bluuebunny/crossref_metadata_2025 huggingface dataset:
Different National Skill Systems
Authors: Bosch Gerhard
Published: March 2017

As sources of legitimation for the assignment of social status, education and training systems are more strongly rooted in particular national traditions than other social institutions. Most typologies of national skill systems focus on the differences in general and vocational education in upper secondary school. However, with increasing investment in preschool education, the expansion of university education and the growing importance of education and training for adults, comparative researchers are paying increasing attention to the education and training system as a whole, with the result that country typologies are necessarily becoming more complex. The chapter shows that we must bid farewell to the myth that the sole objective of education and training reforms is to increase economic efficiency. In modern democracies, reforms of education and training systems are often characterised by conflicts between the protection of status, on the one hand, and increasing equality, on the other.
A New Social Construction of Skill
Authors: Warhurst Chris , Tilly Chris , Gatta Mary
Published: March 2017

There are a number of theoretical positions that inform analyses of skill. One such position is the social construction of skill. When it was first proposed it was driven by feminist concerns about the sex-typing of jobs and women’s exclusion from jobs labelled as skilled. This chapter offers a new social construction of skill. It appreciates that the old social construction of skill has not disappeared but points out that the context within which this construction occurred has changed, with weaker labour unions and the decline in the manufacturing industries. With more service jobs and stronger employers, the chapter argues that in the wealthier countries there have been two shifts: a shift in how skill has been defined and a shift in who has the power to define it. Focusing on gender, race and class, the chapters explains how the social construction of skill has been restructured in three ways. First, more importance is attached to ascription of skill. Second, who is and isn’t deemed to be skilled has changed. Third, the lines between achieved and ascribed skill are increasingly blurred. The chapter finishes by suggesting ways in which the discrimination arising from this new social construction of skill might be addressed.
Human Rights in Technological Times
Authors: Murphy Thérèse
Published: March 2017

Is there enough to say about the law and regulation of technology from the standpoint of international human rights law and practice? And if there is, is anyone interested? These questions are addressed in this chapter. Overall, the aim is to show why, in these technological times, more of us should be interested in international human rights law and practice. To that end, the chapter sketches both what is blocking interest and what could and should be of interest. In so doing, it examines both international human rights law and practice in general, and questions of population, reproduction, and family in particular.
Genetic Engineering and Biological Risks
Authors: Lentzos Filippa
Published: March 2017

This chapter serves three objectives. First, it provides a narrative account of key developments in core bioengineering technologies. Second, it critically interrogates the emergence and evolution of regulatory regimes aimed at responding to perceived risks associated with these technological capabilities, highlighting how these have primarily relied on establishing ‘soft’ forms of control rather than hard edged legal frameworks backed by coercive sanctions, largely in the form of self-regulation by the scientific research community (with some notification provisions to keep the relevant government informed). Third, it provides an analysis of this regulatory evolution, focusing on the narrow construction of risk, and flagging up the possibility of alternative framings, which might have generated more inclusive and deliberative approaches to standard-setting and oversight.
New Life for Character and Story in Sleeping Beauty
Authors: Smith Marian
Published: March 2017

Alexei Ratmansky’s production of Sleeping Beauty was wrought with careful attention to its music and the manuscripts that preserve Petipa’s choreography. This article begins by touching generally on some aspects of the original ballet that Ratmansky has restored: its technique and style, large multi-generational cast, and full embrace of character dancing. Next, it focuses on musical and choreographic characterizations of the felicitous royal family and their servant Catalabutte and their domestic interactions. Then, it considers Ratmansky’s effective use of the episodes of tension and release that Petipa and Tchaikovsky created to push the action forward. It ends with a short discussion of seeming conflicts between choreography and music during musical codettas, These few details show in small part how, in this production, Ratmansky has exposed anew the dramaturgical brilliance of Tchaikovsky and Petipa, and restored to the stage a Beauty that brings story and character to life with extraordinary vividness.
GIS, Remote Sensing, and Landscape Archaeology
Authors: Parcak Sarah H.
Published: March 2017

This chapter examines a number of current practices relating to the use of geographic information systems (GIS) and remote sensing, including developments in LiDAR (Light Detection and Ranging) in landscape archaeology. It explains landscape archaeology and what it encompasses; whether remote sensing and GIS are a formal part of landscape archaeology; whether GIS and remote sensing are the same or completely different subfields; and whether remote sensing covers both satellite and ground-based remote sensing. Also discussed are challenges faced by archaeologists with regards to the application of landscape archaeology. The article also considers the applications of ground-based remote sensing, GIS, photogrammetry, satellite remote sensing, and LiDAR in landscape archaeology; ethical issues in landscape archaeology; the problem of archaeological site looting; the use of open source data; and citizen science approaches to landscape archaeology. Finally, it reflects on the future prospects for landscape archaeology.
Interventions to Prevent and Reduce Physician Burnout: A Systematic Review and Meta-analysis
Authors: West Colin P. , Dyrbye Liselotte N. , Erwin Patricia J. , Shanafelt Tait D.
Published: March 2017

(Abstracted from Lancet 2016;388:2272–2281)

Physician burnout, as documented in national studies, has a prevalence rate exceeding 50% in both physicians in training and practicing physicians. It negatively affects patient care, professionalism, physicians’ own care, and safety.
Obesity Moderates the Effects of Motivational Interviewing Treatment Outcomes in Fibromyalgia
Authors: Kaleth Anthony S. , Slaven James E. , Ang Dennis C.
Published: March 2017

Objective:

Obesity is a common comorbid condition among patients with fibromyalgia (FM). Our objective was to assess if obesity moderates the treatment benefits of exercise-based motivational interviewing (MI) for FM.

Materials and Methods:

This is a secondary data analysis of a completed clinical trial of 198 FM patients who were randomized to receive either MI or attention control (AC). Using body mass index (BMI) to divide participants into obese (BMI≥30 kg/m2) and nonobese (BMI<30 kg m2) groups, mixed linear models were used to determine interaction between treatment arms and obesity status with regards to the primary outcome of global FM symptom severity (Fibromyalgia Impact Questionnaire, FIQ). Secondary measures included pain intensity (Brief Pain Inventory), 6-Minute Walk Test, and self-reported physical activity (Community Health Activities Model Program for Seniors).

Results:

Of the 198 participants, 91 (46%) were nonobese and 107 (54%) were obese. On global FM symptom severity (FIQ), the interaction between treatment arms and obesity status was significant (P=0.02). In the nonobese group, MI was associated with a greater improvement in FIQ than AC. In the obese group, MI participants reported less improvement in FIQ compared with AC. The interaction analysis was also significant for Brief Pain Inventory pain intensity (P=0.01), but not for the walk test and self-reported physical activity.

Discussion:

This is the first study to show that obesity negatively affects the treatment efficacy of MI in patients with FM. Our findings suggest that exercise-based MI may be more effective if initiated after weight loss is achieved.
Patient Turnover
Authors: VanFosson Christopher A. , Yoder Linda H. , Jones Terry L.
Published: March 2017

Patient turnover influences the quality and safety of patient care. However, variations in the conceptual underpinnings of patient turnover limit the understanding of the phenomenon. A concept analysis was completed to clarify the role of patient turnover in relation to outcomes in the acute care hospital setting. The defining attributes, antecedents, consequences, and empirical referents of patient turnover were proposed. Nursing leaders should account for patient turnover in workload and staffing calculations. Further research is needed to clarify the influence of patient turnover on the quality and safety of nursing care using a unified understanding of the phenomenon.
Twenty Years of a Veterans' Spinal Cord Injury Colorectal Clinic: Flexible Sigmoidoscopy and Multiple Hemorrhoid Ligation
Authors: Cosman Bard C. , Cajas-Monson Luis C. , Ramamoorthy Sonia L.
Published: March 2017

BACKGROUND:

Colorectal and anal problems arise in chronic spinal cord injury care. We review 20 years of experience in a colorectal clinic at a veterans medical center treating mostly male veterans who have spinal cord injury.

OBJECTIVE:

We aim to show the results of colorectal interventions in a population with chronic spinal cord injury.

DESIGN:

This study is a retrospective records review.

SETTINGS:

This study was conducted at a Department of Veterans Affairs regional spinal cord injury center.

PATIENTS:

Six hundred forty-one individuals (625 males) made 1208 visits. Mean age was 56 ± 13 years; ages ranged from 21 to 90 years.

INTERVENTIONS:

Flexible sigmoidoscopy was done for diagnosis and screening, and hemorrhoid ligation was performed for symptomatic hemorrhoids.

MAIN OUTCOME MEASURES:

The primary outcomes measured were the frequency, timing, and results of procedures.

RESULTS:

Five hundred forty-eight people had 781 flexible sigmoidoscopies. At first examination, mean age was 65 ± 12 and the duration of injury was 19 ± 15 years. Sixty examinations (7.7%) displayed poor preparation. The interval between adequate-prepared examinations was 5.7 ± 2.0 years. The adenoma detection rate was 4.7%. Two hundred fifteen people had 406 hemorrhoid ligations. At first banding, the mean age was 52 ± 13 and the duration of injury was 20 ± 15 years. Mean number of ligations per procedure was 4.9 ± 2.0; a range of 1 to 20. Nine hemorrhoid operations were done in this period. Regarding the futility of procedures, 250 people died, with a mean age at death of 69 ± 11. The median time between any procedure and death was 4.4 years. Seventeen procedures were done within 6 months of death; these deaths were either unexpected or because of conditions identified at or after the procedure.

LIMITATIONS:

This was a retrospective review of a single institution, it involved a mostly male population, and it used a subjective assessment of bowel preparation.

CONCLUSIONS:

In a spinal cord injury colorectal clinic, sigmoidoscopy can keep screening current, with an acceptable level of poor preparation. The adenoma detection rate may or may not be adequate. Hemorrhoid ligation can be expanded beyond its limits in the non-spinal cord-injured population, including multiple and external banding, taking the place of an operation in most cases. These procedures are well tolerated and rarely futile.
OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF FLAT IRREGULAR PIGMENT EPITHELIUM DETACHMENT IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY
Authors: Bousquet Elodie , Bonnin Sophie , Mrejen Sarah , Krivosic Valérie , Tadayoni Ramin , Gaudric Alain
Published: March 2017

Purpose:

To assess the rate of choroidal neovascularization (CNV) detected by optical coherence tomography angiography (OCTA) in flat irregular pigment epithelium detachment (PED) in chronic central serous chorioretinopathy.

Methods:

Data on all consecutive patients with chronic central serous chorioretinopathy who underwent OCTA over a 1-year period were reviewed. The presence of flat irregular PED, which was defined as an irregular elevation of the retinal pigment epithelium allowing the visualization of a distinct Bruch's membrane was assessed on high-resolution OCT B-scan. Clinical, multimodal imaging, and OCTA data were reviewed by two graders for the detection of CNV.

Results:

Eighty-eight eyes of 61 patients with chronic central serous chorioretinopathy were included. Patient mean age (±SD) was 54.5 ± 12.2 years, and 78.7% were males. Mean subfoveal choroidal thickness (±SD) was 452.6 ± 145.6 μm. Flat irregular PEDs were detected in 59 eyes of 51 patients. OCTA detected the presence of CNV in flat irregular PEDs in 35.6% of cases. Conversely, using the combination of spectral domain optical coherence tomography angiography, fluorescein and indocyanine green angiography, CNV was detected in only 25% of flat irregular PEDs. All hyporeflective flat irregular PEDs on OCT were avascular on OCTA while they were at least partially hyperreflective when associated with CNV.

Conclusion:

One-third of flat irregular PEDs in chronic central serous chorioretinopathy contained CNV. OCTA detected CNV more frequently than the other imaging modalities. Further longitudinal studies are needed to assess the indication of antivascular endothelial growth factor treatments in such cases.
HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy
Authors: Krukowski Karen , Ma Jiacheng , Golonzhka Olga , Laumet Geoffroy O. , Gutti Tanuja , van Duzer John H. , Mazitschek Ralph , Jarpe Matthew B. , Heijnen Cobi J. , Kavelaars Annemieke
Published: March 2017

Chemotherapy-induced peripheral neuropathy is one of the most common dose-limiting side effects of cancer treatment. Currently, there is no Food and Drug Administration–approved treatment available. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase whose function includes regulation of α-tubulin–dependent intracellular mitochondrial transport. Here, we examined the effect of HDAC6 inhibition on established cisplatin-induced peripheral neuropathy. We used a novel HDAC6 inhibitor ACY-1083, which shows 260-fold selectivity towards HDAC6 vs other HDACs. Our results show that HDAC6 inhibition prevented cisplatin-induced mechanical allodynia, and also completely reversed already existing cisplatin-induced mechanical allodynia, spontaneous pain, and numbness. These findings were confirmed using the established HDAC6 inhibitor ACY-1215 (Ricolinostat), which is currently in clinical trials for cancer treatment. Mechanistically, treatment with the HDAC6 inhibitor increased α-tubulin acetylation in the peripheral nerve. In addition, HDAC6 inhibition restored the cisplatin-induced reduction in mitochondrial bioenergetics and mitochondrial content in the tibial nerve, indicating increased mitochondrial transport. At a later time point, dorsal root ganglion mitochondrial bioenergetics also improved. HDAC6 inhibition restored the loss of intraepidermal nerve fiber density in cisplatin-treated mice. Our results demonstrate that pharmacological inhibition of HDAC6 completely reverses all the hallmarks of established cisplatin-induced peripheral neuropathy by normalization of mitochondrial function in dorsal root ganglia and nerve, and restoration of intraepidermal innervation. These results are especially promising because one of the HDAC6 inhibitors tested here is currently in clinical trials as an add-on cancer therapy, highlighting the potential for a fast clinical translation of our findings.
Elevated procalcitonin is associated with bacterial infection during acute liver failure only when unrelated to acetaminophen intoxication
Authors: Mallet Maxime , Haq Maela , Tripon Simona , Bernard Maguy , Benosman Hedi , Thabut Dominique , Rudler Marika
Published: March 2017

Aim

The aim of this study was to evaluate the accuracy of procalcitonin (PCT) in predicting bacterial infection and survival without transplantation upon admission in the ICU for acute liver failure (ALF).

Patients and methods

From January 2009 until October 2015, all cases of ALF patients admitted in our ICU were retrospectively reviewed and included in the study if the PCT level upon admission was available. Patients with pre-existing liver pathology or ALF in a context of already advanced multiorgan failure were excluded. The main clinical and biological characteristics of patients were recorded, as well as the etiology of ALF, diagnosis of bacterial infection (bacteriologically documented or suspected), and outcome.

Results

35 patients were included: 46% men, mean age 42 years, initial prothrombin ratio 31%, PCT 9.8 mg/l (0.7–49), and PCT more than 2 mg/l in 54% of cases. Etiology was acetaminophen intoxication in 18/35 (51%) cases. Sepsis was diagnosed in 9/35 (26%) cases, most frequently pneumonia with 4/9 cases. Survival without liver transplantation (LT) was observed in 28 (80%) cases. The median PCT was not different in patients with or without bacterial infection [6.3 mg/l (0.6–16) vs. 1.2 mg/l (0.8–9.7), P=0.8]. The median PCT was not different in patients who survived without LT [7.1 mg/l (0.9–16.1) vs. 0.75 mg/l (7.7–11.5), P=0.06]. In patients with ALF unrelated to acetaminophen intoxication, the median PCT was higher in patients with bacterial infection [1.1 mg/l (0.9–4) vs. 0.5 mg/l (0.3–0.8), P=0.01], but was similar in patients who did not survive without LT [0.7 mg/l (0.4–1.1) vs. 0.8 mg/l (0.4–2.2), P=0.6]. In the overall cohort, the median C-reactive protein (CRP) and leukocyte count were higher in patients who developed bacterial infection [40 mg/l (19–60) vs. 16 mg/l (6–34), P=0.04; 11.9 G/l (8.3–19) vs. 7.9 G/l (6–12.6), P=0.05]. The median CRP and leukocyte count were not significantly different in survivors versus nonsurvivors without LT.

Conclusion

PCT was an accurate predictor for the diagnosis of bacterial infection only in patients with ALF unrelated to acetaminophen intoxication. CRP was higher in patients who developed infection and could also be an interesting tool in ALF patients.
Attempt to Determine the Prevalence of Two Inborn Errors of Primary Bile Acid Synthesis
Authors: Jahnel Jörg , Zöhrer Evelyn , Fischler Björn , D'Antiga Lorenzo , Debray Dominique , Dezsofi Antal , Haas Dorothea , Hadzic Nedim , Jacquemin Emmanuel , Lamireau Thierry , Maggiore Giuseppe , McKiernan Pat J. , Calvo Pier L. , Verkade Henkjan J. , Hierro Loreto , McLin Valerie , Baumann Ulrich , Gonzales Emmanuel
Published: March 2017

Objective:

Inborn errors of primary bile acid (BA) synthesis are genetic cholestatic disorders leading to accumulation of atypical BA with deficiency of normal BA. Unless treated with primary BA, chronic liver disease usually progresses to cirrhosis and liver failure before adulthood. We sought to determine the prevalence of 2 common disorders, 3β‐hydroxy‐Δ5‐C27‐steroid dehydrogenase (3β‐HSD) and Δ4–3‐oxosteroid‐5β‐reductase (Δ4–3‐oxoR) deficiencies and to describe current diagnostic and treatment strategies among different European paediatric hepatology centres.

Methods:

A total of 52 clinical paediatric centres were approached and 39 centres in 21 countries agreed to participate in the Web‐based survey. The survey comprised questions regarding general information, number of cases, diagnostic, and therapeutic management.

Results:

Seventeen centres located in 11 countries reported patients with inborn errors in primary BA synthesis, 22 centres never had cases diagnosed. In total, we could identify 63 patients; 55 with 3β‐HSD and 8 with Δ4–3‐oxoR deficiency in 21 countries. The minimum estimated combined prevalence of these diseases was 1.13 cases per 10 million (0.99 and 0.14 for 3β‐HSD and Δ4–3‐oxoR deficiencies, respectively). The surveyed colleagues indicated their main challenges to be the rarity of diseases and the lack of convenient laboratory facilities nearby.

Conclusion:

We have identified the largest cohort of patients with 3β‐HSD or Δ4–3‐oxoR deficiency described so far. These diseases are likely underdiagnosed mainly due to unawareness of their existence and the lack of laboratory facilities.
ATIC Gene Polymorphism and Histologic Response to Chemotherapy in Pediatric Osteosarcoma
Authors: Park Jeong A. , Shin Hee Young
Published: March 2017

Accumulating evidence indicates that polymorphisms in folate pathway genes play a role in response to methotrexate (MTX) treatment in various diseases. This study explored the influence of these genetic polymorphisms on treatment outcome in pediatric osteosarcoma. Blood and tissue samples from 48 osteosarcoma patients were obtained, and the following polymorphisms were analyzed; SLC19A1 80G>A, DHFR 829C>T, MTHFR 677C>T, MTHFR 1298A>C, and ATIC 347C>G. We evaluated associations between these candidate gene polymorphisms and treatment outcome, including histologic response and event-free and overall survival, of patients treated with high-dose MTX. Patients with ATIC 347C>G exhibited a good histologic response to chemotherapy (odds ratio, 0.13; 95% confidence interval, 0.017-0.978; P=0.048). However, none of these single nucleotide polymorphisms we examined affected event-free survival or overall survival rates of the patients. Even though the role of single nucleotide polymorphisms of ATIC in chemotherapy-induced tumor necrosis has not been investigated yet, the ATIC 347C>G polymorphism may influence the levels of adenosine after MTX treatment, which may affect the histologic response of osteosarcoma. This relationship warrants validation in a larger, prospective cohort study.
Novel Mutations in SH2D1A Gene in X-linked Lymphoproliferative Syndrome, Diagnosed After B-Cell Non-Hodgkin Lymphoma
Authors: Sharapova Svetlana O. , Fedorova Alina S. , Pashchenko Olga E. , Vahliarskaya Svetlana S. , Guryanova Irina E. , Migas Alexandr A. , Kondratenko Irina V. , Aleinikova Olga V.
Published: March 2017

Background:

X-linked lymphoproliferative disease type I (XLP I) is caused by mutations in the SH2D1A gene and characterized mainly by hypogammaglobulinemia and abnormal response to Epstein-Barr virus with a high predisposition to B-cell non-Hodgkin lymphoma development.

Observations:

In this article, we describe the experience of 2 centers in Belarus and in Russia that follow 3 male patients who were diagnosed with XLP I after lymphoma development and treatment. Three novel mutations c.51G>C (p.E17D), c.192G>T (p.W64C), and c.53insA (p.K18KfsX67) were found in 3 males patients with XLP I. Two of them did not have any signs of immunodeficiency before B-cell non-Hodgkin lymphoma development.

Conclusions:

We propose SH2D1A mutational screening be considered in male patients with or without hypogammaglobulinemia who received rituximab treatment for lymphoma and did not recover immunoglobulin G in a year after B-depleting therapy.
Towards reduced order modelling for predicting the dynamics of coherent vorticity structures within wind turbine wakes
Authors: Debnath M. , Santoni C. , Leonardi S. , Iungo G. V.
Published: March 2017

The dynamics of the velocity field resulting from the interaction between the atmospheric boundary layer and a wind turbine array can affect significantly the performance of a wind power plant and the durability of wind turbines. In this work, dynamics in wind turbine wakes and instabilities of helicoidal tip vortices are detected and characterized through modal decomposition techniques. The dataset under examination consists of snapshots of the velocity field obtained from large-eddy simulations (LES) of an isolated wind turbine, for which aerodynamic forcing exerted by the turbine blades on the atmospheric boundary layer is mimicked through the actuator line model. Particular attention is paid to the interaction between the downstream evolution of the helicoidal tip vortices and the alternate vortex shedding from the turbine tower. The LES dataset is interrogated through different modal decomposition techniques, such as proper orthogonal decomposition and dynamic mode decomposition. The dominant wake dynamics are selected for the formulation of a reduced order model, which consists in a linear time-marching algorithm where temporal evolution of flow dynamics is obtained from the previous temporal realization multiplied by a time-invariant operator.

This article is part of the themed issue ‘Wind energy in complex terrains’.
Wind resource assessment in heterogeneous terrain
Authors: Vanderwel C. , Placidi M. , Ganapathisubramani B.
Published: March 2017

High-resolution particle image velocimetry data obtained in rough-wall boundary layer experiments are re-analysed to examine the influence of surface roughness heterogeneities on wind resource. Two different types of heterogeneities are examined: (i) surfaces with repeating roughness units of the order of the boundary layer thickness (Placidi & Ganapathisubramani. 2015
J. Fluid Mech.
782
, 541–566. (
doi:10.1017/jfm.2015.552
)) and (ii) surfaces with streamwise-aligned elevated strips that mimic adjacent hills and valleys (Vanderwel & Ganapathisubramani. 2015
J. Fluid Mech.
774
, 1–12. (
doi:10.1017/jfm.2015.228
)). For the first case, the data show that the power extraction potential is highly dependent on the surface morphology with a variation of up to 20% in the available wind resource across the different surfaces examined. A strong correlation is shown to exist between the frontal and plan solidities of the rough surfaces and the equivalent wind speed, and hence the wind resource potential. These differences are also found in profiles of

and

(where
U
is the streamwise velocity), which act as proxies for thrust and power output. For the second case, the secondary flows that cause low- and high-momentum pathways when the spacing between adjacent hills is beyond a critical value result in significant variations in wind resource availability. Contour maps of

and

show a large difference in thrust and power potential (over 50%) between hills and valleys (at a fixed vertical height). These variations do not seem to be present when adjacent hills are close to each other (i.e. when the spacing is much less than the boundary layer thickness). The variance in thrust and power also appears to be significant in the presence of secondary flows. Finally, there are substantial differences in the dispersive and turbulent stresses across the terrain, which could lead to variable fatigue life depending on the placement of the turbines within such heterogeneous terrain. Overall, these results indicate the importance of accounting for heterogeneous terrain when siting individual turbines and wind farms.

This article is part of the themed issue ‘Wind energy in complex terrains’.
A Statistical Model of Shared Variability in the Songbird Auditory System
Authors: Buesing Lars , Calabrese Ana , Cunningham John P. , Woolley Sarah M. N. , Paninski Liam
Published: March 2017

Vocal communication evokes robust responses in primary auditory cortex (A1) of songbirds, and single neurons from superficial and deep regions of A1 have been shown to respond selectively to songs over complex, synthetic sounds. However, little is known about how this song selectivity arises and manifests itself on the level of networks of neurons in songbird A1. Here, we examined the network-level coding of song and synthetic sounds in A1 by simultaneously recording the responses of multiple neurons in unanesthetized zebra finches. We developed a latent factor model of the joint simultaneous activity of these neural populations, and found that the shared variability in the activity has a surprisingly simple structure; it is dominated by an unobserved latent source with one degree-of-freedom. This simple model captures the structure of the correlated activity in these populations in both spontaneous and stimulus-driven conditions, and given both song and synthetic stimuli. The inferred latent variability is strongly suppressed under stimulation, consistent with similar observations in a range of mammalian cortical regions.
Genetic variability in the promoter region of TNF-α gene in the reservoir of Junin virus, Calomys musculinus (Rodentia, Cricetidae)
Authors: Chiappero Marina B. , Cabaña Imanol , Calderón Gladys E. , Gardenal Cristina N.
Published: March 2017

In this study, we assessed the genetic variability of the promoter region of TNF-α gene in three natural populations of the cricetid rodentCalomys musculinus. This species is the natural reservoir of Junin virus, the etiological agent of Argentine Hemorrhagic fever. We found different levels of variability and varying signatures of natural selection in populations with different epidemiological histories.
Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity
Authors: Snarr Brendan D. , Baker Perrin , Bamford Natalie C. , Sato Yukiko , Liu Hong , Lehoux Melanie , Gravelat Fabrice N. , Ostapska Hanna , Baistrocchi Shane R. , Cerone Robert P. , Filler Elan E. , Parsek Matthew R. , Filler Scott G. , Howell P. Lynne , Sheppard Donald C.
Published: March 2017

Galactosaminogalactan and Pel are cationic heteropolysaccharides produced by the opportunistic pathogens,Aspergillus fumigatusandPseudomonas aeruginosa, respectively. These exopolysaccharides both contain 1,4-linkedN-acetyl-D-galactosamine and play an important role in biofilm formation by these organisms. Proteins containing glycoside hydrolase domains have recently been identified within the biosynthetic pathway of each exopolysaccharide. Recombinant hydrolase domains from these proteins (Sph3hfromA. fumigatusand PelAhfromP. aeruginosa) were found to degrade their respective polysaccharidesin vitro. We therefore hypothesized that these glycoside hydrolases could exhibit anti-biofilm activity, and further, given the chemical similarity between galactosaminogalactan and Pel, that they might display cross-species activity. Treatment ofA. fumigatuswith Sph3hdisruptedA. fumigatusbiofilms with an EC50of 0.4 nM. PelAhtreatment also disrupted pre-formedA. fumigatusbiofilms with EC50values similar to those obtained for Sph3h. In contrast, Sph3hwas unable to disruptP. aeruginosaPel-based biofilms, despite being able to bind to the exopolysaccharide. Treatment ofA. fumigatushyphae with either Sph3hor PelAhsignificantly enhanced the activity of the antifungals posaconazole, amphotericin B and caspofungin, likely through increasing antifungal penetration of hyphae. Both enzymes were non-cytotoxic and protected A549 pulmonary epithelial cells fromA. fumigatus-inducedcell damage for up to 24 hours. Intratracheal administration of Sph3hwas well tolerated, and reduced pulmonary fungal burden in a neutropenic mouse model of invasive aspergillosis. These findings suggest that glycoside hydrolases can exhibit activity against diverse microorganisms and may be useful as therapeutic agents by degrading biofilms and attenuating virulence.

Significance

The production of biofilms is an important strategy used by both bacteria and fungi to colonize surfaces and to enhance resistance to killing by immune cells and antimicrobial agents. We demonstrate that glycoside hydrolases derived from the opportunistic fungusAspergillus fumigatusand Gram-negative bacteriumPseudomonas aeruginosacan be exploited to disrupt pre-formed fungal biofilms and reduce virulence. Additionally, these glycoside hydrolases can be utilized to potentiate antifungal drugs by increasing their hyphal penetration, to protect human cells from fungal-induced injury and to attenuate virulence ofA. fumigatusin a mouse model of invasive aspergillosis. The findings of this study identify recombinant microbial glycoside hydrolases as promising therapeutics with the potential for anti-biofilm activity against pathogens across different taxonomic kingdoms.
Identification of drug candidates that enhance pyrazinamide activity from a clinical drug library
Authors: Niu Hongxia , Ma Chao , Cui Peng , Shi Wanliang , Zhang Shuo , Feng Jie , Sullivan David , Zhu Bingdong , Zhang Wenhong , Zhang Ying
Published: March 2017

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally despite the availability of the TB therapy.1The current TB therapy is lengthy and suboptimal, requiring a treatment time of at least 6 months for drug susceptible TB and 9-12 months (shorter Bangladesh regimen) or 18-24 months (regular regimen) for multi-drug-resistant tuberculosis (MDR-TB).1The lengthy therapy makes patient compliance difficult, which frequently leads to emergence of drug-resistant strains. The requirement for the prolonged treatment is thought to be due to dormant persister bacteria which are not effectively killed by the current TB drugs, except rifampin and pyrazinamide (PZA) which have higher activity against persisters.2, 3Therefore new therapies should address the problem of insufficient efficacy againstM. tuberculosispersisters, which could cause relapse of clinical disease.4PZA is a critical frontline TB drug that kills persister bacteria5and shortens the TB treatment from 9-12 months to 6 months.6, 7Although several new TB drugs are showing promise in clinical studies, none can replace PZA as they all have to be used together with PZA.7Because of the essentiality of PZA and the high cost of developing new drugs, in this study, we explored the idea of identifying drugs that enhance the anti-persister activity of PZA as an economic alternative approach to developing new drugs for improved treatment by screening an clinical drug library against oldM. tuberculosiscultures enriched with persisters.
Biases in multivariate neural population codes
Authors: Keemink Sander W. , van Rossum Mark C. W.
Published: March 2017

Throughout the nervous system information is typically coded in activity distributed over large population of neurons with broad tuning curves. In idealized situations where a single, continuous stimulus is encoded in a homogeneous population code, the value of an encoded stimulus can be read out without bias. Here we find that when multiple stimuli are simultaneously coded in the population, biases in the estimates of the stimuli and strong correlations between estimates can emerge. Although bias produced via this novel mechanism can be reduced by competitive coding and disappears in the complete absence of noise, the bias diminishes only slowly as a function of neural noise level. A Gaussian Process framework allows for accurate calculation of the bias and shows that a bimodal estimate distribution underlies the bias. The results have implications for neural coding and behavioral experiments.
The Protein Phosphatase 4 complex promotes the Notch pathway andwinglesstranscription
Authors: Hall Eric T. , Pradhan-Sundd Tirthadipa , Samnani Faaria , Verheyen Esther M.
Published: March 2017

The Wnt/Wingless (Wg) pathway controls cell fate specification, tissue differentiation and organ development across organisms. Using anin vivoRNAi screen to identify novel kinase and phosphatase regulators of the Wg pathway, we identified subunits of the serine threonine phosphatase Protein phosphatase 4 (PP4). Knockdown of the catalytic and the regulatory subunits of PP4 cause reductions in the Wg pathway targets Senseless and Distal-less. We find that PP4 regulates the Wg pathway by controlling Notch-drivenwgtranscription. Genetic interaction experiments identified that PP4 likely promotes Notch signaling within the nucleus of the Notch-receiving cell. Although the PP4 complex is implicated in various cellular processes, its role in the regulation of Wg and Notch pathways was previously uncharacterized. Our study identifies a novel role of PP4 in regulating Notch pathway, resulting in aberrations in Notch-mediated transcriptional regulation of the Wingless ligand. Furthermore, we show that PP4 regulates proliferation independent of its interaction with Notch.

Summary statement

The protein phosphatase 4 complex promotes Notch signaling and target gene expression during Drosophila wing development.
The fitness cost of mis-splicing is the main determinant of alternative splicing patterns
Authors: Saudemont Baptiste , Popa Alexandra , Parmley Joanna L. , Rocher Vincent , Blugeon Corinne , Necsulea Anamaria , Meyer Eric , Duret Laurent
Published: March 2017

Most eukaryotic genes are subject to alternative splicing (AS), which may contribute to the production of functional protein variants or to the regulation of gene expression, notably via nonsense-mediated mRNA decay (NMD). However, a fraction of splice variants might correspond to spurious transcripts, and the question of the relative proportion of splicing errors vs. functional splice variants remains highly debated. We propose here a test to quantify the fraction of AS events corresponding to errors. This test is based on the fact that the fitness cost of splicing errors increases with the number of introns in a gene and with expression level. We first analyzed the transcriptome of the intron-rich unicellular eukaryoteParamecium tetraurelia.We show that both in normal and in NMD-deficient cells, AS rates (intron retention, alternative splice site usage or cryptic intron splicing) strongly decrease with increasing expression level and with increasing number of introns. This relationship is observed both for AS events that are detectable by NMD or not, which invalidates the hypothesis of a possible link with the regulation of gene expression. Our results indicate that in genes with a median expression level, 92%-98% of observed splice variants correspond to errors. Interestingly, we observed the same patterns in human transcriptomes. These results are consistent with the mutation-selection-drift theory, which predicts that genes under weaker selective pressure should accumulate more maladaptive substitutions, and therefore should be more prone to errors of gene expression.
Effects of Social Organization, Trap Arrangement and Density, Sampling Scale, and Population Density on Bias in Population Size Estimation Using Some Common Mark-Recapture Estimators
Authors: Gupta Manan , Joshi Amitabh , Vidya T. N. C.
Published: March 2017

Mark-recapture estimators are commonly used for population size estimation, and typically yield unbiased estimates for most solitary species with low to moderate home range sizes. However, these methods assume independence of captures among individuals, an assumption that is clearly violated in social species that show fission-fusion dynamics, such as the Asian elephant. In the specific case of Asian elephants, doubts have been raised about the accuracy of population size estimates. More importantly, the potential problem for the use of mark-recapture methods posed by social organization in general has not been systematically addressed. We developed an individual-based simulation framework to systematically examine the potential effects of type of social organization, as well as other factors such as trap density and arrangement, spatial scale of sampling, and population density, on bias in population sizes estimated by POPAN, Robust Design, and Robust Design with detection heterogeneity. In the present study, we ran simulations with biological, demographic and ecological parameters relevant to Asian elephant populations, but the simulation framework is easily extended to address questions relevant to other social species. We collected capture history data from the simulations, and used those data to test for bias in population size estimation. Social organization significantly affected bias in most analyses, but the effect sizes were variable, depending on other factors. Social organization tended to introduce large bias when trap arrangement was uniform and sampling effort was low. POPAN clearly outperformed the two Robust Design models we tested, yielding close to zero bias if traps were arranged at random in the study area, and when population density and trap density were not too low. Social organization did not have a major effect on bias for these parameter combinations at which POPAN gave more or less unbiased population size estimates. Therefore, the effect of social organization on bias in population estimation could be removed by using POPAN with specific parameter combinations, to obtain population size estimates in a social species.
Mutation supply and the repeatability of selection for antibiotic resistance
Authors: van Dijk Thomas , Hwang Sungmin , Krug Joachim , de Visser J. Arjan G.M. , Zwart Mark P.
Published: March 2017

Whether evolution can be predicted is a key question in evolutionary biology. Here we set out to better understand the repeatability of evolution, which is a necessary condition for predictability. We explored experimentally the effect of mutation supply and the strength of selective pressure on the repeatability of selection from standing genetic variation. Different sizes of mutant libraries of an antibiotic resistance gene, TEM-1 β-lactamase inEscherichia coli,were subjected to different antibiotic concentrations. We determined whether populations went extinct or survived, and sequenced the TEM gene of the surviving populations. The distribution of mutations per allele in our mutant libraries—generated by error-prone PCR—followed a Poisson distribution. Extinction patterns could be explained by a simple stochastic model that assumed the sampling of beneficial mutations was key for survival. In most surviving populations, alleles containing at least one known large-effect beneficial mutation were present. These genotype data also support a model which only invokes sampling effects to describe the occurrence of alleles containing large-effect driver mutations. Hence, evolution is largely predictable given cursory knowledge of mutational fitness effects, the mutation rate and population size. There were no clear trends in the repeatability of selected mutants when we considered all mutations present. However, when only known large-effect mutations were considered, the outcome of selection is less repeatable for large libraries, in contrast to expectations. Furthermore, we show experimentally that alleles carrying multiple mutations selected from large libraries confer higher resistance levels relative to alleles with only a known large-effect mutation, suggesting that the scarcity of high-resistance alleles carrying multiple mutations may contribute to the decrease in repeatability at large library sizes.
MultiDCoX: Multi-factor Analysis of Differential Coexpression
Authors: Liany Herty , Rajapakse Jagath C. , Karuturi R. Krishna Murthy
Published: March 2017

Background

Differential co-expression signifies change in degree of co-expression of a set of genes among different biological conditions. It has been used to identify differential co-expression networks or interactomes. Many algorithms have been developed for single-factor differential co-expression analysis and applied in a variety of studies. However, in many studies, the samples are characterized by multiple factors such as genetic markers, clinical variables and treatments. No algorithm or methodology is available for multi-factor analysis of differential co-expression.

Results

We developed a novel formulation and a computationally efficient greedy search algorithm called MultiDCoX to perform multi-factor differential co-expression analysis of transcriptomic data. Simulated data analysis demonstrates that the algorithm can effectively elicit differentially co-expressed (DCX) gene sets and quantify the influence of each factor on co-expression. MultiDCoX analysis of a breast cancer dataset identified interesting biologically meaningful differentially coexpressed (DCX) gene sets along with genetic and clinical factors that influenced the respective differential co-expression.

Conclusions

MultiDCoX is a space and time efficient procedure to identify differentially co-expressed gene sets and successfully identify influence of individual factors on differential co-expression.

Software

R function will be available upon request.
A shortcut for early macrophage recruitment into tumors by activated oncogenes
Authors: Austenaa Liv , Natoli Gioacchino
Published: March 2017

Macrophages play an important role in tumor promotion, usually acting as facilitators of cancer initiation and progression. However, it is not clear how macrophages impact early phases of tumorigenesis. Using genetically modified mouse models, Guo et al. (pp. 247–259) demonstrated that tumor-initiating cells with an activated Hippo pathway are able to recruit macrophages starting from the very early phases of cancer development, mainly through direct activation of genes encoding macrophage chemoattractants and survival factors. The recruited macrophages were of vital importance for protection of tumor-initiating cells against eradication by lymphocyte-mediated immune surveillance. Such a tight link between macrophages and a pathway controlling organ development and size may reflect the normal role of these cells in tissue morphogenesis.
Fast time-delay measurement for integrated pulsar pulse profiles
Authors: Kang Zhiwei , He Xin , Liu Jin , Tao Tianyuan
Published: March 2017

Purpose

The authors proposed a new method of fast time delay measurement for integrated pulsar pulse profiles in X-ray pulsar-based navigation (XNAV). As a basic observation of exact orientation in XNAV, time of arrival (TOA) can be obtained by time delay measurement of integrated pulsar pulse profiles. Therefore, the main purpose of the paper is to establish a method with fast time delay measurement on the condition of limited spacecraft’s computing resources.

Design/methodology/approach

Given that the third-order cumulants can suppress the Gaussian noise and reduce calculation to achieve precise and fast positioning in XNAV, the proposed method sets the third-order auto-cumulants of standard pulse profile, the third-order cross-cumulants of the standard and the observed pulse profile as basic variables and uses the cross-correlation function of these two variables to estimate the time delay of integrated pulsar pulse profiles.

Findings

The proposed method is simple, fast and has high accuracy in time delay measurement for integrated pulsar pulse profiles. The result shows that compared to the bispectrum algorithm, the method improves the precision of the time delay measurement and reduced the computation time significantly as well.

Practical implications

To improve the performance of time delay estimation in XNAV systems, the authors proposed a novel method for XNAV to achieve precise and fast positioning.

Originality/value

Compared to the bispectrum algorithm, the proposed method can improve the speed and precision of the TOA’s calculation effectively by using the cross-correlation function of integrated pulsar pulse profile’s third-order cumulants instead of Fourier transform in bispectrum algorithm.