bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of group III/IV muscle afferents on small muscle mass exercise performance: a bioenergetics perspective
Authors: Broxterman Ryan M. , Hureau Thomas J. , Layec Gwenael , Morgan David E. , Bledsoe Amber D. , Jessop Jacob E. , Amann Markus , Richardson Russell S.
Published: April 2018

Key points

This investigation assessed the influence of group III/IV muscle afferents on small muscle mass exercise performance from a skeletal muscle bioenergetics perspective.

Group III/IV muscle afferent feedback was attenuated with lumbar intrathecal fentanyl during intermittent isometric single‐leg knee‐extensor all‐out exercise, while 31P‐MRS was used to assess skeletal muscle bioenergetics.

Attenuation of group III/IV muscle afferent feedback improved exercise performance during the first minute of exercise, due to an increase in total ATP production with no change in the ATP cost of contraction. However, exercise performance was not altered during the remainder of the protocol, despite a sustained increase in total ATP production, due to an exacerbated ATP cost of contraction.

These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit of attenuating the muscle afferents is negated.

The direct influence of group III/IV muscle afferents on exercise performance remains equivocal. Therefore, all‐out intermittent isometric single‐leg knee‐extensor exercise and phosphorous magnetic resonance spectroscopy (31P‐MRS) were utilized to provide a high time resolution assessment of exercise performance and skeletal muscle bioenergetics in control conditions (CTRL) and with the attenuation of group III/IV muscle afferent feedback via lumbar intrathecal fentanyl (FENT). In both conditions, seven recreationally active men performed 60 maximal voluntary quadriceps contractions (MVC; 3 s contraction, 2 s relaxation), while knee‐extensor force and 31P‐MRS were assessed during each MVC. The cumulative integrated force was significantly greater (8 ± 6%) in FENT than CTRL for the first minute of the all‐out protocol, but was not significantly different for the second to fifth minutes. Total ATP production was significantly greater (16 ± 21%) in FENT than CTRL throughout the all‐out exercise protocol, due to a significantly greater anaerobic ATP production (11 ± 13%) in FENT than CTRL with no significant difference in oxidative ATP production. The ATP cost of contraction was not significantly different between FENT and CTRL for the first minute of the all‐out protocol, but was significantly greater (29 ± 34%) in FENT than in CTRL for the second to fifth minutes. These findings reveal that group III/IV muscle afferents directly limit exercise performance during small muscle mass exercise, but, due to their critical role in maintaining skeletal muscle contractile efficiency, with time, the benefit from muscle afferent attenuation is negated.
Critical Pedagogy and APA: A Resonant (and Timely) Interdisciplinary Blend
Authors: Connolly Maureen , Harvey William J.
Published: April 2018

Critical pedagogy owes much of its emergence, development, and ongoing relevance to the work of Paulo Freire whose legacy remains relevant for a next generation of scholars who seek to explore issues of inclusion, oppression, social justice, and authentic expression. An interdisciplinary dialogue between critical pedagogy and adapted physical activity is timely, appropriate, and should focus on complex profiles of neurodiversity, mental illness, and mental health, with emphasis on pedagogic practices of practitioners in service delivery and teacher educators who prepare them for professional practice. A case-based scenario approach is used to present practitioner and teacher educator practices. Concrete examples are provided for analyzing and understanding deeper issues and challenges related to neurodiversity in a variety of embodied dimensions in educational and activity contexts. We work with Szostak’s approach to interdisciplinary research and model an analysis strategy that integrates and applies the methodological features of interdisciplinarity, adapted physical activity, and critical pedagogy.
Microbial oxidation of lithospheric organic carbon in rapidly eroding tropical mountain soils
Authors: Hemingway Jordon D. , Hilton Robert G. , Hovius Niels , Eglinton Timothy I. , Haghipour Negar , Wacker Lukas , Chen Meng-Chiang , Galy Valier V.
Published: April 2018

Microbes eat rocks and leave carbon dioxide

The reaction of atmospheric carbon dioxide (CO
2
) with silicate rocks provides a carbon sink that helps counterbalance the release of CO
2
by volcanic degassing. However, some types of rocks contain petrogenic organic carbon, the oxidation of which adds CO
2
to the atmosphere, counteracting the drawdown by silicates. Hemingway
et al.
present evidence from the rapidly eroding Central Range of Taiwan showing that microbes oxidize roughly two-thirds of the petrogenic organic carbon there and that the rate of oxidation increases with the rate of erosion.

Science
, this issue p.
209
Bottom-up synthesis of multifunctional nanoporous graphene
Authors: Moreno César , Vilas-Varela Manuel , Kretz Bernhard , Garcia-Lekue Aran , Costache Marius V. , Paradinas Markos , Panighel Mirko , Ceballos Gustavo , Valenzuela Sergio O. , Peña Diego , Mugarza Aitor
Published: April 2018

Synthesizing graphene nanopores

Nanosize pores in graphene can make its electronic properties more favorable for transistor applications and may also be useful for molecular separations. Moreno
et al
. used Ullmann coupling to polymerize a dibromo-substituted diphenylbianthracene on a gold surface (see the Perspective by Sinitskii). Cyclodehydrogenation of the resulting polymer produced graphene nanoribbons, and cross-coupling of these structures created a nanoporous graphene sheet with pore sizes of about 1 nanometer. Scanning tunneling spectroscopy revealed an electronic structure in which semiconductor bands with an energy gap of 1 electron volt coexist with localized states created by the pores.

Science
, this issue p.
199
; see also p.
154
Tropism for tuft cells determines immune promotion of norovirus pathogenesis
Authors: Wilen Craig B. , Lee Sanghyun , Hsieh Leon L. , Orchard Robert C. , Desai Chandni , Hykes Barry L. , McAllaster Michael R. , Balce Dale R. , Feehley Taylor , Brestoff Jonathan R. , Hickey Christina A. , Yokoyama Christine C. , Wang Ya-Ting , MacDuff Donna A. , Kreamalmayer Darren , Howitt Michael R. , Neil Jessica A. , Cadwell Ken , Allen Paul M. , Handley Scott A. , van Lookeren Campagne Menno , Baldridge Megan T. , Virgin Herbert W.
Published: April 2018

Aiding and abetting norovirus disease

Norovirus is highly infectious and usually causes transient, acute disease. In some individuals, norovirus persists and is associated with inflammatory bowel disorders. While investigating the cell tropism for murine norovirus, Wilen
et al.
discovered that a rare cell type, tuft cells, carrying the CD300lf receptor were the virus's specific target. Tuft cells proliferate in response to the type 2 cytokines interleukin-4 and interleukin-25, which thereby amplify norovirus infection. Moreover, infected tuft cells are resistant to immune clearance. This effect may explain the associated persistent disease symptoms that humans can suffer.

Science
, this issue p.
204
Elastic strain engineering for ultralow mechanical dissipation
Authors: Ghadimi A. H. , Fedorov S. A. , Engelsen N. J. , Bereyhi M. J. , Schilling R. , Wilson D. J. , Kippenberg T. J.
Published: April 2018

Better performance under stress

Engineering stress or strain into materials can improve their performance. Adding mechanical stress to silicon chips, for instance, produces transistors with enhanced electron mobility. Ghadimi
et al.
explore the possibility of enhancing the vibrational properties of a micromechanical oscillator by engineering stress within the structure (see the Perspective by Eichler). By careful design of the micromechanical oscillator, and by building in associated stresses, exceptional vibrational properties can be produced. Such enhanced oscillators could be used as exquisite force sensors.

Science
, this issue p.
764
; see also p.
706
Stephen Hawking (1942–2018)
Authors: Preskill John
Published: April 2018

The world's best-known scientist richly deserved his fame
Obfuscating with transparency
Authors: Berg Jeremy
Published: April 2018

Transparency is critical when it comes to decision-making that broadly affects the public, particularly when it comes to policies purported to be grounded in scientific evidence. The scientific community has been increasingly focused on improving the transparency of research through initiatives that represent good-faith efforts to enhance the robustness of scientific findings and to increase access to and utility of data that underlie research. Yet, concerns about transparency associated with scientific results continue to emerge in political discussions. Most recently in the United States, a new proposal by the Environmental Protection Agency (EPA) would eliminate the use of publications in its policy discussions for which all underlying data are not publicly available. Here, a push for transparency appears actually to be a mechanism for suppressing important scientific evidence in policy-making, thereby threatening the public's well-being.
Suppression by human FOXP3
+
regulatory T cells requires FOXP3-TIP60 interactions
Authors: Bin Dhuban Khalid , d’Hennezel Eva , Nagai Yasuhiro , Xiao Yan , Shao Steven , Istomine Roman , Alvarez Fernando , Ben-Shoshan Moshe , Ochs Hans , Mazer Bruce , Li Bin , Sekine Chiyoko , Berezov Alan , Hancock Wayne , Torgerson Troy R. , Greene Mark I. , Piccirillo Ciriaco A.
Published: April 2018

Targeting the FOXP3-TIP60 interaction may modulate T
reg
activity in IPEX and other autoimmune and inflammatory diseases.
Citrullination of NF-κB p65 promotes its nuclear localization and TLR-induced expression of IL-1β and TNFα
Authors: Sun Bo , Dwivedi Nishant , Bechtel Tyler J. , Paulsen Janet L. , Muth Aaron , Bawadekar Mandar , Li Gang , Thompson Paul R. , Shelef Miriam A. , Schiffer Celia A. , Weerapana Eranthie , Ho I-Cheng
Published: April 2018

Heightened citrullination promotes the expression of inflammatory cytokines in rheumatoid arthritis.
Resident memory CD8
+
T cells in the upper respiratory tract prevent pulmonary influenza virus infection
Authors: Pizzolla Angela , Nguyen Thi H. O. , Smith Jeffrey M. , Brooks Andrew G. , Kedzierska Katherine , Heath William R. , Reading Patrick C. , Wakim Linda M.
Published: April 2018

Nasal tissue–resident memory T cells block influenza virus transmission to the lung, preventing severe pulmonary disease.
Plasmodium
products persist in the bone marrow and promote chronic bone loss
Authors: Lee Michelle S. J. , Maruyama Kenta , Fujita Yukiko , Konishi Aki , Lelliott Patrick M. , Itagaki Sawako , Horii Toshihiro , Lin Jing-wen , Khan Shahid M. , Kuroda Etsushi , Akira Shizuo , Ishii Ken J. , Coban Cevayir
Published: April 2018

Plasmodium
infection causes chronic inflammation and bone loss through
Plasmodium
product accumulation in the bone marrow.
Memory-phenotype CD4
+
T cells spontaneously generated under steady-state conditions exert innate T
H
1-like effector function
Authors: Kawabe Takeshi , Jankovic Dragana , Kawabe Shuko , Huang Yuefeng , Lee Ping-Hsien , Yamane Hidehiro , Zhu Jinfang , Sher Alan , Germain Ronald N. , Paul William E.
Published: April 2018

Memory-phenotype CD4
+
T cells provide early, foreign antigen–independent innate resistance to T
H
1-inducing pathogens.
Amikacin Inhalation as Salvage Therapy for Refractory Nontuberculous Mycobacterial Lung Disease
Authors: Jhun Byung Woo , Yang Bumhee , Moon Seong Mi , Lee Hyun , Park Hye Yun , Jeon Kyeongman , Kwon O Jung , Ahn Jungmin , Moon Il Joon , Shin Sung Jae , Daley Charles L. , Koh Won-Jung
Published: April 2018

Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by
Mycobacterium abscessus
complex (MABC) or
M. avium
complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology (
n
= 48, 62%), followed by MAC (
n
= 20, 26%) and mixed infections (
n
= 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) (
P
= 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy (
P
< 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections (
P
= 0.009), a forced expiratory volume in 1 s of greater than 60% (
P
= 0.008), and the absence of macrolide resistance (
P
= 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity (
n
= 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.
Triclosan Is an Aminoglycoside Adjuvant for Eradication of Pseudomonas aeruginosa Biofilms
Authors: Maiden Michael M. , Hunt Alessandra M. Agostinho , Zachos Mitchell P. , Gibson Jacob A. , Hurwitz Martin E. , Mulks Martha H. , Waters Christopher M.
Published: April 2018

One of the most important clinical obstacles in cystic fibrosis (CF) treatment is antibiotic treatment failure due to biofilms produced by
Pseudomonas aeruginosa
. The ability of this pathogen to survive eradication by tobramycin and pathoadapt into a hyperbiofilm state leading to chronic infections is key to its success. Retrospective studies have demonstrated that preventing this pathoadaptation by improving eradication is essential to extend the lives of CF patients. To identify adjuvants that enhance tobramycin eradication of
P. aeruginosa
, we performed a high-throughput screen of 6,080 compounds from four drug-repurposing libraries. We identified that the Food and Drug Administration (FDA)-approved compound triclosan, in combination with tobramycin, resulted in a 100-fold reduction of viable cells within biofilms at 6 h, but neither compound alone had significant antimicrobial activity against biofilms. This synergistic treatment significantly accelerated the killing of biofilms compared to that with tobramycin treatment alone, and the combination was effective against 6/7 CF clinical isolates compared to tobramycin treatment alone, including a tobramycin-resistant strain. Further, triclosan and tobramycin killed persister cells, causing a 100-fold reduction by 8 h and complete eradication by 24 h. Triclosan also enhances tobramycin killing of multiple
Burkholderia cenocepacia
and
Staphylococcus aureus
clinical isolates grown as biofilms. Additionally, triclosan showed synergy with other aminoglycosides, such as gentamicin or streptomycin. Triclosan is a well-tolerated aminoglycoside adjuvant shown to be safe for human use that could improve the treatment of biofilm-based infections.
The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension
Authors: Suh Hyeon Jeong , Yoon Seo Hyun , Yu Kyung-Sang , Cho Joo-Youn , Park Sang-In , Lee Eunyoung , Lee Jeong-Ok , Koh Youngil , Song Kyoung-Ho , Choe Pyoeng Gyun , Kim Eu Suk , Bang Soo-Mee , Kim Hong Bin , Kim Inho , Kim Nam Joong , Song Sang Hoon , Park Wan Beom , Oh Myoung-don
Published: April 2018

The metabolism of posaconazole is mediated mainly by uridine 5′-diphospho-glucuronosyltransferase (UGT) enzymes, especially UGT1A4. The aim of this study was to investigate the effects of genetic polymorphisms on the posaconazole plasma concentration (PPC). This prospective study was conducted from September 2014 to August 2016. We enrolled patients with acute myeloid leukemia or myelodysplastic syndrome treated with posaconazole oral suspension (200 mg) three times daily for fungal prophylaxis. The patients were examined for the multidrug resistance gene 1 3435C>T and 2677G>T/A variations and the UGT1A4*3 allele by direct sequencing of DNA from peripheral whole-blood samples. We defined poor absorbers to be those with PPCs of <200 ng/ml and the optimal PPC to be ≥700 ng/ml on day 8. The associations between genetic polymorphisms and the PPC were evaluated using multivariate logistic regression analysis including clinical variables. During the study period, 132 patients were enrolled. Six patients (4.5%) were defined as poor absorbers, and 49 patients (37.1%) did not reach the optimal PPC on day 8. In multivariate analysis, the independent risk factors for a poor absorber were at least one UGT1A4*3 allele (adjusted odds ratio [aOR], 18.81; 95% confidence interval [CI], 1.09 to 324.44;
P
= 0.043) and poor oral food intake (aOR per −100 kcal, 1.44; 95% CI, 1.04 to 1.99;
P
= 0.029). There was no statistically significant association between the genetic polymorphisms and achievement of the optimal PPC on day 8. The UGT1A4*3 polymorphism is an independent risk factor for being a poor absorber of posaconazole oral suspension in patients with hematological malignancies.
Spread of Clonally Related Escherichia coli Strains Harboring an IncA/C
1
Plasmid Encoding IMP-8 and Its Recruitment into an Unrelated MCR-1-Containing Isolate
Authors: Elena Alan , Cejas Daniela , Magariños Francisco , Jewtuchowicz Virginia , Facente Andrea , Gutkind Gabriel , Di Conza José , Radice Marcela
Published: April 2018

Ten IMP-8-producing
Escherichia coli
isolates were recovered from surveillance cultures of a neonatal intensive care unit; eight of the isolates were clonally related. A 168.2-kb
bla
IMP-8
plasmid was fully sequenced, and it corresponded to the recently described IncA/C1-ST13 plasmid. This plasmid was detected in all isolates, even in those that were not clonally related. One unrelated isolate was also resistant to colistin and positive for
mcr-1
. This marker was located in a 62.7-kb IncI2 plasmid, which was also fully sequenced.
Identification and Evaluation of Novel Protective Antigens for the Development of a Candidate Tuberculosis Subunit Vaccine
Authors: Stylianou Elena , Harrington-Kandt Rachel , Beglov Julia , Bull Naomi , Pinpathomrat Nawamin , Swarbrick Gwendolyn M. , Lewinsohn Deborah A. , Lewinsohn David M. , McShane Helen
Published: April 2018

The development of a vaccine against tuberculosis (TB), a disease caused by
Mycobacterium tuberculosis
, is urgently needed. The only currently available vaccine,
M. bovis
BCG, has variable efficacy. One approach in the global vaccine development effort is focused on boosting BCG using subunit vaccines. The identification of novel antigens for inclusion in subunit vaccines is a critical step in the TB vaccine development pathway. We selected four novel mycobacterial antigens recognized during the course of human infection. A replication-deficient chimpanzee adenovirus (ChAdOx1) was constructed to express each antigen individually, and these vectors were evaluated for protective efficacy in murine
M. tuberculosis
challenge experiments. One antigen, PPE15 (Rv1039c), conferred significant and reproducible protection when administered alone and as a boost to BCG vaccination. We identified immunodominant epitopes to define the protective immune responses using tetramers and intravascular staining. Lung parenchymal CD4
+
and CD8
+
CXCR3
+
KLRG1
−
T cells, previously associated with protection against
M. tuberculosis
, were enriched in the vaccinated groups compared to the control groups. Further work to evaluate the protective efficacy of PPE15 in more stringent preclinical animal models, together with the identification of further novel protective antigens using this selection strategy, is now merited.
Substrate Specificities and Efflux Efficiencies of RND Efflux Pumps of Acinetobacter baumannii
Authors: Leus Inga V. , Weeks Jon W. , Bonifay Vincent , Smith Lauren , Richardson Sophie , Zgurskaya Helen I.
Published: April 2018

Antibiotic-resistant
Acinetobacter baumannii
causes infections that are extremely difficult to treat. A significant role in these resistance profiles is attributed to multidrug efflux pumps, especially those belonging to the resistance-nodulation-cell division (RND) superfamily of transporters. In this study, we analyzed functions and properties of RND efflux pumps in
A. baumannii
ATCC 17978. This strain is susceptible to antibiotics and does not contain mutations that are commonly selected upon exposure to high concentrations of antibiotics. We constructed derivatives of ATCC 17978 lacking chromosomally encoded RND pumps and complemented these strains by the plasmid-borne genes. We analyzed the substrate selectivities and efficiencies of the individual pumps in the context of native outer membranes and their hyperporinated variants. Our results show that inactivation of AdeIJK provides the strongest potentiation of antibiotic activities, whereas inactivation of AdeFGH triggers the overexpression of AdeAB. The plasmid-borne overproduction complements the hypersusceptible phenotypes of the efflux deletion mutants to the levels of the parental ATCC 17978. Only a few antibiotics strongly benefitted from the overproduction of efflux pumps and antibacterial activities of some of those depended on the synergistic interaction with the low permeability barrier of the outer membrane. Either overproduction or inactivation of efflux pumps change dramatically the lipidome of ATCC 17978. We conclude that efflux pumps of
A. baumannii
are tightly integrated into physiology of this bacterium and that clinical levels of antibiotic resistance in
A. baumannii
isolates are unlikely to be reached solely due to the overproduction of RND efflux pumps.

IMPORTANCE
RND-type efflux pumps are important contributors in development of clinical antibiotic resistance in
A. baumannii
. However, their specific roles and the extent of contribution to antibiotic resistance remain unclear. We analyzed antibacterial activities of antibiotics in strains with different permeability barriers and found that the role of active efflux in antibiotic resistance of
A. baumannii
is limited to a few select antibiotics. Our results further show that the impact of efflux pump overproduction on antibiotic susceptibility is significantly lower than the previously reported for clinical isolates. Additional mechanisms of resistance, in particular those that improve the permeability barriers of bacterial cells and act synergistically with active efflux pumps are likely involved in antibiotic resistance of clinical
A. baumannii
isolates.
Annotated Primary Literature: A Professional Development Opportunity in Science Communication for Graduate Students and Postdocs
Authors: McCartney Melissa , Childers Chazman , Baiduc Rachael R. , Barnicle Kitch
Published: April 2018

Formal training in communicating science to a general audience is not traditionally included in graduate and postdoctoral-level training programs. However, the ability to effectively communicate science is increasingly recognized as a responsibility of professional scientists. We describe a science communication professional development opportunity in which scientists at the graduate-level and above annotate primary scientific literature, effectively translating complex research into an accessible educational tool for undergraduate students. We examined different types of annotator training, each with its own populations and evaluation methods, and surveyed participants about why they participated, the confidence they have in their self-reported science communication skills, and how they plan to leverage this experience to advance their science careers. Additionally, to confirm that annotators were successful in their goal of making the original research article easier to read, we performed a readability analysis on written annotations and compared that with the original text of the published paper. We found that both types of annotator training led to a gain in participants’ self-reported confidence in their science communication skills. Also, the annotations were significantly more readable than the original paper, indicating that the training was effective. The results of this work highlight the potential of annotator training to serve as a value-added component of scientific training at and above the graduate level.
The Pathway To Establishing HIV Latency Is Critical to How Latency Is Maintained and Reversed
Authors: Rezaei Simin D. , Lu Hao K. , Chang J. Judy , Rhodes Ajantha , Lewin Sharon R. , Cameron Paul U.
Published: April 2018

HIV infection requires lifelong antiretroviral therapy because of the persistence of latently infected CD4
+
T cells. The induction of virus expression from latently infected cells occurs following T cell receptor (TCR) activation, but not all latently infected cells respond to TCR stimulation. We compared two models of latently infected cells using an enhanced green fluorescent protein (EGFP) reporter virus to infect CCL19-treated resting CD4
+
(rCD4
+
) T cells (preactivation latency) or activated CD4
+
T cells that returned to a resting state (postactivation latency). We isolated latently infected cells by sorting for EGFP-negative (EGFP
−
) cells after infection. These cells were cultured with antivirals and stimulated with anti-CD3/anti-CD28, mitogens, and latency-reversing agents (LRAs) and cocultured with monocytes and anti-CD3. Spontaneous EGFP expression was more frequent in postactivation than in preactivation latency. Stimulation of latently infected cells with monocytes/anti-CD3 resulted in an increase in EGFP expression compared to that for unstimulated controls using the preactivation latency model but led to a reduction in EGFP expression in the postactivation latency model. The reduced EGFP expression was not associated with reductions in the levels of viral DNA or T cell proliferation but depended on direct contact between monocytes and T cells. Monocytes added to the postactivation latency model during the establishment of latency reduced spontaneous virus expression, suggesting that monocyte-T cell interactions at an early time point postinfection can maintain HIV latency. This direct comparison of pre- and postactivation latency suggests that effective strategies needed to reverse latency will depend on how latency is established.

IMPORTANCE
One strategy being evaluated to eliminate latently infected cells that persist in HIV-infected individuals on antiretroviral therapy (ART) is to activate HIV expression or production with the goal of inducing virus-mediated cytolysis or immune-mediated clearance of infected cells. The gold standard for the activation of latent virus is T cell receptor stimulation with anti-CD3/anti-CD28. However, this stimulus activates only a small proportion of latently infected cells. We show clear differences in the responses of latently infected cells to activating stimuli based on how latent infection is established, an observation that may potentially explain the persistence of noninduced intact proviruses in HIV-infected individuals on ART.
Arc magmatism, tectonism, and tempos in Mesozoic arc crustal sections of the Peninsular and Transverse Ranges, southern California, USA
Authors: Paterson Scott , Clausen Ben , Memeti Vali , Schwartz Joshua J.
Published: April 2018

Welcome to our three-day field trip aimed at exploring Mesozoic magmatism and tectonism in southern California. The broader southern California area is a great place to study Cordilleran-style continental margin arcs built across diverse basements ranging from thinner oceanic to thicker continental crust. We will weave together several themes during this trip: (1) spatial variations, including in the vertical dimension, of arc magmatic and tectonic systems; (2) volcanic-plutonic links; (3) pluton sizes and shapes; (4) emplacement and tectonic/plutonic mass balance issues; and (5) arc magmatic and tectonic tempos. While doing so we plan to discuss/ examine the main components of southern California Mesozoic magmatic systems while discussing temporally and spatially variable (1) melt sources, (2) processes in crustal columns, and (3) tectonic activity, all of which lead to the final preserved arcs.

Bedrock and detrital zircon age patterns in a broad corridor across southern California define magmatic flare-up maxima in the Mojave area at ca. 250 Ma in a SE migrating arc, at ca. 170 Ma in a westward migrating arc, at ca. 100 Ma in the eastward migrating Peninsular Ranges Batholith (PRB), extending from just south of the Transverse Ranges and into Baja California, and additional smaller maxima at 81 and 73 Ma in the Transverse Ranges and Joshua Tree regions that may reflect the western edge of a broad region of melting and magmatism throughout the Basin and Range area.

On this trip we will integrate studies from different areas of these Mesozoic arcs including Baja California (Paterson), the northern PRB (Clausen), the San Gabriel Mountains (Schwartz), and the Joshua Tree National Park area (Memeti and Paterson) with a wealth of new data being published by other groups. Day 1 will examine aspects of the Cretaceous PRB in the Perris block where the edge of the western belt and transition zone is exposed. On Days 2 and 3 we will examine parts of two tilted crustal sections, one in the eastern San Gabriel Mountains and the other in the Little San Bernardino Mountains and Joshua Tree National Park. While visiting these crustal sections we will discuss Late Cretaceous to Early Tertiary events to explore why crustal melting and magma emplacement occurred both inboard and post the main magmatic flare-ups in regions that usually are thought to have transitioned into cold fore arc.
The effect of publication bias magnitude and direction on the certainty in evidence
Authors: Murad Mohammad Hassan , Chu Haitao , Lin Lifeng , Wang Zhen
Published: April 2018

Publication bias occurs when studies with statistically significant results have increased likelihood of being published. Publication bias is commonly associated with inflated treatment effect which lowers the certainty of decision makers about the evidence. In this guide we propose that systematic reviewers and decision makers consider the direction and magnitude of publication bias, as opposed to just the binary determination of the presence of this bias, before lowering their certainty in the evidence. Direction of bias may not always exaggerate the treatment effect. The presence of bias with a trivial magnitude may not affect the decision at hand. Various statistical approaches are available to determine the direction and magnitude of publication bias.
Using Q-methodology to guide the implementation of new healthcare policies
Authors: Alderson Sarah , Foy Robbie , Bryant Louise , Ahmed Shenaz , House Allan
Published: April 2018

There are many challenges in the development, implementation and evaluation of healthcare policy. One challenge is understanding how different stakeholders view a particular policy and what impact these views may have during implementation. Q-methodology is one approach that can be used to help policy makers and researchers actively engage with those who are important in policy implementation, and anticipate their responses. Q-methodology combines qualitative and quantitative research methods to systematically explore and describe the range of viewpoints about a topic. Participants are required to rank a set of predefined statements relating to the topic, according to their own viewpoint. Factor analytic techniques then identify people who are like-minded in the way they view the topic and enable areas of consensus and divergence in viewpoint to be clearly defined. This mapping of viewpoints allows those working in policy implementation to anticipate likely barriers and levers in implementing new policies.
β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
Authors: Senni Nadia , Savall Mathilde , Cabrerizo Granados David , Alves-Guerra Marie-Clotilde , Sartor Chiara , Lagoutte Isabelle , Gougelet Angélique , Terris Benoit , Gilgenkrantz Hélène , Perret Christine , Colnot Sabine , Bossard Pascale
Published: April 2018

Objectives

CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.

Design

We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.

Results

β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.

Conclusions

FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.
Comprehensive analysis of the mutation spectrum in 301 German ALS families
Authors: Müller Kathrin , Brenner David , Weydt Patrick , Meyer Thomas , Grehl Torsten , Petri Susanne , Grosskreutz Julian , Schuster Joachim , Volk Alexander E , Borck Guntram , Kubisch Christian , Klopstock Thomas , Zeller Daniel , Jablonka Sibylle , Sendtner Michael , Klebe Stephan , Knehr Antje , Günther Kornelia , Weis Joachim , Claeys Kristl G , Schrank Berthold , Sperfeld Anne-Dorte , Hübers Annemarie , Otto Markus , Dorst Johannes , Meitinger Thomas , Strom Tim M , Andersen Peter M , Ludolph Albert C , Weishaupt Jochen H
Published: April 2018

Objectives

Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.

Methods

Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.

Results

49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.

Conclusions

We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.
Meeting today’s healthcare leadership challenges: is compassionate, caring and inclusive leadership the answer?
Authors: Edwards Luke David , Till Alex , McKimm Judy
Published: April 2018

The delivery of high quality, compassionate care is imperative for all healthcare organisations and systems. Current thought leadership explores the necessity for compassionate and inclusive leadership as a prerequisite to develop the culture within which this can be achieved. In this article, we explore the background to this thinking and how it might work in practice.
Update of an occupational asthma-specific job exposure matrix to assess exposure to 30 specific agents
Authors: Le Moual Nicole , Zock Jan-Paul , Dumas Orianne , Lytras Theodore , Andersson Eva , Lillienberg Linnéa , Schlünssen Vivi , Benke Geza , Kromhout Hans
Published: April 2018

Objectives

We aimed to update an asthmagen job exposure matrix (JEM) developed in the late 1990s. Main reasons were: the number of suspected and recognised asthmagens has since tripled; understanding of the aetiological role of irritants in asthma and methodological insights in application of JEMs have emerged in the period.

Methods

For each agent of the new occupational asthma-specific JEM (OAsJEM), a working group of three experts out of eight evaluated exposure for each International Standard Classification of Occupations, 1988 (ISCO-88) job code into three categories: ‘high’ (high probability of exposure and moderate-to-high intensity), ‘medium’ (low-to-moderate probability or low intensity) and ‘unexposed’. Within a working group, experts evaluated exposures independently from each other. If expert assessments were inconsistent the final decision was taken by consensus. Specificity was favoured over sensitivity, that is, jobs were classified with high exposure only if the probability of exposure was high and the intensity moderate-to-high. In the final review, all experts checked assigned exposures and proposed/improved recommendations for expert re-evaluation after default application of the JEM.

Results

The OAsJEM covers exposures to 30 sensitisers/irritants, including 12 newly recognised, classified into seven broad groups. Initial agreement between the three experts was mostly fair to moderate (κ values 0.2–0.5). Out of 506 ISCO-88 codes, the majority was classified as unexposed (from 82.6% (organic solvents) to 99.8% (persulfates)) and a minority as ‘high-exposed’ (0.2% (persulfates) to 2.6% (organic solvents)).

Conclusions

The OAsJEM developed to improve occupational exposure assessment may improve evaluations of associations with asthma in epidemiological studies and contribute to assessment of the burden of work-related asthma.
Non-convulsive status epilepticus: mimics and chameleons
Authors: Kinney Michael Owen , Craig John J , Kaplan P W
Published: April 2018

Non-convulsive status epilepticus (NCSE) is an enigmatic condition with protean manifestations. It often goes unrecognised, leading to delays in its diagnosis and treatment. The principal reason for such delay is the failure to consider and request an electroencephalogram (EEG), although occasional presentations have no scalp or surface electroencephalographic correlate. In certain settings with limited EEG availability, particularly out-of-hours, clinicians should consider treating without an EEG. Patients need a careful risk–benefit analysis to assess the risks of neuronal damage and harm versus the risks of adverse effects from various intensities of therapeutic intervention. Specialists in EEG, intensive care or epilepsy are invaluable in the management of patients with possible NCSE.
Forest structure and site conditions of boreal felt lichen (Erioderma pedicellatum) habitat in Cape Breton, Nova Scotia, Canada
Authors: Power T.D. , Cameron R.P. , Neily T. , Toms B.
Published: April 2018

Boreal felt lichen [Erioderma pedicellatum (Hue) P.M. Jorg. (1972)] occurs on mainland Nova Scotia as well as Cape Breton, growing almost entirely on balsam fir [Abies balsamea (L.) Mill.] in wet coastal forests. A Geographical Information System (GIS) based predictive model for E. pedicellatum habitat in Nova Scotia has facilitated surveys and guided conservation. We used this model to examine the relationship between presence of E. pedicellatum and forest structure (tree DBH, height, age, and crown closure, inter-tree distance, basal area of live and dead trees, and percent cover of shrubs, herbs, Sphagnum spp., and other mosses), and site conditions (topographic position, slope, aspect, and drainage) as well as the presence of lichen indicator species. Erioderma pedicellatum sites had significantly older trees, higher density of live trees, lower crown closure, lower basal area of live Picea mariana (Mill.) Britton, Sterns & Poggenb., lower basal area of live trees, higher basal area of dead trees, higher Sphagnum spp. cover, and lower shrub cover than unoccupied habitat. Erioderma pedicellatum sites were significantly less well drained and occurred on steeper slopes with a north or east aspect. Four macrolichens (Coccocarpia palmicola, Platismatia norvegica, Lobaria scrobiculata, and Sphaerophorus globosus) occurred at a significantly higher frequency at E. pedicellatum sites.
What did you say about my mother? The complexities of maternally derived chemical signatures in otoliths
Authors: Hegg Jens C. , Kennedy Brian P. , Chittaro Paul
Published: April 2018

Connecting maternal migratory behavior with the behavior and ecology of their progeny can reveal important details in the ecology of a population. One method for linking maternal migration to early juvenile life history is through maternal chemistry recorded in otoliths. Despite the wide use of maternal signatures to infer anadromy, the duration and dynamics of maternal otolith signatures are not well understood. Shifts in the elemental ratios and strontium isotope (87Sr/86Sr) chemistry in otoliths from juvenile Chinook salmon (Oncorhynchus tshawytscha) correlate with the timing of hatch and emergence, respectively, indicating a chemical marker of these ontological stages. Additionally, analysis of maternal signatures show that maternally derived87Sr/86Sr may be influenced by equilibration of the mother to fresh water, and in some cases the87Sr/86Sr signatures of the eggs can shift substantially after being laid. These results provide guidance in separating maternal and juvenile signatures as researchers increasingly target early juvenile otolith chemistry. These results also caution against the use of87Sr/86Sr alone as a marker of anadromy in populations with major inland migrations.
Seasonal habitat and length influence on the trophic niche of co-occurring tropical tunas in the eastern Atlantic Ocean
Authors: Sardenne Fany , Diaha N’Guessan Constance , Amandé Monin Justin , Zudaire Iker , Couturier Lydie I.E. , Metral Luisa , Le Grand Fabienne , Bodin Nathalie
Published: April 2018

In the Gulf of Guinea, bigeye tuna (Thunnus obesus; BET) and yellowfin tuna (Thunnus albacares; YFT) are an important part of commercial fisheries and play a prominent ecological role as top predators. Using fatty acid profiles and carbon and nitrogen stable isotopes, we examined their trophic niche partitioning in this understudied region. Trophic niche overlap was high (>70%), similar to percentages in other ocean basins. BET occupied a higher trophic position than YFT and fed on deeper prey (high δ15N values and high proportions of monounsaturated fatty acids). The trophic position of YFT decreased slightly in the last 15 years (δ15N values decreased by ∼0.5‰), suggesting a change in epipelagic communities, as observed in the eastern Pacific Ocean. Ontogenic changes were limited to BET. For both species, the dietary proportion of the diatom marker 20:5(n-3) increased in the seasonal upwelling area, highlighting the influence of seasonal habitat on the diet of tuna. The relatively lipid-rich muscle (∼6% dry mass) of Atlantic tropical tuna suggests a richer diet in this region than that of Indian Ocean tropical tuna and (or) differences in energy allocation strategies.
The vibrational spectra of carbon dioxide and nitrous oxide: A Lie algebraic study
Authors: Acharjee Mahua , Choudhury Joydeep , Sen Rupam , Mohanta Bidhan
Published: April 2018

The infrared vibrational levels of nitrous oxide (N2O) and carbon dioxide (CO2) are studied in the framework of Lie algebra. The aim of this work is to compare the frequency obtained in two algebraic models: “the vibron model” and “the mean field approximation of the vibron model”. To compare the two models we choose two triatomic molecules: CO2 of symmetry type D∞h and N2O of symmetry type C∞v. To construct the energy levels in the vibron model, the vibron numbers N for the two molecules are estimated from the harmonic frequency and the anharmonicity constant. After the proper estimation of N, the algebraic interaction parameters for both the molecules are evaluated against a least square fit with the experimental values using MATLAB R2015. Using the algebraic interaction parameters, the vibrational frequencies for the two molecules are calculated. Because CO2 is a linear symmetric triatomic molecule, the higher vibrational levels are largely affected by the mode mixing due to accidental degeneracy. The accidental degeneracy is studied introducing the Majorana and Fermi interaction parameters and the rms deviations are observed. The effects of accidental degeneracy for each of the molecules are not equal. In the second part of this report, the harmonic frequencies of CO2 and N2O are calculated using the mean field approximation. It is found that the results show good agreement.
An overview of structurally complex network-based modeling of public opinion in the “We the Media” era
Authors: Wang Guanghui , Wang Yufei , Liu Yijun , Chi Yuxue
Published: April 2018

As the transmission of public opinion on the Internet in the “We the Media” era tends to be supraterritorial, concealed and complex, the traditional “point-to-surface” transmission of information has been transformed into “point-to-point” reciprocal transmission. A foundation for studies of the evolution of public opinion and its transmission on the Internet in the “We the Media” era can be laid by converting the massive amounts of fragmented information on public opinion that exists on “We the Media” platforms into structurally complex networks of information. This paper describes studies of structurally complex network-based modeling of public opinion on the Internet in the “We the Media” era from the perspective of the development and evolution of complex networks. The progress that has been made in research projects relevant to the structural modeling of public opinion on the Internet is comprehensively summarized. The review considers aspects such as regular grid-based modeling of the rules that describe the propagation of public opinion on the Internet in the “We the Media” era, social network modeling, dynamic network modeling, and supernetwork modeling. Moreover, an outlook for future studies that address complex network-based modeling of public opinion on the Internet is put forward as a summary from the perspective of modeling conducted using the techniques mentioned above.