bluuebunny/crossref_metadata_2025 huggingface dataset:
Can we still learn from the Seven Countries Study?
Authors: Menotti Alessandro , Puddu Paolo Emilio
Published: April 2018

Purpose of review

The Seven Countries Study (SCS) of Cardiovascular Diseases started midway last century and was the pioneer investigation of coronary heart disease (CHD) at international level. The 16 cohorts of middle-aged men enrolled in eight nations of seven countries allowed to show large differences of CHD incidence and mortality across different cultures, partly explained by average levels of serum cholesterol and dietary habits, that is, Western type patterns in the high-risk populations, and Mediterranean or Oriental type in Southern Europe and Japan. Later, critics to the validity of the study were largely based on fake news, wrong or distorted information uncritically transmitted in a cascade of media.

Recent findings

Recent analyses based on 45–50 years of follow-up showed and confirmed that diet patterns were associated with all-cause mortality and age at death; that multivariate coefficients of major risk factors of CHD were not heterogeneous across different populations and cultures; that analysis of competing risks of CHD versus other conditions identified serum cholesterol as the critical determinant; that true CHD manifestations had different determinants compared with Heart Diseases of Uncertain Etiology frequently confused with CHD.

The SCS can still teach investigators and scholars of cardiovascular epidemiology, if old contributions are carefully read and interpreted; it is still recognized as the seminal study in this area at international level although it had limits as any other study but represented the first step into the identification of the relationship of diet with CHD and mortality across populations, and of the Mediterranean diet.
Patient Information Needs and Breast Reconstruction After Mastectomy
Authors: Carr Tracey L. , Groot Gary , Cochran David , Holtslander Lorraine
Published: April 2018

Background

Although many women benefit from breast reconstruction after mastectomy, several studies report women's dissatisfaction with the level of information they were provided with before reconstruction.

Objective

The present meta-synthesis examines the qualitative literature that explores women's experiences of breast reconstruction after mastectomy and highlights women's healthcare information needs.

Methods

After a comprehensive search of 6 electronic databases (CINAHL, Cochrane Library, EMBASE, MEDLINE, PsycINFO, and Scopus), we followed the methodology for synthesizing qualitative research. The search produced 423 studies, which were assessed against 5 inclusion criteria. A meta-synthesis methodology was used to analyze the data through taxonomic classification and constant targeted comparison.

Results

Some 17 studies met the inclusion criteria, and findings from 16 studies were synthesized. The role of the healthcare practitioner is noted as a major influence on women's expectations, and in some instances, women did not feel adequately informed about the outcomes of surgery and the recovery process. In general, women's desire for normality and effective emotional coping shapes their information needs.

Conclusion

The information needs of women are better understood after considering women's actual experiences with breast reconstruction. It is important to inform women of the immediate outcomes of reconstruction surgery and the recovery process.

Implications for Practice

In an attempt to better address women's information needs, healthcare practitioners should discover women's initial expectations of reconstruction as a starting point in the consultation. In addition, the research revealed the importance of the nurse navigator in terms of assisting women through the recovery process.
Granulosa Cell Tumors of the Ovary With Prominent Thecoma-like Foci: A Report of 16 Cases Emphasizing the Ongoing Utility of the Reticulin Stain in the Modern Era
Authors: Stall Jennifer N. , Young Robert H.
Published: April 2018

Sixteen adult granulosa cell tumors which had conspicuous zones of cells with pale cytoplasm imparting a resemblance to thecoma are reported. The neoplasms occurred in patients from 38 to 86 yr of age, the majority being over 55 yr of age. Ten tumors were incidental findings, the remainder being associated with symptoms or signs related to an adnexal mass. All the tumors were unilateral, typically small, usually under 5 cm, with only 3 being larger. With 1 exception they were uniformly solid and were typically entirely or focally yellow on sectioning. Microscopic examination typically showed a nodular pattern of growth constituted by cells with moderate to abundant pale cytoplasm; the cells resembled those seen in most thecomas. The nodules occasionally became confluent and focally a diffuse pattern was seen. Typical foci of adult granulosa cell neoplasia in the form of foci of conspicuous epithelial differentiation were absent or rare in most cases but were seen in subtle form in 6 cases and overtly in 3. A few tumors had other features seen in some thecomas, hyaline plaques, sclerosis, and calcification. Reticulin stains were examined in 13 cases and showed that the thecoma-like foci exhibited a dearth of reticulum indicating that those areas were predominantly of granulosa cell nature. Most adult granulosa cell tumors have cells with scant cytoplasm; occasional tumors have abundant eosinophilic cytoplasm, so-called luteinized adult granulosa cell tumors. That some granulosa cell tumors have the cytoplasmic features described herein has occasionally been noted but the resemblance to thecoma has not been emphasized to the best of our knowledge and in the past such tumors may have been misdiagnosed as thecoma, the referral diagnosis in 6 of our cases. A reticulin stain is of crucial aid in indicating the epithelial nature of the thecoma-like foci in these cases. Given the small size of the majority of the tumors the distinction between a small adult granulosa cell tumor and thecoma does not have significant prognostic or therapeutic implications in most cases but awareness of this feature of a small subset of adult granulosa cell tumors is warranted. Our findings have import to the diagnosis of thecoma which is uncommon if strict criteria, including exclusion of granulosa tumors of the type described, are used.
Efficacy of Elastic Resistance Training Program for the Institutionalized Elderly
Authors: Motalebi Seyedeh Ameneh , Amirzadeh Iranagh Jamileh , Mohammadi Fatemeh , Cheong Loke Seng
Published: April 2018

Objective:

This study aimed to assess the efficacy of a progressive resistance training program on dynamic balance and functional mobility among the institutionalized elderly.

Methods:

A total of 45 institutionalized elderly from a senior welfare home participated in this quasi-experimental study. The exercise group (n = 21) attended a group-based program for 12 weeks, meeting twice a week. A 2-factor repeated-measures analysis of variance and independent and paired t tests were used to analyze the data.

Results:

The results showed a significant improvement for the exercise group in the Reach Test for the forward (%Δ= 18.51%), right (%Δ= 20.0%), and left (%Δ= 17.7%) directions and in the 6-Minute Walk Test (%Δ= 12.09%, all Ps < .001) after the intervention.

Conclusion:

The elastic band training provides a simple and inexpensive exercise program that improves the balance control and consequently functional mobility effectively.
Challenges in estimating the impact of vaccination with sparse data
Authors: Shioda Kayoko , Schuck-Paim Cynthia , Taylor Robert J. , Lustig Roger , Simonsen Lone , Warren Joshua L. , Weinberger Daniel M.
Published: April 2018

Background

The synthetic control (SC) model is a powerful tool to quantify the population-level impact of vaccines, because it can adjust for trends unrelated to vaccination using a composite of control diseases. Because vaccine impact studies are often conducted using smaller subnational datasets, we evaluated the performance of SC models with sparse time series data. To obtain more robust estimates of vaccine effects from noisy time series, we proposed a possible alternative approach, “STL+PCA” method (seasonal-trend decomposition plus principal component analysis), which first extracts smoothed trends from the control time series and uses them to adjust the outcome.

Methods

Using both the SC and STL+PCA models, we estimated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) on pneumonia hospitalizations among cases <12 months and 80+ years of age during 2004-2014 at the subnational level in Brazil. The performance of these models was also compared using simulation analyses.

Results

The SC model was able to adjust for trends unrelated to PCV10 in larger states but not in smaller states. The simulation analysis confirmed that the SC model failed to select an appropriate set of control diseases when the time series were sparse and noisy, thereby generating biased estimates of the impact of vaccination when secular trends were present. The STL+PCA approach decreased bias in the estimates for smaller populations.

Conclusions

Estimates from the SC model might be biased when data are sparse. The STL+PCA model provides more accurate evaluations of vaccine impact in smaller populations.
Microcrystalline hydroxyapatite is not inferior to fluorides in clinical caries prevention: a randomized, double-blind, non-inferiority trial
Authors: Schlagenhauf Ulrich , Kunzelmann Karl-Heinz , Hannig Christian , May Theodor W. , Hösl Helmut , Gratza Mario , Viergutz Gabriele , Nazet Marco , Schamberger Sebastian , Proff Peter
Published: April 2018

Recent evidence for a significant interference of microcrystalline hydroxapatite (HAP) particles with re- and demineralisation processes at the tooth-biofilm interface suggested, that they may be promising candidates for efficacious caries prevention. This multicenter randomized controlled non-inferiority trial evaluated the impact of the 2 x daily use of a HAP dentifrice without fluoride on the progression of enamel caries in adolescent caries-risk patients subjected to orthodontic therapy, with a fluoridated AmF/SnF dentifrice serving as a positive control. Primary study outcome was the occurrence of enamel caries lesions ≥ ICDAS (International Caries Detection and Assessment System) code 1 around orthodontic brackets on the vestibular surfaces of teeth 15-25 within the 168 days observation period. Secondary study outcomes were the occurrence of enamel caries lesion ≥ ICDAS code 2, Plaque Index (PlI) and Gingival Index (GI). Out of 150 recruited patients, 147 were included in the intent to treat analysis (ITT); 133 finished the study per protocol (PP). PP data analysis revealed the occurrence of enamel caries ≥ ICDAS code 1 in 54.7% of the HAP group patients compared to 60.9% of the fluoride control. In the ITT analysis the corresponding numbers were 56.8% (HAP) and 61.6% (control). Non-inferiority testing of the ITT as well as the PP data set proved that the caries preventive efficacy of the HAP dentifrice was not inferior to the protection provided by the fluoridated AmF/SnF control. Regarding all assessed secondary outcomes (enamel caries ≥ ICDAS code 2, GI, PlI) no significant differences between both experimental groups were observed. Within the restraints set by design and study population of this trial microcrystalline HAP as ingredient of toothpaste may thus be regarded a promising supplement to fluorides in clinical caries prevention (ClinicalTrials.gov: NCT02705456).
Population-level HIV incidence estimates using a combination of synthetic cohort and recency biomarker approaches in KwaZulu-Natal, South Africa
Authors: Grebe Eduard , Welte Alex , Johnson Leigh F. , Cutsem Gilles van , Puren Adrian , Ellman Tom , Etard Jean-François ,   the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA), Huerga Helena
Published: April 2018

Introduction

There is a notable absence of consensus on how to generate estimates ofpopulation-level incidence. Incidence is a considerably more sensitive and harder to estimate indicator of epidemiological trends than prevalence. We used a novel hybrid method to estimate HIV incidence by age and sex in a rural district of KwaZulu-Natal, South Africa.

Methods

Our novel method uses an ‘optimal weighting’ of estimates based on an implementation of a particular ‘synthetic cohort’ approach (interpreting the age/time structure of prevalence, in conjunction with estimates of excess mortality) and biomarkers of ‘recent infection’ (combining Lag-Avidity, Bio-Rad Avidity and viral load results to define recent infection, and adapting the method for age-specific incidence estimation). Data were obtained from a population-based cross-sectional HIV survey conducted in Mbongolwane and Eshowe health service areas in 2013.

Results

Using the combined method, we find that age-specific HIV incidence in females rose rapidly during adolescence, from 1.33 cases/100 person-years (95% CI:0.98,1.67) at age 15 to a peak of 5.01/100PY (4.14,5.87) at age 23. In males, incidence was lower, 0.34/100PY (0.00-0.74) at age 15, and rose later, peaking at 3.86/100PY(2.52-5.20) at age 30. Susceptible population-weighted average incidence in females aged 15-29 was estimated at 3.84/100PY (3.36-4.40), in males aged 15-29 at 1.28/100PY(0.68-1.50) and in all individuals aged 15-29 at 2.55/100PY (2.09-2.76). Using the conventional recency biomarker approach, we estimated HIV incidence among females aged 15-29 at 2.99/100PY (1.79-4.36), among males aged 15-29 at 0.87/100PY(0.22-1.60) and among all individuals aged 15-59 at 1.66/100PY (1.13-2.27).

Discussion

HIV incidence was very high in women aged 15-30, peaking in the early 20s. Men had lower incidence, which peaked at age 30. The estimates obtained from the hybrid method are more informative than those produced by conventional analysis of biomarker data, and represents a more optimal use of available data than either the age-continuous biomarker or synthetic cohort methods alone. The method is mainly useful at younger ages, where excess mortality is low and uncertainty in the synthetic cohort estimates is reasonably small.

Conclusion

Application of this method to large-scale population-based HIV prevalence surveys is likely to result in improved incidence surveillance over methods currently in wide use. Reasonably accurate and precise age-specific estimates of incidence are important to target better prevention, diagnosis and care strategies.
Relative sensitivity of explicit re-aiming and implicit motor adaptation
Authors: Hutter Sarah A. , Taylor Jordan A.
Published: April 2018

It has become increasingly clear that learning in visuomotor rotation tasks, which induce an angular mismatch between movements of the hand and visual feedback, largely results from the combined effort of two distinct processes: implicit motor adaptation and explicit re-aiming. However, it remains unclear how these two processes work together to produce trial-by-trial learning. Previous work has found that implicit motor adaptation operates automatically, regardless of task relevancy, and saturates for large errors. In contrast, little is known about the automaticity of explicit re-aiming and its sensitivity to error magnitude. Here we sought to characterize the automaticity and sensitivity function of these two processes to determine how they work together to facilitate performance in a visuomotor rotation task. We found that implicit adaptation scales relative to the visual error, but only for small perturbations – replicating prior work. In contrast, explicit re-aiming scales linearly for all tested perturbation sizes. Furthermore, the consistency of the perturbation appears to diminish both implicit adaptation and explicit re-aiming, but to different degrees. Whereas implicit adaptation always displayed a response to the error, explicit re-aiming was only engaged when errors displayed a minimal degree of consistency. This comports with the idea that implicit adaptation is obligatory and less flexible, while explicit re-aiming is volitional and flexible.
Coupling of ATPase activity, microtubule binding and mechanics in the dynein motor domain
Authors: Niekamp Stefan , Coudray Nicolas , Zhang Nan , Vale Ronald D. , Bhabha Gira
Published: April 2018

The movement of a molecular motor protein along a cytoskeletal track requires communication between enzymatic, polymer-binding, and mechanical elements. Such communication is particularly complex and not well understood in the dynein motor, an ATPase that is comprised of a ring of six AAA domains, a large mechanical element (linker) spanning over the ring, and a microtubule-binding domain (MTBD) that is separated from the AAA ring by a ~135 Å coiled-coil stalk. We identified mutations in the stalk that disrupt directional motion, have microtubule-independent hyperactive ATPase activity, and nucleotide-independent low affinity for microtubules. Cryo-electron microscopy structures of a mutant that uncouples ATPase activity from directional movement reveal that nucleotide-dependent conformational changes occur normally in one half of the AAA ring, but are disrupted in the other half. The large-scale linker conformational change observed in the wild-type protein is also inhibited, revealing that this conformational change is not required for ATP hydrolysis. These results demonstrate an essential role of the stalk in regulating motor activity and coupling conformational changes across the two halves of the AAA ring.
Construct validity of five sentiment analysis methods in the text of encounter notes of patients with critical illness
Authors: Weissman Gary E. , Ungar Lyle H. , Harhay Michael O. , Courtright Katherine R. , Halpern Scott D.
Published: April 2018

Sentiment analysis may offer insights into patient outcomes through the subjective expressions made by clinicians in the text of encounter notes. We analyzed the predictive, concurrent, convergent, and content validity of five sentiment methods in a sample of 791,216 multidisciplinary clinical notes among 40,602 hospitalizations associated with an intensive care unit stay. None of these approaches improved early prediction of in-hospital mortality. However, positive sentiment measured by Pattern (OR 0.09, 95% Cl 0.04 – 0.17), sentimentr (OR 0.37, 95% Cl 0.25 – 0.63), and Opinion (OR 0.25, 95% Cl 0.07 – 0.89) were inversely associated with death on the concurrent day after adjustment for demographic characteristics and illness severity. Median daily lexical coverage ranged from 5.2% to 20.5%. While sentiment between all methods was positively correlated, their agreement was weak. Sentiment analysis holds promise for clinical applications, but will require a novel domain-specific method applicable to clinical text.
CRISPRCloud2: A cloud-based platform for deconvolving CRISPR screen data
Authors: Jeong Hyun-Hwan , Kim Seon Young , Rousseaux Maxime W.C. , Zoghbi Huda Y. , Liu Zhandong
Published: April 2018

The simplicity and cost-effectiveness of CRISPR technology have made high-throughput pooled screening approaches available to many. However, the large amount of sequencing data derived from these studies yields often unwieldy datasets requiring considerable bioinformatic resources to deconvolute data; a feature which is simply not accessible to many wet labs. To address these needs, we have developed a cloud-based webtool CRISPRCloud2 that provides a state-of-the-art accuracy in mapping short reads to CRISPR library, a powerful statistical test that aggregates information across multiple sgRNAs targeting the same gene, a user-friendly data visualization and query interface, as well as easy linking to other CRISPR tools and bioinformatics resources for target prioritization. CRISPRCloud2 is a one-stop shop for labs analyzing CRISPR screen data.
Intron retention as a novel source of cancer neoantigens
Authors: Smart Alicia C. , Margolis Claire A. , Pimentel Harold , He Meng Xiao , Miao Diana , Adeegbe Dennis , Fugmann Tim , Wong Kwok-Kin , Van Allen Eliezer M.
Published: April 2018

Personalized cancer vaccine strategies directed at tumor neoantigens derived from somatic mutations in the DNA are currently under prospective evaluation1, 2. Alterations in tumor RNA, rather than DNA, may also represent a previously-unexplored source of neoantigens. Here, we show that intron retention, a widespread feature of cancer transcriptomes3, 4, represents a novel source of tumor neoantigens. We developed an in silico approach to identify retained intron neoantigens from RNA sequencing data and applied this methodology to tumor samples from patients with melanoma treated with immune checkpoint blockade5, 6, discovering that the retained intron neoantigen burden in these samples augments the DNA-derived, somatic neoantigen burden. We validated the existence of retained intron derived neoantigens by implementing this technique on cancer cell lines with mass spectrometry-derived immunopeptidome data7, 8, revealing that retained intron neoantigens were complexed with MHC I experimentally. Unexpectedly, we observed a trend toward lack of clinical benefit from immune checkpoint blockade in high retained intron load-tumors, which harbored transcriptional signatures consistent with cell cycle dysregulation and DNA damage repair. Our results demonstrate the contribution of transcriptional dysregulation to the overall burden of tumor neoantigens, provide a foundation for augmenting personalized cancer vaccine development with a new class of tumor neoantigens, and demonstrate how global transcriptional dysregulation may impact selective response to immune checkpoint blockade.

Statement of significance

We developed and experimentally validated a computational pipeline to identify a novel class of tumor neoantigens derived from RNA-based intron retention, which is prevalent throughout cancer transcriptomes. The discovery of transcriptionally-derived tumor neoantigens expands the tumor immunopeptidome and contributes potential substrates for personalized cancer vaccine development.
Mechanism of actin polymerization revealed by cryo-EM structures of actin filaments with three different bound nucleotides
Authors: Chou Steven Z. , Pollard Thomas D.
Published: April 2018

We used electron cryo-micrographs to reconstruct actin filaments with bound AMPPNP (β,γ-imidoadenosine 5’-triphosphate, an ATP analog), ADP-Pi (ADP with inorganic phosphate) or ADP to resolutions of 3.4 Å, 3.4 Å and 3.6 Å. Subunits in the three filaments have nearly identical backbone conformations, so assembly rather than ATP hydrolysis or phosphate dissociation is responsible for their flattened conformation in filaments. Polymerization increases the rate of ATP hydrolysis by changing the conformations of the three ATP phosphates and the side chains of Gln137 and His161 in the active site. Flattening also promotes interactions along both the long-pitch and short-pitch helices. In particular, conformational changes in subdomain 3 open up favorable interactions with the DNase-I binding loop in subdomain 2 of the adjacent subunit. Subunits at the barbed end of the filament are likely to be in this favorable conformation, while monomers are not. This difference explains why filaments grow faster at the barbed end than the pointed end. Loss of hydrogen bonds after phosphate dissociation may account for the greater flexibility of ADP-actin filaments.

Significance Statement

Actin filaments comprise a major part of the cytoskeleton of eukaryotic cells and serve as tracks for myosin motor proteins. The filaments assemble from actin monomers with a bound ATP. After polymerization, actin rapidly hydrolyzes the bound ATP and slowly dissociates the γ-phosphate. ADP-actin filaments then disassemble to recycle the subunits. Understanding how actin filaments assemble, disassemble and interact with numerous regulatory proteins depends on knowing the structure of the filament. High quality structures of ADP-actin filaments were available, but not of filaments with bound ATP- or with ADP and phosphate. We determined structures of actin filaments with bound AMPPNP (a slowly hydrolyzed ATP analog), ADP and phosphate and ADP by cryo-electron microscopy. These structures show how conformational changes during actin assembly promote ATP hydrolysis and faster growth at one end of the filament than the other.
Differentiation of vegetative cells into spores: a kinetic model applied toBacillus subtilis
Authors: Gauvry Emilie , Mathot Anne-Gabrielle , Couvert Olivier , Leguérinel Ivan , Jules Matthieu , Coroller Louis
Published: April 2018

Bacterial spores are formed within vegetative cells as thick-walled bodies resistant to physical and chemical treatments which allow the persistence and dissemination of the bacterial species. Spore-forming bacteria are natural contaminants of food raw materials and sporulation can occur in many environments from farm to fork. In order to predict spore formation over time, we developed a model that describes both the kinetics of growth and the differentiation of vegetative cells into spores. The model includes a classical growth model with the addition of only two sporulation-specific parameters: the probability of each vegetative cell to sporulate, and the time needed to form a spore once the cell is committed to sporulation. The growth-sporulation model was evaluated using the spore-forming, Gram positive bacterium,Bacillus subtilisand the biological meaning of the sporulation-specific parameters was validated using a derivative strain that produces the green fluorescent protein as a marker of sporulation initiation. The model accurately describes the growth and the sporulation kinetics in different environmental conditions and further provides valuable, physiological information on the temporal abilities of vegetative cells to differentiate into spores.

Importance

The growth-sporulation model we developed accurately describes growth and sporulation kinetics. It describes the progressive transition from vegetative cells to spores with sporulation parameters which are meaningful and relevant to the sporulation process. The first parameter is the mean time required for a vegetative cell to differentiate into a spore (i.e. the duration of the sporulation process). The second sporulation parameter is the probability of each vegetative cell forming a spore over time. This parameter assesses how efficient the sporulation process is, how fast vegetative cells sporulate and how synchronous the bacterial population is for sporulation. The model constitutes a very interesting tool to describe the growth and the sporulation kinetics in different environmental conditions and it provides qualitative information on the sporulation of a bacterial population over time.
Novel autotrophic organisms contribute significantly to the internal carbon cycling potential of a boreal lake
Authors: Peura Sari , Buck Moritz , Aalto Sanni L , Morales Sergio E. , Nykänen Hannu , Eiler Alexander
Published: April 2018

Oxygen stratified lakes are typical for the boreal zone, and also a major source of greenhouse gas emissions in the region. Due to shallow light penetration, restricting the growth of phototrophic organisms, and large allochthonous organic carbon inputs from the catchment area, the lake metabolism is expected to be dominated by heterotrophic organisms. In this study we test this assumption and show that the potential for autotrophic carbon fixation and internal carbon cycling is high throughout the water column. Further, we show that during the summer stratification carbon fixation can exceed respiration in a boreal lake even below the euphotic zone. Metagenome assembled genomes and 16S profiling of a vertical transect of the lake revealed multiple organisms in oxygen depleted compartment belonging to novel or poorly characterized phyla. Many of these organisms were chemolithotrophic, deriving their energy from reactions related to sulfur, iron and nitrogen transformations. The community as well as the functions were stratified following the redox potentials. The autotrophic potential in the lake metagenome below the oxygenic zone was high, pointing towards a need for revising our concepts of internal carbon cycling in boreal lakes. Further, the importance of chemolithoautotrophy for the internal carbon cycling suggests that many predicted climate change associated changes in the physical properties of the lake, such as altered mixing patterns, likely have consequences for the whole lake metabolism even beyond the impact to the phototrophic community.
Temporal development of Drosophila embryos is highly robust across a wide temperature range
Authors: Chong Jeronica , Amourda Christopher , Saunders Timothy E.
Published: April 2018

Development is a precisely coordinated process in both space and time. Spatial precision has been quantified in a number of developmental systems, and, for example, such data has contributed significantly to our understanding of morphogen gradient interpretation. However, comparatively little quantitative analysis has been performed on timing and temporal coordination during development. Here, we use Drosophila to explore the temporal robustness of embryonic development within physiologically normal temperatures. We find that development is temporally very precise across a wide range of temperatures in all three Drosophila species investigated. However, we find temperature dependence in the heterochronicity. A simple model incorporating history-dependence can explain the developmental temporal trajectories. Interestingly, the history-dependence is temperature specific with either effective negative or positive feedback at different temperatures. We also find that embryos are surprisingly robust to shifting temperatures during embryogenesis. We further identify differences between tropical and temperate species that are suggestive of different potential mechanisms regulating temporal development depending on the local environment. Overall, our data shows that Drosophila embryonic development is temporally robust across a wide range of temperatures but there are species specific differences.
Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation
Authors: Xu Jiheng , Jin Honglei , Li Jingxia , Zhu Junlan , Hua Xiaohui , Tian Zhongxian , Huang Maowen , Yang Rui , Huang Haishan , Huang Chuanshu
Published: April 2018

Although X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.
Temporal Dynamics of the Origin and Domestication of Sweet Potato and Implications for Dispersal to Polynesia
Authors: Muñoz-Rodríguez Pablo , Carruthers Tom , Scotland Robert W.
Published: April 2018

In a study focussed on the origin of Ipomoea batatas (L.) Lam. (the sweet potato) and its close relatives [1], the authors claimed that a specimen of sweet potato collected by Banks and Solander in 1769 in Polynesia was distinct and along with some other varieties had levels of genetic variation of more than 100,000 years. This timeframe, along with several other lines of evidence, was interpreted, by the authors, as questioning human-mediated transport of the sweet potato to Polynesia within the last 1,000 years. This aspect of the paper received widespread media coverage as well as a number of critical remarks, and correspondence. The criticism questioned whether claims in the paper were justified. Here, three authors from the paper take the opportunity to fully explain the reasoning for calling into question the need to invoke human mediated transport of the sweet potato to Polynesia.
Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis
Authors: Alban Tyler J. , Alvarado Alvaro G. , Sorensen Mia D. , Bayik Defne , Volovetz Josephine , Serbinowski Emily , Mulkearns-Hubert Erin E. , Sinyuk Maksim , Hale James S. , Onzi Giovana R. , McGraw Mary , Huang Pengjing , Grabowski Matthew M. , Wathen Connor A. , Radivoyevitch Tomas , Kornblum Harley I. , Kristensen Bjarne W. , Vogelbaum Michael A. , Lathia Justin D.
Published: April 2018

Abstract/Summary

Glioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile of LGGs.
Inter-species conservation of organisation and function between non-homologous regional centromeres
Authors: Tong Pin , Pidoux Alison L. , Toda Nicholas R.T. , Ard Ryan , Berger Harald , Shukla Manu , Torres-Garcia Jesus , Mueller Carolin A. , Nieduszynski Conrad A. , Allshire Robin C.
Published: April 2018

Despite the conserved essential function of centromeres, centromeric DNA itself is not conserved1–4. The histone-H3 variant, CENP-A, is the epigenetic mark that specifies centromere identity5–8. Paradoxically, CENP-A normally assembles on particular sequences at specific genomic locations. To gain insight into the specification of complex centromeres we took an evolutionary approach, fully assembling genomes and centromeres of related fission yeasts. Centromere domain organization, but not sequence, is conserved betweenSchizosaccharomyces pombe, S. octosporusandS. cryophiluswith a central CENP-ACnp1domain flanked by heterochromatic outer-repeat regions. Conserved syntenic clusters of tRNA genes and 5S rRNA genes occur across the centromeres ofS. octosporusandS. cryophilus, suggesting conserved function. Remarkably, non-homologous centromere central-core sequences fromS. octosporusare recognized inS. pombe, resulting in cross-species establishment of CENP-ACnp1chromatin and functional kinetochores. Therefore, despite the lack of sequence conservation,Schizosaccharomycescentromere DNA possesses intrinsic conserved properties that promote assembly of CENP-A chromatin. Thus, centromere DNA can be recognized and function over unprecedented evolutionary timescales.
Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients
Authors: Zeka Fjoralba , Van Goethem Alan , Vanderheyden Katrien , Demuynck Fleur , Lammens Tim , Decock Anneleen , Helsmoortel Hetty H , Vermeulen Joëlle , Noguera Rosa , Berbegall Ana P , Combaret Valérie , Schleiermacher Gudrun , Laureys Geneviève , Schramm Alexander , Schulte Johannes H , Rahmann Sven , Bienertová-Vašků Julie , Mazánek Pavel , Jeison Marta , Ash Shifra , Hogarty Michael D , Moreno-Smith Mirthala , Barbieri Eveline , Shohet Jason , Berthold Frank , Speleman Frank , Fischer Matthias , De Preter Katleen , Mestdagh Pieter , Vandesompele Jo
Published: April 2018

In this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of non-invasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in two independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis and overall survival, revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential expression analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume, suggesting this miRNA signature may be applied to monitor disease burden.
Claudin-4 Reconstituted in Unilamellar Vesicles is Sufficient to Form Tight Interfaces that Partition Membrane Proteins
Authors: Belardi Brian , Son Sungmin , Vahey Michael D. , Wang Jinzhi , Hou Jianghui , Fletcher Daniel A.
Published: April 2018

Tight junctions have been hypothesized to act as molecular fences in the plasma membrane of epithelial cells, helping to form differentiated apical and basolateral domains. While this fence function is believed to arise from the interaction of four-pass transmembrane claudins, the complexity of tight junctions has made direct evidence of their role as a putative diffusion barrier difficult to obtain. Here we address this challenge by reconstituting claudin-4 into giant unilamellar vesicles using microfluidic jetting. We find that reconstituted claudin-4 is sufficient to form adhesive interfaces between unilamellar vesicles without accessory proteins present in vivo. By controlling the molecular composition of the inner and outer leaflets of jetted membranes, we show that claudin-4-mediated interfaces can drive partitioning of extracellular membrane proteins but not of inner or outer leaflet lipids. Our findings indicate that homotypic interactions of claudins and their small size can contribute to the polarization of epithelial cells.
A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus
Authors: Fitzsimmons William , Woods Robert J. , McCrone John T. , Woodman Andrew , Arnold Jamie J. , Yennawar Madhumita , Evans Richard , Cameron Craig E. , Lauring Adam S.
Published: April 2018

Mutation rates can evolve through genetic drift, indirect selection due to genetic hitchhiking, or direct selection on the physicochemical cost of high fidelity. However, for many systems, it has been difficult to disentangle the relative impact of these forces empirically. In RNA viruses, an observed correlation between mutation rate and virulence has led many to argue that their extremely high mutation rates are advantageous, because they may allow for increased adaptability. This argument has profound implications, as it suggests that pathogenesis in many viral infections depends on rare orde novomutations. Here we present data for an alternative model whereby RNA viruses evolve high mutation rates as a byproduct of selection for increased replicative speed. We find that a poliovirus antimutator, 3DG64S, has a significant replication defect and that wild type and 3DG64Spopulations have similar adaptability in two distinct cellular environments. Experimental evolution of 3DG64Sunder r-selection led to reversion and compensation of the fidelity phenotype. Mice infected with 3DG64Sexhibited delayed morbidity at doses well above the LD50, consistent with attenuation by slower growth as opposed to reduced mutational supply. Furthermore, compensation of the 3DG64Sgrowth defect restored virulence, while compensation of the fidelity phenotype did not. Our data are consistent with the kinetic proofreading model for biosynthetic reactions and suggest that speed is more important than accuracy. In contrast to what has been suggested for many RNA viruses, we find that within host spread is associated with viral replicative speed and not standing genetic diversity.

Author Summary

Mutation rate evolution has long been a fundamental problem in evolutionary biology. The polymerases of RNA viruses generally lack proofreading activity and exhibit extremely high mutation rates. Since most mutations are deleterious and mutation rates are tuned by natural selection, we asked why hasn’t the virus evolved to have a lower mutation rate? We used experimental evolution and a murine infection model to show that RNA virus mutation rates may actually be too high and are not necessarily adaptive. Rather, our data indicate that viral mutation rates are driven higher as a result of selection for viruses with faster replication kinetics. We suggest that viruses have high mutation rates, not because they facilitate adaption, but because it is hard to be both fast and accurate.
Plant Hormonomics: Multiple Phytohormone Profiling by Targeted Metabolomics
Authors: Šimura Jan , Antoniadi Ioanna , Široká Jitka , Tarkowská Danu¡e , Strnad Miroslav , Ljung Karin , Novák Ondřej
Published: April 2018

Phytohormones are physiologically important small molecules that play essential roles in intricate signaling networks that regulate diverse processes in plants. We present a method for the simultaneous targeted profiling of 101 phytohormone-related analytes from minute amounts of fresh plant material (less than 20 mg). Rapid and nonselective extraction, fast one-step sample purification, and extremely sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry enable concurrent quantification of the main phytohormone classes: cytokinins, auxins, brassinosteroids, gibberellins, jasmonates, salicylates, and abscisates. We validated this hormonomic approach in salt-stressed and control Arabidopsis (Arabidopsis thaliana) seedlings, quantifying a total of 43 endogenous compounds in both root and shoot samples. Subsequent multivariate statistical data processing and cross-validation with transcriptomic data highlighted the main hormone metabolites involved in plant adaptation to salt stress.
Investigation of high-pressure planetary ices by cryo-recovery. I. An apparatus for X-ray powder diffraction from 40 to 315 K, allowing `cold loading' of samples
Authors: Wood Ian G. , Fortes A. Dominic , Dobson David P. , Wang Weiwei , Pajdzik Lucjan , Cosier John
Published: April 2018

A low-temperature stage for X-ray powder diffraction in Bragg–Brentano reflection geometry is described. The temperature range covered is 40–315 K, with a temperature stability at the sample within ±0.1 K of the set point. The stage operates by means of a Gifford–McMahon (GM) closed-cycle He refrigerator; it requires no refrigerants and so can run for an extended period (in practice at least 5 d) without intervention by the user. The sample is cooled both by thermal conduction through the metal sample holder and by the presence of He exchange gas, at ambient pressure, within the sample chamber; the consumption of He gas is extremely low, being only 0.1 l min−1 during normal operation. A unique feature of this cold stage is that samples may be introduced into (and removed from) the stage at any temperature in the range 80–300 K, and thus materials which are not stable at room temperature, such as high-pressure phases that are recoverable to ambient pressure after quenching to liquid nitrogen temperatures, can be readily examined. A further advantage of this arrangement is that, by enabling the use of pre-cooled samples, it greatly reduces the turnaround time when making measurements on a series of specimens at low temperature.
2-[(4-Chlorophenyl)sulfanyl]-2-methoxy-1-phenylethan-1-one: crystal structure and Hirshfeld surface analysis
Authors: Caracelli Ignez , Zukerman-Schpector Julio , Traesel Henrique J. , Olivato Paulo R. , Jotani Mukesh M. , Tiekink Edward R. T.
Published: April 2018

The title compound, C15H13ClO2S, comprises (4-chlorophenyl)sulfanyl, benzaldehyde and methoxy residues linked at a chiral methine-C atom (the crystal is racemic). A twist in the methine-C—C(carbonyl) bond [O—C—C—O torsion angle = 19.3 (7)°] leads to a dihedral angle of 22.2 (5)° between the benzaldehyde and methine+methoxy residues. The chlorobenzene ring is folded to lie over the O atoms, with the dihedral angle between the benzene rings being 42.9 (2)°. In the crystal, the carbonyl-O atom accepts two C—H...O interactions with methyl- and methine-C—H atoms being the donors. The result is an helical supramolecular chain aligned along the c axis; chains pack with no directional interactions between them. An analysis of the Hirshfeld surface points to the important contributions of weak H...H and C...C contacts to the molecular packing.
Crystal structure of 5-[2-(2,4,6-tribromophenyl)diazenyl]tropolone
Authors: Hill Tania N. , Savig Kelsey L. , Lemmerer Andreas
Published: April 2018

The title compound {systematic name: 2-hydroxy-5-[2-(2,4,6-tribromophenyl)diazen-1-yl]cyclohepta-2,4,6-trien-1-one}, C13H7Br3N2O2, is essentially planar, with an r.m.s. deviation of 0.054 Å. The molecular structure is fixed in the azo tautomer by intramolecular C—H...N interactions, with O—H...O hydrogen bonds creating linked dimers. Charge-transfer interactions are observed, with the segregated stacks linked by Br...Br interactions.
Crystal structure and Hirshfeld surface analysis of a pyridiniminium bromide salt: 1-[2-([1,1′-biphenyl]-4-yl)-2-oxoethyl]-3-methyl-1,4-dihydropyridin-4-iminium bromide
Authors: Sheshadri S. N. , Kwong Huey Chong , Chidan Kumar C. S. , Quah Ching Kheng , Siddaraju B. P. , Veeraiah M. K. , Hamid Muhammad Aiman Bin Abd , Warad Ismail
Published: April 2018

In the cation of the title salt, C20H19N2O+·Br−, the phenyl rings are inclined to one another by 38.38 (8)°, whereas the central phenyl ring and the pyridiniminium ring are almost perpendicular with a dihedral angle of 87.37 (9)°. The N+=C cationic double bond was verified by the shortened bond length of 1.337 (2) Å. In the crystal, the Br− anion is linked to the cation by an N—H...Br hydrogen bond. C—H...O hydrogen bonds link adjacent pyridiniminium cations into inversion dimers with an R
2
2(18) graph-set motif. These dimers are stacked in a phenyl–phenyl T-shaped geometry through C—H...π interactions. A Hirshfeld surface analysis was conducted to verify the contributions of the different intermolecular interactions.