bluuebunny/crossref_metadata_2025 huggingface dataset:
Biogeography of high‐mountain plants in the Carpathians: An emerging phylogeographical perspective
Authors: Ronikier Michał
Published: February 2019

The Carpathians belong to the main elements of the European Alpine System and have an important biogeographical location between the Balkan ranges in the South, the Alps in the West and the Scandinavian range in the North. However, until recently this area was rarely included in detailed phylogeographical studies that could bring insights into its biogeographical history, links with other mountain ranges and contemporary genetic structure of populations. Here, available phylogeographical studies on high‐mountain plants that include data concerning the Carpathians are reviewed in order to (1) discuss regional phylogeographical structure and divergence of the Carpathian populations from those in other European mountain ranges, and (2) outline further perspectives of the Carpathian phylogeography. Analysis of available studies revealed the complexity of the biogeographical history of high‐mountain plants. The studies show a deep phylogeographical structure in the Carpathians, mostly concurring with classical biogeographical boundaries, and suggesting a long‐term isolation and restricted gene flow between the main Carpathian regions. For some species, though, recent dispersal events among isolated mountain ranges were detected. Such contrasting patterns were found at a larger geographical scale as well (e. g., between the Carpathians and the Alps). Several examples suggest the importance of the Carpathians in migration of arctic‐alpine plants from the East and towards the North. In most reviewed studies, however, the Carpathians are only marginally represented and detailed intraspecific studies based on dense population coverage in all disjunct areas of species' ranges are clearly needed to obtain reliable information and confirm the preliminary phylogeographical patterns emerging from the overview presented here.
Epidendrum(Orchidaceae) as a model system for ecological and evolutionary studies in the Neotropics
Authors: Pinheiro Fábio , Cozzolino Salvatore
Published: February 2019

The orchid genus Epidendrum, with 1500 species occurring within the Neotropical region, represents a very promising model system for evolutionary and ecological studies offering an expanded repertoire of research opportunities in the breadth of modern plant biology. Epidendrum displays a significant degree of morphological variation, chromosome number diversity and ecological interactions, which challenges widely held views on reproductive barriers and habitat selection. The widespread geographical distribution of many species and populations offers interesting opportunities to investigate how climatic changes and historic demographic processes shaped the current patterns of genetic and species diversity across different biomes and landscapes. Questions involving chromosome barriers to gene exchange and the role of postzygotic genetic barriers in species cohesion (e.g., the contributions of habitat selection and niche divergence on species cohesion) could be easily addressed when using the variety of natural hybrid zones found across Epidendrum. Several key evolutionary questions could be addressed with this model system, such as the identification of the first stages of adaptive radiation, the evolution of pollination strate gies, the adaptive ecological significance of trait variation and hybridisation, the influence of historical demographic events on lineage diversification and speciation. With the advance of cost–effective molecular techniques and by combining ecological and phenotypic data, researchers can now tackle these questions and foster significant progress in the field of Neotropical plant diversification and evolution.
Evaluation of a structured individualised protocol as a potential cost‐effective diagnostic and therapeutic approach to chronic diarrhoea in the dog
Authors: Bryan Christine E. , Cade Jeb C. , Mackin Andrew J. , Sullivant Alyssa M.
Published: February 2019

Diagnostic investigation and management of chronic diarrhoea in dogs can be cost‐prohibitive to many owners. The objectives of this study were to evaluate evidence‐based, individualised diagnostic and therapeutic protocols for management of dogs with chronic diarrhoea, where financial constraints dictate a budget‐limited approach and where more expensive approaches are deferred until simple affordable protocols are unsuccessful. Twenty‐two client‐owned dogs with chronic (minimum 2 weeks duration) untreated small, large or mixed small/large bowel diarrhoea were enrolled in a budget‐limited step‐wise management protocol (maximum expenditure $300 over 6 weeks), with diagnostic testing and therapeutic trials managed in an individualised and evidence‐based fashion. Success was defined as complete resolution of diarrhoea for a minimum of 1 month. Dogs that failed to respond to a budget‐limited protocol were then enrolled for complete, referral‐level management. Four dogs exited the project early (one death due to caval syndrome, three lost to follow‐up). Thirteen out of the remaining 18 dogs had complete resolution of diarrhoea utilising a budget‐limited approach (success rate 72.2%, confidence intervals 46.5–90.3%) and five dogs were moved on to a referral‐level investigation, with complete resolution of diarrhoea in four out of five. Seventeen out of the 18 dogs therefore responded to a protocol based on a budget‐limited approach followed by extensive investigation only if needed, for an overall success rate of 94.4% (CI72.7–99.9%). Comprehensive investigation of chronic diarrhoea can be deferred while simple affordable diagnostics and therapeutic trials are conducted in stable canine patients and, often, an extensive management approach will be unnecessary.
vChecker: an application-level demand-based co-scheduler for improving the performance of parallel jobs in Xen
Authors: Jiang Peng , He Ligang , Ren Shenyuan , Chen Zhiyan , Mao Rui
Published: February 2019

Big data analysis requires the speedup of parallel computing. However, in the virtualized systems, the power of parallel computing is not fully exploited due to the limit of current VMM schedulers. Xen, one of the most popular virtualization platforms, has been widely used by industry to host parallel job. In practice, the virtualized systems are expected to accommodate both parallel jobs and serial jobs, and resource contention between virtual machines results in severe performance degradation of the parallel jobs.
Moreover, the physical resource is vastly wasted during the communication process due to the ineffective scheduling of parallel jobs. Unfortunately, the existing schedulers of Xen are initially targeting at serial jobs, which are not capable of correctly scheduling the parallel jobs. This paper presents vChecker, an application-level co-scheduler which mitigates the performance degradation of the parallel job and optimizes the utilization of the hardware resource. Our co-scheduler takes number of available CPU cores in one hand, and satisfies need of the parallel jobs in other hand, which helps the credit scheduler of Xen to appropriately schedule the parallel job. As our co-scheduler is implemented at application level, no modifications on the hypervisor is required.
The experimental result shows that the vChecker optimizes the performance of the parallel job in Xen and enhances the utilization of the system.
Ultrastructural Study of Clitoral Cavernous Tissue and Clitoral Blood Flow From Type 1 Diabetic Premenopausal Women on Phosphodiesterase-5 Inhibitor
Authors: Caruso Salvatore , Cianci Antonio , Cianci Stefano , Monaco Caterina , Fava Valentina , Cavallari Vittorio
Published: February 2019

Background

The effects of phosphodiesterase-type 5 (PDE5) inhibitors on the in vivo clitoral structure of women with diabetes have never been investigated.

Aim

To study the in vivo structural and hemodynamic changes of the clitoris in premenopausal women with type 1 diabetes on PDE5 inhibitors.

Methods

38 premenopausal women with type 1 diabetes aged 36 -46 years. A randomized 1:1 study design was used: Study Group (group A) on Tadalafil 5 mg daily, and control group (group B). Blood samples were taken from each woman to measure HbA1c, testosterone, and Free Androgen Index. The women underwent microbiopsy of the clitoral body by means of semiautomatic gun during total anesthesia for surgery therapy of a benign gynecological pathology. The tissue removed was processed for electron microscopy. Translabial color Doppler ultrasound was used to measure the peak systolic velocity (PSV), the end diastolic velocity (EDV), and the pulsatility index (PI) of clitoral arteries.

Main Outcome Measures

Micro-ultrastructure observation of clitoral tissue and color Doppler sonography of clitoral blood flow.

Results

Of the 38 women, 13 (68.4%) of group A and 15 (78.9%) of group B completed the study. Group A showed a mean PSV and EDV increase, and a mean PI decrease with respect to baseline (P < .001). Group B did not show any change in both the parameters (P = NS). By a quantitative study in both groups a variable degree of ultrastructural abnormalities of smooth muscle cells (SMCs) was observed, consisting in increased glycogen and lipoic deposits, cytoplasmic vacuoles, and focal increase of electron density of SMCs. Moreover, the mean SMC thickness of group A (1.83 ± 0.68 µm) was larger than that of group B (1.3 ± 0.41 µm) (P = .02).

Clinical Implications

PDE5 inhibitors could be used to treat diabetic women with genital arousal disorder.

Strengths & Limitations

The study shows a clear effect of PDE5 inhibitors on clitoral SMCs. However, a limit was to not have investigated the sexual function/behavior of women of both groups, this was because of the short time of the study.

Conclusion

This study could help to understand in what way PDE5 inhibitors act on the ultrastructural pathophysiological clitoral cavernous tissue of women with diabetes. It could support PDE5 inhibitor usage in women with genital sexual arousal disorder due to metabolic diseases.
Cutting-edge technology
Authors: Nickels Liz
Published: February 2019

A Sheffield knife manufacturer joined forces with the UK’s foremost additive manufacturing center to develop an innovative way to 3D print a bespoke chef’s knife. Liz Nickels spoke to a project engineer at the AMRC to find out how it was done.
Understanding the credential theft lifecycle
Authors: Esparza Jose Miguel
Published: February 2019

Credential theft is a serious driver of cybercrime today. The world over, different kinds of credentials are used by billions daily to authenticate themselves in their physical and digital lives. From physical keys, to tokens and cards, to digital private keys, session cookies, digital certificates, crypto-currency wallets, login and password combinations, all of these types of credentials are vulnerable to attack.

Credential theft is a serious driver of cybercrime today. The world over, different kinds of credentials are used by billions daily to authenticate themselves in their physical and digital lives.

From physical keys, through tokens and cards, to digital private keys, session cookies, digital certificates, crypto-currency wallets, login and password combinations, all of these types of credentials are vulnerable to attack. But what happens after they are compromised? Jose Miguel Esparza of Blueliv follows the lifespan of stolen credentials, from theft to being exploited for profit.
The burden of colonization and infection by carbapenemase-producing Enterobacteriaceae in the neuro-rehabilitation setting: a prospective six-year experience
Authors: Tedeschi Sara , Trapani Filippo , Liverani Annalisa , Tumietto Fabio , Cristini Francesco , Pignanelli Salvatore , Berlingeri Andrea , Bonavita Jacopo , Belloni Gian Piero , Bartoletti Michele , Giannella Maddalena , Pederzini Roberto , Viale Pierluigi
Published: February 2019

We describe the high burden of carbapenemase-producing Enterobacteriaceae (CPE) colonization and infection in a neuro-rehabilitation hospital in Italy over a 6-year period. Overall, 9.3% of patients were found to be CPE carriers on admission; the rates of CPE in-hospital acquisition and CPE-BSI were 9.2 and 2.9 cases per 10,000 patient days, respectively.
Gesture frequency is linked to story-telling style: evidence from bilinguals
Authors: NICOLADIS ELENA , NAGPAL JAYA , MARENTETTE PAULA , HAUER BRANDON
Published: February 2019

abstract

Individuals differ in how frequently they gesture. It is not clear whether gesture frequency is related to culture, since varied results have been reported. The purpose of this study was to test whether the frequency of representational gestures is linked with story-telling style. Previous research showed individual and cross-cultural differences in story-telling style, some preferring to tell a chronicle (how it happened) or an evaluative story (why it happened). We hypothesized that high gesture frequency might be strongly associated with using a chronicle style, since both rely on visuospatial imagery. Four groups of bilinguals, English as their second language (L2) participated. Their first language (L1) was one of: Mandarin, Hindi, French, or Spanish. Participants watched a cartoon and told the story, once in English, once in L1. The results showed group differences in the rate of gesture use: the Chinese and Hindi L1 participants gestured less frequently than the French and Spanish L1 participants. The participants from Asian cultures were more likely to tell an evaluative story and the Romance-language L1 participants a chronicle. We conclude that these culture/language groups differ in story-telling style. A chronicle style is associated with more gesture production than an evaluative style.
The helminth parasite community of European badgers (Meles meles) in Ireland
Authors: Byrne R.L. , Fogarty U. , Mooney A. , Harris E. , Good M. , Marples N.M. , Holland C.V.
Published: February 2019

The European badger (Meles meles) is Ireland's largest terrestrial carnivore. Since first being identified as a wildlife reservoir of bovine tuberculosis in 1974 there has been an increased research focus into the behaviour of these ecologically important mammals in the Republic of Ireland (ROI). However, to date there has never been an assessment of the helminth parasite community of Irish badgers. This study of 289 badgers found helminth infection to be endemic within the sample population and we report for the first time the prevalence, abundance, intensity and aggregation of helminth infection in ROI. Eight distinct helminth taxa were recorded: Aelurostrongylus falciformis, Crenosoma melesi, Eucoleus aerophilus, Species A, Strongyloides spp., Uncinaria criniformis, and two unidentifiable but morphologically distinct nematodes. All helminths belong to the taxon Nematoda, and this is the first report of an exclusively nematode community across the badger's Eurasian distribution. Infection was not significantly influenced by the host sex, region of origin or season of sampling.
Enhancing Environmental Engagement with Natural Language Interfaces for In-Vehicle Navigation Systems
Authors: Antrobus Vicki , Large David , Burnett Gary , Hare Chrisminder
Published: February 2019

Four on-road studies were conducted in the Clifton area of Nottingham, UK, aiming to explore the relationships between driver workload and environmental engagement associated with ‘active’ and ‘passive’ navigation systems. In a between-subjects design, a total of 61 experienced drivers completed two experimental drives comprising the same three routes (with overlapping sections), staged one week apart. Drivers were provided with the navigational support of a commercially-available navigation device (‘satnav’), an informed passenger (a stranger with expert route knowledge), a collaborative passenger (an individual with whom they had a close, personal relationship) or a novel interface employing a conversational natural language ‘NAV-NLI’ (Navigation Natural Language Interface). The NAV-NLI was created by curating linguistic intercourse extracted from the earlier conditions and delivering this using a ‘Wizard-of-Oz’ technique. This term describes a research experiment in which subjects interact with a computer system that they believe to be autonomous, but which is actually being operated or partially operated by an unseen human being. The different navigational methods were notable for their varying interactivity and the preponderance of environmental landmark information within route directions. Participants experienced the same guidance on each of the two drives to explore changes in reported and observed behaviour. Results show that participants who were more active in the navigation task (collaborative passenger or NAV-NLI) demonstrated enhanced environmental engagement (landmark recognition, route-learning and survey knowledge) allowing them to reconstruct the route more accurately post-drive, compared to drivers using more passive forms of navigational support (SatNav or informed passenger). Workload measures (the Tactile Detection Task (TDT) and the National Aeronautical and Space Administration Task Load Index (NASA-TLX)) indicated no differences between conditions, although SatNav users and collaborative passenger drivers reported lower workload during their second drive. The research demonstrates clear benefits and potential for a navigation system employing two-way conversational language to deliver instructions. This could help support a long-term perspective in the development of spatial knowledge, enabling drivers to become less reliant on the technology and begin to re-establish associations between viewing an environmental feature and the related navigational manoeuvre.
Quercetin influences in vitro maturation, apoptosis and metabolically active mitochondria of goat oocytes
Authors: Silva A.A.A. , Silva M.N.P. , Figueiredo L.B.F. , Gonçalves J.D. , Silva M.J.S. , Loiola M.L.G. , Bastos B.D.M. , Oliveira R.A. , Ribeiro L.G.M. , Barberino R.S , Gouveia B.B. , Monte A.P.O. , Nogueira D.M. , Cordeiro M.F. , Matos M.H.T. , Lopes Júnior E.S.
Published: February 2019

The present study aimed to investigate the effect of quercetin as an alternative antioxidant to cysteamine on in vitro maturation. Oocytes were collected from goat ovaries, destined for in vitro maturation and distributed into three groups: CIS group, oocytes were immersed in MIV base medium; in Groups Q4 and Q8, oocytes were immersed in the medium of the CIS group, adding 4 μM or 8 μM of quercetin, respectively, and cultured for 24 h at 38.5°C with 5% CO2. The CIS and Q4 groups presented the same percentage of expanded cumulus cells, but the per cent in the Q8 group was significantly lower than that of the other groups (P<0.05). The oocyte retraction rate in the Q8 group was higher (P<0.05) than in the CIS and Q4 groups. Treatment with 8 μM of quercetin presented a lower proportion of expanded oocytes than the CIS group and 4 μM of quercetin (P<0.05). The percentage of MII oocytes was higher in the Q4 group than in the CIS group (P<0.05), but the percentages in the CIS and Q8 groups were similar. The rate of apoptosis was higher in the CIS group than in the other groups (P<0.05). In addition, oocytes matured with 4 μM quercetin showed higher mitochondrial activity than matured oocytes in the CIS and Q8 groups (P<0.05). In conclusion, 4 μM of quercetin can be used as an alternative to cysteamine in the in vitro maturation of goat oocytes.
Introduction to the TPLP Special Issue on User-oriented Logic Programming and Reasoning Paradigms
Authors: ELLMAUTHALER STEFAN , SCHULZ CLAUDIA
Published: February 2019

With the rise of machine learning, and more recently the overwhelming interest in deep learning, knowledge representation and reasoning (KRR) approaches struggle to maintain their position within the wider Artificial Intelligence (AI) community. Often considered as part of thegood old-fashioned AI(Haugeland 1985) – like a memory of glorious old days that have come to an end – many consider KRR as no longer applicable (on its own) to the problems faced by AI today (Blackwell 2015; Garneloet al.2016). What they see are logical languages with symbols incomprehensible by most, inference mechanisms that even experts have difficulties tracing and debugging, and the incapability to process unstructured data like text.
THREE PROBLEMS OF OTHER MINDS
Authors: Engelland Chad
Published: February 2019

The traditional problem of other minds is epistemological. What justification can be given for thinking that the world is populated with other minds? More recently, some philosophers have argued for a second problem of other minds that is conceptual. How can we conceive of the point of view of another mind in relation to our own? This article retraces the logic of the epistemological and conceptual problems, and it argues for a third problem of other minds. This is the phenomenological problem which concerns the philosophical (rather than psychological) question of experience. How is another mind experienced as another mind? The article offers dialectical and motivational justification for regarding these as three distinct problems. First, it argues that while the phenomenological problem cannot be reduced to the other problems, it is logically presupposed by them. Second, the article examines how the three problems are motivated by everyday experiences in three distinct ways.
The Madden‐Julian Oscillation in an Aquaplanet‐Like General Circulation Model With and Without Continents
Authors: Das Surajit , Sengupta Debasis , Chakraborty Arindam
Published: February 2019

We have conducted experiments with the Community Atmospheric Model version 5.1 configured as an aquaplanet, with the sun at March equinox, in order to study how the model Madden‐Julian oscillation (MJO) responds to (i) the introduction of continents and (ii) realistic sea surface temperature (SST) distribution. Model results are compared with ERA‐Interim reanalysis and analyzed in terms of the moist static energy (MSE) budget to study the growth and propagation of MJO. With idealized zonally symmetric SST, the aquaplanet model produces a double Intertropical Convergence Zone (ITCZ) and an MJO‐like mode with variance at intraseasonal (30‐ to 96‐day) periods and zonal wave number 1. When we introduce continents with realistic orography and interactive surface temperature, soil moisture, and albedo, the variance of MJO is mainly confined to zonal wave numbers 1 and 2 but reduced by a factor of 3 due to weaker boundary layer moisture convergence. With prescribed climatological January SST boundary condition (which includes Indo‐west Pacific warm pool) in the presence of continents, model MJO variance is enhanced and distributed across zonal wave numbers 1 to 5, in closer agreement with observation. Thus, the presence of land by itself is not enough, but realistic SST distribution is necessary for improved space‐time characteristics of model MJO. Both in simulations and ERA‐Interim data, meridional and vertical advection of MSE promotes eastward movement of MJO. In the model experiments, meridional advection of low‐level MSE anomaly is most significant in the vicinity of the ITCZ, indicating the importance of processes that determine the location of (single or double) ITCZ.
Tailoring Centrality Metrics for Water Distribution Networks
Authors: Giustolisi Orazio , Ridolfi Luca , Simone Antonietta
Published: February 2019

Complex network theory (CNT) is an emerging topic based on the paradigm that quite all the natural and man‐made physical systems work as networks, namely, their features derive from the internal connectivity among vertices exchanging information through edges. Water distribution infrastructures are networked systems connecting the vertices named nodes, by edges named pipes, and transferring water to customers. Therefore, water distribution networks (WDNs) fall into CNT and belongs to the class of spatial networks due to their urban constraints. CNT proposed several centrality metrics for quantifying the importance of vertex and, sometime, edges. Those metrics can be potentially very useful for analyzing the key features of the physical domain (i.e., the network) where WDN hydraulics occurs, but they need to be tailored to consider that (i) pipes/edges are the relevant physical components of the WDNs, (ii) some nodes/vertices (reservoirs and tanks) play a completely different hydraulic role from the majority of nodes (demand and connection nodes), and (iii) pipes/edges have different characteristics (length, diameter, hydraulic resistance, etc.). Accordingly, this work presents and discusses the need of tailoring the most suitable centrality metrics for spatial networks: betweenness, closeness, and degree. Then the capacity of the WDN‐tailored edge betweenness is demonstrated and discussed using two real WDNs, showing that it can extract useful information from the domain, that is, the emerging hydraulic behavior due to the network connectivity structure. Therefore, the WDN‐tailored edge betweenness can assist analysis, planning, and management actions before and after the hydraulic analysis.
PAK4 signaling in health and disease: defining the PAK4–CREB axis
Authors: Won So-Yoon , Park Jung-Jin , Shin Eun-Young , Kim Eung-Gook
Published: February 2019

p21-Activated kinase 4 (PAK4), a member of the PAK family, regulates a wide range of cellular functions, including cell adhesion, migration, proliferation, and survival. Dysregulation of its expression and activity thus contributes to the development of diverse pathological conditions. PAK4 plays a pivotal role in cancer progression by accelerating the epithelial–mesenchymal transition, invasion, and metastasis. Therefore, PAK4 is regarded as an attractive therapeutic target in diverse types of cancers, prompting the development of PAK4-specific inhibitors as anticancer drugs; however, these drugs have not yet been successful. PAK4 is essential for embryonic brain development and has a neuroprotective function. A long list of PAK4 effectors has been reported. Recently, the transcription factor CREB has emerged as a novel effector of PAK4. This finding has broad implications for the role of PAK4 in health and disease because CREB-mediated transcriptional reprogramming involves a wide range of genes. In this article, we review the PAK4 signaling pathways involved in prostate cancer, Parkinson’s disease, and melanogenesis, focusing in particular on the PAK4-CREB axis.
NF-κB-responsive miR-155 induces functional impairment of vascular smooth muscle cells by downregulating soluble guanylyl cyclase
Authors: Park Minsik , Choi Seunghwan , Kim Suji , Kim Joohwan , Lee Dong-Keon , Park Wonjin , Kim Taesam , Jung Jiwon , Hwang Jong Yun , Won Moo-Ho , Ryoo Sungwoo , Kang Seung Goo , Ha Kwon-Soo , Kwon Young-Guen , Kim Young-Myeong
Published: February 2019

Vascular smooth muscle cells (VSMCs) play an important role in maintaining vascular function. Inflammation-mediated VSMC dysfunction leads to atherosclerotic intimal hyperplasia and preeclamptic hypertension; however, the underlying mechanisms are not clearly understood. We analyzed the expression levels of microRNA-155 (miR-155) in cultured VSMCs, mouse vessels, and clinical specimens and then assessed its role in VSMC function. Treatment with tumor necrosis factor-α (TNF-α) elevated miR-155 biogenesis in cultured VSMCs and vessel segments, which was prevented by NF-κB inhibition. MiR-155 expression was also increased in high-fat diet-fed ApoE−/− mice and in patients with atherosclerosis and preeclampsia. The miR-155 levels were inversely correlated with soluble guanylyl cyclase β1 (sGCβ1) expression and nitric oxide (NO)-dependent cGMP production through targeting the sGCβ1 transcript. TNF-α-induced miR-155 caused VSMC phenotypic switching, which was confirmed by the downregulation of VSMC-specific marker genes, suppression of cell proliferation and migration, alterations in cell morphology, and NO-induced vasorelaxation. These events were mitigated by miR-155 inhibition. Moreover, TNF-α did not cause VSMC phenotypic modulation and limit NO-induced vasodilation in aortic vessels of miR-155−/− mice. These findings suggest that NF-κB-induced miR-155 impairs the VSMC contractile phenotype and NO-mediated vasorelaxation by downregulating sGCβ1 expression. These data suggest that NF-κB-responsive miR-155 is a novel negative regulator of VSMC functions by impairing the sGC/cGMP pathway, which is essential for maintaining the VSMC contractile phenotype and vasorelaxation, offering a new therapeutic target for the treatment of atherosclerosis and preeclampsia.
Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling
Authors: Kim Donghee , Li Hui Ying , Lee Jong Han , Oh Yoon Sin , Jun Hee-Sook
Published: February 2019

Mesangial cell proliferation has been identified as a major factor contributing to glomerulosclerosis, which is a typical symptom of diabetic nephropathy (DN). Lysophosphatidic acid (LPA) levels are increased in the glomerulus of the kidney in diabetic mice. LPA is a critical regulator that induces mesangial cell proliferation; however, its effect and molecular mechanisms remain unknown. The proportion of α-SMA+/PCNA+ cells was increased in the kidney cortex of db/db mice compared with control mice. Treatment with LPA concomitantly increased the proliferation of mouse mesangial cells (SV40 MES13) and the expression of cyclin D1 and CDK4. On the other hand, the expression of p27Kip1 was decreased. The expression of Krüppel-like factor 5 (KLF5) was upregulated in the kidney cortex of db/db mice and LPA-treated SV40 MES13 cells. RNAi-mediated silencing of KLF5 reversed these effects and inhibited the proliferation of LPA-treated cells. Mitogen-activated protein kinases (MAPKs) were activated, and the expression of early growth response 1 (Egr1) was subsequently increased in LPA-treated SV40 MES13 cells and the kidney cortex of db/db mice. Moreover, LPA significantly increased the activity of the Ras-related C3 botulinum toxin substrate (Rac1) GTPase in SV40 MES13 cells, and the dominant-negative form of Rac1 partially inhibited the phosphorylation of p38 and upregulation of Egr1 and KLF5 induced by LPA. LPA-induced hyperproliferation was attenuated by the inhibition of Rac1 activity. Based on these results, the Rac1/MAPK/KLF5 signaling pathway was one of the mechanisms by which LPA induced mesangial cell proliferation in DN models.
Ultra-high field MRI reveals mood-related circuit disturbances in depression: a comparison between 3-Tesla and 7-Tesla
Authors: Morris Laurel S. , Kundu Prantik , Costi Sara , Collins Abigail , Schneider Molly , Verma Gaurav , Balchandani Priti , Murrough James W.
Published: February 2019

Ultra-high field 7-Tesla (7 T) MRI has the potential to advance our understanding of neuropsychiatric disorders, including major depressive disorder (MDD). To date, few studies have quantified the advantage of resting state functional MRI (fMRI) at 7 T compared to 3-Tesla (3 T). We conducted a series of experiments that demonstrate the improvement in temporal signal-to-noise ratio (TSNR) of a multi-echo multi-band fMRI protocol with ultra-high field 7 T MRI, compared to a similar protocol using 3 T MRI in healthy controls (HC). We also directly tested the enhancement in ultra-high field 7 T fMRI signal power by examining the ventral tegmental area (VTA), a small midbrain structure that is critical to the expected neuropathology of MDD but difficult to discern with standard 3 T MRI. We demonstrate up to 300% improvement in TSNR and resting state functional connectivity coefficients provided by ultra-high field 7 T fMRI compared to 3 T, indicating enhanced power for detection of functional neural architecture. A multi-echo based acquisition protocol and signal denoising pipeline afforded greater gain in signal power compared to classic acquisition and denoising pipelines. Furthermore, ultra-high field fMRI revealed mood-related neurocircuit disturbances in patients with MDD compared to HC, which were not detectable with 3 T fMRI. Ultra-high field 7 T fMRI may provide an effective tool for studying functional neural architecture relevant to MDD and other neuropsychiatric disorders.
P53-induced miR-1249 inhibits tumor growth, metastasis, and angiogenesis by targeting VEGFA and HMGA2
Authors: Chen Xiaoxiang , Zeng Kaixuan , Xu Mu , Liu Xiangxiang , Hu Xiuxiu , Xu Tao , He Bangshun , Pan Yuqin , Sun Huiling , Wang Shukui
Published: February 2019

MicroRNAs (miRNAs) are important class of functional regulators involved in human cancers development, including colorectal cancer (CRC). Exploring aberrantly expressed miRNAs may provide us with new insights into the initiation and development of CRC by functioning as oncogenes or tumor suppressors. The aim of our study is to discover the expression pattern of miR-1249 in CRC and investigate its clinical significance as well as biological role in CRC progression. In our study, we found that miR-1249 was markedly downregulated in CRC tissues and cell lines, and negatively related to pN stage, pM stage, TNM stage, and overall survival (OS). Moreover, we demonstrated that miR-1249 was a direct transcriptional target of P53 and revealed that P53-induced miR-1249 inhibited tumor growth, metastasis and angiogenesis in vitro and vivo. Additionally, we verified that miR-1249 suppressed CRC proliferation and angiogenesis by targeting VEGFA as well as inhibited CRC metastasis by targeting both VEGFA and HMGA2. Further studying showed that miR-1249 suppressed CRC cell proliferation, migration, invasion, and angiogenesis via VEGFA-mediated Akt/mTOR pathway as well as inhibited EMT process of CRC cells by targeting both VEGFA and HMGA2. Our study indicated that P53-induced miR-1249 may suppress CRC growth, metastasis and angiogenesis by targeting VEGFA and HMGA2, as well as regulate Akt/mTOR pathway and EMT process in the initiation and development of CRC. miR-1249 might be a novel the therapeutic candidate target in CRC treatment.
Oocyte-derived E-cadherin acts as a multiple functional factor maintaining the primordial follicle pool in mice
Authors: Yan Hao , Wen Jia , Zhang Tuo , Zheng Wenying , He Meina , Huang Kun , Guo Qirui , Chen Qian , Yang Yi , Deng Guangcun , Xu Jinrui , Wei Zhiqing , Zhang Hua , Xia Guoliang , Wang Chao
Published: February 2019

In mammals, female fecundity is determined by the size of the primordial follicle (PF) pool, which is established during the perinatal period. As a non-renewable resource, the preservation of dormant PFs is crucial for sustaining female reproduction throughout life. Although studies have revealed that several oocyte-derived functional genes and pathways, such as newborn ovary homeobox (NOBOX) and 3-phosphoinositide-dependent protein kinase-1, participate in maintaining the PF pool, our understanding of the underlying molecular mechanisms is still incomplete. Here, we demonstrate that E-cadherin (E-cad) plays a crucial role in the maintenance of PFs in mice. E-cad is specifically localized to the cytomembrane of oocytes in PFs. Knockdown of E-cad in neonatal ovaries resulted in significant PF loss owing to oocyte apoptosis. In addition, the expression pattern of NOBOX is similar to that of E-cad. Knockdown of E-cad resulted in a decreased NOBOX level, whereas overexpression of Nobox partially rescued the follicle loss induced by silencing E-cad. Furthermore, E-cad governed NOBOX expression by regulating the shuttle protein, β-catenin, which acts as a transcriptional co-activator. Notably, E-cad, which is a transmembrane protein expressed in the oocytes, was also responsible for maintaining the PF structure by facilitating cell–cell adhesive contacts with surrounding pregranulosa cells. In conclusion, E-cad in oocytes of PFs plays an indispensable role in the maintenance of the PF pool by facilitating follicular structural stability and regulating NOBOX expression. These findings shed light on the physiology of sustaining female reproduction.
Autoantibody against β1-adrenoceptor promotes the differentiation of natural regulatory T cells from activated CD4+ T cells by up-regulating AMPK-mediated fatty acid oxidation
Authors: Xu Wenli , Wu Ye , Wang Li , Bai Yan , Du Yunhui , Li Yang , Cao Ning , Zhao Yuhui , Zhang Youyi , Liu Huirong
Published: February 2019

Therapeutic adoptive transfer of natural regulatory T cells (nTreg, CD4+ CD25+ Foxp3+ T cells) or in vivo selective expansion of nTreg cells has been demonstrated to improve the cardiac function in various cardiovascular disease models. The differentiation of nTreg cells is mediated by catecholamines via β1-adrenergic receptor (β1-AR) activation. Autoantibody against β1-adrenoceptor (β1-AA) as a β1-AR agonist is closely associated with the occurrence and deterioration of cardiac dysfunction. However, whether β1-AA has any impact on nTreg cells has not been reported. The aim of the present study was intended to assess the potential impact of β1-AA on nTreg cell differentiation and explore the underlying mechanism. It was found that the expression of multiple proteins involved in nTreg cell differentiation, immunosuppressive function, and migration was up-regulated in mice after β1-AA administration, suggesting that β1-AA may promote nTreg cell activation. In vitro, β1-AA promoted nTreg cell differentiation by up-regulating mitochondrial fatty acid oxidation (FAO) in activated CD4+ T cells via AMP-activated protein kinase (AMPK) activation and mitochondrial membrane potential reduction. In addition, the AMPK agonist facilitated β1-AA-mediated FAO and nTreg cell differentiation. To further confirm the role of AMPK in β1-AA-mediated nTreg cell differentiation, β1-AA was acted on the CD4+ T cells isolated from AMPK-deficient (AMPK−/−) mice. The result showed that the effect of β1-AA on nTreg cell differentiation was attenuated markedly after AMPK knockout. In conclusion, AMPK-mediated metabolic regulation targeting for nTreg cell restoration may be a promising therapeutic target for β1-AA-positive patients with cardiac dysfunction.
MiR-30a regulates cancer cell response to chemotherapy through SNAI1/IRS1/AKT pathway
Authors: Wang Tingting , Chen Gang , Ma Xuemei , Yang Yao , Chen Yali , Peng Yihan , Bai Zhigang , Zhang Zhongtao , Pei Huadong , Guo Wei
Published: February 2019

Despite gemcitabine being the leading chemotherapeutic drug for pancreatic cancer, many patients still relapse due to the drug resistance. We previously reported the molecular link between FKBP51 mediated AKT inhibition and gemcitabine response in pancreatic cancers. However, the upstream regulator of this pathway, especially the involvement of non-coding RNAs in gemcitabine response is still not clear. Here we delineated the miRNA expression profile and key signaling pathways associated with gemcitabine response. Furthermore, we confirmed that miR-30a, one node of this network, regulated cellular response to gemcitabine through SNAI1-IRS1-AKT pathway. MiR-30a directly targeted SNAI1, which activates AKT and ERK through regulating IRS1 in vitro and in vivo. Clinically, miR-30a is downregulated in pancreatic cancer tissue and associated with overall patient survival. We also identified miR-30a as an AKT-FOXO3a-regulated gene that forms a feedback loop. Together, these results demonstrate that miR-30a is an upstream regulator of the Akt pathway with a critical role in cancer etiology and chemoresistance.
Long noncoding RNA EGFR-AS1 promotes cell growth and metastasis via affecting HuR mediated mRNA stability of EGFR in renal cancer
Authors: Wang Anbang , Bao Yi , Wu Zhenjie , Zhao Tangliang , Wang Dong , Shi Jiazi , Liu Bing , Sun Shuhan , Yang Fu , Wang Linhui , Qu Le
Published: February 2019

Long noncoding RNAs (lncRNAs) are implicated in renal cell carcinoma (RCC), but remain largely unclear. Using publicly available transcriptome sequencing data from renal cancer (n = 703) and integrating bioinformatics analyses, we screened and identified a valuable lncRNA, EGFR-AS1. In our validation cohort (n = 204), EGFR-AS1 was significantly upregulated in RCC tissues (P < 0.001). Gain-of-function and loss-of-function studies showed that EGFR-AS1 promoted cell proliferation and invasion in vitro and in vivo. Based on previous studies and sequence complementarity of EGFR with EGFR-AS1, we demonstrated that EGFR-AS1 directly bound to EGFR mRNA and inhibited its degradation. Furthermore, RNA pull-down and mass spectrometry analyses showed that EGFR-AS1 interacted with HuR, which was responsible for the mRNA stability of EGFR. Multivariate analysis suggested that higher EGFR-AS1 expression predicted a poor prognosis in RCC patients (high vs low: P = 0.018, HR = 2.204, 95% CI: 1.145–4.241). In conclusion, EGFR-AS1 enhances the malignant phenotype of RCC cells by enhancing HuR-mediated mRNA stability of EGFR. Our data also provide biological rationales for EGFR-AS1 as a prognostic biomarker and a potential therapeutic target for RCC.
Long non-coding RNA ZNFX1-AS1 promotes the tumor progression and metastasis of colorectal cancer by acting as a competing endogenous RNA of miR-144 to regulate EZH2 expression
Authors: Shi Liangliang , Hong Xiaohua , Ba Li , He Xiaoxiao , Xiong Yin , Ding Qian , Yang Shengli , Peng Gang
Published: February 2019

Mounting evidences indicated that long non-coding RNA is dysregulated and involved in the pathology of tumors. However, the role of lncRNAs in colorectal cancer (CRC) progression is not fully determined. Differentially expressed lncRNA profile in CRC was conducted by lncRNA microarray in 15 pairs of CRC tissues and adjacent normal tissues, and validated by real-time PCR analysis in another 106 pairs of tissues. The biological effect of lncRNA ZNFX1-AS1 was evaluated by in vitro and in vivo assays. The regulation between lncRNA ZNFX1-AS1 and miR-144 was evaluated by a series of experiments. We found that lncRNA ZNFX1-AS1 expression was significantly upregulated in CRC tissues and cell lines, and the expression of lncRNA ZNFX1-AS1 was associated with aggressive tumor phenotype and poor prognosis in CRC. Functionally, knockdown of lncRNA ZNFX1-AS1 inhibited cell proliferation, invasion, in vitro and tumorigenesis and metastasis in vivo. Further investigation demonstrated that lncRNA ZNFX1-AS1 functioned as a competing endogenous RNA (ceRNA) for miR-144, thereby leading to the depression of its endogenous target gene Polycomb group protein enhancer of zeste homolog 2 (EZH2). We found that lncRNA ZNFX1-AS1 is significantly upregulated in CRC, and the newly identified lncRNA ZNFX1-AS1-miR-144-EZH2 axis is involved in the regulation of CRC progression, which might be used as potential therapeutic targets for CRC patients.
LncRNA H19 promotes the committed differentiation of stem cells from apical papilla via miR-141/SPAG9 pathway
Authors: Li Zehan , Yan Ming , Yu Yan , Wang Yanqiu , Lei Gang , Pan Yin , Li Na , Gobin Romila , Yu Jinhua
Published: February 2019

Long noncoding RNAs (lncRNAs) exert significant roles at transcriptional and post-transcriptional levels. Stem cells from apical papilla (SCAPs) differentiate into dentin/bone-like tissues under certain conditions. So far, whether lncRNA-H19 can affect the proliferative behaviors and osteo/odontogenesis of SCAPs, as well as its specific mechanism remain to be elucidated. Here, SCAPs were isolated and transfected with the lentiviruses or packaging vectors. Our results showed that lncRNA-H19 had no significant effect on the proliferative behaviors of SCAPs, as presented by CCK-8 assay, EdU assay and flow cytometry (FCM). Furthermore, alkaline phosphatase (ALP) activity, alizarin red staining, Western blot assay (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and in vivo bone formation assay were conducted to verify the biological influences of H19 on SCAPs. Overexpression of H19 led to the enhanced osteo/odontogenesis of SCAPs, whereas knockdown of H19 inhibited these effects. Mechanistically, H19 competitively bound to miR-141 and prevented SPAG9 from miRNA-mediated degradation, thus significantly elevating phosphorylated levels of p38 and JNK and facilitating the committed differentiation of SCAPs. Taken together, the osteo/odontogenesis of SCAPs was upregulated by overexpression of H19 via miR-141/SPAG9 pathway.
RETRACTED ARTICLE: Long noncoding RNA LINC01234 promotes serine hydroxymethyltransferase 2 expression and proliferation by competitively binding miR-642a-5p in colon cancer
Authors: Lin Changwei , Zhang Yi , Chen Yifei , Bai Yang , Zhang Yi
Published: February 2019

Long noncoding RNAs (lncRNAs) have been indicated as important regulators in various human cancers. However, the overall biological roles and clinical significance of most lncRNAs in colon carcinogenesis are not fully understood. Hence, we investigated the clinical significance, biological function and mechanism of LINC01234 in colon cancer. First, we analyzed LINC01234 alterations in colon cancer tissues and corresponding paracancerous tissues through the analysis of sequencing data obtained from The Cancer Genome Atlas and colon cancer patients. Next, we evaluated the effect of LINC01234 on colon cancer cell proliferation and its regulatory mechanism of serine hydroxymethyltransferase 2 (SHMT2) by acting as a competing endogenous RNA (ceRNA). We found that LINC01234 expression was significantly upregulated in colon cancer tissues and was associated with a shorter survival time. Furthermore, the knockdown of LINC01234 induced proliferation arrest via suppressing serine/glycine metabolism. Mechanistic investigations have indicated that LINC01234 functions as a ceRNA for miR-642a-5p, thereby leading to the derepression of its endogenous target serine hydroxymethyltransferase 2 (SHMT2). LINC01234 is significantly overexpressed in colon cancer, and the LINC01234–miR642a-5p–SHMT2 axis plays a critical role in colon cancer proliferation. Our findings may provide a potential new target for colon cancer diagnosis and therapy.
A genetically encoded single-wavelength sensor for imaging cytosolic and cell surface ATP
Authors: Lobas Mark A. , Tao Rongkun , Nagai Jun , Kronschläger Mira T. , Borden Philip M. , Marvin Jonathan S. , Looger Loren L. , Khakh Baljit S.
Published: February 2019

Adenosine 5′ triphosphate (ATP) is a universal intracellular energy source and an evolutionarily ancient, ubiquitous extracellular signal in diverse species. Here, we report the generation and characterization of single-wavelength genetically encoded fluorescent sensors (iATPSnFRs) for imaging extracellular and cytosolic ATP from insertion of circularly permuted superfolder GFP into the epsilon subunit of F0F1-ATPase from Bacillus PS3. On the cell surface and within the cytosol, iATPSnFR1.0 responds to relevant ATP concentrations (30 μM to 3 mM) with fast increases in fluorescence. iATPSnFRs can be genetically targeted to specific cell types and sub-cellular compartments, imaged with standard light microscopes, do not respond to other nucleotides and nucleosides, and when fused with a red fluorescent protein function as ratiometric indicators. After careful consideration of their modest pH sensitivity, iATPSnFRs represent promising reagents for imaging ATP in the extracellular space and within cells during a variety of settings, and for further application-specific refinements.