bluuebunny/crossref_metadata_2025 huggingface dataset:
Insulin-Like Growth Factor-1–Loaded Polymeric Poly(Lactic-Co-Glycolic) Acid Microspheres Improved Erectile Function in a Rat Model of Bilateral Cavernous Nerve Injury
Authors: Haney Nora M. , Talwar Sudha , Akula Prasad K. , Reddy Amit G. , Pema Geoffroy Sanga , Ninh Thien V. , Rezk Bashir M. , Heidari Zahra , Bouljihad Mostafa T. , Sikka Suresh C. , John Vijay , Abdel-Mageed Asim B. , Hellstrom Wayne J.G.
Published: March 2019

Background

Previous studies have documented improvement in erectile function after bilateral cavernous nerve injury (BCNI) in rats with the use of pioglitazone. Our group determined this improvement to be mediated by the insulin-like growth factor-1 (IGF-1) pathway.

Aim

To eliminate the systemic effects of pioglitazone and evaluate the local delivery of IGF-1 by polymeric microspheres after BCNI in the rat.

Methods

Male Sprague–Dawley rats aged 10–12 weeks were assigned at random to 3 groups: sham operation with phosphate buffered saline (PBS)-loaded microspheres (sham group), crush injury with PBS-loaded microspheres (crush group), and crush injury with IGF-1–loaded microspheres (IGF-1 group). Poly(lactic-co-glycolic) acid microspheres were injected underneath the major pelvic ganglion (MPG). IGF-1 was released at approximately 30 ng/mL/day per MPG per rat.

Outcomes

Functional results were demonstrated by maximal intracavernosal pressure (ICP) normalized to mean arterial pressure (MAP). Protein-level analysis data of IGF-1 receptor (IGF-1R), extracellular signal–regulated kinase (ERK)-1/2, and neuronal nitric oxide synthase (nNOS) were obtained using Western blot analysis and immunohistochemistry for both the cavernosal tissue and the MPG and cavernous nerve (CN).

Results

At 2 weeks after nerve injury, animals treated with IGF-1 demonstrated improved erectile functional recovery (ICP/MAP) at all voltages compared with BCNI (2.5V, P = .001; 5V, P < .001; 7.5V, P < .001). Western blot results revealed that up-regulation of the IGF-1R and ERK-1/2 in both the nervous and erectile tissue was associated with improved erectile function recovery. There were no significant between-group differences in nNOS protein levels in cavernosal tissue, but there was an up-regulation of nNOS in the MPG and CN. Immunohistochemistry confirmed these trends.

Clinical Translation

Local up-regulation of the IGF-1R in the neurovascular bed at the time of nerve injury may help men preserve erectile function after pelvic surgery, such as radical prostatectomy, eliminating the need for systemic therapy.

Strengths & Limitations

This study demonstrates that local drug delivery to the MPG and CN can affect the CN tissue downstream, but did not investigate the potential effects of up-regulation of the growth factor receptors on prostate cancer tissue.

Conclusion

Stimulating the IGF-1R at the level of the CN has the potential to mitigate erectile dysfunction in men after radical prostatectomy, but further research is needed to evaluate the safety of this growth factor in the setting of prostate cancer.
Factors Associated with Sexual Debut in Mexican Adolescents: Results of the National Survey on Drug Use among Students in 2014
Authors: Barragán Virginia , Berenzon Shoshana , Tiburcio Marcela , Bustos Marycarmen , Villatoro Jorge
Published: March 2019

Introduction

Although first sexual experience (understood as first sexual intercourse) is one of the most commonly assessed characteristics of adolescents, recent research emphasizes the importance of understanding other related social factors. This study highlights factors associated with first sexual experience in a nationally representative sample of adolescent students in Mexico.

Aims

The goals of this study were (i) to determine the proportion of adolescents aged 12–17 who had had their first sexual experience; (ii) to identify the factors associated with first sexual experience; and (iii) to analyze the conditions (condom use, substance use) in which first sexual experience takes place.

Method

The data presented in this study are drawn from the 2014 National Survey on Drug Use in Students (Spanish acronym ENCODE), undertaken with the purpose of identifying the prevalence of drug use and associated variables, including sexual activity, in Mexican students. Kaplan-Meier analysis was used to estimate the probability of first sexual experience at a given age, taking sex as an outcome variable and age as a follow-up period. Logistic regression was used to assess possible factors for sexual initiation.

Main Outcome Measures

Validated standard questionnaires were used to assess sociodemographic characteristics, first sexual experience (framed as first sexual intercourse), frequency of sexual relations, sexual partners, sexual preference (framed as preferred sex of partners), substance use, having a physical illness or a behavioral problem, condom or other contraceptive use, as well as the absence or presence of parents, parents’ educational attainment, and parents’ substance use.

Results

A total of 26,187 students aged 12–17 participated. Of this total, 14.8% had already had their first sexual experience, at a median age of 15; 64.5% used some type of contraceptive, and 53.2% used condoms. Proportional probabilities for having first sexual experience using age as a follow-up period showed that the probability of having sex earlier was higher among boys than girls: the probability of having sex at age of 15 was 26.5% for boys and 13.9% for girls. Predictors of first sexual experience included substance use (alcohol OR = 2.5, tobacco OR = 2.6, and other drugs OR = 2.3), having a mother who used drugs (OR= 2.2), sexual preference (female homosexual, OR = 2.2), and sex (male, OR = 2.1).

Conclusions

Boys are more likely to have had a first sexual experience than girls. Future strategies should incorporate specifically targeted elements with different messages that consider adolescents’ sex and age.
Male Sexual Dysfunction Among Egyptian Patients with Chronic Hepatitis C Virus Infection Before and After Direct-Acting Antiviral Drugs
Authors: Elshimi Esam , Morad Wesam , Mohamad Noha Ezzat
Published: March 2019

Background

Chronic hepatitis C virus (HCV) infection is a global health burden that affects quality of life, with a negative impact on sexual functioning (SF).

Aim

To study male sexual dysfunction (MSD) among Egyptian men with chronic HCV infection and the impact of therapy with direct-acting antiviral drugs (DAAs) on their sexual health.

Methods

The self-administered International Index of Erectile Function (IIEF) questionnaire was completed by 400 sexually active male patients with chronic HCV infection without liver cirrhosis before the initiation of therapy with DAAs and then again at the completion of therapy. We compared these baseline questionnaires with those completed by a similar number of age-matched and socioeconomic status–matched controls. In the patients with HCV infection, we also compared IIEF questionnaires completed before and after DAA therapy.

Main Outcome Measure

We determined the proportions of patients and controls who were dissatisfied with their sexual life and the impact of clearing HCV infection on MSD and evaluated the impact of DAA therapy on the total IIEF score and scores in all IIEF domains.

Results

Men with chronic HCV infection before DAA treatment had significantly higher erectile dysfunction (ED) scores compared with controls, and scores increased with age (P < .0001). The average scores in all IIEF domains was significantly lower in the patients compared with controls in all age groups. Men with chronic HCV infection had significantly higher ED scores before cure than after cure (P < .0001).

Clinical Implications

Given the high prevalence of MSD in patients with chronic HCV infection, and given that curing the HCV virus can improve the MSD associated with HCV infection, it is recommended that sexual quality of life in men with HCV be addressed as part of the evaluation protocol before initiation of DAA treatment and again after cure in an effort to improve this particular aspect of quality of life.

Strengths & Limitations

This is the first study to report on MSD in the era of DAA therapy in Egyptian men with chronic HCV infection before the development of cirrhosis, with a relatively large study population. The use of a detailed version of the IIEF questionnaire reinforces the validity of our study.

Conclusion

Chronic HCV infection negatively impacts MSD, affecting all domains of the IIEF, and effects increase with age. The MSD associated with HCV infection is significantly improved in patients who are cleared of the virus. These findings require further confirmation and need to be addressed as part of a comprehensive therapeutic plan to improve patients’ quality of life.
Bioarchaeological Practice and the Curation of Human Skeletal Remains in a Greek Context: The Phaleron Cemetery
Authors: Prevedorou Eleni-Anna , Buikstra Jane E.
Published: March 2019

Human skeletal remains constitute remarkably informative finds, both biologically and socioculturally. Their recovery, preservation, conservation, storage, and analysis are complex issues that need to be addressed within any given biocultural context. Given the country's geography and the long history of human occupation, Greek field archaeology is intense and ongoing, with both rescue and systematic excavations. Human burials are thus frequently encountered in excavations throughout Greece, resulting in the accumulation of osteological material. Some of the common challenges of bioarchaeological research in Greece consist of insufficient time, funding, and documentation in the field; unmet conservation needs and lack of storage space; as well as the long time-gap between excavation and analysis. Here, we give a brief overview of excavation, curation, and bioarchaeological practice within a Greek archaeological framework. We focus on the newly launched Phaleron Bioarchaeological Project on a vast necropolis from the wider Athens region in order to present our methodological approach. Finally, we consider the role of interdisciplinary collaboration in managing large-scale bioarchaeological projects and serving long-term heritage preservation goals.
Excavation and Curation Strategies for Complex Burials in Tropical Environments
Authors: Freiwald Carolyn
Published: March 2019

Bioarchaeologists often are faced with the challenge of managing field excavations and lab analyses of skeletal remains at the same time—along with student and staff training and curation of osteological remains—and cannot be in two places at once. This article presents strategies for the recovery of human remains useful for large projects where multiple burials must be recovered simultaneously, remains are poorly preserved, and complex burial practices such as seated body positions and commingled remains are present. The excavation and curation strategies are presented in the context of the seated burial practice in the Maya region, a funerary tradition that requires detailed documentation of the burial as well as the body in order to understand its meaning. Classic period (AD 250-900) seated burials do not fit a single biological profile; in fact, the taphonomic profile of one seated individual at Actuncan, Belize, suggests a closer relationship to body processing and/or context than to status. Tropical and semitropical environmental conditions also require modified curation procedures, which present ethical challenges as well as physical ones.
Implementing Photogrammetry in Three Bioarchaeological Contexts: Steps for In-Field Documentation
Authors: Novotny Anna C.
Published: March 2019

Human skeletal remains hold a wealth of information about past life-ways, but their documentation and recovery from archaeological contexts is challenging. Four challenges face bioarchaeological field work: poor skeletal preservation; complex mortuary traditions; sub-par excavation conditions; and excavation time limits. Poor preservation often prevents the collection of metric data from skeletons. This project tested whether a bioarchaeologist with basic photography skills and excavation equipment could address these challenges using photogrammetry. Photogrammetry was employed at the ancient Maya sites of Say Kah and Chan Chich, both located in northern Belize, to document human skeletal remains and their archaeological contexts. Steps are provided for implementing photogrammetry in the field, as well as addressing challenges for using the technique during burial documentation. This project produced only one adequate 3-D model and no metric data could be collected. Overall, photogrammetry seems to be a promising method for bioarchaeological research because it is low-cost, effective, and fairly straightforward to learn. The technique was faster than traditional line drawing, but sub-par excavation conditions and dark, small spaces hindered the creation of useful models. Photogrammetry provides an excellent alternative to traditional documentation addressing the challenges of poor skeletal preservation and holding potential for unraveling complex mortuary traditions.
The Elephant in the Room: Coercion
Authors: Kilovaty Ido
Published: March 2019

Dan Efrony and Yuval Shany's article offers some critically important observations on the reception of the Tallinn Manual 2.0 by states, as well as subsequent state practice and opinio juris with regard to the international use of cyber operations. Based on their case studies, Efrony and Shany conclude that states have largely been reluctant to adopt fully the norms, premises, and analogies offered by the Tallinn Manual. The authors argue that there is a “deep uncertainty about the treatment of cyberspace as just another physical space, like land, air, or sea—over which states may exercise sovereignty or control.” The authors further explain that there is an “uneasy fit” between traditional international law regarding internal and external state power, and the regulation of a unterritorial cyberspace. In other words, cyberspace is a sui generis domain, such that analogies to physical-space domains are often ill-suited, and at times doomed to failure.
Political-Legal Order and the Curious Double Character of
China’s Courts
Authors: LI Ling
Published: March 2019

This article provides an analytical account of how politics and law in China are
organically integrated in the institutional architecture of courts as designed
by the Chinese Communist Party (“the Party”). This design allows
the Party to retain its supreme authority in the interpretation, application,
and enforcement of the law through its institutional control over courts. At the
same time, the Party can, under this design, also afford to grant an autonomous
sphere where courts can perform their adjudicative functions with minimal
interference from the Party, as long as the Party is assured of full authority
to determine the scope of the “autonomous-zone,” to impose rules
on it, and to revoke it when necessary. Consequently, courts assume a double
character: a pliant political agent on the one hand and a legal institution of
its own agency on the other.
THE NO FREE LUNCH THEOREM: BAD NEWS FOR (WHITE'S ACCOUNT OF) THE PROBLEM OF INDUCTION
Authors: Schurz Gerhard
Published: March 2019

White (2015) proposes an a priori justification of the reliability of inductive prediction methods based on his thesis of induction-friendliness. It asserts that there are by far more induction-friendly event sequences than induction-unfriendly event sequences. In this paper I contrast White's thesis with the famous no free lunch (NFL) theorem. I explain two versions of this theorem, the strong NFL theorem applying to binary and the weak NFL theorem applying to real-valued predictions. I show that both versions refute the thesis of induction-friendliness. In the conclusion I argue that an a priori justification of the reliability of induction based on a uniform probability distribution over possible event sequences is impossible. In the outlook I consider two alternative approaches: (i) justification externalism and (ii) optimality justifications.
THREE THINGS TO DO WITH KNOWLEDGE ASCRIPTIONS
Authors: Lossau Tammo
Published: March 2019

Any good theory of knowledge ascriptions should explain and predict our judgments about their felicity. I argue that any such explanation must take into account a distinction between three ways of using knowledge ascriptions: (a) to suggest acceptance of the embedded proposition, (b) to explain or predict a subject's behavior or attitudes, or (c) to understand the relation of knowledge as such. The contextual effects on our judgments about felicity systematically differ between these three types of uses. Using such a distinction is, in principle, open to both contextualist and pragmatic invariantist accounts of knowledge ascriptions. However, there are some implications pertaining to the use of the “method of cases” in the debate about knowledge ascriptions.
Laboratory practices for identification and reporting of carbapenem-resistant Enterobacteriaceae in Department of Veterans Affairs facilities
Authors: Fitzpatrick Margaret A. , Suda Katie J. , Ramanathan Swetha , Guihan Marylou , Brown Charnetta , Safdar Nasia , Evans Martin , Jones Makoto M. , Pfeiffer Christopher D. , Klutts J. Stacey , Icardi Michael , Perencevich Eli , Rubin Michael , Evans Charlesnika T. ,   the QUERI CARRIAGE Program
Published: March 2019

Laboratory identification of carbapenem-resistant Enterobacteriaceae (CRE) is a key step in controlling its spread. Our survey showed that most Veterans Affairs laboratories follow VA guidelines for initial CRE identification, whereas 55.0% use PCR to confirm carbapenemase production. Most respondents were knowledgeable about CRE guidelines. Barriers included staffing, training, and financial resources.
Universal evaporation dynamics of ordered arrays of sessile droplets
Authors: Hatte Sandeep , Pandey Keshav , Pandey Khushboo , Chakraborty Suman , Basu Saptarshi
Published: March 2019

Manipulation of an array of surface droplets organised in an ordered structure turns out to be of immense consequence in a wide variety of applications ranging from photonics, near field imaging and inkjet printing on the one hand to bio-molecular analysis and DNA sequencing on the other. While evaporation of a single isolated sessile droplet has been well studied, the collective evaporative dynamics of an ordered array of droplets on a solid substrate remains elusive. Physically, the closed region between the centre and side droplets in the ordered array reduces the mobility of the diffusing vapour, resulting in its accumulation along with enhanced local concentration and a consequent increment in the lifetime of the centre droplet. Here, we present a theoretical model to account for evaporation lifetime scaling in closely placed ordered linear droplet arrays. In addition, the present theory predicts the limiting cases of droplet interaction; namely, critical droplet separation for which interfacial interaction ceases to exist and minimum possible droplet separation (droplets on the verge of coalescence) for which the droplet system achieves maximum lifetime scaling. Further experimental evidence demonstrates the applicability of the present scaling theory to extended dimensions of the droplet array, generalising our physical conjecture. It is also worth noting that the theoretical time scale is applicable across a wide variety of drop–substrate combinations and initial droplet volumes. We also highlight that the scaling law proposed here can be extended seamlessly to other forms of confinement such as an evaporating droplet inside a mini-channel, as encountered in countless applications ranging from biomedical engineering to surface patterning.
China's Conflict Mediation and the Durability of the Principle of Non-Interference: The Case of Post-2014 Afghanistan
Authors: Hirono Miwa
Published: March 2019

China's efforts in conflict mediation are an important test of the durability of the principle of non-interference. By analysing the approaches and means of China's post-2014 mediation efforts in Afghanistan, this article finds that China's behaviour shows it engages in medium-level interference in domestic affairs, but mostly with the host government's concurrence. This is because of the two forms China's mediation takes. In a bilateral context, China's mediation takes the form of “incentivizing mediation,” in which its economic power, and its omnidirectional foreign policy, provide incentives or leverage for warring factions to come to the negotiation table, but which also lets the warring factions formulate their own roadmap to peace talks. In a multilateral context, China sometimes engages in “formulative mediation,” in which the mediators, not the disputing parties, formulate a roadmap to peace talks.
Underwater Terrain Positioning Method Using Maximum a Posteriori Estimation and PCNN Model
Authors: Chen Pengyun , Zhang Pengfei , Ma Teng , Shen Peng , Li Ye , Wang Rupeng , Han Yue , Li Lizhou
Published: March 2019

Conventional underwater navigation and positioning methods for Autonomous Underwater Vehicles (AUVs) either require the installation of acoustic arrays, which make AUVs less independent, or result in cumulative errors. This paper proposes an Underwater Terrain Positioning Method (UTPM) using Maximum a Posteriori (MAP) estimation and a Pulse Coupled Neural Network (PCNN) model for highly accurate navigation by AUVs. The PCNN model is used as a secondary discriminant to effectively identify pseudo-anchor points in flat terrain feature areas and to find the true positioning point, which significantly improves the matching positioning accuracy in these areas. Simulation results show that the proposed method effectively corrects Inertial Navigation System (INS) cumulative errors and has high matching positioning accuracy, which satisfy the requirements of AUV underwater navigation and positioning.
Integration of a recent infection testing algorithm into HIV surveillance in Ireland: improving HIV knowledge to target prevention
Authors: Robinson E. , Moran J. , O'Donnell K. , Hassan J. , Tuite H. , Ennis O. , Cooney F. , Nugent E. , Preston L. , O'Dea S. , Doyle S. , Keating S. , Connell J. , De Gascun C. , Igoe D.
Published: March 2019

Recent infection testing algorithms (RITA) for HIV combine serological assays with epidemiological data to determine likely recent infections, indicators of ongoing transmission. In 2016, we integrated RITA into national HIV surveillance in Ireland to better inform HIV prevention interventions. We determined the avidity index (AI) of new HIV diagnoses and linked the results with data captured in the national infectious disease reporting system. RITA classified a diagnosis as recent based on an AI < 1.5, unless epidemiological criteria (CD4 count <200 cells/mm3; viral load <400 copies/ml; the presence of AIDS-defining illness; prior antiretroviral therapy use) indicated a potential false-recent result. Of 508 diagnoses in 2016, we linked 448 (88.1%) to an avidity test result. RITA classified 12.5% of diagnoses as recent, with the highest proportion (26.3%) amongst people who inject drugs. On multivariable logistic regression recent infection was more likely with a concurrent sexually transmitted infection (aOR 2.59; 95% CI 1.04–6.45). Data were incomplete for at least one RITA criterion in 48% of cases. The study demonstrated the feasibility of integrating RITA into routine surveillance and showed some ongoing HIV transmission. To improve the interpretation of RITA, further efforts are required to improve completeness of the required epidemiological data.
Online symptom checker diagnostic and triage accuracy for HIV and hepatitis C
Authors: Berry A.C. , Cash B.D. , Wang B. , Mulekar M.S. , Van Haneghan A.B. , Yuquimpo K. , Swaney A. , Marshall M. C. , Green W.K.
Published: March 2019

We sought to address the prior limitations of symptom checker accuracy by analysing the diagnostic and triage feasibility of online symptom checkers using a consecutive series of real-life emergency department (ED) patient encounters, and addressing a complex patient population – those with hepatitis C or HIV. We aimed to study the diagnostic and triage accuracy of these symptom checkers in relation to an emergency room physician-determined diagnosis. An ED retrospective analysis was performed on 8363 consecutive adult patients. Eligible patients included: 90 HIV, 67 hepatitis C, 11 both HIV and hepatitis C. Five online symptom checkers were utilised for diagnosis (Mayo Clinic, WebMD, Symptomate, Symcat, Isabel), three with triage capabilities. Symptom checker output was compared with ED physician-determined diagnosis data in regards to diagnostic accuracy and differential diagnosis listing, along with triage advice. All symptom checkers, whether for combined HIV and hepatitis C, HIV alone or hepatitis C alone had poor diagnostic accuracy in regards to Top1 (<20%), Top3 (<35%), Top10 (<40%), Listed at All (<45%). Significant variations existed for each individual symptom checker, as some appeared more accurate for listing the diagnosis in the top of the differential, vs. others more apt to list the diagnosis at all. In regards to ED triage data, a significantly higher percentage of hepatitis C patients (59.7%; 40/67) were found to have an initial diagnosis with emergent criteria than HIV patients (35.6%; 32/90). Symptom checker diagnostic capabilities are quite inferior to physician diagnostic capabilities. Complex patients such as those with HIV or hepatitis C may carry a more specific differential diagnosis, warranting symptom checkers to have diagnostic algorithms accounting for such complexity. Symptom checkers carry the potential for real-time epidemiologic monitoring of patient symptoms, as symptom entries and subsequent symptom checker diagnosis could allow health officials a means to track illnesses in specific patient populations and geographic regions. In order to do this, accurate and reliable symptom checkers are warranted.
Towns, government, legislation and the ‘police’ in Jamaica and the British Atlantic, 1770–1805
Authors: Graham Aaron
Published: March 2019

Urban renewal in the British Isles in the long eighteenth century was based on new municipal powers made possible by parliament. Focusing on Jamaica between 1770 and 1805, which passed legislation for the ‘policing’ – in the broader Scottish sense – of its towns, demonstrates that it was a global phenomenon common to the whole British Atlantic. However, the solutions it produced were also specific to local circumstances. Jamaican elites feared invasion, revolt and the dissolution of the slave society. Their police acts reflected these concerns, and demonstrate the alternative pathway that urban modernity took in this part of the British Atlantic.
Electron Beam Effects on Oxide Thin Films—Structure and Electrical Property Correlations
Authors: Neelisetty Krishna Kanth , Mu Xiaoke , Gutsch Sebastian , Vahl Alexander , Molinari Alan , von Seggern Falk , Hansen Mirko , Scherer Torsten , Zacharias Margit , Kienle Lorenz , Chakravadhanula VS Kiran , Kübel Christian
Published: March 2019

In situtransmission electron microscope (TEM) characterization techniques provide valuable information on structure–property correlations to understand the behavior of materials at the nanoscale. However, understanding nanoscale structures and their interaction with the electron beam is pivotal for the reliable interpretation ofin situ/ex situTEM studies. Here, we report that oxides commonly used in nanoelectronic applications, such as transistor gate oxides or memristive devices, are prone to electron beam induced damage that causes small structural changes even under very low dose conditions, eventually changing their electrical properties as examined viain situmeasurements. In this work, silicon, titanium, and niobium oxide thin films are used forin situTEM electrical characterization studies. The electron beam induced reduction of the oxides turns these insulators into conductors. The conductivity change is reversible by exposure to air, supporting the idea of electron beam reduction of oxides as primary damage mechanism. Through these measurements we propose a limit for the critical dose to be considered forin situscanning electron microscopy and TEM characterization studies.
Failure Evaluation of a SiC/SiC Ceramic Matrix Composite During In-Situ Loading Using Micro X-ray Computed Tomography
Authors: Thornton John , Arhatari Benedicta D. , Sesso Mitchell , Wood Chris , Zonneveldt Matthew , Kim Sun Yung , Kimpton Justin A. , Hall Chris
Published: March 2019

In this study, we have examined ceramic matrix composites with silicon carbide fibers in a melt-infiltrated silicon carbide matrix (SiC/SiC). We subjected samples to tensile loads while collecting micro X-ray computed tomography images. The results showed the expected crack slowing mechanisms and lower resistance to crack propagation where the fibers ran parallel and perpendicular to the applied load respectively. Cracking was shown to initiate not only from the surface but also from silicon inclusions. Post heat-treated samples showed longer fiber pull-out than the pristine samples, which was incompatible with previously proposed mechanisms. Evidence for oxidation was identified and new mechanisms based on oxidation or an oxidation assisted boron nitride phase transformation was therefore proposed to explain the long pull-out. The role of oxidation emphasizes the necessity of applying oxidation resistant coatings on SiC/SiC.
Thylakoids: A Novel Food-Derived Supplement for Obesity – A Mini-Review
Authors: Foshati Sahar , Ekramzadeh Maryam
Published: March 2019

Abstract. Nowadays, overweight and obesity are major epidemic health problems that can bring about some other health issues such as cardiovascular disease which is the first cause of mortality worldwide. Thylakoids are disc-like membranes responsible for photosynthetic light reactions in chloroplasts of green plants. Although only a few animal and human studies have been conducted regarding the impact of thylakoids on overweight- and obesity-related factors, all of them have resulted in positive outcomes. These outcomes are as follows: increment of satiety response; suppression of hunger sensations, particularly hedonic hunger; reduction of body weight and fat; promotion of glucose homeostasis; decrease in serum lipids; attenuation of oxidative stress and inflammation; and modulation of gut microbiota, notably by increasing some helpful bacteria such as Lactobacillus reuteri. It seems that some of these useful effects are related to retarded absorption of dietary fat and carbohydrate caused by thylakoids. There is still a need for more well-designed studies.
Estimating the Frequency of Sudden Stratospheric Warming Events From Surface Observations of the North Atlantic Oscillation
Authors: Domeisen Daniela I.V.
Published: March 2019

Sudden stratospheric warming (SSW) events can exhibit long‐lasting surface impacts that promise improvements in medium‐range to seasonal predictability. Their surface impact is dominated by the negative phase of the North Atlantic Oscillation (NAO). Hence, the question arises if stratospheric variability, and in particular the frequency of SSW events, can in turn be estimated from surface NAO conditions. This is especially relevant for the period before frequent upper air observations became available, while daily surface observations of the NAO date back to 1850. The surface impact is here quantified by NAO characteristics that are commonly observed after SSW events: a switch from a positive to a negative NAO and an extended persistence of the negative NAO, termed NAO events. Two thirds of SSW events are found to be followed by either a persistence or switch NAO event, and a quarter of SSW events are followed by both. On the other hand, less than 25% of winter surface NAO events are preceded by a SSW event. Based on these findings, an index purely based on surface NAO observations is derived that estimates SSW frequency for the satellite era and extends it back to 1850, indicating that decadal stratospheric variability was present for the entire time series, with no significant trend. The minimum in SSW frequency in the 1990s is found to be coincident with the longest absence of NAO events since 1850, indicating that the early 1990s may constitute the longest absence of SSW events for the 150‐year record.
Investigating Transport and Dissipation in the Subauroral E Region With Ionospheric Modification Experiments and Very High Frequency Radar Backscatter
Authors: Hysell D. L. , Munk J. , McCarrick M.
Published: March 2019

Ionospheric modification experiments have been performed at the High‐Frequency Active Auroral Research Program (HAARP) facility in Gakona, Alaska, using a Very High Frequency (VHF) coherent scatter radar in Homer, Alaska, for experimental diagnostics. The experiments were intended to determine the threshold pump electric field required to initiate thermal parametric instability in the E region. The pump power level was ramped systematically to determine the threshold, and the experiment was repeated at four closely spaced pump frequencies. This provided threshold estimates at four E region altitudes. The theory for thermal parametric instability based on the work of Dysthe et al. (1983, https://doi.org/10.1063/1.863993) has been modified for application in the E region. The theory considers magneto‐ionic effects on the pump mode, linear mode conversion theory for upper hybrid wave generation, wave heating, and the effects of transport and dissipation based on fluid theory. The theory amounts to an eigenvalue problem where the eigenvalue is the threshold pump electric field for instability. The theory shows how the threshold depends on ionospheric transport coefficients and on the fractional cooling rate for inelastic electron‐neutral collisions. The theoretical predictions for threshold are roughly consistent with experimental values although the latter are probably affected by excess ionospheric absorption.
Unraveling the biophysical underpinnings to the success of multispecies biofilms in porous environments
Authors: Scheidweiler David , Peter Hannes , Pramateftaki Paraskevi , de Anna Pietro , Battin Tom J
Published: March 2019

Biofilms regulate critical processes in porous ecosystems. However, the biophysical underpinnings of the ecological success of these biofilms are poorly understood. Combining experiments with fluidic devices, sequencing and modeling, we reveal that architectural plasticity enhances space exploitation by multispecies biofilms in porous environments. Biofilms consistently differentiated into an annular base biofilm coating the grains and into streamers protruding from the grains into the pore space. Although different flow-related processes governed the differentiation of these architectures, both BB and streamers were composed of similar bacterial assemblages. This is evidence for architectural plasticity. Architectural plasticity allowed for complementary use of the space provided by the grain–pore complexes, which increased biofilm carrying capacity at the larger scale of the porous system. This increase comes potentially at the cost of a tradeoff. Contrasting time scales of oxygen replenishment and consumption, we show that streamers locally inhibit the growth of the BB downstream from the grains. Our study provides first insights into the biophysical underpinnings to the success of multispecies biofilms in porous environments.
Inhibition of lymphatic proliferation by the selective VEGFR-3 inhibitor SAR131675 ameliorates diabetic nephropathy in db/db mice
Authors: Hwang Seun Deuk , Song Joon Ho , Kim Yaeni , Lim Ji Hee , Kim Min Young , Kim Eun Nim , Hong Yu Ah , Chung Sungjin , Choi Bum Soon , Kim Yong-Soo , Park Cheol Whee
Published: March 2019

Recent studies have demonstrated that chronic inflammation-induced lymphangiogenesis plays a crucial role in the progression of various renal diseases, including diabetic nephropathy. SAR131675 is a selective vascular endothelial cell growth factor receptor-3 (VEGFR-3)-tyrosine kinase inhibitor that acts as a ligand for VEGF-C and VEGF-D to inhibit lymphangiogenesis. In this study, we evaluated the effect of SAR131675 on renal lymphangiogenesis in a mouse model of type 2 diabetes. Male C57BLKS/J db/m and db/db mice were fed either a regular chow diet or a diet containing SAR131675 for 12 weeks from 8 weeks of age. In addition, we studied palmitate-induced lymphangiogenesis in human kidney-2 (HK2) cells and RAW264.7 monocytes/macrophages, which play a major role in lymphangiogenesis in the kidneys. SAR131475 ameliorated dyslipidemia, albuminuria, and lipid accumulation in the kidneys of db/db mice, with no significant changes in glucose and creatinine levels and body weight. Diabetes-induced systemic inflammation as evidenced by increased systemic monocyte chemoattractant protein-1 and tumor necrosis factor-α level was decreased by SAR131475. SAR131475 ameliorated the accumulation of triglycerides and free fatty acids and reduced inflammation in relation to decreased chemokine expression and pro-inflammatory M1 macrophage infiltration in the kidneys. Downregulation of VEGF-C and VEGFR-3 by SAR131475 inhibited lymphatic growth as demonstrated by decreased expression of LYVE-1 and podoplanin that was further accompanied by reduced tubulointerstitial fibrosis, and inflammation in relation to improvement in oxidative stress and apoptosis. Treatment with SAR131475 improved palmitate-induced increase in the expression of VEGF-C, VEGFR-3, and LYVE-1, along with improvement in cytosolic and mitochondrial oxidative stress in RAW264.7 and HK2 cells. Moreover, the enhanced expression of M1 phenotypes in RAW264.7 cells under palmitate stress was reduced by SAR131475 treatment. The results suggest that modulation of lymphatic proliferation in the kidneys is a new treatment approach for type 2 diabetic nephropathy and that SAR131675 is a promising therapy to ameliorate renal damage by reducing lipotoxicity-induced lymphangiogenesis.
TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity
Authors: Medler Juliane , Nelke Johannes , Weisenberger Daniela , Steinfatt Tim , Rothaug Moritz , Berr Susanne , Hünig Thomas , Beilhack Andreas , Wajant Harald
Published: March 2019

Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.
Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process
Authors: Domise Manon , Sauvé Florent , Didier Sébastien , Caillerez Raphaëlle , Bégard Séverine , Carrier Sébastien , Colin Morvane , Marinangeli Claudia , Buée Luc , Vingtdeux Valérie
Published: March 2019

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by synaptic loss that leads to the development of cognitive deficits. Synapses are neuronal structures that play a crucial role in memory formation and are known to consume most of the energy used in the brain. Interestingly, AMP-activated protein kinase (AMPK), the main intracellular energy sensor, is hyper-activated in degenerating neurons in several neurodegenerative diseases, including AD. In this context, we asked whether AMPK hyper-activation could influence synapses' integrity and function. AMPK hyper-activation in differentiated primary neurons led to a time-dependent decrease in pre- and post-synaptic markers, which was accompanied by a reduction in synapses number and a loss of neuronal networks functionality. The loss of post-synaptic proteins was mediated by an AMPK-regulated autophagy-dependent pathway. Finally, this process was also observed in vivo, where AMPK hyper-activation primed synaptic loss. Overall, our data demonstrate that during energetic stress condition, AMPK might play a fundamental role in the maintenance of synaptic integrity, at least in part through the regulation of autophagy. Thus, AMPK might represent a potential link between energetic failure and synaptic integrity in neurodegenerative conditions such as AD.
Circadian control of stress granules by oscillating EIF2α
Authors: Wang Ruiqi , Jiang Xin , Bao Puhua , Qin Meiling , Xu Jin
Published: March 2019

Stress granule formation is important for stress response in normal cells and could lead to chemotherapy resistance in cancer cells. Aberrant stress granule dynamics are also known to disrupt proteostasis, affect RNA metabolism, and contribute to neuronal cell death. Meanwhile, circadian abnormality is an aging-related risk factor for cancer and neurodegeneration. Whether stress granule dynamics are circadian regulated is entirely unknown. Here we show that the formation of stress granules varied by zeitgeber time in mouse liver. Moreover, altering circadian regulation by silencing the core circadian gene Bmal1 in a cell line expressing an endogenous GFP-tagged G3BP1 significantly increased stress granule dynamics, while the overexpression of Bmal1 decreased them. Surprisingly, increased stress granule dynamics and formation by transient decrease of BMAL1 coincided with increased resistance to stress-induced cell death. The circadian regulation of stress granules was mediated by oscillating eIF2α expression. At zeitgeber time when BMAL1 and eIF2α were at nadir, reduction of unphosphorylated eIF2α could significantly alter the ratio of phosphorylated/total eIF2α and quickly lead to increased formation of stress granules. Therefore, diurnal oscillating eIF2α connects the circadian cue to a cellular stress response mechanism that is vital for both neurodegeneration and cancer.
Sustained NF-κB-STAT3 signaling promotes resistance to Smac mimetics in Glioma stem-like cells but creates a vulnerability to EZH2 inhibition
Authors: da Hora Cintia Carla , Pinkham Kelsey , Carvalho Litia , Zinter Max , Tabet Elie , Nakano Ichiro , Tannous Bakhos A. , Badr Christian E.
Published: March 2019

Glioblastoma is an incurable and highly aggressive brain tumor. Understanding therapeutic resistance and survival mechanisms driving this tumor type is key to finding effective therapies. Smac mimetics (SM) emerged as attractive cancer therapeutics particularly for tumor populations that are highly resistant to conventional apoptosis-inducing therapies. We evaluated the therapeutic efficacy of SM on Glioma stem-like cells (GSCs) and showed that this family of compounds stimulates an adaptive response triggered by TNFα. Increased expression of TNFα results in a prolonged and sustained activation of NF-κB and STAT3 signaling thus activating several tumor cell resistance mechanisms in GSCs. We show that STAT3 activation is contingent on EZH2 activation and uncover a synergistic lethality between SM and EZH2 inhibitors. Therapeutic inhibition of EZH2 impaired the viability of SM-treated GSCs. Our study outlines the molecular underpinnings of SM resistance in glioblastoma and provides mechanistic insight to overcome this resistance and increase therapeutic efficacy.
The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression
Authors: Ma Biao , Cheng Hongcheng , Mu Chenglong , Geng Guangfeng , Zhao Tian , Luo Qian , Ma Kaili , Chang Rui , Liu Qiangqiang , Gao Ruize , Nie Junli , Xie Jiaying , Han Jinxue , Chen Linbo , Ma Gui , Zhu Yushan , Chen Quan
Published: March 2019

The interactions between tumor cells with their microenvironments, including hypoxia, acidosis and immune cells, lead to the tumor heterogeneity which promotes tumor progression. Here, we show that SIAH2-NRF1 axis remodels tumor microenvironment through regulating tumor mitochondrial function, tumor-associated macrophages (TAMs) polarization and cell death for tumor maintenance and progression. Mechanistically, low mitochondrial gene expression in breast cancers is associated with a poor clinical outcome. The hypoxia-activated E3 ligase SIAH2 spatially downregulates nuclear-encoded mitochondrial gene expression including pyruvate dehydrogenase beta via degrading NRF1 (Nuclear Respiratory Factor 1) through ubiquitination on lysine 230, resulting in enhanced Warburg effect, metabolic reprogramming and pro-tumor immune response. Dampening NRF1 degradation under hypoxia not only impairs the polarization of TAMs, but also promotes tumor cells to become more susceptible to apoptosis in a FADD-dependent fashion, resulting in secondary necrosis due to the impairment of efferocytosis. These data represent that inhibition of NRF1 degradation is a potential therapeutic strategy against cancer.
ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis
Authors: Hoeman Christine M. , Cordero Francisco J. , Hu Guo , Misuraca Katie , Romero Megan M. , Cardona Herminio J. , Nazarian Javad , Hashizume Rintaro , McLendon Roger , Yu Paul , Procissi Daniele , Gadd Samantha , Becher Oren J.
Published: March 2019

Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, with approximately 25% of DIPGs harboring activating ACVR1 mutations that commonly co-associate with H3.1K27M mutations. Here we show that in vitro expression of ACVR1 R206H with and without H3.1K27M upregulates mesenchymal markers and activates Stat3 signaling. In vivo expression of ACVR1 R206H or G328V with H3.1K27M and p53 deletion induces glioma-like lesions but is not sufficient for full gliomagenesis. However, in combination with PDGFA signaling, ACVR1 R206H and H3.1K27M significantly decrease survival and increase tumor incidence. Treatment of ACVR1 R206H mutant DIPGs with exogenous Noggin or the ACVR1 inhibitor LDN212854 significantly prolongs survival, with human ACVR1 mutant DIPG cell lines also being sensitive to LDN212854 treatment. Together, our results demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile partly due to Stat3 activation, and identify LDN212854 as a promising compound to treat DIPG.
Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
Authors: Lee Ernest Y. , Zhang Changsheng , Di Domizio Jeremy , Jin Fan , Connell Will , Hung Mandy , Malkoff Nicolas , Veksler Veronica , Gilliet Michel , Ren Pengyu , Wong Gerard C. L.
Published: March 2019

Amphiphilicity in ɑ-helical antimicrobial peptides (AMPs) is recognized as a signature of potential membrane activity. Some AMPs are also strongly immunomodulatory: LL37-DNA complexes potently amplify Toll-like receptor 9 (TLR9) activation in immune cells and exacerbate autoimmune diseases. The rules governing this proinflammatory activity of AMPs are unknown. Here we examine the supramolecular structures formed between DNA and three prototypical AMPs using small angle X-ray scattering and molecular modeling. We correlate these structures to their ability to activate TLR9 and show that a key criterion is the AMP’s ability to assemble into superhelical protofibril scaffolds. These structures enforce spatially-periodic DNA organization in nanocrystalline immunocomplexes that trigger strong recognition by TLR9, which is conventionally known to bind single DNA ligands. We demonstrate that we can “knock in” this ability for TLR9 amplification in membrane-active AMP mutants, which suggests the existence of tradeoffs between membrane permeating activity and immunomodulatory activity in AMP sequences.