355 research outputs found
Zebrafish cerebrospinal fluid mediates cell survival through a retinoid signaling pathway
Cerebrospinal fluid (CSF) includes conserved factors whose function is largely unexplored. To assess the role of CSF during embryonic development, CSF was repeatedly drained from embryonic zebrafish brain ventricles soon after their inflation. Removal of CSF increased cell death in the diencephalon, indicating a survival function. Factors within the CSF are required for neuroepithelial cell survival as injected mouse CSF but not artificial CSF could prevent cell death after CSF depletion. Mass spectrometry analysis of the CSF identified retinol binding protein 4 (Rbp4), which transports retinol, the precursor to retinoic acid (RA). Consistent with a role for Rbp4 in cell survival, inhibition of Rbp4 or RA synthesis increased neuroepithelial cell death. Conversely, ventricle injection of exogenous human RBP4 plus retinol, or RA alone prevented cell death after CSF depletion. Zebrafish rbp4 is highly expressed in the yolk syncytial layer, suggesting Rbp4 protein and retinol/RA precursors can be transported into the CSF from the yolk. In accord with this suggestion, injection of human RBP4 protein into the yolk prevents neuroepithelial cell death in rbp4 loss-of-function embryos. Together, these data support the model that Rbp4 and RA precursors are present within the CSF and used for synthesis of RA, which promotes embryonic neuroepithelial survival
Auditory verbal hallucinations and childhood trauma subtypes across the psychosis continuum:a cluster analysis
Introduction: A strong link between voice-hearing experience and childhood trauma has been established. The aim of this study was to identify whether there were unique clusters of childhood trauma subtypes in a sample across the clinical spectrum of auditory verbal hallucinations (AVH) and to examine clinical and phenomenological features across these clusters. Methods: Combining two independent international datasets (the Netherlands and Australia), childhood trauma subtypes were examined using hierarchical cluster analysis. Clinical and phenomenological characteristics were compared across emerging clusters using MANOVA and chi-squared analyses. Results: The total sample (n = 413) included 166 clinical individuals with a psychotic disorder and AVH, 122 non-clinical individuals with AVH and 125 non-clinical individuals without AVH. Three clusters emerged: (1) low trauma (n = 299); (2) emotion-focused trauma (n = 71); (3) multi-trauma (n = 43). The three clusters differed significantly on their AVH ratings of amount of negative content, with trend-level effects for loudness, degree of negative content and degree of experienced distress. Furthermore, perceptions of voices being malevolent, benevolent and resistance towards voices differed significantly. Conclusion: The data revealed different types of childhood trauma had different relationships between clinical and phenomenological features of voice-hearing experiences. Thus, implicating different mechanistic pathways and a need for tailored treatment approaches
Factors predisposing to humoral autoimmunity against brain-antigens in health and disease Analysis of 49 autoantibodies in over 7000 subjects
Background:Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in >7000 individuals.Methods:Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher’s exact tests and logistic regression analyses were used.Results:Study of N=7025 subjects (55.8% male; 41±16 years) revealed N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR=1.303; 95% CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) was seen for most AB (e.g. amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR=1.55; 95% CI [1.058-2.271]) and disease likelihood (OR=1.43; 95% CI [1.032-1.985]). APOE4 carriers (∼19%) had lower seropositivity (OR=0.766; 95% CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR=1.599; 95% CI [1.022-2.468]).Conclusions:Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease
Genetic markers of Munc13 protein family member, BAIAP3, are gender-specifically associated with anxiety and benzodiazepine abuse in mouse and man
Anxiety disorders and substance abuse, including benzodiazepine use disorder, frequently occur together. Unfortunately, treatment of anxiety disorders still includes benzodiazepines, and patients with an existing comorbid benzodiazepine use disorder or a genetic susceptibility for benzodiazepine use disorder may be at risk of adverse treatment outcomes. The identification of genetic predictors for anxiety disorders, and especially for benzodiazepine use disorder, could aid the selection of the best treatment option and improve clinical outcomes. The brain-specific angiogenesis inhibitor I–associated protein 3 (Baiap3) is a member of the mammalian uncoordinated 13 (Munc13) protein family of synaptic regulators of neurotransmitter exocytosis, with a striking expression pattern in amygdalae, hypothalamus and periaqueductal gray. Deletion of Baiap3 in mice leads to enhanced seizure propensity and increased anxiety, with the latter being more pronounced in female than in male animals. We hypothesized that genetic variation in human BAIAP3 may also be associated with anxiety. By using a phenotype-based genetic association study, we identified two human BAIAP3 single-nucleotide polymorphism risk genotypes (AA for rs2235632, TT for rs1132358) that show a significant association with anxiety in women and, surprisingly, with benzodiazepine abuse in men. Returning to mice, we found that male, but not female, Baiap3 knockout (KO) mice develop tolerance to diazepam more quickly than control animals. Analysis of cultured Baiap3 KO hypothalamus slices revealed an increase in basal network activity and an altered response to diazepam withdrawal. Thus, Baiap3/BAIAP3 is gender specifically associated with anxiety and benzodiazepine use disorder, and the analysis of Baiap3/BAIAP3-related functions may help elucidate mechanisms underlying the development of both disorders
A single gene defect causing claustrophobia
Claustrophobia, the well-known fear of being trapped in narrow/closed spaces, is often considered a conditioned response to traumatic experience. Surprisingly, we found that mutations affecting a single gene, encoding a stress-regulated neuronal protein, can cause claustrophobia. Gpm6a-deficient mice develop normally and lack obvious behavioral abnormalities. However, when mildly stressed by single-housing, these mice develop a striking claustrophobia-like phenotype, which is not inducible in wild-type controls, even by severe stress. The human GPM6A gene is located on chromosome 4q32-q34, a region linked to panic disorder. Sequence analysis of 115 claustrophobic and non-claustrophobic subjects identified nine variants in the noncoding region of the gene that are more frequent in affected individuals (P=0.028). One variant in the 3′untranslated region was linked to claustrophobia in two small pedigrees. This mutant mRNA is functional but cannot be silenced by neuronal miR124 derived itself from a stress-regulated transcript. We suggest that loosing dynamic regulation of neuronal GPM6A expression poses a genetic risk for claustrophobia
Human genomics of the humoral immune response against polyomaviruses
Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press.Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.Peer reviewe
Pion radii in nonlocal chiral quark model
The electromagnetic radius of the charged pion and the transition radius of
the neutral pion are calculated in the framework of the nonlocal chiral quark
model. It is shown in this model that the contributions of vector mesons to the
pion radii are noticeably suppressed in comparison with a similar contribution
in the local Nambu--Jona-Lasinio model. The form-factor for the process
gamma*pi+pi- is calculated for the -1 GeV^2<q^2<1.6 GeV^2. Our results are in
satisfactory agreement with experimental data.Comment: 7 pages, 7 figure
Quantum Interference Controlled Molecular Electronics
Quantum interference in coherent transport through single molecular rings may
provide a mechanism to control current in molecular electronics. We investigate
its applicability by using a single-particle Green function method combined
with ab initio electronic structure calculations. We find that the quantum
interference effect (QIE) depends strongly on the interaction between molecular
pi states and contact sigma states. It is absent in small molecular rings with
Au leads, such as benzene, due to strong pi-sigma hybridization, while it is
preserved in large rings, such as [18]annulene, which then could be used to
realize QIE transistors.Comment: 5 pages, published version, small revision
Multiplicity correlations of intermediate-mass fragments with pions and fast protons in 12C + 197Au
Low-energy pi+ (E < 35 MeV) from 12C+197Au collisions at incident energies
from 300 to 1800 MeV per nucleon were detected with the Si-Si(Li)-CsI(Tl)
calibration telescopes of the INDRA multidetector. The inclusive angular
distributions are approximately isotropic, consistent with multiple
rescattering in the target spectator. The multiplicity correlations of the
low-energy pions and of energetic protons (E > 150 MeV) with intermediate-mass
fragments were determined from the measured coincidence data. The deduced
correlation functions 1 + R \approx 1.3 for inclusive event samples reflect the
strong correlations evident from the common impact-parameter dependence of the
considered multiplicities. For narrow impact-parameter bins (based on
charged-particle multiplicity), the correlation functions are close to unity
and do not indicate strong additional correlations. Only for pions at high
particle multiplicities (central collisions) a weak anticorrelation is
observed, probably due to a limited competition between these emissions.
Overall, the results are consistent with the equilibrium assumption made in
statistical multifragmentation scenarios. Predictions obtained with
intranuclear cascade models coupled to the Statistical Multifragmentation Model
are in good agreement with the experimental data.Comment: 9 pages, 11 figures, subm. to EPJ
The Spitzer Spectroscopic Survey of S-type Stars
S-type AGB stars are thought to be in the transitional phase between M-type
and C-type AGB stars. Because of their peculiar chemical composition, one may
expect a strong influence of the stellar C/O ratio on the molecular chemistry
and the mineralogy of the circumstellar dust. In this paper, we present a large
sample of 87 intrinsic galactic S-type AGB stars, observed at infrared
wavelengths with the Spitzer Space Telescope, and supplemented with
ground-based optical data. On the one hand, we derive the stellar parameters
from the optical spectroscopy and photometry, using a grid of model
atmospheres. On the other, we decompose the infrared spectra to quantify the
flux-contributions from the different dust species. Finally, we compare the
independently determined stellar parameters and dust properties. For the stars
without significant dust emission, we detect a strict relation between the
presence of SiS absorption in the Spitzer spectra and the C/O ratio of the
stellar atmosphere. These absorption bands can thus be used as an additional
diagnostic for the C/O ratio. For stars with significant dust emission, we
define three groups, based on the relative contribution of certain dust species
to the infrared flux. We find a strong link between group-membership and C/O
ratio. We show that these groups can be explained by assuming that the
dust-condensation can be cut short before silicates are produced, while the
remaining free atoms and molecules can then form the observed magnesium
sulfides or the carriers of the unidentified 13 and 20 micron features.
Finally, we present the detection of emission features attributed to molecules
and dust characteristic to C-type stars, such as molecular SiS, hydrocarbons
and magnesium sulfide grains. We show that we often detect magnesium sulfides
together with molecular SiS and we propose that it is formed by a reaction of
SiS molecules with Mg.Comment: Accepted for publication in A&
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