bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic and biochemical analysis of an international cohort of individuals with variants in NAA10 and NAA15
Authors: Cheng Hanyin , Gottlieb Leah , Marchi Elaine , Kleyner Robert , Bhardwaj Puja , Rope Alan F , Rosenheck Sarah , Moutton Sébastien , Philippe Christophe , Eyaid Wafaa , Alkuraya Fowzan S , Toribio Janet , Mena Rafael , Prada Carlos E , Stessman Holly , Bernier Raphael , Wermuth Marieke , Kauffmann Birgit , Blaumeiser Bettina , Kooy R Frank , Baralle Diana , Mancini Grazia M S , Conway Simon J , Xia Fan , Chen Zhao , Meng Linyan , Mihajlovic Ljubisa , Marmorstein Ronen , Lyon Gholson J
Published: May 2019

N-alpha-acetylation is one of the most common co-translational protein modifications in humans and is essential for normal cell function. NAA10 encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. The auxiliary and regulatory subunits of the NatA complex are NAA15 and Huntington-interacting protein (HYPK), respectively. Through a genotype-first approach with exome sequencing, we identified and phenotypically characterized 30 individuals from 30 unrelated families with 17 different de novo or inherited, dominantly acting missense variants in NAA10 or NAA15. Clinical features of affected individuals include variable levels of intellectual disability, delayed speech and motor milestones and autism spectrum disorder. Additionally, some subjects present with mild craniofacial dysmorphology, congenital cardiac anomalies and seizures. One of the individuals is an 11-year-old boy with a frameshift variant in exon 7 of NAA10, who presents most notably with microphthalmia, which confirms a prior finding with a single family with Lenz microphthalmia syndrome. Biochemical analyses of variants as part of the human NatA complex, as well as enzymatic analyses with and without the HYPK regulatory subunit, help to explain some of the phenotypic differences seen among the different variants.
Characterization of Stool Virome in Children Newly Diagnosed With Moderate to Severe Ulcerative Colitis
Authors: Tokarz Rafal , Hyams Jeffrey S , Mack David R , Boyle Brendan , Griffiths Anne M , LeLeiko Neal S , Sauer Cary G , Shah Sapana , Markowitz James , Baker Susan S , Rosh Joel , Baldassano Robert N , Kugathasan Subra , Walters Thomas , Tagliafierro Teresa , Sameroff Stephen , Lee Bohyun , Che Xiaoyu , Oleynik Alexandra , Denson Lee A , Lipkin W Ian
Published: May 2019

Background

Viral infections have been suggested as possible triggers for the onset of ulcerative colitis (UC).

Methods

We employed VirCapSeq-Vert, a high-throughput sequencing virus capture platform, to examine the stool virome of children with newly diagnosed moderate to severe UC. We surveyed fecal samples collected at presentation, after symptom remission, and from a control group diagnosed with irritable bowel syndrome.

Results

Seventy subjects with UC (mean age 13 years, 45 had moderate symptoms, 25 had severe, 69 of 70 had a Mayo endoscopy subscore 2/3) were studied. We detected a wide range of animal viruses that were taxonomically classified into 12 viral families. A virus was present in 50% of fecal samples collected at presentation, 41% of samples collected after remission, and 40% of samples in our control group. The most frequently identified viruses were diet-based gyroviruses. The UC cohort had a significantly higher prevalence of anelloviruses compared with the control cohort. However, we did not identify a single virus that can be implicated in the onset of UC and did not find an association between UC disease severity and viral presence.

Conclusion

Presence of virus in stool was not associated with the onset of pediatric UC.
Contrasting Responses of Lizards to Divergent Ecological Stressors Across Biological Levels of Organization
Authors: Telemeco Rory S , Simpson Dasia Y , Tylan Catherine , Langkilde Tracy , Schwartz Tonia S
Published: May 2019

It is frequently hypothesized that animals employ a generalized “stress response,” largely mediated by glucocorticoid (GC) hormones, such as corticosterone, to combat challenging environmental conditions. Under this hypothesis, diverse stressors are predicted to have concordant effects across biological levels of an organism. We tested the generalized stress response hypothesis in two complementary experiments with juvenile and adult male Eastern fence lizards (Sceloporus undulatus). In both experiments, animals were exposed to diverse, ecologically-relevant, acute stressors (high temperature or red imported fire ants, Solenopsis invicta) and we examined their responses at three biological levels: behavioral; physiological (endocrine [plasma corticosterone and blood glucose concentrations] and innate immunity [complement and natural antibodies]); and cellular responses (gene expression of a panel of five heat-shock proteins in blood and liver) at 30 or 90 min post stress initiation. In both experiments, we observed large differences in the cellular response to the two stressors, which contrasts the similar behavioral and endocrine responses. In the adult experiment for which we had innate immune data, the stressors affected immune function independently, and they were correlated with CORT in opposing directions. Taken together, these results challenge the concept of a generalized stress response. Rather, the stress response was context specific, especially at the cellular level. Such context-specificity might explain why attempts to link GC hormones with life history and fitness have proved difficult. Our results emphasize the need for indicators at multiple biological levels and whole-organism examinations of stress.
Reference levels of ecosystem indicators at multispecies maximum sustainable yield
Authors: Briton Florence , Shannon Lynne , Barrier Nicolas , Verley Philippe , Shin Yunne-Jai
Published: May 2019

We investigate reference points for ecosystem indicators in support of an Ecosystem Approach to Fishery. In particular, we assess indicator capacity to detect when the Multispecies Maximum Sustainable Yield (MMSY) is reached, under a wide range of multispecies fishing strategies. The analysis was carried out using a simulation approach based on the ecosystem model OSMOSE in the southern Benguela. We show that the 13 ecosystem indicators have reference points at MMSY that are highly variable across fishing strategies. The state of the ecosystem at MMSY is so variable across fishing strategies that it is not possible to set reference points without considering the fishing strategy. However, strategy-specific reference points were found to constitute robust proxies for MMSY in more than 90% of the simulated fishing strategies. For instance, under the current fishing strategy in the southern Benguela, robust reference points at MMSY could be identified for the following indicators: mean length of fish, mean lifespan, biomass over catch ratio, trophic level of the surveys, mean trophic index, proportion of predatory fish, intrinsic vulnerability index, and mean maximum length.
Automorphism Groups of Compact Complex Surfaces
Authors: Prokhorov Yuri , Shramov Constantin
Published: May 2019

We study automorphism groups and birational automorphism groups of compact complex surfaces. We show that the automorphism group of such a surface $X$ is always Jordan, and the birational automorphism group is Jordan unless $X$ is birational to a product of an elliptic and a rational curve.
Removing One Barrier to Protecting Sex Partners in HIV Remission Studies With a Treatment Interruption
Authors: Eyal Nir
Published: May 2019

Only a few of the recommendations made in this supplement are implemented in ongoing HIV remission studies that involve an analytical treatment interruption. The absence of these recommendations in protocols puts sexual partners of study participants at serious risk. This paper addresses one possible barrier to implementation: a certain misunderstanding among sponsors and research entities.
Potentiation of Phase Variation in Multiple Outer-Membrane Proteins During Spread of the Hyperinvasive Neisseria meningitidis Serogroup W ST-11 Lineage
Authors: Green Luke R , Dave Neelam , Adewoye Adeolu B , Lucidarme Jay , Clark Stephen A , Oldfield Neil J , Turner David P J , Borrow Ray , Bayliss Christopher D
Published: May 2019

Background

Since 2009, increases in the incidence of invasive meningococcal disease have occurred in the United Kingdom due to a sublineage of the Neisseria meningitidis serogroup W ST-11 clonal complex (hereafter, the “original UK strain”). In 2013, a descendent substrain (hereafter, the “2013 strain”) became the dominant disease-causing variant. Multiple outer-membrane proteins of meningococci are subject to phase-variable switches in expression due to hypermutable simple-sequence repeats. We investigated whether alterations in phase-variable genes may have influenced the relative prevalence of the original UK and 2013 substrains, using multiple disease and carriage isolates.

Methods

Repeat numbers were determined by either bioinformatics analysis of whole-genome sequencing data or polymerase chain reaction amplification and sizing of fragments from genomic DNA extracts. Immunoblotting and sequence-translation analysis was performed to identify expression states.

Results

Significant increases in repeat numbers were detected between the original UK and 2013 strains in genes encoding PorA, NadA, and 2 Opa variants. Invasive and carriage isolates exhibited similar repeat numbers, but the absence of pilC gene expression was frequently associated with disease.

Conclusions

Elevated repeat numbers in outer-membrane protein genes of the 2013 strain are indicative of higher phase-variation rates, suggesting that rapid expansion of this strain was due to a heightened ability to evade host immune responses during transmission and asymptomatic carriage.
Six habits of highly successful health information technology: powerful strategies for design and implementation
Authors: Ray Jessica M , Ratwani Raj M , Sinsky Christine A , Frankel Richard M , Friedberg Mark W , Powsner Seth M , Rosenthal David I , Wachter Robert M , Melnick Edward R
Published: May 2019

Healthcare information technologies are now a routine component of patient–clinician interactions. Originally designed for operational functions including billing and regulatory compliance, these systems have had unintended consequences including increased exam room documentation, divided attention during the visit, and use of scribes to alleviate documentation burdens. In an age in which technology is ubiquitous in everyday life, we must re-envision healthcare technology to support both clinical operations and, above all, the patient–clinician relationship. We present 6 habits for designing user-centered health technologies: (1) put patient care first, (2) assemble a team with the right skills, (3) relentlessly ask WHY, (4) keep it simple, (5) be Darwinian, and (6) don’t lose the forest for the trees. These habits should open dialogues between developers, implementers, end users, and stakeholders, as well as outline a path for better, more usable technology that puts patients and their clinicians back at the center of care.
Developing a Simple Burn Model in Rats of Different Ages
Authors: Zheng Bo , Shen Chuanan , Sun Jiachen , Guo Wenjing , Jin Yiduo , Niu Yuezeng
Published: May 2019

This article describes a simple and safe model of partial and full thickness burn injury in rats of different ages, which will be essential in our future burn research to explore the age-related mechanism of wound repair and new therapies for burn injuries. A self-made metal column, which was heated in a boiling water bath, was applied for different time periods to the lower back of rats of different ages in burn creation. Wounds were observed visibly at different time points postburn. Biopsies were obtained and examined at 72-hour postburn to determine the depth of burns. The contact durations producing the desired depth of injury in the rat model under constant temperature and pressure were: 3 seconds (deep second degree) and 5 seconds (third degree) in 1-month-old rats; 3 seconds (superficial second degree), 5 seconds (deep second degree), and 7–9 seconds (third degree) in 2-month-old rats; 3–5 seconds (superficial second degree), 7–9 seconds (deep second degree), and 11–13 seconds (third degree) in 12- and 18-month-old rats. This reliable and reproducible experimental model produces consistent burn injuries in rats of different ages by regulating the contact durations, which will help us to understand the underlying pathophysiology of burn injuries and develop novel therapeutic modalities for burn patients of different ages.
Use of Tilapia Skin as a Xenograft for Pediatric Burn Treatment: A Case Report
Authors: Costa Bruno Almeida , Lima Júnior Edmar Maciel , de Moraes Filho Manoel Odorico , Fechine Francisco Vagnaldo , de Moraes Maria Elisabete Amaral , Silva Júnior Francisco Raimundo , do Nascimento Soares Maria Flaviane Araújo , Rocha Marina Becker Sales
Published: May 2019

Burns represent the fifth most common cause of nonfatal childhood injuries in the world. The Nile tilapia skin (Oreochromis niloticus) is widely available in Brazil and demonstrated, in previous studies, noninfectious microbiota, morphological structure similar to that of human skin, and good outcomes when used as a xenograft for treatment of experimental burns in rats. A 3-year-old boy was admitted to a burn treatment center in Fortaleza, Brazil, with scalds in the left side of the face, neck, anterior thorax, abdomen, and left arm. Involvement of 18% of total body surface area with superficial partial thickness burns was calculated. After local Institutional Review Board approval and written permission from the patient’s legal caregiver were obtained, application of tilapia skin as an occlusive dressing was performed. Good adherence of tilapia skin to the wound bed was detected. The patient was discharged from the hospital with a total of 10 days required for the complete re-epithelialization of his superficial partial thickness burn. No adverse effects were noted. We believe that further studies conducted by our researchers will allow this innovative, low-cost, widely available and easy to apply biomaterial to firm itself as a relevant option in the therapeutic arsenal of pediatric burns, producing significant social and financial impact for the health system.
Greening the WTO Environmental Goods Agreement, Tariff Concessions, and Policy Likeness
Authors: Mavroidis Petros C , Neven Damien J
Published: May 2019

This paper considers the Asian Pacific Economic Cooperation (APEC) and Environmental Goods Agreement agreements, which grant tariff concession through Harmonized System classifications beyond the six-digit level (‘ex outs’) in favour of ‘green’ goods and discuss how these initiatives fit into the WTO legal regime. Even if the practical significance of the APEC agreement should not be overestimated as it involves modest tariff concessions over a subset of goods, which are not heavily traded, these agreements involve a paradigm shift to the extent that they use tariff concessions negotiated on a plurilateral basis as a policy instrument to meet public policy concern, instead of making market access conditional on meeting national regulations. We find that there is a tension between the current definition of likeness for the enforcement of most favoured nation provisions and the use of ex outs and a risk that improved market access for ex outs could be seen a de facto discrimination. One way out of this conundrum is to define likeness in terms of policy rationales.
Outcome of maintenance systemic chemotherapy with drug-free interval for metastatic urothelial carcinoma
Authors: Abe T , Minami K , Harabayashi T , Sazawa A , Chiba H , Kikuchi H , Miyata H , Matsumoto R , Osawa T , Maruyama S , IshizakiIshizaki J , Mochizuki T , Chiba S , Akino T , Murakumo M , Miyajima N , Tsuchiya K , Murai S , Shinohara N
Published: May 2019

Objective

Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1–3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC).

Methods

Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences.

Results

The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1–29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC.

Conclusions

In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.
Volumetric imaging parameters are significant for predicting the pathological complete response of preoperative concurrent chemoradiotherapy in local advanced rectal cancer
Authors: Wu Fengpeng , Wang Jun , Yang Congrong , Zhou Chaoxi , Niu Wenbo , Zhang Jianfeng , Wang Guanglin , Yang Yafan , Wang Guiying
Published: May 2019

Preoperative concurrent chemoradiotherapy (CCRT) as the standard treatment for locally advanced rectal cancer (LARC) has been widely used in clinic. Its efficiency influences the prognosis and the selection of subsequent treatment. The current criteria for evaluating the prognosis of patients with extremely sensitive preoperative CCRT include the clinical complete remission response (cCR) and pathological complete response (pCR), but those with cCR may not necessarily achieve pCR, and the pCR can be confirmed only after surgery. Some scholars believe that patients with pCR after CCRT can be categorized as ‘watch and wait’. Therefore, it is extremely important to find a way to predict the pCR status of patients before therapy. In this study, we examined the expression of stem cell markers and obtained direct and derivative volumetric imaging parameters before treatment. Subsequently, these factors and the general clinical data were adopted into a regression model, and the correlation between them and the pCR was analyzed. We found that the pCR of LARC was positively correlated with tumor compactness (TC), whereas it was negatively correlated with approximate tumor volume (ATV), real tumor volume (RTV), total surface area of the tumor (TSA) and tumor maximum longitudinal length (TML). In these meaningful predictors, the positive predictive values and the negative predictive values of TC were 74.73% and 94.61%, respectively. Compared with other possible predictors, TC is the most encouraging predictor of pCR. Our findings provide a way for clinicians to predict the sensitivity of preoperative CCRT and will help to select individualized treatment options for LARC patients.
False-Negative Urine Human Chorionic Gonadotropin Testing in the Clinical Laboratory
Authors: Herskovits Adrianna Z , Chen Yigu , Latifi Niloofar , Ta Robert M , Kriegel Gila
Published: May 2019

Background

Human chorionic gonadotropin (hCG) assays are used to detect pregnancy, and urine point-of-care tests are frequently used to triage patients. Under certain conditions, urine tests can fail to detect pregnancy, which can have serious consequences for patient management.

Objectives

To understand the prevalence of different factors contributing to false-negative urinary hCG testing results at our institution.

Methods

Clinical data for patients with negative urine hCG results and subsequent positive or equivocal serum hCG results within a 1-year period were reviewed.

Results

Out of 9447 negative urine hCG results, 11 potential missed diagnoses were identified, with early gestational age as the most common factor, followed by β-core hook effects.

Conclusions

Although false-negative urine hCG test results are rare, understanding the commonly encountered reasons for inaccurate testing results can help clinical centers develop strategies to minimize risk for patients.
Physical Therapy Practice Patterns for Military Service Members with Lower Limb Loss
Authors: Farrokhi Shawn , Mazzone Brittney , Moore Jacqueline L , Shannon Kaeley , Eskridge Susan
Published: May 2019

Introduction

Military service members with limb loss have unrestricted access to physical therapy (PT) services. Identifying PT interventions used based on clinical rationale and patient needs/goals can provide insight towards developing best practice guidelines. The purpose of this study was to identify preferred PT practice patterns for military service members with lower limb loss.

Materials and Methods

This was a retrospective cohort study and was approved by the Naval Health Research Center (NHRC) Institutional Review Board. Data for 495 service members with lower limb loss was analyzed. Frequency of PT visits and units of treatment received were quantified in 3-month increments during the first year after injury and compared for individuals with unilateral limb loss distal to the knee (DIST), unilateral limb loss proximal to the knee (PROX), and bilateral limb loss (BILAT).

Results

A total of 86,145 encounters occurred during the first year after injury. Active treatments were included in 94.0% of all treatments, followed by manual therapy (15.1%), patient education (11.5%) and modalities (2.4%). The highest number of encounters, consisting of active and manual therapy, was received by the DIST group within the first 3 months, while after the first 3 months, the BILAT group had higher encounters and received more active and manual therapy. Utilization of patient education was higher in the PROX and BILAT groups compared to the DIST group throughout the first year after injury.

Conclusions

Service members with limb loss utilize PT services often within the first year after injury. Trends of PT practice are most likely influenced by comorbidities and healing time variance between levels of amputation.
Optimal neighbourhood to nurture giants: a fundamental link between star-forming galaxies and direct collapse black holes
Authors: Agarwal Bhaskar , Cullen Fergus , Khochfar Sadegh , Ceverino Daniel , Klessen Ralf S
Published: May 2019

Massive 104–5 M⊙ black hole seeds resulting from the direct collapse of pristine gas require a metal-free atomic cooling halo with extremely low H2 fraction, allowing the gas to cool isothermally in the presence of atomic hydrogen. In order to achieve this chemo-thermodynamical state, the gas needs to be irradiated by both Lyman–Werner (LW) photons in the energy range of 11.2–13.6 eV capable of photodissociating H2 and 0.76 eV photons capable of photodetaching H−. Employing cosmological simulations capable of creating the first galaxies in high resolution, we explore if there exists a subset of galaxies that favour direct collapse black hole (DCBH) formation in their vicinity. We find a fundamental relation between the maximum distance at which a galaxy can cause DCBH formation and its star formation rate (SFR), which automatically folds in the chemo-thermodynamical effects of both H2 photodissociation and H− photodetachment. This is in contrast to the approximately three order of magnitude scatter seen in the LW flux parameter computed at the maximum distance, which is synonymous with a scatter in ‘Jcrit’. Thus, computing the rates and/or the LW flux from a galaxy is no longer necessary to identify neighbouring sites of DCBH formation, as our relation allows one to distinguish regions where DCBH formation could be triggered in the vicinity of a galaxy of a given SFR.
An analysis of binary microlensing event OGLE-2015-BLG-0060
Authors: Tsapras Y , Cassan A , Ranc C , Bachelet E , Street R , Udalski A , Hundertmark M , Bozza V , Beaulieu J P , Marquette J B , Euteneuer E , Bramich D M , Dominik M , Figuera Jaimes R , Horne K , Mao S , Menzies J , Schmidt R , Snodgrass C , Steele I A , Wambsganss J , Mróz P , Szymański M K , Soszyński I , Skowron J , Pietrukowicz P , Kozłowski S , Poleski R , Ulaczyk K , Pawlak M , Jørgensen U G , Skottfelt J , Popovas A , Ciceri S , Korhonen H , Kuffmeier M , Evans D F , Peixinho N , Hinse T C , Burgdorf M J , Southworth J , Tronsgaard R , Kerins E , Andersen M I , Rahvar S , Wang Y , Wertz O , Rabus M , Calchi Novati S , D’Ago G , Scarpetta G , Mancini L , Abe F , Asakura Y , Bennett D P , Bhattacharya A , Donachie M , Evans P , Fukui A , Hirao Y , Itow Y , Kawasaki K , Koshimoto N , Li M C A , Ling C H , Masuda K , Matsubara Y , Muraki Y , Miyazaki S , Nagakane M , Ohnishi K , Rattenbury N , Saito To , Sharan A , Shibai H , Sullivan D J , Sumi T , Suzuki D , Tristram P J , Yamada T , Yonehara A ,   The RoboNet team,   The OGLE collaboration,   The MiNDSTEp collaboration,   The MOA collaboration, Bramich D M , Dominik M , Jaimes R Figuera , Horne K , Mao S , Menzies J , Schmidt R , Snodgrass C , Steele I A , Wambsganss J , Mróz P , Szymański M K , Soszyński I , Skowron J , Pietrukowicz P , Kozłowski S , Poleski R , Ulaczyk K , Pawlak M , Jørgensen U G , Skottfelt J , Popovas A , Ciceri S , Korhonen H , Kuffmeier M , Evans D F , Peixinho N , Hinse T C , Burgdorf M J , Southworth J , Tronsgaard R , Kerins E , Andersen M I , Rahvar S , Wang Y , Wertz O , Rabus M , Novati S Calchi , D'Ago G , Scarpetta G , Mancini L , Abe F , Asakura Y , Bennett D P , Bhattacharya A , Donachie M , Evans P , Fukui A , Hirao Y , Itow Y , Kawasaki K , Koshimoto N , Li M C A , Ling C H , Masuda K , Matsubara Y , Muraki Y , Miyazaki S , Nagakane M , Ohnishi K , Rattenbury N , Saito T o , Sharan A , Shibai H , Sullivan D J , Sumi T , Suzuki D , Tristram P J , Yamada T , Yonehara A
Published: May 2019

We present the analysis of stellar binary microlensing event OGLE-2015-BLG-0060 based on observations obtained from 13 different telescopes. Intensive coverage of the anomalous parts of the light curve was achieved by automated follow-up observations from the robotic telescopes of the Las Cumbres Observatory. We show that, for the first time, all main features of an anomalous microlensing event are well covered by follow-up data, allowing us to estimate the physical parameters of the lens. The strong detection of second-order effects in the event light curve necessitates the inclusion of longer-baseline survey data in order to constrain the parallax vector. We find that the event was most likely caused by a stellar binary-lens with masses $M_{\star 1} = 0.87 \pm 0.12 \, \mathrm{M}_{\odot }$ and $M_{\star 2} = 0.77 \pm 0.11 \, \mathrm{M}_{\odot }$. The distance to the lensing system is 6.41 ± 0.14 kpc and the projected separation between the two components is 13.85 ± 0.16 au. Alternative interpretations are also considered.
Operon Concatenation Is an Ancient Feature That Restricts the Potential to Rearrange Bacterial Chromosomes
Authors: Brandis Gerrit , Cao Sha , Hughes Diarmaid
Published: May 2019

The last common ancestor of the Gammaproteobacteria carried an important 40-kb chromosome section encoding 51 proteins of the transcriptional and translational machinery. These genes were organized into eight contiguous operons (rrnB-tufB-secE-rpoBC-str-S10-spc-alpha). Over 2 Gy of evolution, in different lineages, some of the operons became separated by multigene insertions. Surprisingly, in many Enterobacteriaceae, much of the ancient organization is conserved, indicating a strong selective force on the operons to remain colinear. Here, we show for one operon pair, tufB-secE in Salmonella, that an interruption of contiguity significantly reduces growth rate. Our data show that the tufB-secE operons are concatenated by an interoperon terminator–promoter overlap that plays a significant role regulating gene expression. Interrupting operon contiguity interferes with this regulation, reducing cellular fitness. Six operons of the ancestral chromosome section remain contiguous in Salmonella (tufB-secE-rpoBC and S10-spc-alpha) and, strikingly, each of these operon pairs is also connected by an interoperon terminator–promoter overlap. Accordingly, we propose that operon concatenation is an ancient feature that restricts the potential to rearrange bacterial chromosomes and can select for the maintenance of a colinear operon organization over billions of years.
A distal enhancer maintaining Hoxa1 expression orchestrates retinoic acid-induced early ESCs differentiation
Authors: Su Guangsong , Guo Dianhao , Chen Jun , Liu Man , Zheng Jian , Wang Wenbin , Zhao Xueyuan , Yin Qingqing , Zhang Lei , Zhao Zhongfang , Shi Jiandang , Lu Wange
Published: May 2019

Retinoic acid (RA) induces rapid differentiation of embryonic stem cells (ESCs), partly by activating expression of the transcription factor Hoxa1, which regulates downstream target genes that promote ESCs differentiation. However, mechanisms of RA-induced Hoxa1 expression and ESCs early differentiation remain largely unknown. Here, we identify a distal enhancer interacting with the Hoxa1 locus through a long-range chromatin loop. Enhancer deletion significantly inhibited expression of RA-induced Hoxa1 and endoderm master control genes such as Gata4 and Gata6. Transcriptome analysis revealed that RA-induced early ESCs differentiation was blocked in Hoxa1 enhancer knockout cells, suggesting a requirement for the enhancer. Restoration of Hoxa1 expression partly rescued expression levels of ∼40% of genes whose expression changed following enhancer deletion, and ∼18% of promoters of those rescued genes were directly bound by Hoxa1. Our data show that a distal enhancer maintains Hoxa1 expression through long-range chromatin loop and that Hoxa1 directly regulates downstream target genes expression and then orchestrates RA-induced early differentiation of ESCs. This discovery reveals mechanisms of a novel enhancer regulating RA-induced Hoxa genes expression and early ESCs differentiation.
Brain Marker Links Stress and Nicotine Abstinence
Authors: Allenby Cheyenne , Falcone Mary , Ashare Rebecca L , Cao Wen , Bernardo Leah , Wileyto E Paul , Pruessner Jens , Loughead James , Lerman Caryn
Published: May 2019

Background

Subjective stress is a well-documented predictor of early smoking relapse, yet our understanding of stress and tobacco use is limited by reliance on self-reported measures of stress. We utilized a validated functional neuroimaging paradigm to examine whether stress exposure during early abstinence alters objective measures of brain function.

Methods

Seventy-five participants underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during the Montreal Imaging Stress Task (MIST) on two occasions: once during smoking satiety and once following biochemically confirmed 24-hour abstinence (order counterbalanced). The primary outcome measure was brain response during stress (vs. control) blocks of the MIST, assessed using whole-brain analysis corrected for multiple comparisons using clusters determined by Z ≥ 3.1.

Results

Abstinence (vs. satiety) was associated with significantly increased activation in the left inferior frontal gyrus, a brain region associated with inhibitory control. Abstinence-induced change in brain response to stress was positively associated with change in self-reported stress.

Conclusions

This study provides objective evidence that the brain response to stress is altered during the first 24 hours of a quit attempt compared to smoking satiety.

Implications

These results point to the potential value of inoculating smokers with stress management training prior to a quit attempt.
Tolerance to Cyclic Desiccation in Lichen Microalgae is Related to Habitat Preference and Involves Specific Priming of the Antioxidant System
Authors: Hell Aline F , Gasulla Francisco , Gonz�lez-Hourcade Mar�a , del Campo Eva M , Centeno Danilo C , Casano Leonardo M
Published: May 2019

Oxidative stress is a crucial challenge for lichens exposed to cyclic desiccation and rehydration (D/R). However, strategies to overcome this potential stress are still being unraveled. Therefore, the physiological performance and antioxidant mechanisms of two lichen microalgae, Trebouxia sp. (TR9) and Coccomyxa simplex (Csol), were analyzed. TR9 was isolated from Ramalina farinacea, a Mediterranean fruticose epiphytic lichen adapted to xeric habitats, while Csol is the phycobiont of Solorina saccata, a foliaceous lichen that grows on humid rock crevices. The tolerance to desiccation of both species was tested by subjecting them to different drying conditions and to four consecutive daily cycles of D/R. Our results show that a relative humidity close to that of their habitats was crucial to maintain the photosynthetic rates. Concerning antioxidant enzymes, in general, manganese superoxide dismutases (MnSODs) were induced after desiccation and decreased after rehydration. In TR9, catalase (CAT)-A increased, and its activity was maintained after four cycles of D/R. Ascorbate peroxidase activity was detected only in Csol, while glutathione reductase increased only in TR9. Transcript levels of antioxidant enzymes indicate that most isoforms of MnSOD and FeSOD were induced by desiccation and repressed after rehydration. CAT2 gene expression was also upregulated and maintained at higher levels even after four cycles of D/R in accordance with enzymatic activities. To our knowledge, this is the first study to include the complete set of the main antioxidant enzymes in desiccation-tolerant microalgae. The results highlight the species-specific induction of the antioxidant system during cyclic D/R, suggesting a priming of oxidative defence metabolism.
Mining university rankings: Publication output and citation impact as their basis
Authors: Robinson-Garcia Nicolas , Torres-Salinas Daniel , Herrera-Viedma Enrique , Docampo Domingo
Published: May 2019

World university rankings have become well-established tools that students, university managers, and policy makers read and use. Each ranking claims to have a unique methodology capable of measuring the ‘quality’ of universities. The purpose of this article is to analyze to which extent these different rankings measure the same phenomenon and what it is that they are measuring. For this, we selected a total of seven world university rankings and performed a principal component analysis. After ensuring that despite their methodological differences, they all come together to a single component; we hypothesized that bibliometric indicators could explain what is being measured. Our analyses show that ranking scores from whichever of the seven league tables under study can be explained by the number of publications and citations received by the institution. We conclude by discussing policy implications and opportunities on how a nuanced and responsible use of rankings can help decision-making at the institutional level
Antiphospholipid antibody levels in early systemic lupus erythematosus: are they associated with subsequent mortality and vascular events?
Authors: Pericleous Charis , D’Souza Amrita , McDonnell Thomas , Ripoll Vera M , Leach Oliver , Isenberg David , Giles Ian , Rahman Anisur
Published: May 2019

Objectives

aPL are present in between 20 and 30% of patients with SLE. They can cause vascular events (VE) or pregnancy morbidity. aCL and anti-beta-2-glycoprotein I (anti-β2GPI) are measured in clinical practice. Domain I (DI) of β2GPI is the main site for aPL binding. We investigated the prevalence of IgG anti-DI, aCL and anti-β2GPI antibodies in early SLE and their association with mortality and development of VE.

Methods

Samples from 501 patients with SLE that had been obtained and stored early during their disease were tested for IgG anti-DI, aCL and anti-β2GPI antibodies by ELISA. LA status and history of VE were obtained by reviewing medical records. Kaplan–Meier analysis was used to investigate mortality and occurrence of VE, comparing groups with and without aPL in early disease.

Results

Of 501 patients, 190 (38%) had at least one of these aPL, of whom 112 had anti-DI alone. Of 276 patients with complete vascular history, 83 had experienced VE. The 39 patients who were double or triple-ELISA-positive for any combination of the three aPL were more likely to have or develop lupus anticoagulant (P<0.0001) than those who were single-ELISA-positive or negative. In Kaplan–Meier analysis, they showed a trend towards developing more VE (P = 0.06).

Conclusion

IgG anti-DI antibodies were present in early serum samples from 29% of patients and were more common than IgG aCL or anti-β2GPI. There was some evidence suggesting that double or triple-ELISA-positivity for these antibodies identified a group with worse outcomes.
The ‘Dog Doctors’ of Edwardian London: Elite Canine Veterinary Care in the Early Twentieth Century
Authors: Skipper Alison
Published: May 2019

This article offers the first historical account of Edwardian London’s elite canine veterinarians. Previous historiography identifies increasing veterinary interest in dogs as a mid-twentieth century phenomenon. Despite tension with the mainstream profession, however, an earlier group of specialist veterinarians provided sophisticated canine medical care to London society. Their activities included the policing and investigation of two key threats to the fashionable and lucrative ‘dog fancy’: the devastating infectious disease distemper and the issue of ‘faking’ (show ring cosmetic fraud). This prestigious work gave the canine veterinarians a competitive advantage over their various rivals and enabled the dog fancy to combat the unintended consequences of its own practices on the canine body. This article consequently reveals an early instance of veterinary specialisation, co-driven by client demands and professional politics, and foregrounds the importance of canine biology in the social history of pedigree dog breeding.
Phylogenomic Relationships of Diploids and the Origins of Allotetraploids in Dactylorhiza (Orchidaceae)
Authors: Brandrud Marie K , Baar Juliane , Lorenzo Maria T , Athanasiadis Alexander , Bateman Richard M , Chase Mark W , Hedrén Mikael , Paun Ovidiu
Published: May 2019

Disentangling phylogenetic relationships proves challenging for groups that have evolved recently, especially if there is ongoing reticulation. Although they are in most cases immediately isolated from diploid relatives, sets of sibling allopolyploids often hybridize with each other, thereby increasing the complexity of an already challenging situation. Dactylorhiza (Orchidaceae: Orchidinae) is a genus much affected by allopolyploid speciation and reticulate phylogenetic relationships. Here, we use genetic variation at tens of thousands of genomic positions to unravel the convoluted evolutionary history of Dactylorhiza. We first investigate circumscription and relationships of diploid species in the genus using coalescent and maximum likelihood methods, and then group 16 allotetraploids by maximum affiliation to their putative parental diploids, implementing a method based on genotype likelihoods. The direction of hybrid crosses is inferred for each allotetraploid using information from maternally inherited plastid RADseq loci. Starting from age estimates of parental taxa, the relative ages of these allotetraploid entities are inferred by quantifying their genetic similarity to the diploids and numbers of private alleles compared with sibling allotetraploids. Whereas northwestern Europe is dominated by young allotetraploids of postglacial origins, comparatively older allotetraploids are distributed further south, where climatic conditions remained relatively stable during the Pleistocene glaciations. Our bioinformatics approach should prove effective for the study of other naturally occurring, nonmodel, polyploid plant complexes.
Analysis of Spounaviruses as a Case Study for the Overdue Reclassification of Tailed Phages
Authors: Barylski Jakub , Enault François , Dutilh Bas E , Schuller Margo BP , Edwards Robert A , Gillis Annika , Klumpp Jochen , Knezevic Petar , Krupovic Mart , Kuhn Jens H , Lavigne Rob , Oksanen Hanna M , Sullivan Matthew B , Jang Ho Bin , Simmonds Peter , Aiewsakun Pakorn , Wittmann Johannes , Tolstoy Igor , Brister J Rodney , Kropinski Andrew M , Adriaenssens Evelien M
Published: May 2019

Tailed bacteriophages are the most abundant and diverse viruses in the world, with genome sizes ranging from 10 kbp to over 500 kbp. Yet, due to historical reasons, all this diversity is confined to a single virus order—Caudovirales, composed of just four families: Myoviridae, Siphoviridae, Podoviridae, and the newly created Ackermannviridae family. In recent years, this morphology-based classification scheme has started to crumble under the constant flood of phage sequences, revealing that tailed phages are even more genetically diverse than once thought. This prompted us, the Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV), to consider overall reorganization of phage taxonomy. In this study, we used a wide range of complementary methods—including comparative genomics, core genome analysis, and marker gene phylogenetics—to show that the group of Bacillus phage SPO1-related viruses previously classified into the Spounavirinae subfamily, is clearly distinct from other members of the family Myoviridae and its diversity deserves the rank of an autonomous family. Thus, we removed this group from the Myoviridae family and created the family Herelleviridae—a new taxon of the same rank. In the process of the taxon evaluation, we explored the feasibility of different demarcation criteria and critically evaluated the usefulness of our methods for phage classification. The convergence of results, drawing a consistent and comprehensive picture of a new family with associated subfamilies, regardless of method, demonstrates that the tools applied here are particularly useful in phage taxonomy. We are convinced that creation of this novel family is a crucial milestone toward much-needed reclassification in the Caudovirales order.
AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats
Authors: Qin Chunhua , Aslamkhan Amy G , Pearson Kara , Tanis Keith Q , Podtelezhnikov Alexei , Frank Erika , Pacchione Stephen , Pippert Todd , Glaab Warren E , Sistare Frank D
Published: May 2019

Aryl hydrocarbon receptor (AhR) activation is associated with carcinogenicity of non-genotoxic AhR-activating carcinogens such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and is often observed with drug candidate molecules in development and raises safety concerns. As downstream effectors of AhR signaling, the expression and activity of Cyp1a1 and Cyp1a2 genes are commonly monitored as evidence of AhR activation to inform carcinogenic risk of compounds in question. However, many marketed drugs and phytochemicals are reported to induce these Cyps modestly and are not associated with dioxin-like toxicity or carcinogenicity. We hypothesized that a threshold of AhR activation needs to be surpassed in a sustained manner in order for the dioxin-like toxicity to manifest, and a simple liver gene expression signature based on Cyp1a1 and Cyp1a2 from a short-term rat study could be used to assess AhR activation strength and differentiate tumorigenic dose levels from non-tumorigenic ones. To test this hypothesis, short-term studies were conducted in Wistar Han rats with 2 AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels, and 3 AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses used in their reported 2-year rat carcinogenicity studies. A threshold of AhR activation was identified in rat liver that separated a meaningful “tumorigenic-strength AhR signal” from a statistically significant AhR activation signal that was not associated with dioxin-like carcinogenicity. These studies also confirmed the importance of the sustainability of AhR activation for carcinogenic potential. A sustained activation of AhR above the threshold could thus be used in early pharmaceutical development to identify dose levels of drug candidates expected to exhibit dioxin-like carcinogenic potential.
Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data
Authors: Delhomme Tiffany M. , Avogbe Patrice H. , Gabriel Aurélie , Alcala Nicolas , Leblay Noemie , Voegele Catherine , Vallée Maxime , Chopard Priscilia , Chabrier Amélie , Abedi-Ardekani Behnoush , Gaborieau Valérie , Holcatova Ivana , Janout Vladimir , Foretová Lenka , Milosavljevic Sasa , Zaridze David , Mukeriya Anush , Brambilla Elisabeth , Brennan Paul , Scelo Ghislaine , Fernandez-Cuesta Lynnette , Byrnes Graham , Le Calvez-Kelm Florence , McKay James D. , Foll Matthieu
Published: May 2019

The emergence of Next-Generation Sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analyzing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub plateform: https://github.com/IARCbioinfo/needlestack.
A Novel Method for Calculating Mean Erythrocyte Age Using Erythrocyte Creatine
Authors: Kameyama Masashi , Koga Masafumi , Okumiya Toshika
Published: May 2019

Backgrounds

Erythrocyte creatine (EC) decreases reflecting erythrocyte age.

Methods

We developed an EC model, which showed a bi- or mono-exponential relationship between mean erythrocyte age (MRBC) andEC. We reanalyzed the previously published data of 21 patients with hemolytic anemia which includedECand51Cr half-life.

Results

MRBCand logeECshowed excellent significant linearity (r= −0.9475,p <0.001), showing that it can be treated as a mono-exponential relationship within the studied range (EC: 1.45 – 11.76µmol/g Hb). We established an equation to obtainMRBC(days) fromEC(µmol/g Hb),MRBC= −22.84 logeEC+ 65.83.

Conclusion

This equation allows calculation ofMRBCbased on EC which has practical applications such as the diagnosis of anemia.