Biology subjects

Schmidt, H.

Publications and source records attributed to Schmidt, H..

At least 73 records · Page 4Linked to original sources

bioRxiv2020

Computational Properties of the Visual Microcircuit

The neocortex is organized around layered microcircuits consisting of a variety of excitatory and inhibitory neuronal types which perform rate-and oscillation based computations. Using modeling, we show that both superficial and deep layers of the primary mouse visual cortex implement two ultrasensitive and bistable switches built on mutual inhibitory connectivity motives between SST, PV and VIP cells. The switches toggle pyramidal neurons between high and low firing rate states that are synchronized across layers through translaminar connectivity. Moreover, inhibited and disinhibited states are characterized by low- and high frequency oscillations, respectively, with layer-specific differences in frequency and power which show asymmetric changes during state transitions. These findings are consistent with a number of experimental observations and embed firing rate together with oscillatory changes within a switch interpretation of the microcircuit.

neuroscience↗

bioRxiv2020

Spontaneous restoration of functional β-cell mass in obese SM/J mice

Maintenance of functional {beta}-cell mass is critical to preventing diabetes, but the physiological mechanisms that cause {beta}-cell populations to thrive or fail in the context of obesity are unknown. High fat-fed SM/J mice spontaneously transition from hyperglycemic-obese to normoglycemic-obese with age, providing a unique opportunity to study {beta}-cell adaptation. Here, we characterize insulin homeostasis, islet morphology, and {beta}-cell function during SM/Js diabetic remission. As they resolve hyperglycemia, obese SM/J mice dramatically increase circulating and pancreatic insulin levels while improving insulin sensitivity. Immunostaining of pancreatic sections reveals that obese SM/J mice selectively increase {beta}-cell mass but not -cell mass. Obese SM/J mice do not show elevated {beta}-cell mitotic index, but rather elevated -cell mitotic index. Functional assessment of isolated islets reveals that obese SM/J mice increase glucose stimulated insulin secretion, decrease basal insulin secretion, and increase islet insulin content. These results establish that {beta}-cell mass expansion and improved {beta}-cell function underlie the resolution of hyperglycemia, indicating that obese SM/J mice are a valuable tool for exploring how functional {beta}-cell mass can be recovered in the context of obesity.

physiology↗

bioRxiv2020

Cutting out the middle clam: lucinid endosymbiotic bacteria are also associated with seagrass roots worldwide

Seagrasses and lucinid bivalves inhabit highly reduced sediments with elevated sulphide concentrations. Lucinids house symbiotic bacteria (Ca. Thiodiazotropha) capable of oxidising sediment sulphide, and their presence in sediments has been proposed to promote seagrass growth by decreasing otherwise phytotoxic sulphide levels. However, vast and productive seagrass meadows are present in ecosystems where lucinids do not occur. Hence, we hypothesised that seagrasses themselves host sulphur-oxidising bacteria that could secure their survival when lucinids are absent. We analysed newly generated and publicly available 16S rRNA gene sequences from seagrass roots and sediments across 14 seagrass species and 10 countries and found that persistent and colonising seagrasses across the world harbour sulphur-oxidising Ca. Thiodiazotropha, regardless of the presence of lucinids. We used fluorescence in situ hybridisation to visually confirm the presence of Ca. Thiodiazotropha on roots of Halophila ovalis, a colonising seagrass species with wide geographical, water depth range, and sedimentary sulphide concentrations. We provide the first evidence that Ca. Thiodiazotropha are commonly present on seagrass roots, providing a mechanism for seagrasses to alleviate sulphide stress globally.

plant biology↗

bioRxiv2020

Ephaptic coupling in white matter fibre bundles modulates axonal transmission delays

Axonal connections are widely regarded as faithful transmitters of neuronal signals with fixed delays. The reasoning behind this is that extra-cellular potentials caused by spikes travelling along axons are too small to have an effect on other axons. Here we devise a computational framework that allows us to study the effect of extracellular potentials generated by spike volleys in axonal fibre bundles on axonal transmission delays. We demonstrate that, although the extracellular potentials generated by single spikes are of the order of microvolts, the collective extracellular potential generated by spike volleys can reach several millivolts. As a consequence, the resulting depolarisation of the axonal membranes increases the velocity of spikes, and therefore reduces axonal delays between brain areas. Driving a neural mass model with such spike volleys, we further demonstrate that only ephaptic coupling can explain the reduction of stimulus latencies with increased stimulus intensities, as observed in many psychological experiments. Author summaryAxonal fibre bundles that connect distant cortical areas contain millions of densely packed axons. When synchronous spike volleys travel through such fibre bundles, the extracellular potential within the bundles is perturbed. We use computer simulations to examine the magnitude and shape of this perturbation, and demonstrate that it is sufficiently strong to affect axonal transmission speeds. Since most spikes within a spike volley are positioned in an area where the extracellular potential is negative (relative to a distant reference), the resulting depolarisation of the axonal membranes accelerates the spike volley on average. This finding is in contrast to previous studies of ephaptic coupling effects between axons, where ephaptic coupling was found to slow down spike propagation. Our finding has consequences for information transmission and synchronisation between cortical areas.

neuroscience↗

bioRxiv2019

IQ-TREE 2: New models and efficient methods for phylogenetic inference in the genomic era

IQ-TREE (http://www.iqtree.org) is a user-friendly and widely used software package for phylogenetic inference using maximum likelihood. Since the release of version 1 in 2014, we have continuously expanded IQ-TREE to integrate a plethora of new models of sequence evolution and efficient computational approaches of phylogenetic inference to deal with genomic data. Here, we describe notable features of IQ-TREE version 2 and highlight the key advantages over other software.

evolutionary biology↗

bioRxiv2019

A Mean-Field Description of Bursting Dynamics in Spiking Neural Networks with Short-Term Adaptation

Bursting plays an important role in neural communication. At the population level, macro-scopic bursting has been identified in populations of neurons that do not express intrinsic bursting mechanisms. For the analysis of such phase transitions, mean-field descriptions of macroscopic bursting behavior pose a valuable tool. In this article, we derive mean-field descriptions of populations of spiking neurons in which collective bursting behavior arises via short-term adaptation mechanisms. Specifically, we consider synaptic depression and spike-frequency adaptation in networks of quadratic integrate-and-fire neurons. We characterize the emerging bursting behavior using bifurcation analysis and validate our mean-field derivations by comparing the microscopic and macroscopic descriptions of the population dynamics. Hence, we provide mechanistic descriptions of phase transitions between bursting and non-bursting population dynamics which play important roles in both healthy neural communication and neurological disorders.

neuroscience↗

bioRxiv2019

Natural brown adipose expansion and remission of hyperglycemia in obese SM/J mice

Disruption of glucose homeostasis increases the risk of type II diabetes, cardiovascular disease, stroke, and cancer. We leverage a novel rodent model, the SM/J mouse, to understand glycemic control in obesity. On a high fat diet, obese SM/J mice initially develop impaired glucose tolerance and elevated fasting glucose. Strikingly, their glycemic dysfunction resolves by 30 weeks of age despite persistence of obesity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. This occurs naturally and spontaneously on a high fat diet, with no temperature or genetic manipulation. When the brown adipose depot is removed from normoglycemic obese mice, fasting blood glucose and glucose tolerance revert to unhealthy levels, and animals become insulin resistant. We identified 267 genes whose expression changes in the brown adipose when the mice resolve their unhealthy glycemic parameters, and find the expanded tissue has a healthier expression profile of cytokines and extracellular matrix genes. We describe morphological, physiological, and transcriptomic changes that occur during the unique brown adipose expansion and remission of glycemic dysfunction in obese SM/J mice. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity. Significance StatementSome obese individuals maintain normal glycemic control. Despite being obese, these individuals have low risk for metabolic complications, including type-II diabetes. If we better understood why some obese people maintain normoglycemia then we might develop new approaches for treating metabolic complications associated with obesity. However, the causative factors underlying glycemic control in obesity remain unknown. We discovered that, despite persistence of the obese state, SM/J mice enter into diabetic remission: returning to normoglycemia and reestablishing glucose tolerance and improving insulin sensitivity. A prominent phenotype is that they dramatically expand their brown adipose depots as they resolve glycemic dysfunction. Understanding this phenomenon in mice will open the door for innovative therapies aimed at improving glycemic control in obesity.

physiology↗

bioRxiv2019

A high-quality genome assembly from short and long reads for the non-biting midge Chironomus riparius (Diptera)

BackgroundChironomus riparius is of great importance as a study species in various fields like ecotoxicology, molecular genetics, developmental biology and ecology. However, only a fragmented draft genome exists to date, hindering the recent rush of population genomic studies in this species.\n\nFindingsMaking use of 50 NGS datasets, we present a hybrid genome assembly from short and long sequence reads that make C. riparius genome one of the most contiguous Dipteran genomes published, the first complete mitochondrial genome of the species and the respective recombination rate as one of the first insect recombination rates at all.\n\nConclusionsThe genome and associated resources will be highly valuable to the broad community working with dipterans in general and chironomids in detail. The estimated recombination rate will help evolutionary biologist gain a better understanding of commonalities and differences of genomic patterns in insects.

genomics↗

bioRxiv2019

Development of a Confinable Gene-Drive System in the Human Disease Vector, Aedes aegypti.

Aedes aegypti, the principal mosquito vector for many arboviruses that causes yellow fever, dengue, Zika, and chikungunya, increasingly infects millions of people every year. With an escalating burden of infections and the relative failure of traditional control methods, the development of innovative control measures has become of paramount importance. The use of gene drives has recently sparked significant enthusiasm for the genetic control of mosquito populations, however no such system has been developed in Ae. aegypti. To fill this void and demonstrate efficacy in Ae. aegypti, here we develop several CRISPR-based split-gene drives for use in this vector. With cleavage rates up to 100% and transmission rates as high as 94%, mathematical models predict that these systems could spread anti-pathogen effector genes into wild Ae. aegypti populations in a safe, confinable and reversible manner appropriate for field trials and effective for controlling disease. These findings could expedite the development of effector-linked gene drives that could safely control wild populations of Ae. aegypti to combat local pathogen transmission.\n\nSignificance StatementAe. aegypti is a globally distributed arbovirus vector spreading deadly pathogens to millions of people annually. Current control methods are inadequate and therefore new technologies need to be innovated and implemented. With the aim of providing new tools for controlling this pest, here we engineered and tested several split gene drives in this species. These drives functioned at very high efficiency and may provide a tool to fill the void in controlling this vector. Taken together, our results provide compelling path forward for the feasibility of future effector-linked split-drive technologies that can contribute to the safe, sustained control and potentially the elimination of pathogens transmitted by this species.

bioengineering↗

bioRxiv2019

Flotillin-dependent lipid-raft microdomains are required for functional phagolysosomes against fungal infections

Lipid rafts form signaling platforms on biological membranes with incompletely characterized role in immune response to infection. Here we report that lipid raft microdomains are essential components of the phagolysosomal membrane of macrophages. Genetic deletion of the lipidraft chaperons flotillin-1 and flotillin-2 demonstrate that the assembly of both major defense complexes vATPase and NADPH oxidase on the phagolysosomal membrane requires lipid rafts. Furthermore, we discovered a new virulence mechanism leading to the dysregulation of lipid-raft formation by melanized wild-type conidia of the important human-pathogenic fungus Aspergillus fumigatus. This results in reduced phagolysosomal acidification. Phagolysosomes with ingested melanized conidia contain a reduced amount of free Ca2+ ions as compared to phagolysosomes with melanin-free conidia. In agreement with a role of Ca2+ for generation of functional lipid rafts, we show that Ca2+-dependent calmodulin activity is required for lipid-raft formation on the phagolysosome. We identified a single nucleotide polymorphism in the human FLOT1 gene that results in heightened susceptibility for invasive aspergillosis in hematopoietic stem-cell transplant recipients. Collectively, flotillin-dependent lipid rafts on the phagolysosomal membrane play an essential role in protective antifungal immunity in humans.

microbiology↗

bioRxiv2019

Action Potential Propagation and Synchronisation inMyelinated Axons

With the advent of advanced MRI techniques it has become possible to study axonal white matter non-invasively and in great detail. Measuring the various parameters of the long-range connections of the brain opens up the possibility to build and refine detailed models of large-scale neuronal activity. One particular challenge is to find a mathematical description of action potential propagation that is sufficiently simple, yet still biologically plausible to model signal transmission across entire axonal fibre bundles. We develop a mathematical framework in which we replace the Hodgkin-Huxley dynamics by a spike-diffuse-spike model with passive sub-threshold dynamics and explicit, threshold-activated ion channel currents. This allows us to study in detail the influence of the various model parameters on the action potential velocity and on the entrainment of action potentials between ephaptically coupled fibres without having to recur to numerical simulations. Specifically, we recover known results regarding the influence of axon diameter, node of Ranvier length and internode length on the velocity of action potentials. Additionally, we find that the velocity depends more strongly on the thickness of the myelin sheath than was suggested by previous theoretical studies. We further explain the slowing down and synchronisation of action potentials in ephaptically coupled fibres by their dynamic interaction. In summary, this study presents a solution to incorporate detailed axonal parameters into a whole-brain modelling framework.\n\nAuthor summaryWith more and more data becoming available on white-matter tracts, the need arises to develop modelling frameworks that incorporate these data at the whole-brain level. This requires the development of efficient mathematical schemes to study parameter dependencies that can then be matched with data, in particular the speed of action potentials that cause delays between brain regions. Here, we develop a method that describes the formation of action potentials by threshold activated currents, often referred to as spike-diffuse-spike modelling. A particular focus of our study is the dependence of the speed of action potentials on structural parameters. We find that the diameter of axons and the thickness of the myelin sheath have a strong influence on the speed, whereas the length of myelinated segments and node of Ranvier length have a lesser effect. In addition to examining single axons, we demonstrate that action potentials between nearby axons can synchronise and slow down their propagation speed.

neuroscience↗

bioRxiv2019

Dynamic network properties of the interictal brain determine whether seizures appear focal or generalised

ObjectiveCurrent explanatory concepts suggest seizures emerge from ongoing dynamics of brain networks. It is unclear how brain network properties determine focal or generalised seizure onset, or how network properties can be described in a clinically-useful manner. Understanding network properties would cast light on seizure-generating mechanisms and allow to quantify in the clinic the extent to which a seizure is focal or generalised.\n\nMethods68 people with epilepsy and 38 healthy controls underwent 19 channel scalp EEG recording. Functional brain networks were estimated in each subject using phase-locking between EEG channels in the 6-9Hz band from segments of 20s without interictal discharges. Simplified brain dynamics were simulated using a computer model. We introduce three concepts: Critical Coupling (Cc), the ability of a network to generate seizures; Onset Index (OI), the tendency of a region to generate seizures; and Participation Index (PI), the tendency of a region to become involved in seizures.\n\nResultsCc was lower in both patient groups compared with controls. OI and PI were more variable in focal-onset than generalised-onset cases. No regions showed higher OI and PI in generalised-onset cases than in healthy controls; in focal cases, the regions with highest OI and PI corresponded to the side of seizure onset.\n\nConclusionsProperties of interictal functional networks from scalp EEG can be estimated using a computer model and used to predict seizure likelihood and onset patterns. Our framework, consisting of three clinically-meaningful measures, could be implemented in the clinic to quantify the diagnosis and seizure onset pattern.

neuroscience↗

bioRxiv2018

The CryoEM Structure of the Ribosome Maturation Factor Rea1

The biogenesis of the 60S ribosomal subunit is initiated in the nucleus where rRNAs and proteins form pre-60S particles. These pre-60S particles mature by transiently interacting with various assembly factors. The ~5000 amino-acid AAA+ ATPase Rea1 (or Midasin) generates force to mechanically remove assembly factors from pre-60S particles, which promotes their export to the cytosol. Here we present three Rea1 cryoEM structures. We visualize the Rea1 engine, a hexameric ring of AAA+ domains, and identify an -helical bundle of AAA2 as a major ATPase activity regulator. The -helical bundle interferes with nucleotide induced conformational changes that create a docking site for the substrate binding MIDAS domain of Rea1 on the AAA+ ring. Furthermore, we reveal the architecture of the Rea1 linker, which is involved in force generation and extends from the AAA+ ring. The data presented here provide insights into the mechanism of one of the most complex ribosome maturation factors.

molecular biology↗

bioRxiv2018

Planar cell polarity pathway and development of the human visual cortex

The radial unit hypothesis provides a framework for global (proliferation) and regional (distribution) expansion of the primate cerebral cortex. Using principal component analysis (PCA), we have identified cortical regions with shared variance in their surface area and cortical thickness, respectively, segmented from magnetic resonance images obtained in 23,800 participants. We then carried out meta-analyses of genome-wide association studies of the first two principal components for each phenotype. For surface area (but not cortical thickness), we have detected strong associations between each of the components and single nucleotide polymorphisms in a number of gene loci. The first (global) component was associated mainly with loci on chromosome 17 (9.5e-32 [≤] p [≤] 2.8e-10), including those detected previously as linked with intracranial volume and/or general cognitive function. The second (regional) component captured shared variation in the surface area of the primary and adjacent secondary visual cortices and showed a robust association with polymorphisms in a locus on chromosome 14 containing Disheveled Associated Activator of Morphogenesis 1 (DAAM1; p=2.4e-34). DAAM1 is a key component in the planar-cell-polarity signaling pathway. In follow-up studies, we have focused on the latter finding and established that: (1) DAAM1 is highly expressed between 12th and 22nd post-conception weeks in the human cerebral cortex; (2) genes co-expressed with DAAM1 in the primary visual cortex are enriched in mitochondria-related pathways; and (3) volume of the lateral geniculate nucleus, which projects to regions of the visual cortex staining for cytochrome oxidase (a mitochondrial enzyme), correlates with the surface area of the visual cortex in major-allele homozygotes but not in carriers of the minor allele. Altogether, we speculate that, in concert with thalamocortical input to cortical subplate, DAAM1 enables migration of neurons to cytochrome-oxidase rich regions of the visual cortex, and, in turn, facilitates regional expansion of this set of cortical regions during development.

neuroscience↗

bioRxiv2018

Meta-analysis of genetic association with diagnosed Alzheimer’s disease identifies novel risk loci and implicates Abeta, Tau, immunity and lipid processing

Late-onset Alzheimers disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3-8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and A{beta} processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10-7) indicating that additional rare variants remain to be identified.

genetics↗

bioRxiv2018

Network mechanisms underlying the role of oscillations in cognitive tasks

Oscillatory activity robustly correlates with task demands during many cognitive tasks. However, not only are the network mechanisms underlying the generation of these rhythms poorly understood, but it is also still unknown to what extent they may play a functional role, as opposed to being a mere epiphenomenon. Here we study the mechanisms underlying the influence of oscillatory drive on network dynamics related to cognitive processing in simple working memory (WM), and memory recall tasks. Specifically, we investigate how the frequency of oscillatory input interacts with the intrinsic dynamics in networks of recurrently coupled spiking neurons to cause changes of state: the neuronal correlates of the corresponding cognitive process. We find that slow oscillations, in the delta and theta band, are effective in activating network states associated with memory recall by virtue of the hysteresis in sweeping through a saddle-node bifurcation. On the other hand, faster oscillations, in the beta range, can serve to clear memory states by resonantly driving transient bouts of spike synchrony which destabilize the activity. We leverage a recently derived set of exact mean-field equations for networks of quadratic integrate-and-fire neurons to systematically study the bifurcation structure in the periodically forced spiking network. Interestingly, we find that the oscillatory signals which are most effective in allowing flexible switching between network states are not smooth, pure sinusoids, but rather burst-like, with a sharp onset. We show that such periodic bursts themselves readily arise spontaneously in networks of excitatory and inhibitory neurons, and that the burst frequency can be tuned via changes in tonic drive. Finally, we show that oscillations in the gamma range can actually stabilize WM states which otherwise would not persist.\n\nAuthor SummaryOscillations are ubiquitous in the brain and often correlate with distinct cognitive tasks. Nonetheless their role in shaping network dynamics, and hence in driving behavior during such tasks is poorly understood. Here we provide a comprehensive study of the effect of periodic drive on neuronal networks exhibiting multistability, which has been invoked as a possible circuit mechanism underlying the storage of memory states. We find that oscillatory drive in low frequency bands leads to robust switching between stored patterns in a Hopfield-like model, while oscillations in the beta band suppress sustained activity altogether. Furthermore, inputs in the gamma band can lead to the creation of working-memory states, which otherwise do not exist in the absence of oscillatory drive.

neuroscience↗

bioRxiv2017

Dephosphorylation is the Mechanism of Fibroblast Growth Factor Inhibition of Guanylyl Cyclase-B

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations of guanylyl cyclase-B (GC-B, also called NPRB or NPR2) cause dwarfism. FGF exposure inhibits GC-B activity in a chondrocyte cell line, but the mechanism of the inactivation is not known. Here, we report that FGF exposure causes dephosphorylation of GC-B in rat chondrosarcoma cells, which correlates with a rapid, potent and reversible inhibition of C-type natriuretic peptide-dependent activation of GC-B. Cells expressing a phosphomimetic mutant of GC-B that cannot be inactivated by dephosphorylation because it contains glutamate substitutions for all known phosphorylation sites showed no decrease in GC-B activity in response to FGF. We conclude that FGF rapidly inactivates GC-B by a reversible dephosphorylation mechanism, which may contribute to the signaling network by which activated FGFR3 causes dwarfism.\n\nHighlightsO_LIGuanylyl Cyclase-B is expressed in rat chondrosarcoma cells\nC_LIO_LIFGF2 induces a rapid, potent, and reversible inhibition of GC-B\nC_LIO_LIFGF2 treatment causes GC-B dephosphorylation\nC_LIO_LIFGF2 does not inhibit a dephosphorylation-resistant form of GC-B\nC_LIO_LIDephosphorylation is the mechanism of FGF2-dependent inhibition of GC-B\nC_LI\n\nAbbreviations

biochemistry↗

bioRxiv2017

A frequency-dependent mobilization of heterogeneous pools of synaptic vesicles shapes presynaptic plasticity

The segregation of the readily releasable pool of synaptic vesicles (RRP) in sub-pool which are differentially poised for exocytosis shapes short-term plasticity at depressing synapses. Here, we used in vitro recording and modeling of synaptic activity at the facilitating mice cerebellar granule cell to Purkinje cell synapse to demonstrate the existence of two sub-pools of vesicles in the RRP that can be differentially recruited upon fast changes in the stimulation frequency. We show that upon low-frequency stimulation, a population of fully-releasable vesicles is silenced, leading to full blockage of synaptic transmission. A second population of vesicles, reluctant to release by simple stimuli, is recruited in a millisecond time scale by high-frequency stimulation to support an ultrafast recovery of neurotransmitter release after low-frequency depression. The frequency-dependent mobilization or silencing of sub-pools of vesicles in granule cell terminals should play a major role in the filtering of sensorimotor information in the cerebellum.

neuroscience↗