bluuebunny/crossref_metadata_2025 huggingface dataset:
Toward an Over-parameterized Direct-Fit Model of Visual Perception
Authors: Li Xin
Published: October 2022

In this paper, we revisit the problem of computational modeling of simple and complex cells for an over-parameterized and direct-fit model of visual perception. Unlike conventional wisdom, we highlight the difference in parallel and sequential binding mechanisms between simple and complex cells. A new proposal for abstracting them into space partitioning and composition is developed as the foundation of our new hierarchical construction. Our construction can be interpreted as a product topology-based generalization of the existing k-d tree, making it suitable for brute-force direct-fit in a high-dimensional space. The constructed model has been applied to several classical experiments in neuroscience and psychology. We provide an anti-sparse coding interpretation of the constructed vision model and show how it leads to a dynamic programming (DP)-like approximate nearest-neighbor search based on 𝓁∞-optimization. We also briefly discuss two possible implementations based on asymmetrical (decoder matters more) auto-encoder and spiking neural networks (SNN), respectively.
Development of Enterovirus anti-viral agents that target the viral 2C protein
Authors: Kejriwal Rishabh , Evans Tristan , Calabrese Joshua , Swistak Lea , Alexandrescu Lauren , Cohen Michelle , Rahman Nahian , Henriksen Niel , Dash Radha Charan , Hadden M. Kyle , Stonehouse Nicola J. , Rowlands David J. , Kingston Natalie J. , Hartnoll Madeline , Dobson Samuel J. , White Simon J.
Published: October 2022

The enterovirus (EV) genus includes a number of important human and animal pathogens. EV-A71, EV-D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide causing a range of upper respiratory, skin, neuromuscular diseases, including acute flaccid myelitis, and hand-foot-and-mouth disease. There are no FDA-approved anti-viral therapeutics for these enteroviruses. In this study, we describe novel broad spectrum anti-viral compounds targeting the conserved non-structural viral protein 2C that have low micro-molar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.
Mucins shed from the laminated layer in cystic echinococcosis are captured by Kupffer cells via the lectin receptor Clec4F
Authors: Barrios Anabella A. , Mouhape Camila , Schreiber Leonard , Zhang Linyun , Nell Juliane , Suárez-Martins Mariana , Schlapp Geraldine , Meikle María Noel , Mulet Ana Paula , Hsu Tsui-Ling , Hsieh Shie-Liang , Mourglia-Ettlin Gustavo , González Carlos , Crispo Martina , Barth Thomas F. E. , Casaravilla Cecilia , Jenkins Stephen J. , Díaz Álvaro
Published: October 2022

Cystic echinococcosis is caused by the larval stages (hydatids) of cestode parasites belonging to the species clusterEchinococcus granulosus sensu lato, withE. granulosus sensu strictobeing the main infecting species. Hydatids are bladder-like structures that attain large sizes within various internal organs of livestock ungulates and humans. Hydatids are protected by the massive acellular laminated layer (LL), composed mainly by mucins. Parasite growth requires LL turnover, and abundant LL-derived particles are found at infection sites in infected humans, raising the question of how LL materials are dealt with by the hosts. In this article, we show thatE. granulosus sensu strictoLL mucins injected into mice are taken up by Kupffer cells, the liver macrophages exposed to the vascular space. This uptake is largely dependent on the intact mucin glycans and on Clec4F, a C-type lectin receptor which in rodents is selectively expressed in Kupffer cells. This uptake mechanism operates on mucins injected both in soluble form i.v. and in particulate form i.p. In mice harbouring intraperitoneal infections by the same species, LL mucins were found essentially only at the infection site and in the liver, where they were taken up by Kupffer cells via Clec4F. Therefore, shed LL materials circulate in the host and Kupffer cells can act as a sink for these materials even when the parasite grows in sites other than the liver.
Escalation of alcohol intake is associated with regionally decreased insular cortex activity but not associated with changes in taste quality
Authors: Mukherjee A , Paladino MS , McSain SL , Gilles-Thomas EA , Lichte DD , Camadine RD , Willock S , Sontate K , Honeycutt SC , Loney GC
Published: October 2022

Background

Intermittent access to ethanol (EtOH) drives persistent escalation of intake and rapid transition from moderate to compulsive-like drinking. Intermittent EtOH drinking may facilitate escalation in part by altering aversion-sensitive neural substrates, such as the insular cortex (IC), thus driving greater approach toward stimuli previously treated as aversive.

Methods

We conducted a series of experiments in rats to examine behavioral and neural responses associated with escalation of EtOH intake. First, taste reactivity analyses quantified the degree that intermittent brief-access ethanol exposure (BAEE) alters sensitivity to the aversive properties of EtOH. Next, we determined whether pharmacological IC inhibition facilitated EtOH escalation. Finally, given that IC is primary gustatory cortex, we employed psychophysical paradigms to assess whether escalation of EtOH intake induced changes in EtOH taste. These paradigms measured changes in sensitivity to the intensity of EtOH taste and whether escalation shifts the salient taste quality of EtOH by measuring the degree that the taste of EtOH generalized to a sucrose-like (‘sweet’) or quinine-like (‘bitter’) percept.

Results

We found a near complete loss of aversive oromotor responses in EtOH-exposed relative to -naïve rats. Additionally, we observed significantly reduced expression of EtOH-induced c-Fosexpression in the posterior IC in exposed rats relative to naïve rats. Inhibition of the IC resulted in a modest, but statistically reliable increase in acceptance of higher EtOH concentrations in naïve rats. Finally, we found no evidence of changes in the psychophysical assessment of the taste of EtOH in exposed, relative to naïve, rats.

Conclusions

Our results demonstrate that neural activity within the IC adapts following escalation of EtOH intake in a manner that correlates with reduced sensitivity to the aversive hedonic properties of EtOH. These data further establish that IC may be driving exposure-induced escalations in EtOH intake and directly contributing to development of compulsive-like EtOH drinking.
Towards Greater Neuroimaging Classification Transparency via the Integration of Explainability Methods and Confidence Estimation Approaches
Authors: Ellis Charles A. , Miller Robyn L. , Calhoun Vince D.
Published: October 2022

The field of neuroimaging has increasingly sought to develop artificial intelligence-based models for neurological and neuropsychiatric disorder automated diagnosis and clinical decision support. However, if these models are to be implemented in a clinical setting, transparency will be vital. Two aspects of transparency are (1) confidence estimation and (2) explainability. Confidence estimation approaches indicate confidence in individual predictions. Explainability methods give insight into the importance of features to model predictions. In this study, we integrate confidence estimation and explainability approaches for the first time. We demonstrate their viability for schizophrenia diagnosis using resting state functional magnetic resonance imaging (rs-fMRI) dynamic functional network connectivity (dFNC) data. We compare two confidence estimation approaches: Monte Carlo dropout (MCD) and MC batch normalization (MCBN). We combine them with two gradient-based explainability approaches, saliency and layer-wise relevance propagation (LRP), and examine their effects upon explanations. We find that MCD often adversely affects model gradients, making it ill-suited for integration with gradient-based explainability methods. In contrast, MCBN does not affect model gradients. Additionally, we find many participant-level differences between regular explanations and the distributions of explanations for combined explainability and confidence estimation approaches. This suggests that a similar confidence estimation approach used in a clinical context with explanations only output for the regular model would likely not yield adequate explanations. We hope that our findings will provide a starting point for the integration of the two fields, provide useful guidance for future studies, and accelerate the development of transparent neuroimaging clinical decision support systems.
Intracellular reactive oxygen species (intraROS)-aided localized cell death contributing to immune responses against wheat powdery mildew pathogen
Authors: Li Yinghui , Roychowdhury Rajib , Govta Liubov , Jaiwar Samidha , Wei Zhen-Zhen , Shams Imad , Fahima Tzion
Published: October 2022

Reactive oxygen species (ROS) and hypersensitive response (HR) mediated cell death have long been known to play critical roles in plant immunity to pathogens. Wheat powdery mildew caused byBlumeria graminisf. sp.tritici(Bgt) is a destructive wheat pathogen. Here, we report a quantitative analysis of the proportion of infected cells with local apoplastic ROS (apoROS) versus intracellular ROS (intraROS) accumulation in various wheat accessions that carry different disease resistance genes (R genes), at a series of time points post-infection. The proportion of apoROS accumulation was 70-80% of the infected wheat cells detected in both compatible and incompatible host-pathogen interactions. However, intensive intraROS accumulation followed by localized cell death responses were detected in 11-15% of the infected wheat cells, mainly in wheat lines that carried nucleotide-binding leucine-rich repeat (NLR) R genes (e.g.Pm3F, Pm41, TdPm60, MIIW72, Pm69). The lines that carry unconventional R genes,Pm24(Wheat Tandem Kinase 3) andpm42(a recessive R gene), showed very less intraROS responses, while 11% ofPm24line infected epidermis cells still showed HR cell death, suggesting that different resistance pathways are activated there. Here, we also demonstrated that ROS could not act as a strong systemic signal for inducing high resistance toBgtin wheat, although it induced the expression of pathogenesis-related (PR)genes. These results provide new insights on the contribution of intraROS and localized cell death to immune responses against wheat powdery mildew.
A single amino acid change drives left- right asymmetry in Bilateria
Authors: Truchado-García Marta , Perry Kimberly J. , Cavodeassi Florencia , Kenny Nathan J. , Henry Jonathan Q. , Grande Cristina
Published: October 2022

Asymmetries are essential for proper organization and function of organ systems. Genetic studies in deuterostomes have shown signaling through the Nodal/Smad2 pathway plays a key, conserved role in the establishment of body asymmetries. While Nodal signaling is required for the establishment of left-right asymmetry (LRA) across bilaterian species, little is known about the regulation of Nodal signaling in spiralians. Here, we identified orthologs of the egf-cfc gene, a master regulator of the Nodal pathway in vertebrates, in several invertebrate species, the first evidence of its presence in non-deuterostomes. Our functional experiments indicate that despite being present, egf-cfc does not play a role in the establishment LRA in gastropods. However, experiments in zebrafish suggest that a single amino acid mutation in the egf-cfc gene in the deuterostome common ancestor was the necessary step in inducing a gain-of-function in LRA regulation. This study shows that that the egf-cfc gene likely appeared in the bilaterian stem lineage, before being adopted as a master mechanism to regulate the Nodal pathway and the establishment of LRA in deuterostomes.
Improving polygenic risk prediction in admixed populations by explicitly modeling ancestral-specific effects via GAUDI
Authors: Sun Quan , Rowland Bryce T. , Chen Jiawen , Mikhaylova Anna V. , Avery Christy , Peters Ulrike , Lundin Jessica , Matise Tara , Buyske Steve , Tao Ran , Mathias Rasika A. , Reiner Alexander P. , Auer Paul L. , Cox Nancy J. , Kooperberg Charles , Thornton Timothy A. , Raffield Laura M. , Li Yun
Published: October 2022

Polygenic risk scores (PRS) have shown successes in clinics, but most PRS methods have focused only on individuals with one primary continental ancestry, thus poorly accommodating recently-admixed individuals. Here, we develop GAUDI, a novel penalized-regression-based method specifically designed for admixed individuals by explicitly modeling ancestry-specific effects and jointly estimating ancestry-shared effects. We demonstrate marked advantages of GAUDI over other methods through comprehensive simulation and real data analyses.
Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect
Authors: Faulkner Geoffrey J.
Published: October 2022

A recent study (Takahashi et al., Neuron, 2022) concluded LINE-1 (L1) retrotransposon activation drives cerebellar ataxia and neurodegeneration. This position was based on L1 upregulation in ataxia telangiectasia (AT) patient cerebellum samples, as measured by RNA-seq, and observation of ataxia and neurodegeneration in mice where cerebellar L1 expression was induced via dCas9-CRISPR. Here, a re-analysis of the RNA-seq data, which were obtained by rRNA depletion rather than polyA+ selection, revealed a high fraction (38.4%) of intronic reads. Significantly (p=0.034) more intronic reads were present in the AT data than the matched controls. This finding provides an alternative and robust explanation for a key result reported by Takahashi et al.: intronic L1 sequences are abundant in pre-mRNAs, and more pre-mRNAs were retained in the AT libraries. This apparent batch effect deserves further examination, as claims of L1-mediated pathogenesis could shape future efforts to treat AT by trying to attenuate L1 activity.
Early cellular mechanism of type I interferon-driven susceptibility to tuberculosis
Authors: Kotov Dmitri I. , Lee Ophelia V. , Fattinger Stefan A. , Langner Charlotte , Guillen Jaresley V. , Peters Joshua M. , Moon Andres , Burd Eileen M. , Witt Kristen C. , Stetson Daniel B. , Jaye David L. , Bryson Bryan D. , Vance Russell E.
Published: October 2022

Mycobacterium tuberculosis(Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN duringMtbinfection in mice and non-human primates, and pDCs localize near humanMtbgranulomas. Depletion of pDCs reducesMtbburdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) known to activate pDCs. Cell type-specific disruption of the type I IFN receptor suggests IFNs act on IMs to inhibitMtbcontrol. Single cell RNA-seq indicates type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical forMtbcontrol. We propose pDC-derived type I IFNs act on IMs to drive bacterial replication, further neutrophil recruitment, and active tuberculosis disease.
Dopamine signaling regulates predator-driven changes inCaenorhabditis elegans’egg laying behavior
Authors: Pribadi Amy , Rieger Michael A. , Rosales Kaila , Reddy Kirthi C. , Chalasani Sreekanth H.
Published: October 2022

Prey respond to predators by altering their behavior to optimize their own fitness and survival. Specifically, prey are known to avoid predator-occupied territories to reduce their risk of harm or injury to themselves and their progeny. We probe the interactions betweenCaenorhabditis elegansand its naturally cohabiting predatorPristionchus uniformisto reveal the pathways driving changes in prey behavior. WhileC. elegansprefers to lay its eggs on a bacteria food lawn, the presence of a predator inside a lawn inducesC. elegansto lays more eggs away from that lawn. We confirm that this change in egg laying is in response to bites from predators, rather than to predatory secretions. Moreover, predator-exposed prey continue to lay their eggs away from the dense lawn even after the predator is removed, indicating a form of learning. Next, we find that mutants in dopamine synthesis significantly reduce egg laying behavior off the lawn in both predator-free and predator-inhabited lawns, which we can rescue by transgenic complementation or supplementation with exogenous dopamine. Moreover, we find that dopamine is likely released from multiple dopaminergic neurons and requires combinations of both D1-(DOP-1), and D2-like (DOP-2 and DOP-3) dopamine receptors to alter predator-induced egg laying behavior, whereas other combinations modify baseline levels of egg laying behavior. Together, we show that dopamine signaling can alter both predator-free and predator-induced foraging strategies, implying a role for this pathway in defensive behaviors.
Novel triplex nucleic acid lateral flow immuno-assay (NALFIA) for rapid detection of Nipah virus, Middle East respiratory syndrome coronavirus and Reston ebolavirus
Authors: Chingtham Santhalembi , Kulkarni Diwakar D , Sumi TS , Mishra Anamika , Pateriya Atul K , Singh Vijendra Pal , Raut Ashwin Ashok
Published: October 2022

We report the development of the first triplex Nucleic Acid Lateral Flow Assay (NALFIA) for detection of genomes of Nipah virus (NiV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Reston ebolavirus (REBOV), intended for screening of bats as well as other hosts and reservoirs of these three viruses. Our triplex NALFIA is a two-step assay format wherein the target nucleic acid in sample is first amplified using tagged primers, and the tagged ds DNA amplicons are captured by immobilized antibodies on NALFIA device resulting to signal development from binding of streptavidin-colloidal gold conjugate to biotin tag on the captured amplicons. Triplex amplification of N gene of NiV, UpE gene of MERS-CoV, and Vp40 gene of REBOV was optimized using primers adapted from validated real-time RT-PCR assays of previous studies and the compatible combinations of hapten-labels and antibodies for triplex NALFIA device were identified. Digoxigenin, rhodamine red and alexa fluor 488 were identified as suitable 5’ labels on forward primers. The lowest copy number detected by the triplex NALFIA with 2 μl of triplex RT-PCR product were up to 8.21e4 for NiV N target, 7.09e1 for MERS-CoV UpE target, and 1.83e4 for REBOV Vp40 target. Using simulated samples and Taqman real-time RT-PCR as standard, the sensitivity and positive predictive values were found to be 100% for MERS-CoV UpE and REBOV Vp40 targets and 91% for NiV N target while the specificity and negative predictive values were 100% for MERS-CoV UpE targets and REBOV Vp40, and 93.3% for NiV N target.
Commitment in the PINK1/Parkin mitophagy decision circuit
Authors: Waters Christopher S. , Angenent Sigurd B. , Altschuler Steven J. , Wu Lani F.
Published: October 2022

Mechanisms that prevent accidental degradation of healthy mitochondria by the PINK1/Parkin mitophagy pathway are poorly understood. On the surface of damaged mitochondria, PINK1 accumulates and acts as the input signal to a positive feedback loop of Parkin recruitment, which in turn promotes mitochondrial degradation via mitophagy. However, PINK1 is also present on healthy mitochondria where it could errantly recruit Parkin and thereby activate this positive feedback loop. Here, we quantitatively mapped the relationship between PINK1 input levels and Parkin recruitment dynamics using live-cell microscopy and mathematical modeling. We found that Parkin is recruited to the mitochondria only if PINK1 levels exceed a threshold and only after a delay that is inversely proportional to PINK1 levels. The threshold and delay provide a “two-factor authentication” step for PINK1/Parkin activation. These properties arise from the PINK1/Parkin circuit topology and provide a mechanism for cells to assess damage signals before committing to mitophagy.
Chemoproteomics-guided development of SLC15A4 inhibitors with anti-inflammatory activity
Authors: Lazar Daniel C. , Wang Wesley W. , Chiu Tzu-Yuan , Li Weichao , Jadhav Appaso M. , Wozniak Jacob M. , Gazaniga Nathalia , Theofilopoulos Argyrios N. , Teijaro John R. , Parker Christopher G.
Published: October 2022

SLC15A4 is an endolysosome-resident transporter that is intimately linked with autoinflammation and autoimmunity. Specifically, SLC15A4 is critical for Toll-like receptor (TLR) 7, 8, and 9 as well as the nucleotide-binding oligomerization domain-containing protein (NOD) 2 signaling in several immune cell subsets. Notably, SLC15A4 is essential for the development of systemic lupus erythematosus in murine models and is associated with autoimmune conditions in humans. Despite its therapeutic potential, to our knowledge no pharmacological tools have been developed that target SLC15A4. Here, we use an integrated chemical proteomics approach to develop a suite of chemical tools, including first-in-class functional inhibitors, for SLC15A4. We demonstrate SLC15A4 inhibitors suppress endosomal TLR and NOD functions in a variety of human and mouse immune cells and provide early evidence of their ability to suppress inflammation in vivo and in clinical settings. Our findings establish SLC15A4 as a druggable target for the treatment of autoimmune/autoinflammatory conditions.

One-Sentence Summary

Discovery and characterization of SLC15A4 inhibitors with anti-inflammatory activity.
Lifespan Extension in Female Mice By Early, Transient Exposure to Adult Female Olfactory Cues
Authors: Garratt Michael , Erturk Ilkim , Alonzo Roxann , Zufall Frank , Leinders-Zufall Trese , Pletcher Scott D. , Miller Richard A.
Published: October 2022

Several previous lines of research have suggested, indirectly, that mouse lifespan is particularly susceptible to endocrine or nutritional signals in the first few weeks of life, as tested by manipulations of litter size, growth hormone levels, or mutations with effects specifically on early-life growth rate. The pace of early development in mice can also be influenced by exposure of nursing and weanling mice to olfactory cues. In particular, odors of same-sex adult mice can in some circumstances delay maturation. We hypothesized that olfactory information might also have a sex-specific effect on lifespan, and we show here that lifespan of female mice can be increased significantly by odors from adult females administered transiently, i.e. from 3 days until 60 days of age. Female lifespan was not modified by male odors, nor was male lifespan susceptible to odors from adults of either sex. Conditional deletion of the G protein Gαo in the olfactory system, which leads to impaired accessory olfactory system function and blunted reproductive priming responses to male odors in females, did not modify the effect of female odors on female lifespan. Our data provide support for the idea that very young mice are susceptible to influences that can have long-lasting effects on disease resistance, and provide the first example of lifespan extension by olfactory cues in mice.
Low-cost and highly efficient: A method for high-quality nucleic acid isolation from cotton fibres
Authors: Ahmed Mukhtar , Sarwar Muhammad Bilal , Ashfaq Ramla , Ahmed Adnan , Yanang X. , Fanglu M. , Salah-ud-Din  , Sajid Muhammad , Syed Quratulain , Abidi Syed Hussain , Wang Xuede
Published: October 2022

Gene expression analyses to study the development of cotton fibers require high-quality nucleic acid. The conventional methods of nucleic acid extraction results in sub-quality nucleic acids with low yields. Young fibers are rich in polyphenols and sugars that react with nucleic acid to form phenols and insoluble substances. Furthermore, mature fibers contain more than 95% cellulose, hindering the nucleic acid isolation. Cytoplasm collapse and cellulose deposition also result in a very low yield of nucleic acid. Three different methods of RNA isolation from different cotton tissues were compared in this study to determine the best and most efficient one. The integrity and quality of RNA were analyzed using UV spectrum, agarose gel electrophoresis, RIN values, PCR, and Northern blot hybridization. RNA of functional quality was observed when using the high ion and pH method, with an A260/A280 ratio up to 1.87 and an average yield of 0.68 mg g-1 from fiber cells. From leaves, we found an A260/A280 ratio of 2.02 and an average yield of 6.35 mg g-1, which is suitable for molecular biology experiments. The extraction buffer with a high ion density and pH value include Tris-HCl, LiCl, EDTA, SDS, sodium deoxycholate, Nonident P-40, mercaptoethanol, and PVP. The addition of sodium deoxycholate and Nonider-40 (NP-40) enhances the density of other salt compounds and elevates the pH value. The results depicted that the high ion and pH method is a simple and effective way to extract a copious amount of high-quality RNA from polysaccharide-rich tissues. This method is also suitable for the extraction of cotton genomic DNA with high purity. Genomic DNA extracted from cotton using this method showed an A260/A230 ratio up to 2.09 and a yield of 1.44 mg g-1. This method is useful for isolating DNA and RNA from cotton fibers and produces high yields and quality at a comparatively low cost.
Integrative Multi-Omics Approaches for Identifying Cervical Cancer Therapeutic Targets
Authors: Duppala Santosh Kumari , Yadala Rajesh , Velingkar Aayushi , Suravajhala Prashanth , Pawar Smita C , Vuree Sugunakar
Published: October 2022

After breast cancer, cervical cancer (CC) is one of the most common malignancies in women globally. Over 90% of chronic infections are caused by human papillomavirus (HPV) and its subtypes. Extensive research efforts are required to identify the treatment targets and prognostic indicators for recurring and metastatic cancers. It may be possible because of omics methods, including genomes, epigenomics, transcriptomics, proteomics, and metabolomics. High throughput (HT) data on the differential mRNA and miRNA expression and their crucial interrelationships enable promising integration and interpretation of the results. Clinical data and multi-omics have risen to the top of the heap in delivering molecular and cellular activities. They aid in comparing data from different omics approaches and bridging the gap between genotype and phenotype. Therefore, multi-omic techniques may improve the knowledge of the molecular basis of the physiology and primary cause of disease, revealing a new route for the prognosis, diagnosis, prevention, and therapy of human diseases.
BioDiscViz : a visualization support and consensus signature selector for BioDiscML results
Authors: Bouirdene Sophiane , Leclercq Mickael , Quitté Léopold , Bilodeau Steve , Droit Arnaud
Published: October 2022

Machine learning (ML) algorithms are powerful tools to find complex patterns and biomarker signatures where conventional statistical methods may fail to identify them. While the ML field made significant progress, state of the art methodologies to build efficient and non-overfitting models are not always applied in the litterature. To this purpose, automatic programs, such as BioDiscML, have been designed to identify biomarker signatures and correlated features while escaping overfitting using multiple evaluation strategies, such as cross validation, bootstrapping and repeated holdout. To further improve BioDiscML and reach a broader audience, better visualization support and flexibility in choosing the best models and signatures are needed. Thus, to provide researchers with an easily accessible and usable tool for in depth investigation of the results from BioDiscML outputs, we developed a visual interaction tool called BioDiscViz. This tool provides summaries, tables and graphics, in the form of Principal Component Analysis (PCA) plots, heatmaps and boxplots for the best model and the correlated features. Furthermore, this tool also provides visual support to extract a consensus signature from BioDiscML models using a combination of filters. BioDiscViz will be a great visual support for research implying machine learning, hence new opportunities in this field by opening it to a broader community.
Communication between the nucleus and the mitochondria via NDUFS4 alternative splicing in gastric cancer cells
Authors: Papadaki V. , Erpapazoglou Z. , Kokkori M. , Rogalska M. , Tsakiri E. , Akhtorab H. , Smoot D. T. , Papanikolopoulou K. , Samiotaki M. , Kafasla P.
Published: October 2022

A constant communication between the nucleus and the mitochondria allows both organelles to ensure cellular homeostasis and adaptation to mitochondrial stress. Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving a large number of nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein that regulates AS of distinct subsets of genes in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic analyses and RNA-seq profiles of IQGAP1KO and parental cells show that IQGAP1KO alters a specific AS event of the mitochondrial respiratory chain complex I subunit NDUFS4 and downregulates a subset of complex I subunits. In IQGAP1KO cells, respiratory complex I intermediates accumulate resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial complex I activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 partially restores NDUFS4 AS pattern and expression and reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of complex I activity through AS regulation.
Rattractor - Instant guidance of a rat into a virtual cage using a deep brain stimulation
Authors: Sudo Naoki , Fujiwara Sei-etsu , Isoyama Takashi , Fukayama Osamu
Published: October 2022

We developed “Rattractor” (rat attractor), a system to apply electrical stimuli to the deep brain of a rat as it stays in a specified region or a virtual cage to demonstrate an instant electrophysiological feedback controller for animals.

Two wire electrodes were implanted in the brains of nine rats. The electrodes targeted the medial forebrain bundle (MFB), which is a part of the reward system in the deep brain. Following the recovery period, the rats were placed in a plain field where they could move freely, but wired to a stimulation circuit. An image sensor installed over the field detected the subject’s position, which triggered the stimulator such that the rat remained within the virtual cage. We conducted a behavioral experiment to evaluate the sojourn ratio of rats residing in the region. Thereafter, a histological analysis of the rat brain was performed to confirm the position of the stimulation sites in the brain.

Seven rats survived the surgery and the recovery period without technical failures such as connector breaks. We observed that three of them tended to stay in the virtual cage during stimulation, and this effect was maintained for two weeks. Histological analysis revealed that the electrode tips were correctly placed in the MFB region of the rats. The other four subjects showed no apparent preference for the virtual cage. In these rats, we did not find electrode tips in the MFB, or could not determine their positions.

Almost half of the rats tended to remain inside the virtual cage when position-related reward stimuli were triggered in the MFB region. Notably, our system did not require previous training or sequential interventions to affect the behavioral preferences of subjects. This process is similar to the situation in which sheep are chased by a shepherd dog in the desired direction.
In vivocalcium imaging shows that satellite glial cells have increased activity in painful states
Authors: Jager Sara E. , Goodwin George , Chisholm Kim I. , Denk Franziska
Published: October 2022

Satellite glial cells (SGCs) are important for proper neuronal function of primary sensory neurons to whom they provide homeostatic support. Most research of SGC function has been performed within vitrostudies, but recent advances in calcium imaging and transgenic mouse models have enabled this firstin vivostudy of single cell SGC function in mouse models of inflammation and neuropathic pain.

We found that in naïve condition SGCs do not respond in a time-locked fashion to neuronal firing. In painful inflammatory and neuropathic states we detected time-locked signals in a subset of SGCs, but only with suprathreshold stimulation of the sciatic nerve. Surprisingly therefore, we conclude that most calcium signals in SGCs seem to develop at arbitrary intervals not directly linked to neuronal activity patterns.

More in line with expectations, our experiments also revealed that the number of active SGCs was increased under conditions of inflammation or nerve injury. This could reflect the increased requirement for homeostatic support across dorsal root ganglion neuron populations, which are more active during such painful states.
Spatiotemporal orchestration of multicellular transcriptional programs and communications in the early stage of spinal cord injury
Authors: Wang Zeqing , Li Zhuxia , Luan Tianle , Cui Guizhong , Shu Shunpan , Liang Yiyao , Xiao Jingshu , Zhang Kai , Yu Wei , Cui Jihong , Li Ang , Peng Guangdun , Fang Yanshan
Published: October 2022

While spinal cord injury (SCI) involves a complex cascade of cellular and pathological changes that last for months to years, the most dramatic and comprehensive molecular rewiring and multicellular re-organization occur in the first few days, which determine the overall progression and prognosis of SCI, yet remain poorly understood. Here, we resolved the spatiotemporal architecture of multicellular gene expression in a mouse model of acute SCI, and revealed the coordinated gene co-expression networks, the upstream regulatory programs, andin situcell-cell interactions that underlay the anatomic disorganization as well as the immune and inflammatory responses conferring the secondary injury. The spatial transcriptomic analysis highlights that the genes and cell types in the white matter (WM) play a more active and predominant role in the early stage of SCI. In particular, we identified a distinct population of WM-originated,Igfbp2-expressing reactive astrocytes, which migrated to the grey matter and expressed multiple axon/synapse-supporting molecules that may foster neuron survival and spinal cord recovery in the acute phase. Together, our dataset and analyses not only showcase the spatially-defined molecular features endowing the cell (sub)types with new biological significance but also provide a molecular atlas for disentangling the spatiotemporal organization of the mammalian SCI and advancing the injury management.
Development of serum substitute medium for bone tissue engineering
Authors: Ansari Sana , Ito Keita , Hofmann Sandra
Published: October 2022

In tissue engineering, cells are grown often on scaffolds and subjected to chemical/mechanical stimuli. Most such cultures still use fetal bovine serum (FBS) despite its known disadvantages including ethical concerns, safety issues, and variability in composition, which greatly influences the experimental outcomes. To overcome the disadvantages of using FBS, chemically defined serum substitute medium needs to be developed. Development of such medium depends on cell type and application - which makes it impossible to define one universal serum substitute medium for all cells in any application. Here, we developed a serum substitute medium for bone tissue engineering (BTE) in a step-by-step process. Essential components were added to the medium while human bone marrow mesenchymal stromal cells (hBMSCs, osteoblast progenitor cells) were cultured in two-dimensional (2D) and three-dimensional (3D) substrates. In a 3-week culture, the developed serum substitute medium worked equally well as FBS containing medium in term of cell attachment to the substrate, cell survival, osteoblast differentiation, and deposition of extracellular matrix. In the next step, the use of serum substitute medium was evaluated when culturing cells under mechanical loading in the form of shear stress. The outcomes showed that the application of shear stress is essential to improve extracellular matrix formation while using serum substitute medium. The developed serum substitute medium could pave the way in replacing FBS for BTE studies eliminating the use of controversial FBS and providing a better-defined chemical environment for BTE studies.

Graphical abstract
Characterizing the Morphology of Costa Rican Stingless Bees to Parameterize the InVEST Crop Pollination Model
Authors: Sun Christopher , Chaplin-Kramer Rebecca
Published: October 2022

The InVEST Crop Pollination model operates on land use and land cover (LULC) characteristics, using available nesting sites and floral resources within a specified flight range to gauge the abundance and yield of bees species. In this study, we parameterize the InVEST Crop Pollination model to validate predictions of relative pollinator abundance in Costa Rica. Flight ranges of bee species are required as model inputs, yet are not readily available in literature compared to morphological attributes such as body length. To harness the availability of morphological data, we express the flight range of any given species as a function of its morphological attributes through a series of regressions, allowing for the estimation of flight ranges of species for which this metric is unknown. After proper parameterization, the model-predicted relative pollinator abundances of three species—Tetragonisca angustula, Partamona orizabaensis, and Trigona corvina—are compared against field data. A single proto-pollinator is then constructed as a representative species for analysis at a broader level, with model predictions validated against the total pollinator abundance across the entire spatial distribution represented by the field data. The model performs with a higher accuracy on the proto-pollinator compared to the individual species, revealing that there is surprisingly minimal added value from estimating individual flight ranges for each species. Rather, generalizing the biodiverse assortment of Costa Rican bees may yield better approximations for relative pollinator abundance.
Circadian modulation by time-restricted feeding restores brain transcription and slows amyloid deposition in a mouse model of Alzheimer’s disease
Authors: Whittaker Daniel S. , Akhmetova Laila , Romero Haylie , Welsh David K. , Colwell Christopher S. , Desplats Paula
Published: October 2022

Alzheimer’s disease (AD) is a tragic neurodegenerative disease affecting more than 5 million Americans. Circadian disruptions impact nearly all AD patients, with reversal of sleep/wake cycles and agitation in the evening being common disturbances that manifest early in disease. These alterations support a role for circadian dysfunction as a driver of AD, emphasizing a critical need to investigate the therapeutic potential of circadian-modulating interventions. One of the most powerful regulators of the circadian system is the daily feed/fast cycle. Here we show that time-restricted feeding (TRF) without caloric restriction, improved key disease components including behavior, disease pathology and transcription in the APP23 mouse model of Alzheimer’s disease. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and hyperactivity, and normalizing transcription of circadian, AD and neuroinflammation-associated genes in APP23 mice. Thus, our study unveils for the first time that circadian modulation through timed feeding has far-reaching effects beyond metabolism and affects the brain as the substrate for neurodegeneration. Since the pleiotropic effects of TRF can substantially modify disease trajectory, this intervention has immediate translational value, addressing the crucial need for accessible approaches to reduce or halt AD progression.
Anticancer drug doxorubicin spontaneously reacts with GTP and dGTP
Authors: Mejia German , Su Linjia , Pandey Popular , Dit Fouque Kevin Jeanne , McGoron Anthony , Fernandez-Lima Francisco , He Jin , Mebel Alex , Leng Fenfei
Published: October 2022

Here we reported a spontaneous reaction between anticancer drug doxorubicin and GTP or dGTP. Incubation of doxorubicin with GTP or dGTP at 37 °C or above yields a covalent product: the doxorubicin-GTP or -dGTP conjugate where a covalent bond is formed between the C14 position of doxorubicin and the 2-amino group of guanine. Density functional theory calculations show the feasibility of this spontaneous reaction. Fluorescence imaging studies demonstrate that the doxorubicin-GTP and -dGTP conjugates cannot enter nuclei although they rapidly accumulate in human SK-OV-3 and NCI/ADR-RES cells. Consequently, the doxorubicin-GTP and -dGTP conjugates are less cytotoxic than doxorubicin. We also demonstrate that doxorubicin binds to ATP, GTP, and other nucleotides with a dissociation constant (Kd) in the sub-millimolar range. Since human cells contain millimolar levels of ATP and GTP, these results suggest that doxorubicin may target ATP and GTP, energy molecules that support essential processes in living organisms.
Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions
Authors: Goral R. Oliver , Harper Kathryn M. , Bernstein Briana J. , Fry Sydney A. , Lamb Patricia W. , Moy Sheryl S. , Cushman Jesse D. , Yakel Jerrel L.
Published: October 2022

Altered signaling or function of acetylcholine (ACh) has been reported in various neurological diseases, including Alzheimer’s disease, Tourette syndrome, epilepsy among others. Many neurons that release ACh also co-transmit the neurotransmitter gamma-aminobutyrate (GABA) at synapses in the hippocampus, striatum, and medial prefrontal cortex (mPFC). Although ACh transmission is crucial for higher brain functions such as learning and memory, the role of co-transmitted GABA from ACh neurons in brain function remains unknown. Thus, the overarching goal of this study was to investigate how a systemic loss of GABA co-transmission from ACh neurons affected the behavioral performance of mice. To do this, we used a conditional knock-out mouse of the vesicular GABA transporter (vGAT) crossed with the ChAT-Cre driver line to selectively ablate GABA co-transmission at ACh synapses. In a comprehensive series of standardized behavioral assays, we compared Cre-negative control mice with Cre-positive vGAT knock-out mice of both sexes. Loss of GABA co-transmission from ACh neurons did not disrupt the animal’s sociability, motor skills or sensation. However, in the absence of GABA co-transmission, we found significant alterations in social, spatial and fear memory as well as a reduced reliance on striatum-dependent response strategies in a T-maze. In addition, male CKO mice showed increased locomotion. Taken together, the loss of GABA co-transmission leads to deficits in higher brain functions and behaviors. Therefore, we propose that ACh/GABA co-transmission modulates neural circuitry involved in the affected behaviors.
Scratch-AID: A Deep-learning Based System for Automatic Detection of Mouse Scratching Behavior with High Accuracy
Authors: Yu Huasheng , Xiong Jingwei , Ye Adam Yongxin , Cranfill Suna Li , Cannonier Tariq , Gautam Mayank , Zhang Marina , Bilal Rayan , Park Jong-Eun , Xue Yuji , Polam Vidhur , Vujovic Zora , Dai Daniel , Ong William , Ip Jasper , Hsieh Amanda , Mimouni Nour , Lozada Alejandra , Sosale Medhini , Ahn Alex , Ma Minghong , Ding Long , Arsuaga Javier , Luo Wenqin
Published: October 2022

Mice are the most commonly used model animals for itch research and for development of antiitch drugs. Most labs manually quantify mouse scratching behavior to assess itch intensity. This process is labor-intensive and limits large-scale genetic or drug screenings. In this study, we developed a new system, Scratch-AID (Automatic Itch Detection), which could automatically identify and quantify mouse scratching behavior with high accuracy. Our system included a custom-designed videotaping box to ensure high-quality and replicable mouse behavior recording and a convolutional recurrent neural network (CRNN) trained with frame-labeled mouse scratching behavior videos, induced by nape injection of chloroquine (CQ). The best trained network achieved 97.6% recall and 96.9% precision on previously unseen test videos. Remarkably, Scratch-AID could reliably identify scratching behavior in other major mouse itch models, including the acute cheek model, the histaminergic model, and a chronic itch model. Moreover, our system detected significant differences in scratching behavior between control and mice treated with an anti-itch drug. Taken together, we have established a novel deep learning-based system that is ready to replace manual quantification for mouse scratching behavior in different itch models and for drug screening.
Activity of tonically active neurons in the primate striatum reflects interaction between time processing and reward prediction
Authors: Martel A.-C , Apicella P.
Published: October 2022

The striatum and its dopaminergic input participate in temporal processing and numerous studies provide evidence that interactions between dopamine and acetylcholine are critical for striatal functioning. However, the role of local cholinergic innervation of the striatum in behaviors requiring precise timing has not been specifically investigated. Here, we recorded from presumed striatal cholinergic interneurons, identified as tonically active neurons (TANs), in two male rhesus monkeys performing self-initiated movements after specified learned time intervals have elapsed since a visual cue. We found that 38% of all recorded TANs responded to the cue with a pause in firing and the strength of these responses could be modulated according to the duration of the interval being timed and the accuracy of time estimates. By examining the TAN response to the reward itself and by recording from TANs during a Pavlovian procedure in which no action was required, we found evidence that TAN activity modulation may potentially reflect differences in the animal’s prediction of reward. Thus, besides their well-known role in predicting and detecting rewarding events, TANs may generate signals related to the processing of time. Our findings suggest a role of the local cholinergic circuitry in the representation of time within the striatum.