bluuebunny/crossref_metadata_2025 huggingface dataset:
Non‐invasive optical assessment of viscosity of middle ear effusions in otitis media
Authors: Monroy Guillermo L. , Pande Paritosh , Shelton Ryan L. , Nolan Ryan M. , Spillman Darold R. , Porter Ryan G. , Novak Michael A. , Boppart Stephen A.
Published: March 2016

Eustachian tube dysfunction can cause fluid to collect within the middle ear cavity and form a middle ear effusion (MEE). MEEs can persist for weeks or months and cause hearing loss as well as speech and learning delays in young children. The ability of a physician to accurately identify and characterize the middle ear for signs of fluid and/or infection is crucial to provide the most appropriate treatment for the patient. Currently, middle ear infections are assessed with otoscopy, which provides limited and only qualitative diagnostic information. In this study, we propose a method utilizing cross‐sectional depth‐resolved optical coherence tomography to noninvasively measure the diffusion coefficient and viscosity of colloid suspensions, such as a MEE. Experimental validation of the proposed technique on simulated MEE phantoms with varying viscosity and particulate characteristics is presented, along with some preliminary results from in vivo and ex vivo samples of human MEEs.

In vivo Optical Coherence Tomography (OCT) image of a human tympanic membrane and Middle Ear Effusion (MEE) (top), with a CCD image of the tympanic membrane surface (inset). Below is the corresponding time‐lapse M‐mode OCT data acquired along the white dotted line over time, which can be analyzed to determine the Stokes–Einstein diffusion coefficient of the effusion.

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In vivo Optical Coherence Tomography (OCT) image of a human tympanic membrane and Middle Ear Effusion (MEE) (top), with a CCD image of the tympanic membrane surface (inset). Below is the corresponding time‐lapse M‐mode OCT data acquired along the white dotted line over time, which can be analyzed to determine the Stokes–Einstein diffusion coefficient of the effusion.
Photodynamic therapy in the upper aerodigestive tract. Overview and outlook
Authors: Volgger Veronika , Betz Christian Stephan
Published: March 2016

The gold standard in the treatment of (pre)malignancies of the upper aerodigestive tract (UADT) is either surgery or (chemo)radiotherapy. Nevertheless, there are special indications where an alternative treatment, such as photodynamic therapy (PDT), might be as effective for and better tolerated by the patients concerned. This article aims to present a contemporary and comprehensive review on the role of photodynamic therapy in the treatment of (pre)malignancies of the UADT. PubMed was searched for “photodynamic therapy larynx/oral cavity/oropharynx/head and neck” in 01/2016. PDT can be efficient in the treatment of recurrent, residual or multiple carcinomas of the UADT without other treatment options. It has also been used with success in the treatment of early oral or laryngeal carcinomas, widespread precancerous lesions or “difficult‐to‐treat” skin cancer, even though these treatments are off‐label. For now, unsolved scientific and economical challenges hinder the methods spread. In special cases, PDT is a highly effective method to treat head and neck (pre)malignancies. Nevertheless, further clinical studies are needed to better define its true value in head and neck oncology.

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Targeted hypoglossal nerve stimulation for the treatment of obstructive sleep apnea: Six‐month results
Authors: Friedman Michael , Jacobowitz Ofer , Hwang Michelle S. , Bergler Wolfgang , Fietze Ingo , Rombaux Philippe , Mwenge Gimbada B. , Yalamanchali Sreeya , Campana John , Maurer Joachim T.
Published: March 2016

Objectives/Hypothesis

This feasibility study was designed to show the preliminary safety and efficacy of targeted hypoglossal neurostimulation (THN), and to identify baseline predictors of successful therapy.

Study Design

Open‐label, prospective, multicenter, single‐arm cohort study, conducted at seven centers in the U.S.A. and Europe.

Methods

Forty‐six participants with moderate to severe obstructive sleep apnea (OSA), failing or intolerant of continuous positive airway pressure, were implanted. Primary (Apnea‐Hypopnea Index [AHI], Oxygen Desaturation Index [ODI]) and secondary (Arousal Index, Epworth Sleepiness Scale Index, Sleep Apnea Quality of Life Index) outcomes were measured at baseline and compared at 6 months. Data were analyzed to identify participant characteristics that would predict success with therapy.

Results

Sixty‐seven adverse events (AEs) were observed among 36 participants; most of the AEs were related to the implant procedure and resolved without sequelae; one device replacement was necessary. Forty‐three participants showed significant (P < .01) decreases in both AHI and ODI at 6 months; 35% (15 of 43) met criteria for AHI responders and 40% (17 of 43) for ODI responders. Significant improvement was observed in all the secondary endpoints. Predictors‐of‐success selection criteria were identified as baseline AHI < 65/hr, baseline apnea index ≤ 30, baseline body mass index < 35, and <15 events/hr of SpO2 decrease > 10%. Seven participants met these criteria; 86% (6 of 7) were AHI responders and 86% (6 of 7) were ODI responders, indicating that THN therapy can be efficacious in a carefully selected population of OSA patients.

Conclusions

This feasibility study suggests that THN therapy is likely to be safe and effective in selected patients.

Level of Evidence

2b Laryngoscope, 126:2618–2623, 2016
Histoanatomical characteristics to increase the success in transoral surgery for hypopharyngeal cancer
Authors: Chitose Shun‐ichi , Sato Kiminori , Fukahori Mioko , Sueyoshi Shintaro , Kurita Takashi , Ono Takeharu , Shin Buichiro , Mihashi Ryota , Umeno Hirohito
Published: March 2016

Objectives/Hypothesis

Transoral laser microsurgery (TLM) for hypopharyngeal cancer results in a lower incidence of complications than conventional open surgery. However, additional knowledge regarding the histoanatomical characteristics of the hypopharynx is necessary to prevent severe complications during TLM. The purpose of this study is to investigate the histoanatomical characteristics of the hypopharynx for TLM.

Study Design

Histoanatomical study.

Methods

Whole organ serial sections of three hypopharynges and larynges from autopsy cases were subjected to hematoxylin & eosin and Elastica van Gieson staining. Surgical histoanatomy of the hypopharynx was observed with each section, and the histoanatomical characteristics directly related to TLM performance were examined microscopically.

Results

The histological structures of muscle layers showed obvious differences between each hypopharyngeal subsite. The posterolateral wall had two kinds of pharyngeal elevator muscles. These fasciae were connected to the perichondrium of the thyroid cartilage. The anterolateral wall between the superior horn and the lamina of the thyroid cartilage had no muscle layer. The superior laryngeal artery and the internal branch of the superior laryngeal nerve run into the larynx and hypopharynx at that site. The inner perichondrium of the thyroid cartilage was present beneath the mucosa. The dihedral angle of the anterior piriform fossa had a deep propria mucosa and paraglottic space. The postcricoid wall consisted of a multilayered structure, including cricoid cartilage covered with laryngeal muscles and mucosa.

Conclusion

A precise understanding of the histoanatomical characteristics of the hypopharynx increases the success of TLM, decreases complication rates, and improves laryngeal preservation.

Level of Evidence

N/A. Laryngoscope, 126:1783–1789, 2016
Risk factors for residual obstructive sleep apnea after adenotonsillectomy in children
Authors: Imanguli Matin , Ulualp Seckin O.
Published: March 2016

Objectives/Hypothesis

To determine the prevalence of residual obstructive sleep apnea (OSA) in children who had adenotonsillectomy (AT) and to identify the risk factors for residual OSA after AT.

Study Design

Retrospective chart review.

Methods

Children with OSA who had AT at a tertiary care children's hospital were reviewed. Data pertaining to demographics, past medical history, body mass index, tonsil and adenoid size, and polysomnography were obtained. Residual OSA was defined as apnea hypopnea index (AHI) greater than 2. The rate of residual OSA and risk factors for residual OSA were assessed.

Results

One hundred sixty‐nine children with OSA underwent polysomnography before and after AT. The prevalence of residual OSA was 38%. The prevalence of residual OSA in obese patients (49%) was higher than that of nonobese patients (27%) (P = .02). Patients with neurological/developmental/craniofacial abnormalities had higher prevalence of residual OSA (44%) than patients without comorbidities (33%) (P < .05). The prevalence of residual OSA in patients with severe OSA (42%) was higher than patients with moderate (29%) or mild OSA (0%) (P = .03). Teenage patients (67%) had a higher prevalence of residual OSA than toddlers (27%), preschooler (33%), and middle childhood groups (29%) (P = .03).

Conclusions

The majority of children had improvement in OSA after AT. The choice of AHI threshold used to define residual OSA influenced the prevalence of residual OSA. Teenagers and children with obesity, comorbidities including neurological/developmental/craniofacial abnormalities alone or in combination with asthma, or severe OSA have a high risk of residual OSA.

Level of Evidence

4 Laryngoscope, 126:2624–2629, 2016
Leg Movements During General Anesthesia
Authors: Vanegas‐Arroyave Nora , Zaghloul Kareem A , Hallett Mark , Lungu Codrin
Published: March 2016

View Supplementary Video 1

The authors describe a case of atypical leg movements during general anesthesia. The differential diagnosis of this presentation includes rhythmic movement phenomena, such as leg myoclonus, alternating leg muscle activation, and periodic leg movements of sleep. The patient had a history of tremor‐predominant Parkinson's disease since age 43 years. He underwent deep brain stimulation surgery at the National Institutes of Health after an overnight dopaminergic medication withdrawal. Shortly after anesthetic induction, he developed periodic, involuntary movements of his legs that were stereotyped, bilateral and synchronous. The movements were characterized by partial flexion of the ankle, knee, and hip for 3 or 4 seconds at intervals of 5 to 10 seconds. After cessation of the anesthetic infusion, his movements promptly subsided. The total duration of the event was approximately 2 minutes. There were no residual motor or sensory deficits on neurologic examination. Although the exact mechanism responsible for the described observation requires further investigation, this phenomenology should be known, because its occurrence under intravenous anesthetics could be confused for other, pathophysiologically different phenomena.
From amino acid sequence to bioactivity: The biomedical potential of antitumor peptides
Authors: Blanco‐Míguez Aitor , Gutiérrez‐Jácome Alberto , Pérez‐Pérez Martín , Pérez‐Rodríguez Gael , Catalán‐García Sandra , Fdez‐Riverola Florentino , Lourenço Anália , Sánchez Borja
Published: March 2016

Chemoprevention is the use of natural and/or synthetic substances to block, reverse, or retard the process of carcinogenesis. In this field, the use of antitumor peptides is of interest as, (i) these molecules are small in size, (ii) they show good cell diffusion and permeability, (iii) they affect one or more specific molecular pathways involved in carcinogenesis, and (iv) they are not usually genotoxic. We have checked the Web of Science Database (23/11/2015) in order to collect papers reporting on bioactive peptide (1691 registers), which was further filtered searching terms such as “antiproliferative,” “antitumoral,” or “apoptosis” among others. Works reporting the amino acid sequence of an antiproliferative peptide were kept (60 registers), and this was complemented with the peptides included in CancerPPD, an extensive resource for antiproliferative peptides and proteins. Peptides were grouped according to one of the following mechanism of action: inhibition of cell migration, inhibition of tumor angiogenesis, antioxidative mechanisms, inhibition of gene transcription/cell proliferation, induction of apoptosis, disorganization of tubulin structure, cytotoxicity, or unknown mechanisms. The main mechanisms of action of those antiproliferative peptides with known amino acid sequences are presented and finally, their potential clinical usefulness and future challenges on their application is discussed.
Process Pharmacology: A Pharmacological Data Science Approach to Drug Development and Therapy
Authors: Lötsch Jörn , Ultsch Alfred
Published: March 2016

A novel functional‐genomics based concept of pharmacology that uses artificial intelligence techniques for mining and knowledge discovery in “big data” providing comprehensive information about the drugs’ targets and their functional genomics is proposed. In “process pharmacology”, drugs are associated with biological processes. This puts the disease, regarded as alterations in the activity in one or several cellular processes, in the focus of drug therapy. In this setting, the molecular drug targets are merely intermediates. The identification of drugs for therapeutic or repurposing is based on similarities in the high‐dimensional space of the biological processes that a drug influences. Applying this principle to data associated with lymphoblastic leukemia identified a short list of candidate drugs, including one that was recently proposed as novel rescue medication for lymphocytic leukemia. The pharmacological data science approach provides successful selections of drug candidates within development and repurposing tasks.
An Expedient Approach to Synthesize Aryl‐α‐ketoamides from Acetophenones and N,N‐Dimethylformamide
Authors: Liu Weibing , Xu Songsen , Chen Cui , Zhu Zhibo
Published: March 2016

A novel oxidative coupling of acetophenones with N,N‐dimethylformamide to synthesize aryl‐α‐ketoamides was developed by using copper oxide and iodine as the additives. For this conversion, DMF works not only as the solvent but also as the surrogate of dimethylamine. Besides, additional oxidants, such as peroxides or dioxygen, are not necessary, and atmospheric oxygen acts as the oxidant.
Unsymmetrically substituted room temperature discotic liquid crystals based on hexa–peri–hexabenzocoronene core
Authors: Setia Shilpa , Pal Santanu Kumar
Published: March 2016

The first discotic system based‐on alkoxy (tri‐ & di‐) substituted hexa‐peri‐hexabenzocoronene (HBC) that self‐organizes into room temperature columnar structure is reported. Tri‐ and di‐ substituted HBC derivatives showed reddish and yellowish green fluorescence under long wavelength (365 nm) UV light illumination in solution as well as in thin films in the liquid crystalline (LC) state at room temperature, respectively. Thermotropic LC behavior of these compounds was studied by differential scanning calorimetry, polarized optical microscopy and small‐ and wide‐angle X‐ray scattering. Tri‐alkoxy derivative was found to self‐organize into a highly ordered columnar rectangular mesophase, while the other (di‐) possessed a columnar hexagonal mesophase, indicating that in spite of their non‐planarity, the aromatic cores in the mesophase are tightly packed to give highly ordered phases. This system is a promising candidate as an active component of organic light emitting devices, due to its facile processability, low band gap, luminescence and exceptionally higher ordered self‐organization behavior in the mesophase derived from X‐ray scattering studies.
All-Arthroscopic Modified Rotator Interval Slide for Massive Anterosuperior Cuff Tears Using the Subdeltoid Space: Surgical Technique and Early Results
Authors: Corpus Keith T. , Taylor Samuel A. , O'Brien Stephen J. , Gulotta Lawrence V.
Published: March 2016

Background

Traditional intra-articular arthroscopic repair techniques for massive anterosuperior rotator cuff tears are technically demanding and necessitate sacrifice of the rotator interval to enable visualization. An interval slide allows mobilization through release of the medial aspect of the rotator interval, while leaving the lateral, bridging fibers intact.

Questions/Purposes

The purpose of this study was to report a novel, arthroscopic, open-equivalent technique using the subdeltoid space to address these tears along with early clinical results.

Methods

A retrospective review of prospectively collected data identified 11 consecutive arthroscopic massive anterosuperior rotator cuff repairs with a concomitant biceps tenodesis performed by the senior surgeon using a uniform technique. Outcome measures included range of motion, visual analog scale for pain, rotator cuff strength, American Shoulder and Elbow Surgeons (ASES) outcome scale, and Short Form-12 (SF-12).

Results

Average length of follow-up was 22.2 months (range 12.5–30.0 months). Visual analog scale (VAS) pain scores, ASES, and SF-12 all demonstrated significant improvement from pre-op to final follow-up from 6.2 to 0.9 ( p < 0.05), 27.4 to 82.8 ( p < 0.05), and 26.6 to 45.5 ( p < 0.05) respectively. Average forward flexion improved from 145° to 160° ( p < 0.05). Seven of the nine patients with a positive preoperative belly press had a negative test at final follow-up. Nine of the 10 patients with a positive lift off test demonstrated a negative test on final follow-up. Ninety-one percent reported they were satisfied with their outcome.

Conclusions

The described modified all-arthroscopic subdeltoid approach for anterosuperior cuff repairs enabled an open-equivalent interval slide technique that preserved the bridging lateral fibers of the rotator interval and demonstrated promising early-term clinical results.
Deformable plate tectonics and regional geodynamic model of the Arctic region and Northeastern Asia
Authors: Lobkovsky L.I.
Published: March 2016

The difficulties and contradictions of the classical concept of plate tectonics are discussed. It was shown the postulate of rigid plates and Euler’s theorem on the motion of rigid body with one fixed point, which is the basis of the kinematic description of plate tectonics, cannot be universally applied, e.g., to the analysis of Cretaceous reconstructions of the North Atlantic and Arctic. The second postulate of the existence of lithosphere as separate and distinct tectonic plates, which is equivalent to the assumption on the continuity of all plate boundaries, is not satisfied. This study provides a generalization of the theory of classical plate tectonics, in which plates are treated as deformable bodies, the concept of deformable plate tectonics. The study also discusses a new regional geodynamic model for the Cretaceous and Cenozoic evolution of lithosphere beneath Arctic and Northeastern Asia. The model is based on the assumption of a laterally extended convection cell in the upper mantle driven by a conveyor-belt-like process of subduction of the Pacific plate. The proposed model provides a physically sound explanation for the standard tectonomagmatic processes, such as island arc roll-back and opening of back-arc basins, formation of continental rift zones and igneous provinces at great distances (over 1000 km) from subduction zones, etc.
The role of dynamometamorphism in the formation of ore deposits (by the example of the Tishinka and Ridder-Sokol’noe pyrite deposits in Rudny Altai)
Authors: Zinoviev S.V.
Published: March 2016

Dynamometamorphic lithologic transformations of ores and ore-hosting rocks are substantiated by the example of the Tishinka deposit and the upper beds of the Ridder-Sokol’noe deposit in Rudny Altai. The lenticular and lenticular-banded morphology of orebodies in the deposits is due to the in situ redeposition of ore substance in the form of bodies oriented concordantly with the direction of the maximum tangential stresses and, correspondingly, the general strike of the deformation-metamorphic structures. It is shown that dynamometamorphism is not only the structure- and rock-forming factor but also plays a great role in the concentration and localization of ores, favoring the formation of rich ore deposits in zones of intense deformations and structural and geochemical transformations. The age of the main phases of dynamometamorphic impact and the time of formation of the deposit orebodies are estimated. For the Tishinka deposit, it is 294–301 and 279–288 Ma (Early Permian), and for the lenticular orebodies of the upper beds of the Ridder–Sokol’noe deposit, ~ 307 Ma (Late Carboniferous).
Architects of fact and fiction
Authors: Hill Jonathan
Published: March 2016

Conceiving a design as both a history and a fiction is not exclusive to the analogy of architecture to landscape. But it is central to this tradition because of the simultaneous and interdependent emergence in the early eighteenth century of new art forms, each of them a creative and questioning response to empiricism's detailed investigation of subjective experience and the natural world: the picturesque landscape, analytical history and English novel, which its early advocates conceived as a fictional autobiography and characterised as a history not a story. The conjunction of new art forms stimulated a lyrical environmentalism that profoundly influenced subsequent centuries, and is increasing relevant today due to anthropogenic climate change, which is now the principal means to consider the relations between nature and culture.

While a prospect of the future is implicit in many histories and novels, it is explicit in a design, which is always imagined before it is built. Creative architects have often looked to the past to imagine the future, studying an earlier architecture not to replicate it but to understand and transform it, revealing its relevance to the present. Twenty-first century architects need to appreciate the shock of the old as well as the shock of the new.
The architectural essay film
Authors: Haralambidou Penelope
Published: March 2016

Recent advancements in digital technology, have not only deeply transformed the production of film and architecture but brought the two disciplines closer than ever before. The digital has allowed ground-breaking, if not hasty, changes in the way that architecture is not only produced, but also designed and conceived. In contrast, however, to the extensive use of computational design to interrogate the formal, material and structural possibilities of architecture, this article explores how new time-based media and computer generated imagery in film can unlock the story-telling, political and philosophical potential of architecture. I will focus on three projects – Agit-Prop (2014) by Liam Davis, Wates House (2014) by Daniel Cotton and my project Déjà vu (2009) – which combine techniques and tropes from both cinema and design as a means for reflection and commentary in architecture.

Originally coined by the German artist Hans Richter in the 1940s, the term ‘essay film’ describes an intimate, allusive and idiosyncratic genre at the margins between fiction and documentary. Richter poignantly suggests that the essay film makes the invisible world of thoughts and ideas visible on the screen; it produces complex thought-reflections that are not necessarily bound to reality, but can also be contradictory, irrational, and fantastical. Dealing with political and philosophical issues, the essay film is cinema at its most engaged and liberated.

Examining the three projects in comparison to examples of essay films that reflect on architecture or the city, such as Dziga Vertov’s, Man with a Movie Camera (1929), Wim Wender’s, If Buildings Could Talk (2010), and Alain Resnais’s, Toute la mémoire du monde (1956), my aim is to propose a new hybrid genre lying at the boundaries between architectural design, theory and film, what I call: the ‘architectural essay film’.
Chronotyp und Depression bei Jugendlichen – ein Review
Authors: Keller Lena Katharina , Zöschg Sarah , Grünewald Barbara , Roenneberg Till , Schulte-Körne Gerd
Published: March 2016

Zusammenfassung. Depressive Erkrankungen gehen mit vielen Symptomen einher, die in Bezug zu einer tageszeitlichen Rhythmik und dem Schlafverhalten stehen. Die vielfältigen Zusammenhänge zwischen Schlaf, Depression und Tagesrhythmik sind nicht eindeutig geklärt. In den Forschungsarbeiten der letzten Jahre kommt dem Chronotyp eine besondere Bedeutung zu. Als biologisches Maß der inneren Uhr kann der Chronotyp – basierend auf Schlafzeiten – mit dem Munich ChronoType Questionnaire (MCTQ) bestimmt werden, als subjektive Präferenz für bestimmte Tageszeiten wird er mit dem Morningness-Eveningness-Questionnaire (MEQ) erfasst. Durch eine systematische Literaturrecherche konnten Studien identifiziert werden, die überwiegend einen Zusammenhang zwischen einem späten Chronotyp und depressiven Symptomen und depressiven Störungen zeigen. Dies ist besonders für Jugendliche relevant, da sich der Chronotyp zur Adoleszenz hin stark verändert. Bisher ist nicht geklärt, was am Zusammenhang zwischen Chronotyp und depressiver Störung Ursache und Wirkung ist und welche Faktoren als Moderator oder Mediator fungieren. Möglicherweise ist der Zusammenhang bidirektional: Einerseits ziehen sich Patienten mit depressiven Störungen häufig zurück und sind weniger Tageslicht ausgesetzt, was ihren Chronotyp später werden lässt. Andererseits führt eine Diskrepanz von Innenzeit (festgelegt durch die innere Uhr) und Außenzeit (z. B. durch Schul- und Arbeitszeiten) zu Problemen wie einer verringerten Schlafqualität und schlechteren Schulnoten, die wiederum im Zusammenhang mit Depressivität stehen können.
Current Carbon Emissions Unprecedented in 66 Million Years
Authors: Wendel JoAnna
Published: March 2016

An ancient carbon dioxide release associated with a much hotter Earth than today took place at only a tenth the pace of our present atmospheric carbon buildup, a new study confirms.
ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells
Authors: Luo N , Guo J , Chen L , Yang W , Qu X , Cheng Z
Published: March 2016

Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of ovarian cancer. ARHGAP10 is a member of RhoGAP proteins and inactivates Cdc42 by converting GTP-bound form to GDP-bound form. Here, we aimed to evaluate ARHGAP10 expression profile and functions in ovarian cancer. The decreased expression of ARHGAP10 was found in 77.3% (58/75) of ovarian cancer tissues, compared with their non-tumorous counterparts. Furthermore, overall survival in ovarian cancer patients with higher expression of ARHGAP10 was longer than those with lower expression. Ectopic expression of ARHGAP10 in two ovarian cancer cell lines with lower expression of ARHGAP10 (A2780 and HO-8910) dramatically suppressed cell proliferation in vitro. In nude mice, its stable overexpression significantly inhibited the tumorigenicity of A2780 cells. We further demonstrated that overexpression of ARHGAP10 significantly inhibited cell adhesion, migration and invasion, resulted in cell arrest in G1 phase of cell cycle and a significant increase of apoptosis. Moreover, ARHGAP10 interacted with Cdc42 and overexpression of ARHGAP10 inhibited the activity of Cdc42 in A2780 cells. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that KEGG cell cycle, replication and base excision repair (BER) pathways were correlatively with the ARHGAP10 expression, which was further confirmed in ovarian cancer cells by western blotting. Hence, ARHGAP10 may serve as a tumor suppressor through inactivating Cdc42, as well as inhibiting cell cycle, replication and BER pathways. Our data suggest an important role of ARHGAP10 in the molecular etiology of cancer and implicate the potential application of ARHGAP10 in cancer therapy.
MiR-485-3p and miR-485-5p suppress breast cancer cell metastasis by inhibiting PGC-1α expression
Authors: Lou C , Xiao M , Cheng S , Lu X , Jia S , Ren Y , Li Z
Published: March 2016

Breast cancer is the worldwide leading cause of cancer mortality in women. The majority of deaths from breast cancer arise from metastasis of local tumors. Cancer cells support their rapid proliferation by diverting metabolites into anabolic pathways, but during cancer metastasis, the proliferative program of invasive cancer cells is suspended for a migratory phenotype. In this study, we demonstrated that both mature forms of miRNA-485, miR-485-3p and miR-485-5p were involved in regulating mitochondrial respiration, cell migration and cell invasion in breast cancer cells by directly targeting and inhibiting the expression of PGC-1α. Specifically, the expression levels of both miR-485-3p and miR-485-5p were decreased in breast cancer tissues. Overexpression of miR-485-3p and miR-485-5p suppressed mitochondrial respiration and potential for cell migration and invasion in vitro, and also inhibited spontaneous metastasis of breast cancer cells in vivo. The suppression of mitochondrial respiration and cell invasion could be partially relieved by restoration of PGC-1α expression.
GW627368X inhibits proliferation and induces apoptosis in cervical cancer by interfering with EP4/EGFR interactive signaling
Authors: Parida S , Pal I , Parekh A , Thakur B , Bharti R , Das S , Mandal M
Published: March 2016

PGE2, the major product of cyclooxygenases implicated in carcinogenesis, is significantly upregulated in cervical cancer. PGE2 via prostanoid receptor EP4 stimulates proliferation and motility while inhibiting apoptosis and immune surveillance. It promotes angiogenesis by stimulating the production of pro-angiogenic factors. The present study demonstrates GW627368X, a highly selective competitive EP4 antagonist, which hinders cervical cancer progression by inhibiting EP4/epithelial growth factor receptor (EGFR) interactive signaling. GW627368X reduced protein kinase A (PKA) phosphorylation which in turn leads to decreased cAMP response element-binding protein (CREB) activation. Decreased PKA phosphorylation also directly enhanced Bax activity and in part reduced glycogen synthase kinase 3 (GSK3)β phosphorylation. Owing to the interactive signaling between EP4 and EGFR, GW627368X lowered EGFR phosphorylation in turn reducing Akt, mitogen-activated protein kinase (MAPK) and GSK3β activity significantly. Sublethal dose of GW627368X was found to reduce the nuclear translocation of β-catenin in a time dependent manner along with time-dependent decrease in cytoplasmic as well as whole-cell β-catenin. Decreased CREB and β-catenin transcriptional activity restricts the aberrant transcription of key genes like EP4, cyclooxygenase (COX)-2, vascular endothelial growth factor and c-myc, which ultimately control cell survival, proliferation and angiogenesis. Reduced activity of EGFR resulted in enhanced expression of 15-hydroxyprostaglandin dehydrogenase increasing PGE2 degradation thereby blocking a positive feedback loop. In xenograft model, dose-dependent decrease in cancer proliferation was observed characterized by reduction in tumor mass and volume and a marked decrease in Ki67 expression. A diminished CD31 specific staining signified decreased tumor angiogenesis. Reduced expression of pAkt, pMAPK, pEGFR and COX-2 validated in vitro results. GW627368X therefore effectively inhibits tumor survival, motility, proliferation and angiogenesis by blocking EP4/EGFR interactive signaling. EP4 is a potent therapeutic target in cervical cancer and can be explored in combination with conventional therapies to attain superior outcomes and to overcome complications associated with organ toxicities, therapeutic resistance and disease relapse.
Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation
Authors: Arosio Paolo , Michaels Thomas C. T. , Linse Sara , Månsson Cecilia , Emanuelsson Cecilia , Presto Jenny , Johansson Jan , Vendruscolo Michele , Dobson Christopher M. , Knowles Tuomas P. J.
Published: March 2016

It is increasingly recognized that molecular chaperones play a key role in modulating the formation of amyloid fibrils, a process associated with a wide range of human disorders. Understanding the detailed mechanisms by which they perform this function, however, has been challenging because of the great complexity of the protein aggregation process itself. In this work, we build on a previous kinetic approach and develop a model that considers pairwise interactions between molecular chaperones and different protein species to identify the protein components targeted by the chaperones and the corresponding microscopic reaction steps that are inhibited. We show that these interactions conserve the topology of the unperturbed reaction network but modify the connectivity weights between the different microscopic steps. Moreover, by analysing several protein-molecular chaperone systems, we reveal the striking diversity in the microscopic mechanisms by which molecular chaperones act to suppress amyloid formation.
Fish optimize sensing and respiration during undulatory swimming
Authors: Akanyeti O. , Thornycroft P. J. M. , Lauder G. V. , Yanagitsuru Y. R. , Peterson A. N. , Liao J. C.
Published: March 2016

Previous work in fishes considers undulation as a means of propulsion without addressing how it may affect other functions such as sensing and respiration. Here we show that undulation can optimize propulsion, flow sensing and respiration concurrently without any apparent tradeoffs when head movements are coupled correctly with the movements of the body. This finding challenges a long-held assumption that head movements are simply an unintended consequence of undulation, existing only because of the recoil of an oscillating tail. We use a combination of theoretical, biological and physical experiments to reveal the hydrodynamic mechanisms underlying this concerted optimization. Based on our results we develop a parsimonious control architecture that can be used by both undulatory animals and machines in dynamic environments.
ELL targets c-Myc for proteasomal degradation and suppresses tumour growth
Authors: Chen Yu , Zhou Chi , Ji Wei , Mei Zhichao , Hu Bo , Zhang Wei , Zhang Dawei , Wang Jing , Liu Xing , Ouyang Gang , Zhou Jiangang , Xiao Wuhan
Published: March 2016

Increasing evidence supports that ELL (eleven–nineteen lysine-rich leukaemia) is a key regulator of transcriptional elongation, but the physiological function of Ell in mammals remains elusive. Here we show that ELL functions as an E3 ubiquitin ligase and targets c-Myc for proteasomal degradation. In addition, we identify that UbcH8 serves as a ubiquitin-conjugating enzyme in this pathway. Cysteine 595 of ELL is an active site of the enzyme; its mutation to alanine (C595A) renders the protein unable to promote the ubiquitination and degradation of c-Myc. ELL-mediated c-Myc degradation inhibits c-Myc-dependent transcriptional activity and cell proliferation, and also suppresses c-Myc-dependent xenograft tumour growth. In contrast, the ELL(C595A) mutant not only loses the ability to inhibit cell proliferation and xenograft tumour growth, but also promotes tumour metastasis. Thus, our work reveals a previously unrecognized function for ELL as an E3 ubiquitin ligase for c-Myc and a potential tumour suppressor.
Disentanglement of growth dynamic and thermodynamic effects in LaAlO3/SrTiO3 heterostructures
Authors: Xu Chencheng , Bäumer Christoph , Heinen Ronja Anika , Hoffmann-Eifert Susanne , Gunkel Felix , Dittmann Regina
Published: March 2016

The influence of non-equilibrium and equilibrium processes during growth of LaAlO3/SrTiO3 (LAO/STO) heterostructures is analyzed. We investigate the electronic properties of LAO/STO heterostructures obtained at constant growth conditions after annealing in different oxygen atmospheres within the typical growth window (1 × 10−4 mbar –1 × 10−2 mbar). The variation of annealing conditions is found to cause a similar change of electronic properties as observed for samples grown in different oxygen pressure. The results indicate that equilibrium defect formation is the dominant process for establishing the properties of the two-dimensional electron gas (2DEG), while growth dynamics play a minor role in the typical LAO/STO growth regime. Furthermore, the effects of non-equilibrium processes occurring during growth are investigated in detail by quenching just-grown LAO/STO heterostructures directly after growth. We show that during growth the sample is pushed into a non-equilibrium state. After growth, the sample then relaxes towards equilibrium, while the relaxation rate strongly depends on the ambient pressure. The observed relaxation behavior is mainly associated with a reoxidation of the STO bulk, while the 2DEG is formed immediately after the growth.
Genome-Wide Identification of R2R3-MYB Genes and Expression Analyses During Abiotic Stress in Gossypium raimondii
Authors: He Qiuling , Jones Don C. , Li Wei , Xie Fuliang , Ma Jun , Sun Runrun , Wang Qinglian , Zhu Shuijin , Zhang Baohong
Published: March 2016

The R2R3-MYB is one of the largest families of transcription factors, which have been implicated in multiple biological processes. There is great diversity in the number of R2R3-MYB genes in different plants. However, there is no report on genome-wide characterization of this gene family in cotton. In the present study, a total of 205 putative R2R3-MYB genes were identified in cotton D genome (Gossypium raimondii), that are much larger than that found in other cash crops with fully sequenced genomes. These GrMYBs were classified into 13 groups with the R2R3-MYB genes from Arabidopsis and rice. The amino acid motifs and phylogenetic tree were predicted and analyzed. The sequences of GrMYBs were distributed across 13 chromosomes at various densities. The results showed that the expansion of the G. Raimondii R2R3-MYB family was mainly attributable to whole genome duplication and segmental duplication. Moreover, the expression pattern of 52 selected GrMYBs and 46 GaMYBs were tested in roots and leaves under different abiotic stress conditions. The results revealed that the MYB genes in cotton were differentially expressed under salt and drought stress treatment. Our results will be useful for determining the precise role of the MYB genes during stress responses with crop improvement.
Thermal erosion of cratonic lithosphere as a potential trigger for mass-extinction
Authors: Guex Jean , Pilet Sebastien , Müntener Othmar , Bartolini Annachiara , Spangenberg Jorge , Schoene Blair , Sell Bryan , Schaltegger Urs
Published: March 2016

The temporal coincidence between large igneous provinces (LIPs) and mass extinctions has led many to pose a causal relationship between the two. However, there is still no consensus on a mechanistic model that explains how magmatism leads to the turnover of terrestrial and marine plants, invertebrates and vertebrates. Here we present a synthesis of ammonite biostratigraphy, isotopic data and high precision U-Pb zircon dates from the Triassic-Jurassic (T-J) and Pliensbachian-Toarcian (Pl-To) boundaries demonstrating that these biotic crises are both associated with rapid change from an initial cool period to greenhouse conditions. We explain these transitions as a result of changing gas species emitted during the progressive thermal erosion of cratonic lithosphere by plume activity or internal heating of the lithosphere. Our petrological model for LIP magmatism argues that initial gas emission was dominated by sulfur liberated from sulfide-bearing cratonic lithosphere before CO2became the dominant gas. This model offers an explanation of why LIPs erupted through oceanic lithosphere are not associated with climatic and biotic crises comparable to LIPs emitted through cratonic lithosphere.
A model to assess the efficacy of vaccines for control of liver fluke infection
Authors: Turner Joanne , Howell Alison , McCann Cathy , Caminade Cyril , Bowers Roger G. , Williams Diana , Baylis Matthew
Published: March 2016

Fasciola hepatica, common liver fluke, infects cattle and sheep causing disease and production losses costing approximately $3billion annually. Current control relies on drugs designed to kill the parasite. However, resistance is evident worldwide and widespread in some areas. Work towards a vaccine has identified several antigens of F. hepatica that show partial efficacy in terms of reducing worm burden and egg output. A critical question is what level of efficacy is required for such a vaccine to be useful? We have created the first mathematical model to assess the effectiveness of liver fluke vaccines under simulated field conditions. The model describes development of fluke within a group of animals and includes heterogeneity in host susceptibility, seasonal exposure to metacercariae and seasonal changes in temperature affecting metacercarial survival. Our analysis suggests that the potential vaccine candidates could reduce total fluke burden and egg output by up to 43% and 99%, respectively, on average under field conditions. It also suggests that for a vaccine to be effective, it must protect at least 90% of animals for the whole season. In conclusion, novel, partial, vaccines could contribute substantially towards fasciolosis control, reducing usage of anthelmintics and thus delaying the spread of anthelmintic resistance.
Trace fossil evidence of coral-inhabiting crabs (Cryptochiridae) and its implications for growth and paleobiogeography
Authors: Klompmaker Adiël A. , Portell Roger W. , van der Meij Sancia E.T.
Published: March 2016

Members of the Cryptochiridae are small, fragile, symbiotic crabs that live in domiciles in modern corals. Despite their worldwide occurrence with over 50 species known today, their fossil record is unknown. We provide the first unambiguous evidence of cryptochirids in the fossil record through their crescentic pits, typical for certain cryptochirids, in Western Atlantic fossil corals, while the Eocene genus Montemagrechirus is excluded from the Cryptochiridae and referred to Montemagrechiridae fam. nov. Nine Pleistocene corals with crescentic pits originate from Florida (USA) and single specimens with pits come from the late Pleistocene of Cuba and the late Pliocene of Florida, all of which are measured for growth analyses. These pits represent trace fossils named Galacticus duerri igen. nov., isp. nov. A study of modern cryptochirid domicile shape (crescentic pit, circular-oval pit, or a true gall) shows that species within crab genera tend to inhabit the same pit shape. Crescentic pits in corals occur not only in the Western Atlantic today, but also in the Indo-West Pacific and in the Eastern Pacific. Thus, examination of Cenozoic fossil coral collections from these regions should yield further examples of cryptochirid pits, which would help to constrain the antiquity of this cryptic crab family.
Insects for breakfast and whales for dinner: the diet and body condition of dingoes on Fraser Island (K’gari)
Authors: Behrendorff Linda , Leung Luke K.-P. , McKinnon Allan , Hanger Jon , Belonje Grant , Tapply Jenna , Jones Darryl , Allen Benjamin L.
Published: March 2016

Top-predators play stabilising roles in island food webs, including Fraser Island, Australia. Subsidising generalist predators with human-sourced food could disrupt this balance, but has been proposed to improve the overall health of the island’s dingo (Canis lupus dingo) population, which is allegedly ‘starving’ or in ‘poor condition’. We assess this hypothesis by describing the diet and health of dingoes on Fraser Island from datasets collected between 2001 and 2015. Medium-sized mammals (such as bandicoots) and fish were the most common food items detected in dingo scat records. Stomach contents records revealed additional information on diet, such as the occurrence of human-sourced foods. Trail camera records highlighted dingo utilisation of stranded marine fauna, particularly turtles and whales. Mean adult body weights were higher than the national average, body condition scores and abundant-excessive fat reserves indicated a generally ideal-heavy physical condition, and parasite loads were low and comparable to other dingo populations. These data do not support hypotheses that Fraser Island dingoes have restricted diets or are in poor physical condition. Rather, they indicate that dingoes on Fraser Island are capable of exploiting a diverse array of food sources which contributes to the vast majority of dingoes being of good-excellent physical condition.
Accurate Learning with Few Atlases (ALFA): an algorithm for MRI neonatal brain extraction and comparison with 11 publicly available methods
Authors: Serag Ahmed , Blesa Manuel , Moore Emma J. , Pataky Rozalia , Sparrow Sarah A. , Wilkinson A. G. , Macnaught Gillian , Semple Scott I. , Boardman James P.
Published: March 2016

Accurate whole-brain segmentation, or brain extraction, of magnetic resonance imaging (MRI) is a critical first step in most neuroimage analysis pipelines. The majority of brain extraction algorithms have been developed and evaluated for adult data and their validity for neonatal brain extraction, which presents age-specific challenges for this task, has not been established. We developed a novel method for brain extraction of multi-modal neonatal brain MR images, named ALFA (Accurate Learning with Few Atlases). The method uses a new sparsity-based atlas selection strategy that requires a very limited number of atlases ‘uniformly’ distributed in the low-dimensional data space, combined with a machine learning based label fusion technique. The performance of the method for brain extraction from multi-modal data of 50 newborns is evaluated and compared with results obtained using eleven publicly available brain extraction methods. ALFA outperformed the eleven compared methods providing robust and accurate brain extraction results across different modalities. As ALFA can learn from partially labelled datasets, it can be used to segment large-scale datasets efficiently. ALFA could also be applied to other imaging modalities and other stages across the life course.
Small molecule-mediated up-regulation of microRNA targeting a key cell death modulator BNIP3 improves cardiac function following ischemic injury
Authors: Lee Se-Yeon , Lee Seahyoung , Choi Eunhyun , Ham Onju , Lee Chang Youn , Lee Jiyun , Seo Hyang-Hee , Cha Min-Ji , Mun Bohyun , Lee Yunmi , Yoon Cheesoon , Hwang Ki-Chul
Published: March 2016

Genetic ablation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), an essential regulator of cardiac cell death, is an effective way to prevent cardiac cell death triggered by pathologic conditions. However, currently there exists no known means, such as inhibitors, to down-regulate BNIP3 in mature heart. Here, we report that a small molecule inducer of microRNA-182 (miR-182) suppressed ischemia/reperfusion (I/R)-induced cardiac cell death by down-regulating BNIP3. We first selected miR-182 as a potent BNIP3-targeting miRNA based on miRNA-target prediction databases and empirical data. The subsequent screening of small molecules for inducing miR-182 expression identified Kenpaullone as a hit compound. Both exogenous miR-182 and Kenpaullone significantly suppressed hypoxia-induced cardiomyocyte death in vitro. To investigate the effect of changing substituents of Kenpaullone on miR-182 expression, we synthesized 9 derivatives of Kenpaullone. Among these derivatives, compound 5 showed significantly improved ability to induce miR-182 expression. The results of the in vivo study showed that compound 5 significantly improved heart function following I/R-injury in rats. Our study provides strong evidence that the small molecule-mediated up-regulation of miRNAs is a viable strategy to down-regulate target proteins with no known chemical inhibitor and that compound 5 may have potential to prevent I/R-inflicted cardiac cell death.