bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network controllability measures of subnetworks: implications for neurosciences
Authors: Stocker Julia Elina , Nozari Erfan , van Vugt Marieke , Jansen Andreas , Jamalabadi Hamidreza 
Published: September 2022

AbstractRecent progress in network sciences has made it possible to apply key findings from control theory to the study of networks. Referred to as network control theory, this framework describes how the interactions between interconnected system elements and external energy sources, potentially constrained by different optimality criteria, result in complex network behavior. A typical example is the quantification of the functional role certain brain regions or symptoms play in shaping the temporal dynamics of brain activity or the clinical course of a disease, a property that is quantified in terms of the so-called controllability metrics. Critically though, contrary to the engineering context in which control theory was originally developed, a mathematical understanding of the network nodes and connections in neurosciences cannot be assumed. For instance, in the case of psychological systems such as those studied to understand the psychiatric disorders, a potentially large set variables are unknown. As such, while the measures offered by network control theory would be mathematically correct, in that they can be calculated with high precision, they could have little translational values with respect to their putative role suggested by controllability metrics. It is therefore critical to understand if and how the controllability metrics computer over subnetworks would deviate, if access to the complete set of variables, as in neurosciences, cannot be taken for granted. In this paper, we use a host of simulations based on synthetic as well as structural MRI data to study the potential deviation of controllability metrics in sub-compared to the full networks. Specifically, we estimate average- and modal-controllability, two of the most widely used controllability measures in neurosciences, in a large number of settings where we systematically vary network type, network size, and edge density. We find out, across all network types we test, that average and modal controllability are systematically, either over- or underestimated depending on the number of nodes in the sub- and full network and the edge density. Finally, we provide a formal theoretical proof that our observations generalize to any network type and discuss the ramifications of this systematic bias and potential solutions to alleviate the problem.
Subtype-specific roles of ellipsoid body ring neurons in sleep regulation in Drosophila
Authors: Yan Wei , Lin Hai , Yu Junwei , Wiggin Timothy D. , Wu Litao , Meng Zhiqiang , Liu Chang , Griffith Leslie C. 
Published: September 2022

ABSTRACTThe ellipsoid body (EB) is a major structure of the central complex of the Drosophila melanogaster brain. 22 subtypes of EB ring neurons have been identified based on anatomical and morphological characteristics with light-level microscopy and EM connectomics. A few studies have associated ring neurons with the regulation of sleep homeostasis and structure. However, cell type-specific and population interactions in the regulation of sleep remain unclear. Employing a unbiased thermogenetic screen of collected EB drivers, we found: 1) multiple ring neurons are involved in the modulation of amount of sleep and structure in a synergistic manner; 2) analysis of data for ΔP(doze)/ ΔP(wake) using a mixed Gaussian model detected 5 clusters of GAL4 drivers which had similar effects on sleep pressure and/or depth: lines driving arousal contained R4m neurons, whereas lines that increased sleep pressure had R3m cells; 3) a general linear model analysis correlating ring cell subtype and activity-dependent changes in sleep parameters across all the lines identified several cell types significantly associated with specific sleep effects: R3p for daytime sleep promotion, and R4m for nighttime wake-promoting; and 4) another subclass, R3d cells present in 5HT7-GAL4+ neurons and in GAL4 lines from our screen which exclusively affect sleep structure, were found to contribute to fragmentation of sleep during both day and night. Thus, multiple subtypes of ring neurons distinctively control sleep amount and/or structure, and the unique highly interconnected structure of the EB and its connections with other regions of brain suggest a local-network model worth future investigation.SIGNIFICANCE STATEMENTHow multiple brain regions, with many cell types, can coherently regulate sleep remains unclear, but identification of cell type-specific roles can generate opportunities for understanding the principles of integration and cooperation. The ellipsoid body (EB) of the fly brain exhibits a high level of connectivity and functional heterogeneity yet is able to tune multiple behaviours in real-time, including sleep. Leveraging the powerful genetic tools available in Drosophila and recent progress in the characterization of the morphology and connectivity of EB ring neurons, we identify several EB subtypes specifically associated with distinct aspects of sleep. Our findings will aid in revealing the rules of coding and integration in the brain.
Core species and interactions prominent in fish-associated microbiome dynamics
Authors: Yajima Daii , Fujita Hiroaki , Hayashi Ibuki , Shima Genta , Suzuki Kenta , Toju Hirokazu 
Published: September 2022

AbstractIn aquatic ecosystems, the health of fish depends greatly on the dynamics of microbial community structure in the background environment. Nonetheless, finding microbes with profound impacts on fish’s performance out of thousands of candidate species remains a major challenge. We here show that time-series analyses of microbial population dynamics illuminate core components and structure of fish-associated microbiomes. By targeting eel aquaculture microbiomes as model systems, we reconstructed the population dynamics of 9,605 bacterial and 303 archaeal species/strains across 128 days. Due to the remarkable increase/decrease of constituent microbial populations, the taxonomic compositions of microbiomes changed drastically through time. We then found that some specific microbial taxa showed positive relationship with eels’ activity level even after excluding cofounding effects of environmental parameters (pH and dissolved oxygen level) on population dynamics. In particular, a vitamin B12-producing bacteria,Cetobacterium somerae, consistently showed strong positive associations with eels’ activity level across the replicate time-series of the five aquaculture tanks. Network theoretical and metabolic modeling analyses further suggested that the highlighted bacterium formed compartments of close microbe-to-microbe interactions with some other bacterial taxa, forming potential core microbiomes with positive impacts on eels. Overall, these results suggest that integration of microbiology, ecological theory, and network science allows us to explore core species and interactions embedded within complex dynamics of fish-associated microbiomes.
Emergence of syntax and word prediction in an artificial neural circuit of the cerebellum
Authors: Ohmae Keiko , Ohmae Shogo 
Published: September 2022

ABSTRACTThe cerebellum, interconnected with the cerebral neocortex, plays a vital role in human-characteristic cognition such as language processing, but knowledge about the underlying circuit computation of the cerebellum remains very limited. Here, to understand the computation underlying the cerebellar language processing, we developed a biologically-constrained cerebellar artificial neural network (cANN) model, which implemented the recently identified cerebello-cerebellar recurrent pathway. We found that while cANN acquires prediction of future words, another function of syntactic recognition emerges in the middle layer of the prediction circuit. The recurrent pathway of the cANN was essential for the two language functions, whereas cANN variants with further biological constraints preserved these functions. Considering the uniform structure of cerebellar circuitry across all functional domains, the single-circuit computation, which is the common basis of the two language functions, can be generalized to fundamental cerebellar functions of prediction and grammar-like rule extraction from sequences, that underpin a wide range of cerebellar motor and cognitive functions. This is a pioneering study to understand the circuit computation of human-characteristic cognition by biologically-constrained ANNs, which can lead new therapeutic interventions for human cognitive dysfunction.
CLT-seq as a universal homopolymer-sequencing concept reveals poly(A)-tail-tuned ncRNA regulation
Authors: Su Qiang , Long Yi , Wang Jun , Gou Deming 
Published: September 2022

ABSTRACTDynamic tuning of the poly(A) tail is a crucial mechanism for controlling translation and stability of eukaryotic mRNA. Achieving a comprehensive understanding of how this regulation occurs requires unbiased abundance quantification of poly(A)-tail transcripts and simple poly(A)-length measurement using high-throughput sequencing platforms. Current methods have limitations due to complicated setups and elaborate library preparation plans. To address this, we introduce Central Limit Theorem (CLT)-managed RNA-seq (CLT-seq), a simple and straightforward homopolymer-sequencing method. In CLT-seq, an anchor-free oligo(dT) primer rapidly binds to and unbinds from anywhere along the poly(A) tail string, leading to position-directed reverse transcription with equal probability. The CLT mechanism enables the synthesized poly(T) lengths, which correspond to the templated segment of the poly(A) tail, to distribute normally. Based on a well-fitted pseudogaussian-derived poly(A)-poly(T) conversion model, the actual poly(A)-tail profile is reconstructed from the acquired poly(T)-length profile through matrix operations. CLT-seq follows a simple procedure without requiring RNA-related pre-treatment, enrichment, or selection, and the CLT-shortened poly(T) stretches are more compatible with existing sequencing platforms. This proof-of-concept approach facilitates direct homopolymer base-calling and features unbiased RNA-seq. Therefore, CLT-seq provides unbiased, robust, and cost-efficient transcriptome-wide poly(A)-tail profiling. We demonstrate that CLT-seq on the most common Illumina platform delivers reliable poly(A)-tail profiling at a transcriptome-wide scale in human cellular contexts. We find that the poly(A)-tail-tuned ncRNA regulation undergoes a dynamic, complex process similar to mRNA regulation. Overall, CLT-seq offers a simplified, effective, and economical approach to investigate poly(A)-tail regulation, with potential implications for understanding gene expression and identifying therapeutic targets.
Correlated somatosensory input in parvalbumin/pyramidal cells in mouse motor cortex
Authors: Goz Roman U. , Hooks Bryan M. 
Published: September 2022

ABSTRACTIn mammalian cortex, feedforward excitatory connections recruit feedforward inhibition. This is often carried by parvalbumin (PV+) interneurons, which may densely connect to local pyramidal (Pyr) neurons. Whether this inhibition affects all local excitatory cells indiscriminately or is targeted to specific subnetworks is unknown. Here, we test how feedforward inhibition is recruited by using 2-channel circuit mapping to excite cortical and thalamic inputs to PV+ interneurons and Pyr neurons in female and male mouse motor cortex. Single Pyr and PV+ neurons receive input from both cortex and thalamus. Connected pairs of PV+ interneurons and excitatory Pyr neurons receive correlated cortical and thalamic inputs. While PV+ interneurons are more likely to form local connections to Pyr neurons, Pyr neurons are much more likely to form reciprocal connections with PV+ interneurons that inhibit them. This suggests that Pyr neurons are embedded in local subnetworks. Excitatory inputs to M1 can thus target inhibitory networks in a specific pattern which permits recruitment of feedforward inhibition to specific subnetworks within the cortical column.SIGNIFICANCE STATEMENTIncoming sensory information to motor cortex (M1) excites neurons to plan and control movements. This input also recruits feedforward inhibition. Whether inhibition indiscriminately suppresses cortical excitation or forms specific subnetworks is unclear. Specific differences in connectivity in circuits promoting different movements might assist in motor control. We show that input to connected pairs of pyramidal (Pyr) excitatory neurons and parvalbumin (PV+) inhibitory interneurons is more strongly correlated than non-connected pairs, suggesting the integration of interneurons into specific cortical subnetworks. Despite sparse connections between these cells, pyramidal neurons are vastly more likely (3x) to excite PV+ cells connected to them. Thus, inhibition integrates into specific circuits in motor cortex, suggesting that separate, specific circuits exist for recruitment of feedforward inhibition.
Two gustatory receptors involved in host plant recognition of silkworm larvae
Authors: Endo Haruka , Tsuneto Kana , Yamagishi Takayuki , Mang Dingze , Ito Katsuhiko , Nagata Shinji , Sato Ryoichi 
Published: September 2022

AbstractHerbivorous insects can identify their host plants by sensing plant secondary metabolites as chemical cues. We previously reported the two-factor host acceptance system of the silkwormBombyx morilarvae. The chemosensory neurons in the maxillary palp (MP) of the larvae detect mulberry secondary metabolites, chlorogenic acid (CGA), and isoquercitrin (ISQ), with ultrahigh sensitivity, for host plant recognition and feeding initiation. Nevertheless, the molecular basis for the ultrasensitive sensing of these compounds remains unknown. In this study, we demonstrated that two gustatory receptors (Grs), BmGr6 and BmGr9, are responsible for sensing the mulberry compounds with attomolar sensitivity for host plant recognition by silkworm larvae. Calcium imaging assay using cultured cells expressing the silkworm putative sugar receptors (BmGr4-10) revealed that BmGr6 and BmGr9 serve as receptors for CGA and ISQ with attomolar sensitivity in human embryonic kidney 293T cells. CRISPR/Cas9-mediated knockout (KO) of BmGr6 and BmGr9 resulted in a low probability of making a test bite of the mulberry leaves, suggesting that they lost the ability to recognize host leaves specifically. Electrophysiological recordings showed that the loss of host recognition ability in the Gr-KO strains was due to a drastic decrease in MP sensitivity toward ISQ in BmGr6-KO larvae and toward CGA and ISQ in BmGr9-KO larvae. Our findings unraveled that the two Grs, which have been regarded as sugar receptors, are molecules responsible for detecting plant phenolics in host plant recognition.
3D in vitro blood-brain-barrier model for investigating barrier insults
Authors: Wei Wei , Cardes Fernando , Hierlemann Andreas , Modena Mario M. 
Published: September 2022

AbstractThe blood-brain-barrier (BBB) prevents that harmful substances in the blood enter the brain, and barrier disruption has been associated with a variety of central-nervous-system diseases. In vitro BBB models enable to recapitulate the BBB behavior in a controlled environment to investigate how the barrier reacts to stress events and external insults. Here, we present a human-cell-based BBB platform with integrated, transparent electrodes to monitor barrier tightness in real time at high spatiotemporal resolution. The BBB model includes human cerebral endothelial cells and primary human pericytes and astrocytes in a three-dimensional arrangement within a pump-free, open microfluidic platform. With our platform, we demonstrate that oxygen-glucose deprivation (OGD), which mimics the characteristics of an ischemic insult, induces a rapid remodeling of the cellular actin structures and subsequent morphological changes in the endothelial cells. High-resolution live imaging showed the formation of large actin stress-fiber bundles in the endothelial layer during OGD application, which ultimately led to cell shrinkage and barrier breakage. Simultaneous electrical measurements showed a rapid decrease of the barrier electrical resistance before the appearance of the stress fibers, which indicates that the barrier function is compromised already before the appearance of drastic morphological changes. The results demonstrate that our BBB platform recapitulates the main barrier functions in vitro and can be used to investigate the rapid reorganization of the BBB upon application of external stimuli.
Miniaturised structured illumination microscopy using two 3-axis MEMS micromirrors
Authors: Tinning Peter , Donnachie Mark , Christopher Jay , Uttamchandani Deepak , Bauer Ralf 
Published: September 2022

AbstractWe present the development and performance characterisation of a novel structured illumination microscope (SIM) in which the grating pattern is generated using two optical beams controlled via 2 micro-electro-mechanical system (MEMS) three-axis scanning micromirrors. The implementation of MEMS micromirrors to accurately and repeatably control angular, radial and phase positioning delivers flexible control of the fluorescence excitation illumination, with achromatic beam delivery through the same optical path, reduced spatial footprint and cost-efficient integration being further benefits. Our SIM architecture enables the direct implementation of multi-colour imaging in a compact and adaptable package. The two-dimensional SIM system approach is enabled by a pair of 2 mm aperture electrostatically actuated three-axis micromirrors having static angular tilt motion along the x- and y- axes and static piston motion along the z-axis. This allows precise angular, radial and phase positioning of two optical beams, generating a fully controllable spatial interference pattern at the focal plane by adjusting the positions of the beam in the back-aperture of a microscope objective. This MEMS-SIM system was applied to fluorescent bead samples and cell specimens, and was able to obtain a variable lateral resolution improvement between 1.3 and 1.8 times the diffraction limited resolution.
Cell-based optimisation and characterisation of genetically encoded, location-based biosensors for Cdc42 or Rac activity
Authors: Mahlandt Eike K. , Kreider-Letterman Gabriel , Chertkova Anna O. , Garcia-Mata Rafael , Goedhart Joachim 
Published: September 2022

AbstractRac and Cdc42 are Rho GTPases which regulate the formation of lamellipoda and filopodia and are therefore crucial in processes such as cell migration. Relocation-based biosensors for Rac and Cdc42 have not been characterized well in terms of their specificity or affinity. In this study, we identify relocation sensor candidates for either Rac or Cdc42. We compared their (i) ability to bind the constitutively active Rho GTPases, (ii) specificity for Rac and Cdc42 and (iii) relocation efficiency in cell-based assays. Subsequently, the relocation efficiency was improved by a multi-domain approach. For Rac1 we found a sensor candidate with low relocation efficiency. For Cdc42 we found several sensors with sufficient relocation efficiency and specificity. These optimized sensors enable the wider application of Rho GTPase relocation sensors, which was showcased by the detection of local endogenous Cdc42 activity at assembling invadopodia. Moreover, we tested several fluorescent proteins and HaloTag for their influence on the recruitment efficiency of the Rho location sensor, to find optimal conditions for a multiplexing experiment. The characterization and optimization of relocation sensors will broaden their application and acceptance.
Exploration of O-GlcNAc-transferase (OGT) glycosylation sites reveals a target sequence compositional bias
Authors: Chong P. Andrew , Nosella Michael , Vanama Manasvi , Ruiz-Arduengo Roxana , Forman-Kay Julie D. 
Published: September 2022

AbstractO-GlcNAc transferase (OGT) is an essential glycosylating enzyme that catalyzes the addition of N-acetylglucosamine to serine or threonine residues of nuclear and cytoplasmic proteins. The enzyme glycosylates a broad range of peptide sequences and prediction of glycosylation sites has proven challenging. The lack of an experimentally verified set of polypeptide sequences that are not glycosylated by OGT has made prediction of legitimate glycosylation sites more difficult. Here, we tested a number of intrinsically disordered protein regions as substrates of OGT to establish a set of sequences that are not glycosylated by OGT. The negative data set suggests an amino acid compositional bias for OGT targets. This compositional bias was validated by modifying the amino acid composition of the protein Fused in sarcoma (FUS) to enhance glycosylation. NMR experiments demonstrate that the tetratricopeptide repeat (TPR) region of OGT can bind FUS and that glycosylation-promoting mutations enhance binding. These results provide evidence that the TPR recognizes disordered segments of substrates with particular compositions to promote glycosylation, providing insight into the broad specificity of OGT.
Identification of a novel family of benzimidazole species-selective Complex I inhibitors as potential anthelmintics
Authors: Davie Taylor , Serrat Xènia , Snider Jamie , Štagljar Igor , Hirano Hiroyuki , Watanabe Nobumoto , Osada Hiroyuki , Fraser Andrew G 
Published: September 2022

AbstractSoil-transmitted helminths (STHs) includingAscaris, hookworm, and whipworm are major human pathogens infecting over a billion people worldwide1,2. There are few existing classes of anthelmintics and resistance is increasing3–5— there is thus an urgent need for new classes of these drugs. Here we focus on identifying compounds that interfere with the unusual anaerobic metabolism that STHs use to survive the highly hypoxic conditions of the host gut6–9. This requires rhodoquinone (RQ), a quinone electron carrier that is not made or used by the STH hosts10. We previously showed thatC. elegansalso uses this rhodoquinone-dependent metabolism (RQDM)11and established a high throughput assay for RQDM11. We screened a collection of 480 natural products for compounds that kill worms specifically when they rely on RQDM — these 480 are representatives of a full library of ~25,000 natural products and derivatives12,13. We identify several classes of compound including a novel family of species selective inhibitors of Complex I. These Complex I inhibitors are based on a benzimidazole core but unlike commercial benzimidazole anthelmintics they do not target microtubules14–17. We screened over 1,200 benzimidazoles and identify the key structural requirements for species selective Complex I inhibition. We suggest that these novel benzimidazole species-selective Complex I inhibitors may be potential anthelmintics.
Optimized fluorescent proteins for 4-color and photoconvertible live-cell imaging in Neurospora crassa
Authors: Wang Ziyan , Bartholomai Bradley M. , Loros Jennifer J. , Dunlap Jay C. 
Published: September 2022

AbstractFungal cells are quite unique among life in their organization and structure, and yet implementation of many tools recently developed for fluorescence imaging in animal systems and yeast has been slow in filamentous fungi. Here we present analysis of properties of fluorescent proteins in Neurospora crassa as well as describing genetic tools for the expression of these proteins that may be useful beyond cell biology applications. The efficacy of ten different fluorescent protein tags were compared in a constant context of genomic and intracellular location; six different promoters are described for the assessment of the fluorescent proteins and varying levels of expression, as well as a customizable bidirectional promoter system. We present an array of fluorescent proteins suitable for use across the visible light spectrum to allow for 4-color imaging, in addition to a photoconvertible fluorescent protein that enables a change in the color of a small subset of proteins in the cell. These tools build on the rich history of cell biology research in filamentous fungi and provide new tools to help expand research capabilities.