Miracle-dz/UniFAR-FTUs huggingface dataset:
The dominant axes of lifetime behavioral variation in honey bees

Insect colonies are decentralized systems that employ task allocation, whereby individuals undertake different roles to fulfil colony needs, such as honey bee “nurses”, “nest workers”, and “foragers”. However, the extent to which individuals can be well-classified by discrete “roles”, how they change behavior from day-to-day, over entire lifetimes, and with environmental conditions, is poorly understood. Using long-term automated tracking of over 4,200 individually-identified bees Apis mellifera, we use behavioral metrics to quantify and compare behavior. We show that individuals exhibit behavioral variation along two dominant axes that represent nest substrate use and movement within the nest. Across lifetimes, we find that individuals differ in foraging onset, and that certain bees exhibit lifelong consistencies in their movement patterns. Furthermore, we examine a period of sudden nectar availability where the honey stores tripled over 6 days, and see that the colony exhibits a distributed shift in activity that did not require a large-scale colony reorganization. Our quantitative approach shows how collective units differ over days and lifetimes, and how sources of variation and variability contribute to the colony’s robust yet flexible response.
Neural Coding of Cognitive Control: The Representational Similarity Analysis Approach

Cognitive control relies on distributed and potentially high-dimensional frontoparietal task representations. Yet, the classical cognitive neuroscience approach in this domain has focused on aggregating and contrasting neural measures - either via univariate or multivariate methods - along highly abstracted, 1D factors (e.g., Stroop congruency). Here, we present representational similarity analysis (RSA) as a complementary approach that can powerfully inform representational components of cognitive control theories. We review several exemplary uses of RSA in this regard. We further show that most classical paradigms, given their factorial structure, can be optimized for RSA with minimal modification. Our aim is to illustrate how RSA can be incorporated into cognitive control investigations to shed new light on old questions.
Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a “dying-back” axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN. HIGHLIGHTS Paclitaxel induces intra-axonal calcium flux Sarm1-dependent cADPR production promotes axonal calcium elevation and degeneration Antagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo
β-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remains challenging. Here, we show that beta-resorcylic acid (β-RA), a natural phenolic compound, competes in vivo with 4-hydroxybenzoic acid, the natural precursor of Coenzyme Q biosynthesis. This leads to a decrease of demethoxyubiquinone, an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, β-RA rescues the phenotype of Coq9R239X mice, a model of primary mitochondrial encephalopathy. Moreover, we observe that long-term treatment with β-RA also reduces the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to a prevention of hepatic steatosis and an increase in survival at the old stage of life. The reduction in WAT content is due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and a stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that β-RA acts through different cellular mechanisms, with effects on mitochondrial metabolism, and it may be used for the treatment of primary Coenzyme Q deficiency, overweight, and hepatic steatosis.
Specific Transcriptomic Signatures and Dual Regulation of Steroidogenesis Between Fetal and Adult Mouse Leydig Cells

Leydig cells (LC) are the main testicular androgen-producing cells. In eutherian mammals, two types of LCs emerge successively during testicular development, fetal Leydig cells (FLCs) and adult Leydig cells (ALCs). Both display significant differences in androgen production and regulation. Using bulk RNA sequencing, we compared the transcriptomes of both LC populations to characterise their specific transcriptional and functional features. Despite similar transcriptomic profiles, a quarter of the genes show significant variations in expression between FLCs and ALCs. Non-transcriptional events, such as alternative splicing was also observed, including a high rate of intron retention in FLCs compared to ALCs. The use of single-cell RNA sequencing data also allowed the identification of nine FLC-specific genes and 50 ALC-specific genes. Expression of the corticotropin-releasing hormone 1 (Crhr1) receptor and the ACTH receptor melanocortin type 2 receptor (Mc2r) specifically in FLCs suggests a dual regulation of steroidogenesis. The androstenedione synthesis by FLCs is stimulated by luteinizing hormone (LH), CRH and ACTH whereas the testosterone synthesis by ALCs is dependent exclusively on LH. Overall, our study provides a useful database to explore LC development and function.
Exploration of Clinical Breakpoint of Danofloxacin for Glaesserella parasuis in Plasma and in PELF

Background To establish the clinical breakpoint (CBP) of danofloxacin to G. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacodynamic cutoff value (COPD) and clinical cutoff value (COCL), was obtained in the present study. Methods The ECV was calculated using ECOFFinder base on MIC distribution of 347 G. parasuis collected from disease pigs. The COPD was established base on in vivo and ex vivo pharmacokinetic (PK) - pharmacodynamic (PD) modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The COCL was established based on the relationship between possibility of cure (POC) and MIC in the clinical trials using “WindoW” approach, nonlinear regression and CART analysis. Results The MIC50 and MIC90 of danofloxacin against 347 G. parasuis were 2 μg/mL and 8 μg/mL, respectively. The ECV value was set up as 8 μg/mL using ECOFFinder. Concentration-time curve of danofloxacin indicated a two-compartment model for PK analysis. The PK parameters of the maximum concentration (Cmax) and area under concentration-time curve (AUC) in PELF were 3.67 ± 0.25 μg/mL and 24.28 ± 2.70 h·μg/mL, higher than those in plasma (0.67 ± 0.01μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (Tmax) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The COPD in plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The COCL calculated by WindoW approach, nonlinear regression and CART analysis were 0.125∼4 μg/mL, 0.428 μg/mL and 0.56 μg/mL, respectively. The 0.5 μg/mL was selected as eligible COCL. The ECV is much higher than the COPD and COCL, and the clinical breakpoint based on data in plasma was large different with that of in PELF. Conclusions Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that epidemiological danofloxacin-resistant G. parasuis may lead to the ineffective treatment by danofloxacin. Importance G. parasuis, a gram-negative respiratory pathogen, can colonize in the upper respiratory tract in swine and cause Glasser’s disease. As the abuse of antibiotics, antimicrobial resistant G. parasuis emerged in different degrees, which brought serious threat to global economy and public health. Danofloxacin in quinolones are one of the best choices for treatment of G. parasuis infection, because of their strong bactericidal activity and good absorption into blood and great distribution in the lung. However, the clinical breakpoint (CBP) for danofloxacin against G. parasuis had not yet been established by clinical laboratory of standard Institute (CLSI) and European Commission of antimicrobial susceptibility testing (EUCAST). Our study firstly established three cutoff values of danofloxacin against G. parasuis. It suggested that epidemiological danofloxacin-resistant G. parasuis may lead to the ineffective treatment by danofloxacin.
Disruption of the surfactant protein A receptor SP-R210L (CD245α/MYO18Aα) alters respiratory function and iron sequestration in alveolar macrophages of aged mice

Previous studies demonstrated that the host defense collectins, surfactant protein A and complement component 1q, modulate tissue-dependent macrophage activation, pathogen clearance, and regulatory macrophage functions through the receptor SP-R210, which consists of two isoforms SP-R210L and SP-R210S. These isoforms are encoded by alternatively spliced mRNAs of the Myo18a MYO18A gene in mice and humans. The present study in conditional transgenic mice revealed novel age-related functions of the SP-R210L isoform in modulating pulmonary mechanics, iron sequestration in alveolar macrophages (AMs), and life-long maintenance of the alveolar macrophage population. Our findings support the novel idea that SP-R210L-deficient AMs undergo bi-directional epigenetic adaptation that results in chronic dysregulation of broncho-alveolar function, immune homeostasis, and maintenance of oncotic balance at the airway-capillary interface. Disruption of SP-R210L increases the risk for development of severe interstitial lung disease during development and aging.
Dynamic reconfiguration of macaque brain networks during free-viewing of natural scenes

Natural vision involves the activation of a wide range of higher-level regions processing objects, motion, faces and actions. Here, we pursue a data-driven approach to explore how higher-level visual processes relate to the underlying structural and functional connectivity. Using a free-viewing paradigm in four awake rhesus macaque monkeys, we investigate how different visual scenes change functional connectivity. Additionally, we explore how such functional connectivity, as measured through fMRI, is related to the structural connectivity, as measured through diffusion weighted imaging. At first, we evaluate the consistency of the elicited free-viewing pattern using standard analytical techniques. We also evaluate the underlying structural connectivity via diffusion data by tracking white matter bundle projections from the visual cortex. We then reconstruct free-viewing and structural networks and quantify their properties. Centrality measures over the entire fMRI time-series revealed a consistent functional network engaged during free-viewing that included widespread hub regions across frontal (FEF, 46v), parietal (LIP, Tpt), and occipitotemporal cortex (MT, V4 and TE) among others. Interestingly, a small number of highly-weighted and long-length inter-hemispheric connections indicated the presence of long-range integrative properties during free-viewing. We hypothesized that during free-viewing, networks had the capacity to change their local and distal connections depending on the on-going changes in visual scenes. To capture these network dynamics, we depart from the static modular architecture of the structural networks and demonstrate that hubs in free-viewing networks reorganize according to the presence of objects, motion, and faces in the movie scenes indicating poly-functional properties. Lastly, we compare each NHP subject network and observe high consistency between individuals across the same network type with closer correspondence between structural networks (e.g., diffusion based and those partially assembled from tract-tracing). In summary, our network analyses revealed ongoing changes in large-scale functional organization present during free-viewing in the macaque monkey and highlight the advantages of multi-contrast imaging in awake monkeys for investigating dynamical processes in visual cognition. To further promote the use of naturalistic free-viewing paradigms and increase the development of macaque neuroimaging resources, we share our datasets in the PRIME-DE consortium.
Rapid diversification of the Australian Amitermes group during late Cenozoic climate change

Late Cenozoic climate change led to the progressive aridification of Australia over the past 15 million years. This gradual biome turnover fundamentally changed Australia’s ecosystems, opening new niches and prompting diversification of plants and animals. One example is the Australian Amitermes Group (AAG), consisting of the Australian Amitermes and affiliated genera. Although it represents the most speciose and diverse higher termite group in Australia, little is known about its evolutionary history. We used ancestral range reconstruction and diversification analyses to illuminate 1) the origin and phylogenetic relationships of the AAG, 2) biogeographical processes leading to the current continent-wide distribution, and 3) timing and pattern of diversification in the context of late Cenozoic climate change. By estimating the first time-calibrated phylogeny, we show that the AAG is a monophyletic group, whose ancestor arrived ~11-10 million years ago from Southeast Asia. Ancestral range reconstruction indicates that Australia’s monsoon region was the launching point for a continental radiation that has been shaped by range expansions and within-area speciation rather than vicariance. We found that multiple arid species diversified from mesic and tropical ancestors in the Plio-Pleistocene, but also observed diversification in the opposite direction. Finally, we show that two pulses of rapid diversification coincided with past climate change during the late Miocene and early Pliocene. Consistent with rapid diversification, species accumulation slowed, likely caused by progressive niche saturation. This study provides a stepping stone for predicting the future response of Australia’s termite fauna in the face of human-mediated climate change.
Genome-scale modeling of Pseudomonas aeruginosa PA14 unveils its broad metabolic capabilities and role of metabolism in drug potentiation

P. aeruginosa is an opportunistic human pathogen that is one of the leading causes of hospital-acquired infections. We have developed an updated genome-scale model (GEM) of Pseudomonas aeruginosa PA14 for systems-study of the pathogen. We used both automated and semi-manual approaches to reconstruct and curate the model. After an extensive literature research, we added organism-specific reactions (e.g., phenazine transport and redox metabolism, cofactor metabolism, carnitine metabolism, oxalate production, etc.) to the model. This effort led to a highly curated, three-compartment, and mass-and-charge balanced BiGG model of PA14 that contains 1509 genes, 1779 metabolic reactions and 1151 unique metabolites. The model (iSD1509) has the largest genome coverage of P. aeruginosa PA14 to date with 424 more genes than the previous model (iPau1129). It is also the most accurate with prediction accuracies as high as 92.4% (for gene essentiality) and 93.5% (for substrate utilization). The model simulates growth in both aerobic and anaerobic conditions. It predicts the biosynthesis of the virulence factor phenazine as a process for the pathogen to grow in low-oxygen environment. Further, a mechanism for the overproduction of a drug susceptibility biomarker (gluconate) can be elucidated by the principles of optimal growth. Finally, the model also simulates drug activity potentiation and protection by fumarate and glyoxylate, respectively, and provides mechanistic explanations for these processes. Overall, iSD1509 can be utilized to decipher the metabolic mechanisms associated with virulence and antibiotic susceptibility of P. aeruginosa PA14 to aid in the development of effective intervention strategies.
A phased genome assembly for allele-specific analysis in Trypanosoma brucei

Many eukaryotic organisms are diploid or even polyploid, i.e. they harbour two or more independent copies of each chromosome. Yet, to date most reference genome assemblies represent a mosaic consensus sequence in which the homologous chromosomes have been collapsed into one sequence. This procedure generates sequence artefacts and impedes analyses of allele-specific mechanisms. Here, we report the allele-specific genome assembly of the diploid unicellular protozoan parasite Trypanosoma brucei. As a first step, we called variants on the allele-collapsed assembly of the T. brucei Lister 427 isolate using short-read error-corrected PacBio reads. We identified 96 thousand heterozygote variants across the genome (average of 4.2 variants / kb), and observed that the variant density along the chromosomes was highly uneven. Several long (>100 kb) regions of loss-of-heterozigosity (LOH) were identified, suggesting recent recombination events between the alleles. By analysing available genomic sequencing data of multiple Lister 427 derived clones, we found that most LOH regions were conserved, except for some that were specific to clones adapted to the insect lifecycle stage. Surprisingly, we also found that some Lister 427 clones were aneuploid. We found evidence of trisomy in chromosome five (chr 5), chr 2, chr 6 and chr 7. Moreover, by analysing RNA-seq data, we showed that the transcript level is proportional to the ploidy, evidencing the lack of a general expression control at the transcript level in T. brucei. As a second step, to generate an allele-specific genome assembly, we used two powerful datatypes for haplotype reconstruction: raw long reads (PacBio) and chromosome conformation (Hi-C) data. With this approach, we were able to assign 99.5% of all heterozygote variants to a specific homologous chromosome, building a 66 Mb long T. brucei Lister 427 allele-specific genome assembly. Hereby, we identified genes with allele-specific premature termination codons and showed that differences in allele-specific expression at the level of transcription and translation can be accurately monitored with the fully phased genome assembly. The obtained reference-grade allele-specific genome assembly of T. brucei will enable the analysis of allele-specific phenomena, as well as the better understanding of recombination and evolutionary processes. Furthermore, it will serve as a standard to ‘benchmark’ much needed automatic genome assembly pipelines for highly heterozygous wild species isolates.
Transcriptome Profiling Reveals CD73 and Age-Driven Changes in Neutrophil Responses against Streptococcus pneumoniae

Neutrophils are required for host resistance against Streptococcus pneumoniae, but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is downregulated in neutrophils (also known as polymorphonuclear leukocytes [PMNs]) from aged mice. ABSTRACT Neutrophils are required for host resistance against Streptococcus pneumoniae, but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is downregulated in neutrophils (also known as polymorphonuclear leukocytes [PMNs]) from aged mice. This study explored transcriptional changes in neutrophils induced by S. pneumoniae to identify pathways controlled by CD73 and dysregulated with age. Pure bone marrow-derived neutrophils isolated from wild-type (WT) young and old and CD73 knockout (CD73KO) young mice were mock challenged or infected with S. pneumoniae ex vivo. RNA sequencing (RNA-Seq) was performed to identify differentially expressed genes (DEGs). We found that infection triggered distinct global transcriptional changes across hosts that were strongest in CD73KO neutrophils. Surprisingly, there were more downregulated than upregulated genes in all groups upon infection. Downregulated DEGs indicated a dampening of immune responses in old and CD73KO hosts. Further analysis revealed that CD73KO neutrophils expressed higher numbers of long noncoding RNAs (lncRNAs) than those in WT controls. Predicted network analysis indicated that CD73KO-specific lncRNAs control several signaling pathways. We found that genes in the c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) pathway were upregulated upon infection in CD73KO mice and in WT old mice, but not in WT young mice. This corresponded to functional differences, as phosphorylation of the downstream AP-1 transcription factor component c-Jun was significantly higher in neutrophils from infected CD73KO mice and old mice. Importantly, inhibition of JNK/AP-1 rescued the ability of these neutrophils to kill S. pneumoniae. Together, our findings revealed that the ability of neutrophils to modify their gene expression to better adapt to bacterial infection is in part regulated by CD73 and declines with age.
A multifaceted role of progranulin in regulating amyloid-beta dynamics and responses

Progranulin deficiency leads to decreased levels of human APP and Aβ in a sex- and age-dependent manner and enhanced inflammatory and lysosomal responses in the plaque-associated microglia. Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN polymorphisms are associated with Alzheimer’s disease. PGRN is highly expressed in the microglia near Aβ plaques and influences plaque dynamics and microglial activation. However, the detailed mechanisms remain elusive. Here we report that PGRN deficiency reduces human APP and Aβ levels in the young male but not female mice. PGRN-deficient microglia exhibit increased expression of markers associated with microglial activation, including CD68, galectin-3, TREM2, and GPNMB, specifically near Aβ plaques. In addition, PGRN loss leads to up-regulation of lysosome proteins and an increase in the nuclear localization of TFE3, a transcription factor involved in lysosome biogenesis. Cultured PGRN-deficient microglia show enhanced nuclear translocation of TFE3 and inflammation in response to Aβ fibril treatment. Taken together, our data revealed a sex- and age-dependent effect of PGRN on APP metabolism and a role of PGRN in regulating lysosomal activities and inflammation in plaque-associated microglia.