bluuebunny/crossref_metadata_2025 huggingface dataset:
Eigenfunction expansions of ultradifferentiable functions and ultradistributions. II. Tensor representations
Authors: Dasgupta Aparajita , Ruzhansky Michael
Published: May 2018

In this paper we analyse the structure of the spaces of coefficients of eigenfunction expansions of functions in Komatsu classes on compact manifolds, continuing the research in our paper [Trans. Amer. Math. Soc. 368 (2016), pp.8481-8498]. We prove that such spaces of Fourier coefficients are perfect sequence spaces. As a consequence we describe the tensor structure of sequential mappings on spaces of Fourier coefficients and characterise their adjoint mappings. In particular, the considered classes include spaces of analytic and Gevrey functions, as well as spaces of ultradistributions, yielding tensor representations for linear mappings between these spaces on compact manifolds.
Effect of Antiretroviral Therapy on Plasma Concentrations of Chloroquine and Desethyl-chloroquine
Authors: Ippolito Matthew M , Jacobson Jeffrey M , Lederman Michael M , Winterberg Markus , Tarning Joel , Shapiro Theresa A , Flexner Charles
Published: May 2018

The effect of antiretroviral therapy (ART) on chloroquine and desethyl-chloroquine plasma concentrations was evaluated in clinical trial participants. Concentrations did not differ among participants receiving protease inhibitor–based ART (n = 9), efavirenz-based ART (n = 15), or other ART (n = 8) and those not receiving ART (n = 31). Efavirenz seemed to inhibit chloroquine desethylation.
Competing teammates: food in New Zealand sports settings
Authors: Carter Mary-Ann , Signal Louise N , Edwards Richard , Hoek Janet
Published: May 2018

Despite the global popularity of sport, we know surprisingly little about food in sports settings. This two-phased study analysed the foods available in New Zealand sports settings. Phase one included a systematic literature review and 18 interviews with key informants from national and regional sporting organizations. Phase two involved 37 key informant interviews with stakeholders from two exemplar sports, rugby and netball and direct observations at netball and rugby venues. This study found most foods and beverages at New Zealand sports events were energy-dense and nutrient-poor. Caterers’ control over food provision, socio-cultural attitudes which view unhealthy foods as normal, and a dominant profit motive, appear to be the key factors influencing the food environment in sports settings. Food environments in sport settings provide frequent opportunities to purchase and consume energy-dense, nutrient-poor foods. The research shows we have competing players in the sports context—unhealthy food and healthy physical activity. Achieving sustainable healthy change in sports settings will be challenging when the prevailing attitude normalizes the unhealthy environment. Nutrition policies in sports clubs are urgently needed to increase the availability of healthy food. This requires support from health agencies and leadership from national sports organizations. Given the international nature of the food industry and sport, these findings from New Zealand may assist other countries to better understand the nature of food in sport and adopt appropriate interventions to reduce the obesogenic environment that is sport.
Suspected Exposure to Filoviruses Among People Contacting Wildlife in Southwestern Uganda
Authors: Smiley Evans Tierra , Tutaryebwa Leonard , Gilardi Kirsten V , Barry Peter A , Marzi Andrea , Eberhardt Meghan , Ssebide Benard , Cranfield Michael R , Mugisha Obed , Mugisha Emmanuel , Kellermann Scott , Mazet Jonna A K , Johnson Christine K
Published: May 2018

Background

Human and filovirus host interactions remain poorly understood in areas where Ebola hemorrhagic fever outbreaks are likely to occur. In the Bwindi region of Uganda, a hot spot of mammalian biodiversity in Africa, human livelihoods are intimately connected with wildlife, creating potential for exposure to filoviruses.

Methods

We tested samples from 331 febrile patients presenting to healthcare facilities near Bwindi Impenetrable Forest, Uganda, by polymerase chain reaction (PCR) analysis and Western blot, using recombinant glycoprotein antigens for Ebola virus (EBOV), Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus. Behavioral data on contact with wildlife were collected to examine risk factors for filovirus seropositivity.

Results

All patients were negative for active filovirus infection, by PCR analysis. However, patients were seroreactive to SUDV (4.7%), EBOV (5.3%), and BDBV (8.9%), indicating previous exposure. Touching duikers was the most significant risk factor associated with EBOV seropositivity, while hunting primates and touching and/or eating cane rats were significant risk factors for SUDV seropositivity.

Conclusions

People in southwestern Uganda have suspected previous exposure to filoviruses, particularly those with a history of wildlife contact. Circulation of filoviruses in wild animals and subsequent spillover into humans could be more common than previously reported.
Using Birth Cohort Data to Assess the Impact of the UK 2008–2010 Economic Recession on Smoking During Pregnancy
Authors: Uphoff Eleonora P , Small Neil , Pickett Kate E
Published: May 2018

Introduction

Despite the well-known link between stress and smoking, evidence for associations between economic recession, financial stress, and smoking is contradictory. In this study, we assess whether women were more likely to continue smoking during pregnancy if they were exposed to the UK 2008–2010 economic recession during pregnancy than those who were unexposed, and whether this relationship is mediated by financial stress.

Methods

We used cross-sectional data on 2775 pregnant women who were regular smokers before pregnancy and who were enrolled in the UK Born in Bradford cohort study between March 2007 and December 2010. The cutoff date for exposure to recession was set as August 1, 2008, based on local and national economic data. Multivariable logistic regression analysis included potential confounders: maternal age, parity, cohabitation, ethnicity, and maternal age. The mediating role of financial stress was analyzed using “worse off financially” and a “difficult financial situation” as indicators of financial stress in Sobel–Goodman mediation tests with bootstrap resampling.

Results

After taking into account potential confounders, exposure to recession was associated with continued smoking during pregnancy (OR = 1.19, 95% CI = 1.01 to 1.41, p = 0.03). A worse financial situation and a difficult financial situation were identified as mediators, explaining 8.4% and 17.6%, respectively, of the relationship between exposure to recession and smoking during pregnancy.

Conclusions

Smoking during pregnancy is associated with exposure to the UK 2008–2010 economic recession during pregnancy, and this relationship is partly mediated by financial stress.

Implications

Health inequalities in smoking during pregnancy are affected by economic recession, as those who are most likely to smoke are also most likely to experience the financial stress resulting from economic recession. Socioeconomic conditions at the societal and individual level are important targets when aiming to reduce rates of smoking during pregnancy.
Electronic Cigarette and Cigarette Social Environments and Ever Use of Each Product: A Prospective Study of Young Adults in Southern California
Authors: Urman Robert , McConnell Rob , Unger Jennifer B , Cruz Tess B , Samet Jonathan M , Berhane Kiros , Barrington-Trimis Jessica L
Published: May 2018

Background

A supportive youth cigarette social environment, for example, friends’ approval of use, leads to cigarette use initiation, and cigarette users develop a more supportive social environment. Whether there is a bidirectional relationship of electronic cigarette (e-cigarette) social environment with e-cigarette use has not been studied.

Methods

Prospective data were collected from 1441 Children’s Health Study participants in 2014 (median age = 17.3 years) and at follow-up 1.5 years later. Associations were examined of (1) supportive e-cigarette social environment with subsequent e-cigarette use initiation and (2) baseline e-cigarette use with supportive e-cigarette social environment at follow-up (among those with a nonsupportive baseline social environment).

Results

Participants with three to four friends using e-cigarettes at baseline (vs. no friends) had an odds ratio (OR) of 4.08 of subsequent initiation (95% confidence interval [CI] = 1.96 to 8.49); those with best friends who would have a very friendly (vs. unfriendly) reaction to e-cigarette use had an OR of 2.54 of initiation (95% CI = 1.57 to 4.10); and those with someone in the home using e-cigarettes had an OR of 1.94 of initiation (95% CI = 1.19 to 3.15). Participants who had ever used e-cigarettes at baseline developed a supportive social environment at follow-up (OR of 2.06 of having any friends who used e-cigarettes [95% CI = 1.29 to 3.30] and OR of 2.33 of having friends who were friendly toward use [95% CI = 1.32 to 4.11]). Similar bidirectional associations were observed between ever cigarette use and a supportive cigarette social environment.

Conclusions

The bidirectional relationship between a supportive e-cigarette social environment and ever use of e-cigarettes was similar to that previously observed between cigarette social environment and cigarette use.

Implications

Disrupting the social acceptability of youth e-cigarette use merits consideration as a strategy for preventing initiation of e-cigarette use, just as the social denormalization of cigarette use has proven to be effective in preventing cigarette initiation.
Physical Activity, Sedentary Time, and Associated Factors in Recipients of Solid-Organ Transplantation
Authors: van Adrichem Edwin J , Dekker Rienk , Krijnen Wim P , Verschuuren Erik A M , Dijkstra Pieter U , van der Schans Cees P
Published: May 2018

Background

Short-term survival after solid-organ transplantation has substantially improved, and the focus has shifted to long-term survival, including the role of physical activity (PA). Knowledge about PA and sedentary time in recipients of solid-organ transplantation is limited, and identification of the levels and associated factors is necessary for intervention development.

Objective

The objectives of this study were to investigate the level of PA and sedentary time in recipients of solid-organ transplantation and to identify factors associated with these behaviors.

Design

The design consisted of a cross-sectional survey.

Methods

Questionnaires on PA level, sedentary time, and potential associated factors were used for recipients of solid-organ transplantation (kidney, liver, lung, and heart [N = 656]). Multiple regression analyses with a variable selection procedure were used.

Results

Fewer than 60% of the recipients fulfilled the PA guideline. Factors significantly associated with a lower level of PA included being a woman, younger age (nonlinear), not actively working or being retired, physical limitations, and low expectations and self–confidence. Factors significantly associated with less sedentary time included exercise self-efficacy and not actively working or being retired. Significantly associated with more sedentary time were a high education level, fear of negative effects, physical limitations, and the motivator “health and physical outcomes.” The type of transplantation did not significantly influence either of the outcome measures.

Limitations

The design did not allow for causal inferences to be made. The studied associated factors were limited to individual and interpersonal factors. Self-reported measures of PA and sedentary time were used.

Conclusions

In intervention development directed at increasing the level of PA and reducing sedentary time in recipients of solid-organ transplantation, attention should be paid to physical limitations, fear of negative effects, low expectations and self-confidence, health and physical outcomes, and exercise self-efficacy.
Two stage reconstruction of flexor tendon injuries in zone II after missed injury or failed repair
Authors: Abed Yasser Youssef , Nour Khaled Ayman , Ahmed Moheib Saed , El Negery Abed Abd el latif
Published: May 2018

Background:

Reconstruction of flexor tendon injury of the hand after failed tendon repair or missed injury is a technically challenging problem. Repair of the tendon within the thin tight pulley system usually invites the formation of adhesion and failure of repair. A combination of a technique described by Paneva-Holevich and Hunter has been used for this problem with variable results.

Methods:

Twenty-five flexor tendons in 20 patients were reconstructed using a two-stage reconstruction of the flexor tendon injury. The preoperative condition of the finger was evaluated using Boyes and Stark grading modified by Wehbe et al. and all had a poor prognosis. The primary tendon injury was missed in nine patients. Primary tendon repair failed in seven patients and free tendon graft failed in three. One patient had two operative interventions: one failed primary tendon repair and one failed free tendon graft. The dominant hand was affected in (70%) of patients.

Results:

The average time between the original injury and the first stage operation was 10.6 mo. The mean follow-up after the second stage was 72 mo. The mean strength of pinch grip and power grip were 92.4% and 94.8%, respectively. The mean pulp to distal flexion crease distance was 12.32 mm. According to Buck-Gramcko scoring, excellent results were achieved in 18 fingers (72%), good in five fingers (20%), fair in one (4%), and poor in one (4%). No additional surgery was required after the second stage.

Conclusions:

The two-stage pedicled flexor digitorum superficialis technique provided a reliable and effective method for reconstruction of failed repair or missed injury of the flexor tendon in the hand in zone II. The modification of the technique presented in this study achieved a high rate of excellent and good results without increasing the rate of complications. Patient compliance is critical for the success of this procedure.
Nipple-Areola Complex Sensation after Nipple-sparing Mastectomy
Authors: Chirappapha Prakasit , Srichan Pongsakorn , Lertsithichai Panuwat , Thaweepworadej Panya , Sukarayothin Thongchai , Leesombatpaiboon Monchai , Kongdan Youwanush
Published: May 2018

Background:

Nipple-sparing mastectomy (NSM) has been proven to be oncologically safe for treating breast cancer. This procedure had been developed to optimize the esthetic outcome and reduce feeling mutilation after mastectomy. Risks of necrotic complications and diminishing nipple-areola complex (NAC) sensation are common complications affecting the patient’s satisfaction after the surgery. The evaluation of NAC sensation should be also investigated.

Methods:

We prospectively analyzed 55 NSMs that were performed on 52 patients for both therapeutic and prophylactic indications in Ramathibodi Hospital from May 2007 to September 2015. Patients’ demographics, operative details, oncologic outcome, and postoperative complications, focusing on NAC sensation and necrotic complications, were analyzed.

Results:

Forty-seven NSMs (87%) were performed for therapeutic indications, and another 7 NSMs (13%) were risk-reducing operations. Of the 43 patients performing NSM for breast cancer treatment, 33 patients (77%) had invasive cancer and 11 patients (23%) had ductal carcinoma in situ. One subareola base tissue was found an occult cancer, and the NAC was then removed. There were 3 locoregional recurrences after a median follow-up time of 24 months (range, 2–104 months). The NAC sensation was evaluated in a total of 35 patients. Twenty-five patients (46%) underwent serial evaluation after 6 months of operation, and 10 patients were evaluated at more than 1 year after operation. In the first 6 months, 11 patients (44%) showed partial sensation recovery, and 3 more patients had partial recovery after 1-year follow-up. Only 1 patient (2%) had complete sensation recovery in all area of the NAC. In late evaluation group, 7 out of 10 patients had partial recovery. Most pain sensation remained in the lower aspect of the areola away from surgical incision.

Conclusions:

NSM is technically feasible in selected patients with low rates of NAC removal. Some patients can preserve the NAC sensation. Long-term outcome should receive follow-up.
Early Versus Standard Colonoscopy
Authors: van Rongen Inge , Thomassen Bregje J.W. , Perk Lars E.
Published: May 2018

Goals:

The aim of our study was to examine differences in length of hospital stay (LOHS) between patients with lower gastrointestinal bleeding who received either an early colonoscopy (within 24 h of presentation) or a standard colonoscopy (within 1 to 3 d).

Background:

Diagnostic management of lower gastrointestinal bleeding has been extensively debated in recent literature, especially whether colonoscopy within 24 hours of presentation is feasible and safe.

Study:

In this single center, nonblinded, randomized controlled trial, patients presenting at the emergency department with acute hematochezia were eligible if they required hospital admission. A total of 132 patients were included. Primary outcome was LOHS. Secondary outcomes included yield of colonoscopy, blood transfusion requirements, recurrent bleedings, complications, interventions related to complications, and 30-day mortality. The follow-up period was 1 month.

Results:

In total, 63 patients were randomized for <24 hours colonoscopy and 69 for standard colonoscopy. In the intention to treat analysis, LOHS was significantly lower in patients that underwent an early colonoscopy, compared with the standard group: median 2.0 days (inter quartile range, 2.0 to 4.0) versus median 3.0 days (inter quartile range, 2.0 to 4.0) (P=0.009). Recurrent bleedings and hospital readmissions were significantly more frequent in the <24-hour group: 13% versus 3% (P=0.04) and 11% versus 2% (P=0.02), respectively. No difference was observed regarding the number of patients diagnosed with a confirmed or presumptive bleeding source. In both groups, blood transfusion rate was similar and 30-day mortality was 0.

Conclusions:

Early colonoscopy reduces LOHS, but also results in lower clinical efficacy compared with standard colonoscopy.
Clinical and Radiographic Response of Extramedullary Leukemia in Patients Treated With Gemtuzumab Ozogamicin
Authors: McNeil Michael J. , Parisi Marguerite T. , Hijiya Nobuko , Meshinchi Soheil , Cooper Todd , Tarlock Katherine
Published: May 2018

Extramedullary leukemia (EML) is common in pediatric acute leukemia and can present at diagnosis or relapse. CD33 is detected on the surface of myeloid blasts in many patients with acute myelogenous leukemia and is the target of the antibody drug conjugate gemtuzumab ozogamicin (GO). Here we present 2 patients with CD33+ EML treated with GO. They achieved significant response, with reduction of EML on both clinical and radiographic exams, specifically 18fluorine fluorodeoxyglucose positron emission tomography/computed tomography, demonstrating potential for targeted therapy with GO as a means of treating EML in patients with CD33+ leukemia and the utility of 18fluorine fluorodeoxyglucose positron emission tomography/computed tomography monitoring in EML.
The nicotinic acetylcholine receptor: a typical ‘allosteric machine’
Authors: Changeux Jean-Pierre
Published: May 2018

The concept of allosteric interaction was initially proposed to account for the inhibitory feedback mechanism mediated by bacterial regulatory enzymes. In contrast with the classical mechanism of competitive, steric, interaction between ligands for a common site, allosteric interactions take place between topographically distinct sites and are mediated by a discrete and reversible conformational change of the protein. The concept was soon extended to membrane receptors for neurotransmitters and shown to apply to the signal transduction process which, in the case of the acetylcholine nicotinic receptor (nAChR), links the ACh binding site to the ion channel. Pharmacological effectors, referred to as allosteric modulators, such as Ca
2+
ions and ivermectin, were discovered that enhance the transduction process when they bind to sites distinct from the orthosteric ACh site and the ion channel. The recent X-ray and electron microscopy structures, at atomic resolution, of the resting and active conformations of several homologues of the nAChR, in combination with atomistic molecular dynamics simulations reveal a stepwise quaternary transition in the transduction process with tertiary changes modifying the boundaries between subunits. These interfaces host orthosteric and allosteric modulatory sites which structural organization changes in the course of the transition. The nAChR appears as a typical allosteric machine. The model emerging from these studies has led to the conception and development of several new pharmacological agents.

This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
Intra-molecular pathways of allosteric control in Hsp70s
Authors: Mayer Matthias P.
Published: May 2018

The 70 kDa heat-shock protein (Hsp70) is undoubtedly the most versatile of all molecular chaperones. Hsp70 is involved in numerous cellular protein folding processes, accompanying proteins throughout their lifespan from de novo folding at the ribosome to degradation at the proteasome, surveilling protein stability and functionality. Several properties of this ATP-dependent chaperone constitute the molecular basis for this versatility. With its substrate binding domain (SBD), Hsp70 transiently interacts with a short degenerative linear sequence motif found practically in all proteins and, in addition, with more folded protein conformers. Binding to polypeptides is tightly regulated by ATP binding and hydrolysis in the nucleotide binding domain, which is coupled to the SBD by an intricate allosteric mechanism. Hsp70 is regulated by a host of J-cochaperones, which act as targeting factors by regulating the ATPase activity of Hsp70 in synergism with the substrates themselves, and by several families of nucleotide exchange factors. In this review, I focus on the allosteric mechanism, which allows Hsp70s to interact with substrates with ultrahigh affinity through a non-equilibrium mode of action and summarize what mutagenesis and structural studies have taught us about the pathways and mechanics of interdomain communication.

This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
Folding cooperativity and allosteric function in the tandem-repeat protein class
Authors: Perez-Riba Albert , Synakewicz Marie , Itzhaki Laura S.
Published: May 2018

The term allostery was originally developed to describe structural changes in one binding site induced by the interaction of a partner molecule with a distant binding site, and it has been studied in depth in the field of enzymology. Here, we discuss the concept of action at a distance in relation to the folding and function of the solenoid class of tandem-repeat proteins such as tetratricopeptide repeats (TPRs) and ankyrin repeats. Distantly located repeats fold cooperatively, even though only nearest-neighbour interactions exist in these proteins. A number of repeat-protein scaffolds have been reported to display allosteric effects, transferred through the repeat array, that enable them to direct the activity of the multi-subunit enzymes within which they reside. We also highlight a recently identified group of tandem-repeat proteins, the RRPNN subclass of TPRs, recent crystal structures of which indicate that they function as allosteric switches to modulate multiple bacterial quorum-sensing mechanisms. We believe that the folding cooperativity of tandem-repeat proteins and the biophysical mechanisms that transform them into allosteric switches are intimately intertwined. This opinion piece aims to combine our understanding of the two areas and develop ideas on their common underlying principles.

This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
The substrate specificity of eukaryotic cytosolic chaperonin CCT
Authors: Willison Keith R.
Published: May 2018

The cytosolic chaperonin CCT (chaperonin containing TCP-1) is an ATP-dependent double-ring protein machine mediating the folding of members of the eukaryotic cytoskeletal protein families. The actins and tubulins are obligate substrates of CCT because they are completely dependent on CCT activity to reach their native states. Genetic and proteomic analysis of the CCT interactome in the yeast
Saccharomyces cerevisiae
revealed a CCT network of approximately 300 genes and proteins involved in many fundamental biological processes. We classified network members into sets such as substrates, CCT cofactors and CCT-mediated assembly processes. Many members of the 7-bladed propeller family of proteins are commonly found tightly bound to CCT isolated from human and plant cells and yeasts. The anaphase promoting complex (APC/C) cofactor propellers, Cdh1p and Cdc20p, are also obligate substrates since they both require CCT for folding and functional activation.
In vitro
translation analysis in prokaryotic and eukaryotic cell extracts of a set of yeast propellers demonstrates their highly differential interactions with CCT and GroEL (another chaperonin). Individual propeller proteins have idiosyncratic interaction modes with CCT because they emerged independently with neo-functions many times throughout eukaryotic evolution. We present a toy model in which cytoskeletal protein biogenesis and folding flux through CCT couples cell growth and size control to time dependent cell cycle mechanisms.

This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
Optic nerve intraneural stimulation allows selective visual cortex activation
Authors: Gaillet Vivien , Cutrone Annarita , Vagni Paola , Artoni Fiorenzo , Pinto Sandra Alejandra Romero , Di Paola Dario Lipucci , Micera Silvestro , Ghezzi Diego
Published: May 2018

Retinal prostheses have been developed to restore a functional form of vision in patients affected by outer retinal layer dystrophies. Other approaches, namely optic nerve, thalamic, and cortical prostheses are under investigation to expand this toolbox both as clinical devices and as tools for fundamental research. Optic nerve stimulation is attractive since it bypasses the entire retinal network and directly activates nerve fibers. At the same time, it still takes advantage of the high-level information processing occurring downstream in the visual cortex. Here we show that a new intraneural electrode array (OpticSELINE) is effective in inducing the activation of the visual cortex upon electrical stimulation of the optic nerve. We also demonstrate that intraneural optic nerve stimulation induces selective cortical activation patterns depending on the stimulating electrode, thus suggesting that the OpticSELINE possesses spatial selectivity in fiber stimulation. In conclusion, the OpticSELINE can be used both as visual prosthesis for blind patients and as tool to further investigate the effect of the electrical stimulation in the visual system.
Structure for Energy Cycle: A unique status of Second Law of Thermodynamics for living systems
Authors: Bai Shu-Nong , Ge Hao , Qian Hong
Published: May 2018

Distinguishing things from beings, or matters from lives, is a fundamental question. Extending E. Schrödinger’sneg-entropyand I. Prigogine’sdissipative structure, we propose a chemical kinetic view that the earliest “live” process is essentially a special interaction between a pair of specific components under a corresponding, particular environmental conditions. The interaction exists as an inter-molecular-force-bond complex (IMFBC) that couples two separate chemical processes: One is the spontaneous formation of an IMFBC driven by the decrease of Gibbs free energy as a dissipative process; while the other is the disassembly of the IMFBC driven thermodynamically by free energy input from the environment. The two processes that are coupled by the IMFBC were originated independently and considered non-living on Earth, but the IMFBC coupling of the two can be considered as the earliest form of metabolism: This forms the first landmark on the path from things to a being. The dynamic formation and dissemblance of the IMFBCs, as composite individuals, follows a principle designated as “… structure for energy for structure for energy…”, the cycle continues, shortly “structure for energy cycle”. With additional features derived from an IMFBC, such as multiple intermediates, autocatalytic ability of one individual upon the formation of another, aqueous medium, and mutual beneficial relationship between formation of polypeptides and nucleic acids, etc., the IMFBC-centered “live” process spontaneously evolved into more complex living organisms with the characteristics one currently knows.
matchSCore: Matching Single-Cell Phenotypes Across Tools and Experiments
Authors: Mereu Elisabetta , Iacono Giovanni , Guillaumet-Adkins Amy , Moutinho Catia , Lunazzi Giulia , Santos Catarina P. , Miguel-Escalada Irene , Ferrer Jorge , Real Francisco X. , Gut Ivo , Heyn Holger
Published: May 2018

Single-cell transcriptomics allows the identification of cellular types, subtypes and states through cell clustering. In this process, similar cells are grouped before determining co-expressed marker genes for phenotype inference. The performance of computational tools is directly associated to their marker identification accuracy, but the lack of an optimal solution challenges a systematic method comparison. Moreover, phenotypes from different studies are challenging to integrate, due to varying resolution, methodology and experimental design. In this work we introduce matchSCore (https://github.com/elimereu/matchSCore), an approach to match cell populations fast across tools, experiments and technologies. We compared 14 computational methods and evaluated their accuracy in clustering and gene marker identification in simulated data sets. We further used matchSCore to project cell type identities across mouse and human cell atlas projects. Despite originating from different technologies, cell populations could be matched across data sets, allowing the assignment of clusters to reference maps and their annotation.
Antibiotic-induced dysbiosis predicts mortality in an animal model ofClostridium difficileinfection
Authors: Burdet Charles , Sayah-Jeanne Sakina , Nguyen Thu Thuy , Hugon Perrine , Sablier-Gallis Frédérique , Saint-Lu Nathalie , Corbel Tanguy , Ferreira Stéphanie , Pulse Mark , Weiss William , Andremont Antoine , Mentré France , Gunzburg Jean de
Published: May 2018

Background

Antibiotic disruption of the intestinal microbiota favors colonization byClostridium difficile. Using a charcoal-based adsorbent to decrease intestinal antibiotic concentrations, we studied the relationship between antibiotic concentrations in feces and the intensity of dysbiosis, and quantified the link between this intensity and mortality.

Methods

We administered either moxifloxacin (n=70) or clindamycin (n=60) to hamsters by subcutaneous injection from day 1 (D1) to D5, and challenged them with aC. difficiletoxigenic strain at D3. Hamsters received various doses of a charcoal-based adsorbent, DAV131A, to modulate intestinal antibiotic concentrations. Gut dysbiosis was evaluated at D0and D3using diversity indices determined from 16S rRNA gene profiling. Survival was monitored until D16. We analyzed the relationship between fecal antibiotic concentrations and dysbiosis at the time ofC. difficilechallenge and studied their capacity to predict subsequent death of the animals.

Results

Increasing doses of DAV131A reduced fecal concentrations of both antibiotics, lowered dysbiosis and increased survival from 0% to 100%. Mortality was related to the level of dysbiosis (p<10−5for the change of Shannon index in moxifloxacin-treated animals and p<10−9in clindamycin-treated animals). The Shannon diversity index and unweighted UniFrac distance best predicted death, with areas under the ROC curve of 0.89 [95%CI, 0.82;0.95] and 0.95 [0.90;0.98], respectively.

Conclusions

Altogether, moxifloxacin and clindamycin disrupted the diversity of the intestinal microbiota with a dependency to the DAV131A dose; mortality afterC. difficilechallenge was related to the intensity of dysbiosis in a similar manner with the two antibiotics.
Intercellular Signaling Network Underlies Biological Time Across Multiple Temporal Scales
Authors: Millstein Joshua , Summa Keith C. , Yang Xia , Zhu Jun , Mi Huaiyu , Vitaterna Martha H. , Turek Fred W. , Zhang Bin
Published: May 2018

Motivation

Cellular, physiological and molecular processes must be organized and regulated across multiple time domains throughout the lifespan of an organism. The technological revolution in molecular biology has led to the identification of numerous genes implicated in the regulation of diverse temporal biological processes. However, it is natural to question whether there is an underlying regulatory network governing multiple timescales simultaneously.

Results

Using queries of relevant databases and literature searches, a single dense multiscale temporal regulatory network was identified involving core sets of genes that regulate circadian, cell cycle, and aging processes. The network was highly enriched for genes involved in signal transduction (P = 1.82e-82), with p53 and its regulators such as p300 and CREB binding protein forming key hubs, but also for genes involved in metabolism (P = 6.07e-127) and cellular response to stress (P = 1.56e-93). These results suggest an intertwined molecular signaling network that affects biological time across multiple temporal scales in response to environmental stimuli and available resources.

Contact

joshua.millstein@usc.edu

Supplementary information

Supplementary data are available online.
High-throughput Analysis of Arabidopsis Stem Vibrations to Identify Mutants with Altered Mechanical Properties
Authors: Nakata Miyuki T. , Takahara Masahiro , Sakamoto Shingo , Yoshida Kouki , Mitsuda Nobutaka
Published: May 2018

Mechanical properties are rarely used as quantitative indices for the large-scale mutant screening of plants, even in the model plant Arabidopsis thaliana. The mechanical properties of plant stems generally influence their vibrational characteristics. Here, we developed Python-based software, named AraVib, for the high-throughput analysis of free vibrations of plant stems, focusing specifically on Arabidopsis stem vibrations, and its extended version, named AraVibS, to identify mutants with altered mechanical properties. These programs can be used without knowledge of Python and require only an inexpensive handmade setting stand and an iPhone/iPad with a high-speed shooting function for data acquisition. Using our system, we identified an nst1 nst3 double-mutant lacking secondary cell walls in fiber cells and a wrky12 mutant displaying ectopic formation of secondary cell wall compared with wild type by employing only two growth traits (stem height and fresh weight) in addition to videos of stem vibrations. Furthermore, we calculated the logarithmic decrement, the damping ratio, the natural frequency and the stiffness based on the spring-mass-damper model from the video data using AraVib. The stiffness was estimated to be drastically decreased in nst1 nst3, which agreed with previous tensile test results. However, in wrky12, the stiffness was significantly increased. These results demonstrate the effectiveness of our new system. Because our method can be applied in a high-throughput manner, it can be used to screen for mutants with altered mechanical properties.
Self-similarity and multifractality in human brain activity: a wavelet-based analysis of scale-free brain dynamics☆
Authors: La Rocca Daria , Zilber Nicolas , Abry Patrice , van Wassenhove Virginie , Ciuciu Philippe
Published: May 2018

Background

The temporal structure of macroscopic brain activity displays both oscillatory and scale-free dynamics. While the functional relevance of neural oscillations has been largely investigated, both the nature and the role of scale-free dynamics in brain processing have been disputed.

New Method

Here, we offer a novel method to rigorously enrich the characterization of scale-free brain activity using a robust wavelet-based assessment of self-similarity and multifractality. For this, we analyzed human brain activity recorded with magnetoencephalography (MEG) while participants were at rest or performing a task.

Results

First, we report consistent infraslow (from 0.1 to 1.5 Hz) scalefree dynamics (i.e., self-similarity and multifractality) in resting-state and task data. Second, we observed a fronto-occipital gradient of self-similarity reminiscent of the known hierarchy of temporal scales from sensory to higherorder cortices; the anatomical gradient was more pronounced in task than in rest. Third, we observed a significant increase of multifractality during task as compared to rest. Additionally, the decrease in self-similarity and the increase in multifractality from rest to task were negatively correlated in regions involved in the task, suggesting a shift from structured global temporal dynamics in resting-state to locally bursty and non Gaussian scalefree structures during task.

Comparison with Existing Method(s)

We showed that the wavelet leader based multifractal approach extends power spectrum estimation methods in the way of characterizing finely scale-free brain dynamics.

Conclusions

Altogether, our approach provides novel fine-grained characterizations of scale-free dynamics in human brain activity.

Highlights

We estimated scale-free human brain dynamics using wavelet-leader formalism.

High-to-low self-similarity defined a fronto-occipital gradient.

The gradient was enhanced in task compared to resting-state.

Scale-free brain dynamics showed multifractal properties.

Self-similarity decreased whereas multifractality increased from rest to task.
Integrative analysis of single cell expression data reveals distinct regulatory states in bidirectional promoters
Authors: Ardakani Fatemeh Behjati , Kattler Kathrin , Nordström Karl , Gasparoni Nina , Gasparoni Gilles , Fuchs Sarah , Sinha Anupam , Barann Matthias , Ebert Peter , Fischer Jonas , Hutter Barbara , Zipprich Gideon , Felder Bärbel , Eils Jürgen , Brors Benedikt , Lengauer Thomas , Manke Thomas , Rosenstiel Philip , Walter Jörn , Schulz Marcel H.
Published: May 2018

Background

Bidirectional promoters (BPs) are prevalent in eukaryotic genomes. However, it is poorly understood how the cell integrates different epigenomic information, such as transcription factor (TF) binding and chromatin marks, to drive gene expression at BPs. Single cell sequencing technologies are revolutionizing the field of genome biology. Therefore, this study focuses on the integration of single cell RNA-seq data with bulk ChIP-seq and other epigenetics data, for which single cell technologies are not yet established, in the context of BPs.

Results

We performed integrative analyses of novel human single cell RNA-seq (scRNA-seq) data with bulk ChIP-seq and other epigenetics data. scRNA-seq data revealed distinct transcription states of BPs that were previously not recognized. We find associations between these transcription states to distinct patterns in structural gene features, DNA accessibility, histone modification, DNA methylation and TF binding profiles.

Conclusions

Our results suggest that a complex interplay of all of these elements is required to achieve BP-specific transcriptional output in this specialized promoter configuration. Further, our study implies that novel statistical methods can be developed to deconvolute masked subpopulations of cells measured with different bulk epigenomic assays using scRNA-seq data.
Coiled Coil-Mediated Assembly of an Icosahedral Protein Cage with Extremely High Thermal and Chemical Stability
Authors: Cristie-David Ajitha S. , Chen Junjie , Nowak Derek B. , Park Sung I. , Banaszak Holl Mark M. , Su Min , Marsh E. Neil G.
Published: May 2018

The organization of protein molecules into higher-order nanoscale architectures is ubiquitous in Nature and represents an important goal in synthetic biology. Here we describe the symmetry-directed design of a hollow protein cage with dimensions similar to those of many icosahedral viruses. The cage was constructed based on icosahedral symmetry by genetically fusing a trimeric protein (TriEst) to a small pentameric de novo-designed coiled coil domain, separated by a flexible oligo-glycine linker sequence. Screening a small library of designs in which the linker length varied from 2 to 12 residues identified a construct containing 8 glycine residues (Ico8) that formed well-defined cages. Characterization by dynamic light scattering, negative stain and cryo EM, and by atomic force and IR-photo-induced force microscopy established that Ico8 assembles into a flexible hollow cage with comprising 60-subunits with overall icosahedral geometry. Unexpectedly, the cages were found to encapsulate DNA, even though neither protein component binds nucleic acids on its own. Notably, the cages formed by Ico8 proved to be extremely stable towards thermal and chemical denaturation: whereas TriEst was unfolded by heating (Tm ~75 °C) or denatured by 1.5 M guanidine hydrochloride, the Ico8 cages remained folded even at 120 °C or in 8 M guanidine hydrochloride. The encapsulation of DNA and increased stability of the cages are new properties that emerge from the higher order structure of the protein cage, rather than being intrinsic to the components from which it is constructed.
N-linked glycosylation of the antagonist Short gastrulation increases the functional complexity of BMP signals
Authors: Negreiros E. , Herszterg S. , Hwa K. , Câmara A. , Dias W.B. , Carneiro K. , Bier E. , Todeschini A. , Araujo H.
Published: May 2018

Disorders of N-linked glycosylation are increasingly reported in the literature. However, targets responsible for the associated developmental and physiological defects are largely unknown. Bone Morphogenetic Proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.

Summary Statement

N-glycosylation restricts the function of Short gastrulation during Drosophila development by controlling the amount of extracellular protein. This adds another layer of complexity to regulation of Bone Morphogenetic Protein signals.
Detection and analysis of ancient segmental duplications in mammalian genomes
Authors: Pu Lianrong , Lin Yu , Pevzner Pavel A.
Published: May 2018

Although segmental duplications (SDs) represent hotbeds for genomic rearrangements and emergence of new genes, there are still no easy-to-use tools for identifying SDs. Moreover, while most previous studies focused on recently emerged SDs, detection of ancient SDs remains an open problem. We developed an SDquest algorithm for SD finding and applied it to analyzing SDs in human, gorilla, and mouse genomes. Our results demonstrate that previous studies missed many SDs in these genomes and show that SDs account for at least 6.05% of the human genome (version hg19), a 17% increase as compared to the previous estimate. Moreover, SDquest classified 6.42% of the latest GRCh38 version of the human genome as SDs, a large increase as compared to previous studies. We thus propose to re-evaluate evolution of SDs based on their accurate representation across multiple genomes. Toward this goal, we analyzed the complex mosaic structure of SDs and decomposed mosaic SDs into elementary SDs, a prerequisite for follow-up evolutionary analysis. We also introduced the concept of the breakpoint graph of mosaic SDs that revealed SD hotspots and suggested that some SDs may have originated from circular extrachromosomal DNA (ecDNA), not unlike ecDNA that contributes to accelerated evolution in cancer.
Treatment outcome and prognostic factors of tonsillectomy for palmoplantar pustulosis and pustulotic arthro‐osteitis: A retrospective subjective and objective quantitative analysis of 138 patients
Authors: Takahara Miki , Hirata Yui , Nagato Toshihiro , Kishibe Kan , Katada Akihiko , Hayashi Tatsuya , Kishibe Mari , Ishida‐Yamamoto Akemi , Harabuchi Yasuaki
Published: May 2018

Pustulosis palmaris et plantaris (PPP) and pustulotic arthro‐osteitis (PAO) are tonsil‐related diseases. Treatment outcome of tonsillectomy and prognostic factors influencing the outcome have not been analyzed quantitatively. We evaluated those using the Palmoplantar Pustulosis Area and Severity Index (PPPASI). At 1, 3, 6, 12, 24 and more than 24 months post‐tonsillectomy, 20 (31%), 34 (48%), 70 (60%), 57 (80%), 36 (95%) and 23 (96%) patients realized 80% or more improvement of PPP skin lesions, respectively, and eight (17%), 23 (36%), 30 (50%), 38 (79%), 12 (100%) and four (100%) patients showed 80% or more improvement of PPPASI (i.e. PPPASI% ≥ 80%), respectively. At 1, 3, 6, 12 and more than 12 months post‐tonsillectomy, 19 (73%), 21 (66%), 27 (73%), 19 (79%) and 15 (83%) patients realized a disappearance of PAO‐induced arthralgia, respectively. Kaplan–Meier analysis of 80 patients with PPP revealed that, at 12 and 24 months post‐tonsillectomy, lesions disappeared (i.e. PPPASI = 0) in 38% and 66% of patients, respectively, and lesions improved by 80% or more (i.e. PPPASI% ≥ 80%) in 71% and 95% of patients, respectively. The log–rank test and univariate and multivariate analyses showed that smoking cessation post‐tonsillectomy and PAO were significant predictive factors for the early disappearance of skin lesions. This report is the first demonstrating objective evidence of the great efficacy of tonsillectomy to improve PPP skin lesions. Even post‐tonsillectomy, smoking inhibited the early disappearance of the lesions.