bluuebunny/crossref_metadata_2025 huggingface dataset:
Colonic afferent input and dorsal horn neuron activation differs between the thoracolumbar and lumbosacral spinal cord
Authors: Harrington Andrea M. , Caraballo Sonia Garcia , Maddern Jessica E. , Grundy Luke , Castro Joel , Brierley Stuart M.
Published: June 2019

The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli.

NEW & NOTEWORTHY In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.
Mild hypothermia causes a shift in the alternative splicing of cold-inducible RNA-binding protein transcripts in Syrian hamsters
Authors: Horii Yuuki , Shimaoka Hiroki , Horii Kazuhiro , Shiina Takahiko , Shimizu Yasutake
Published: June 2019

Cold-shock proteins are thought to participate in the cold-tolerant nature of hibernating animals. We previously demonstrated that an alternative splicing may allow rapid induction of functional cold-inducible RNA-binding protein (CIRBP) in the hamster heart. The purpose of the present study was to determine the major cause of the alternative splicing in Syrian hamsters. RT-PCR analysis revealed that CIRBP mRNA is constitutively expressed in the heart, brain, lung, liver, and kidney of nonhibernating euthermic hamsters with several alternative splicing variants. In contrast, the short variant containing an open-reading frame for functional CIRBP was dominantly found in the hibernating animals. Keeping the animals in a cold and dark environment did not cause a shift in the alternative splicing. Induction of hypothermia by central administration of an adenosine A1-receptor agonist reproduced the shift in the splicing pattern. However, the agonist failed to shift the pattern when body temperature was kept at 37°C, suggesting that central adenosine A1receptors are not directly linked to the shift of the alternative splicing. Rapid reduction of body temperature to 10°C by isoflurane anesthesia combined with cooling did not alter the splicing pattern, but maintenance of mild hypothermia (~28°C) for 2 h elicited the shift in the pattern. The results suggest that animals need to be maintained at mild hypothermia for an adequate duration to induce the shift in the alternative splicing. This is applicable to natural hibernation because hamsters entering hibernation show a gradual decrease in body temperature, being maintained at mild hypothermia for several hours.
Skeletal muscle energetics are compromised only during high-intensity contractions in the Goto-Kakizaki rat model of type 2 diabetes
Authors: Lewis Matthew T. , Kasper Jonathan D. , Bazil Jason N. , Frisbee Jefferson C. , Wiseman Robert W.
Published: June 2019

Type 2 diabetes (T2D) presents with hyperglycemia and insulin resistance, affecting over 30 million people in the United States alone. Previous work has hypothesized that mitochondria are dysfunctional in T2D and results in both reduced ATP production and glucose disposal. However, a direct link between mitochondrial function and T2D has not been determined. In the current study, the Goto-Kakizaki (GK) rat model of T2D was used to quantify mitochondrial function in vitro and in vivo over a broad range of contraction-induced metabolic workloads. During high-frequency sciatic nerve stimulation, hindlimb muscle contractions at 2- and 4-Hz intensities, the GK rat failed to maintain similar bioenergetic steady states to Wistar control (WC) rats measured by phosphorus magnetic resonance spectroscopy, despite similar force production. Differences were not due to changes in mitochondrial content in red (RG) or white gastrocnemius (WG) muscles (cytochrome c oxidase, RG: 22.2 ± 1.6 vs. 23.3 ± 1.7 U/g wet wt; WG: 10.8 ± 1.1 vs. 12.1 ± 0.9 U/g wet wt; GK vs. WC, respectively). Mitochondria isolated from muscles of GK and WC rats also showed no difference in mitochondrial ATP production capacity in vitro, measured by high-resolution respirometry. At lower intensities (0.25–1 Hz) there were no detectable differences between GK and WC rats in sustained energy balance. There were similar phosphocreatine concentrations during steady-state contraction and postcontractile recovery (τ = 72 ± 6 s GK versus 71 ± 2 s WC). Taken together, these results suggest that deficiencies in skeletal muscle energetics seen at higher intensities are not due to mitochondrial dysfunction in the GK rat.
Renal iron accelerates the progression of diabetic nephropathy in the HFE gene knockout mouse model of iron overload
Authors: Chaudhary Kapil , Chilakala Aruna , Ananth Sudha , Mandala Ashok , Veeranan-Karmegam Rajalakshmi , Powell Folami L. , Ganapathy Vadivel , Gnana-Prakasam Jaya P.
Published: June 2019

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease associated with high mortality worldwide. Increases in iron levels have been reported in diabetic rat kidneys as well as in human urine of patients with diabetes. In addition, a low-iron diet or iron chelators delay the progression of DN in patients with diabetes and in animal models of diabetes. Possible maladaptive mechanisms of organ damage by tissue iron accumulation have not been well studied. We recently reported that iron induced the retinal renin-angiotensin system (RAS) and accelerated the progression of diabetic retinopathy. However, whether iron regulates the systemic RAS is unknown. To explore if iron alters the expression of intrarenal RAS and its role in the progression of DN, we used the high Fe iron (HFE) knockout mouse, a genetic model of systemic iron overload. We found that diabetes upregulated the expression of iron regulatory proteins and augmented tissue iron accumulation in the kidneys of both type 1 and type 2 diabetic mouse models. Iron accumulation in the kidneys of HFE knockout mice was associated with increase in serum and intrarenal renin expression. Induction of diabetes in HFE knockout mice using streptozotocin caused a much higher accumulation of renal iron and accelerated the progression of nephropathy compared with diabetic wild-type mice. Treatment of diabetic mice with the iron chelator deferiprone reversed the renin upregulation and reduced kidney injury. Thus, our results establish a new link between renal iron and RAS activity. Exploring the mechanisms of iron-induced RAS activation further may have a significant therapeutic impact on hypertension and DN.
The Role of CDR1as in Proliferation and Differentiation of Human Umbilical Cord-Derived Mesenchymal Stem Cells
Authors: Yang Lunyu , Bin Zhang , Hui Shi , Rong Li , You Benshuai , Wu Peipei , Han Xinye , Qian Hui , Xu Wenrong
Published: June 2019

Mesenchymal stem cells derived from human umbilical cord (hucMSCs) are considered a promising tool for regenerative medicine. circRNAs as newly discovered noncoding RNAs are involved in multiple biological processes. However, little has been known about the function of circRNAs in the proliferation and differentiation of hucMSCs. In this study, we selected several circRNAs expressed in MSCs from circBase and found that CDR1as expression level was markedly significant. We observed that, compared with that of uninduced hucMSCs, the CDR1as expression level of induced hucMSCs decreased with cell induction differentiation. By using siRNA to knock down CDR1as of hucMSCs, we discovered that proliferation was inhibited but the apoptosis increased. In addition, we found that the expression of stemness transcription factors (STFs) was downregulated after CDR1as knockdown and the adipogenesis and osteogenesis potential of hucMSCs was impaired. Our findings suggest that CDR1as takes a part in maintaining proliferation and differentiation of hucMSCs, providing clues for MSC modification and further for stem cell therapy and tissue regeneration.
Effects of Er,Cr:YSGG and Diode Lasers on Clinical Parameters and Gingival Crevicular Fluid IL-1β and IL-37 Levels in Generalized Aggressive Periodontitis
Authors: Talmac Ahmet Cemil , Calisir Metin , Eroglu Emre Gurkan , Ertugrul Abdullah Seckin
Published: June 2019

Aim. The objective of the current study is to analyze the correlation between cytokine levels and periodontal parameters in aggressive periodontitis patients before and after periodontal treatment that was performed by using two different laser therapies. Materials and Methods. Twenty-six generalized aggressive periodontitis patients were treated with three different methods (SRP, SRP+diode laser, and SRP+Er,Cr:YSGG laser) applied to three different half-jaws in the same patients. Pre- and posttreatment clinical periodontal parameters and GCF IL-1β and IL-37 levels were measured. Results. There was a statistically significant decrease (p<0.05) between pretreatment and posttreatment clinical periodontal parameters and IL-1β and IL-37 levels. When the reduction rates of IL-37 and IL-1β levels after treatment were evaluated, the decrease in IL-37 and IL-1β levels after treatment was lowest in the SRP group and highest in the SRP+Er,Cr:YSGG group. In addition, the amount of decrease in IL-1β in SRP+diode and SRP+Er,Cr:YSGG groups was found to be higher than that in IL-37. Furthermore, there was a positive correlation between IL-37 and IL-1β in all groups (p<0.01). Conclusion. Er,Cr:YSGG laser is more effective than diode laser for the treatment of aggressive periodontitis. IL-37 and IL-1β are cytokines that function together and thus must be evaluated together.
Temperature Driven Transformation in Dextran-Graft-PNIPAM/Embedded Silver Nanoparticle Hybrid System
Authors: Chumachenko V. , Kutsevol N. , Harahuts Iu , Soloviov D. , Bulavin L. , Yeshchenko O. , Naumenko A. , Nadtoka O. , Marinin A.
Published: June 2019

During the last decade, stimuli-responsible polymers based on poly(N-isopropylacrylamide) having conformational transition in the range of physiological temperature have been discussed as novel drug delivery nanosystems. A star-like copolymer with a dextran core and grafted poly(N-isopropylacrylamide) arms (D-g-PNIPAM) was synthesized, characterized, and used as a matrix for silver sol preparation. The comparative study of the behavior of individual D-g-PNIPAM and the nanohybrid system D-g-PNIPAM/silver nanoparticles has been done in the temperature range near the lower critical solution temperature (LCST). The methods of Dynamic Light Scattering, small angle X-ray scattering, and UV-VIS absorption spectroscopy have been used. The existence of single nanoparticles and aggregated nanoparticles located in a limited polymer macromolecular volume was established. The increase of the temperature leads to slight aggregation of the silver nanoparticles at the LCST transition. Single nanoparticles do not aggregate with the temperature increase. The thermally induced collapse of end-grafted poly(N-isopropylacrylamide) chains above the LCST do not affect significantly the size characteristics of silver nanoparticles incorporated into the polymer matrix.
Role of Microbiome in Modulating Immune Responses in Cancer
Authors: Bose Mukulika , Mukherjee Pinku
Published: June 2019

The complex interactions between genes and the environment play important roles in disease susceptibility and progression. One of the chronic diseases that is affected by this gene-environment interplay is cancer. However, our knowledge about these environmental factors remains limited. The microorganisms that inhabit our bodies have recently been acknowledged to play a crucial role as an environmental factor, to which we are constantly exposed. Studies have revealed significant differences in the relative abundance of certain microbes in cancer cases compared with controls. It has been reported that changes in the composition of normal gut microbiota can increase/decrease cancer susceptibility and progression by diverse mechanisms including, but not limited to, inflammation—a well-known hallmark of carcinogenesis. The microbiota can also affect the response to various treatments including immunotherapy. The microbiome-immune-cancer axis will continue to provide insight into the basic mechanisms of carcinogenesis. In this review, we provide a brief understanding of the mechanisms by which microbiota affects cancer development, progression, and treatment.
Ethanolic Extract of Senna velutina Roots: Chemical Composition, In Vitro and In Vivo Antitumor Effects, and B16F10-Nex2 Melanoma Cell Death Mechanisms
Authors: Castro David Tsuyoshi Hiramatsu , Campos Jaqueline Ferreira , Damião Marcio José , Torquato Heron Fernandes Vieira , Paredes-Gamero Edgar Julian , Carollo Carlos Alexandre , Rodrigues Elaine Guadelupe , de Picoli Souza Kely , dos Santos Edson Lucas
Published: June 2019

Cutaneous melanoma is among the most aggressive types of cancer, and its rate of occurrence increases every year. Current pharmacological treatments for melanoma are not completely effective, requiring the identification of new drugs. As an alternative, plant-derived natural compounds are described as promising sources of new anticancer drugs. In this context, the objectives of this study were to identify the chemical composition of the ethanolic extract of Senna velutina roots (ESVR), to assess its in vitro and in vivo antitumor effects on melanoma cells, and to characterize its mechanisms of action. For these purposes, the chemical constituents were identified by liquid chromatography coupled to high-resolution mass spectrometry. The in vitro activity of the extract was assessed in the B16F10-Nex2 melanoma cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and based on the apoptotic cell count; DNA fragmentation; necrostatin-1 inhibition; intracellular calcium, pan-caspase, and caspase-3 activation; reactive oxygen species (ROS) levels; and cell cycle arrest. The in vivo activity of the extract was assessed in models of tumor volume progression and pulmonary nodule formation in C57Bl/6 mice. The chemical composition results showed that ESVR contains flavonoid derivatives of the catechin, anthraquinone, and piceatannol groups. The extract reduced B16F10-Nex2 cell viability and promoted apoptotic cell death as well as caspase-3 activation, with increased intracellular calcium and ROS levels as well as cell cycle arrest at the sub-G0/G1 phase. In vivo, the tumor volume progression and pulmonary metastasis of ESVR-treated mice decreased over 50%. Combined, these results show that ESVR had in vitro and in vivo antitumor effects, predominantly by apoptosis, thus demonstrating its potential as a therapeutic agent in the treatment of melanoma and other types of cancer.
Assessment of Airborne Bacterial and Fungal Communities in Selected Areas of Teaching Hospital, Kandy, Sri Lanka
Authors: Sivagnanasundaram Premina , Amarasekara R. W. K. , Madegedara R. M. D. , Ekanayake Anuradha , Magana-Arachchi D. N.
Published: June 2019

Nosocomial infections, in lay term known as hospital acquired infections, are caused mainly by airborne pathogens found in healthcare facilities and their surroundings. The aim of this study was to quantify and identify bacteria and fungi in a hospital, which is an understudied area of air quality in Sri Lanka. Air samples were collected in agar medium and petri plates containing sterile filter papers. The number of culturable and total airborne microorganisms was estimated by manual counting and fluorescent microscopy, respectively. The morphologically distant bacteria and fungi were identified by DNA sequencing. The statistical analysis revealed significant variances between studied sites (p < 0.05) where Outpatients Department and Respiratory Unit showed higher levels of airborne microbial load. Culturable microbial count was higher at noon (hospital visiting hours) compared to other sampling periods (after hospital visiting hours) within the hospital. Total count of airborne microbes was found to be the highest during the afternoon. The most sensitive zones such as Operating Theatre and Intensive Care Unit showed considerably higher counts of airborne microbes. Identification by molecular means revealed the presence of human pathogens in the hospital air including Bacillus sp, Micrococcus sp, Pseudomonas sp, Staphylococcu ssp, Exiguobacterium sp, Enterobacter sp, Escherichia sp, Sphingomonas sp, Massilia sp, Kocuria sp, Fusarium sp, and Aspergillus sp. In conclusion, the results from this study indicate that the hospital air was generally contaminated. Therefore, the implementation of proactive policies and strategies are needed to monitor hospital air quality in sensitive zones as well as other areas of the hospitals.
Gender and Its Role in the Resilience of Local Medical Systems of the Fulni-ô People in NE Brazil: Effects on Structure and Functionality
Authors: Torres-Avilez Wendy , Nascimento André Luiz Borba do , Santoro Flavia Rosa , Medeiros Patricia Muniz de , Albuquerque Ulysses Paulino
Published: June 2019

Ethnobotanical studies focused on understanding how local medical systems are functionally maintained suggest that utilitarian redundancy and knowledge transmission are factors that influence the resilience of the system. However, to date, there have not been any studies that analyze these factors in relation to the variables that influence the variation of knowledge. Given the above, this study aims to analyze the influence of gender in the resilience of the system, using utilitarian redundancy and knowledge transmission as factors. Information from 198 married couples (396 people) was collected from the indigenous community of Fulni-ô (NE Brazil). Knowledge between men and women was analyzed based on the total number of known plants, therapeutic targets, information units, utilitarian redundancy, models of transmission, and sharing for each gender. Fulni-ô men know a greater number of plants, therapeutic targets treated with plants, and information units than women. They also had greater utilitarian redundancy. However, regarding knowledge transmission, sharing among women was greater, transmission is related to gender, and there is no difference between the numbers of models of knowledge information. In the system of local medical knowledge, gender exerts an important role in the resilience of the system. This study shows that men have a greater contribution to the structure and function of the system; however, both genders contribute to the flow of information in the system, which makes both genders important in the feedback of information.
IL-10 Dampens the Th1 and Tc Activation through Modulating DC Functions in BCG Vaccination
Authors: Xu Hui , Jia Yanjuan , Li Yonghong , Wei Chaojun , Wang Wanxia , Guo Rui , Jia Jing , Wu Yu , Li Zhenhao , Wei Zhenhong , Qi Xiaoming , Li Yuanting , Gao Xiaoling
Published: June 2019

BCG, the only registered vaccine against Mycobacterial Tuberculosis (TB) infection, has been questioned for its protective efficacy for decades. Although lots of efforts were made to improve the BCG antigenicity, few studies were devoted to understand the role of host factors in the variability of the BCG protection. Using the IL-10KO mice and pulmonary tuberculosis infection model, we have addressed the role of IL-10 in the BCG vaccination efficacy. The data showed that IL-10-deficient dendritic cells (DCs) could promote the immune responses through upregulation of the surface costimulatory molecule expression and play an orchestra role through activating CD4+T cell. IL-10-deficient mice had higher IFN γ, TNF α, and IL-6 production after BCG vaccination, which was consistent with the higher proportion of IFN γ+CD3+, IFN γ+CD4+, and IFN γ+CD8+ T cells in the spleen. Particularly, the BCG-vaccinated IL-10KO mice showed less inflammation after TB challenge compared to WT mice, which was supported by the promoted Th1 and Tc, as well as the downregulated Treg responses in IL-10 deficiency. In a conclusion, we demonstrated the negative relationship between Th1/Tc responses with IL-10 production. IL-10 deficiency restored the type 1 immune response through DC activation, which provided better protection against TB infection. Hence, our study offers the first experimental evidence that, contrary to the modulation of BCG, host immunity plays a critical role in the BCG protective efficacy against TB.
Mechanical Behavior of Cemented Sand Reinforced with Different Polymer Fibers
Authors: Lv Xiangfeng , Yang Xiaohui , Zhou Hongyuan , Zhang Shuo
Published: June 2019

In this study, the specimens of cemented sand were prepared by reinforcing it separately with different contents (0.5%, 1.0%, 1.5%, and 2.0%) of three different polymer fibers (polyamide, polyester, and polypropylene) prepared as filaments of different lengths (6, 9, and 12 mm). Then, these specimens were tested, and the improvement effects of the three fibers on the engineering-mechanical behavior of the cemented sand were analyzed and compared. The different microstructures and chemical compositions of the fiber-reinforced cemented sand specimens were investigated using electron microscopy and X-ray diffraction. Compression tests were performed to obtain the stress-strain curves of the specimens. Comparative analysis was performed on the variation patterns of the mechanical parameters (such as unconfined compressive strength and peak strain) of the specimens. Quantitative analysis was performed on the effect of fiber content and fiber filament length on the failure mode of the specimens. It was shown that the inclusion of fibers led to a change from brittle failure to ductile failure. The macro- and microexperimental results revealed that polypropylene fiber had the best improvement effect on the mechanical behavior of the cemented sand, followed by polyester fiber and polyamide fiber. In particular, the cemented sand specimen reinforced with 1.5% polypropylene fiber prepared as 9 mm length filaments had a brittleness index of 0.0578, exhibited ductile failure (in contrast to the brittle failure of the nonreinforced cemented sand), and yielded the highest unconfined compressive strength and shear strength among the specimens.
Study of Surface Structure Changes for Selected Ceramics Used in the CAD/CAM System on the Degree of Microbial Colonization, In Vitro Tests
Authors: Dobrzynski Maciej , Pajaczkowska Magdalena , Nowicka Joanna , Jaworski Aleksander , Kosior Piotr , Szymonowicz Maria , Kuropka Piotr , Rybak Zbigniew , Bogucki Zdzislaw A. , Filipiak Jaroslaw , Targonska Sara , Ciupa-Litwa Aneta , Han Anna , Wiglusz Rafal J.
Published: June 2019

In the article has been presented an analysis of susceptibility of selected dental materials, made in the CAD/CAM technology. The morphology and structural properties of selected dental materials and their composites were determined by using XRPD (X-ray powder diffraction) techniques, as well as the IR (infrared) spectroscopy. Moreover, an adhesion as well as development of biofilm by oral microorganisms has been studied. It has been shown that a degree of the biofilm development on the tested dental materials depended on microorganism genus and species. Streptococcus mutans has demonstrated the best adhesion to the tested materials in comparison with Candida albicans and Lactobacillus rhamnosus. However, the sintered materials such as IPS e.max® and the polished IPS e.max® have showed the best “anti-adhesive properties” in relation to S. mutans and L. rhamnosus that have not formed the biofilm on the polished IPS e.max® sample. Furthermore, S. mutans have not formed the biofilm on both surfaces. On the contrary to S. mutans and L. rhamnosus, C. albicans has demonstrated the adhesive properties in relation to the above-mentioned surfaces. Moreover, in contrast to S. mutans and C. albicans, L. rhamnosus has not formed the biofilm on the polished IPS Empress material.
Retinoblastoma Inactivation Induces a Protumoral Microenvironment via Enhanced CCL2 Secretion
Authors: Li Fengkai , Kitajima Shunsuke , Kohno Susumu , Yoshida Akiyo , Tange Shoichiro , Sasaki Soichiro , Okada Nobuhiro , Nishimoto Yuuki , Muranaka Hayato , Nagatani Naoko , Suzuki Misa , Masuda Sayuri , Thai Tran C. , Nishiuchi Takumi , Tanaka Tomoaki , Barbie David A. , Mukaida Naofumi , Takahashi Chiaki
Published: June 2019

Cancer cell–intrinsic properties caused by oncogenic mutations have been well characterized; however, how specific oncogenes and tumor suppressors impact the tumor microenvironment (TME) is not well understood. Here, we present a novel non–cell-autonomous function of the retinoblastoma (RB) tumor suppressor in controlling the TME. RB inactivation stimulated tumor growth and neoangiogenesis in a syngeneic and orthotropic murine soft-tissue sarcoma model, which was associated with recruitment of tumor-associated macrophages (TAM) and immunosuppressive cells such as Gr1+CD11b+ myeloid-derived suppressor cells (MDSC) or Foxp3+ regulatory T cells (Treg). Gene expression profiling and analysis of genetically engineered mouse models revealed that RB inactivation increased secretion of the chemoattractant CCL2. Furthermore, activation of the CCL2–CCR2 axis in the TME promoted tumor angiogenesis and recruitment of TAMs and MDSCs into the TME in several tumor types including sarcoma and breast cancer. Loss of RB increased fatty acid oxidation (FAO) by activating AMP-activated protein kinase that led to inactivation of acetyl-CoA carboxylase, which suppresses FAO. This promoted mitochondrial superoxide production and JNK activation, which enhanced CCL2 expression. These findings indicate that the CCL2–CCR2 axis could be an effective therapeutic target in RB-deficient tumors.

Significance:

These findings demonstrate the cell-nonautonomous role of the tumor suppressor retinoblastoma in the tumor microenvironment, linking retinoblastoma loss to immunosuppression.
Tumor Angiogenesis Is Differentially Regulated by Phosphorylation of Endothelial Cell Focal Adhesion Kinase Tyrosines-397 and -861
Authors: Pedrosa Ana-Rita , Bodrug Natalia , Gomez-Escudero Jesus , Carter Edward P. , Reynolds Louise E. , Georgiou Paraskivi Natalia , Fernandez Isabelle , Lees Delphine M. , Kostourou Vassiliki , Alexopoulou Annika N. , Batista Silvia , Tavora Bernardo , Serrels Bryan , Parsons Maddy , Iskratsch Thomas , Hodivala-Dilke Kairbaan M.
Published: June 2019

Expression of focal adhesion kinase (FAK) in endothelial cells (EC) is essential for angiogenesis, but how FAK phosphorylation at tyrosine-(Y)397 and Y861 regulate tumor angiogenesis in vivo is unknown. Here, we show that tumor growth and angiogenesis are constitutively reduced in inducible, ECCre+;FAKY397F/Y397F–mutant mice. Conversely, ECCre+;FAKY861F/Y861F mice exhibit normal tumor growth with an initial reduction in angiogenesis that recovered in end-stage tumors. Mechanistically, FAK-Y397F ECs exhibit increased Tie2 expression, reduced Vegfr2 expression, decreased β1 integrin activation, and disrupted downstream FAK/Src/PI3K(p55)/Akt signaling. In contrast, FAK-Y861F ECs showed decreased Vegfr2 and Tie2 expression with an enhancement in β1 integrin activation. This corresponds with a decrease in Vegfa–stimulated response, but an increase in Vegfa+Ang2- or conditioned medium from tumor cell–stimulated cellular/angiogenic responses, mimicking responses in end-stage tumors with elevated Ang2 levels. Mechanistically, FAK-Y861F, but not FAK-Y397F ECs showed enhanced p190RhoGEF/P130Cas-dependent signaling that is required for the elevated responses to Vegfa+Ang2. This study establishes the differential requirements of EC-FAK-Y397 and EC-FAK-Y861 phosphorylation in the regulation of EC signaling and tumor angiogenesis in vivo.

Significance:

Distinct motifs of the focal adhesion kinase differentially regulate tumor blood vessel formation and remodeling.
Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition
Authors: Scott Gary K. , Yau Christina , Becker Beatrice C. , Khateeb Sana , Mahoney Sophia , Jensen Martin Borch , Hann Byron , Cowen Bryan J. , Pegan Scott D. , Benz Christopher C.
Published: June 2019

Proline dehydrogenase (PRODH) is a p53-inducible inner mitochondrial membrane flavoprotein linked to electron transport for anaplerotic glutamate and ATP production, most critical for cancer cell survival under microenvironmental stress conditions. Proposing that PRODH is a unique mitochondrial cancer target, we structurally model and compare its cancer cell activity and consequences upon exposure to either a reversible (S-5-oxo: S-5-oxo-2-tetrahydrofurancarboxylic acid) or irreversible (N-PPG: N-propargylglycine) PRODH inhibitor. Unlike 5-oxo, the suicide inhibitor N-PPG induces early and selective decay of PRODH protein without triggering mitochondrial destruction, consistent with N-PPG activation of the mitochondrial unfolded protein response. Fly and breast tumor (MCF7)-xenografted mouse studies indicate that N-PPG doses sufficient to phenocopy PRODH knockout and induce its decay can be safely and effectively administered in vivo. Among breast cancer cell lines and tumor samples, PRODH mRNA expression is subtype dependent and inversely correlated with glutaminase (GLS1) expression; combining inhibitors of PRODH (S-5-oxo and N-PPG) and GLS1 (CB-839) produces additive if not synergistic loss of cancer cell (ZR-75-1, MCF7, DU4475, and BT474) growth and viability. Although PRODH knockdown alone can induce cancer cell apoptosis, the anticancer potential of either reversible or irreversible PRODH inhibitors is strongly enhanced when p53 is simultaneously upregulated by an MDM2 antagonist (MI-63 and nutlin-3). However, maximum anticancer synergy is observed in vitro when the PRODH suicide inhibitor, N-PPG, is combined with both GLS1-inhibiting and a p53-upregulating MDM2 antagonist. These findings provide preclinical rationale for the development of N-PPG–like PRODH inhibitors as cancer therapeutics to exploit synthetic lethal interactions with p53 upregulation and GLS1 inhibition.
Digitalis Therapy and Risk of Recurrent Ventricular Tachyarrhythmias and ICD Therapies in Atrial Fibrillation and Heart Failure
Authors: Schupp Tobias , Behnes Michael , Weiss Christel , Nienaber Christoph , Reiser Linda , Bollow Armin , Taton Gabriel , Reichelt Thomas , Ellguth Dominik , Engelke Niko , Rusnak Jonas , Weidner Kathrin , Akin Muharrem , Mashayekhi Kambis , Borggrefe Martin , Akin Ibrahim
Published: June 2019

Objective: This study sought to assess the impact of treatment with digitalis on recurrences of ventricular tachyarrhythmias in implantable cardioverter defibrillator (ICD) recipients with atrial fibrillation (AF) and heart failure (HF). Background: The data regarding outcomes of digitalis therapy in ICD recipients are limited. Methods: A large retrospective registry was used, including consecutive ICD recipients with episodes of ventricular tachyarrhythmia between 2002 and 2016. Patients treated with digitalis were compared to patients without digitalis treatment. The primary prognostic outcome was first recurrence of ventricular tachyarrhythmia at 5 years. Kaplan-Meier and multivariable Cox regression analyses were applied. Results: A total of 394 ICD recipients with AF and/or HF was included (26% with digitalis treatment and 74% without). Digitalis treatment was associated with decreased freedom from recurrent ventricular tachy­arrhythmias (HR = 1.423; 95% CI 1.047–1.934; p = 0.023). Accordingly, digitalis treatment was associated with decreased freedom from appropriate ICD therapies (HR = 1.622; 95% CI 1.166–2.256; p = 0.004) and, moreover, higher rates of rehospitalization (38 vs. 21%; p = 0.001) and all-cause mortality (33 vs. 20%; p = 0.011). Conclusion: Among ICD recipients suffering from AF and HF, treatment with digitalis was associated with increased rates of recurrent ventricular tachyarrhythmias and ICD therapies. However, the endpoints may also have been driven by interactions between digitalis, AF, and HF.
Suicidal Carbon Monoxide Poisoning Using Motor Vehicle Exhaust in an Open Space
Authors: Żaba Czesław , Świderski Paweł , Sommerfeld-Klatta Karina , Żaba Zbigniew , Pluta-Hadas Katarzyna , Urbaniak Monika
Published: June 2019

Objectives: A rare case of a suicidal use of gases from the car exhaust system of the car petrol engine in an open space is presented. Clinical Presentation and Intervention: To verify suicidal intent of poisoning, an experimental reconstruction of the crime scene was performed. This demonstrated that appropriately long exposure to carbon monoxide with unfavorable weather conditions can cause acute carbon monoxide poisoning in an open space. Conclusions: This case was studied to observe the pattern of fatal carbon monoxide poisoning in an open space. This might be helpful for forensic medicine, emergency medicine, and occupational medicine.
Evolution and Ontogenesis: The Deontic Niche of Human Development
Authors: Packer Martin J. , Cole Michael
Published: June 2019

We explore contemporary evolutionary perspectives on children’s psychological development, questioning the view that high-fidelity, inter-individual transmission of information explains the cumulative character of human cultures, and children’s ontogenesis within these cultures. We argue that humans construct an environmental niche that is unique in being composed of institutions, which function to coordinate activity over multiple time scales. Institutions involve not simply customs or conventions but a deontology of future-binding rights, responsibilities, duties, and obligations. The origins of institutions can be traced in hominin evolution to Paleolithic hunter-gatherers, where kinship, the first institution, made possible community support of an extended and demanding form of ontogenesis. Since the human environmental niche is an institutional reality, children today need to acquire the ability to understand and act effectively within institutions. We propose that this ability emerges not as an adaptation solely to past conditions but through differentiation and reintegration of an “extended ontogenetic system” of which the child is a constituent, leading to a quality of self-consciousness on the part of the child that makes possible the ability to live in an institutional reality.
Critical Diagnoses in Ophthalmic Pathology: Suspected Important Unanticipated Diagnoses in Surgically Removed Eyes
Authors: Margo Curtis E.
Published: June 2019

Aim: To describe the 5-year profile of anatomic critical diagnoses from an ophthalmic pathology laboratory and raise awareness of the challenges of establishing guidelines for these diagnoses. Methods: Medical records of patients who had consecutively submitted surgically removed globes or eviscerated eyes from 1 October 2009 to 31 October 2014 were examined for a critical diagnosis, as defined by a verbal communication for a serious, unanticipated diagnosis.Important discordant anatomic and clinical diagnoses were reviewed to determine whether the anatomic finding was truly unanticipated. Results: During the study period, 313 eyes were submitted to the laboratory as primary specimens. Twenty (6.4%) had critical (alert) diagnoses. Six of the 20 anatomic diagnoses (30%) were known or suspected prior to surgery but were not communicated on the pathology request form. Five diagnoses (25%) were not clinically suspect before surgery. In 9 cases (45%) medical-care providers were alerted to the critical findings but insufficient clinical information was provided about preoperative conditions. Conclusions: The proportion of critical diagnoses among surgically removed eyes is small, but not inconsequential. Some “critical alerts” would be unnecessary if relevant clinical information was provided when the tissue is submitted to the laboratory. Laboratory guidelines for critical values in surgical pathology should be flexible since they need to anticipate the vicissitudes of clinical practice. Surgeons need to appreciate that relevant clinical information must be provided to pathologists because it can play a role in formulating anatomic diagnoses.
Novel Nanofluidic IgE Assay versus a Reference Method: A Real-World Comparison
Authors: Roethlisberger Samuel , Karoui Olfa , Mapelli Daria , Audran Régine , Aubert Vincent , Girard Laurie D. , Rebeaud Fabien , Leimgruber Annette , Buss Guillaume , Duc Joël , Langner-Viviani Felicitas , Maerki Iwan , Spertini François
Published: June 2019

Background: Clinically meaningful specific IgE determination is an important step in the diagnosis of allergic diseases. While patient’s history and skin prick tests are available during the medical visit, most IgE immunoassays require hours to several days to be available. Recent developments in the field of nanofluidic technology open new horizons for point-of-care management of this unmet medical need. Objective: This study aimed to compare IgE diagnostic agreement between a nanofluidic assay (abioSCOPE®) and a laboratory reference method (Phadia Laboratory System®) in a real-world clinical setting. Methods: Sera from 105 patients whose routine allergy diagnostic workup required a blood sampling were used to compare the novel nanofluidic IgE assay to a reference method in a blind manner for a panel of five respiratory allergens. To assess the agreement between methods, patient records were reviewed by four independent experts to establish the final diagnosis. Experts were blinded to the IgE serological method used, but had access to patient history, skin prick tests, and blood test results. Results: Analytic agreement between the two methods was 81% for the tested panel of allergens (ranging from 77 to 89%). The overall agreement in clinical diagnosis decision taken by the expert panel was 94.6% with the nanofluidic IgE assay when compared to the reference method. Conclusion: The nanofluidic IgE assay, as determined through an evaluation based on clinical history, skin prick tests, and IgE measurement, is a valuable tool for allergy experts to identify patients’ sensitization patterns at the point of care, and for routine IgE diagnostic workup.
Sympathetic Transduction in Type 2 Diabetes Mellitus
Authors: Young Benjamin E. , Holwerda Seth W. , Vranish Jennifer R. , Keller David M. , Fadel Paul J.
Published: June 2019

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index–matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both
P
>0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D −statin), indicated that T2D −statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg,
P
=0.01) and control (control: 2.8±0.3 mm Hg,
P
=0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D −statin patients (T2D −statin: −3.3±0.6 mL/(min·mm Hg), T2D +statin: −1.6±0.3 mL/(min·mm Hg),
P
=0.03; control −2.2±0.3 mL/(min·mm Hg),
P
=0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.
Worlds of Advice
Authors: Siddique Soofia
Published: June 2019

This article situates the nineteenth-century Urdu writer Nazir Ahmad’s Chand Pand as a piece of advice literature on an Arabic-Persian continuum, and equally a text of its time and place. Linguistic features of its discourse show that, as a self-conscious performance of the possibilities of Urdu, it imparts culturally resonant ways of inhabiting a multifarious world, and inscribes an expansive and inclusive view of culture. In particular, the narrative organization of the focal section “A Brief Account of the World” is strongly evocative of a conceptual organization of the world by concentric circles that is comparable to the view of human sociality invoked by the tenth-eleventh century Persian ethicist Miskawayh and illuminates the location of Nazir Ahmad’s text in the continuum of ethics (akhlaq) literature. At the same time, beside these signs of literary cosmopolitanism, I argue that Nazir Ahmad’s account of the world stakes a claim for the irreducible particularity of places and their associated textures of life, and offers a view of the world that supports “place-based thinking or imagination” (Dirlik) as opposed to the potentially obfuscating abstraction of globalized “space.”
On Islands and Deserts
Authors: Leperlier Tristan
Published: June 2019

This article argues for the necessity for world literature and postcolonial studies to examine both global hierarchies of literary legitimacy and those local practices which might challenge them, and give perspectives for other significant geographies. To do so, it focuses on the bilingual and transnational Algerian literary field; this requires different levels of interconnected analysis, namely of the two linguistic subfields, the intermediary level of national literary field and the two Francophone and Arabophone transnational literary fields. Trajectories and literary works of three very different yet linked writers, Rachid Boudjedra, Tahar Djaout and Tahar Ouettar, are examined in turn. The article traces both the global and linguistic inequalities to which they were subjected as well as their practices in order to argue that they reveal unexpected vectors of circulation between spaces and languages. Finally, this piece explores how and why each writer reinvents a world within their desert novels, that is, by narrating wanderings in the desert that are also explorations of national identity.
A re-evaluated taxon: Genetic values and morphological characters support the recognition of the Canary Island juniper of the phoenicea group at a specific level
Authors: ROMO ANGEL , MAZUR MAŁGORZATA , SALVÀ-CATARINEU MONTSERRAT , BORATYŃSKI ADAM
Published: June 2019

Analyses based on cone, seed and needle characteristics revealed that J. canariensis Guyot in Mathou & Guyot is distinct from both the Circum-Mediterranean J. turbinata and West-Mediterranean J. phoenicea. The genetic differences between these three taxa, which make up the aggregate of J. phoenicea, are found also at a high level. These data support the recognition of the Canarian juniper at the specific level. A key is proposed, in which taxa of the J. phoenicea aggregate can be distinguished on the basis of morphological traits.                The nomenclatural name: Juniperus phoenicea subsp. canariensis, widely employed in the literature, is validly published. Besides we adduce that Juniperus canariensis Knight ex Godron, is not a validly published name, and therefore can not be considered an earlier homonym of J. canariensis Guyot in Mathou & Guyot.
Cluzobra matilei sp. n. from French Guyana, with notes on congeners (Diptera: Mycetophilidae)
Authors: KURINA OLAVI
Published: June 2019

Five Cluzobra Edwards species were recorded from the Kaw Mountains in French Guyana. Cluzobra matilei sp. n. is described, with colour photographs and line drawings. The new species is compared with the closely related species C. variegata and C. vicina.
A new species of the lizard genus Bachia (Squamata: Gymnophthalmidae) from the Cerrados of Central Brazil
Authors: RODRIGUES MIGUEL TREFAUT , CAMACHO AGUSTÍN , NUNES PEDRO MURILO SALES , RECODER RENATO SOUSA , TEIXEIRA JR. MAURO , VALDUJO PAULA H. , GHELLERE JOSÉ MÁRIO B. , MOTT TAMÍ , NOGUEIRA CRISTIANO
Published: June 2019

A new species of Bachia of the bresslaui group, is described from Estação Ecológica Serra Geral do Tocantins, a recently created protected area in the Central Brazilian Cerrados of state of Tocantins. The new species is most similar to Bachia psamophila from which it differs in limb morphology and head and body scalation. As in Bachia psamophila the shovelshaped snout of the new species is highly prominent, an adaptation related to its psamophilous habits.
A new subgenus and three new species of catocaline noctuids from China (Lepidoptera, Noctuidae: Catocalinae)
Authors: KONONENKO VLADIMIR , FIBIGER MICHAEL
Published: June 2019

Based on the collection of the Zoological Research Institute and Museum Alexander Koenig, Germany, Bonn, two new species of the genera Lygephila Billberg, 1820 and Apopestes Hübner, [1823] are described from China. The new taxa belong to the subfamily Catocalinae, tribe Toxocampini: Lygephila stueningi, sp. n., Lygephila longicoecum sp. n., and Apopestes curiosa sp. n. The new subgnenus Sinocampa, subgen. n. (type species Lygephila longicoecum, sp. n.) of the genus Lygephila is described. The adults and male and female genitalia are illustrated, and distribution maps of the new species are presented.