Cholinergic neurons of the medial forebrain are considered important contributors to brain plasticity and neuromodulation. A reduction of cholinergic innervation can lead to pathophysiological ...changes of neurotransmission and is observed in Alzheimer's disease. Here we report on six patients with mild to moderate Alzheimer's disease (AD) treated with bilateral low-frequency deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM). During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period, clinical outcome was assessed by neuropsychological examination using the Alzheimer's Disease Assessment Scale-cognitive subscale as the primary outcome measure. Electroencephalography and (18)F-fluoro-desoxyglucose positron emission tomography were, besides others, secondary endpoints. On the basis of stable or improved primary outcome parameters twelve months after surgery, four of the six patients were considered responders. No severe or non-transitional side effects related to the stimulation were observed. Taking into account all limitations of a pilot study, we conclude that DBS of the NBM is both technically feasible and well tolerated.
Massive outflows of neutral atomic hydrogen (H
I
) have been observed in absorption in a number of radio galaxies and are considered a signature of active galactic nucleus (AGN) feedback. These ...outflows on kiloparsec scales have not been investigated in great detail as they require high-angular-resolution observations to be spatially resolved. In some radio AGN, they are likely to be the result of the radio jets interacting with the interstellar medium. We have used the global very-long-baseline-interferometry (VLBI) array to map the H
I
outflow in a small sample of young and restarted radio galaxies that we previously observed with the Very Large Array and the Westerbork Synthesis Radio Telescope at a lower resolution. Here we report on our findings for
4C 52.37
and
3C 293
and we discuss the sample including the previously published
4C 12.50
and
3C 236
. For
4C 52.37
, we present the first ever H
I
VLBI observations, which recovered the majority of the outflowing H
I
gas in the form of clouds toward the central 100 pc of the AGN. The clouds are blueshifted by up to ∼600 km s
−1
with respect to the systemic velocity.
3C 293
is largely resolved out in our VLBI observation, but toward the VLBI core we detect some outflowing H
I
gas blueshifted with respect to the systemic velocity by up to ∼300 km s
−1
. We also find indications of outflowing gas toward the other parts of the western lobe suggesting that the H I outflow is extended. Overall, we find that the fraction of H
I
gas recovered by our VLBI observations varies significantly within our sample, ranging from complete (
4C 12.50
) to marginal (
3C 293
). However, in all cases we find evidence for a clumpy structure of both the outflowing and the quiescent gas, consistent with predictions from numerical simulations. All the outflows include at least a component of relatively compact clouds with masses in the range of 10
4
− 10
5
M
⊙
. The outflowing clouds are often already observed at a few tens of parsecs (in projection) from the core. We find indications that the H
I
outflow might have a diffuse component, especially in larger sources. Our results support the interpretation that we observe these AGNs at different stages in the evolution of the interaction between the jet and the interstellar medium and this is reflected in the properties of the outflowing gas as predicted by numerical simulations.
The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional ...assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer‐reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state‐of‐the‐art handbook for basic and clinical researchers.
Anti-Müllerian hormone (Amh) is in mammals known as a TGFβ type of glycoprotein processed to yield a bioactive C-terminal homodimer that directs regression of Müllerian ducts in the male fetus and ...regulates steroidogenesis and early stages of folliculogenesis. Here, we report on the zebrafish Amh homologue. Zebrafish, as all teleost fish, do not have Müllerian ducts. Antibodies raised against the N- and C-terminal part of Amh were used to study the processing of endogenous and recombinant Amh. The N-terminally directed antibody detected a 27-kDa protein, whereas the C-terminally directed one recognized a 32-kDa protein in testes extracts, both apparently not glycosylated. The C-terminal fragment was present as a monomeric protein, because reducing conditions did not change its apparent molecular mass. Recombinant zebrafish Amh was cleaved with plasmin to N- and C-terminal fragments that after deglycosylation were similar in size to endogenous Amh fragments. Mass spectrometry and N-terminal sequencing revealed a 21-residue N-terminal leader sequence and a plasmin cleavage site after Lys or Arg within Lys-Arg-His at position 263–265, which produce theoretical fragments in accordance with the experimental results. Experiments using adult zebrafish testes tissue cultures showed that plasmin-cleaved, but not uncleaved, Amh inhibited gonadotropin-stimulated androgen production. However, androgens did not modulate amh expression that was, on the other hand, down-regulated by Fsh. Moreover, plasmin-cleaved Amh inhibited androgen-stimulated proliferation as well as differentiation of type A spermatogonia. In conclusion, zebrafish Amh is processed to become bioactive and has independent functions in inhibiting both steroidogenesis and spermatogenesis.
•More than 10,000 cometary particles have been collected and imaged by COSIMA.•The collected particles exhibit a complex typology, dominated by clusters.•The collected particles present similarities ...with micrometeorites and IDP's.
The COSIMA mass spectrometer on board the ROSETTA orbiter has collected dust in the near coma of comet 67P/Churyumov-Gerasimenko since August 11, 2014. The collected dust particles are identified by taking images with a microscope (COSISCOPE) under grazing incidence illumination before and after exposure of the target to cometary dust. More than 10,000 dust particles >14 µm in size collected from August 11, 2014 to April 3, 2015 have been detected on three distinct target assemblies, including ∼500 dust particles with sizes ranging from 50 to more than 500 µm, that can be resolved by COSISCOPE (pixel size 14 µm). During this period, the heliocentric distance decreased from 3.5 AU to less than 2 AU. The collection efficiency on targets covered with “metal black” has been very high, due to the low relative velocity of incoming dust. Therefore, the COSISCOPE observations provide the first optical characterization of an unbiased sample of particles collected in the inner coma of a comet. The typology of particles >100 µm in size is dominated by clusters with a wide range of structure and strength, most originating from the disruption of large aggregates (>1 mm in size) shortly before collection. A generic relationship between these clusters and IDPs/Antarctic meteorites is likely in the framework of accretion models. About 15% of particles larger than 100 µm are compact particles with two likely contributions, one being linked to clusters and another leaving the cometary nucleus as single compact particles.
The energetic feedback that is generated by radio jets in active galactic nuclei (AGNs) has been suggested to be able to produce fast outflows of atomic hydrogen (H I) gas, which can be studied in ...absorption at high spatial resolution. We have used the Very Large Array (VLA) and a global very long baseline interferometry (VLBI) array to locate and study in detail the H I outflow discovered with the Westerbork Synthesis Radio Telescope (WSRT) in the restarted radio galaxy 3C 236. Based on the VLA data, we confirm a blueshifted wing of the H I with a width of ~1000 km s−1. This H I outflow is partially recovered by the VLBI observation. In particular, we detect four clouds with masses of 0.28 − 1.5 × 104M⊙ with VLBI that do not follow the regular rotation of most of the H I. Three of these clouds are located, in projection, against the nuclear region on scales of ≲40 pc, while the fourth is cospatial to the southeast lobe at a projected distance of ~270 pc. Their velocities are between 150 and 640 km s−1 blueshifted with respect to the velocity of the disk-related H I. These findings suggest that the outflow is at least partly formed by clouds, as predicted by some numerical simulations, and that it originates already in the inner (few tens of pc) region of the radio galaxy. Our results indicate that the entire outflow might consist of many clouds, possibly with comparable properties as those clearly detected, but distributed at larger radii from the nucleus where the lower brightness of the lobe does not allow us to detect them. However, we cannot rule out a diffuse component of the outflow. Because 3C 236 is a low-excitation radio galaxy, it is less likely that the optical AGN is able to produce strong radiative winds. This leaves the radio jet as the main driver for the H I outflow.
Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a ...prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFβ superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.
Cardiac hypertrophy is a mechanism to compensate for increased cardiac work load, that is, after myocardial infarction or upon pressure overload. However, in the long run cardiac hypertrophy is a ...prevailing risk factor for the development of heart failure. During pathological remodelling processes leading to heart failure, decompensated hypertrophy, death of cardiomyocytes by apoptosis or necroptosis and fibrosis as well as a progressive dysfunction of cardiomyocytes are apparent. Interestingly, the induction of hypertrophy, cell death or fibrosis is mediated by similar signalling pathways. Therefore, tiny changes in the signalling cascade are able to switch physiological cardiac remodelling to the development of heart failure. In the present review, we will describe examples of these molecular switches that change compensated hypertrophy to the development of heart failure and will focus on the importance of the signalling cascades of the TGFbeta superfamily in this process. In this context, potential therapeutic targets for pharmacological interventions that could attenuate the progression of heart failure will be discussed.
Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, ...invasion, metastasis and chemoresistance. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of-functions activities. Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 mouse model expressing an inactivatable R248Q hotspot mutation (floxQ) to show that tumours depend on sustained mutp53 expression. Upon tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/- (R248Q allele) and H/H (R172H allele) mice by 59% and 48%, respectively, but not their corresponding p53(-/-) littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumour apoptosis and prevention of T-cell lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.
Supermassive black holes (SMBH) are essential for the production of jets in radio-loud active galactic nuclei (AGN). Theoretical models based on (Blandford & Znajek 1977, MNRAS, 179, 433) extract the ...rotational energy from a Kerr black hole, which could be the case for NGC 1052, to launch these jets. This requires magnetic fields on the order of 103G to 104G. We imaged the vicinity of the SMBH of the AGN NGC 1052 with the Global Millimetre VLBI Array and found a bright and compact central feature that is smaller than 1.9 light days (100 Schwarzschild radii) in radius. Interpreting this as a blend of the unresolved jet bases, we derive the magnetic field at 1 Schwarzschild radius to lie between 200 G and ~ 8.3 × 104 G consistent with Blandford & Znajek models.
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