bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Effectiveness of Using a Progressive Muscle Relaxation Technique on the Self-Efficacy of Breastfeeding in Mothers With Preterm Infants
Authors: Karbandi Soheila , Hosseini Seyedeh Maryam , Hosseini Seyedeh Asieh , Sadeghi Farshad , Hesari Maryam , Masoudi Reza
Published: June 2017

Background:

Breast milk is a God-given gift that conveys a mother’s love and compassion and that is made according to the needs and age of the child. Mothers who are interested in the welfare of their newborns tend to breastfeed their children. Training programs have been shown to improve breastfeeding self-efficacy in terms of both duration and amount.

Purpose:

The aim of this study was to evaluate the effect of using the progressive muscle relaxation (PMR) technique on the self-efficacy of breastfeeding in mothers with preterm infants.

Methods:

A clinical trial approach was used. Sixty mothers with preterm infants were randomly assigned to either the intervention or control group. The clinical trial ran for a period of 2 months for both groups. At 24–72 hours postpartum, the researcher used the Jacobson method to provide 30–45 minutes of individual training to the intervention group participants on PMR. Under the Jacobson method, mothers contract the 16 groups of muscles until they experience the feeling of pressure and then relax these muscles. The tools used in this study were the standard questionnaire of Dennis breastfeeding self-efficacy, which was completed by the participants at baseline, at the end of the fourth week, and during the eighth week. Data were analyzed using SPSS software.

Results:

No significant difference was observed between the intervention and control groups in terms of demographic variables (p > .05). Independent t tests found no significant difference between the two groups (p = .45) in terms of mean score of maternal breastfeeding self-efficacy at pretest and significantly higher scores for the intervention group than the control group at both 4 (p = .001) and 8 (p < .001) weeks posttest. Furthermore, the analysis of variance test showed significant differences in the mean score of breastfeeding self-efficacy for the intervention group between pretest and the first posttest and between the first posttest and the second posttest, respectively (p < .001).

Conclusions/Implications for Practice:

Considering the effect of relaxation training on the breastfeeding self-efficacy of mothers with preterm infants, training and performing these exercises as an effective and low-cost method to improve the health of mothers, particularly mothers of preterm infants, are recommended. The PMR technique facilitates the self-efficacy of breastfeeding in mothers with preterm infants and should be considered as an effective strategy to improve nursing care and the provision of better support services for mothers who breastfeed their infants.
Racial Disparities and Sociodemographic Differences in Incidence and Survival Among Pediatric Patients in the United States With Primary Liver Cancer
Authors: Nautsch Felix , Ludwig Johannes M. , Xing Minzhi , Johnson Kevin M. , Kim Hyun S.
Published: June 2017

Background:

Primary liver cancer, including Hepatoblastoma (HB) and hepatocellular carcinoma (HCC), in pediatric populations is often fatal. The outcomes are poor despite universal health care access in pediatric patients.

Aim:

We investigated the sociodemographic factors affecting outcomes in pediatric patients with primary liver cancer.

Materials and Methods:

This is a large population database study of Surveillance, Epidemiology, and End Results cancer registry data from 1973 to 2011. HB and HCC were analyzed regarding age, sex, race, geographic area, and treatment-related information including survival.

Results:

In total, 998 patients, the median age at time of diagnosis was 1 year for HB [0-19; 95% confidence interval (CI), 1.5-1.9] and 14 years for HCC (0-19; 95% CI, 12.1-13.3) (P<0.001). Overall Survival (OS) in HB was 374 months (25% failures 19) versus HCC 21 months (25% failures 5; P<0.0001). In HCC, the fibrolamellar subgroup OS was 41 months (32-.) versus 16 months (11-21) in all others [hazard ratio (HR) 2.0; P=0.005]. Diagnosis between 2000 and 2011 (HB: 25% failures not reached; HCC: 38) versus diagnosis 1973 to 1999 (HB: 374; HCC: 12) had different survival (P=0.01; HR 1.9). For HB, OS in patients with age of diagnosis under 2, 25% failures was not reached versus 374 months over the age of 2 (HR 1.7; P<0.0007). African American children with HB had OS of 67 (17-.) versus all others (25% failures 21) and 48% of African American children were diagnosed after the age of 2 versus 34% of whites (HR 1.9; P=0.01).

Conclusions:

Later diagnosis and decreased survival in African American children with HB warrants further research.
Update on the supraclavicular flap
Authors: Wirtz Nicholas E. , Khariwala Samir S.
Published: June 2017

Purpose of review

The purpose of this study is to describe the supraclavicular flap and its utility in head and neck reconstruction in the context of recent studies.

Recent findings

Current literature regarding the supraclavicular flap has described its expanded uses in a variety of head and neck reconstructive settings. Its reliability and limited morbidity have been well demonstrated, and it has been cited as a reasonable alternative to other reconstructive options including, in some situations, free tissue transfer.

The supraclavicular flap has shown dependability in reconstruction of defects in the head and neck, and it warrants consideration among reconstructive surgeons, especially for circumstances in which free tissue or other pedicled flaps are less than ideal.
Modernizing Field Services for Human Immunodeficiency Virus and Sexually Transmitted Infections in the United States
Authors: Golden Matthew R. , Katz David A. , Dombrowski Julia C.
Published: June 2017

Public health field services for sexually transmitted infections (STIs) have not adequately evolved to address the expanding scale of the STI problem, its concentration among men who have sex with men, the emergence of new communication technologies and the availability of antiretroviral therapy as a cornerstone of human immunodeficiency virus (HIV) prevention. Field services need to modernize. Modernization should seek to expand field services objectives beyond sex partner STI testing and treatment to include: HIV testing of persons with bacterial STI and their partners, including efforts to promote frequent HIV/STI testing; increased condom access; linkage and relinkage to HIV care and promotion of viral suppression; preexposure prophylaxis promotion; linkage to long-acting contraception; and referral for health insurance. Field services programs cannot advance these new objectives while simultaneously doing all of the work they have traditionally done. Modernization will require a willingness to reconsider some longstanding aspects of field services work, including the centrality of face-to-face interviews and field investigations. Health departments seeking to modernize will need to carefully assess their ongoing activities and reorganize to align the use of field services resources with program priorities. In some instances, this may require reorganization to allow the staff greater specialization and closer integration with surveillance activities. Adapting programs will require new staff training, improvements in data management systems, and a greater investment in monitoring and evaluation. Although modernization is likely to evolve over many years, the time to start is now.
Further Exploration of the Complexities of Large B-Cell Lymphomas With MYC Abnormalities and the Importance of a Blastoid Morphology
Authors: Moore Erika M. , Aggarwal Nidhi , Surti Urvashi , Swerdlow Steven H.
Published: June 2017

The 2016 World Health Organization classification recognized “high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements” (double/triple-hit lymphoma [DTHL]) and “high-grade B-cell lymphoma, not otherwise specified,” which includes non-DTHL with a “blastoid” or “intermediate” cytology. Although extensively studied, many questions remain, including which cases belong in these categories, which factors mitigate their adverse prognosis, and when to perform fluorescence in situ hybridization studies. Therefore, the clinicopathologic features of 187 large B-cell lymphomas with MYC, BCL2, and BCL6 fluorescence in situ hybridization were investigated. There were 47 DTHLs, 36 cases with MYC and BCL2 and/or BCL6 extra signals (ES) and/or rearrangements (ES group, excludes DTHLs), 9 with MYC rearrangements only (single-hit lymphoma), and 95 with no MYC abnormalities (NM). Patients with DTHLs, but not single-hit lymphomas, had a significantly worse prognosis compared with those with NM (P=0.0079). The ES group with at least 1 rearrangement had a worse prognosis compared with the NM/ES without rearrangement group (P<0.02). Blastoid, but not intermediate cases, were enriched in DTHLs (P<0.0001) and had a significantly worse prognosis even among DTHLs (P=0.0282). The prognosis of the diffuse large B-cell lymphoma and intermediate groups was similar. International Prognostic Index score was of prognostic importance for the entire group and for DTHLs (P=0.0074). About 93% of DTHLs were of GCB type but 24% had <40% MYC+ cells. Among the DTHLs, MYC+BCL2+ double expressor cases had a worse prognosis (P=0.0328). These results highlight the importance of morphologic, phenotypic, and clinical variations among the DTHLs and suggest that a diagnosis equivalent to DTHL should not be made based solely on ES for MYC and BCL2 and/or BCL6.
Role of Lymphovascular Invasion in Pattern C Invasive Endocervical Adenocarcinoma
Authors: Roma Andres A. , Park Kay J. , Xie Hao , De Vivar Andrea D. , Alvarado-Cabrero Isabel , Rutgers Joanne K.L. , Barbuto Denise , Silva Elvio G.
Published: June 2017

Lymphovascular invasion (LVI) has been reported as an independent predictor of patient outcome in cervical carcinoma. However, not all studies support independent significance, especially in multivariable analyses. A risk stratification system recently introduced for endocervical adenocarcinoma was reported to better predict risk of lymph node (LN) metastasis. A subset of patients with tumors with pattern C features had LN metastasis and died of disease. In this study, we determined whether LVI had any additional significance in this subset of tumors. A total of 127 patients with pattern C tumors and at least 12-month follow-up were included. Tumors were separated into 3 subgroups. Those with no LVI and negative LNs represented 41 cases; most patients (36, 88%) were alive with no evidence of disease at last follow-up, whereas 4 (10%) died of disease, all after tumor recurrence/metastasis. Tumors with LVI, but negative LNs, represented 55 cases; recurrences were seen in 10 (18%) patients, of which 5 (50%) of them died of disease; remaining 5 patients are alive with persistent disease. Tumors with both LVI and positive LNs represented 31 cases; recurrences were seen in 13 (42%) patients; 11 (85%) patients died of disease and 2 are alive with persistent disease. One additional patient who presented with advanced stage also died of disease. Tumor size, horizontal spread, and LN status were significantly associated with outcome in univariate, but not in multivariable analysis; depth of invasion was not a predictor of outcome. Tumors with no LVI and negative LNs behaved significantly less aggressively than tumors with both LVI and positive LNs (P<0.01). LVI status (independent of LN status) was not significantly associated with patient outcome, although approached significance (P=0.06). In conclusion, LVI is a prerequisite for LN metastasis; however, by itself is not sufficient to predict tumor aggressiveness, whereas over 50% of patients with positive LNs died of disease. Stratifying pattern C tumors into subgroups based on LVI and LN status could further determine treatment in patients with pattern C tumors.
Measuring Left Ventricular Size in Non–Electrocardiographic-gated Chest Computed Tomography
Authors: Torres Felipe S. , Folador Luciano , Eifer Diego A. , Foppa Murilo , Hanneman Kate
Published: June 2017

Non–electrocardiographic (ECG)-gated computed tomography (CT) of the chest is one of the most commonly performed imaging studies. Although the heart is included in every CT study, cardiac findings are commonly underreported in radiology reports. Left ventricular size is one of the most important prognostic markers in multiple cardiac diseases and can be measured on almost all non–ECG-gated multidetector chest CT studies. This review will discuss the available evidence on different measurements of left ventricular size obtained on non–ECG-gated CT of the chest. Measurement thresholds, technical issues, and potential problems are emphasized, with practical recommendations.
Thoracic Imaging After Bariatric Surgery
Authors: Galgano Samuel J. , Sonavane Sushilkumar K. , Sanyal Rupan , Singh Satinder P. , Menias Christine O. , Bhalla Sanjeev
Published: June 2017

Obesity and its association with long-term health problems constitutes one of the major challenges in medicine. Though diet regulation and exercise are the primary treatment strategies, surgery is the most reliable long-term solution. Although bariatric surgical complications continue to decline, prompt recognition is essential to optimize patient outcomes. Despite their relative rarity, it is important to recognize thoracic complications, as several of these can result in severe morbidity and mortality. This article describes common bariatric surgical procedures performed, their expected postoperative appearances, and intrathoracic complications.
Preparatory responses to socially determined, mutually exclusive possibilities in chimpanzees and children
Authors: Suddendorf Thomas , Crimston Jessica , Redshaw Jonathan
Published: June 2017

The capacity to imagine and prepare for alternative future possibilities is central to human cognition. Recent research suggests that between age 2 and 4 children gradually begin to demonstrate a capacity to prepare for two simple, mutually exclusive alternatives of an immediate future event. When children were given the opportunity to catch a target an experimenter dropped into an inverted Y-shaped tube, 2-year olds—as well as great apes—tended to cover only one of the exits, whereas 4-year-olds spontaneously and consistently prepared for both possible outcomes. Here we gave children, age 2 to 4 years, and chimpanzees a different opportunity to demonstrate potential competence. Given that social behaviour is particularly full of uncertainty, we developed a version of the task where the outcome was still unpredictable yet obviously controlled by an experimenter. Participants could ensure they would catch the target by simply covering two tube exits. While 4-year-olds demonstrated competence, chimpanzees and the younger children instead tended to cover only one exit. These results substantiate the conclusion that the capacity for simultaneous preparation for mutually exclusive event outcomes develops relatively late in children and they are also in line with the possibility that our close animal relatives lack this capacity.
Optically ambidextrous circularly polarized reflection from the chiral cuticle of the scarab beetleChrysina resplendens
Authors: Finlayson Ewan D. , McDonald Luke T. , Vukusic Pete
Published: June 2017

The evolution of structural colour mechanisms in biological systems has given rise to many interesting optical effects in animals and plants. The instance of the scarab beetleChrysina resplendensis particularly distinctive. Its exoskeleton has a bright, golden appearance and reflects both right-handed and left-handed circularly polarized light concurrently. The chiral nanostructure responsible for these properties is a helicoid, in which birefringent dielectric planes are assembled with an incremental rotation. This study correlates details of the beetle's circularly polarized reflectance spectra directly with physical aspects of its structural morphology. Electron micrography is used to identify and measure the physical dimensions of the key constituent components. These include a chiral multilayer configuration comprising two chirped, left-handed helicoids that are separated by a birefringent retarder. A scattering matrix technique is used to simulate the system's optical behaviour in which the roles of each component of the morphological substructure are elucidated by calculation of the fields throughout its depth.
Regularly configured structures with polygonal prisms for three-dimensional auxetic behaviour
Authors: Kim Junhyun , Shin Dongheok , Yoo Do-Sik , Kim Kyoungsik
Published: June 2017

We report here structures, constructed with regular polygonal prisms, that exhibit negative Poisson’s ratios. In particular, we show how we can construct such a structure with regular
n
-gonal prism-shaped unit cells that are again built with regular
n
-gonal component prisms. First, we show that the only three possible values for
n
are 3, 4 and 6 and then discuss how we construct the unit cell again with regular
n
-gonal component prisms. Then, we derive Poisson’s ratio formula for each of the three structures and show, by analysis and numerical verification, that the structures possess negative Poisson’s ratio under certain geometric conditions.
Structural-mechanical remodelling of GDP-microtubules by kinesin
Authors: Peet Daniel R. , Burroughs Nigel J. , Cross Robert A.
Published: June 2017

Kinesin-1 is a nanoscale molecular motor that walks towards the fast growing (plus) ends of microtubules (MTs), hauling molecular cargo to specific reaction sites in cells. Kinesin-driven transport is central to the self-organisation of eukaryotic cells and shows great promise as a tool for nano-engineering1,2. Recent work hints that kinesin may also play a role in modulating the stability of its MT track, bothin vitro3-5andin vivo6, but results are conflicting7-9and mechanisms are unclear. Here we report a new dimension to the kinesin-MT interaction, whereby strong-state (ATP-bound and apo) kinesin-1 motor domains inhibit the shrinkage of GDP-MTs by up to 2 orders of magnitude and expand their lattice spacing by ~1.6%. Our data reveal an unexpected new mechanism by which the mechanochemical cycles of kinesin and tubulin interlock, allowing motile kinesins to influence the structure, stability and mechanics of their MT track.
Intrinsically disordered regions contribute promiscuous interactions to RNP granule assembly
Authors: Protter David S. W. , Rao Bhalchandra S. , Treeck Briana Van , Lin Yuan , Mizoue Laura , Rosen Michael K. , Parker Roy
Published: June 2017

Eukaryotic cells contain large RNA-protein assemblies referred to as RNP granules, whose assembly is promoted by both traditional protein interactions and intrinsically disordered protein domains. Using RNP granules as an example, we provide evidence for an assembly mechanism of large cellular structures wherein specific protein-protein or protein-RNA interactions act together with promiscuous interactions of intrinsically disordered regions (IDRs). This synergistic assembly mechanism illuminates RNP granule assembly, and explains why many components of RNP granules, and other large dynamic assemblies, contain IDRs linked to specific protein-protein or protein-RNA interaction modules. We suggest assemblies based on combinations of specific interactions and promiscuous IDRs are common features of eukaryotic cells.
Some empirical arguments demonstrating that the latent period varies over the course of a plant disease epidemic
Authors: Suffert Frédéric , Thompson Robin N.
Published: June 2017

The latent period is a crucial life history trait, particularly for polycyclic plant diseases, because it determines how many complete monocycles could theoretically occur during an epidemic. Many empirical studies have focused on the variation of the latent period with pathogen or host genotype, or changes in response to environmental factors. The focus on these aspects is unsurprising, as these factors classically form the three parts of the epidemiological triangle. Experiments in controlled conditions are generally used to assess pathogenicity and host susceptibility, and also provide the opportunity to measure the distribution of latent periods in epidemiological systems. Once estimated for one or several pairs of host-pathogen genotypes, the mean value of this important trait is usually considered to be fixed and is often used “as is” in epidemiological models. We show here that the latent period can display non-negligible variability over the course of a disease epidemic, and that this variability has multiple sources, some of which have complex, antagonistic impacts. We develop arguments for four sources of variation that challenge the implicit assumption that the latent period remains constant: daily fluctuations in leaf temperature, nature of inoculum, host stage or age of host tissues, intra-population competition and selection for aggressiveness traits. We focus on the wheat fungal disease Septoria tritici blotch (Zymoseptoria tritici), making use of empirical datasets collected during the first author’s own research projects and a targeted literature review. Such empirical epidemiological knowledge is new and potentially important for modelers. While some studies have demonstrated that the distribution of latent periods around the mean value has consequences for epidemiological dynamics, we show that it might also be important for epidemiological modelers to account for changes in this mean value during an annual epidemic. These results may be of critical importance for improving outbreak forecasting.
Low rate of somatic mutations in a long-lived oak tree
Authors: Sarkar Namrata , Schmid-Siegert Emanuel , Iseli Christian , Calderon Sandra , Gouhier-Darimont Caroline , Chrast Jacqueline , Cattaneo Pietro , Schütz Frédéric , Farinelli Laurent , Pagni Marco , Schneider Michel , Voumard Jérémie , Jaboyedoff Michel , Fankhauser Christian , Hardtke Christian S. , Keller Laurent , Pannell John R. , Reymond Alexandre , Robinson-Rechavi Marc , Xenarios Ioannis , Reymond Philippe
Published: June 2017

Because plants do not possess a proper germline, deleterious somatic mutations can be passed to gametes and a large number of cell divisions separating zygote from gamete formation in long-lived plants may lead to many mutations. We sequenced the genome of two terminal branches of a 234-year-old oak tree and found few fixed somatic single-nucleotide variants (SNVs), whose sequential appearance in the tree could be traced along nested sectors of younger branches. Our data suggest that stem cells of shoot meristems are robustly protected from accumulation of mutations in trees.
Differing strategies used by motor neurons and glia to achieve robust development of an adult neuropil in Drosophila
Authors: Enriquez Jonathan , Rio Laura Quintana , Blazeski Richard , Mason Carol , Mann Richard S.
Published: June 2017

In both vertebrates and invertebrates, neurons and glia are generated in a stereotyped order from dedicated progenitors called neural stem cells, but the purpose of invariant lineages is not understood. Here we show that three of the stem cells that produce leg motor neurons inDrosophilaalso generate a specialized subset of glia, the neuropil glia, which wrap and send processes into the neuropil where motor neuron dendrites arborize. The development of the neuropil glia and leg motor neurons is highly coordinated. However, although individual motor neurons have a stereotyped birth order and transcription factor code, both the number and individual morphologies of the glia born from these lineages are highly plastic, even though the final structure they contribute to is highly stereotyped. We suggest that the shared lineages of these two cell types facilitates the assembly of complex neural circuits, and that the two different birth order strategies – hardwired for motor neurons and flexible for glia – are important for robust nervous system development and homeostasis.
Serology reflects a decline in the prevalence of trachoma in two regions of The Gambia
Authors: Migchelsen Stephanie J , Sepúlveda Nuno , Martin Diana L , Cooley Gretchen , Gwyn Sarah , Pickering Harry , Joof Hassan , Makalo Pateh , Bailey Robin , Burr Sarah E. , Mabey David CW , Solomon Anthony W , Roberts Chrissy h
Published: June 2017

Trachoma is caused byChlamydia trachomatis(Ct). It is targeted for global elimination as a public health problem. In 2014, a population-based cross-sectional study was performed in two previously trachoma-endemic areas of The Gambia. Participants of all ages from Lower River Region (LRR) (N = 1028) and Upper River Region (URR) (N = 840) underwent examination for trachoma and had blood collected for detection of antibodies against the Ct antigen Pgp3, by ELISA. Overall, 30 (1.6%) individuals had active trachoma; the prevalence in children aged 1–9 years was 3.4% (25/742) with no statistically significant difference in prevalence between the regions. There was a significant difference in overall seroprevalence by region: 26.2% in LRR and 17.1% in URR (p<0.0001). In children 1-9 years old, seroprevalence was 4.4% in LRR and 3.9% in URR. Reversible catalytic models using information on age-specific seroprevalence demonstrated a decrease in the transmission of Ct infection in both regions, possibly reflecting the impact of improved access to water, health and sanitation as well as mass drug administration campaigns. Serological testing for antibodies to Ct antigens is potentially useful for trachoma programmes, but consideration should be given to the coendemicity of sexually transmitted Ct infections.
A vacuum-actuated microtissue stretcher for long-term exposure to oscillatory strain within a 3D matrix
Authors: Walker Matthew , Godin Michel , Pelling Andrew E.
Published: June 2017

Although our understanding of cellular behavior in response to extracellular biological and mechanical stimuli has greatly advanced using conventional 2D cell culture methods, these techniques lack physiological relevance. We developed the microtissue vacuum-actuated stretcher (MVAS) to probe cellular behavior within a 3D multicellular environment composed of innate matrix protein, and in response to continuous uniaxial stretch. The MVAS consists of an array of fifty self-assembled microtissues bordered by vacuum chambers. When a vacuum is applied, the microtissues stretch in plane allowing live imaging. The MVAS is highly suitable for biomedical research and pharmaceutical discovery due to a high-throughput array format and scalable fabrication steps outlined in this paper. We validated our approach by characterizing the bulk microtissue strain, the microtissue strain field and single cell strain, and by assessing F-actin expression in response to chronic cyclic strain of 10%. The MVAS was shown to be capable of delivering reproducible dynamic bulk strain amplitudes up to 13% and the strain field had local maxima around each of the cantilevers. The strain at the single cell level was found to be 10.4% less than the microtissue axial strain due to cellular rotation. Chronic cyclic strain produced a 35% increase in F-actin expression consistent with previously observed cytoskeletal reinforcement in 2D cell culture. The MVAS may further our understanding of the reciprocity shared between cells and their environment, which is critical to meaningful biomedical research and successful therapeutic approaches.
Akt/PKB enhances non-canonical Wnt signals by compartmentalizing β-Catenin
Authors: Aznar Nicolas , Sun Nina , Dunkel Ying , Ear Jason , Buschman Matthew D. , Ghosh Pradipta
Published: June 2017

Cellular proliferation is antagonistically regulated by canonical and non-canonical Wnt signals; their dysbalance triggers cancers. It is widely believed that the PI3-K→ Akt pathway enhances canonical Wnt signals by affecting transcriptional activity and stability of β-catenin. Here we demonstrate that the PI3-K→Akt pathway also enhances non-canonical Wnt signals by compartmentalizing β-catenin. By phosphorylating the phosphoinositide(PI)-binding domain of a multimodular signal transducer, Daple, Akt abolishes Daple’s ability to bind PI3-P-enriched endosomes that engage dynein motor complex for long-distance trafficking of β-catenin/E-cadherin complexes to pericentriolar recycling endosomes (PCREs). Phosphorylation compartmentalizes Daple/β-catenin/E-cadherin complexes to cell-cell contact sites, enhances non-canonical Wnt signals, and thereby, suppresses colony growth. Dephosphorylation compartmentalizes β-catenin on PCREs, a specialized compartment for prolonged unopposed canonical Wnt signaling, and enhances colony growth. Cancer-associated Daple mutants that are insensitive to Akt mimic a constitutively dephosphorylated state. This work not only identifies Daple as a platform for crosstalk between Akt and the non-canonical Wnt pathway, but also reveals the impact of such crosstalk during cancer initiation and progression.
Evolutionary persistence of DNA methylation for millions of years after ancient loss of ade novomethyltransferase
Authors: Catania Sandra , Dumesic Phillip A. , Pimentel Harold , Nasif Ammar , Stoddard Caitlin I. , Burke Jordan E. , Diedrich Jolene K. , Cook Sophie , Shea Terrance , Geinger Elizabeth , Lintner Robert , Yates John R. , Hajkova Petra , Narlikar Geeta J. , Cuomo Christina A. , Pritchard Jonathan K. , Madhani Hiten D.
Published: June 2017

Cytosine methylation of DNA is a widespread modification of DNA that plays numerous critical roles, yet has been lost many times in diverse eukaryotic lineages. In the yeastCryptococcus neoformans, CG methylation occurs in transposon-rich repeats and requires the DNA methyltransferase, Dnmt5. We show that Dnmt5 displays exquisite maintenance-type specificityin vitroandin vivoand utilizes similarin vivocofactors as the metazoan maintenance methylase Dnmt1. Remarkably, phylogenetic and functional analysis revealed that the ancestral species lost the gene for ade novomethylase, DnmtX, between 50-150 MYA. We examined how methylation has persisted since the ancient loss of DnmtX. Experimental and comparative studies reveal efficient replication of methylation patterns inC. neoformans, rare stochastic methylation loss and gain events, and the action of natural selection. We propose that an epigenome has been propagated for >50 MY through a process analogous to Darwinian evolution of the genome.
Predicting DNA Hybridization Kinetics from Sequence
Authors: Zhang Jinny X. , Fang John Z. , Duan Wei , Wu Lucia R. , Zhang Angela W. , Dalchau Neil , Yordanov Boyan , Petersen Rasmus , Phillips Andrew , Zhang David Yu
Published: June 2017

Hybridization is a key molecular process in biology and biotechnology, but to date there is no predictive model for accurately determining hybridization rate constants based on sequence information. To approach this problem systematically, we first performed 210 fluorescence kinetics experiments to observe the hybridization kinetics of 100 different DNA target and probe pairs (subsequences of theCYCSandVEGFgenes) at temperatures ranging from 28 °C to 55 °C. Next, we rationally designed 38 features computable based on sequence, each feature individually correlated with hybridization kinetics. These features are used in our implementation of a weighted neighbor voting (WNV) algorithm, in which the hybridization rate constant of an unknown sequence is predicted based on similarity reactions with known rate constants (a.k.a. labeled instances). Automated feature selection and weighting optimization resulted in a final 6-feature WNV model, which can predict hybridization rate constants of new sequences to within a factor of 2 with ≈74% accuracy and within a factor of 3 with ≈92% accuracy, based on leave-one-out cross-validation. Predictive understanding of hybridization kinetics allows more efficient design of nucleic acid probes, for example in allowing sparse hybrid-capture panels to more quickly and economically enrich desired regions from genomic DNA.
Synaptic mechanisms of interference in working memory
Authors: Kilpatrick Zachary P
Published: June 2017

Information from preceding trials of cognitive tasks can bias performance in the current trial, a phenomenon referred to as interference. Subjects performing visual working memory tasks exhibit interference in their trial-to-trial response correlations: the recalled target location in the current trial is biased in the direction of the target presented on the previous trial. We present modeling work that (a) develops a probabilistic inference model of this history-dependent bias, and (b) links our probabilistic model to computations of a recurrent network wherein short-term facilitation accounts for the dynamics of the observed bias. Network connectivity is reshaped dynamically during each trial, providing a mechanism for generating predictions from prior trial observations. Applying timescale separation methods, we can obtain a low-dimensional description of the trial-to-trial bias based on the history of target locations. The model has response statistics whose mean is centered at the true target location across many trials, typical of such visual working memory tasks. Furthermore, we demonstrate task protocols for which the plastic model performs better than a model with static connectivity: repetitively presented targets are better retained in working memory than targets drawn from uncorrelated sequences.
Non-competitive resource exploitation within-mosquito shapes evolution of malaria virulence
Authors: Costa G. , Gildenhard M. , Eldering M. , Lindquist R.L. , Hauser A.E. , Sauerwein R. , Goosmann C. , Brinkmann V. , Levashina E.A.
Published: June 2017

Malaria is a fatal human parasitic disease transmitted by a mosquito vector. The evolution of within-host malaria virulence has been the focus of many empirical and theoretical studies. However, the vector’s contribution to virulence evolution is not well understood. Here we explored how within-vector resource exploitation impacts evolutionary trajectories of within-hostPlasmodiumvirulence. We developed a nested model of within-vector dynamics and malaria epidemiology, which predicted that non-competitive resource exploitation within-vector restricts within-host parasite virulence. To validate our model, we experimentally manipulated mosquito lipid trafficking and gauged within-vector parasite development, within-host infectivity and virulence. We found that mosquito-derived lipids determine within-host parasite virulence by shaping development and metabolic activity of transmissible sporozoites. Our findings uncover the role of within-vector environment in regulating within-hostPlasmodiumvirulence and identifyPlasmodiummetabolic traits that may contribute to the evolution of malaria virulence.
NetMHCpan 4.0: Improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data
Authors: Jurtz Vanessa , Paul Sinu , Andreatta Massimo , Marcatili Paolo , Peters Bjoern , Nielsen Morten
Published: June 2017

Cytotoxic T cells are of central importance in the immune system’s response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC (major histocompatibility complex) class I molecules. Peptide binding to MHC molecules is the single most selective step in the antigen presentation pathway. On the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has therefore attracted large attention.

In the past, predictors of peptide-MHC interaction have in most cases been trained on binding affinity data. Recently an increasing amount of MHC presented peptides identified by mass spectrometry has been published containing information about peptide processing steps in the presentation pathway and the length distribution of naturally presented peptides. Here, we present NetMHCpan-4.0, a method trained on both binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increased predictive performance compared to state-of-the-art when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.
Challenges in estimating heritability of phase polyphenism: insights from measured and simulated data in the desert locust
Authors: Jourdan-Pineau Hélène , Pélissié Benjamin , Chapuis Elodie , Chardonnet Floriane , Pagès Christine , Foucart Antoine , Blondin Laurence , Piou Cyril , Chapuis Marie-Pierre
Published: June 2017

Quantitative genetics experiments aim at understanding and predicting the evolution of phenotypic traits. Running such experiments often bring the same questions: Should I bother with maternal effects? Could I estimate those effects? What is the best crossing scheme to obtain reliable estimates? Can I use molecular markers to spare time in the complex task of keeping track of the experimental pedigree?

We explored those practical issues in the desert locust,Schistocerca gregariausing morphologic and coloration traits, known to be influenced by maternal effects. We ran quantitative genetic analyses with an experimental dataset and used simulations to explore i) the efficiency of animal models to accurately estimate both heritability and maternal effects, ii) the influence of crossing schemes on the precision of estimates and iii) the performance of a marker-based method compared to the pedigree-based method.

The simulations indicated that maternal effects deeply affect heritability estimates and very large datasets are required to properly distinguish and estimate maternal effects and heritabilities. In particular, ignoring maternal effects in the animal model resulted in overestimation of heritabilities and a high rate of false positives whereas models specifying maternal variance suffer from lack of power. Maternal effects can be estimated more precisely than heritabilities but with low power. To obtain better estimates, bigger datasets are required and, in the presence of maternal effects, increasing the number of families over the number of offspring per families is recommended. Our simulations also showed that, in the desert locust, using relatedness based on available microsatellite markers may allow reasonably reliable estimates while rearing locusts in group.

In the light of the simulation results, our experimental dataset suggested that maternal effects affected various phase traits. However the statistical limitations, revealed by the simulation approach, didn’t allow precise variance estimates. We stressed out that doing simulations is a useful step to design an experiment in quantitative genetics and interpret the outputs of the statistical models.
An optimized pipeline for parallel image-based quantification of gene expression and genotyping afterin situhybridization
Authors: Dobrzycki Tomasz , Krecsmarik Monika , Bonkhofer Florian , Patient Roger , Monteiro Rui
Published: June 2017

Advances in genome engineering have resulted in the generation of numerous zebrafish mutant lines. A commonly used method to assess gene expression in the mutants is in situ hybridization (ISH). Because the embryos can be distinguished by genotype after ISH, comparing gene expression between wild type and mutant siblings can be done blinded and in parallel. Such experimental design reduces the technical variation between samples and minimises the risk of bias. This approach, however, requires an efficient method of genomic DNA extraction from post-ISH fixed zebrafish samples to ascribe phenotype to genotype. Here we describe a method to obtain PCR-quality DNA from 95-100% of zebrafish embryos, suitable for genotyping after ISH. In addition, we provide an image analysis protocol for quantifying gene expression of ISH-probed embryos, adaptable for the analysis of different expression patterns. Finally, we show that intensity-based image analysis enables accurate representation of the variability of gene expression detected by ISH and that it can complement quantitative methods like qRT-PCR. By combining genotyping after ISH and computer-based image analysis, we have established a high-confidence, unbiased methodology to assign gene expression levels to specific genotypes, and applied it to the analysis of molecular phenotypes of newly generatedlmo4amutants.

SUMMARY STATEMENT

Our optimized protocol to genotype zebrafish mutant embryos after in situ hybridization and digitally quantify the in situ signal will help to standardize existing experimental designs and methods of analysis.
Loss of CaMKI function disrupts salt aversive learning inC. elegans
Authors: Lim Jana P. , Fehlauer Holger , Glauser Dominique A. , Brunet Anne , Goodman Miriam B.
Published: June 2017

The ability to adapt behavior to environmental fluctuations is critical for survival of organisms ranging from invertebrates to mammals.Caenorhabditis eleganscan learn to avoid sodium chloride when it is paired with starvation. This behavior is likely advantageous to avoid areas without food. While some genes have been implicated in this salt aversive learning behavior, critical genetic components, and the neural circuit in which they act, remain elusive. Here, we show that the sole worm ortholog of mammalian CaMKI/IV, CMK-1, is essential for salt aversive learning behavior inC. elegans. We find that CMK-1 acts in the primary salt-sensing ASE neurons to regulate this behavior. By characterizing the intracellular calcium dynamics in ASE neurons using microfluidics, we find that loss ofcmk-1leads to an altered pattern of sensory-evoked calcium responses that may underlie salt aversive learning. Our study implicates the conserved CaMKI/CMK-1 as an essential cell-autonomous regulator for behavioral plasticity to environmental salt inC. elegans.

Significance Statement

Like other animals, the nematodeCaenorhabditis elegansdepends on salt for survival and navigates toward high concentrations of this essential mineral. Because salt generates osmotic stress at high concentrations, it also threatens the survival of small terrestrial animals likeC. elegans. A growing body of evidence indicates thatC. elegansbalances these factors through a process called salt aversive learning. We show that this behavior depends on expression of a calcium/calmodulin-dependent kinase, CMK-1, in the ASE salt sensing neurons and that salt-induced calcium signals in the ASE neurons are less sensitive to salt conditioning in animals lacking CMK-1 function. Our study identifies CMK-1 and sensory neurons as key factors in this form of behavioral plasticity.
Dopamine, Inference, and Uncertainty
Authors: Gershman Samuel J.
Published: June 2017

The hypothesis that the phasic dopamine response reports a reward prediction error has become deeply entrenched. However, dopamine neurons exhibit several notable deviations from this hypothesis. A coherent explanation for these deviations can be obtained by analyzing the dopamine response in terms of Bayesian reinforcement learning. The key idea is that prediction errors are modulated by probabilistic beliefs about the relationship between cues and outcomes, updated through Bayesian inference. This account can explain dopamine responses to inferred value in sensory preconditioning, the effects of cue pre-exposure (latent inhibition) and adaptive coding of prediction errors when rewards vary across orders of magnitude. We further postulate that orbitofrontal cortex transforms the stimulus representation through recurrent dynamics, such that a simple error-driven learning rule operating on the transformed representation can implement the Bayesian reinforcement learning update.
Egr1 deficiency induces browning of inguinal subcutaneous white adipose tissue in mice
Authors: Milet Cécile , Bléher Marianne , Allbright Kassandra , Orgeur Mickael , Coulpier Fanny , Duprez Delphine , Havis Emmanuelle
Published: June 2017

Beige adipocyte differentiation within white adipose tissue, referred to as browning, is seen as a possible mechanism for increasing energy expenditure. The molecular regulation underlying the thermogenic browning process has not been entirely elucidated. Here, we identify the zinc finger transcription factor EGR1 as a negative regulator of the beige fat program. Loss ofEgr1in mice promotes browning in the absence of external stimulation and activatesUcp1that encodes the key thermogenic mitochondrial uncoupling protein-1. Moreover, EGR1 is recruited to the proximal region of theUcp1promoter in subcutaneous inguinal white adipose tissue. Transcriptomic analysis of subcutaneous inguinal white adipose tissue in the absence ofEgr1identifies the molecular signature of white adipocyte browning downstream ofEgr1deletion and highlights a concomitant increase of beige differentiation marker and decrease in extracellular matrix gene expression. Conversely,Egr1overexpression in mesenchymal stem cells decreases beige adipocyte differentiation, while increasing extracellular matrix production. These results uncover the role ofEgr1in blocking energy expenditure via directUcp1transcription regulation and highlightEgr1as a therapeutic target for counteracting obesity.
Effects of temperature, mechanical motion and source positional jitter on the resolving power of beamline 02B at the SSRF
Authors: Guo Zhi , Meng Xiangyu , Wang Yong , Liu Haigang , Zhang Xiangzhi , Li Zhongliang , Xue Lian , Tai Renzhong
Published: June 2017

A detailed analysis of the effects of temperature excursions, instrumental mechanical motion and source position jitter on the energy-resolving power of beamline 02B at the Shanghai Synchrotron Radiation Facility (SSRF) is presented in this study. This beamline uses a bending-magnet-based source and includes a variable-line-spacing grating monochromator with additional optics. Expressions are derived for the monochromator output photon energy shifts for each of the performance challenges considered. The calculated results indicate that measured temperature excursions of ±1 K produce an energy shift of less than 11% of the system's energy resolution. Mechanical displacements and vibrations measured at amplitudes of less than 0.5 µm produce changes of less than 5%, while measured source location jitter results in a change of less than 10%. Spectroscopic test experiments at 250 and 400 eV provide energy resolutions of over 104. This analysis, combined with the measured results, confirms the operational stability of the beamline, indicating that it meets the performance requirements for experimental use.
X-ray reflectivity measurement of interdiffusion in metallic multilayers during rapid heating
Authors: Liu J. P. , Kirchhoff J. , Zhou L. , Zhao M. , Grapes M. D. , Dale D. S. , Tate M. D. , Philipp H. T. , Gruner S. M. , Weihs T. P. , Hufnagel T. C.
Published: June 2017

A technique for measuring interdiffusion in multilayer materials during rapid heating using X-ray reflectivity is described. In this technique the sample is bent to achieve a range of incident angles simultaneously, and the scattered intensity is recorded on a fast high-dynamic-range mixed-mode pixel array detector. Heating of the multilayer is achieved by electrical resistive heating of the silicon substrate, monitored by an infrared pyrometer. As an example, reflectivity data from Al/Ni heated at rates up to 200 K s−1 are presented. At short times the interdiffusion coefficient can be determined from the rate of decay of the reflectivity peaks, and it is shown that the activation energy for interdiffusion is consistent with a grain boundary diffusion mechanism. At longer times the simple analysis no longer applies because the evolution of the reflectivity pattern is complicated by other processes, such as nucleation and growth of intermetallic phases.