julilili42/papers huggingface dataset:
Experimental Determination of Isotope Enrichment Factors – Bias from Mass Removal by Repetitive Sampling
2016-11-22

Application of compound-specific stable isotope approaches often involves comparisons of isotope enrichment factors (ε). Experimental determination of ε-values is based on the Rayleigh equation, which relates the change in measured isotope ratios to the decreasing substrate fractions and is valid for closed systems. Even in well-controlled batch experiments, however, this requirement is not necessarily fulfilled, since repetitive sampling can remove a significant fraction of the analyte. For volatile compounds the need for appropriate corrections is most evident, and various methods have been proposed to account for mass removal and for volatilization into the headspace. In this study we use both synthetic and experimental data to demonstrate that the determination of ε-values according to current correction methods is prone to considerable systematic errors even in well-designed experimental setups. Application of inappropriate methods may lead to incorrect and inconsistent ε-values entailing misinterpretations regarding the processes underlying isotope fractionation. In fact, our results suggest that artifacts arising from inappropriate data evaluation might contribute to the variability of published ε-values. In response, we present novel, adequate methods to eliminate systematic errors in data evaluation. A model-based sensitivity analysis serves to reveal the most crucial experimental parameters and can be used for future experimental design to obtain correct ε-values allowing mechanistic interpretations.
Echocardiography for Less-Invasive Implantation of Left Ventricular Assist Devices
2016-11-22

New surgical techniques aim for less-invasive implantation of left ventricular assist devices (LVADs) via small surgical incision sites. Echocardiography plays an important role during patient selection and guidance of the procedure. The surgical incision site can be identified preoperatively by transthoracic echocardiography. Intraoperative identification of left ventricular apex, de-airing, and monitoring heart function is performed by transesophageal echocardiography. This article highlights special echocardiographic considerations during less-invasive LVAD implantation surgeries.
The rate and effect of de novo mutations in a colonizing lineage of Arabidopsis thaliana
2016-11-22

Because colonizations and invasions are often associated with genetic bottlenecks, they offer an opportunity to directly observe de novo mutations and their subsequent fate. North America has recently been colonized by Arabidopsis thaliana, and many of the individuals found today belong to a single lineage, HPG1. To determine substitution rates under natural conditions in this lineage, we have sequenced 100 HPG1 genomes from plants collected between 1863 and 2006. We infer that the last common HPG1 ancestor lived in the early 17th century, most likely the time when HPG1 began to colonize N. America. Demographic reconstructions infer substantial population size fluctuations during the past four centuries. Even though changing demographics can undermine the effect of natural selection, we observed that mutations at coding sites were at lower frequency than mutations at other sites, consistent with the effect of purifying selection. Exceptionally, some mutations rose to high frequency and some had measurable effects in root development, consistent with positive selection acting over mutations with an adaptive value. Our work showcases how by applying genomics methods to a combination of modern and historic samples we can learn about plant colonisations and invasions and observe evolution in action.
Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design
2016-11-23

Rationale Optimal secondary prevention of embolic stroke of undetermined source is not established. The current standard in these patients is acetylsalicylic acid, despite high prevalence of yet undetected paroxysmal atrial fibrillation. Aim The ATTICUS randomized trial is designed to determine whether the factor Xa inhibitor apixaban administered within 7 days after embolic stroke of undetermined source, is superior to acetylsalicylic acid for prevention of new ischemic lesions documented by brain magnetic resonance imaging within 12 months after index stroke. Design Prospective, randomized, blinded, parallel-group, open-label, German multicenter phase III trial in approximately 500 patients with embolic stroke of undetermined source. A key inclusion criterion is the presence or the planned implantation of an insertable cardiac monitor. Patients are 1:1 randomized to apixaban or acetylsalicylic acid and treated for a 12-month period. It is an event-driven trial aiming for core-lab adjudicated primary outcome events. Study outcomes The primary outcome is the occurrence of at least one new ischemic lesion identified by axial T2-weighted FLAIR magnetic resonance imaging and/or axial DWI magnetic resonance imaging at 12 months when compared with the baseline magnetic resonance imaging. Key secondary outcomes are the combination of recurrent ischemic strokes, hemorrhagic strokes, systemic embolism; combination of MACE including recurrent stroke, myocardial infarction, and cardiovascular death and combination of major and clinically relevant non-major bleeding defined according to ISTH, and change of cognitive function and quality of life (EQ-5D, Stroke Impact Scale). Discussion Embolic stroke of undetermined source is caused by embolic disease and associated with a high risk of recurrent ischemic strokes and clinically silent cerebral ischemic lesions. ATTICUS will investigate the impact of atrial fibrillation detected by insertable cardiac monitor and the effects of early anticoagulation with apixaban compared with antiplatelet therapy with acetylsalicylic acid on the incidence of new ischemic lesion after embolic stroke of undetermined source.
Sensory and Working Memory Representations of Small and Large Numerosities in the Crow Endbrain
2016-11-23

Neurons in the avian nidopallium caudolaterale (NCL), an endbrain structure that originated independently from the mammalian neocortex, process visual numerosities. To clarify the code for number in this anatomically distinct endbrain area in birds, neuronal responses to a broad range of numerosities were analyzed. We recorded single-neuron activity from the NCL of crows performing a delayed match-to-sample task with visual numerosities as discriminanda. The responses of &gt;20% of randomly selected neurons were modulated significantly by numerosities ranging from one to 30 items. Numerosity-selective neurons showed bell-shaped tuning curves with one of the presented numerosities as preferred numerosity regardless of the physical appearance of the items. The resulting labeled-line code exhibited logarithmic compression obeying the Weber–Fechner law for magnitudes. Comparable proportions of selective neurons were found, not only during stimulus presentation, but also in the delay phase, indicating a dominant role of the NCL in numerical working memory. Both during sensory encoding and memorization of numerosities in working memory, NCL activity predicted the crows' number discrimination performance. These neuronal data reveal striking similarities across vertebrate taxa in their code for number despite convergently evolved and anatomically distinct endbrain structures. SIGNIFICANCE STATEMENT Birds are known for their capabilities to process numerical quantity. However, birds lack a six-layered neocortex that enables primates with numerical competence. We aimed to decipher the neuronal code for numerical quantity in the independently and distinctly evolved endbrain of birds. We recorded the activity of neurons in an endbrain association area termed nidopallium caudolaterale (NCL) from crows that assessed and briefly memorized numerosities from one to 30 dots. We report a neuronal code for sensory representation and working memory of numerosities in the crow NCL exhibiting several characteristics that are surprisingly similar to the ones found in primates. Our data suggest a common code for number in two different vertebrate taxa that has evolved based on convergent evolution.
Anxiety, disgust and negative emotions influence food intake in humans
2016-11-23

A growing body of research has shown that the emotion of disgust is adaptive since it protects humans from pathogens. The possible role of anxiety and other positive and negative emotions in pathogen avoidance remain less clear. We investigated individual food acceptance after a disgust-evoking experience (a trout dissection) in a real-life setting by assessing the taking of a portion of trout. The unique contribution is that both state and trait disgust influence the likelihood of taking food after being disgusted. Participants who were more anxious, disgust sensitive or predisposed to more negative emotions avoided food after dissection significantly more frequently than their more positively affected counterparts. Males tended to accept food more often than females. Overall, these results suggest that anxiety, disgust and additional negative emotions are important in human food avoidance and that both anxiety and emotions can be considered as adaptive from an evolutionary perspective.
Sequential chemotherapy followed by reduced‐intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT
2016-11-23

Summary This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia ( AML ) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced‐intensity conditioning ( RIC ) and allogeneic haematopoietic stem cell transplantation ( HSCT ). The transplants in 77 patients were from matched sibling donors ( MSD s) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti‐T‐cell antibodies. The incidence of acute graft‐ versus ‐host disease ( GVHD ) of grades II ‒ IV was 32·1% and that of chronic GVHD was 30·2%. The 3‐year probability of non‐relapse mortality ( NRM ) was 25·9%, that of relapse was 48·5%, that of GVHD ‐free and relapse‐free survival ( GRFS ) was 17·8% and that of leukaemia‐free survival ( LFS ) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II ‒ IV [hazard ratio ( HR ) = 1·98, P = 0·017] and suffered less relapses ( HR = 0·62, P = 0·01) than MSD recipients. Treatment with anti‐T‐cell antibodies reduced NRM ( HR = 0·35, P = 0·01) and improved survival ( HR = 0·49, P = 0·01), GRFS ( HR = 0·37, P = 0·0004) and LFS ( HR = 0·46, P = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti‐T‐cell antibodies seems promising in patients with refractory AML .
Enhanced laboratory capacity development: a boost for effective tuberculosis control in resource-limited settings
2016-11-23

Both routine and research tuberculosis (TB) laboratory capacity urgently need to be expanded in large parts of Sub-Saharan Africa. In 2009, the Centre de Recherches Médicales de Lambaréné (CERMEL) took a strategic decision to expand its activities by building TB laboratory capacity to address research questions and to improve routine diagnostic and treatment capacity. Over the past 7 years, a standard laboratory has been developed that is contributing significantly to TB diagnosis, treatment, and control in Gabon; training has also been provided for TB research staff in Central Africa. CERMEL has a cordial relationship with the Gabon National TB Control Programme (PNLT), which has culminated in a successful Global Fund joint application. This endeavour is considered a model for similar developments needed in areas of high TB prevalence and where TB control remains poor to date.
Comparison of treatment response, remission rate and drug adherence in polyarticular juvenile idiopathic arthritis patients treated with etanercept, adalimumab or tocilizumab
2016-11-24

In clinical practice, etanercept is most frequently used as first-line biologic. Adalimumab/etanercept/tocilizumab showed comparable efficacy toward polyJIA. Overall, tolerance was acceptable. Interestingly, compliance was highest with tocilizumab and lowest with adalimumab. This study provides the first indication for the comparison of different biologic agents in polyarticular JIA based on observational study data with all their weaknesses and demonstrates the need for well-controlled head-to-head studies for confirmation.
Activating concepts by activating experiential traces: investigations with a series of anagram solution tasks
2016-11-24

According to the experiential-simulations view of language, words automatically activate experiential traces that stem from the reader’s interactions with their referents. Here, we focus on the corresponding influence in the opposite direction. By means of an anagram-solving task we investigated whether activating spatial experiential traces would activate the corresponding concepts, which in turn facilitates access to associated words. Participants solved anagrams of nouns associated with the ocean or the sky (e.g. dolphin = “ dplhion” or cloud = “ cdulo”). In six experiments we provided additional context information such as positional information (presenting the anagram at the top or the bottom of the screen), or pictorial information that either matched the ocean and sky theme or not, or both positional and pictorial information. Anagrams were solved faster when the position of the anagram was congruent with the location of the noun’s referent in the real world, but only when presented on the background of an ocean-sky picture. Thus, activating experiential traces indeed seems to activate related concepts but positional information alone is not enough to find facilitation in an anagram solving task. Rather what is needed is a whole set of traces that sufficiently narrow down the number of related concepts.
VENTX induces expansion of primitive erythroid cells and contributes to the development of acute myeloid leukemia in mice
2016-11-24

Homeobox genes are key regulators in normal and malignant hematopoiesis. The human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus laevis Xvent-2 gene, was shown to be highly expressed in normal myeloid cells and in patients with acute myeloid leukemia. We now demonstrate that constitutive expression of VENTX suppresses expression of genes responsible for terminal erythroid differentiation in normal CD34+ stem and progenitor cells. Transplantation of bone marrow progenitor cells retrovirally engineered to express VENTX caused massive expansion of primitive erythroid cells and partly acute erythroleukemia in transplanted mice. The leukemogenic potential of VENTX was confirmed in the AML1-ETO transplantation model, as in contrast to AML1-ETO alone co-expression of AML1-ETO and VENTX induced acute myeloid leukemia, partly expressing erythroid markers, in all transplanted mice. VENTX was highly expressed in patients with primary human erythroleukemias and knockdown of VENTX in the erythroleukemic HEL cell line significantly blocked cell growth. In summary, these data indicate that VENTX is able to perturb erythroid differentiation and to contribute to myeloid leukemogenesis when co-expressed with appropriate AML oncogenes and point to its potential significance as a novel therapeutic target in AML.
Connectivity map of bipolar cells and photoreceptors in the mouse retina
2016-11-25

In the mouse retina, three different types of photoreceptors provide input to 14 bipolar cell (BC) types. Classically, most BC types are thought to contact all cones within their dendritic field; ON-BCs would contact cones exclusively via so-called invaginating synapses, while OFF-BCs would form basal synapses. By mining publically available electron microscopy data, we discovered interesting violations of these rules of outer retinal connectivity: ON-BC type X contacted only ~20% of the cones in its dendritic field and made mostly atypical non-invaginating contacts. Types 5T, 5O and 8 also contacted fewer cones than expected. In addition, we found that rod BCs received input from cones, providing anatomical evidence that rod and cone pathways are interconnected in both directions. This suggests that the organization of the outer plexiform layer is more complex than classically thought.
Interference‐free mass spectrometric detection of capillary isoelectric focused proteins, including charge variants of a model monoclonal antibody
2016-11-25

CIEF represents an elegant technique especially for the separation of structural similar analytes, whereas MS is a state‐of‐the‐art instrumentation for the identification and characterization of biomolecules. The combination of both techniques can be realized by hyphenating CIEF with CZE‐ESI‐MS applying a mechanical valve. During the CZE step, the remaining ESI‐interfering components of the CIEF electrolyte are separated from the analytes prior to MS detection. In this work, a multiple heart‐cut approach is presented expanding our previous single heart‐cut concept resulting in a dramatical reduction of analysis time. Moreover, different sample transfer loop volumes are systematically compared and discussed in regard to peak width and transfer efficiency. With this major enhancement, model proteins (1.63–9.75 mg/L), covering a wide pI range (5–10), and charge variants from a deglycosylated model antibody were analyzed on intact level. The promising CIEF‐CZE‐MS setup is expected to be applicable in different bioanalytical fields, e.g. for the fast and information rich characterization of therapeutic antibodies.
Characterizing the morbid genome of ciliopathies
2016-11-28

Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies.
Pseudomonas aeruginosa Airway Infection Recruits and Modulates Neutrophilic Myeloid-Derived Suppressor Cells
2016-11-28

<i>Pseudomonas aeruginosa</i> is an opportunistic pathogen that causes infections mainly in patients with cystic fibrosis (CF) lung disease. Despite innate and adaptive immune responses upon infection, <i>P. aeruginosa</i> is capable of efficiently escaping host defenses, but the underlying immune mechanisms remain poorly understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells that are functionally characterized by their potential to suppress T- and natural killer (NK)-cell responses. Here we demonstrate, using an airway <i>in vivo</i> infection model, that <i>P. aeruginosa</i> recruits and activates neutrophilic MDSCs, which functionally suppress T-cell responses. We further show that the CF gene defect (CF transmembrane conductance regulator, CFTR) modulates the functionality, but not the recruitment or generation of neutrophilic MDSCs. Collectively, we define a mechanism by which <i>P. aeruginosa</i> airway infection undermines host immunity by modulating neutrophilic MDSCs <i>in vivo</i>.
Characterization of the Canine MHC Class I DLA-88*50101 Peptide Binding Motif as a Prerequisite for Canine T Cell Immunotherapy
2016-11-28

There are limitations in pre-clinical settings using mice as a basis for clinical development in humans. In cancer, similarities exist between humans and dogs; thus, the dog patient can be a link in the transition from laboratory research on mouse models to clinical trials in humans. Knowledge of the peptides presented on MHC molecules is fundamental for the development of highly specific T cell-based immunotherapies. This information is available for human MHC molecules but is absent for the canine MHC. In the present study, we characterized the binding motif of dog leukocyte antigen (DLA) class I allele DLA-88*50101, using human C1R and K562 transfected cells expressing the DLA-88*50101 heavy chain. MHC class I immunoaffinity-purification revealed 3720 DLA-88*50101 derived peptides, which enabled the determination of major anchor positions. The characterized binding motif of DLA-88*50101 was similar to HLA-A*02:01. Peptide binding analyses on HLA-A*02:01 and DLA-88*50101 via flow cytometry showed weak binding of DLA-88*50101 derived peptides to HLA-A*02:01, and vice versa. Our results present for the first time a detailed peptide binding motif of the canine MHC class I allelic product DLA-88*50101. These data support the goal of establishing dogs as a suitable animal model for the evaluation and development of T cell-based cancer immunotherapies, benefiting both dog and human patients.
Recent advances in subtyping tumors of the central nervous system using molecular data
2016-11-28

Primary brain tumors account for substantial morbidity and mortality. They often infiltrate the brain diffusely, continue growing, and cause adverse events, such as headaches, seizures, and neurological deficits. The classification of primary brain tumors, based for decades on histology, has been fundamentally changed by the World Health Organization in 2016 by incorporation of molecular data. Areas covered: Literature from glioblastomas, high- and low-grade astrocytic, oligodendroglial, glioneuronal and ependymal tumors from the last five years were reviewed. Results from comprehensive molecular profiling of neoplasms and impact of recent molecular subtyping on neuropathological diagnosis are presented. Expert commentary: The identification of frequent acquired mutations shows that adult and pediatric glioblastomas have divergent biology with differing prognoses. Astrocytoma and oligodendroglioma are more closely related than previously thought. Molecular profiling now enables the precise classification of most diffuse gliomas into three clinically and therapeutically different subtypes according to the presence or absence of IDH mutation and 1p/19q codeletion. New subgroups with different clinical outcomes and anatomic locations have emerged in ependymomas and pediatric embryonal tumors.
Pediatric Necrotizing Fasciitis: Restitutio Ad Integrum after Early Diagnosis and Aggressive Surgical Treatment
2016-11-28

Necrotizing fasciitis (NF) is a severe, life-threatening infectious condition. Diagnosis is difficult due to unspecific symptoms yet crucial for favorable outcomes. We report a case of a 1 year old, previously healthy boy, where early suspicion of NF led to prompt aggressive therapy and consecutive restitutio ad integrum.
Tumour response in metastatic renal cell carcinoma treated with tyrosine kinase inhibitors – assessment of intra-tumour heterogeneity
2016-11-28

Intra-tumour heterogeneity is a common molecular phenomenon in metastatic clear cell renal carcinoma (mRCC), representing the genetic complexity of a tumour with multiple metastatic sites. The present commentary discusses the observed phenomena of phenotypic intra-tumour heterogeneity in mRCC patients treated with the tyrosine kinase inhibitors sunitinib or pazopanib. Here, drug response can be different on the level of each evaluated metastasis in the individual patient. This questions the currently used radiologic staging systems of RECIST criteria and demands for a modification of radiologic response assessment with the consequence of a patient-tailored therapy in the clinical setting.Please see related article: http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0729-9 .