julilili42/papers huggingface dataset:
Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy
2014-02-24

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.
Towards a Treatment of Stress Urinary Incontinence: Application of Mesenchymal Stromal Cells for Regeneration of the Sphincter Muscle
2014-02-24

Stress urinary incontinence is a significant social, medical, and economic problem. It is caused, at least in part, by degeneration of the sphincter muscle controlling the tightness of the urinary bladder. This muscular degeneration is characterized by a loss of muscle cells and a surplus of a fibrous connective tissue. In Western countries approximately 15% of all females and 10% of males are affected. The incidence is significantly higher among senior citizens, and more than 25% of the elderly suffer from incontinence. When other therapies, such as physical exercise, pharmacological intervention, or electrophysiological stimulation of the sphincter fail to improve the patient’s conditions, a cell-based therapy may improve the function of the sphincter muscle. Here, we briefly summarize current knowledge on stem cells suitable for therapy of urinary incontinence: mesenchymal stromal cells, urine-derived stem cells, and muscle-derived satellite cells. In addition, we report on ways to improve techniques for surgical navigation, injection of cells in the sphincter muscle, sensors for evaluation of post-treatment therapeutic outcome, and perspectives derived from recent pre-clinical studies.
Simultaneous acquisition of image and navigator slices using CAIPIRINHA for 4D MRI
2014-02-24

Purpose Respiratory organ motion is still the major challenge of various image‐guided treatments in the abdomen. Dynamic organ motion tracking, necessary for the treatment control, can be performed with volumetric time‐resolved MRI that sequentially acquires one image and one navigator slice. Here, a novel imaging method is proposed for truly simultaneous high temporal resolution acquisition. Methods A standard balanced steady state free precession sequence was modified to simultaneously acquire two superimposed slices with different phase cycles, namely an image and a navigator slice. Instead of multiband RF pulses, two separate RF pulses were used for the excitation. Images were reconstructed using offline CAIPIRINHA reconstruction. Phantom and in vivo measurements of healthy volunteers were performed and evaluated. Results Phantom and in vivo measurements showed good image quality with high signal‐to‐noise ratio (SNR) and no reconstruction issues. Conclusion We present a novel imaging method for truly simultaneous acquisition of image and navigator slices for four‐dimensional (4D) MRI of organ motion. In this method, the time lag between the sequential acquisitions is eliminated, leading to an improved accuracy of organ motion models, while CAIPIRINHA reconstruction results in an improved SNR compared with an existing 4D MRI approach. Magn Reson Med 73:669–676, 2015. © 2014 Wiley Periodicals, Inc.
Does temporal preparation speed up visual processing? Evidence from the N2pc
2014-02-24

Abstract A growing number of studies show that temporal preparation, which denotes processes of anticipation and preparation for an upcoming stimulus, facilitates perceptual processing. Recently, it has been hypothesized that this perceptual benefit arises due to an acceleration of early perceptual processing. Whereas this idea receives some direct support from a recent study showing that temporal preparation reduces the latency of early auditory ERPs , supportive evidence regarding the visual modality lacks so far. To further investigate this acceleration account, we measured the latency of early visual ERPs in a visual search task. We observed that temporal preparation, manipulated via constant foreperiods, reduced the latency of early visual ERPs , specifically the N2pc as an index of attentional target processing. This finding supports a modality‐independent acceleration of perceptual processing by temporal preparation.
Love is a battlefield: programmed cell death during fertilization
2014-02-24

Plant development and growth is sustained by the constant generation of tremendous amounts of cells, which become integrated into various types of tissues and organs. What is all too often overlooked is that this thriving life also requires the targeted degeneration of selected cells, which undergo cell death according to genetically encoded programmes or environmental stimuli. The side-by-side existence of generation and demise is particularly evident in the haploid phase of the flowering plants cycle. Here, the lifespan of terminally differentiated accessory cells contrasts with that of germ cells, which by definition live on to form the next generation. In fact, with research in recent years it is becoming increasingly clear that the gametophytes of flowering plants constitute an attractive and powerful system for investigating the molecular mechanisms underlying selective cell death.
Associations between Grawe's general mechanisms of change and Young's early maladaptive schemas in psychotherapy research: A comparative study of change processes
2014-02-24

Resource activation experiences seem to be especially crucial in fostering alterations in EMS, as this change mechanism demonstrated significant associations with several schema domains. Future research should investigate these aspects in more detail using observer-based micro-process analyses.
Was the Early Eocene proboscidean Numidotherium koholense semi-aquatic or terrestrial? Evidence from stable isotopes and bone histology
2014-02-24

The Early Eocene deposits of El Kohol, Algeria, have yielded numerous remains of Numidotherium koholense , one of the most primitive and oldest known proboscideans in Africa. The Upper Eocene proboscideans of the Fayum locality (Egypt), Barytherium sp. and Moeritherium sp., were recently interpreted as aquatic or semi-aquatic, according to the stable isotopic compositions ( δ 13 C and δ 18 O) of their tooth enamel. These data led us to reinvestigate the adaptations of N. koholense . Stable isotopic analysis and observations of histological sections of its long bones reveal that it was essentially terrestrial. According to its position within the phylogenetic tree of Eocene proboscideans, the adaptation to semi-aquatic life appears to have evolved independently in different lineages of Middle and Upper Eocene proboscideans during their adaptive radiation in Africa. Moreover, these new results reopen the debate about the hypothesis that Eocene to Recent proboscideans are derived from semi-aquatic ancestors. Le gisement de l’Eocène inférieur d’El Kohol (Algérie) a livré de nombreux restes de Numidotherium koholense , l’un des proboscidiens les plus primitifs et les plus anciens de la radiation de cet ordre en Afrique. Les proboscidiens de l’Eocène supérieur du Fayum en Égypte, comme Barytherium sp. et Moeritherium sp. étaient semi-aquatiques d’après des données des isotopes stables ( δ 13 C et δ 18 O) de leur émail dentaire. Ces données nous ont conduits à réexaminer le mode de vie de N. koholense . Les analyses des isotopes stables et l’examen des coupes histologiques des os longs révèlent qu’il était plutôt terrestre. Compte-tenu de la position qu’il occupe dans l’arbre phylogénétique des proboscidiens éocènes, l’adaptation à la vie semi-aquatique serait donc développée indépendamment dans différentes lignées de proboscidiens primitifs au cours de leur radiation adaptative éocène. Par ailleurs, ces résultats rouvrent le débat concernant l’hypothèse de l’adaptation semi-aquatique de l’ancêtre des proboscidiens primitifs.
Comparison of the mating behaviour of a bush cricket in the laboratory and the field: Calling activity and mating frequency of a long-winged species, Phaneroptera falcata (Ensifera: Tettigoniidae)
2014-02-24

Bush crickets are a model group for testing hypotheses in sexual selection, but much of the information is based on laboratory observations on wingless or short-winged species, which may restrict their generality. Here we describe aspects of the mating behaviour of the long-winged European bush cricket Phaneroptera falcata (Poda, 1761). Both in the laboratory and the field, diel calling followed a normal, though slightly left-skewed distribution, peaking about three hours after sunset or lights-off. Under bright greenhouse conditions, when the light was suddenly switched off, calling occurred only after the onset of darkness. Decreasing light intensity may trigger the start of calling activity. In the field, calling decreased from midnight onwards, which may be related to a decrease in temperature. The sequence of events during copulation was identical in the laboratory and the field. However, in two of 14 copulations documented in the field, a pre-copulatory behaviour was observed that resembled the putative removal and ingestion of rival sperm. Previous suggestions that P. falcata (Poda) is monogamous are rejected on the basis of both laboratory and field results. In the laboratory males and females mated every 2.3 and 3.6 days, respectively. We introduce a simple way to calculate the average frequency of mating in the field, based on the observation that at any one time 3% of all the individuals are recorded mating and copulation lasts 15 min. We estimate that on average P. falcata (Poda) mates once per day. More generally, our results show it is important for evolutionary conclusions to measure behaviourial data in the field.
Activated Platelets Interfere with Recruitment of Mesenchymal Stem Cells to Apoptotic Cardiac Cells via High Mobility Group Box 1/Toll-like Receptor 4-mediated Down-regulation of Hepatocyte Growth Factor Receptor MET
2014-02-25

Recruitment of mesenchymal stem cells (MSC) following cardiac injury, such as myocardial infarction, plays a critical role in tissue repair and may contribute to myocardial recovery. However, the mechanisms that regulate migration of MSC to the site of tissue damage remain elusive. Here, we demonstrate in vitro that activated platelets substantially inhibit recruitment of MSC toward apoptotic cardiac myocytes and fibroblasts. The alarmin high mobility group box 1 (HMGB1) was released by platelets upon activation and mediated inhibition of the cell death-dependent migratory response through Toll-like receptor (TLR)-4 expressed on the MSC. Migration of MSC to apoptotic cardiac myocytes and fibroblasts was driven by hepatocyte growth factor (HGF), and platelet activation was followed by HMGB1/TLR-4-dependent down-regulation of HGF receptor MET on MSC, thereby impairing HGF-driven MSC recruitment. We identify a novel mechanism by which platelets, upon activation, interfere with MSC recruitment to apoptotic cardiac cells, a process that may be of particular relevance for myocardial repair and regeneration.
CD4:8 Ratio >5 Is Associated With a Dominant Naive T-Cell Phenotype and Impaired Physical Functioning in CMV-Seropositive Very Elderly People: Results From the BELFRAIL Study
2014-02-25

A subset of older people is at increased risk of hospitalization and dependency. Emerging evidence suggests that immunosenescence reflected by an inverted CD4:8 ratio and cytomegalovirus (CMV) seropositivity plays an important role in the pathophysiology of functional decline. Nevertheless, the relation between CD4:8 ratio and functional outcome has rarely been investigated. Here, CD4:8 ratio and T-cell phenotypes of 235 community-dwelling persons aged ≥81.5 years in the BELFRAIL study and 25 younger persons (mean age 28.5 years) were analyzed using polychromatic flow cytometry. In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV. This underscores the notion that in very elderly people, not merely CMV infection but also the state of its accompanying immune dysregulation is of crucial importance with regard to physical impairment.
Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in paediatric patients
2014-02-25

The efficacy of ECP in the treatment of chronic GvHD in paediatric patients after haematopoietic stem cell transplantation based on RCTs can currently not be evaluated since we have found no such studies. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this patient population will be challenging due to the limited number of patients, the variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical grounds in favour of ECP are made, people should be carefully monitored for beneficial and harmful effects and efforts should be made to share this information with other clinicians, for example by setting up registries for paediatric patients that are treated with ECP.
Splicing factor hnRNP A2 activates the Ras-MAPK-ERK pathway by controlling A-Raf splicing in hepatocellular carcinoma development
2014-02-26

In recent years, it has become clear that splicing factors play a direct role in cancer development. We showed previously that splicing factors SRSF1, SRSF6, and hnRNP A2/B1 are up-regulated in several cancers and can act as oncogenes when up-regulated. Here we examined the role of splicing factors hnRNP A1/A1b and hnRNP A2/B1 in hepatocellular carcinoma (HCC). We show that the splicing factors hnRNP A1 and hnRNP A2 are up-regulated in HCC tumors derived from inflammation-induced liver cancer mouse model. Overexpression of hnRNP A1 or hnRNP A2, but not the splicing isoform hnRNP B1, induced tumor formation of immortalized liver progenitor cells, while knockdown of these proteins inhibited anchorage-independent growth and tumor growth of human liver cancer cell lines. In addition, we found that cells overexpressing hnRNP A2 showed constitutive activation of the Ras-MAPK-ERK pathway. In contrast, knockdown of hnRNP A2 inhibited the Ras-MAPK-ERK pathway and prevented ERK1/2 activation by EGF. Moreover, we found that hnRNP A2 regulates the splicing of A-Raf , reducing the production of a short dominant-negative isoform of A-Raf and elevating the full-length A-Raf transcript. Taken together, our data suggest that hnRNP A2 up-regulation in HCC induces an alternative splicing switch that down-regulates a dominant-negative isoform of A-Raf, leading to activation of the Raf-MEK-ERK pathway and cellular transformation.
Alkynyliodonium Salt Mediated Alkynylation of Azlactones: Fast Access to Cα-Tetrasubstituted α-Amino Acid Derivatives
2014-02-26

An efficient electrophilic alkynylation of azlactones (oxazol-5(4H)-ones) is developed using alkynyl(phenyl)iodonium salts as the electrophilic alkyne source. After remarkably short reaction times, the desired alkyne functionalized azlactones are obtained in 60-97% yield and can be transformed easily into a variety of quaternary α-amino acid derivatives.
Reconstructing the Life of an Unknown (ca. 500 Years-Old South American Inca) Mummy – Multidisciplinary Study of a Peruvian Inca Mummy Suggests Severe Chagas Disease and Ritual Homicide
2014-02-26

The paleopathological, paleoradiological, histological, molecular and forensic investigation of a female mummy (radiocarbon dated 1451-1642 AD) provides circumstantial evidence for massive skull trauma affecting a young adult female individual shortly before death along with chronic infection by Trypanosoma cruzi (Chagas disease). The mummy (initially assumed to be a German bog body) was localized by stable isotope analysis to South America at/near the Peruvian/Northern Chilean coast line. This is further supported by New World camelid fibers attached to her plaits, typical Inca-type skull deformation and the type of Wormian bone at her occiput. Despite an only small transverse wound of the supraorbital region computed tomography scans show an almost complete destruction of face and frontal skull bones with terrace-like margins, but without evidence for tissue reaction. The type of destruction indicates massive blunt force applied to the center of the face. Stable isotope analysis indicates South American origin: Nitrogen and hydrogen isotope patterns indicate an extraordinarily high marine diet along with C4-plant alimentation which fits best to the coastal area of Pacific South America. A hair strand over the last ten months of her life indicates a shift to a more "terrestric" nutrition pattern suggesting either a move from the coast or a change in her nutrition. Paleoradiology further shows extensive hypertrophy of the heart muscle and a distended large bowel/rectum. Histologically, in the rectum wall massive fibrosis alternates with residual smooth muscle. The latter contains multiple inclusions of small intracellular parasites as confirmed by immunohistochemical and molecular ancient DNA analysis to represent a chronic Trypanosoma cruzi infection. This case shows a unique paleopathological setting with massive blunt force trauma to the skull nurturing the hypothesis of a ritual homicide as previously described in South American mummies in an individual that suffered from severe chronic Chagas disease.
A continental risk assessment of West Nile virus under climate change
2014-02-27

Abstract Since first introduced to North America in 1999, West Nile virus ( WNV ) has spread rapidly across the continent, threatening wildlife populations and posing serious health risks to humans. While WNV incidence has been linked to environmental factors, particularly temperature and rainfall, little is known about how future climate change may affect the spread of the disease. Using available data on WNV infections in vectors and hosts collected from 2003–2011 and using a suite of 10 species distribution models, weighted according to their predictive performance, we modeled the incidence of WNV under current climate conditions at a continental scale. Models were found to accurately predict spatial patterns of WNV that were then used to examine how future climate may affect the spread of the disease. Predictions were accurate for cases of human WNV infection in the following year (2012), with areas reporting infections having significantly higher probability of presence as predicted by our models. Projected geographic distributions of WNV in North America under future climate for 2050 and 2080 show an expansion of suitable climate for the disease, driven by warmer temperatures and lower annual precipitation that will result in the exposure of new and naïve host populations to the virus with potentially serious consequences. Our risk assessment identifies current and future hotspots of West Nile virus where mitigation efforts should be focused and presents an important new approach for monitoring vector‐borne disease under climate change.
Constraining the area of rapid and deep‐seated exhumation at the St. Elias syntaxis, Southeast Alaska, with detrital zircon fission‐track analysis
2014-02-27

Abstract The Chugach‐St. Elias orogen, Southeast Alaska/Southwest Yukon, formed in response to the ongoing Yakutat microplate subduction‐collision with the North American Plate. Due to heavy glaciation, the region is a prime location to study active convergent orogenesis and climate‐tectonic interactions. This study focuses on the long‐term distribution of deformation in the St. Elias syntaxis area, where dextral motion along the plate‐bounding Fairweather Fault transitions into convergence. We present 2718 new zircon fission‐track single‐grain ages from 26 glaciofluvial outwash samples. The grain ages range from 293 Ma to 0.2 Ma, and each sample contains two to five age populations with peaks between 267 ± 64 Ma and 1.2 ± 0.7 Ma (1 σ ). The rocks of the Yakutat microplate are dominated by latest Cretaceous and Eocene fission‐track ages, while the rocks of the North American Plate in the syntaxis region reveal two exhumation phases at ~5.1 Ma and ~2.7 Ma. The spatial pattern of ≤5 Ma cooling ages shows that the area of rapid and deep exhumation at the St. Elias syntaxis is more extensive than previously known and confined to the south by the Fairweather Fault, to the west by the Seward Glacier catchment, and to the east possibly by the inferred Connector Fault. The area seems to be ~4800 km 2 large and may extend farther to the north. The new zircon fission‐track data further suggest a transpressional plate boundary since ~30 Ma and the onset of plate collision 15–12 Ma.