Biology subjects

Fischer, J.

Publications and source records attributed to Fischer, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2022

Male Guinea baboon tracking of female whereabouts

In group-living species, evolution puts a premium on the ability of individuals to track the state, whereabouts, and interactions of others. The value of social information might vary with the degree of competition within and between groups, however. We investigated male monitoring of female location in wild Guinea baboons (Papio papio). Guinea baboons live in socially tolerant multi-level societies with one-male-units comprising 1-6 females and young at the core. Using field playback experiments, we first tested whether male Guinea baboons (N=14) responded more strongly to playbacks of associated vs. non-associated females, which was the case. In the second and core experiment, we tested whether males (N=22 males, N=62 trials) keep track of the whereabouts of associated females by playing back unit females calls from locations that were either consistent or inconsistent with the actual position of the female. Contrary to predictions, males responded equally strongly in both conditions. While males seem to recognize their females by voice, they might lack the attention or motivation to track their females movement patterns. These results reinforce the view that the value of social information may vary substantially with the distribution of power in a society. While highly competitive regimes necessitate high attention to deviations from expected patterns, egalitarian societies allow for a certain degree of obliviousness.

animal behavior and cognition↗

bioRxiv2022

MALE-MALE SOCIAL BONDING, COALITIONARY SUPPORT AND REPRODUCTIVE SUCCESS IN WILD GUINEA BABOONS

Male-male bonds may confer substantial fitness benefits. The adaptive value of these relationships is often attributed to coalitionary support, which aids in rank ascension and female defence, ultimately resulting in greater reproductive success. We investigated the link between male-male sociality and both coalitionary support and reproductive success in wild Guinea baboons. This species lives in a tolerant multi-level society with reproductive units comprising a male and 1-6 females at the core. Males are philopatric, form differentiated, stable, and equitable affiliative relationships ( strong bonds) with other males, and lack a clear rank hierarchy. Here, we analysed behavioural and paternity data for 30 males and 50 infants collected over four years in the Niokolo-Koba National Park, Senegal. Strongly bonded males supported each other more frequently during conflicts, but strong bonds did not promote reproductive success. Instead, males that spent less time socializing with other males were associated with a higher number of females and sired more offspring. Notably, reproductively active males still maintained bonds with other males, but adjusted their social investment in relation to life-history stage. Long-term data will be needed to test if the adaptive value of male bonding lies in longer male tenure and/or in promoting group cohesion.

animal behavior and cognition↗

bioRxiv2022

Extending Bayesian Elo-rating to quantify dominance hierarchy steepness

The steepness of dominance hierarchies provides information about the degree of competition within animal social groups and is thus an important concept in socioecology. The currently most widely-used metrics to quantify steepness are based on Davids scores (DS) derived from dominance interaction networks. One serious drawback of these DS-based metrics is that they are biased, i.e., network density systematically decreases steepness values. Here, we provide a novel approach to estimate steepness based on Elo-ratings, implemented in a Bayesian framework (STEER: Steepness estimation with Elo-rating). Our new metric has two key advantages. First, STEER is unbiased, precise and more robust to data density than DS-based steepness. Second, it provides explicit probability distributions of the estimated steepness coefficient, which allows uncertainty assessment. In addition, it relies on the same underlying concept and is on the same scale as the original measure, and thus allows comparison to existing published results. We evaluate and validate performance of STEER by means of experimentation on empirical and artificial data sets and compare its performance to that of several other steepness estimators. Our results suggest that STEER provides a considerable improvement over existing methods to estimate dominance hierarchy steepness. We provide an R package EloSteepness to calculate the new steepness measure, and also show an example of using steepness in a comparative analysis.

animal behavior and cognition↗

bioRxiv2021

Hunting the plant surrender signal activating apoplexy in grapevines after Neofusicoccum parvum infection

O_LIApoplectic breakdown from Grapevines Trunk Diseases (GTDs) has become a serious challenge to viticulture in consequence to drought stress. We hypothesise that fungal aggressiveness is controlled by a chemical communication between host and colonising fungus. C_LIO_LIWe introduce the new concept of a "plant surrender signal" accumulating in host plants under stress and triggering aggressive behaviour of the strain Neofusicoccum parvum (Bt-67) causing Botryosphaeriaceae-related dieback in grapevines. C_LIO_LIUsing a cell-based experimental system (Vitis cells) and bioactivity-guided fractionation, we identify trans-ferulic acid, a monolignol precursor, as "surrender signal". We show that this signal specifically activates secretion of the fungal phytotoxin Fusicoccin A. We show further that this phytotoxin, mediated by 14-3-3 proteins, activates programmed cell death in Vitis cells. C_LIO_LIWe arrive at a model pinpointing the chemical communication driving apoplexy in Botryosphaeriaceae-Vitis interaction and define the channelling of phenylpropanoid pathway from the lignin precursor, trans-ferulic acid to the phytoalexin transresveratrol as target for future therapy. C_LI

cell biology↗

bioRxiv2021

Robust and annotation-free analysis of isoform variation using short-read scRNA-seq data

Although alternative splicing is a fundamental and pervasive aspect of gene expression in higher eukaryotes, it is often omitted from single-cell studies due to quantification challenges inherent to commonly used short-read sequencing technologies. Here, we undertake the analysis of alternative splicing across numerous diverse murine cell types from two large-scale single-cell datasets--the Tabula Muris and BRAIN Initiative Cell Census Network--while accounting for understudied technical artifacts and unannotated isoforms. We find strong and general cell-type-specific alternative splicing, complementary to total gene expression but of similar discriminatory value, and identify a large volume of novel isoforms. We specifically highlight splicing variation across different cell types in primary motor cortex neurons, bone marrow B cells, and various epithelial cells; and show that the implicated transcripts include many genes which do not display total expression differences. To elucidate the regulation of alternative splicing, we build a custom predictive model based on splicing factor activity, recovering several known interactions while generating new hypotheses, including potential regulatory roles for novel alternative splicing events in critical genes including Khdrbs3 and Rbfox1. We make our results available using public interactive browsers to spur further exploration by the community.

genomics↗

bioRxiv2021

Kinetic Interval Measurement: A Tool to Characterize Thermal Reversion Dynamics of Light-switchable Fluorescent Proteins

Light-switchable proteins like Light-Oxygen-Voltage (LOV) domains can be used to control protein interactions and have been applied in vivo to manipulate cell behavior. The switching between dark and light state of LOV domains depends on temperature or their chemical microenvironment and can be tuned by point mutations. Here, we present a method called Kinetic Interval Measurement (KIM) to quantify the thermal reversion dynamics of light-switchable proteins by using a custom microplate reader. We show that this versatile method can be used to determine the reversion half-life of the excited state of LOV proteins in a reproducible, fast and simple manner consuming only small amounts of protein. The sensitivity of the method allows to report on changes in temperature and imidazole concentration as well as the photoswitching dynamics of LOV proteins in living cells.

biophysics↗

bioRxiv2021

S. Typhimurium impairs glycolysis-mediated acidification of phagosomes to evade macrophage defense

Regulation of the cellular metabolism is now recognized as a crucial mechanism for the homeostasis of innate and adaptive immune cells upon diverse extracellular stimuli. Macrophages, for instance, increase glycolysis upon stimulation with pathogen-associated molecular patterns (PAMPs). Conceivably, pathogens also counteract these metabolic changes for their own survival in the host. However, despite this dynamic interplay in host-pathogen interactions, the role of immunometabolism in the context of intracellular bacterial infections is still unclear. Here, employing unbiased metabolomic and transcriptomic approaches, we investigated the role of metabolic adaptations of macrophages upon Salmonella enterica serovar Typhimurium (S. Typhimurium) infections. Importantly, our results suggested that S. Typhimurium abrogates glycolysis and its modulators such as insulin-signaling to impair macrophage defense. Mechanistically, glycolytic enzyme aldolase A is critical for v-ATPase assembly and the acidification of phagosomes upon S. Typhimurium infection, and impairment in the glycolytic machinery eventually leads to decreased bacterial clearance and antigen presentation in macrophages. Collectively, our results highlight a vital molecular link between metabolic adaptation and phagosome maturation in macrophages, which is targeted by S. Typhimurium to evade cell-autonomous defense.

microbiology↗

bioRxiv2020

A recombinant protein SARS-CoV-2 candidate vaccine elicits high-titer neutralizing antibodies in macaques.

Vaccines that generate robust and long-lived protective immunity against SARS-CoV-2 infection are urgently required. We assessed the potential of vaccine candidates based on the SARS-CoV-2 spike in cynomolgus macaques (M. fascicularis) by examining their ability to generate spike binding antibodies with neutralizing activity. Antigens were derived from two distinct regions of the spike S1 subunit, either the N-terminal domain (NTD) or an extended C-terminal domain containing the receptor-binding domain (RBD) and were fused to the human IgG1 Fc domain. Three groups of 2 animals each were immunized with either antigen, alone or in combination. The development of antibody responses was evaluated through 20 weeks post-immunization. A robust IgG response to the spike protein was detected as early as 2 weeks after immunization with either protein and maintained for over 20 weeks. Sera from animals immunized with antigens derived from the RBD were able to prevent binding of soluble spike proteins to the ACE2 receptor, shown by in vitro binding assays, while sera from animals immunized with the NTD alone lacked this activity. Crucially, sera from animals immunized with the RBD but not the NTD had potent neutralizing activity against SARS-CoV-2 pseudotyped virus, with titers in excess of 10,000, greatly exceeding that typically found in convalescent humans. Neutralizing activity persisted for more than 20 weeks. These data support the utility of spike subunit-based antigens as a vaccine for use in humans.

immunology↗

bioRxiv2020

RNA-Sieve: A likelihood-based deconvolution of bulk gene expression data using single-cell references

Direct comparison of bulk gene expression profiles is complicated by distinct cell type mixtures in each sample which obscure whether observed differences are actually due to changes in expression levels themselves or simply due to differing cell type compositions. Single-cell technology has made it possible to measure gene expression in individual cells, achieving higher resolution at the expense of increased noise. If carefully incorporated, such single-cell data can be used to deconvolve bulk samples to yield accurate estimates of the true cell type proportions, thus enabling one to disentangle the effects of differential expression and cell type mixtures. Here, we propose a generative model and a likelihood-based inference method that uses asymptotic statistical theory and a novel optimization procedure to perform deconvolution of bulk RNA-seq data to produce accurate cell type proportion estimates. We demonstrate the effectiveness of our method, called RNA-Sieve, across a diverse array of scenarios involving real data and discuss extensions made uniquely possible by our probabilistic framework, including a demonstration of well-calibrated confidence intervals.

genomics↗

bioRxiv2020

Human-specific ARHGAP11B is necessary and sufficient for human-type basal progenitor levels in primate brain organoids

Based on studies in various animal models, including developing ferret neocortex (Kalebic et al., 2018), the human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of its contribution to this expansion during primate evolution is unknown. Here we addressed this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. Interference with ARHGAP11Bs function in human cerebral organoids caused a massive decrease, down to a chimpanzee level, in the proliferation and abundance of basal progenitors, the progenitors thought to have a key role in neocortex expansion. Conversely, ARHGAP11B expression in chimpanzee cerebral organoids resulted in a doubling of cycling basal progenitors. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to maintain the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.

developmental biology↗

bioRxiv2020

Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Natures treasures, however, could be used more effectively. Yet, reliable pipelines for large scale target prediction of natural products are still rare. We have developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs) - a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17{beta}-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target prediction and guidance on using the respective tools.

bioinformatics↗

bioRxiv2020

Vocal convergence in the multi-level society of Guinea baboons

The extent to which nonhuman primate vocalizations are amenable to modification through experience is relevant for understanding the substrate from which human speech evolved. We examined the vocal behaviour of Guinea baboons, Papio papio, ranging in the Niokolo Koba National Park in Senegal. Guinea baboons live in a multi-level society, with units nested within parties nested within gangs. We investigated whether the acoustic structure of grunts of 27 male baboons of two gangs varied with party/gang membership and genetic relatedness. Males in this species are philopatric, resulting in increased male relatedness within gangs and parties. Grunts from members were more similar within than across social levels (N = 351 dyads for comparison within and between gangs, and N = 169 dyads within and between parties), but the effect sizes were small. Yet, acoustic similarity did not correlate with genetic relatedness, suggesting that higher amounts of social interactions rather than genetic relatedness promote the observed vocal convergence. We consider this convergence a result of sensory-motor integration and suggest this to be an implicit form of vocal learning shared with humans, in contrast to the goal-directed and intentional explicit form of vocal learning unique to human speech acquisition.

animal behavior and cognition↗

bioRxiv2020

Human and macaque pairs coordinate differently in a dyadic decision game with face-to-face action visibility

Many real-world decisions in social contexts are made while observing a partners actions. To study dynamic interactions during such decisions, we developed a setup where two agents seated face-to-face engage in game-theoretical tasks on a shared transparent touchscreen display ("transparent games"). We compared human and macaque pairs in a transparent version of the coordination game "Bach-or-Stravinsky", which entails a conflict about which of two individually-preferred opposing options to choose to achieve coordination. Most human pairs developed coordinated behavior and adopted dynamic turn-taking to equalize the payoffs. All macaque pairs converged on simpler, static coordination. Remarkably, two animals learned to coordinate dynamically after training with a human confederate. This pair selected the faster agents preferred option, exhibiting turn-taking behavior that was captured by modeling the visibility of the partners action before ones own movement. Such competitive turn-taking was unlike the prosocial turn-taking in humans, who equally often initiated switches to and from their preferred option. Thus, the dynamic coordination is not restricted to humans, but can occur on the background of different social attitudes and cognitive capacities in rhesus monkeys. Overall, our results illustrate how action visibility promotes emergence and maintenance of coordination when agents can observe and time their mutual actions.

neuroscience↗

bioRxiv2019

Numerous post-translational modifications of RNA polymerase II subunit Rpb4 link transcription to post-transcriptional mechanisms

Rpb4/7 binds RNA Polymerase II (Pol II) transcripts co-transcriptionally and accompanies them throughout their lives. By virtue of its capacity to interact with key regulators (e.g., Pol II, eIF3, Pat1) both temporarily and spatially, Rpb4/7 regulates the major stages of the mRNA lifecycle. Here we show that Rpb4/7 can undergo over 100 combinations of post-translational modifications (PTMs). Remarkably, the Rpb4/7 PTMs repertoire changes as the mRNA/Rpb4/7 complex progresses from one stage to the next. A mutagenesis approach in residues that undergo PTMs suggests that temporal Rpb4 PTMs regulate its interactions with key regulators of gene expression that control transcriptional and post-transcriptional stages. Moreover, one mutant type specifically affects mRNA synthesis despite its normal association with Pol II, whereas the other affects both mRNA synthesis and decay; both types disrupt the balance between mRNA synthesis and decay ( mRNA buffering) and the cells capacity to respond to the environment. Taken together, we propose that temporal Rpb4/7 PTMs are involved in cross talks among the various stages of the mRNA lifecycle.

molecular biology↗

bioRxiv2019

Coordination during group departures and group progressions in the tolerant multilevel society of wild Guinea baboons (Papio papio)

ObjectivesMost primate species live in groups, and temporal and spatial coordination of activities of individuals is essential for maintaining group cohesion, and there is still considerable debate to which degree social organization, the extent of despotism, and resource distribution shape group coordination processes. As different baboon species exhibit considerable variation in all of these factors, they constitute an excellent test case to resolve this debate.\n\nMaterials and MethodsWe analyzed group departures and progressions of Guinea baboons, Papio papio, in the Niokolo Koba National Park in Senegal. Guinea baboons live in a multi-level society with strong male bonds and a lack of a clear dominance hierarchy between males.\n\nResultsTwo-thirds of departures were initiated by adult males, and one third by adult females. Although initiators were more likely to signal than followers, signaling did not affect the initiation success. During group progression, males that were not affiliated with females were predominantly found in the front, while affiliated males, females and young were observed more frequently closer to the center of the group, and no preferences for rear positions. Overall, affiliated subjects were more likely to depart and travel together.\n\nDiscussionThe group departures in Guinea baboons differed strikingly from the elaborate negotiation behaviors among male hamadryas baboons, Papio hamadryas. We did not observe that specific individuals dominated the group coordination. Neither social organization, variation in despotism, nor resource distribution alone explain variation between species. Future studies should test whether specific combinations of factors promote the occurrence of negotiation processes.\n\nResearch HighlightsO_LIIn wild Guinea baboons, both adult males and females initiated group departures\nC_LIO_LIInitiators signaled during departures, but this did not affect initiation success\nC_LIO_LISolitary males were predominantly found at the front during group progression\nC_LI

animal behavior and cognition↗

bioRxiv2019

Development of a monkey avatar to study social perception in macaques

Following the expanding use and applications of virtual reality in every-day life, dynamic virtual stimuli are of increasing interest in cognitive studies. They allow for control of features such as gaze, expression and movement, which may help to overcome limitations of using either static or poorly controlled real stimuli. In using virtual stimuli however, one must be careful to avoid the uncanny valley effect - where realistic stimuli can be perceived as eerie, and induce an aversion response. At the same time, it is important to establish whether responses to virtual stimuli mirror responses to depictions of a real conspecific. In the current study, we describe the development of a new avatar with realistic features for nonhuman primates, the primatar. As a first step towards validation, we assessed how monkeys respond to images of this avatar compared to images of real monkeys, and an unrealistic avatar. We also compared responses between original images and scrambled as well as obfuscated versions of these images. We measured looking time to images in six free moving long-tailed macaques (Macaca fascicularis) and eye movement exploration behaviour in three rhesus macaques (Macaca mulatta). Both groups showed more of such signs of overt attention to original images than scrambled or obfuscated images. In addition, we assessed whether the realistic avatar created an uncanny valley effect through decreased looking time, finding that in both groups, monkeys did not differentiate between real, realistic or unrealistic images. These results provide support for further development of our avatar for use in social cognition studies, and more generally for cognitive research with virtual stimuli in nonhuman primates. Future research needs to shed light on the source of the inconsistent findings for the uncanny valley effect in macaques, to elucidate the roots of this mechanism in humans.

animal behavior and cognition↗

bioRxiv2019

Cytoplasmic mRNA decay factors modulate RNA polymerase II processivity in 5’ and 3’ gene regions in yeast

mRNA levels are determined by the balance between mRNA synthesis and decay. Factors that mediate both processes, including the 5 to 3 exonuclease Xrn1, are responsible for the cross talk between the two processes in a manner that buffers steady-state mRNA levels. However, these proteins roles in transcription remain elusive and controversial. Applying NET-seq to yeast cells, we show that Xrn1 functions mainly as a transcriptional activator and that its disruption manifests via the reduction of RNA polymerase II (Pol II) occupancy downstream of transcription start sites. We combine our data and novel mathematical modeling of transcription to suggest that transcription initiation and elongation of targeted genes is modulated by Xrn1. Furthermore, Pol II occupancy markedly increases near cleavage and polyadenylation sites in xrn1{Delta} cells while its activity decreases, a characteristic feature of backtracked Pol II. We also provide indirect evidence that Xrn1 is involved in transcription termination downstream of polyadenylation sites. Two additional decay factors, Dhh1 and Lsm1, seem to function similarly to Xrn1 in transcription, perhaps as a complex, while the decay factors Ccr4 and Rpb4 also perturb transcription in other ways. Interestingly, DFs are capable of differentiating between SAGA- and TFIID-dominated promoters. These two classes of genes respond differently to XRN1 deletion in mRNA synthesis and differentially utilize mRNA decay pathways, raising the possibility that one distinction between the two types of genes lies in the mechanism(s) that balance these processes.

genomics↗

bioRxiv2019

First report on the effective intraperitoneal therapy of insulin-dependent diabetes mellitus in pet dogs using \"Neo-Islets\", aggregates of adipose stem and pancreatic islet cells

We previously reported that allogeneic, intraperitoneally administered \"Neo-Islets,\" composed of cultured pancreatic islet cells co-aggregated with high numbers of immunoprotective and cytoprotective Adipose-derived Stem Cells, reestablished, through omental engraftment, redifferentiation and splenic and omental up-regulation of Regulatory T-cells, normoglycemia in autoimmune Type-1 Diabetic Non-Obese Diabetic (NOD) mice without the use of immunosuppressive agents or encapsulation devices. Based on these observations, we are currently testing this Neo-Islet technology in an FDA guided Pilot Study (INAD 012-776) in insulin-dependent, spontaneously diabetic pet dogs by the intraperitoneal administration of 2x10e5 Neo-Islets/kilogram body weight to metabolically controlled (blood glucose, triglycerides, thyroid and adrenal functions) animals under sedation and local anesthesia and ultrasound guidance. We report here initial observations on the first 4 Neo-Islet-treated, insulin dependent pet dogs that are now in the intermediate-term follow-up phase of the study (> 6 months post treatment). Current results indicate that in dogs, Neo-Islets appear to engraft, redifferentiate and physiologically produce insulin, and are neither rejected by auto- or allo-immune attacks, as evidenced by (a) an absent IgG response to the allogeneic cells contained in the administered Neo-Islets, and (b) progressively improved glycemic control that achieves up to a 50% reduction in daily insulin needs paralleled by a significant fall in serum glucose levels. This is accomplished without the use of anti-rejection drugs or encapsulation devices. No adverse or serious adverse events related to the Neo-Islet administration have been observed to date. We conclude that this minimally invasive therapy has significant translational relevance to veterinary and clinical Type 1 Diabetes Mellitus by achieving complete and at this point partial glycemic control in two species, i.e., diabetic mice and dogs, respectively.

cell biology↗