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Trypanosoma brucei is a protozoan flagellate that is transmitted by tsetse flies into the mammalian bloodstream. The parasite has a huge impact on human health both directly by causing African sleeping sickness and indirectly, by infecting domestic cattle. The biology of trypanosomes involves some highly unusual, nuclear-localised processes. These include polycistronic transcription without classical promoters initiated from regions defined by histone variants, trans-splicing of all transcripts to the exon of a spliced leader RNA, transcription of some very abundant proteins by RNA polymerase I and antigenic variation, a switch in expression of the cell surface protein variants that allows the parasite to resist the immune system of its mammalian host. Here, we provide the nuclear proteome of procyclic Trypanosoma brucei, the stage that resides within the tsetse fly midgut. We have performed quantitative label-free mass spectrometry to score 764 significantly nuclear enriched proteins in comparison to whole cell lysates. A comparison with proteomes of several experimentally characterised nuclear and non-nuclear structures and pathways confirmed the high quality of the dataset: the proteome contains about 80% of all nuclear proteins and less than 2% false positives. Using motif enrichment, we found the amino acid sequence KRxR present in a large number of nuclear proteins. KRxR is a sub-motif of a classical eukaryotic monopartite nuclear localisation signal and could be responsible for nuclear localization of proteins in Kinetoplastida species. As a proof of principle, we have confirmed the nuclear localisation of six proteins with previously unknown localisation by expressing eYFP fusion proteins. While proteome data of several T. brucei organelles have been published, our nuclear proteome closes an important gap in knowledge to study trypanosome biology, in particular nuclear-related processes.
The aim of the present study was to examine whether fostering positive activating affect during multimedia learning enhances learning outcome. University students were randomly assigned to either a multimedia learning environment designed to induce positive activating affect through the use of “warm” colours and rounded shapes () or an affectively neutral environment that used achromatic colours and sharp edges (). Participants learned about the topic of functional neuroanatomy for 20 minutes and had to answer several questions for comprehension and transfer afterwards. Affective states as well as achievement goal orientations were investigated before and after the learning phase using questionnaires. The results show that participants in the affectively positive environment were superior in comprehension as well as transfer when initial affect was strong. Preexperimental positive affect was therefore a predictor of comprehension and a moderator for transfer. Goal orientations did not influence these effects. The findings support the idea that positive affect, induced through the design of the particular multimedia learning environment, can facilitate performance if initial affective states are taken into account.
Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.
An efficient multigrid finite-differences scheme for solving elliptic Fredholm partial integro-differential equations (PIDE) is discussed. This scheme combines a second-order accurate finite difference discretization of the PIDE problem with a multigrid scheme that includes a fast multilevel integration of the Fredholm operator allowing the fast solution of the PIDE problem. Theoretical estimates of second-order accuracy and results of local Fourier analysis of convergence of the proposed multigrid scheme are presented. Results of numerical experiments validate these estimates and demonstrate optimal computational complexity of the proposed framework.
5’-3’ decay is the major mRNA decay pathway in many eukaryotes, including trypanosomes. After deadenylation, mRNAs are decapped by the nudix hydrolase DCP2 of the decapping complex and finally degraded by the 5’-3’ exoribonuclease. Uniquely, trypanosomes lack homologues to all subunits of the decapping complex, while deadenylation and 5’-3’ degradation are conserved. Here, I show that the parasites use an ApaH-like phosphatase (ALPH1) as their major mRNA decapping enzyme. The protein was recently identified as a novel trypanosome stress granule protein and as involved in mRNA binding. A fraction of ALPH1 co-localises exclusively with the trypanosome 5’-3’ exoribonuclease XRNA to a special granule at the posterior pole of the cell, indicating a connection between the two enzymes. RNAi depletion of ALPH1 is lethal and causes a massive increase in total mRNAs that are deadenylated, but have not yet started 5’-3’ decay. These data suggest that ALPH1 acts downstream of deadenylation and upstream of mRNA degradation, consistent with a function in mRNA decapping. In vitro experiments show that recombinant, N-terminally truncated ALHP1 protein, but not a catalytically inactive mutant, sensitises the capped trypanosome spliced leader RNA to yeast Xrn1, but only if an RNA 5’ polyphosphatase is included. This indicates that the decapping mechanism of ALPH1 differs from the decapping mechanism of Dcp2 by leaving more than one phosphate group at the mRNA’s 5’ end. This is the first reported function of a eukaryotic ApaH-like phosphatase, a bacterial-derived class of enzymes present in all phylogenetic super-groups of the eukaryotic kingdom. The substrates of eukaryotic ApaH-like phosphatases are unknown. However, the substrate of the related bacterial enzyme ApaH, diadenosine tetraphosphate, is highly reminiscent of a eukaryotic mRNA cap.
Background:
Fear of cancer progression/recurrence (FOP/FCR) is considered one of the most prevalent sources of distress in cancer survivors and associated with lower quality of life and functional impairment. Detailed measures of FOP/FCR are needed because little is known about the knowledge of FOP/FCR, its associations with the patient–doctor relationship, and the rate of adequate therapy. Colorectal cancer (CRC) is one of the most prevalent cancer entities, and oral capecitabine is widely prescribed as treatment. Therefore, we initiated a pilot study to expand the literature on FOP/FCR in CRC outpatients receiving capecitabine and to generate hypotheses for future investigations.
Methods:
This study included 58 patients treated at a comprehensive cancer center. FOP/FCR was assessed with the Fear of Progression Questionnaire (FOP-Q-SF). Satisfaction with the relationships with doctors was assessed with the Patient–Doctor Relationship Questionnaire-9 (PRDQ-9). Levels of side effects were rated by the patients on a visual analog scale. Clinical data were extracted from the charts.
Results:
A total of 19 out of 58 patients (36%) suffered from FOP/FCR according to our assessment. Levels of FOP/FCR seemed to be mostly moderate to high. Only four out of the 19 distressed patients (21%) were treated accordingly. Typical side effects of oncological treatment were associated with higher FOP/FCR. Satisfaction with doctor–patient relationships was not associated with FOP/FCR. Regarding single items of FOP/FCR, three out of the five most prevalent fears were associated with close relatives.
Discussion:
FOP/FCR occurred frequently in more than one in three patients, but was mostly untreated in this sample of consecutive outpatients with CRC receiving oral capecitabine. In detail, most fears were related to family and friends. In addition to an unmet need of patients, our data indicate sources of distress not considered thus far. If replicated in larger studies, results may help to inform intervention development and improve patient care.
Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell plus T cell transplantation (allo-HSCT). In this study, we investigated the requirement for CD28 co-stimulation of donor CD4\(^{+}\) conventional (CD4\(^{+}\)CD25\(^{-}\)Foxp3\(^{-}\), Tconv) and regulatory (CD4\(^{+}\)CD25\(^{+}\)Foxp3\(^{+}\), Treg) T cells in aGvHD using tamoxifen-inducible CD28 knockout (iCD28KO) or wild-type (wt) littermates as donors of CD4\(^{+}\) Tconv and Treg. In the highly inflammatory C57BL/6 into BALB/c allo-HSCT transplantation model, CD28 depletion on donor CD4\(^{+}\) Tconv reduced clinical signs of aGvHD, but did not significantly prolong survival of the recipient mice. Selective depletion of CD28 on donor Treg did not abrogate protection of recipient mice from aGvHD until about day 20 after allo-HSCT. Later, however, the pool of CD28-depleted Treg drastically declined as compared to wt Treg. Consequently, only wt, but not CD28-deficient, Treg were able to continuously suppress aGvHD and induce long-term survival of the recipient mice. To our knowledge, this is the first study that specifically evaluates the impact of CD28 expression on donor Treg in aGvHD. Moreover, the delayed kinetics of aGvHD lethality after transplantation of iCD28KO Treg provides a novel animal model for similar disease courses found in patients after allo-HSCT.
Multiple-level amputations of the upper extremity represent a surgical challenge generally only attempted in young patients. This case demonstrates a successful replantation in an elderly woman. The postoperative course was complicated by disseminated intravascular coagulopathy most likely due to inadequate resuscitation. Hand trauma is often underestimated in its general severity. Upper extremity amputations need to be handled similar to polytraumatized patients.
MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.
In this study, polarimetric Synthetic Aperture Radar (PolSAR) data at X-, C- and L-Bands, acquired by the satellites: TerraSAR-X (2011), Radarsat-2 (2011), ALOS (2010) and ALOS-2 (2016), were used to characterize the tundra land cover of a test site located close to the town of Tuktoyaktuk, NWT, Canada. Using available in situ ground data collected in 2010 and 2012, we investigate PolSAR scattering characteristics of common tundra land cover classes at X-, C- and L-Bands. Several decomposition features of quad-, co-, and cross-polarized data were compared, the correlation between them was investigated, and the class separability offered by their different feature spaces was analyzed. Certain PolSAR features at each wavelength were sensitive to the land cover and exhibited distinct scattering characteristics. Use of shorter wavelength imagery (X and C) was beneficial for the characterization of wetland and tundra vegetation, while L-Band data highlighted differences of the bare ground classes better. The Kennaugh Matrix decomposition applied in this study provided a unified framework to store, process, and analyze all data consistently, and the matrix offered a favorable feature space for class separation. Of all elements of the quad-polarized Kennaugh Matrix, the intensity based elements K0, K1, K2, K3 and K4 were found to be most valuable for class discrimination. These elements contributed to better class separation as indicated by an increase of the separability metrics squared Jefferys Matusita Distance and Transformed Divergence. The increase in separability was up to 57% for Radarsat-2 and up to 18% for ALOS-2 data.