A Marriage of Old and New: Chemostats and Microarrays Identify a New Model System for Ammonium Toxicity

Toxicity is related to an organism's ability to rid itself of the offending molecules. This primer provides insights into how this can be monitored by highlighting the case of ammonium toxicity

Fatty Acid Synthase Impacts the Pathobiology of Candida parapsilosis In Vitro and during Mammalian Infection

Cytosolic fungal fatty acid synthase is composed of two subunits α and β, which are encoded by Fas1 and Fas2 genes. In this study, the Fas2 genes of the human pathogen Candida parapsilosis were deleted using a modified SAT1 flipper technique. CpFas2 was essential in media lacking exogenous fatty acids and the growth of Fas2 disruptants (Fas2 KO) was regulated by the supplementation of different long chain fatty acids, such as myristic acid (14∶0), palmitic acid (16∶0), and Tween 80, in a dose-specific manner. Lipidomic analysis revealed that Fas2 KO cells were severely restricted in production of unsaturated fatty acids. The Fas2 KO strains were unable to form normal biofilms and were more efficiently killed by murine-like macrophages, J774.16, than the wild type, heterozygous and reconstituted strains. Furthermore, Fas2 KO yeast were significantly less virulent in a systemic murine infection model. The Fas2 KO cells were also hypersensitive to human serum, and inhibition of CpFas2 in WT C. parapsilosis by cerulenin significantly decreased fungal growth in human serum. This study demonstrates that CpFas2 is essential for C. parapsilosis growth in the absence of exogenous fatty acids, is involved in unsaturated fatty acid production, influences fungal virulence, and represents a promising antifungal drug target

Dorsolateral prefrontal cortex contributes to the impaired behavioral adaptation in alcohol dependence

Substance-dependent individuals often lack the ability to adjust decisions flexibly in response to the changes in reward contingencies. Prediction errors (PEs) are thought to mediate flexible decision-making by updating the reward values associated with available actions. In this study, we explored whether the neurobiological correlates of PEs are altered in alcohol dependence. Behavioral, and functional magnetic resonance imaging (fMRI) data were simultaneously acquired from 34 abstinent alcohol-dependent patients (ADP) and 26 healthy controls (HC) during a probabilistic reward-guided decision-making task with dynamically changing reinforcement contingencies. A hierarchical Bayesian inference method was used to fit and compare learning models with different assumptions about the amount of task-related information subjects may have inferred during the experiment. Here, we observed that the best-fitting model was a modified Rescorla-Wagner type model, the “double-update” model, which assumes that subjects infer the knowledge that reward contingencies are anti-correlated, and integrate both actual and hypothetical outcomes into their decisions. Moreover, comparison of the best-fitting model's parameters showed that ADP were less sensitive to punishments compared to HC. Hence, decisions of ADP after punishments were loosely coupled with the expected reward values assigned to them. A correlation analysis between the model-generated PEs and the fMRI data revealed a reduced association between these PEs and the BOLD activity in the dorsolateral prefrontal cortex (DLPFC) of ADP. A hemispheric asymmetry was observed in the DLPFC when positive and negative PE signals were analyzed separately. The right DLPFC activity in ADP showed a reduced correlation with positive PEs. On the other hand, ADP, particularly the patients with high dependence severity, recruited the left DLPFC to a lesser extent than HC for processing negative PE signals. These results suggest that the DLPFC, which has been linked to adaptive control of action selection, may play an important role in cognitive inflexibility observed in alcohol dependence when reinforcement contingencies change. Particularly, the left DLPFC may contribute to this impaired behavioral adaptation, possibly by impeding the extinction of the actions that no longer lead to a reward

A Multi-Scale Model for Correlation in B Cell VDJ Usage of Zebrafish

The zebrafish (\emph{Danio rerio}) is one of the model animals for study of immunology because the dynamics in the adaptive immune system of zebrafish are similar to that in higher animals. In this work, we built a multi-scale model to simulate the dynamics of B cells in the primary and secondary immune responses of zebrafish. We use this model to explain the reported correlation between VDJ usage of B cell repertoires in individual zebrafish. We use a delay ordinary differential equation (ODE) system to model the immune responses in the 6-month lifespan of a zebrafish. This mean field theory gives the number of high affinity B cells as a function of time during an infection. The sequences of those B cells are then taken from a distribution calculated by a "microscopic" random energy model. This generalized $NK$ model shows that mature B cells specific to one antigen largely possess a single VDJ recombination. The model allows first-principles calculation of the probability, $p$, that two zebrafish responding to the same antigen will select the same VDJ recombination. This probability $p$ increases with the B cell population size and the B cell selection intensity. The probability $p$ decreases with the B cell hypermutation rate. The multi-scale model predicts correlations in the immune system of the zebrafish that are highly similar to that from experiment.Comment: 29 pages, 10 figures, 1 tabl

Impact of Genetic Background on Allele Selection in a Highly Mutable Candida albicans Gene, PNG2

In many microbes rapid mutation of highly mutable contingency genes continually replenishes a pool of variant alleles from which the most suitable are selected, assisting in rapid adaptation and evasion of the immune response. In some contingency genes mutability is achieved through DNA repeats within the coding region. The fungal human pathogen Candida albicans has 2600 repeat-containing ORFs. For those investigated (ALS genes, HYR1, HYR2, CEK1, RLM1) many protein variants with differing amino acid repeat regions exist, as expected for contingency genes. However, specific alleles dominate in different clades, which is unexpected if allele variation is used for short-term adaptation. Generation of new alleles of repeat-containing C. albicans ORFs has never been observed directly. Here we present evidence for restrictions on the emergence of new alleles in a highly mutable C. albicans repeat-containing ORF, PNG2, encoding a putative secreted or cell surface glycoamidase. In laboratory cultures new PNG2 alleles arose at a rate of 2.8×10−5 (confidence interval 3.3×10−6−9. 9×10−5) per cell per division, comparable to rates measured for contingency genes. Among 80 clinical isolates 17 alleles of different length and 23 allele combinations were distinguishable; sequence differences between repeat regions of identical size suggest the existence of 36 protein variants. Specific allele combinations predominated in different genetic backgrounds, as defined by DNA fingerprinting and multilocus sequence typing. Given the PNG2 mutation rate, this is unexpected, unless in different genetic backgrounds selection favors different alleles. Specific alleles or allele combinations were not preferentially associated with C. albicans isolates from particular body sites or geographical regions. Our results suggest that the mutability of PNG2 is not used for short-term adaptation or evasion of the immune system. Nevertheless the large number of alleles observed indicates that mutability of PNG2 may assist C. albicans strains from different genetic backgrounds optimize their interaction with the host in the long term

Informing wetland management with waterfowl movement and sanctuary use responses to human-induced disturbance

Long-term environmental management to prevent waterfowl population declines is informed by ecology, movement behavior and habitat use patterns. Extrinsic factors, such as human-induced disturbance, can cause behavioral changes which may influence movement and resource needs, driving variation that affects management efficacy. To better understand the relationship between human-based disturbance and animal movement and habitat use, and their potential effects on management, we GPS tracked 15 dabbling ducks in California over ~4-weeks before, during and after the start of a recreational hunting season in October/November 2018. We recorded locations at 2-min intervals across three separate 24-h tracking phases: Phase 1) two weeks before the start of the hunting season (control (undisturbed) movement); Phase 2) the hunting season opening weekend; and Phase 3) a hunting weekend two weeks after opening weekend. We used GLMM models to analyze variation in movement and habitat use under hunting pressure compared with ‘normal’ observed patterns prior to commencement of hunting. We also compared responses to differing levels of disturbance related to the time of day (high - shooting/~daytime); moderate - non-lethal (~crepuscular); and low - night). During opening weekend flight (% time and distance) more than doubled during moderate and low disturbance and increased by ~50% during high disturbance compared with the pre-season weekend. Sanctuary use tripled during moderate and low disturbance and increased ~50% during high disturbance. Two weeks later flight decreased in all disturbance levels but was only less than the pre-season levels during high disturbance. In contrast, sanctuary use only decreased at night, although not to pre-season levels, while daytime doubled from ~45% to \u3e80%. Birds adjust rapidly to disturbance and our results have implications for energetics models that estimate population food requirements. Management would benefit from reassessing the juxtaposition of essential sanctuary and feeding habitats to optimize wetland management for waterfowl

Like-charge attraction through hydrodynamic interaction

We demonstrate that the attractive interaction measured between like-charged colloidal spheres near a wall can be accounted for by a nonequilibrium hydrodynamic effect. We present both analytical results and Brownian dynamics simulations which quantitatively capture the one-wall experiments of Larsen and Grier (Nature 385, p. 230, 1997).Comment: 10 pages, 4 figure

Bidirectional control of saccadic eye movements by the disconnected cerebral hemispheres

The present investigation demonstrates that callosotomy patient J.W. can generate either leftward or rightward saccades in response to color cues presented unilaterally. When asked to name the colors, performance was at chance for left visual field presentations, demonstrating a disability in interhemispheric transfer of chromatic information. The successful control of saccadic direction based on discriminative color cues that appear confined to a single hemisphere may suggest a capacity for bidirectional control of saccadic eye movements in the disconnected cerebral hemispheres.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46564/1/221_2004_Article_BF00231667.pd

Density growth in Kantowski-Sachs cosmologies with cosmological constant

In this work the growth of density perturbations in Kantowski-Sachs cosmologies with a positive cosmological constant is studied, using the 1+3 and 1+1+2 covariant formalisms. For each wave number we obtain a closed system for scalars formed from quantities that are zero on the background and hence are gauge-invariant. The solutions to this system are then analyzed both analytically and numerically. In particular the effects of anisotropy and the behaviour close to a bounce in the cosmic scale factor are considered. We find that typically the density gradient in the bouncing directions experiences a local maximum at or slightly after the bounce.Comment: 33 pages, 17 picture

SARS‐CoV‐2 receptor ACE 2 and TMPRSS 2 are primarily expressed in bronchial transient secretory cells

The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to RHO GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis