As model organism-based research shifts from forward to reverse genetics approaches, largely due to the ease of genome editing technology, a low frequency of abnormal phenotypes is being observed in ...lines with mutations predicted to lead to deleterious effects on the encoded protein. In zebrafish, this low frequency is in part explained by compensation by genes of redundant or similar function, often resulting from the additional round of teleost-specific whole genome duplication within vertebrates. Here we offer additional explanations for the low frequency of mutant phenotypes. We analyzed mRNA processing in seven zebrafish lines with mutations expected to disrupt gene function, generated by CRISPR/Cas9 or ENU mutagenesis methods. Five of the seven lines showed evidence of altered mRNA processing: one through a skipped exon that did not lead to a frame shift, one through nonsense-associated splicing that did not lead to a frame shift, and three through the use of cryptic splice sites. These results highlight the need for a methodical analysis of the mRNA produced in mutant lines before making conclusions or embarking on studies that assume loss of function as a result of a given genomic change. Furthermore, recognition of the types of adaptations that can occur may inform the strategies of mutant generation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Immune cells congregate at specific loci to fight infections during inflammatory responses, a process that must be transient and self-resolving. Cell dispersal promotes resolution, but it remains ...unclear how transition from clustering to dispersal is regulated. Here we show, using quantitative live imaging in zebrafish, that differential ligand-induced trafficking of chemokine receptors such as Cxcr1 and Cxcr2 orchestrates the state of neutrophil congregation at sites of tissue damage. Through receptor mutagenesis and biosensors, we show that Cxcr1 promotes clustering at wound sites, but is promptly desensitized and internalized, which prevents excess congregation. By contrast, Cxcr2 promotes bidirectional motility and is sustained at the plasma membrane. Persistent plasma membrane residence of Cxcr2 prolongs downstream signaling and is required for sustained exploratory motion conducive to dispersal. Thus, differential trafficking of two chemokine receptors allows coordination of antagonistic cell behaviors, promoting a self-resolving migratory response.
Context.
The light curves of tidally locked hot Jupiters transiting fast-rotating, early-type stars are a rich source of information about both the planet and star, with full-phase coverage enabling ...a detailed atmospheric characterisation of the planet. Although it is possible to determine the true spin–orbit angle Ψ – a notoriously difficult parameter to measure – from any transit asymmetry resulting from gravity darkening induced by the stellar rotation, the correlations that exist between the transit parameters have led to large disagreements in published values of Ψ for some systems.
Aims.
We aimed to study these phenomena in the light curves of the ultra-hot Jupiter MASCARA-1 b, which is characteristically similar to well-studied contemporaries such as KELT-9 b and WASP-33 b.
Methods.
We obtained optical CHaracterising ExOPlanet Satellite (CHEOPS) transit and occultation light curves of MASCARA-1 b, and analysed them jointly with a
Spitzer
/IRAC 4.5 μm full-phase curve to model the asymmetric transits, occultations, and phase-dependent flux modulation. For the latter, we employed a novel physics-driven approach to jointly fit the phase modulation by generating a single 2D temperature map and integrating it over the two bandpasses as a function of phase to account for the differing planet–star flux contrasts. The reflected light component was modelled using the general ab initio solution for a semi-infinite atmosphere.
Results.
When fitting the CHEOPS and
Spitzer
transits together, the degeneracies are greatly diminished and return results consistent with previously published Doppler tomography. Placing priors informed by the tomography achieves even better precision, allowing a determination of Ψ = 72.1
−2.4
+2.5
deg. From the occultations and phase variations, we derived dayside and nightside temperatures of 3062
−68
+66
K and 1720 ± 330 K, respectively.Our retrieval suggests that the dayside emission spectrum closely follows that of a blackbody. As the CHEOPS occultation is too deep to be attributed to blackbody flux alone, we could separately derive geometric albedo A
g
= 0.171
−0.068
+0.066
and spherical albedo A
s
= 0.266
−0.100
+0.097
from the CHEOPS data, and Bond albedoA
B
= 0.057
−0.101
+0.083
from the
Spitzer
phase curve.Although small, the
A
g
and
A
s
indicate that MASCARA-1 b is more reflective than most other ultra-hot Jupiters, where H
−
absorption is expected to dominate.
Conclusions.
Where possible, priors informed by Doppler tomography should be used when fitting transits of fast-rotating stars, though multi-colour photometry may also unlock an accurate measurement of Ψ. Our approach to modelling the phase variations at different wavelengths provides a template for how to separate thermal emission from reflected light in spectrally resolved
James Webb
Space Telescope phase curve data.
Abstract
Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant ...focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.
López-Rivera et al. discover differences in genetic architecture across major epileptic brain lesion types. They describe novel somatic chromosomal alterations, identify novel genes and genotype–phenotype associations, and provide support for the role of genetics in the histopathological diagnosis of epileptic lesions.
The neural crest (NC) is a vertebrate-specific cell type that contributes to a wide range of different tissues across all three germ layers. The gene regulatory network (GRN) responsible for the ...formation of neural crest is conserved across vertebrates. Central to the induction of the NC GRN are AP-2 and SoxE transcription factors. NC induction robustness is ensured through the ability of some of these transcription factors to compensate loss of function of gene family members. However the gene regulatory events underlying compensation are poorly understood. We have used gene knockout and RNA sequencing strategies to dissect NC induction and compensation in zebrafish. We genetically ablate the NC using double mutants of tfap2a;tfap2c or remove specific subsets of the NC with sox10 and mitfa knockouts and characterise genome-wide gene expression levels across multiple time points. We find that compensation through a single wild-type allele of tfap2c is capable of maintaining early NC induction and differentiation in the absence of tfap2a function, but many target genes have abnormal expression levels and therefore show sensitivity to the reduced tfap2 dosage. This separation of morphological and molecular phenotypes identifies a core set of genes required for early NC development. We also identify the 15 somites stage as the peak of the molecular phenotype which strongly diminishes at 24 hpf even as the morphological phenotype becomes more apparent. Using gene knockouts, we associate previously uncharacterised genes with pigment cell development and establish a role for maternal Hippo signalling in melanocyte differentiation. This work extends and refines the NC GRN while also uncovering the transcriptional basis of genetic compensation via paralogues.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The German health interview and examination survey for adults (DEGS1) with the mental health module (DEGS1-MH) is the successor to the last survey of mental disorders in the general German population ...15 years ago (GHS-MHS). This paper reports the basic findings on the 12-month prevalence of mental disorders, associated disabilities and self-reported healthcare utilization.
A representative national cohort (age range 18-79 years, n = 5,317) was selected and individuals were personally examined (87.5 % face to face and 12.5 % via telephone) by a comprehensive clinical interview using the composite international diagnostic interview (CIDI) questionnaire.
The overall 12-month prevalence of mental disorders was 27.7 % with substantial differences between subgroups (e.g. sex, age, socioeconomic status). Mental disorders were found to be particularly impairing (elevated number of disability days). Less than 50 % of those affected reported to be in contact with health services due to mental health problems within the last 12 months (range 10-40 % depending on the number of diagnoses).
Mental disorders were found to be commonplace with a prevalence level comparable to that found in the 1998 predecessor study but several further adjustments will have to be made for a sound methodological comparison between the studies. Apart from individual distress, elevated self-reported disability indicated a high societal disease burden of mental disorders (also in comparison with many somatic diseases). Despite a relatively comprehensive and well developed mental healthcare system in Germany there are still optimisation needs for treatment rates.
To better understand the social norms surrounding fantasizing behavior, the current research aimed to assess how acceptable various types of fantasizing (romantic or sexual) are perceived. ...Understanding and abiding by social norms helps people avoid criticism, social sanctions, and ostracism. Thus, better understanding the social norms surrounding various types of fantasies can help people better navigate their social worlds, especially with respect to sexuality, dating, and relationships. Participants (n = 828) reported how acceptable, violating, and bothersome they perceived sexual and romantic fantasizing to be towards themselves and others. Results suggest that despite the current sentiment on socially and morally unacceptable physical acts, mental acts of fantasizing are not perceived as unacceptable or violating. No gender differences arose between men and women’s perceptions of fantasy acceptability. Demographic differences in perceived fantasy acceptability by race, sexual orientation, relationship status, and age are discussed. These findings deepen the understanding of how society views fantasizing behavior and help begin to define boundaries for acceptable versus violating thoughts.
ABSTRACT The potentially hazardous asteroid (185851) 2000 DP107 was the first binary near-Earth asteroid to be imaged. Radar observations in 2000 provided images at 75 m resolution that revealed the ...shape, orbit, and spin-up formation mechanism of the binary. The asteroid made a more favorable flyby of the Earth in 2008, yielding images at 30 m resolution. We used these data to obtain shape models for the two components and to improve the estimates of the mutual orbit, component masses, and spin periods. The primary has a sidereal spin period of 2.7745 0.0007 hr and is roughly spheroidal with an equivalent diameter of 863 m . It has a mass of kg and a density of 1381 244 kg m−3. It exhibits an equatorial ridge similar to the (66391) 1999 KW4 primary; however, the equatorial ridge in this case is not as regular and has a ∼300 m diameter concavity on one side. The secondary has a sidereal spin period of 1.77 0.02 days commensurate with the orbital period. The secondary is slightly elongated and has overall dimensions of m (6% uncertainties). Its mass is kg and its density is 1047 230 kg m−3. The mutual orbit has a semimajor axis of 2.659 0.08 km, an eccentricity of 0.019 0.01, and a period of 1.7556 0.0015 days. The normalized total angular momentum of this system exceeds the amount required for the expected spin-up formation mechanism. An increase of angular momentum from non-gravitational forces after binary formation is a possible explanation. The two components have similar radar reflectivity, suggesting a similar composition consistent with formation by spin-up. The secondary appears to exhibit a larger circular polarization ratio than the primary, suggesting a rougher surface or subsurface at radar wavelength scales.
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