bluuebunny/crossref_metadata_2025 huggingface dataset:
Global change and terrestrial plant community dynamics
Authors: Franklin Janet , Serra-Diaz Josep M. , Syphard Alexandra D. , Regan Helen M.
Published: March 2016

Significance

Global terrestrial vegetation plays a critical role in biogeochemical cycles and provides important ecosystem services. Vegetation has been altered by anthropogenic global change drivers including land-use change, altered disturbance regimes, invasive species, and climate change, for decades to centuries, or in some cases millennia. Vegetation responses to land use and disturbance can be more immediate than to climate change and can be long lasting. The effect of global warming on water balance may have a stronger influence than the direct effects of temperature on vegetation. Models deployed at multiple ecological scales, populations, communities, and landscapes will be required to forecast vegetation responses and feedbacks to accelerated global change.
Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles
Authors: Wang Ming , Zuris John A. , Meng Fantao , Rees Holly , Sun Shuo , Deng Pu , Han Yong , Gao Xue , Pouli Dimitra , Wu Qi , Georgakoudi Irene , Liu David R. , Xu Qiaobing
Published: March 2016

Significance

The therapeutic potential of protein-based genome editing is dependent on the delivery of proteins to appropriate intracellular targets. Here we report that combining bioreducible lipid nanoparticles and negatively supercharged Cre recombinase or anionic Cas9:single-guide (sg)RNA complexes drives the self-assembly of nanoparticles for potent protein delivery and genome editing. The design of bioreducible lipids facilitates the degradation of nanoparticles inside cells in response to the reductive intracellular environment, enhancing the endosome escape of protein. In addition, modulation of protein charge through either genetic fusion of supercharged protein or complexation of Cas9 with its inherently anionic sgRNA allows highly efficient protein delivery and effective genome editing in mammalian cells and functional recombinase delivery in the rodent brain.
Cyclic nucleotide-gated channel 18 is an essential Ca
2+
channel in pollen tube tips for pollen tube guidance to ovules in
Arabidopsis
Authors: Gao Qi-Fei , Gu Li-Li , Wang Hui-Qin , Fei Cui-Fang , Fang Xiang , Hussain Jamshaid , Sun Shu-Jing , Dong Jing-Yun , Liu Hongtao , Wang Yong-Fei
Published: March 2016

Significance

In flowering plants, pollen tubes deliver paired sperm cells into ovules for double fertilization by perceiving and responding to multiple attractants secreted from the ovules. Ca
2+
gradients in pollen tube tips are essential for pollen tube guidance, and plasma membrane Ca
2+
channels in the pollen tube tips are the core components for the regulation of the Ca
2+
gradients by mediating and regulating external Ca
2+
influx. Therefore, the Ca
2+
channels are essential for pollen tube guidance. However, the molecular identities of the Ca
2+
channels remain to be addressed. In this research, we found that cyclic nucleotide-gated channel 18, out of eight Ca
2+
channels present in pollen tubes, is the main one essential for pollen tube guidance in
Arabidopsis
.
Gold surfaces and nanoparticles are protected by Au(0)–thiyl species and are destroyed when Au(I)–thiolates form
Authors: Reimers Jeffrey R. , Ford Michael J. , Halder Arnab , Ulstrup Jens , Hush Noel S.
Published: March 2016

Significance

Synthetic design strategies for gold surface protection and nanoparticle formation require knowledge of how protectant ligands bind. Sulfur compounds may protect gold surfaces using a weakly bound (physisorbed) form or a strongly bound (chemisorbed) one often assumed to be Au(I)–thiolate. However, chemical reaction conditions optimized for Au(I)–thiolate protection instead etch surfaces to produce molecular thin films. All experimental and calculated evidence indicates that chemisorbed surface species are actually bound mainly by strong van der Waals (aurophilic-like) forces. This understanding unifies gold–sulfur surface chemistry with that of all other ligands and also with that of gold compounds, forming the basis for future methodological developments. It is applied to predict intermediate species during the Brust–Schiffrin nanoparticle synthesis that are subsequently observed spectroscopically.
Disruption of lipid homeostasis in the Gram-negative cell envelope activates a novel cell death pathway
Authors: Sutterlin Holly A. , Shi Handuo , May Kerrie L. , Miguel Amanda , Khare Somya , Huang Kerwyn Casey , Silhavy Thomas J.
Published: March 2016

Significance

The cell envelope of Gram-negative bacteria contains two membranes and a cell wall located in the aqueous compartment between them. The outer membrane (OM) functions as a barrier that contributes to antibiotic resistance. We describe a dominant mutation in a gene for an OM lipoprotein that leads to cell death under starvation conditions in medium with limited cation concentrations. We show that death occurs not by rapid cell lysis but by a previously uncharacterized mechanism involving flow of material from the inner membrane to the OM that results in rupture of the inner membrane and the slow leakage of cytoplasmic contents. Our study highlights the vital need for balanced synthesis across the Gram-negative envelope and may empower the development of new therapeutics.
Biophysical principles predict fitness landscapes of drug resistance
Authors: Rodrigues João V. , Bershtein Shimon , Li Anna , Lozovsky Elena R. , Hartl Daniel L. , Shakhnovich Eugene I.
Published: March 2016

Significance

Development of predictive models of antibiotic resistance is challenging due to a lack of understanding of the relationship between molecular and fitness effects of mutations (the genotype–phenotype gap). Here we close the genotype–phenotype gap for an essential enzyme, dihydrofolate reductase (DHFR), which is an important target of the common antibiotic trimethoprim. We show that IC
50
of trimethoprim resistance of
Escherichia coli
can be predicted, with high accuracy, from a unique combination of molecular properties of stepwise-resistant DHFR variants. These results show that the challenge to predict de novo evolutionary dynamics of antibiotic resistance lies in the need for accurate prediction of the effects of mutations on the molecular properties of target enzymes.
Role of bacteriophage T4 baseplate in regulating assembly and infection
Authors: Yap Moh Lan , Klose Thomas , Arisaka Fumio , Speir Jeffrey A. , Veesler David , Fokine Andrei , Rossmann Michael G.
Published: March 2016

Significance

This study examines how the high-energy, dome-shaped infectious form of the bacteriophage T4 baseplate assembles as opposed to how it assembles in the low-energy, star-shaped form that occurs after infection. Normal expectations would be that a molecular assembly occurs as a result of loss of energy. However, a virus has to be poised in a high-energy form to fight its way into a host. Our investigations of T4 have now shown how bacteriophage T4 can assemble into a high-energy form and how the structure of the components directs the sequential conformational changes that gain access to the host, an
Escherichia coli
bacterium.
Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis
Authors: Dong Xiaonan , Cheng Adam , Zou Zhongju , Yang Yih-Sheng , Sumpter Rhea M. , Huang Chou-Long , Bhagat Govind , Virgin Herbert W. , Lira Sergio A. , Levine Beth
Published: March 2016

Significance

We show that the autophagy-related protein Beclin 2 functions as a newly described cellular regulator of viral G protein-coupled receptors (GPCRs) and as a suppressor of viral GPCR-driven tumorigenesis. Beclin 2 functions in regulating Kaposi’s sarcoma-associated herpesvirus-encoded GPCR levels, proinflammatory signaling, and oncogenic activity in mice by facilitating viral GPCR endolysosomal trafficking. This Beclin 2-dependent endolysosomal trafficking and degradation of an oncogenic viral protein may represent a broader and heretofore unappreciated role of the endolysosomal trafficking machinery in innate immunity (by defending against microbial virulence factors) and in tumor suppression (by degrading oncogenic cell surface receptors).
Restrictions on definiteness in the grammars of German-Turkish heritage speakers
Authors: Kupisch Tanja , Belikova Alyona , Özçelik Öner , Stangen Ilse , White Lydia
Published: March 2016

This paper reports on a study investigating restrictions on definiteness (the Definiteness Effect) in existential constructions in the two languages of Turkish heritage speakers in Germany. Turkish and German differ in how the Definiteness Effect plays out. Definite expressions in German may not occur in affirmative or negative existentials, whereas in Turkish the restriction applies only to affirmative existentials. Participants were adults and fell into two groups: simultaneous bilinguals (2L1) who acquired German before age 3 and early sequential bilinguals (2L1) who acquired German after age 4; there were also monolingual controls. The tasks involved acceptability judgments. Subjects were presented with contexts, each followed by a sentence to be judged, including grammatical and ungrammatical existentials. Results show that the bilinguals, regardless of age of acquisition, make judgments appropriate for each language. They reject definite expressions in negative existentials in German and accept them in Turkish, suggesting distinct grammars.
Lifelong bilingualism, cognitive reserve and Alzheimer’s disease
Authors: Gold Brian T.
Published: March 2016

Increasing our understanding about neuroprotective lifestyle variables has become a practical imperative in our aging society. Cognitive reserve (CR) refers to the use brain resources in a way that allows for coping with neuropathology and maintaining cognitive functioning. A growing body of evidence suggests that bilingualism may represent a form of CR against Alzheimer’s disease (AD). The purpose of the present review is to summarize both behavioral and neuroimaging evidence for bilingualism as a reserve variable against AD. The potential influences of literacy, intelligence, immigration status are discussed. Evidence is reviewed suggesting that bilingualism may delay clinical AD symptoms by protecting against age-related declines in the brain’s executive control circuitry. It is suggested that such potential beneficial effects within executive control systems may enable bilinguals to circumvent the typical effects of AD pathology on symptom expression for several years.
Individual differences in cognitive control advantages of elderly late Dutch-English bilinguals
Authors: Keijzer Merel C. J. , Schmid Monika S.
Published: March 2016

This study addresses a gap in the literature on executive function advantages among bilingual speakers by investigating a group of elderly, long-term, immersed bilinguals. Our participants are native Dutch speakers who emigrated to Australia as adults and have spent many years in that country. They are compared on a range of cognitive and linguistic measures to native Dutch and native English control groups. We argue that, due to the massive differences in the bilingual experience, group analyses may fall short of capturing the full picture. We argue instead for a more qualitative approach, which takes into account as detailed a picture of bilingual development, daily language habits and, in particular, code-switching habits as possible.
Inhibitory effects of geranium essential oil and its major component, citronellol, on degranulation and cytokine production by mast cells
Authors: Kobayashi Yuko , Sato Harumi , Yorita Mika , Nakayama Hiroto , Miyazato Hironari , Sugimoto Keiichiro , Jippo Tomoko
Published: March 2016

We investigated the effects of geranium essential oil (GEO) on anaphylaxis. GEO can exert antioxidant and anti-inflammatory effects, but its roles in allergic reactions are incompletely understood. Here, we used mouse cells to show that GEO inhibited the degranulation of cultured mast cells (CMCs). Citronellol is the major component of GEO and inhibited CMC degranulation. The l-enantiomer of citronellol more effectively suppressed CMC degranulation than did d-citronellol. We also examined whether citronellol could inhibit the immunoglobulin (Ig) E-induced production of tumor necrosis factor (TNF)-α. Treatment with various concentrations of citronellol before CMC activation with IgE significantly inhibited the induction of TNF-α in a dose-dependent manner. Mechanistically, citronellol suppressed the phosphorylation of mitogen-activated protein kinase (ERK), which is critical for ERK activation and the production of inflammatory cytokines in mast cells. These findings suggest that citronellol may represent a candidate compound for the effective treatment of allergic diseases.
Enthymemes in the Orators
Authors: Fredal James
Published: March 2016

A theoretical bias pervades enthymeme. Most studies of the enthymeme are thoroughly Aristotelian and syllogistic, while the study of enthymemes in ancient oratory is virtually nonexistent. Yet the Attic orators used enthymemes commonly and consistently, and as practitioners, they have something to teach us about enthymemes that theorists can’t. In this article, I begin an examination of oratorical enthymemes and the variety of their use and offer a preliminary understanding of the “oratorical enthymeme” as a rhetorical technique. I conclude by briefly touching on the connections between oratorical enthymemes and ancient theory.
Low‐intensity electrical muscle stimulation induces significant increases in muscle strength and cardiorespiratory fitness
Authors: Miyamoto Toshiaki , Kamada Hiroyuki , Tamaki Akira , Moritani Toshio
Published: March 2016

The aim of this study was to investigate the effect of low‐intensity exercise training using belt electrode skeletal muscle electrical stimulation on muscle strength and cardiorespiratory fitness in healthy subjects. Nineteen healthy subjects were allocated into control or intervention groups; in both groups the participants kept regular physical activity while the intervention group underwent 30 min B‐SES training at 3–4 METs for four weeks. Knee extensor muscle strength and cardiorespiratory endurance during incremental exercise test were measured at baseline and after four weeks for all participants. The relative change of knee extensor muscle strength in the intervention group was significantly higher than control group (p < .05). Also, oxygen uptake at ventilator threshold and peak oxygen uptake during incremental exercise test significantly increased in the intervention group when compared with control group (p < .05). This study showed that prolonged low‐intensity B‐SES training resulted in significant increases in muscle strength and cardiorespiratory fitness in healthy subjects. Our present work suggested that B‐SES training could assist patients who might have difficulty performing adequate voluntary exercise because of excessive obesity, orthopaedic problems and chronic diseases such as cardiovascular disease and type 2 diabetes. An intervention study conducted for such patients is strongly recommended.
On the Blessing of Abstraction
Authors: Gershman Samuel J.
Published: March 2016

The “blessing of abstraction” refers to the observation that acquiring abstract knowledge sometimes proceeds more quickly than acquiring more speciﬁc knowledge. This observation can be formalized and reproduced by hierarchical Bayesian models. The key notion is that more abstract layers of the hierarchy have a larger “effective” sample size, because they combine information across multiple speciﬁc instances lower in the hierarchy. This notion relies on speciﬁc variables being relatively concentrated around the abstract “overhypothesis”. If the variables are highly dispersed, then the effective sample size for the abstract layers will not be appreciably larger than for the speciﬁc layers. Moreover, the blessing of abstraction is counterbalanced by the fact that data are more informative about lower levels of the hierarchy, because there is necessarily less stochasticity intervening between speciﬁc variables and the data. Thus, in certain cases abstract knowledge will be acquired more slowly than speciﬁc knowledge. This paper reports an experiment that shows how manipulating dispersion can produce both fast and slow acquisition of abstract knowledge in the same paradigm.
Thermodynamics of towers of hyperbolic type
Authors: Pesin Y. , Senti S. , Zhang K.
Published: March 2016

We introduce a class of continuous maps

f
f

of a compact topological space

X
X

admitting inducing schemes of hyperbolic type and describe the associated tower constructions. We then establish a thermodynamic formalism, i.e., we describe a class of real-valued potential functions

φ
\varphi

on

X
X

such that

f
f

possesses a unique equilibrium measure

μ
φ

\mu _\varphi

, associated to each

φ
\varphi

, which minimizes the free energy among the measures that are liftable to the tower. We also describe some ergodic properties of equilibrium measures including decay of correlations and the Central Limit Theorem. We then study the liftability problem and show that under some additional assumptions on the inducing scheme every measure that charges the base of the tower and has sufficiently large entropy is liftable. Our results extend those obtained in previous works of the first and second authors for inducing schemes of expanding types and apply to certain multidimensional maps. Applications include obtaining the thermodynamic formalism for Young’s diffeomorphisms, the Hénon family at the first bifurcation and the Katok map. In particular, we obtain the exponential decay of correlations for equilibrium measures associated to the geometric potentials with

t
0

>
t
>
1

t_0> t>1

for some

t
0

>
0

t_0>0

.
SASpy: a PyMOL plugin for manipulation and refinement of hybrid models against small angle X-ray scattering data
Authors: Panjkovich Alejandro , Svergun Dmitri I.
Published: March 2016

Summary: Complex formation and conformational transitions of biological macromolecules in solution can be effectively studied using the information about overall shape and size provided by small angle X-ray scattering (SAXS). Hybrid modeling is often applied to integrate high-resolution models into SAXS data analysis. To facilitate this task, we present SASpy, a PyMOL plugin that provides an easy-to-use graphical interface for SAXS-based hybrid modeling. Through a few mouse clicks in SASpy, low-resolution models can be superimposed to high-resolution structures, theoretical scattering profiles and fits can be calculated and displayed on-the-fly. Mouse-based manual rearrangements of complexes are conveniently applied to rapidly check and interactively refine tentative models. Interfaces to automated rigid-body and flexible refinement of macromolecular models against the experimental SAXS data are provided.

Availability and implementation: SASpy is available as open source at: github.com/emblsaxs/saspy/. Working installations of both PyMOL (www.pymol.org) and ATSAS (www.embl-hamburg.de/biosaxs/download.html) are required.

Contact:  apanjkovich@embl-hamburg.de or svergun@embl-hamburg.de
Elongator Plays a Positive Role in Exogenous NAD-Induced Defense Responses inArabidopsis
Authors: An Chuanfu , Ding Yezhang , Zhang Xudong , Wang Chenggang , Mou Zhonglin
Published: March 2016

Extracellular NAD is emerging as an important signal molecule in animal cells, but its role in plants has not been well-established. Although it has been shown that exogenous NAD+activates defense responses in Arabidopsis, components in the exogenous NAD+-activated defense pathway remain to be fully discovered. In a genetic screen for mutants insensitive to exogenous NAD+(ien), we isolated a mutant named ien2. Map-based cloning revealed that IEN2 encodes ELONGATA3 (ELO3)/AtELP3, a subunit of the Arabidopsis Elongator complex, which functions in multiple biological processes, including histone modification, DNA (de)methylation, and transfer RNA modification. Mutations in the ELO3/AtELP3 gene compromise exogenous NAD+-induced expression of pathogenesis-related (PR) genes and resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326, and transgenic expression of the coding region of ELO3/AtELP3 in elo3/Atelp3 restores NAD+responsiveness to the mutant plants, demonstrating that ELO3/AtELP3 is required for exogenous NAD+-induced defense responses. Furthermore, mutations in genes encoding the other five Arabidopsis Elongator subunits (ELO2/AtELP1, AtELP2, ELO1/AtELP4, AtELP5, and AtELP6) also compromise exogenous NAD+-induced PR gene expression and resistance to P. syringae pv. maculicola ES4326. These results indicate that the Elongator complex functions as a whole in exogenous NAD+-activated defense signaling in Arabidopsis.
Bacterial Outer Membrane Vesicles Induce Plant Immune Responses
Authors: Bahar Ofir , Mordukhovich Gideon , Luu Dee Dee , Schwessinger Benjamin , Daudi Arsalan , Jehle Anna Kristina , Felix Georg , Ronald Pamela C.
Published: March 2016

Gram-negative bacteria continuously pinch off portions of their outer membrane, releasing membrane vesicles. These outer membrane vesicles (OMVs) are involved in multiple processes including cell-to-cell communication, biofilm formation, stress tolerance, horizontal gene transfer, and virulence. OMVs are also known modulators of the mammalian immune response. Despite the well-documented role of OMVs in mammalian-bacterial communication, their interaction with plants is not well studied. To examine whether OMVs of plant pathogens modulate the plant immune response, we purified OMVs from four different plant pathogens and used them to treat Arabidopsis thaliana. OMVs rapidly induced a reactive oxygen species burst, medium alkalinization, and defense gene expression in A. thaliana leaf discs, cell cultures, and seedlings, respectively. Western blot analysis revealed that EF-Tu is present in OMVs and that it serves as an elicitor of the plant immune response in this form. Our results further show that the immune coreceptors BAK1 and SOBIR1 mediate OMV perception and response. Taken together, our results demonstrate that plants can detect and respond to OMV-associated molecules by activation of their immune system, revealing a new facet of plant-bacterial interactions.
Fungicide and Cultivar Effects on Sudden Death Syndrome and Yield of Soybean
Authors: Kandel Yuba R. , Wise Kiersten A. , Bradley Carl A. , Chilvers Martin I. , Tenuta Albert U. , Mueller Daren S.
Published: March 2016

The effect of fungicides on severity of sudden death syndrome (SDS; caused by Fusarium virguliforme), plant establishment, and soybean yield was evaluated in 12 field experiments conducted in Illinois, Indiana, Iowa, Michigan, and Ontario in 2013 and 2014. Two soybean cultivars that differed in susceptibility to SDS were planted in fields with a history of SDS or with artificial augmentation of F. virguliforme. Efficacy of seed, in-furrow, and foliar-applied fungicides was assessed. SDS levels varied across locations and years. Fluopyram applied on the seed or in-furrow reduced foliar disease index maximum up to 95% in 5 of the 12 experiments. In three experiments with significant (P < 0.10) treatment effect, fluopyram seed treatment improved yields up to 11% compared with the base seed treatment comprising prothioconazole + penflufen + metalaxyl and clothianidin + Bacillus firmus. Meta-analysis also indicated that the fluopyram seed treatment and in-furrow application were effective at reducing SDS and increasing yield relative to the control; however, the baseline disease influenced the yield and disease response to fungicide treatments. Treatment effect was not significant when disease pressure was low. The concentration of F. virguliforme DNA in soybean roots, measured by a specific real-time quantitative polymerase chain reaction assay, was not different among fungicide treatments in 9 of 10 experiments. Moderately resistant cultivars had less disease than susceptible cultivars, indicating that resistant cultivars in combination with fluopyram seed treatment or in-furrow application could provide effective management of SDS.
Mobile Phone Messaging During Unobserved “Home” Induction to Buprenorphine
Authors: Tofighi Babak , Grossman Ellie , Sherman Scott , Nunes Edward V. , Lee Joshua D.
Published: March 2016

The deployment of health information technologies promises to optimize clinical outcomes for populations with substance use disorders. Electronic health records, web-based counseling interventions, and mobile phone applications enhance the delivery of evidence-based behavioral and pharmacological treatments, with minimal burden to clinical personnel, infrastructure, and work flows. This clinical case shares a recent experience utilizing mobile phone text messaging between an office-based buprenorphine provider in a safety net ambulatory clinic and a patient seeking buprenorphine treatment for opioid use disorder. The case highlights the use of text message-based physician–patient communication to facilitate unobserved “home” induction onto buprenorphine.
Dexmedetomidine for the Treatment of Hyperactive Delirium Refractory to Haloperidol in Nonintubated ICU Patients: A Nonrandomized Controlled Trial*
Authors: Carrasco Genís , Baeza Nacho , Cabré Lluís , Portillo Eugenia , Gimeno Gemma , Manzanedo David , Calizaya Milagros
Published: March 2016

Objectives:

To evaluate the clinical effectiveness, safety, and cost of dexmedetomidine for the treatment of agitated delirium refractory to haloperidol in nonintubated critically ill patients.

Design:

Nonrandomized, controlled trial.

Setting:

Intensive care department of a tertiary care nonprofit hospital.

Patients:

All consecutive admissions to a medical-surgical ICU with a diagnosis of agitated delirium.

Interventions:

Initial haloperidol titration: all patients received IV bolus doses of haloperidol until agitation was controlled (Richmond Agitation Sedation Scale scoring range, 0 to −2) or reaching the maximum daily dose. Group comparison: patient responders to haloperidol (control group) were compared with nonresponders (dexmedetomidine group).

Measurements and Main Results:

A total of 132 nonintubated patients were treated with haloperidol in the initial haloperidol titration phase. Forty-six patients (34.8%; 95% CI, 26.0–43.1%) did not respond to haloperidol, and 86 patients (65.2%; 95% CI, 56.3–73.0%) were responders. During the group comparison phase, dexmedetomidine achieved a higher percentage of time in satisfactory sedation levels than did haloperidol (92.7% [95% CI, 84.5–99.8%] vs 59.3% [95% CI, 48.6–69.3%], respectively; p = 0.0001). Haloperidol was associated with 10 cases (11.6% [95% CI, 6.5–21.2%]) of oversedation and two (2.0% [0.4–8%]) of corrected QT lengthening. Direct cost of dexmedetomidine was 17 times greater than haloperidol, but it achieved a mean savings of $4,370 per patient due to the reduction in length of ICU stay.

Conclusions:

In the study conditions, dexmedetomidine shows to be useful as a rescue drug for treating agitation due to delirium in nonintubated patients in whom haloperidol has failed, and it seems to have a better effectiveness, safety, and cost-benefit profile than does haloperidol.
Initial experience with combined BRAF and MEK inhibition with stereotactic radiosurgery for BRAF mutant melanoma brain metastases
Authors: Patel Bindiya G. , Ahmed Kamran A. , Johnstone Peter A.S. , Yu Hsiang-Hsuan Michael , Etame Arnold B.
Published: March 2016

The combined use of the BRAF inhibitor dabrafenib and MEK inhibitor trametinib has been found to improve survival over dabrafenib alone. The management of melanoma brain metastases continues to present challenges. In this study, we report our initial experience in the management of melanoma brain metastases with stereotactic radiosurgery (SRS) with the use of BRAF and MEK inhibitors. We identified six patients treated with SRS for 17 brain metastases within 3 months of BRAF and MEK inhibitor administration. The median planning target volume was 0.42 cm3 (range: 0.078–2.08 cm3). The median treatment dose was 21 Gy (range 18–24 Gy). The median follow-up of all lesions from SRS was 10.6 months (range 5.8–28.5 months). One lesion was found to undergo local failure 21.7 months following SRS treatment. The median overall survival was 20.0 months (range 6.1–31.8 months) from the time of SRS treatment and 23.1 months (range: 12.1–30.9 months) from the date of BRAFi and MEKi administration. There was no evidence of increased nor unexpected toxicity with the two modalities combined. In this initial experience of melanoma brain metastases treated with BRAF and MEK inhibition with SRS, we find the two modalities can be combined safely. These outcomes should be assessed further in prospective evaluations.
Knowledge, Behavior, and Free-Living Amoebae Contamination of Cosmetic Contact Lens Among University Wearers in Thailand: A Cross-Sectional Study
Authors: Mahittikorn Aongart , Kittichathanakul Thanuntorn , To-Im Jongdee , Nacapunchai Duangporn
Published: March 2016

Objective:

To assess the general knowledge, behavior, and presence of potentially pathogenic amoebae in cosmetic contact lens (CCL) wearers.

Methods:

One hundred CCL asymptomatic wearers were randomly selected. A questionnaire regarding their lens use, and a pair of their CCL was obtained. Identification of free-living amoeba (FLA) strains was based on morphological diagnosis, enflagellation tests (for non-Acanthamoeba strains), and sequencing of the small-subunit rRNA gene fragments.

Results:

Most (92%) of the participants surveyed were women, and the average age of the participants was 21.5±0.2 years. The CCL wearers generally showed a moderate (47%) or good (35%) level of knowledge, and good (51%) or excellent (40%) use of CCL. Two CCL samples were positive for Acanthamoeba genotype T3 or Vahlkampfia. The Acanthamoeba-contaminated CCL was from a wearer who used saline for treating lenses, and the Vahlkampfia-contaminated CCL was from a wearer who used CCL while swimming.

Conclusions:

This is the first report of the presence of potentially pathogenic FLA in used CCL from asymptomatic wearers in Thailand. Although there was satisfactory knowledge and practice of lens care use, the public should be aware of CCL contaminated with potentially pathogenic FLA that can directly or indirectly cause keratitis.
Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms
Authors: Kalangara Jerry P. , Galor Anat , Levitt Roy C. , Covington Derek B. , McManus Katherine T. , Sarantopoulos Constantine D. , Felix Elizabeth R.
Published: March 2016

Objective:

The purpose of this study was to examine the severity and quality of ocular pain complaints in patients with dry eye symptoms.

Methods:

Subjects with clinically relevant dry eye symptoms (dryness, discomfort, tearing) of unknown origin seen in the Miami Veterans Affairs eye clinic were administered questionnaires for dry eye symptoms and ocular pain and underwent a standardized ocular examination. Qualities and severity ratings of ocular pain in subjects with idiopathic dry eye were compared with similar measures from published data in other chronic pain populations.

Results:

The study sample consisted of 154 subjects, of which 91% were men and ranged in age from 27 to 89 (mean age=61). Fifty-three percent of participants reported an average ocular pain of at least moderate intensity (numerical rating scale≥4), with specific characteristics (i.e., “burning” spontaneous pain) reported at frequencies comparable to prevalent chronic neuropathic pain syndromes as reported in the literature. Significant correlations were found between ocular pain metrics and dry eye symptom severity scores (r=0.57–0.66). Dry eye signs, however, did not generally correlate with ocular pain severity.

Conclusions:

A significant proportion of subjects with idiopathic dry eye symptoms reported moderate or greater ocular pain intensity, with most endorsing descriptors commonly used by patients with nonocular neuropathic pain conditions. Identifying subgroups of dry eye patients based on the presence and characteristics of ocular pain complaints may improve dry eye subclassification and better individualize treatment strategies.
Efficacy of Epithelium-Off and Epithelium-On Corneal Collagen Cross-Linking in Pediatric Keratoconus
Authors: Eraslan Muhsin , Toker Ebru , Cerman Eren , Ozarslan Deniz
Published: March 2016

Objectives:

To evaluate the efficacy of riboflavin/ultraviolet A epithelium-off (epi-off) and epithelium-on (epi-on) corneal collagen cross-linking (CXL) in progressive pediatric keratoconus.

Methods:

Thirty-six eyes of 27 patients aged 18 years or younger (12–18 years) diagnosed with progressive keratoconus and treated with epi-off (n=18 eyes) or epi-on (n=18 eyes) CXL were included in this study. All patients were followed up for 24 months postoperatively.

Results:

At 24-month follow-up, the mean corrected distance visual acuity (CDVA) improved from 0.24±0.17 to 0.17±0.11 logMAR in the epi-off group (P=0.032). In the epi-on group, CDVA improved from 0.33±0.23 to 0.26±0.20 logMAR (P=0.012), but the improvement was not significantly different between groups (P>0.05). In the epi-off group, all mean K values improved: K1 (Δ=−0.63 D, P=0.024), K2 (Δ=−0.73 D, P=0.008), and Kmax (Δ=−1.4 D, P=0.035), whereas in the epi-on group, Kmax and K2 did not change significantly and K1 (Δ=0.68 D, P=0.029) significantly worsened. Postoperative mild corneal haze occurred in 5 eyes (28%) in the epi-off group. No postoperative complications were observed in the epi-on group. In 94.4% of the epi-off group, keratoconus regressed (44.4%) or stabilized (50.0%), whereas in the epi-on group, only 66.6% regressed (33.3%) or stabilized (33.3%), and the difference was significant (P=0.038).

Conclusions:

The efficacy of the epi-on procedure in terms of its ability to halt keratoconus progression appears to be 0.70 of the efficacy of epi-off CXL.
Correlates of the timed 25 foot walk in a multiple sclerosis outpatient rehabilitation clinic
Authors: Bethoux Francois A. , Palfy Dylan M. , Plow Matthew A.
Published: March 2016

The Timed 25 Foot Walk (T25FW), a test of maximum walking speed on a short distance, is commonly used to monitor ambulation status and to assess treatment outcomes in multiple sclerosis (MS). The main aim of this study was to determine how walking speed on the T25FW correlates with other clinician-reported and patient-reported measures in an outpatient MS rehabilitation clinic. We analyzed cross-sectional data systematically collected during a physiatry evaluation for the management of spasticity and walking limitations. In addition to demographic variables and the Expanded Disability Status Scale (EDSS), measures of body functions [lower extremity manual muscle testing (LE MMT), lower extremity Modified Ashworth Scale, Fatigue Severity Scale, leg pain], and measures of activity and quality of life (reported frequency of falls, Incapacity Status Scale, Rivermead Mobility Index, EQ5D health questionnaire, and Patient Health Questionnaire-9 items) were administered. A multivariate regression analysis was carried out. 199 patients were included in the analysis [age 49.41 (9.89) years, disease duration 15.40 (10.22) years, EDSS score 5.6 (1.2), and T25FW speed 70.93 (44.13) cm/s]. Both EDSS and LE MMT were correlated significantly with T25FW speed (R
2=0.692, P<0.001). After adjusting for EDSS and LE MMT, lower T25FW speed was associated with higher Incapacity Status Scale scores (R
2=0.316, P<0.001), lower Rivermead Mobility Index scores (R
2=0.540, P<0.001), and higher frequency of falls. EQ5D and Patient Health Questionnaire-9 items were not significantly associated with T25FW speed. Our findings support the clinical relevance of the T25FW in the rehabilitation of patients with MS.
Animal and human innovation: novel problems and novel solutions
Authors: Reader Simon M. , Morand-Ferron Julie , Flynn Emma
Published: March 2016

This theme issue explores how and why behavioural innovation occurs, and the consequences of innovation for individuals, groups and populations. A vast literature on human innovation exists, from the development of problem-solving in children, to the evolution of technology, to the cultural systems supporting innovation. A more recent development is a growing literature on animal innovation, which has demonstrated links between innovation and personality traits, cognitive traits, neural measures, changing conditions, and the current state of the social and physical environment. Here, we introduce these fields, define key terms and discuss the potential for fruitful exchange between the diverse fields researching innovation. Comparisons of innovation between human and non-human animals provide opportunities, but also pitfalls. We also summarize some key findings specifying the circumstances in which innovation occurs, discussing factors such as the intrinsic nature of innovative individuals and the environmental and socio-ecological conditions that promote innovation, such as necessity, opportunity and free resources. We also highlight key controversies, including the relationship between innovation and intelligence, and the notion of innovativeness as an individual-level trait. Finally, we discuss current research methods and suggest some novel approaches that could fruitfully be deployed.
The coevolution of innovation and technical intelligence in primates
Authors: Navarrete Ana F. , Reader Simon M. , Street Sally E. , Whalen Andrew , Laland Kevin N.
Published: March 2016

In birds and primates, the frequency of behavioural innovation has been shown to covary with absolute and relative brain size, leading to the suggestion that large brains allow animals to innovate, and/or that selection for innovativeness, together with social learning, may have driven brain enlargement. We examined the relationship between primate brain size and both technical (i.e. tool using) and non-technical innovation, deploying a combination of phylogenetically informed regression and exploratory causal graph analyses. Regression analyses revealed that absolute and relative brain size correlated positively with technical innovation, and exhibited consistently weaker, but still positive, relationships with non-technical innovation. These findings mirror similar results in birds. Our exploratory causal graph analyses suggested that technical innovation shares strong direct relationships with brain size, body size, social learning rate and social group size, whereas non-technical innovation did not exhibit a direct relationship with brain size. Nonetheless, non-technical innovation was linked to brain size indirectly via diet and life-history variables. Our findings support ‘technical intelligence’ hypotheses in linking technical innovation to encephalization in the restricted set of primate lineages where technical innovation has been reported. Our findings also provide support for a broad co-evolving complex of brain, behaviour, life-history, social and dietary variables, providing secondary support for social and ecological intelligence hypotheses. The ability to gain access to difficult-to-extract, but potentially nutrient-rich, resources through tool use may have conferred on some primates adaptive advantages, leading to selection for brain circuitry that underlies technical proficiency.
Innovation cascades: artefacts, organization and attributions
Authors: Lane David A.
Published: March 2016

Innovation cascades inextricably link the introduction of new artefacts, transformations in social organization, and the emergence of new functionalities and new needs. This paper describes a positive feedback dynamic, exaptive bootstrapping, through which these cascades proceed, and the characteristics of the relationships in which the new attributions that drive this dynamic are generated. It concludes by arguing that the exaptive bootstrapping dynamic is the principal driver of our current Innovation Society.
From mechanisms to function: an integrated framework of animal innovation
Authors: Tebbich Sabine , Griffin Andrea S. , Peschl Markus F. , Sterelny Kim
Published: March 2016

Animal innovations range from the discovery of novel food types to the invention of completely novel behaviours. Innovations can give access to new opportunities, and thus enable innovating agents to invade and create novel niches. This in turn can pave the way for morphological adaptation and adaptive radiation. The mechanisms that make innovations possible are probably as diverse as the innovations themselves. So too are their evolutionary consequences. Perhaps because of this diversity, we lack a unifying framework that links mechanism to function. We propose a framework for animal innovation that describes the interactions between mechanism, fitness benefit and evolutionary significance, and which suggests an expanded range of experimental approaches. In doing so, we split innovation into factors (components and phases) that can be manipulated systematically, and which can be investigated both experimentally and with correlational studies. We apply this framework to a selection of cases, showing how it helps us ask more precise questions and design more revealing experiments.
Multiple genetic changes underlie the evolution of long-tailed forest deer mice
Authors: Kingsley Evan P. , Kozak Krzysztof M. , Pfeifer Susanne P. , Yang Dou-Shuan , Hoekstra Hopi E.
Published: March 2016

Understanding both the role of selection in driving phenotypic change and its underlying genetic basis remain major challenges in evolutionary biology. Here we focus on a classic system of local adaptation in the North American deer mouse,Peromyscus maniculatus, which occupies two main habitat types, prairie and forest. Using historical collections we demonstrate that forest-dwelling mice have longer tails than those from non-forested habitats, even when we account for individual and population relatedness. Based on genome-wide SNP capture data, we find that mice from forested habitats in the eastern and western parts of their range form separate clades, suggesting that increased tail length evolved independently from a short-tailed ancestor. Two major changes in skeletal morphology can give rise to longer tails—increased number and increased length of vertebrae—and we find that forest mice in the east and west have both more and longer caudal vertebrae, but not trunk vertebrae, than nearby prairie forms. Using a second-generation intercross between a prairie and forest pair, we show that the number and length of caudal vertebrae are not correlated in this recombinant population, suggesting that variation in these traits is controlled by separate genetic loci. Together, these results demonstrate convergent evolution of the long-tailed forest phenotype through multiple, distinct genetic mechanisms (controlling vertebral length and vertebral number), thus suggesting that these morphological changes—either independently or together—are adaptive.
A Bayesian approach for analysis of whole-genome bisulphite sequencing data identifies disease-associated changes in DNA methylation
Authors: Rackham Owen J.L. , Langley Sarah R. , Oates Thomas , Vradi Eleni , Harmston Nathan , Srivastava Prashant K. , Behmoaras Jacques , Dellaportas Petros , Bottolo Leonardo , Petretto Enrico
Published: March 2016

DNA methylation is a key epigenetic modification involved in gene regulation whose contribution to disease susceptibility remains to be fully understood. Here, we present a novel Bayesian smoothing approach (called ABBA) to detect differentially methylated regions (DMRs) from whole-genome bisulphite sequencing (WGBS). We also show how this approach can be leveraged to identify disease-associated changes in DNA methylation, suggesting mechanisms through which these alterations might affect disease. From a data modeling perspective, ABBA has the distinctive feature of automatically adapting to different correlation structures in CpG methylation levels across the genome whilst taking into account the distance between CpG sites as a covariate. Our simulation study shows that ABBA has greater power to detect DMRs than existing methods, providing an accurate identification of DMRs in the large majority of simulated cases. To empirically demonstrate the method’s efficacy in generating biological hypotheses, we performed WGBS of primary macrophages derived from an experimental rat system of glomerulonephritis and used ABBA to identify >1,000 disease-associated DMRs. Investigation of these DMRs revealed differential DNA methylation localized to a 600bp region in the promoter of theIfitm3gene. This was confirmed by ChIP-seq and RNA-seq analyses, showing differential transcription factor binding at theIfitm3promoter by JunD (an established determinant of glomerulonephritis) and a consistent change inIfitm3expression. Our ABBA analysis allowed us to propose a new role forIfitm3in the pathogenesis of glomerulonephritis via a mechanism involving promoter hypermethylation that is associated withIfitm3repression in the rat strain susceptible to glomerulonephritis.
Personalized Risk Prediction for Type 2 Diabetes: the Potential of Genetic Risk Scores
Authors: Läll Kristi , Mägi Reedik , Morris Andrew , Metspalu Andres , Fischer Krista
Published: March 2016

Purpose

The study aims to develop a Genetic Risk Score (GRS) for the prediction of Type 2 Diabetes (T2D) that could be used for risk assessment in general population.

Methods

Using the results of genome-wide association studies, we develop adoubly-weightedGRS for the prediction of T2D risk, aiming to capture the effect of 1000 single nucleotide polymorphisms. The GRS is evaluated in the Estonian Biobank cohort (n=10273), analysing its effect on prevalent and incident T2D, while adjusting for other predictors. We assessed the effect of GRS on all-cause and cardiovascular mortality and its association with other T2D risk factors, and conducted the reclassification analysis.

Results

The adjusted hazard for incident T2D is 1.90 (95% CI 1.48, 2.44) times higher and for cardiovascular mortality 1.27 (95% CI 1.10, 1.46) times higher in the highest GRS quintile compared to the rest of the cohort. No significant association between BMI and GRS is found in T2D-free individuals. Adding GRS to the prediction model for 5-year T2D risks results in continuous Net Reclassification Improvement of 0.26 (95% CI 0.15, 0.38).

Conclusion

The proposed GRS would considerably improve the accuracy of T2D risk prediction when added to the set of predictors used so far.