Biology subjects

Weiss, A.

Publications and source records attributed to Weiss, A..

48 records · Page 3Linked to original sources

bioRxiv2020

Personality, Subjective Well-Being, and the Serotonin 1a Receptor Gene in Common Marmosets (Callithrix jacchus)

Studies of personality traits in common marmosets (Callithrix jacchus) indicate that there are five or six constructs--sociability, dominance, neuroticism, openness, and two related to conscientiousness--that define personality in common marmosets. The present study attempted to determine whether our earlier study of laboratory-housed individuals only yielded three domains--Dominance, Sociability, and Neuroticism--because of a low amount of between-subjects variance. We therefore increased our sample size from 77 to 128. In addition, we ascertained the reliability and validity of ratings and whether polymorphisms related to the serotonin 1a receptor were associated with personality. We found Sociability, Dominance, and Negative Affect factors that resembled three domains found in previous studies, including ours. We also found an Openness and Impulsiveness factor, the latter of which bore some resemblance to Conscientiousness, and two higher-order factors, Pro-sociality and Boldness. Further analyses could not exclude the possibility that Pro-sociality and Boldness represented a higher-level of personality organization. Correlations between personality factors and well-being were consistent with the definitions of the factors. There were no significant associations between personality and genotype. These results are consistent with the possibility that common marmoset personality structure varies as a function of rearing or housing variables that have not yet been investigated systematically.

animal behavior and cognition↗

bioRxiv2019

Systematic mapping of genetic interactions for de novo fatty acid synthesis

The de novo synthesis of fatty acids has emerged as a therapeutic target for various diseases including cancer. While several translational efforts have focused on direct perturbation of de novo fatty acid synthesis, only modest responses have been associated with mono-therapies. Since cancer cells are intrinsically buffered to combat metabolic stress, cells may adapt to loss of de novo fatty acid biosynthesis. To explore cellular response to defects in fatty acid synthesis, we used pooled genome-wide CRISPR screens to systematically map genetic interactions (GIs) in human HAP1 cells carrying a loss-of-function mutation in FASN, which catalyzes the formation of long-chain fatty acids. FASN mutant cells showed a strong dependence on lipid uptake that was reflected by negative GIs with genes involved in the LDL receptor pathway, vesicle trafficking, and protein glycosylation. Further support for these functional relationships was derived from additional GI screens in query cell lines deficient for other genes involved in lipid metabolism, including LDLR, SREBF1, SREBF2, ACACA. Our GI profiles identified a potential role for a previously uncharacterized gene LUR1 (C12orf49) in exogenous lipid uptake regulation. Overall, our data highlights the genetic determinants underlying the cellular adaptation associated with loss of de novo fatty acid synthesis and demonstrate the power of systematic GI mapping for uncovering metabolic buffering mechanisms in human cells.

systems biology↗

bioRxiv2019

Population genomic evidence that human and animal infections in Africa come from the same populations of Dracunculus medinensis

BackgroundGuinea worm - Dracunculus medinensis - was historically one of the major parasites of humans and has been known since antiquity. Now, Guinea worm is on the brink of eradication, as efforts to interrupt transmission have reduced the annual burden of disease from millions of infections per year in the 1980s to only 30 human cases reported globally last year. Despite the enormous success of eradication efforts to date, one complication has arisen. Over the last few years, hundreds of dogs have been found infected with this previously apparently anthroponotic parasite, almost all in Chad. Moreover, the relative numbers of infections in humans and dogs suggests that dogs may be key in maintaining transmission in that country.\n\nResultsIn an effort to shed light on this peculiar epidemiology of Guinea worm in Chad, we have sequenced and compared the genomes of worms from dog, human and other animal infections. Confirming previous work with other molecular markers, we show that all of these worms are D. medinensis, and that the same population of worms are causing both infections, can confirm the suspected transmission between host species and detect signs of a population bottleneck due to the eradication efforts. The diversity of worms in Chad appears to exclude the possibility that there were no, or very few, worms present in the country during a 10-year absence of reported cases.\n\nConclusionsThis work reinforces the importance of adequate surveillance of both human and dog populations in the Guinea worm eradication campaign and suggests that control programs should stay aware of the possible emergence of unusual epidemiology as they approach elimination.

genomics↗

bioRxiv2019

Interacting with volatile environments stabilizes hidden-state inference and its brain signatures

Making accurate decisions in uncertain environments requires identifying the generative cause of sensory cues, but also the expected outcomes of possible actions. Although both cognitive processes can be formalized as Bayesian inference, they are commonly studied using different experimental frameworks, making their formal comparison difficult. Here, by framing a reversal learning task either as cue-based or outcome-based inference, we found that humans perceive the same volatile environment as more stable when inferring its hidden state by interaction with uncertain outcomes than by observation of equally uncertain cues. Multivariate patterns of magnetoencephalo-graphic (MEG) activity reflected this behavioral difference in the neural interaction between inferred beliefs and incoming evidence, an effect originating from associative regions in the temporal lobe. Together, these findings indicate that the degree of control over the sampling of volatile environments shapes human learning and decision-making under uncertainty.

neuroscience↗

bioRxiv2019

High-throughput fluorescence-based screen identifies the neuronal microRNA miR-124 as a positive regulator of alphavirus infection

Micro (mi)RNAs are small regulatory RNAs, which act as guide for the RISC complex to modulate the expression of target genes. In addition to their role in maintaining essential physiological functions in the cell, miRNAs can also regulate viral infections. They can do so directly by targeting RNAs of viral origin or indirectly by targeting RNAs from the host and this can result in a positive or negative outcome for the virus. Here, we performed a miRNA genome-wide screen in order to identify cellular miRNAs involved in the regulation of arbovirus infection in human cells. We identified sixteen miRNAs showing a positive effect on the virus, among which a number of neuron-specific ones such as miR-124. We confirmed that overexpression of miR-124 increases Sindbis virus (SINV) viral production and that this effect is mediated by its seed sequence. We further demonstrated that the SINV genome possesses a binding site for miR-124-3p. Both inhibition of miR-124-3p or silent mutations to disrupt this binding site in the viral RNA abolished the positive regulation. We also proved that miR-124 inhibition reduces SINV infection in human differentiated neuronal cells. Finally, we showed that the proviral effect of miR-124 is conserved for other medically relevant alphaviruses. Indeed, inhibition of miR-124 expression reduces chikungunya virus (CHIKV) viral production in human cells. Altogether, our work expands the panel of positive regulation of the viral cycle by direct binding of host miRNAs to the viral RNA and provides new insights into the role of cellular miRNAs as regulators of alphavirus infection.\n\nSIGNIFICANCE STATEMENTArthropod-borne (arbo) viruses are part of a class of pathogens that are transmitted to their final hosts by insects. Because of climate change, the habitat of some of these insects, such as mosquitoes, is shifting, thereby facilitating the emergence of viral epidemics. Among the pathologies associated with arboviruses infection, neurological diseases like meningitis or encephalitis represent a significant health burden. Using a genome-wide miRNA screen, we identified the neuronal miR-124 as a positive regulator of the Sindbis and chikungunya alphaviruses. We also showed that this effect was in part direct, thereby opening novel avenues to treat alphaviruses infection.

molecular biology↗

bioRxiv2019

Physical activity and screen time in children who survived cancer - A report from the Swiss Childhood Cancer Survivor Study

BackgroundPhysical activity (PA) can reduce the risk of chronic adverse health conditions in childhood cancer survivors. We examined physical activity and sedentary screen time behavior in a nationwide study in Switzerland.\n\nProceduresThe Swiss Childhood Cancer Survivor Study sent questionnaires to parents of all Swiss resident [≥]5 year-survivors diagnosed 1995-2010. We assessed physical activity including compulsory school sport, recreational sport, commuting to school, and time spent with screen media in those aged 5-15 years, and compared results to international recommendations.\n\nResultsWe included 766 survivors with a median age at diagnosis of 2.8 (interquartile range 1.4-5.0) years and a median age at study of 12.5 (10.0-14.3) years. Median PA time was 7.3 (4.8-10.0) hours/week and median screen time 1.4 (0.8-2.0) hours/day. Compulsory school sport hours and walking or cycling to school contributed significantly to total PA. 55% of survivors met PA and 68% screen time recommendations. PA was lower for children living in regions of Switzerland speaking French or Italian compared to German, and for those who had a relapse or musculoskeletal/neurological conditions. Screen time was higher in males, and children with lower parental education and a migration background.\n\nConclusionsPA and sedentary screen watching were associated with social factors and PA also with clinical risk factors. Structural preventions that afford active commuting to school and sufficient school sport are essential, as is counselling vulnerable survivor groups such as those with musculoskeletal and neurological problems, and those who have had a relapse.

epidemiology↗

bioRxiv2018

Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis

How pathogenic CD4 T cells in Rheumatoid Arthritis (RA) develop remains poorly understood. We used Nur77--a marker of T cell antigen receptor (TCR) signaling--to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into IL-17 producing cells. Moreover, the enhanced autoreactivity was associated with upregulation of IL-6 cytokine signaling machinery. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyper-responsive to IL-6. This suggests that, despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6 which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA. Additionally, endogenous Nur77 protein expression was enriched in a subset of synovial CD4 T cells from arthritic joints in SKG mice, consistent with antigen-activated T cells. This was was extended to patients with seropositive RA, suggesting that pathogenic CD4 T cells are enriched in RA joints and are likely recognizing an intra-articular auto-antigen(s).

immunology↗

bioRxiv2018

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Idiopathic pulmonary fibrosis is a fatal, incurable lung disease in which the intricate alveolar network of the human lung is progressively replaced by fibrotic scars, eventually leading to respiratory failure. Myofibroblasts are the effector cells that lead to abnormal deposition of extracellular matrix proteins and therefore mediate fibrotic disease not only in the lung but also in other organs. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug, metformin, exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGF{beta}1 action, suppressing collagen formation, activating PPAR{gamma} signaling and inducing lipogenic differentiation in lung myofibroblasts derived from human patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-tolipofibroblast transdifferentiation. Detailed pathway analysis showed that the reduction of collagen synthesis was largely AMPK-dependent, whereas the transdifferentiation of myo- to lipofibroblasts occurred in a BMP2-PPAR{gamma}-dependent fashion and was largely AMPK-independent. Our data report an unprecedented role for metformin in lung fibrosis, thus warranting further therapeutic evaluation.

cell biology↗

bioRxiv2018

Switch-like activation of Bruton’s tyrosine kinase by membrane-mediated dimerization

The transformation of molecular binding events into cellular decisions is the basis of most biological signal transduction. A fundamental challenge faced by these systems is that protein-ligand chemical affinities alone generally result in poor sensitivity to ligand concentration, endangering the system to error. Here, we examine the lipid-binding pleckstrin homology and Tec homology (PH-TH) module of Brutons tyrosine kinase (Btk) Using fluorescence correlation spectroscopy (FCS) and membrane-binding kinetic measurements, we identify a self-contained phosphatidylinositol (3,4,5)-trisphosphate (PIP3) sensing mechanism that achieves switch-like sensitivity to PIP3 levels, surpassing the intrinsic affinity discrimination of PIP3:PH binding. This mechanism employs multiple PIP3 binding as well as dimerization of Btk on the membrane surface. Mutational studies in live cells confirm that this mechanism is critical for activation of Btk in vivo. These results demonstrate how a single protein module can institute a minimalist coincidence detection mechanism to achieve high-precision discrimination of ligand concentration.

biophysics↗

bioRxiv2018

Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen

To obtain a comprehensive map of the intrinsic specificities of tyrosine kinase domains, we developed a high-throughput method that uses bacterial surface-display and next-generation sequencing to analyze the specificity of any tyrosine kinase against a library of thousands of peptides derived from human tyrosine phosphorylation sites. Using this approach, we identified a difference in the electrostatic recognition of substrates between the cytoplasmic Src-family tyrosine kinases Lck and c-Src. This divergence likely reflects the specialization of Lck to act in concert with the tyrosine kinase ZAP-70 in T cell receptor signaling. The current understanding of substrate recognition by tyrosine kinases emphasizes the role of localization by non-catalytic domains, but our results point to the importance of direct recognition at the kinase active site in fine-tuning specificity. Our method provides a simple approach that leverages next-generation sequencing to readily map the specificity of any tyrosine kinase at the proteome level.

biochemistry↗

bioRxiv2017

Genetic contribution to two factors of neuroticism is associated with affluence, better health, and longer life

Neuroticism is a personality trait that describes the tendency to experience negative emotions. Individual differences in neuroticism are moderately stable across much of the life course1; the trait is heritable2-5, and higher levels are associated with psychiatric disorders6-8, and have been estimated to have an economic burden to society greater than that of substance abuse, mood, or anxiety disorders9. Understanding the genetic architecture of neuroticism therefore has the potential to offer insight into the causes of psychiatric disorders, general wellbeing10, and longevity. The broad trait of neuroticism is composed of narrower traits, or factors. It was recently discovered that, whereas higher scores on the broad trait of neuroticism are associated with earlier death, higher scores on a worry/vulnerability factor are associated with living longer11. Here, we examine the genetic architectures of two neuroticism factors--worry/vulnerability and anxiety/tension--and how they contrast with the architecture of the general factor of neuroticism. We show that, whereas the polygenic load for general factor of neuroticism is associated with an increased risk of coronary artery disease (CAD), major depressive disorder, and poorer self-rated health, the genetic variants associated with high levels of the anxiety/tension and worry/vulnerability factors are associated with affluence, higher cognitive ability, better self-rated health, and longer life. We also identify the first genes associated with factors of neuroticism that are linked with these positive outcomes that show no relationship with the general factor of neuroticism.

genetics↗

bioRxiv2017

Evaluation and Design of Genome-wide CRISPR/Cas9 Knockout Screens

The adaptation of CRISPR/Cas9 technology to mammalian cell lines is transforming the study of human functional genomics. Pooled libraries of CRISPR guide RNAs (gRNAs), targeting human protein-coding genes and encoded in viral vectors, have been used to systematically create gene knockouts in a variety of human cancer and immortalized cell lines, in an effort to identify whether these knockouts cause cellular fitness defects. Previous work has shown that CRISPR screens are more sensitive and specific than pooled library shRNA screens in similar assays, but currently there exists significant variability across CRISPR library designs and experimental protocols. In this study, we re-analyze 17 genome-scale knockout screens in human cell lines from three research groups using three different genome-scale gRNA libraries, using the Bayesian Analysis of Gene Essentiality (BAGEL) algorithm to identify essential genes, to refine and expand our previously defined set of human core essential genes, from 360 to 684 genes. We use this expanded set of reference Core Essential Genes (CEG2), plus empirical data from six CRISPR knockout screens, to guide the design of a sequence-optimized gRNA library, the Toronto KnockOut version 3.0 (TKOv3) library. We demonstrate the high effectiveness of the library relative to reference sets of essential and nonessential genes as well as other screens using similar approaches. The optimized TKOv3 library, combined with the CEG2 reference set, provide an efficient, highly optimized platform for performing and assessing gene knockout screens in human cell lines.

systems biology↗