julilili42/papers huggingface dataset:
Proteomic analysis of Rac1 signaling regulation by guanine nucleotide exchange factors
2016-05-06

The small GTPase Rac1 is implicated in various cellular processes that are essential for normal cell function. Deregulation of Rac1 signaling has also been linked to a number of diseases, including cancer. The diversity of Rac1 functioning in cells is mainly attributed to its ability to bind to a multitude of downstream effectors following activation by Guanine nucleotide Exchange Factors (GEFs). Despite the identification of a large number of Rac1 binding partners, factors influencing downstream specificity are poorly defined, thus hindering the detailed understanding of both Rac1's normal and pathological functions. In a recent study, we demonstrated a role for 2 Rac-specific GEFs, Tiam1 and P-Rex1, in mediating Rac1 anti- versus pro-migratory effects, respectively. Importantly, via conducting a quantitative proteomic screen, we identified distinct changes in the Rac1 interactome following activation by either GEF, indicating that these opposing effects are mediated through GEF modulation of the Rac1 interactome. Here, we present the full list of identified Rac1 interactors together with functional annotation of the differentially regulated Rac1 binding partners. In light of this data, we also provide additional insights into known and novel signaling cascades that might account for the GEF-mediated Rac1-driven cellular effects.
Increase or Decrease of fMRI Activity in Adult Attention Deficit/ Hyperactivity Disorder: Does It Depend on Task Difficulty?
2016-05-06

Our results indicate distinct activation differences between untreated adult attention deficit/hyperactivity disorder patients and matched healthy controls during a working memory task. These differences might reflect compensatory efforts by the patients, who are performing at the same level as the healthy controls. We furthermore found a positive effect of methylphenidate on the activation of a frontal region of interest. These observations contribute to a more thorough understanding of adult attention deficit/hyperactivity disorder and provide impulses for the evaluation of therapy-related changes.
Monitoring of 30 marker candidates in early Parkinson disease as progression markers
2016-05-07

Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.
Ancient and modern DNA reveal dynamics of domestication and cross-continental dispersal of the dromedary
2016-05-09

Significance The dromedary is one of the largest domesticates, sustainably used in arid and hostile environments. It provides food and transport to millions of people in marginal agricultural areas. We show how important long-distance and back-and-forth movements in ancient caravan routes shaped the species’ genetic diversity. Using a global sample set and ancient mitochondrial DNA analyses, we describe the population structure in modern dromedaries and their wild extinct ancestors. Phylogenetic analyses of ancient and modern dromedaries suggest a history of restocking from wild animals from the southeast coast of the Arabian Peninsula. Dromedaries now extend the list of species for which classic models of domestication from a single center and from wild conspecific individuals in isolation are rejected.
Prevalence of reduced kidney function and albuminuria in older adults: the Berlin Initiative Study
2016-05-09

Abstract Background: Although CKD is said to increase among older adults, epidemiologic data on kidney function in people ≥70 years of age are scarce. The Berlin Initiative Study (BIS) aims to fill this gap by evaluating the CKD burden in older adults. Methods: The BIS is a prospective population-based cohort study whose participants are members of Germany's biggest insurance company. This cross-sectional analysis (i) gives a detailed baseline characterization of the participants, (ii) analyses the representativeness of the cohort's disease profile, (iii) assesses GFR and albuminuria levels across age categories, (iv) associates cardiovascular risk factors with GFR as well as albuminuria and (v) compares means of GFR values according to different estimating equations with measured GFR. Results: A total of 2069 participants (52.6% female, mean age 80.4 years) were enrolled: 26.1% were diabetic, 78.8% were on antihypertensive medication, 8.7% had experienced a stroke, 14% a myocardial infarction, 22.6% had cancer, 17.8% were anaemic and 26.5% were obese. The distribution of comorbidities in the BIS cohort was very similar to that in the insurance ‘source population’. Creatinine and cystatin C as well as the albumin:creatinine ratio (ACR) increased with increasing age. After multivariate adjustments, reduced GFR and elevated ACR were associated with most cardiovascular risk factors. The prevalence of a GFR &amp;lt;60 mL/min/1.73 m2 ranged from 38 to 62% depending on the estimation equation used. Conclusions: The BIS is a very well-characterized, representative cohort of older adults. Participants with an ACR ≥30 had significantly higher odds for most cardiovascular risk factors compared with an ACR &amp;lt;30 mg/g. Kidney function declined and ACR rose with increasing age.
Enhanced ADCC and NK Cell Activation of an Anticarcinoma Bispecific Antibody by Genetic Insertion of a Modified IL-15 Cross-linker
2016-05-09

Previously, we constructed a bispecific NK-cell-engager (BiKE) bearing single-chain variable fragments (scFv) against CD16 on NK cells and EpCAM on tumor cells. This BiKE facilitated antigen-specific antibody-dependent cell-mediated cytotoxicity (ADCC) but did not induce NK cell expansion. We incorporated a modified interleukin-15 cross-linker to create a trispecific construct (TriKE) in order to improve activation, proliferation, and survival of NK cells. Synthesis and assembly of hybrid genes encoding the TriKE was accomplished using DNA-shuffling and DNA-ligation techniques. The TriKE was tested for specificity, efficacy, proliferative capability, and cytokine profile using functional assays. The molecular modifications improved yield without compromising binding to EpCAM(+) HT-29 colorectal carcinoma cells. (51)Chromium-release and degranulation assays showed better killing rates with TriKE compared to BiKE. TriKE was more active in a variety of different carcinoma cell lines. TriKE showed the ability to stimulate expansion of CD56(+)CD3(-) NK cells. BiKE and TriKE showed enhanced but not supraphysiologic levels of cytokine secretion. 1615EpCAM TriKE drives enhanced ADCC while significantly improving proliferation, activation, and survival of NK cell effectors. The TriKE provides a selectively delivered self-sustaining signal at the NK/tumor cell synapse. Targeted cytokine stimulation, rather than systemic cytokine administration, may impact toxicity in patients rendering the TriKE a promising new off-the-shelf carcinoma therapy.
Genomic Profiles of Diversification and Genotype–Phenotype Association in Island Nematode Lineages
2016-05-09

Understanding how new species form requires investigation of evolutionary forces that cause phenotypic and genotypic changes among populations. However, the mechanisms underlying speciation vary and little is known about whether genomes diversify in the same ways in parallel at the incipient scale. We address this using the nematode, Pristionchus pacificus, which resides at an interesting point on the speciation continuum (distinct evolutionary lineages without reproductive isolation), and inhabits heterogeneous environments subject to divergent environmental pressures. Using whole genome re-sequencing of 264 strains, we estimate FST to identify outlier regions of extraordinary differentiation (∼1.725 Mb of the 172.5 Mb genome). We find evidence for shared divergent genomic regions occurring at a higher frequency than expected by chance among populations of the same evolutionary lineage. We use allele frequency spectra to find that, among lineages, 53% of divergent regions are consistent with adaptive selection, whereas 24% and 23% of such regions suggest background selection and restricted gene flow, respectively. In contrast, among populations from the same lineage, similar proportions (34-48%) of divergent regions correspond to adaptive selection and restricted gene flow, whereas 13-22% suggest background selection. Because speciation often involves phenotypic and genomic divergence, we also evaluate phenotypic variation, focusing on pH tolerance, which we find is diverging in a manner corresponding to environmental differences among populations. Taking a genome-wide association approach, we functionally validate a significant genotype-phenotype association for this trait. Our results are consistent with P. pacificus undergoing heterogeneous genotypic and phenotypic diversification related to both evolutionary and environmental processes.
miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer
2016-05-09

Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.
Expanding an Efficient, Electrically Driven and CNT‐Tagged P450 System into the Third Dimension: A Nanowired CNT‐Containing and Enzyme‐Stabilising 3 D Sol–Gel Electrode
2016-05-09

Abstract Although electrochemically catalysed P450 reactions have been described, their efficiency and applicability remained limited. This is mostly due to low enzyme activity, laborious protein immobilisation and the small electrode surface. We established a novel protein immobilisation method for a determined orientation and electrical wiring of the enzyme without post‐expression modification. By genetic introduction of an anchor‐peptide our method is applicable for screening medium to large mutant libraries and detection by an electrode system. The system was expanded by using wired carbon nanotubes within a sol‐gel matrix to create a three dimensional electrode.
Development of anin situthermal conductivity measurement system for exploration of the shallow subsurface
2016-05-09

In this study, we attempted to develop an in situ thermal conductivity measurement system that can be used for subsurface thermal exploration. A new thermal probe was developed for mapping both the spatial and temporal variability of thermal conductivity, via direct push methods in the unconsolidated shallow subsurface. A robust, hollow cylindrical probe was constructed and its performance was tested by carrying out thermal conductivity measurements on materials with known properties. The thermal conductivity of the investigated materials can be worked out by measuring the active power consumption (in alternating current system) and temperature of the probe over fixed time intervals. A calibration method was used to eliminate any undesired thermal effects regarding the size of the probe, based on mobile thermal analyzer thermal conductivity values. Using the hollow cylindrical probe, the thermal conductivity results obtained had an error of less than 2.5% for solid samples (such as Teflon, Agar Jelly and Nylatron).
Loss of auditory sensitivity from inner hair cell synaptopathy can be centrally compensated in the young but not old brain
2016-05-10

A dramatic shift in societal demographics will lead to rapid growth in the number of older people with hearing deficits. Poorer performance in suprathreshold speech understanding and temporal processing with age has been previously linked with progressing inner hair cell (IHC) synaptopathy that precedes age-dependent elevation of auditory thresholds. We compared central sound responsiveness after acoustic trauma in young, middle-aged, and older rats. We demonstrate that IHC synaptopathy progresses from middle age onward and hearing threshold becomes elevated from old age onward. Interestingly, middle-aged animals could centrally compensate for the loss of auditory fiber activity through an increase in late auditory brainstem responses (late auditory brainstem response wave) linked to shortening of central response latencies. In contrast, old animals failed to restore central responsiveness, which correlated with reduced temporal resolution in responding to amplitude changes. These findings may suggest that cochlear IHC synaptopathy with age does not necessarily induce temporal auditory coding deficits, as long as the capacity to generate neuronal gain maintains normal sound-induced central amplitudes.
Exercise-Induced Secretion of FGF21 and Follistatin Are Blocked by Pancreatic Clamp and Impaired in Type 2 Diabetes
2016-05-10

Exercise-induced increases in plasma FGF21 and follistatin are attenuated by the pancreatic clamp, indicating important roles for glucagon and insulin as upstream regulators. For follistatin, an additional regulatory mechanism must exist. Our data further show that exercise-induced FGF21 and follistatin secretion are impaired in patients with T2D. The magnitude of changes in glucagon and insulin or the sensitivity to these hormones seems central in the regulation of FGF21 and follistatin in humans.
Roadmap on biosensing and photonics with advanced nano-optical methods
2016-05-10

This roadmap, through the contributions of ten groups worldwide, contains different techniques,\\n\\t\\t\\t\\t methods and materials devoted to sensing in nanomedicine. Optics is used in different ways in\\n\\t\\t\\t\\t the detection schemes. Raman, fluorescence and infrared spectroscopies, plasmonics, second\\n\\t\\t\\t\\t harmonic generation and optical tweezers are all used in applications from single molecule\\n\\t\\t\\t\\t detection (both in highly diluted and in highly concentrated solutions) to single cell\\n\\t\\t\\t\\t manipulation. In general, each optical scheme, through device miniaturization and\\n\\t\\t\\t\\t electromagnetic field localization, exploits an intrinsic optical enhancement mechanism in order\\n\\t\\t\\t\\t to increase the sensitivity and selectivity of the device with respect to the complex molecular\\n\\t\\t\\t\\t construct. The materials used for detection include nanoparticles and nanostructures fabricated\\n\\t\\t\\t\\t with different 2D and 3D lithographic methods. It is shown that sensitivity to a single molecule is\\n\\t\\t\\t\\t already accessible whether the system under study is a single cell or a multitude of cells in a\\n\\t\\t\\t\\t molecular mixture. Throughout the roadm
Brain State-Dependent Closed-Loop Modulation of Paired Associative Stimulation Controlled by Sensorimotor Desynchronization
2016-05-10

These results could be relevant for developing closed-loop therapeutic approaches such as the application of brain state-dependent, paired associative stimulation (PAS) in the context of neurorehabilitation.
Cerebral Glucose Metabolism is Associated with Verbal but not Visual Memory Performance in Community-Dwelling Older Adults
2016-05-10

Increasing evidence suggests that Alzheimer's disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18F]-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD.
Closer view of the IGR J11014-6103 outflows
2016-05-10

The complex X-ray system IGR J11014-6103 (a.k.a. the Lighthouse nebula) is\\ncomposed of a bow-shock pulsar wind nebula (PWN) as well as large-scale\\njet-like features, all launched by IGR J11014-6103 which is moving\\nsupersonically in the interstellar medium. Previous observations suggested that\\nthe jet features stem from a ballistic jet of relativistic particles. In order\\nto confirm the nature of the jet and the marginally detected counter-jet, we\\nobtained a new deep 250 ks Chandra observation of the Lighthouse nebula. We\\nperformed detailed spatial and spectral analysis of all X-ray components of the\\nsystem. The X-ray PWN is now better resolved and shows a clear bi-modal\\nmorphology. The overall helical pattern of the main jet is confirmed. However,\\nthere are large deviations from a simple helical model at small and large\\nscales. Significant extended emission is now detected, encompassing the main\\njet all along its length. The brightness dip of the main jet at ~50" distance\\nfrom the pulsar is confirmed, the extended emission however prevents\\nconclusions about the coherence at this position of the jet. The counter-jet is\\nnow detected at high statistical significance. In addition, we found two\\nsmall-scale "arcs" departing from the pulsar towards the jets. We also looked\\nfor possible bow-shock emission in front of the pulsar, with a short VLT/FORS2\\nH-alpha observation. No clear emission is found, most likely because of\\ncontamination from a diffuse surrounding nebulosity. The results of our X-ray\\nanalysis show that current expectations from a ballistic nature of the jets can\\nexplain satisfactorily some of the observational evidences but cannot fully\\nreproduce the observations. The alternative scenario (diffusion of particles\\nalong preexisting magnetic field lines in the surrounding medium) however also\\ncontinues to suffer from conflicts with the observations.\\n
A young supernova remnant illuminating nearby molecular clouds with cosmic rays
2016-05-10

The Supernova Remnant (SNR) HESS J1731-347 displays strong non-thermal TeV\\ngamma-ray and X-ray emission, thus the object is at present time accelerating\\nparticles to very high energies. A distinctive feature of this young SNR is the\\nnearby (~30 pc in projection) extended source HESS J1729-345, which is\\ncurrently unidentified but is in spatial projection coinciding with known\\nmolecular clouds (MC). We model the SNR evolution to explore if the TeV\\nemission from HESS J1729-345 can be explained as emission from runaway hadronic\\ncosmic rays (CRs) that are illuminating these MCs. The observational data of\\nHESS J1729-345 and HESS J1731-347 can be reproduced using core-collapse SN\\nmodels for HESS J1731-347. Starting with different progenitor stars and their\\npre-supernova environment, we model potential SNR evolution histories along\\nwith the CR acceleration in the SNR and the diffusion of the CRs. A simplified\\n3-dimensional structure of the MCs is introduced based on 12CO data, adopting a\\ndistance of 3.2 kpc to the source. A Monte Carlo-based diffusion model for the\\nescaping CRs is developed to deal with the inhomogeneous environment. The fast\\nSNR forward shock speed as implied from the X-ray data can easily be explained\\nwhen employing scenarios with progenitor star masses between 20 and 25 solar\\nmasses, where the SNR shock is still expanding inside the main sequence\\n(MS)-bubble at present time. The TeV spectrum of HESS J1729-345 is\\nsatisfactorily fitted by the emission from the highest-energy CRs that have\\nescaped the SNR, using a standard galactic CR diffusion coefficient in the\\ninter-clump medium. The TeV image of HESS J1729-345 can be explained with a\\nreasonable 3-dimensional structure of MCs. The TeV emission from the SNR itself\\nis dominated by leptonic emission in this model. We also explore scenarios\\nwhere the shock is starting to encounter the dense MS progenitor wind bubble\\nshell.\\n
Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis
2016-05-10

Summary The predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (Tregs) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD4+CD25+forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 117; 23 + 0 – 36 + 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of Treg frequencies and gestational age. Tregs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased Treg frequency in preterm infants with clinical early-onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect Treg frequencies. Our data suggest that Tregs apparently play an important role in maintaining maternal-fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.