumers. The historical sweep of our study allows for an analysis of continuities and changes in pharmaceutical governance. The focus on South Africa highlights how the concept of pharmacopolitics can usefully be extended to transnational—as well as local—medical histories. Through the diversity of our sources, and the breadth of their chronology, we aim to historicise modern pharmaceutical practices in South Africa, from the late colonial era to the Post-Apartheid present.
COPD, airflow limitation and chronic bronchitis in farmers: a systematic review and meta-analysis
Authors: Guillien Alicia , Soumagne Thibaud , Dalphin Jean-Charles , Degano Bruno
Published: November 2018

Introduction

The current definition of chronic obstructive pulmonary disease (COPD) associates persistent airflow limitation and chronic respiratory symptoms. Agricultural work has been associated with an increased risk of developing COPD, but the prevalence and definition of the disease vary greatly between studies. This meta-analysis aimed to assess the association between agricultural work and COPD using the most widely used definitions of the disease.

Methods

Inclusion criteria were: (1) design: cross-sectional or longitudinal, (2) groups: at least one group of farmers and a control group of non-farmers, (3) outcome: prevalence or unadjusted OR of COPD, airflow limitation and/or chronic bronchitis, (4) study subjects: groups of exposed subjects comprising ≥30 individuals and with a mean age ≥40 years and (5) language: English and French language, full-length, original publications in peer-reviewed journals.

Results

In total, 22 manuscripts were included in the meta-analysis. Eight studies assessed only the prevalence of airflow limitation, nine assessed only the prevalence of chronic bronchitis and four assessed the prevalence of both these parameters. Only one assessed the prevalence of COPD according to its current definition, and this study also provided the prevalence of airflow limitation. Ten studies showed a positive association between farming exposure and airflow limitation or chronic bronchitis, and 12 showed no association (OR (95% CI)=1.77 (1.50 to 2.08), p<0.001). Cattle, swine, poultry and crop farming were associated with either airflow limitation or chronic bronchitis.

Conclusion

Although some features of COPD are associated with some agricultural work, well-designed studies with appropriate diagnostic criteria should be conducted to draw strong conclusions about the relationship between COPD and farming.
Absence of chest pain and long-term mortality in patients with acute myocardial infarction
Authors: Björck Lena , Nielsen Susanne , Jernberg Tomas , Zverkova-Sandström Tatiana , Giang Kok Wai , Rosengren Annika
Published: November 2018

Objective

Chest pain is the predominant symptom in patients with acute myocardial infarction (AMI). A lack of chest pain in patients with AMI is associated with higher in-hospital mortality, but whether this outcome is sustained throughout the first years after onset is unknown. Therefore, we aimed to investigate long-term mortality in patients hospitalised with AMI presenting with or without chest pain.

Methods

All AMI cases registered in the SWEDEHEART registry between 1996 and 2010 were included in the study. In total, we included 172 981 patients (33.5% women) with information on symptom presentation.

Results

Patients presenting without chest pain (12.7%) were older, more often women and had more comorbidities, prior medications and complications during hospitalisation than patients with chest pain. Short-term and long-term mortality rates were higher in patients without chest pain than in patients with chest pain: 30-day mortality, 945 versus 236/1000 person-years; 5-year mortality, 83 versus 21/1000 person-years in patients <65 years. In patients ≥65 years, 30-day mortality was 2294 versus 1140/1000 person-years; 5-year mortality, 259 versus 109/1000 person-years. In multivariable analysis, presenting without chest pain was associated with an overall 5-year HR of 1.85 (95% CI 1.81 to 1.89), with a stronger effect in younger compared with older patients, as well as in patients without prior AMI, heart failure, stroke, diabetes or hypertension.

Conclusion

Absence of chest pain in patients with AMI is associated with more complications and higher short-term and long-term mortality rates, particularly in younger patients, and in those without previous cardiovascular disease.
Provenance and depositional environment of organic-rich calcareous black shale of the Late Ordovician Macasty Formation, western Anticosti Basin, eastern Canada
Authors: Hattori Keiko , Desrochers André , Pedro Janice
Published: November 2018

The organic-rich Macasty shale in the Gulf of St. Lawrence was deposited in the Late Ordovician during the Taconic orogeny. The orogeny involved explosive volcanism and thrusting of allochthonous rocks in the eastern margin of North America. Neodymium isotope compositions of the shale show that the provenance is predominantly Grenvillian granite–gneissic rocks, which were widely exposed north of the basin, with little contribution from Taconic igneous rocks. The bulk composition and the presence of detrital kaolinite suggest that the Grenvillian source rocks underwent intense weathering before erosion. Fine-grained detritus was deposited in the Anticosti Basin, where abundant organic activity kept the sediment–water interface under anoxic conditions. This proposed interpretation is supported by the enrichment of redox-sensitive elements, such as As, V, and U, and by high δ34S for pyrite. Calcite cement formed in the pore space of sediments during the diagenesis at temperatures below 60 °C. The low-temperature diagenetic conditions are consistent with the preservation of abundant organic matter in the shale.
Revision of root-associated microfungi of Pinus wallichiana in Kashmir Himalaya
Authors: Koukol Ondřej
Published: November 2018

Fungi associated with roots of Pinus wallichiana A.B. Jackson were evaluated for the first time in the recently published study by Tyub et al. (2018, Can. J. For. Res. 48(8): 923–929, doi: 10.1139/cjfr-2018-0084 ). A culture-free approach using RFLP profiling and the sequencing analysis of DNA extracted from fine root tips was used to identify ectomycorrhizal and other species present in the roots; however, numerous inconsistences in the interpretation of presented results indicated that the names assigned to particular sequences were incorrect. Therefore, sequences belonging to ascomycete microfungi (predominantly members of Helotiales) obtained in the study were reanalyzed to confirm their identification. A simple phylogenetic analysis also utilizing closely related sequences from GenBank showed that the sequences from this study were mostly misidentified (i.e., placed in different clades than sequences having the same name but originating from taxonomic studies). Erroneous conclusions resulting from misidentified species and limited knowledge of relevant literature were corrected. Despite numerous inconsistences, the study of Tyub et al. (2018) brought valuable data about fungal diversity and potential taxonomic novelties among helotialean fungi associated with coniferous roots.
Can accelerated expansion of the universe be due to spacetime vorticity?
Authors: Mirza Babur M.
Published: November 2018

We present here a general relativistic mechanism for accelerated cosmic expansion and the Hubble’s parameter. It is shown that spacetime vorticity coupled to the magnetic field density in galaxies causes the galaxies to recede from one another at a rate equal to the Hubble’s constant. We therefore predict an oscillatory universe, with zero curvature, without assuming violation of Newtonian gravity at large distances or invoking dark energy/dark matter hypotheses. The value of the Hubble’s constant, along with the scale of expansion, as well as the high isotropy of CMB radiation are deduced from the model.
Interval Methods in Knowledge Representation
Authors: Kreinovich Vladik
Published: November 2018

Please send your abstracts (or copies of papers that you want to see reviewed here) to vladik@utep.edu, or by regular mail to Vladik Kreinovich, Department of Computer Science, University of Texas at El Paso, El Paso, TX 79968, USA.
The Rattray Volcanics: Mid-Jurassic fissure volcanism in the UK Central North Sea
Authors: Quirie Ailsa K. , Schofield Nick , Hartley Adrian , Hole Malcolm J. , Archer Stuart G. , Underhill John R. , Watson Douglas , Holford Simon P.
Published: November 2018

The Middle Jurassic Rattray Volcanic Province is located at the triple junction of the North Sea continental rift system. It has previously been thought to be sourced from three large central volcanoes: the Glenn, Fisher Bank and Ivanhoe volcanic centres. Re-interpretation using 3D seismic and well data shows that no volcanic centres are present and the Rattray Volcanics were instead sourced in fissure eruptions from linear vents, including the Buchan–Glenn Fissure System, a
c.
25 km long zone of WSW–ENE-striking linear fissure vents and associated small volcanic edifices across the Buchan–Glenn Horst. The orientation of the fissures is broadly parallel to the Highland Boundary Fault, which intersects the Rattray Volcanics at the Buchan–Glenn Fissure System, implying that Mid-Jurassic magmatism exploited pre-existing crustal structural anisotropies established during the Caledonian Orogeny. The lack of large intrusive complexes beneath the Rattray Volcanics indicates that the pre-Middle Jurassic sedimentary sequences (e.g. the Devonian–Carboniferous Old Red Sandstone Group, the Permian Rotliegend and Zechstein groups and the Triassic Skagerrak Formation) extend further than previously supposed and therefore the presence of possible subvolcanic reservoir and source rock units within the triple junction of the Central North Sea may have been overlooked.
F
lux
Authors: Silva Nuno , Marques Eduardo R. B. , Lopes Luís M. B.
Published: November 2018

F
lux
is a platform for dynamically reconfigurable crowd-sensing using mobile devices like smartphones and tablets, programmed under a notion of region-based sensing. Each region is defined by a set of physical constraints that determine the sensing scope, e.g., based on device position or other environmental variables, plus a set of periodic tasks that perform the actual sensing. The resulting behavior is inherently dynamic: as a device’s state changes, e.g., moves in space, it enters and/or leaves different regions, thereby changing the set of active tasks; moreover, regions can be added, deleted, and reprogrammed on-the-fly. F
lux
makes use of a domain-specific language for sensing tasks that is compiled into abstract bytecode, later executed by a low-footprint virtual machine within a device, guaranteeing runtime safety by construction. For region/task dissemination, F
lux
employs a broker that holds a changeable region configuration plus gateways that mirror the configuration throughout different network access points to which devices connect. Sensing data is streamed by devices to gateways and then back to the broker. Live or archived data streams are in turn fed by the broker to data-processing clients, which interface with the broker using a publish/subscribe API. We conducted two case-study experiments illustrating F
lux
: a single-region deployment to monitor WiFi signal quality, and a multi-region deployment to monitor noise, temperature, and places-of-interest based on device movement.
Entering the Modern Era of Gene Therapy
Authors: Anguela Xavier M. , High Katherine A.
Published: November 2018

Gene therapies are gaining momentum as promising early successes in clinical studies accumulate and examples of regulatory approval for licensing increase. Investigators are advancing with cautious optimism that effective, durable, and safe therapies will provide benefit to patients—not only those with single-gene disorders but those with complex acquired diseases as well. While the strategies being translated from the lab to the clinic are numerous, this review focuses on the clinical research that has forged the gene therapy field as it currently stands.
Geometrically Nonlinear Analysis of Beam Structures via Hierarchical One-Dimensional Finite Elements
Authors: Hui Y. , De Pietro G. , Giunta G. , Belouettar S. , Hu H. , Carrera E. , Pagani A.
Published: November 2018

The formulation of a family of advanced one-dimensional finite elements for the geometrically nonlinear static analysis of beam-like structures is presented in this paper. The kinematic field is axiomatically assumed along the thickness direction via a Unified Formulation (UF). The approximation order of the displacement field along the thickness is a free parameter that leads to several higher-order beam elements accounting for shear deformation and local cross-sectional warping. The number of nodes per element is also a free parameter. The tangent stiffness matrix of the elements is obtained via the Principle of Virtual Displacements. A total Lagrangian approach is used and Newton-Raphson method is employed in order to solve the nonlinear governing equations. Locking phenomena are tackled by means of a Mixed Interpolation of Tensorial Components (MITC), which can also significantly enhance the convergence performance of the proposed elements. Numerical investigations for large displacements, large rotations, and small strains analysis of beam-like structures for different boundary conditions and slenderness ratios are carried out, showing that UF-based higher-order beam theories can lead to a more efficient prediction of the displacement and stress fields, when compared to two-dimensional finite element solutions.
Synergistic Inhibition of Mild Steel Corrosion in Seawater and Acidic Medium by Cathodic Protection and Monodora myristica Using Zinc Anode
Authors: Ukpong Imoh , Bamgboye Omolara , Soriyan Oladega
Published: November 2018

The synergistic inhibition of mild steel corrosion in seawater and 0.1M sulphuric acid by the cathodic protection and Monodora myristica was carried out through the weight loss and the linear polarization resistance (LPR) measurement. The results showed that in seawater, the synergism was not too effective for the protection of steel, whereas in 0.1M sulphuric acid, there was a great synergism between cathodic protection and the oil extracts of Monodora myristica, having an efficiency (IE%) of 102.89% at 15 mL of the oil extracts. For the linear polarization resistance (LPR), in most of the cases, there was a slight shift of the corrosion potential (Ecorr) and the open circuit potential (OPC) toward the positive as the volume of the oil extracts increased, thereby causing a change in the cathodic and the anodic Tafel slopes, which showed that the inhibitor is a mixed- type inhibitor. The corrosion current density (icorr) decreases as the volumes of the oil extract increase. Langmuir adsorption isotherm fitted best with an R2 of 1 unit, indicating a good agreement with the experimental data and with Langmuir adsorption isotherm.
Novel Calcium Phosphate Cement with Metformin-Loaded Chitosan for Odontogenic Differentiation of Human Dental Pulp Cells
Authors: Qin Wei , Chen Jia-Yao , Guo Jia , Ma Tao , Weir Michael D. , Guo Dong , Shu Yan , Lin Zheng-Mei , Schneider Abraham , Xu Hockin H. K.
Published: November 2018

Metformin is an old and widely accepted first-line drug for treating type 2 diabetes. Our previous studies demonstrate that metformin can stimulate the osteo/odontogenic differentiation of human-induced pluripotent stem cell-derived mesenchymal stem cells and human dental pulp cells (DPCs). Due to the rapid dilution of metformin from the defect area, the aim of this study was to develop a drug delivery system with controlled release of metformin to promote cell viability and odontogenic differentiation of DPCs favoring dentin regeneration. Calcium phosphate cement (CPC) containing chitosan and metformin as a scaffold was synthesized. DPCs were seeded onto the scaffold, and the viability and proliferation were evaluated at several time points. For osteogenic differentiation analysis, alkaline phosphatase (ALP) activity was tested, cells were stained with Alizarin Red, and the expression of odontogenic markers was evaluated by real-time polymerase chain reaction. DPCs remained viable and attached well to the CPC-chitosan composite scaffold. Moreover, the addition of metformin to the CPC-chitosan composite did not adversely affect cell proliferation, compared to that of CPC control. Our data further revealed that the novel CPC-chitosan-metformin composite enhanced the odontogenic differentiation of DPCs, as evidenced by higher ALP activity, elevated expression of odontoblastic markers, and strong mineral deposition. These results suggest that the new CPC-chitosan-metformin composite is a highly promising scaffold with the potential for tissue engineering applications including dentin regeneration.
Overview of Air Pollution Assessment in Northern Europe (Lithuania) by Passive Diffusion Sampling
Authors: Byčenkienė Steigvilė , Jasinevičienė Dalia , Perkauskas Donatas
Published: November 2018

The regional air pollution study in Lithuania provided a comprehensive overview of air quality in Lithuania (in Vilnius (capital) and rest of territory) when 375 monitoring sites at different representative locations (urban, suburban, and residential) were equipped with diffusion samplers. The samples were analyzed for sulfur dioxide (SO2) and nitrogen dioxide (NO2) concentration. The measurement results show that the mean concentrations of SO2 in all investigation sites during the study period did not exceed the annual limit value of 20.0 μg·m−3 and were below the lower assessment threshold value of 8.0 μg·m−3. The mean concentrations of NO2 in Vilnius agglomeration exceeded the annual limit value of 40 μg·m−3 at seven sites and in zone–at three sites with the intensive traffic flow, located near to highway. Comparison of SO2 and NO2 concentration levels was performed for 2004-2005 and 2010-2011. The level of nitrogen dioxide concentrations has decreased by 34, 26, 24, and 49% during the next six years in the city of Vilnius, and the concentration of SO2 in the air environment decreased by 40–60%.
PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness
Authors: Shen Jianfeng , Zhao Wei , Ju Zhenlin , Wang Lulu , Peng Yang , Labrie Marilyne , Yap Timothy A. , Mills Gordon B. , Peng Guang
Published: November 2018

PARP inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of ssDNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments because of unresolved DNA lesions, which in turn activated the DNA-sensing cGAS–STING pathway and stimulated production of type I IFNs to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.

Significance:

This work uncovers the mechanism behind the clinical efficacy of PARPi in patients with both BRCA-wild-type and BRCA-mutant tumors and provides a rationale for combining PARPi with immunotherapy in patients with cancer.
Serum miRNA–based Prediction of Axillary Lymph Node Metastasis in Breast Cancer
Authors: Shiino Sho , Matsuzaki Juntaro , Shimomura Akihiko , Kawauchi Junpei , Takizawa Satoko , Sakamoto Hiromi , Aoki Yoshiaki , Yoshida Masayuki , Tamura Kenji , Kato Ken , Kinoshita Takayuki , Kitagawa Yuko , Ochiya Takahiro
Published: November 2018

Purpose:

Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.

Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set.

Results:

An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84–0.92), a specificity of 0.69 (0.61–0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set.

Conclusions:

Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.
Batf3-Dependent Genes Control Tumor Rejection Induced by Dendritic Cells Independently of Cross-Presentation
Authors: Theisen Derek J. , Ferris Stephen T. , Briseño Carlos G. , Kretzer Nicole , Iwata Arifumi , Murphy Kenneth M. , Murphy Theresa L.
Published: November 2018

The BATF3-dependent cDC1 lineage of conventional dendritic cells (cDC) is required for rejection of immunogenic sarcomas and for rejection of progressive sarcomas during checkpoint blockade therapy. One unique function of the cDC1 lineage is the efficient cross-presentation of tumor-derived neoantigens to CD8+ T cells, but it is not clear that this is the only unique function of cDC1 required for tumor rejection. We previously showed that BATF3 functions during cDC1 lineage commitment to maintain IRF8 expression in the specified cDC1 progenitor. However, since cDC1 progenitors do not develop into mature cDC1s in Batf3−/− mice, it is still unclear whether BATF3 has additional functions in mature cDC1 cells. A transgenic Irf8-Venus reporter allele increases IRF8 protein concentration sufficiently to allow autonomous cDC1 development in spleens of Batf3−/− mice. These restored Batf3−/− cDC1s are transcriptionally similar to control wild-type cDC1s but have reduced expression of a restricted set of cDC1-specific genes. Restored Batf3−/− cDC1s are able to cross-present cell-associated antigens both in vitro and in vivo. However, Batf3−/− cDC1 exhibit altered characteristics in vivo and are unable to mediate tumor rejection. These results show that BATF3, in addition to regulating Irf8 expression to stabilize cDC1 lineage commitment, also controls expression of a small set of genes required for cDC1-mediated tumor rejection. These BATF3-regulated genes may be useful targets in immunotherapies aimed at promoting tumor rejection.
A Case of Rapid Progressive Kidney Dysfunction with Severely Calcified Stenotic Aorta
Authors: Harada Makoto , Miyashita Yusuke , Ichikawa Tohru , Kobayashi Mamoru
Published: November 2018

Coral reef aorta is rare type of atherosclerotic diseases with severe calcification in the visceral part of the aorta. We present a case of coral reef aorta with severe abdominal aortic stenosis in a 67-year-old man. The patient presented with hypertension, claudication, and rapid progression of renal dysfunction over several months. Angiography revealed a severely stenotic suprarenal abdominal aorta resulting in renal ischemia and dysfunction. In addition, his right kidney was completely atrophied. After open surgical repair of the stenotic aorta including renal artery reconstruction, renal function did not improve. There was stenotic anastomosis to the renal artery. After endovascular therapy to the stenotic anastomosis, renal function dramatically improved. Stenotic coral reef aorta may be the cause of kidney dysfunction. In addition, surgical complication of stenotic anastomosis may be successfully treated by endovascular therapy.
Application and Benefits of Web-Mediated Symptom Reporting for Patients Undergoing Immunotherapy: A Clinical Example
Authors: Denis Fabrice , Koontz Bridget F. , Letellier Christophe
Published: November 2018

Two randomized studies of symptom monitoring during chemotherapy or during second line treatment and follow-up via web-based patient-reported outcomes (PROs) was previously demonstrated to lengthen survival. We are presenting here a patient with advanced and recurrent lung cancer who was followed for 4 years by PROs for relapse and adverse events detection. We report how the web-mediated follow-up helped to detect dangerous pulmonary embolism, relapse and pseudo-progression to immunotherapy by self-reported symptom tracking and specific algorithms triggering notifications to medical team, allowing early management of events. We particularly describe how a discordance between objective clinical improvement under immunotherapy assessed by the application allowed to detect pseudo-progression on imaging and allowed maintenance of the treatment during more than 1-year, although imaging report could have led to stop an effective therapy. The progression observed in the routine imaging was indeed in clear contradiction with improvements in patient’s global status as assessed by the reduced PRO-score computed from patient self-reported symptoms. The ability of e-health tools based on symptoms reporting for tumor response assessment should be assessed in trials to help physician in decision of stopping or continuing therapy.
Microvascular Capillary Plexus Findings of Commotio Retinae on Optical Coherence Tomography Angiography
Authors: Mansour Ahmad M. , Shields Carol L.
Published: November 2018

Optical coherence tomography (OCT) and histopathology features of commotio retinae (CR) have been established, but alterations of the microvascular macular capillary plexus on OCT angiography (OCTA) has not been previously studied. We present a 46-year-old man who sustained a tennis ball injury to the right eye with visual acuity reduction to 20/30 and grey-white deep macular discoloration, suggestive of CR. Spectral-domain OCT (SD-OCT) showed increased reflectivity and thickness of the ellipsoid zone (junction of photoreceptor inner and outer segments). OCTA revealed no apparent microvascular alterations (right versus left eye) in the foveal avascular zone superficial (0.42 vs. 0.43 mm2) and deep (0.45 vs. 0.44 mm2), superficial foveal capillary density (34.1 vs. 32.6%), and superficial parafoveal capillary density (55.2 vs. 52.2%). Deep macular capillary plexus and choriocapillaris were qualitatively comparable between the two eyes. At 2 months’ follow-up, SD-OCT had normalized. CR is characterized by disruption of the ellipsoid zone without detectable alteration of the capillary plexuses.
Early Second-Trimester Peptidomic Identification of Serum Peptides for Potential Prediction of Gestational Diabetes Mellitus
Authors: Yin Lingfeng , Huai Yingying , Zhao Chun , Ding Hongjuan , Jiang Tao , Shi Zhonghua
Published: November 2018

Background/Aims: Early screening and diagnosis is important for minimizing gestational adverse outcomes. Routine screening of gestational diabetes mellitus (GDM) at 24–28 weeks with 75 g oral glucose challenge test (OGCT) leaves limited time for intervention and prevention. This study aims to analyze maternal serum peptides in the early second-trimester for prediction of gestational diabetes mellitus (GDM). Methods: Serum samples were collected from 16-18-week pregnant women that visited Nanjing Maternity and Child Health Care Hospital from April to August 2015. According to gestational outcome with or without GDM in late pregnancy, 200 of serum samples from GDM mothers and controls were randomly divided into two subgroups. Peptidomic identification of serum peptides was performed by combining ultrafiltration and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate the differentially-expressed peptides between two groups. Results: A total of 297 identified peptides, originating from 228 proteins, were significantly differentially expressed in the GDM group compared with control. These precursor proteins may play critical roles in cell death of cortical neurons, elongation of cellular protrusions, and stabilization of microtubules. Major networks identified included those involving lipid metabolism, molecular transport and small molecule biochemistry. Conclusion: We provide for the first time a validated peptidome profile of early second-trimester serum in normal and GDM mothers, and we investigated the potential serum biomarkers for GDM. We concluded that 297 peptides could serve as potential biomarkers for GDM.
Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease
Authors: Vera Manel , Torramade-Moix Sergi , Martin-Rodriguez Susana , Cases Aleix , Cruzado Josep M. , Rivera Jose , Escolar Gines , Palomo Marta , Diaz-Ricart Maribel
Published: November 2018

Background/Aims: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. Methods: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. Results: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. Conclusion: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.
Galangin Alleviates Liver Ischemia-Reperfusion Injury in a Rat Model by Mediating the PI3K/AKT Pathway
Authors: Li Yang , Tong Liquan , Zhang Jingyan , Zhang Yafeng , Zhang Feng 
Published: November 2018

Background/Aims: Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. There are numerous causes of liver I/R injury, but the mechanism is unknown. Galangin (GA) is a flavonoid, a polyphenolic compound widely distributed in medicinal herbs that has anti-inflammatory, antioxidant, and antitumor activity. This study evaluated the protective effect of GA on hepatic I/R injury. Methods: An I/R model was created in male Wistar rats by clamping the hepatoportal vein, hepatic artery and hepatic duct for 30 min followed by reperfusion for 2 h. A hypoxia/restoration (H/R) model was established in buffalo rat liver (BRL) cells by hypoxia for 4 h followed by normoxic conditions for 10 h. The extent of liver injury was assayed by serum ALT/AST, hepatic histology, and MPO activity. Oxidative stress was assayed by serum superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA). Expression of apoptosis-related proteins in BRL cells was assayed in western blots. Expression of AKT and p-AKT proteins in vivo and vitro were assayed in western blots. Results: GA significantly decreased ALT/AST expression, reversed changes in oxidative stress markers induced by I/R, and mediated caspase-3 activity expression of apoptosis-related proteins in vivo and in vitro. Methylthiazol tetrazolium (MTT) assay, flow cytometry, and Hoechst 33258 staining confirmed that GA inhibited apoptosis of BRL cells. GA also increased the expression of phosphorylated AKT after H/R. Conclusion: GA reduced liver I/R injury both in vivo and vitro and inhibited BRL cell apoptosis. PI3K/AKT signaling have been involved. GA may protect against liver I/R and be a potential therapeutic candidate.
Protective Effects of Morus Root Extract (MRE) Against Lipopolysaccharide-Activated RAW264.7 Cells and CCl4-Induced Mouse Hepatic Damage
Authors: Tseng Tsui-Hwa , Lin Wea-Lung , Chang Che-Kai , Lee Ko-Chao , Tung Shui-Yi , Kuo Hsing-Chun
Published: November 2018

Background/Aims: Inflammation is one of the main contributors to chronic diseases such as cancer. It is of great value to identify the potential activity of various medicinal plants for regulating or blocking uncontrolled chronic inflammation. We investigated whether the root extract of Morus australis possesses antiinflammatory and antioxidative stress potential and hepatic protective activity. Methods: The microwave-assisted extractionwere was used to prepare the ethanol extract from the dried root of Morus australis (MRE), including polyphenolic and flavonoid contents. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells was examined the anti-inflammatory and anti-oxidative potential of MRE. CCl4-induced mouse hepatic damage were performed to detect the hepatic protective potential in vivo. Immunohistochemistry (IHC) and western blot assays were used to detect target proteins. Results: MRE contained approximately 23% phenolic compounds and 3% flavonoids. The major flavonoid component of MRE was morusin. MRE and morusin inhibited lipopolysaccharide-induced production of nitrite and prostaglandin E2 in RAW264.7 cells. MRE and morusin also suppressed the formation of intracellular reactive oxygen species and the expression of iNOS and COX-2. In an in vivo study, a thiobarbituric acid reactive substances assay showed that MRE inhibited CCl4-induced oxidative stress and expression of nitrotyrosine. MRE also decreased CCl4-induced hepatic iNOS and COX-2 expression, as well as CCl4-induced hepatic inflammation and necrosis in mice. Conclusion: MRE exhibited antiinflammatory and hepatic protective activity.
Two new species of phytoseid mites Euseius (Acari: Phytoseiidae) from Kerala, India
Authors: Santhosh P.P. , Sadanandan Mary Anithalatha , Rahul M.P.
Published: November 2018

Two new species of phytoseiid mites, Euseius pariyarensis sp. nov. and E. curcasae sp. nov., collected from the medicinal plants Saraca indica L. and Jatropha curcas L. respectively, are described from the Kerala State of India.  The morphological features of the two species are described with appropriate illustrations.