Reducing image artefacts in concurrent TMS/fMRI by passive shimming

A significant problem in the concurrent application of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) is the image artefact caused by the effect of the TMS-coil on the homogeneity of the static magnetic field (B0). The resulting field inhomogeneity can lead to spatial distortions and local signal loss in echo-planar (EP) images. Here we demonstrate that passive shimming using thin patches of austenitic stainless steel can reduce the effect of the TMS-coil on B0 by ~ 80%, thus essentially eliminating the associated artefact. Initially the effect of the TMS-coil on B0 was measured using the phase of gradient echo images. Consequently the ideal distribution for the steel was simulated using the magnetic properties of the steel and the effects of the TMS-coil. Finally we demonstrate the effect of two different implementations of the passive shim on a spherical phantom and in vivo

CCR2 of Tumor Microenvironmental Cells Is a Relevant Modulator of Glioma Biology.

Glioblastoma multiforme (GBM) shows a high influx of tumor-associated macrophages (TAMs). The CCR2/CCL2 pathway is considered a relevant signal for the recruitment of TAMs and has been suggested as a therapeutic target in malignant gliomas. We found that TAMs of human GBM specimens and of a syngeneic glioma model express CCR2 to varying extents. Using a Ccr2-deficient strain for glioma inoculation revealed a 30% reduction of TAMs intratumorally. This diminished immune cell infiltration occurred with augmented tumor volumes likely based on increased cell proliferation. Remaining TAMs in Ccr2-/- mice showed comparable surface marker expression patterns in comparison to wildtype mice, but expression levels of inflammatory transcription factors (Stat3, Irf7, Cox2) and cytokines (Ifnβ, Il1β, Il12α) were considerably affected. Furthermore, we demonstrated an impact on blood vessel integrity, while vascularization of tumors appeared similar between mouse strains. The higher stability and attenuated leakiness of the tumor vasculature imply improved sustenance of glioma tissue in Ccr2-/- mice. Additionally, despite TAMs residing in the perivascular niche in Ccr2-/- mice, their pro-angiogenic activity was reduced by the downregulation of Vegf. In conclusion, lacking CCR2 solely on tumor microenvironmental cells leads to enhanced tumor progression, whereby high numbers of TAMs infiltrate gliomas independently of the CCR2/CCL2 signal

Screening of DUB activity and specificity by MALDI-TOF mass spectrometry

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs

The ATP-Binding Cassette Proteins of the Deep-Branching Protozoan Parasite Trichomonas vaginalis

The ATP binding cassette (ABC) proteins are a family of membrane transporters and regulatory proteins responsible for diverse and critical cellular process in all organisms. To date, there has been no attempt to investigate this class of proteins in the infectious parasite Trichomonas vaginalis. We have utilized a combination of bioinformatics, gene sequence analysis, gene expression and confocal microscopy to investigate the ABC proteins of T. vaginalis. We demonstrate that, uniquely among eukaryotes, T. vaginalis possesses no intact full-length ABC transporters and has undergone a dramatic expansion of some ABC protein sub-families. Furthermore, we provide preliminary evidence that T. vaginalis is able to read through in-frame stop codons to express ABC transporter components from gene pairs in a head-to-tail orientation. Finally, with confocal microscopy we demonstrate the expression and endoplasmic reticulum localization of a number of T. vaginalis ABC transporters

The link between rejection sensitivity and borderline personality disorder:A systematic review and meta-analysis

OBJECTIVE: People with Borderline Personality Disorder (BPD) may experience heightened rejection sensitivity (RS), a disposition developing from repeated childhood rejecting experiences. It is not known whether the full RS model accounts for the cognitive-affective experiences common in BPD. This systematic review extends upon previous reviews, firstly by assessing the link between childhood rejecting experiences and adult RS, and secondly by considering the link between BPD and RS in both non-clinical and clinical samples.METHOD: Two research questions were devised, and searches based on predetermined criteria were conducted using PsycNET, PubMed, SCOPUS, and Web of Science. Data were extracted by one researcher and 20% was inter-rated, with high levels of agreement. Forty-three papers were systematically reviewed, and 31 included in meta-analysis and meta-regression.RESULTS: Studies assessing the link between childhood rejection and RS are limited; however, emotional abuse and neglect appears linked with RS. Pooled effect sizes suggest RS is linked with BPD (r = .326), with strong effect sizes when comparing clinical and control samples (r = .655). Qualitative synthesis suggests this may be mediated by executive control, although further research is required. The small number of studies considering the full RS model with regard to BPD suggests the interaction between emotional abuse and neglect affects rejection sensitivity; however, outcomes are inconsistent.CONCLUSIONS: Childhood rejection, particularly emotional abuse and neglect, appears to be linked to rejection sensitivity, and rejection sensitivity is linked to BPD. However, this may not be linear. Implications for clinical practice and research are discussed.PRACTITIONER POINTS: Rejection sensitivity is consistently linked with BPD, in clinical and non-clinical samples. Supporting mentalization or improved theory of mind may offer a therapeutic target for this disposition. Considering the causes and effects of rejection sensitivity may offer a non-blaming explanation of interpersonal difficulties in BPD and could be utilized as part of formulation and the therapeutic relationship. However, the possible interaction between emotional abuse and neglect and rejection sensitivity suggests rejection sensitivity is not always apparent for people with BPD. Idiosyncratic formulation should consider this. The literature included in the review is limited to Western populations with a high proportion of females, which may limit generalizability. Measures of rejection sensitivity included in the review were restricted to self-report, which may be subject to bias. Furthermore, measures of childhood rejection were retrospective in nature due to the exclusion of child samples. Further research should consider longitudinal and observational study designs.</p

Fundamental deficits of auditory perception in Wernicke’s aphasia

Objective: This work investigates the nature of the comprehension impairment in Wernicke’s aphasia, by examining the relationship between deficits in auditory processing of fundamental, non-verbal acoustic stimuli and auditory comprehension. Wernicke’s aphasia, a condition resulting in severely disrupted auditory comprehension, primarily occurs following a cerebrovascular accident (CVA) to the left temporo-parietal cortex. Whilst damage to posterior superior temporal areas is associated with auditory linguistic comprehension impairments, functional imaging indicates that these areas may not be specific to speech processing but part of a network for generic auditory analysis. Methods: We examined analysis of basic acoustic stimuli in Wernicke’s aphasia participants (n = 10) using auditory stimuli reflective of theories of cortical auditory processing and of speech cues. Auditory spectral, temporal and spectro-temporal analysis was assessed using pure tone frequency discrimination, frequency modulation (FM) detection and the detection of dynamic modulation (DM) in “moving ripple” stimuli. All tasks used criterion-free, adaptive measures of threshold to ensure reliable results at the individual level. Results: Participants with Wernicke’s aphasia showed normal frequency discrimination but significant impairments in FM and DM detection, relative to age- and hearing-matched controls at the group level (n = 10). At the individual level, there was considerable variation in performance, and thresholds for both frequency and dynamic modulation detection correlated significantly with auditory comprehension abilities in the Wernicke’s aphasia participants. Conclusion: These results demonstrate the co-occurrence of a deficit in fundamental auditory processing of temporal and spectrotemporal nonverbal stimuli in Wernicke’s aphasia, which may have a causal contribution to the auditory language comprehension impairment Results are discussed in the context of traditional neuropsychology and current models of cortical auditory processing

Fine Tuning of Globin Gene Expression by DNA Methylation

Expression patterns in the globin gene cluster are subject to developmental regulation in vivo. While the γ(A) and γ(G) genes are expressed in fetal liver, both are silenced in adult erythrocytes. In order to decipher the role of DNA methylation in this process, we generated a YAC transgenic mouse system that allowed us to control γ(A) methylation during development. DNA methylation causes a 20-fold repression of γ(A) both in non-erythroid and adult erythroid cells. In erythroid cells this modification works as a dominant mechanism to repress γ gene expression, probably through changes in histone acetylation that prevent the binding of erythroid transcription factors to the promoter. These studies demonstrate that DNA methylation serves as an elegant in vivo fine-tuning device for selecting appropriate genes in the globin locus. In addition, our findings provide a mechanism for understanding the high levels of γ-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate γ-globin expression in patients with β-hemoglobinopathies

Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies

Distinction of Microglia and Macrophages in Glioblastoma: Close Relatives, Different Tasks?

For decades, it has been known that the tumor microenvironment is significant for glioma progression, namely the infiltration of myeloid cells like microglia and macrophages. Hence, these cell types and their specific tasks in tumor progression are subject to ongoing research. However, the distribution of the brain resident microglia and the peripheral macrophages within the tumor tissue and their functional activity are highly debated. Results depend on the method used to discriminate between microglia and macrophages, whereby this specification is already difficult due to limited options to distinguish between these both cell populations that show mostly the same surface markers and morphology. Moreover, there are indications about various functions of microglia and macrophages but again varying on the method of discrimination. In our review, we summarize the current literature to determine which methods have been applied to differentiate the brain resident microglia from tumor-infiltrated macrophages. Furthermore, we compiled data about the proportion of microglia and macrophages in glioma tissues and ascertained if pro- or anti-tumoral effects could be allocated to one or the other myeloid cell population. Recent research made tremendous efforts to distinguish microglia from recruited macrophages. For future studies, it could be essential to verify which role these cells play in brain tumor pathology to proceed with novel immunotherapeutic strategies