628 research outputs found
Expressionsmuster Gewebe-spezifischer Antigene in Thymus-Epithelzellen der Maus
Ziel dieser Arbeit war es, die Expression verschiedener Gewebe-spezifischer Gene in Thymus-Epithelzellen auf Einzelzellebene zu untersuchen. mRNA und Proteinexpression wurde fĂŒr Insulin, P1A, PLP, MOG, Somatostatin und S100beta gefunden. Diese Antigene (bis auf MOG) wurden in medullĂ€ren Epithelzellen des Thymus exprimiert, die Frequenz der exprimierenden Zellen betrug 100 PLP und S100beta wurden ebenfalls in kortikalen Thymus-Epithelzellen detektiert, jedoch keins dieser Antigene wurde in dendritischen Zellen detektiert. Bis auf MOG wurden alle Antigene in medullĂ€ren Epithelzellen koexprimiert. Diese Ergebnisse demonstrieren, dass die ektopische Genexpression in medullĂ€ren Epithelzellen des Thymus nicht strikt reguliert wird. Es wird vermutet, dass epigenetische Ănderungen fĂŒr die ektopische Genexpression verantwortlich sind (VerĂ€nderungen des Methylierungsstatus, Ăberexpression der DNA-abhĂ€ngigen RNA-Polymerase). Die hohe Frequenz der ektopisch exprimierenden Zellen belegt ĂŒberdies, dass die medullĂ€ren Epithelzellen in der Lage sind, ohne Beteiligung der hĂ€matopoetischen Zellen Toleranz zu induzieren. Ferner wurden deutliche Unterschiede in der ExpressionsstĂ€rke bei Autoantigenen und Nicht-Autoantigenen gefunden, wobei die Autoantigene deutlich schwĂ€cher exprimiert wurden
The Human Formin FHOD1 Contains a Bipartite Structure of FH3 and GTPase-Binding Domains Required for Activation
SummaryFormins induce the nucleation and polymerization of unbranched actin filaments. They share three homology domains required for profilin binding, actin polymerization, and regulation. Diaphanous-related formins (DRFs) are activated by GTPases of the Rho/Rac family, whose interaction with the N-terminal formin domain is thought to displace a C-terminal Diaphanous-autoregulatory domain (DAD). We have determined the structure of the N-terminal domains of FHOD1 consisting of a GTPase-binding domain (GBD) and the DAD-recognition domain FH3. In contrast to the formin mDia1, the FHOD1-GBD reveals a ubiquitin superfold as found similarly in c-Raf1 or PI3 kinase. This GBD is recruited by Rac and Ras GTPases in cells and plays an essential role for FHOD1-mediated actin remodeling. The FHOD1-FH3 domain is composed of five armadillo repeats, similarly to other formins. Mutation of one residue in the predicted DAD-interaction surface efficiently activates FHOD1 in cells. These results demonstrate that DRFs have evolved different molecular solutions to govern their autoregulation and GTPase specificity
Dominant negative mutant Cyclin T1 proteins inhibit HIV transcription by specifically degrading Tat
This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
Psychosocial stressors and protective factors for major depression in youth: evidence from a case-control study
Background: Severe adverse life events, such as traumatic experiences, are well-known stressors implicated in (youth) major depression (MD). However, to date, far less is known about the role of more common psychosocial stressors in the context of MD, which are part of everyday life during youth. In addition, it is not well-understood whether and how distinct stressors interact with protective factors in youths diagnosed with MD. Thus, the present study aimed at examining several specific psychosocial stressors implicated in a first-episode juvenile MD and addressed the question whether protective factors might moderate the relationship between stressors and a diagnosis of MD.
Methods: One-hundred male and female youths with MD and 101 typically developing (TD) controls (10-18 years) were included. A large number of qualitatively different psychosocial stressors occurring in various areas of life were assessed via self-report. Moreover, we also investigated sociodemographic and pre- and postnatal stressors, as well as the presence of familial affective disorders via parental-report. Social support and a positive family climate were conceptualized as protective factors and were assessed via self-report.
Results: Results showed that the proportion of youths experiencing specific psychosocial stressors was higher in the MD than in the TD group. In particular, the proportion of youths indicating changes at home or at school, experiences of violence, delinquent behavior, as well as the proportion of youths who were exposed to sociodemographic stressors was higher in the MD than in the TD group. Moreover, the percentage of youths with a family history of an affective disorder, or whose mothers experienced psychological burdens during/after pregnancy was elevated in the MD group. Youths with MD experienced less social support and a less positive family climate than their TD peers. These factors, however, did not buffer the influence of specific stressors on MD.
Conclusion: We could show that next to more severe adverse life events, more common psychosocial stressors are linked to youth MD. Importantly, by identifying distinct stressors in youth MD, our results can increase treatment and prevention efforts aiming to improve the outcomes in youths affected by MD or in at-risk individuals
Elimusertib has anti-tumor activity in preclinical patient-derived pediatric solid tumor models
The small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), elimusertib, is currently being tested clinically in various cancer entities in adults and children. Its preclinical anti-tumor activity in pediatric malignancies, however, is largely unknown. We here assessed the preclinical activity of elimusertib in 38 cell lines and 32 patient-derived xenograft (PDX) models derived from common pediatric solid tumor entities. Detailed in vitro and in vivo molecular characterization of the treated models enabled the evaluation of response biomarkers. Pronounced objective response rates were observed for elimusertib monotherapy in PDX, when treated with a regimen currently used in clinical trials. Strikingly, elimusertib showed stronger anti-tumor effects than some standard of care chemotherapies, particularly in alveolar rhabdomysarcoma PDX. Thus, elimusertib has strong preclinical anti-tumor activity in pediatric solid tumor models, which may translate to clinically meaningful responses in patients
Situating language register across the ages, languages, modalities, and cultural aspects: Evidence from complementary methods
In the present review paper by members of the collaborative research center âRegister: Language Users' Knowledge of Situational-Functional Variationâ (CRC 1412), we assess the pervasiveness of register phenomena across different time periods, languages, modalities, and cultures. We define âregisterâ as recurring variation in language use depending on the function of language and on the social situation. Informed by rich data, we aim to better understand and model the knowledge involved in situation- and function-based use of language register. In order to achieve this goal, we are using complementary methods and measures. In the review, we start by clarifying the concept of âregisterâ, by reviewing the state of the art, and by setting out our methods and modeling goals. Against this background, we discuss three key challenges, two at the methodological level and one at the theoretical level: (1) To better uncover registers in text and spoken corpora, we propose changes to established analytical approaches. (2) To tease apart between-subject variability from the linguistic variability at issue (intra-individual situation-based register variability), we use within-subject designs and the modeling of individuals' social, language, and educational background. (3) We highlight a gap in cognitive modeling, viz. modeling the mental representations of register (processing), and present our first attempts at filling this gap. We argue that the targeted use of multiple complementary methods and measures supports investigating the pervasiveness of register phenomena and yields comprehensive insights into the cross-methodological robustness of register-related language variability. These comprehensive insights in turn provide a solid foundation for associated cognitive modeling.Peer Reviewe
Molecular Design, Functional Characterization and Structural Basis of a Protein Inhibitor Against the HIV-1 Pathogenicity Factor Nef
Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as âwrapping Nefâ, is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
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