title: MDA-LDL vaccination induces athero-protective germinal center-derived antibody responses

abstract: Atherosclerosis is a chronic inflammatory disease of the arteries that can lead to thrombosis, infarction and stroke and is the leading cause of mortality worldwide. Immunization of pro-atherogenic mice with malondialdehyde-modified low-density lipoprotein (MDA-LDL) neo-antigen is athero-protective. However, the immune response to MDA-LDL and the mechanisms responsible for this athero-protection are not completely understood. Here, we find that immunization of mice with MDA-LDL elicits memory B cells, plasma cells, and switched anti-MDA-LDL antibodies as well as clonal expansion and affinity maturation, indicating that MDA-LDL triggers a bona fide germinal center antibody response. Further, Prdm1fl/fl Aicda-Cre+/ki Ldlr-/- pro-atherogenic chimeras, which lack germinal center-derived plasma cells, show accelerated atherosclerosis. Finally, we show that MDA-LDL immunization is not athero-protective in mice lacking germinal-center derived plasma cells. Our findings give further support to the development of MDA-LDL-based vaccines for the prevention or treatment of atherosclerosis.


title: Antigen experience relaxes the organisational structure of the T cell receptor repertoire

abstract: The creation and evolution of the T cell receptor repertoire within an individual combines stochastic and deterministic processes. We systematically examine the structure of the repertoire in different T cell subsets in young, adult and LCMV infected mice, from the perspective of variable gene usage, nucleotide sequences and amino acid motifs. Young individuals share a high level of organization, especially in the frequency distribution of variable genes and amino acid motifs. In adult mice, this structure relaxes and is replaced by idiotypic evolution of the effector and regulatory repertoire. The repertoire of CD4+ regulatory T cells was more similar to naive cells in young mice, but became more similar to effectors with age. Finally, we observed a dramatic restructuring of the repertoire following infection with LCMV. We hypothesize that the stochastic process of recombination and thymic selection initially impose a strong structure to the repertoire, which gradually relaxes following asynchronous responses to different antigens during life.

category: immunology


title: Limited adaptive evolution of Staphylococcus aureus during transition from colonization to invasive infection

abstract:
Staphylococcus aureus carriage is a risk factor for invasive infections. Unique genetic elements favoring the transition from colonizing to invasive phenotype have not yet been identified and phenotypic traits are understudied. We therefore assessed pheno- and genotypic profiles of eleven S. aureus isolate pairs sampled from colonized patients simultaneously suffering from invasive S. aureus infections. Ten out of 11 isolate pairs presented the same spa and MLST suggesting colonization as origin for the invasive infection. Systematic analysis of colonizing and invasive isolate pairs showed similar adherence, hemolysis and reproductive fitness properties, minimal genetic differences, identical antibiotic tolerance and bacterial virulence in Galleria mellonella. Our results provide insights into the similar phenotype associated with limited adaptive genetic evolution between the colonizing and invasive isolates. Disruption of the physical barriers mucosa or skin were identified in the majority of patients further emphasizing colonization as a major risk factor for invasive disease.

ImportanceS. aureus is a major pathogen of humans causing a wide range of disease. The failure to develop a vaccine and antibiotic warrant the exploration of novel treatment strategies. Asymptomatic colonization of the human nasal passages is a major risk factor for invasive disease and decolonization procedures have shown efficacy in preventing invasive infections. However, the transition of S. aureus from a benign colonizer of the nasal passages to a major pathogen is not well understood and host as well as bacterial properties have been discussed as being relevant for this behavioral change. We conducted a thorough investigation of patient-derived strain pairs reflecting colonizing and invasive isolates in a given patient. Although we identified limited genetic adaptation in certain strains as well as slight differences in adherence capacity of colonizing and invasive isolates, our work suggests that barrier breaches are a key event in the disease continuum of S. aureus.

category: microbiology


title: Temporal cell fate determination in the spinal cord is mediated by the duration of Notch signalling

abstract: During neural development, progenitor cells generate different types of neurons in specific time windows. Despite the characterisation of many of the transcription factor networks involved in these differentiation events, the mechanism behind their temporal regulation is poorly understood. To address this question, we studied the temporal differentiation of the simple lateral floor plate (LFP) domain in the zebrafish spinal cord. LFP progenitors sequentially generate early-born Kolmer-Agduhr" (KA") interneurons and late-born V3 interneurons. Analysis using a Notch signalling reporter demonstrates that these cell populations have distinct Notch signalling profiles. Not only do V3 cells receive higher total levels of Notch response, but they collect this response over a longer duration compared to V3 cells. To test whether the duration of Notch signalling determines the temporal cell fate specification, we combined a transgene that constitutively activates Notch signalling in the ventral spinal cord with a heat shock inducible Notch signalling terminator to switch off Notch response at any given time. Sustained Notch signalling results in expanded LFP progenitors while KA" and V3 interneurons fail to specify. Early termination of Notch signalling leads to exclusively KA" cell fate, despite the high level of Notch signalling, whereas late attenuation of Notch signalling drives only V3 cell fate. This suggests that the duration of Notch signalling is instructive in cell fate specification. Interestingly, knockdown experiments reveal a role for the Notch ligand Jag2b in maintaining LFP progenitors and limiting their differentiation into KA" and V3 cells. Our results indicate that Notch signalling is required for neural progenitor maintenance while a specific attenuation timetable defines the fate of the postmitotic progeny.

category: developmental biology


title: CircSry regulates spermatogenesis by enhancing γH2AX expression via sponging miR-138-5p

abstract: Sry on the Y chromosome is the master switch in sex determination in mammals. It has been well established that Sry encodes a transcription factor that is transiently expressed in somatic cells of male gonad, inducing a series of events that lead to the formation of testes. In the testis of adult mice, Sry is expressed as a circular RNA (circRNA) transcript, a type of noncoding RNA that forms a covalently linked continuous loop. However, the physiological function of this Sry circRNA (circSry) remains unknown since its discovery in 1993. Here we show that circSry is mainly expressed in the spermatocytes, but not in mature sperms and Sertoli cells. Loss of circSry led to the reduction of sperm number and the defect of germ cell development. The expression of {gamma}H2AX was decreased and failure of XY body formation was noted in circSry KO germ cells. Further study demonstrates that circSry regulates H2AX mRNA indirectly in pachytene spermatocytes through sponging miR-138-5p. Our study demonstrates that, in addition to its well-known sex-determination function, Sry also plays important role in spermatogenesis as a circRNA.


title: Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4.

abstract: Regenerating coronary blood vessels has the potential to ameliorate ischemic heart disease, yet there is currently no method of stimulating clinically effective cardiac angiogenesisis. Endocardial cells-- a particularly plastic cell type during development--line the heart lumen and are natural coronary vessel progenitors. Their intrinsic angiogenic potential is lost in adults, but studying the endocardial- to-coronary developmental pathway could identify methods of re-instating this process in diseased hearts. Here, we use a combination of mouse genetics and scRNAseq of lineage-traced endothelial cells to identify novel regulators of endocardial angiogenesis and precisely assess the role of Cxcl12/Cxcr4 signaling. Time-specific lineage tracing demonstrated that endocardial cells differentiated earlier than previously thought, largely at mid-gestation. A new mouse line reporting the activity of Cxcr4 revealed that, despite widespread Cxcl12 and Cxcr4 expression, only a small subset of these coronary endothelial cells activated the receptor, which were mostly in arteries. In accordance with these two findings, Cxcr4 deletion in the endocardial lineage only affected artery formation and only when deleted before mid-gestation. Integrating scRNAseq data of coronary endothelial cells from the endocardial lineage at both mid- and late-gestation identified a transitioning population that was specific to the earlier timepoint that specifically expressed Bmp2. Recombinant Bmp2 stimulated endocardial angiogenesis in an in vitro explant assay and in neonatal mouse hearts upon myocardial infarction. Our data shed light on how understanding the molecular mechanisms underlying endocardial-to-coronary transitions can identify new potential therapeutic targets that could promote revascularization of the injured heart.


title: TGFβ signaling is required for sclerotome resegmentation during development of the spinal column in Gallus gallus.

abstract: We previously showed the importance of TGF{beta} signaling in development of the mouse axial skeleton. Here, we provide the first direct evidence that TGF{beta} signaling is required for resegmentation of the sclerotome using chick embryos. Lipophilic fluorescent tracers, DiO and DiD, were microinjected into adjacent somites of embryos treated with or without TGF{beta}R1 inhibitor, SB431542, at developmental day E2.5 (HH16). Lineage tracing of labeled cells was observed over the course of 4 days until the completion of resegmentation at E6.5 (HH32). Vertebrae were malformed and intervertebral discs were small and misshapen in SB431542 injected embryos. Hypaxial myofibers were also increased in thickness after treatment with the inhibitor. Inhibition of TGF{beta} signaling resulted in alterations in resegmentation that ranged between full, partial, and slanted shifts in distribution of DiO or DiD labeled cells within vertebrae. Patterning of rostro- caudal markers within sclerotome was disrupted at E3.5 after treatment with SB431542 with rostral domains expressing both rostral and caudal markers. We propose that TGF{beta} signaling regulates rostro-caudal polarity and subsequent resegmentation in sclerotome during spinal column development.


title: Muscle systems and motility of early animals highlighted by cnidarians from the basal Cambrian

abstract: Although fossil evidence suggest that various animal groups were able to move actively through their environment in the early stages of their evolution, virtually no direct information is available on the nature of their muscle systems. The origin of jellyfish swimming, for example, is of great concern to biologists. Exceptionally preserved muscles are described here in benthic peridermal olivooid medusozoans from the basal Cambrian of China (Kuanchuanpu Formation, ca. 535 Ma) that have direct equivalent in modern medusozoans. They consist of circular fibers distributed over the bell surface (subumbrella) and most probably have a myoepithelial origin. This is the oldest record of a muscle system in cnidarians and more generally in animals. This basic system was probably co-opted by younger early Cambrian jellyfish to develop capacities for the jet-propelled swimming within the water column. Additional lines of fossil evidence obtained from ecdysozoans (worms and panarthropods) show that the muscle systems of early animals underwent a rapid diversification through the early Cambrian and increased their capacity to colonize a wide range of habitats both within the water column and sediment at a critical time of their evolutionary radiation.

category: evolutionary biology


title: sumSTAAR: a flexible framework for gene-based association studies using GWAS summary statistics

abstract:
Gene-based association analysis is an effective gene mapping tool. Many gene-based methods have been proposed recently. However, their power depends on the underlying genetic architecture, which is rarely known in complex traits, and so it is likely that a combination of such methods could serve as a universal approach. Several frameworks combining different gene-based methods have been developed. However, they all imply a fixed set of methods, weights and functional annotations. Moreover, most of them use individual phenotypes and genotypes as input data. Here, we introduce sumSTAAR, a framework for gene-based association analysis using summary statistics obtained from genome-wide association studies (GWAS). It is an extended and modified version of STAAR framework proposed by Li and colleagues in 2020. The sumSTAAR framework offers a wider range of gene-based methods to combine. It allows the user to arbitrarily define a set of these methods, weighting functions and probabilities of genetic variants being causal. The methods used in the framework were adapted to analyse genes with large number of SNPs to decrease the running time. The framework includes the polygene pruning procedure to guard against the influence of the strong GWAS signals outside the gene. We also present new improved matrices of correlations between the genotypes of variants within genes. These matrices estimated on a sample of 265,000 individuals are a state-of-the-art replacement of widely used matrices based on the 1000 Genomes Project data.

AUTHOR SUMMARYGene-based association analysis is an effective gene mapping tool. Quite a few frameworks have been proposed recently for gene-based association analysis using a combination of different methods. However, all of these frameworks have at least one of the disadvantages: they use a fixed set of methods, they cannot use functional annotations, or they use individual phenotypes and genotypes as input data. To overcome these limitations, we propose sumSTAAR, a framework for gene-based association analysis using GWAS summary statistics. Our framework allows the user to arbitrarily define a set of the methods and functional annotations. Moreover, we adopted the methods for the analysis of genes with a large number of SNPs to decrease the running time. The framework includes the polygene pruning procedure to guard against the influence of the strong GWAS signals outside the gene. We also present new improved matrices of correlations between the genotypes of variants within genes, which now allows to include ultra-rare variants in analysis.

category: genetics


title: Genomic adaptation of the picoeukaryote Pelagomonas calceolata to temperate iron-poor oceans revealed by a chromosome-scale genome sequence.

abstract: The smallest phytoplankton species are key actors in oceans biogeochemical cycling and their abundance and distribution are affected with global environmental changes. Picoalgae (cells <2{micro}m) of the Pelagophyceae class encompass coastal species causative of harmful algal blooms while others are cosmopolitan and abundant in open ocean ecosystems. Despite the ecological importance of Pelagophytes, only a few genomic references exist limiting our capacity to identify them and study their adaptation mechanisms in a changing environment. Here, we report the complete chromosome-scale assembled genome sequence of Pelagomonas calceolata. We identified unusual large low-GC and gene-rich regions potentially representing centromeres. These particular genomic structures could be explained by the absence of genes from a recombination pathway involving double Holiday Junctions. We identified a large repertoire of genes involved in inorganic nitrogen sensing and uptake and several genes replacing iron-requiring proteins potentially explaining P. calceolata ecological success in oligotrophic waters. Finally, based on this high-quality assembly, we evaluated P. calceolata relative abundance in all oceans using environmental Tara Oceans datasets. Our results suggest that P. calceolata is one of the most abundant eukaryotic species in the oceans with a relative abundance favoured by high temperature and iron-poor conditions. Climate change projections based on its relative abundance suggest an extension of the P. calceolata habitat toward the poles at the end of this century. Collectively, these findings reveal the ecological importance of P. calceolata and lay the foundation for a global scale analysis of the adaptation and acclimation strategies of picoalgae in a changing environment.

category: genomics


title: A deep learning-based framework for estimating fine-scale germline mutation rates

abstract: Germline mutation rates are essential for genetic and evolutionary analyses. Yet, estimating accurate fine-scale mutation rates across the genome is a great challenge, due to relatively few observed mutations and intricate relationships between predictors and mutation rates. Here we present MuRaL (Mutation Rate Learner), a deep learning-based framework to predict fine-scale mutation rates using only genomic sequences as input. Harnessing human germline variants for comprehensive assessment, we show that MuRaL achieves better predictive performance than current state-of-the-art methods. Moreover, MuRaL can build models with relatively few training mutations and a moderate number of sequenced individuals. It can leverage transfer learning to build models with further less training data and time. We apply MuRaL to produce genome-wide mutation rate profiles for four species - Homo sapiens, Macaca mulatta, Arabidopsis thaliana and Drosophila melanogaster, demonstrating its high applicability. The generated mutation rate profiles and open source software can greatly facilitate related research.


title: Type S Non Ribosomal Peptide Synthetases for the rapid generation of tailor-made peptide libraries

abstract: Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatized as inefficient, time-, labour- and cost-intensive. Combinatorial chemistry, on the other hand, can produce new molecules in greater numbers, cheaper and in less time than traditional natural product discovery, but also fails to meet current medical needs due to the limited biologically relevant chemical space that can be addressed. Consequently, methods for the high throughput generation of new-to-nature natural products would offer a new approach to identifying novel bioactive chemical entities for the hit to lead phase of drug discovery programms. As a follow-up to our previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), we now envisaged the de novo generation of non-ribosomal peptides (NRPs) on an unreached scale. Using synthetic zippers, we split NRPS in up to three subunits and rapidly generated different bi- and tripartite NRPS libraries to produce 49 peptides, peptide derivatives, and de novo peptides at good titres up to 145 mgL-1. A further advantage of type S NRPSs not only is the possibility to easily expand the created libraries by re-using previously created type S NRPS, but that functions of individual domains as well as domain-domain interactions can be studied and assigned rapidly.

category: bioengineering


title: OC_Finder: A deep learning-based software for osteoclast segmentation, counting, and classification

abstract: Osteoclasts are multinucleated cells that exclusively resorb bone matrix proteins and minerals on the bone surface. They differentiate from monocyte/macrophage-lineage cells in the presence of osteoclastogenic cytokines such as the receptor activator of nuclear factor-{kappa}B ligand (RANKL) and are stained positive for tartrate-resistant acid phosphatase (TRAP). In vitro, osteoclast formation assays are commonly used to assess the capacity of osteoclast precursor cells for differentiating into osteoclasts wherein the number of TRAP-positive multinucleated cells are counted as osteoclasts. Osteoclasts are manually identified on cell culture dishes by human eyes, which is a labor-intensive process. Moreover, the manual procedure is not objective and result in lack of reproducibility. To accelerate the process and reduce the workload for counting the number of osteoclasts, we developed OC_Finder, a fully automated system for identifying osteoclasts in microscopic images. OC_Finder consists of segmentation and classification steps. OC_Finder detected osteoclasts differentiated from wild-type and Sh3bp2KI/+ precursor cells at a 99.4% accuracy for segmentation and at a 98.1% accuracy for classification. The number of osteoclasts classified by OC_Finder was at the same accuracy level with manual counting by a human expert. Together, successful development of OC_Finder suggests that deep learning is a useful tool to perform prompt and accurate unbiased classification and detection of specific cell types in microscopic images.

category: bioinformatics


title: Data-driven discovery of targets for bipotent anticancer drugs identifies Estrogen Related Receptor Alpha

abstract:
Drugs that kill tumors through multiple mechanisms have potential for broad clinical benefits, with a reduced propensity to resistance. We developed BipotentR, a computational approach to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway. Using tumor metabolism as proof-of-principle, BipotentR identified 38 candidate immune-metabolic regulators by combining epigenomes with bulk and single-cell tumor transcriptomes from patients. Inhibition of top candidate ESRRA (Estrogen Related Receptor Alpha) killed tumors by direct effects on energy metabolism and two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+T cells into tumors. ESRRA is activated in immune-suppressive and immunotherapy-resistant tumors of many types, suggesting broad clinical relevance. We also applied BipotentR to angiogenesis and growth-suppressor pathways, demonstrating a widely applicable approach to identify drug targets that act simultaneously through multiple mechanisms. BipotentR is publicly available at http://bipotentr.dfci.harvard.edu/.

One-Sentence SummaryBipotentR identifies targets for bipotent anticancer drugs, as shown by the energy and immune effects of ESRRA inhibition.

category: cancer biology


title: The mitochondrial deubiquitinase USP30 regulates AKT/mTOR signaling

abstract: Mitophagy is an intracellular mechanism to maintain mitochondrial health by removing dysfunctional mitochondria. The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, and USP30 antagonizes this Parkin-dependent mitophagy. AKT/mTOR signaling is a master regulator of cell proliferation, differentiation, survival, and growth. Although mounting evidence showed mitophagy and AKT/mTOR signaling interact with each other during mitophagy, the specific mechanisms between Parkin/USP30 and AKT/mTOR signaling have not been elucidated. This research artificially expressed Parkin and USP30 in Hela cells and compared AKT/mTOR and apoptosis signals between Hela cells, HeLa Parkin cells, and Hela Parkin USP30 cells during mitophagy. The studys results suggest that Parkin promotes AKT degradation via ubiquitination, which induces cell apoptosis during mitochondrial stress. On the contrary, USP30 protects AKT via deubiquitination. These findings provide new insights into Parkin and USP30s role in cell apoptosis and physiological and pathological functions of USP30 beyond mitophagy.

category: pharmacology and toxicology


title: Effect of OTR4120 on pulmonary fibrosis in mice

abstract:
BackgroundAcute respiratory distress syndrome (ARDS) can be related to airway remodeling caused by pulmonary fibrosis and systemic inflammation. Etiologies of ARDS are multifaceted such as idiopathic pulmonary fibrosis or as recently the SARS-CoV-2 infection. Antifibrotic drugs may be a better approach to slow the fibrotic process but they often have poor efficacy in patients, and the mortality rate remains high, up to 40% within 5 years of diagnosis.

Here, we tested the antifibrotic effect of a ReGeneTaring Agents named OTR4120 in a bleomycin-induced mouse model of pulmonary fibrosis.

MethodsSwiss mice were randomly divided into four experimental groups: saline-treated control group, an OTR4120 group, a bleomycin-induced fibrosis group without OTR4120, and a bleomycin-induced fibrosis groups with OTR4120 (intravenous injections every 3 days starting at day 11 post bleomycin I.P. injection). Lungs were compared using the lung/body weight index, and the extend of interstitial injury area was graded using histopathological assessment of haematoxylin & eosin-stained lung tissue sections. Lung tissue Collagen I and Collagen III levels, and blood cytokine levels were measured using a Collagen colorimetric kit and a Cytokine colorimetric kit, respectively.

ResultsThe group treated by OTR4120 alone were used as a control. The clincal signs in all animals resoved gradually on day 17 after bleomycin injections and 6 days after OTR4120 treatment, and disappeared almost completetly at day 24 after bleomycin injections and day 13 after OTR4120 treatment. Lung/body weight index values were significantly lower in the bleomycin-OTR4120 treated group versus the bleomycin group (7.31, 9.97 and 7.63 mg/g, p-value< 0.01; respectively). Histopathological analyses suggest that OTR4120 treatment ameliorated the increased inflammatory cell infiltration, and attenuated the reduction in interstitial thickening, associated with bleomycin-induced fibrosis. Collagen III and cytokine levels were decreased in the OTR4120 group versus the fibrotic (bleomycin only) group. OTR4120-treated animals were less affected in their behavior, did not loose weight nor appetite, and recovered overall activities within 6 days of OTR4120 treatment, while none of the vehicle-treated animals recovered to normal.

ConclusionOTR4120 is a potential candidate to reduce lung fibrosis.

category: physiology


title: Copper microRNAs govern the formation of giant feeding cells induced by the root knot nematode Meloidogyne incognita in Arabidopsis thaliana

abstract: miR408 and miR398 are two conserved microRNAs which expression is activated by the SPL7 transcription factor in response to copper starvation. We identified these two microRNAs families as upregulated in Arabidopsis thaliana and Solanum lycopersicum roots infected by root-knot nematodes. These endoparasites induce the dedifferentiation of a few root cells and the reprogramming of their gene expression to generate giant feeding cells. By combining functional approaches, we deciphered the signaling cascade involving these microRNAs, their regulator and their targets. MIR408 expression was located within nematode-induced feeding cells in which it co-localised with SPL7 expression and was regulated by copper. Moreover, infection assays with mir408 and spl7 KO mutants or lines expressing targets rendered resistant to cleavage by miR398 demonstrated the essential role of the SPL7/MIR408/MIR398 module in the formation of giant feeding cells. Our findings reveals how perturbation of plant copper homeostasis, via the SPL7/MIR408/MIR398 module, governs the formation of nematode-induced feeding cells.

category: plant biology


title: A method for identifying environmental stimuli and genes responsible for genotype-by-environment interactions from a large-scale multi-environment data set

abstract:
It has not been fully understood in real fields what environment stimuli cause the genotype-by-environment (G x E) interactions, when they occur, and what genes react to them. Large-scale multi-environment data sets are attractive data sources for these purposes because they potentially experienced various environmental conditions. Here we developed a data-driven approach termed Environmental Covariate Search Affecting Genetic Correlations (ECGC) to identify environmental stimuli and genes responsible for the G x E interactions from large-scale multi-environment data sets. ECGC was applied to a soybean (Glycine max) data set that consisted of 25,158 records collected at 52 environments. ECGC illustrated what meteorological factors shaped the G x E interactions in six traits including yield, flowering time, and protein content and when they were involved. For example, it illustrated the relevance of precipitation around sowing dates and hours of sunshine just before maturity to the interactions observed for yield. Moreover, genome-wide association mapping on the sensitivities to the identified stimuli discovered candidate and known genes responsible for the G x E interactions. Our results demonstrate the capability of data-driven approaches to bring novel insights on the G x E interactions observed in fields.

Key messageThe proposed method is able to identify environmental stimuli and genes responsible for the G x E interactions observed in multi-environmental trials. The method is based on similarity search between genetic correlation and environmental stimuli among environments.


title: Identification of new leaf intrinsic yield genes using cross-species network analysis in plants

abstract: Plant leaves differ in their size, form and structure, and the processes of cell division and cell expansion contribute to this diversity. Leaf transcriptional networks covering cell division and cell expansion in Arabidopsis thaliana, maize (Zea mays) and aspen (Populus tremula) were compared to identify candidate genes that are conserved in plant growth and ultimately have the potential to increase biomass (intrinsic yield, IY). Our approach revealed that genes showing strongly conserved co-expression were mainly involved in fundamental leaf developmental processes such as photosynthesis, translation, and cell proliferation. Next, known intrinsic yield genes (IYGs) together with cross-species conserved networks were used to predict novel potential Arabidopsis leaf IYGs. Using an in-depth literature screening, 34 out of 100 top predicted IYGs were confirmed to affect leaf phenotype if mutated or overexpressed and thus represent novel potential IYGs. Globally, these new IYGs were involved in processes mostly covering cell cycle, plant defense responses, gibberellin, auxin and brassinosteroid signaling. Application of loss-of-function lines and phenotypic characterization confirmed two newly predicted IYGs to be involved in leaf growth (NPF6.4 and LATE MERISTEM IDENTITY2). In conclusion, the presented network approach offers an integrative cross-species strategy to identify new yield genes and to accelerate plant breeding.


title: SCARECROW maintains the stem cell niche in Arabidopsis root by ensuring telomere integrity

abstract:
Stem cells are the ultimate source of the cells in various tissues and organs, and thus are essential to postembryonic plant growth and development. SCARECROW (SCR) is a plant-specific transcription regulator well known for its role in stem-cell renewal in plant roots, but the mechanism by which SCR exerts this function is still unclear. To address this question, we carried out a genetic screen for mutants that no longer express SCR in the stem-cell niche in the Arabidopsis root, and one of the mutants is characterized herein. Using marker-assisted mapping, whole genome sequencing, and complementation tests, we pinpointed the causal mutation in this mutant at TEN1, which encodes telomere-end protecting factor. By sequence alignment of TEN1 homologs in a wide range of eukaryotes, we identified two novel motifs. The importance of these motifs was examined through site-directed mutagenesis of a conserved amino acid, and through complementation tests, which showed that G100 is required for TEN1 stability. Interestingly, we found that TEN1 expression was dramatically reduced in the scr mutant. Two components in the same protein complex as TEN1, STN1 and CTC1, were found to be also dramatically downregulated in scr, as well as telomerase. Further studies showed that loss of STN1, CTC1 and telomerase also caused defects in the root stem cells. In line with these findings, the scr mutant was hypersensitive to DNA damage reagents such as Zeocin. These results together suggest that SCR maintains root stem cells by promoting expression of genes that ensures genome integrity.

One sentence summaryThis study reveals a role for the root development regulator SCARECROW in maintaining the expression of telomere-end protecting factors and a connection between genome integrity and stem-cell maintenance in Arabidopsis root.


title: Hi-C Resolution Enhancement with Genome Sequence Data

abstract: The increasing interest in chromatin conformation inside the nucleus and the availability of genome-wide experimental data make it possible to develop computational methods that can increase the quality of the data and thus overcome the limitations of high experimental costs. Here we develop a deep-learning approach for increasing Hi-C data resolution by appending additional information about genome sequence. In this approach, we utilize two different deep-learning algorithms: the image-to-image model, which enhances Hi-C resolution by itself, and the sequence-to-image model, which uses additional information about the underlying genome sequence for further resolution improvement. Both models are combined with the simple head model that provides a more accurate enhancement of initial low-resolution Hi-C data. The code is freely available in a GitHub repository: https://github.com/koritsky/DL2021_HI-C.

category: systems biology


title: Constructing the hierarchy of predictive auditory sequences in the marmoset brain

abstract: Our brains constantly generate predictions of sensory input that are compared with actual inputs, propagate the prediction-errors through a hierarchy of brain regions, and subsequently update the internal predictions of the world. However, the essential feature of predictive coding, the notion of hierarchical depth and its neural mechanisms, remains largely unexplored. Here, we investigated the hierarchical depth of predictive auditory processing by combining functional magnetic resonance imaging (fMRI) and high-density whole-brain electrocorticography (ECoG) in marmoset monkeys during an auditory local-global paradigm in which the temporal regularities of the stimuli were designed at two hierarchical levels. The prediction-errors and prediction updates were examined as neural responses to auditory mismatches and omissions. Using fMRI, we identified a hierarchical gradient along the auditory pathway: midbrain and sensory regions represented local, short-time-scale predictive processing followed by associative auditory regions, whereas anterior temporal and prefrontal areas represented global, long-time-scale sequence processing. The complementary ECoG recordings confirmed the activations at cortical surface areas and further differentiated the signals of prediction-error and update, which were transmitted via putatively bottom-up {gamma} and top-down {beta} oscillations, respectively. Furthermore, omission responses caused by absence of input, reflecting solely the two levels of prediction signals that are unique to the hierarchical predictive coding framework, demonstrated the hierarchical predictions in the auditory, temporal, and prefrontal areas. Thus, our findings support the hierarchical predictive coding framework, and outline how neural circuits and spatiotemporal dynamics are used to represent and arrange a hierarchical structure of auditory sequences in the marmoset brain.

category: neuroscience


title: The pre-existing human antibody repertoire to computationally optimized influenza H1 hemagglutinin vaccines

abstract:
The computationally optimized broadly reactive antigen (COBRA) approach has previously been used to generate hemagglutinin (HA) immunogens for several influenza subtypes that expand vaccine-elicited antibody breadth. As nearly all individuals have pre-existing immunity to influenza viruses, influenza-specific memory B cells will likely be recalled upon COBRA HA vaccination. We determined the epitope specificity and repertoire characteristics of pre-existing human B cells to H1 COBRA HA antigens. Cross-reactivity between wild type HA and H1 COBRA HA proteins were observed at both the oligoclonal B cell level and for a subset of isolated monoclonal antibodies (mAbs). The mAbs bound five distinct epitopes on the pandemic A/California/04/2009 head and stem domains, and the majority of the mAbs had HAI and neutralizing activity against pandemic H1 strains. Two head-directed mAbs, CA09-26 and CA09-45, had HAI and neutralizing activity against a pre-pandemic H1 strain. One mAb, P1-05, targets the stem region of H1 HA proteins, but does not compete with known stem-targeting H1 mAbs. We determined that mAb P1-05 recognizes a recently discovered membrane proximal epitope on HA, the anchor epitope, and we identified similar mAbs using B cell repertoire sequencing. In addition, the trimerization domain distance from HA was critical to recognition of this epitope by P1-05. Overall, these data indicate that seasonally vaccinated individuals possess a population of functional H1 COBRA HA- reactive B cells that target head, central stalk, and anchor epitopes, and demonstrate the importance of structure-based assessment of subunit protein vaccine candidates to ensure accessibility of optimal protein epitopes.

SignificanceInfluenza imposes significant human and economic costs every year. The current seasonal vaccine elicits primarily strain-specific antibodies, and year to year vaccine effectiveness is variable. The COBRA approach could provide longer protection and obviate the requirement for annual vaccination. Whereas COBRA HAs have previously been evaluated in animal models, the pre-existing COBRA HA-reactive human B cell population has yet to be elucidated, and is important to identify specific B cells that may be recalled by H1 HA COBRA vaccination. This work demonstrates that seasonally vaccinated individuals possess a functional B cell population targeting both head and stem domains that could be recalled with COBRA HA immunogens.


title: Metabolic demand regulates selective cell death in Parkinson's Disease

abstract: Parkinsons Disease (PD) is a debilitating neurodegenerative condition that affects over 10 million people across the world, causing tremors and muscle weakness. Its mechanisms are unknown, but one key feature is selective cell death: neurons in the Substantia Nigra Pars Compacta (SNc) die, but their neighbors, the cells in the Ventral Tegmental Area (VTA), remain healthy. To study this phenomenon, we used an established single neuron model of the SNc, adapting its biophysical and bioenergetic properties to match that of the VTA. We discovered that reducing calcium influx correlates with higher ATP and lower ROS concentrations in the cell, suggesting in silico the importance of calcium influx in metabolic stress and selective vulnerability for Parkinsons Disease. Future efforts may target calcium channel inhibition as a therapeutic strategy, although caution is needed with potential metabolic side effects.


title: Going Beyond the Point Neuron: Active Dendrites and Sparse Representations for Continual Learning

abstract: Biological neurons integrate their inputs on dendrites using a diverse range of non-linear functions. However the majority of artificial neural networks (ANNs) ignore biological neurons structural complexity and instead use simplified point neurons. Can dendritic properties add value to ANNs? In this paper we investigate this question in the context of continual learning, an area where ANNs suffer from catastrophic forgetting (i.e., ANNs are unable to learn new information without erasing what they previously learned). We propose that dendritic properties can help neurons learn context-specific patterns and invoke highly sparse context-specific subnetworks. Within a continual learning scenario, these task-specific subnetworks interfere minimally with each other and, as a result, the network remembers previous tasks significantly better than standard ANNs. We then show that by combining dendritic networks with Synaptic Intelligence (a biologically motivated method for complex weights) we can achieve significant resilience to catastrophic forgetting, more than either technique can achieve on its own. Our neuron model is directly inspired by the biophysics of sustained depolarization following dendritic NMDA spikes. Our research sheds light on how biological properties of neurons can be used to solve scenarios that are typically impossible for traditional ANNs to solve.


title: Radical pairs may explain reactive oxygen species-mediated effects of hypomagnetic field on neurogenesis

abstract:
Exposures to a hypomagnetic field can affect biological processes. Recently, it has been observed that hypomagnetic field exposure can adversely affect adult hippocampal neurogenesis and hippocampus-dependent cognition in mice. In the same study, the role of reactive oxygen species (ROS) in hypomagnetic field effects has been demonstrated. However, the mechanistic reasons behind this effect are not clear. This study proposes a radical pair mechanism based on a flavin-superoxide radical pair to explain the modulation of ROS production and the attenuation of adult hippocampal neurogenesis in a hypomagnetic field. The results of our calculations favor a singlet-born radical pair over a triplet-born radical pair. Our model predicts hypomagnetic field effects on the triplet/singlet yield of comparable strength as the effects observed in experimental studies on adult hippocampal neurogenesis. Our predictions are also in qualitative agreement with experimental results on superoxide concentration and other observed ROS effects. We also predict the effects of applied magnetic fields and oxygen isotopic substitution on adult hippocampal neurogenesis. Our findings strengthen the idea that nature might harness quantum resources in the context of the brain.

Author summaryExposure to magnetic fields influences many neurobiological processes. The formation of new neurons (neurogenesis) in the hippocampal region of the adult brain plays a crucial role in learning and memory. It can be adversely affected by shielding the earths magnetic field, and this effect is intimately related to ROS concentration. In this study, we have developed a quantum mechanical model to explain this magnetic field dependence of adult hippocampal neurogenesis. Our model is also consistent with the observed ROS effects.


title: Social-affective features drive human representations of observed actions

abstract: Humans observe actions performed by others in many different visual and social settings. What features do we extract and attend when we view such complex scenes, and how are they processed in the brain? To answer these questions, we curated two large-scale sets of naturalistic videos of everyday actions and estimated their perceived similarity in two behavioral experiments. We normed and quantified a large range of visual, action-related and social-affective features across the stimulus sets. Using a cross-validated variance partitioning analysis, we found that social-affective features predicted similarity judgments better than, and independently of, visual and action features in both behavioral experiments. Next, we conducted an electroencephalography (EEG) experiment, which revealed a sustained correlation between neural responses to videos and their behavioral similarity. Visual, action, and social-affective features predicted neural patterns at early, intermediate and late stages respectively during this behaviorally relevant time window. Together, these findings show that social-affective features are important for perceiving naturalistic actions, and are extracted at the final stage of a temporal gradient in the brain.


title: Distinct Representations of Body and Head motion are Dynamically Encoded by Purkinje cell Populations in the Macaque Cerebellum

abstract: The ability to accurately control our posture and perceive spatial orientation during self-motion requires knowledge of the motion of both the head and body. However, whereas the vestibular sensors and nuclei directly encode head motion, no sensors directly encode body motion. Instead, the integration of vestibular and neck proprioceptive inputs is necessary to transform vestibular information into the body-centric reference frame required for postural control. The anterior vermis of the cerebellum is thought to play a key role in this transformation, yet how its Purkinje cells integrate these inputs or what information they dynamically encode during self-motion remains unknown. Here we recorded the activity of individual anterior vermis Purkinje cells in alert monkeys during passively applied whole-body, body-under-head, and head-on-body rotations. Most neurons dynamically encoded an intermediate representation of self-motion between head and body motion. Notably, these neurons responded to both vestibular and neck proprioceptive stimulation and showed considerable heterogeneity in their response dynamics. Furthermore, their vestibular responses demonstrated tuning in response to changes in head-on-body position. In contrast, a small remaining percentage of neurons sensitive only to vestibular stimulation unambiguously encoded head-in-space motion across conditions. Using a simple population model, we establish that combining responses from 40 Purkinje cells can explain the responses of their target neurons in deep cerebellar nuclei across all self-motion conditions. We propose that the observed heterogeneity in Purkinje cells underlies the cerebellums capacity to compute the dynamic representation of body motion required to ensure accurate postural control and perceptual stability in our daily lives.


title: Internally Generated Time in the Rodent Hippocampus is Logarithmically Compressed

abstract: The Weber-Fechner law proposes that our perceived sensory input increases with physical input on a logarithmic scale. Hippocampal "time cells" carry a record of recent experience by firing sequentially during a circumscribed period of time after a triggering stimulus. Different cells have "time fields" at different delays up to at least tens of seconds. Past studies suggest that time cells represent a compressed timeline by demonstrating that fewer time cells fire late in the delay and their time fields are wider. This paper asks whether the compression of time cells obeys the Weber-Fechner Law. Time cells were studied with a hierarchical Bayesian model that simultaneously accounts for the firing pattern at the trial level, cell level, and population level. This procedure allows separate estimates of the within-trial receptive field width and the across-trial variability. The analysis at the trial level suggests the time cells represent an internally coherent timeline as a group. Furthermore, even after isolating across-trial variability, time field width increases linearly with delay. Finally, we find that the time cell population is distributed evenly on a logarithmic time scale. Together, these findings provide strong quantitative evidence that the internal neural temporal representation is logarithmically compressed and obeys a neural instantiation of the Weber-Fechner Law.


title: Transposable elements continuously remodel the regulatory landscape, transcriptome, and function of decidual stromal cells

abstract: Gene expression evolution underlies the origin, divergence, and conservation of biological characters including cell-types, tissues, and organ systems. Previously we showed that large-scale gene expression changes in decidual stromal cells contributed to the origins of pregnancy in eutherians and the divergence of pregnancy traits in primates (Marini[c] et al., 2021; Mika et al., 2021a, 2021b), and that transposable elements likely contributed to these gene expression changes (Mika et al., 2021a). Here we show that two large waves of TEs remodeled the transcriptome and regulatory landscape of decidual stromal cells, including a major wave in primates. Genes nearby TE-derived regulatory elements are among the most progesterone responsive in the genome and play essential roles in orchestrating progesterone responsiveness and the core function of decidual cells by donating progesterone receptor binding sites to the genome. We tested the regulatory abilities of 89 TE consensus sequences and found nearly all acted as repressors in mammalian cells but that treatment with histone deacetylase inhibitors unmasked latent enhancer functions. These data indicate TEs have played an important role in the development, evolution, and function of primate decidual stromal cells and suggest a two-step model in which latent enhancer functions of TEs are unmasked after they lose primary repressors functions.


title: Population structure in the MHC region

abstract: In his 1972 "The apportionment of human diversity", Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection on specific genes and genomic regions can alter the apportionment of diversity. We examine genetic diversity at the HLA loci, located within the MHC region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The SNPs within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, with low FST values. However, when we analyze haplotypes defined by these SNPs (i.e., which define "HLA alleles"), we find marked differences in frequencies between geographic regions. These differences are not reflected in the FST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting FST. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We explore the case of Brazils bone-marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry.


title: Zn2+ triggered two-step mechanism of CLIC1 membrane insertion and activation into chloride channels

abstract: The CLIC protein family displays the unique feature of altering its structure from a soluble form to a membrane-bound chloride channel. CLIC1, a member of this family, is found in the cytoplasm or in internal and the plasma membranes, with membrane relocalisation linked to endothelial disfunction, tumour proliferation and metastasis. The molecular switch promoting CLIC1 activation remains unclear. Here, cellular chloride efflux assays and immunofluorescence microscopy studies have identified Zn2+ intracellular release as the trigger for CLIC1 activation and membrane relocalisation. Biophysical assays confirmed specific binding to Zn2+, inducing membrane association and enhancing chloride efflux in a pH dependent manner. Together, our results identify a two-step mechanism with Zn2+ binding as the molecular switch promoting CLIC1 membrane insertion, followed by pH activation of chloride efflux.

category: biochemistry


title: Investigating the genetic and environmental basis of head micromovements during MRI

abstract:
IntroductionHead motion during magnetic resonance imaging is heritable. Further, it shares phenotypical and genetic variance with body mass index (BMI) and impulsivity. Yet, to what extent this trait is related to single genetic variants and physiological or behavioral features is unknown. We investigated the genetic basis of head motion in a meta-analysis of genome-wide association studies. Further, we tested whether physiological or psychological measures, such as respiratory rate or impulsivity, mediated the relationship between BMI and head motion.

MethodsWe conducted a genome-wide association meta-analysis for mean and maximal framewise head displacement (FD) in seven population neuroimaging cohorts (UK Biobank, LIFE-Adult, Rotterdam Study cohort 1-3, Austrian Stroke Prevention Family Study, Study of Health in Pomerania; total N = 35.109). We performed a pre-registered analysis to test whether respiratory rate, respiratory volume, self-reported impulsivity and heart rate mediated the relationship between BMI and mean FD in LIFE-Adult.

ResultsNo variant reached genome-wide significance for neither mean nor maximal FD. Neither physiological nor psychological measures mediated the relationship between BMI and head motion.

ConclusionBased on these findings from a large meta-GWAS and pre-registered follow-up study, we conclude that the previously reported genetic correlation between BMI and head motion relies on polygenic variation, and that neither psychological nor simple physiological parameters explain a substantial amount of variance in the association of BMI and head motion. Future imaging studies should thus rigorously control for head motion at acquisition and during preprocessing.


title: Involvement of mechanical cues in the migration of Cajal-Retzius cells in the marginal zone during neocortical development

abstract: Emerging evidence points to coordinated action of chemical and mechanical cues during brain development. At early stages of neocortical development, angiogenic factors and chemokines such as CXCL12, ephrins, and semaphorins assume crucial roles in orchestrating neuronal migration and axon elongation of postmitotic neurons. Here we explore the intrinsic mechanical properties of the developing marginal zone of the pallium in the migratory pathways and brain distribution of the pioneer Cajal-Retzius cells. These pioneer neurons are generated in several proliferative regions in the developing brain (e.g., the cortical hem and the pallial subpallial boundary) and migrate tangentially in the preplate/marginal zone covering the upper portion of the neocortex. These cells play crucial roles in correct neocortical layer formation by secreting several molecules such as Reelin. Our results indicate that the motogenic properties of Cajal-Retzius cells and their perinatal distribution in the marginal zone are also modulated by both chemical and mechanical factors, by the specific mechanical properties of Cajal-Retzius cells, and by the differential stiffness of the migratory routes. Indeed, cells originating in the cortical hem display higher migratory capacities than those generated in the pallial subpallial boundary which may be involved in the differential distribution of these cells in the dorsal-lateral axis in the developing marginal zone.


title: The toll-like receptor 7 agonist imiquimod increases ethanol self-administration and induces expression of toll-like receptor related genes

abstract:
BackgroundThere is growing evidence that immune signaling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption.

MethodsWe administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine 1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and 2) whether TLR7 activation could modulate operant alcohol self-administration.

ResultsInterferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2 and 24 h post-injection regardless of alcohol history, while TLR3 and 7 gene expression changes were region- and sex-specific. The pro-inflammatory cytokine TNF was increased 24h post-injection in rats with an alcohol self-administration history but this effect did not persist after four injections, suggesting molecular tolerance. In both males and females, ethanol consumption was increased 24 h after imiquimod injections with sex-specific differences: in females this effect emerged following the first injection but in males this increase did not occur until the third injection, suggesting sex differences in adaptation to repeated TLR7 activation. Notably, imiquimod reliably induced weight loss, indicating that sickness behavior persisted across repeated injections.

ConclusionThese findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm, and suggest that TLR7 and IRF7 signaling pathways may be a viable druggable target for treatment of AUD.


title: Behavioral and slice electrophysiological assessment of DREADD ligand, deschloroclozapine (DCZ), in rats.

abstract: Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) have become a premier neuroscience research tool in the past decade for their utility in providing reversible manipulations of cellular activity following experimenter-controlled delivery of a DREADD-specific ligand. However, the commonly used DREADD ligand, clozapine-N-oxide (CNO), has metabolic and off-target effects that may confound experimental results and interpretations. Moreover, CNO has relatively poor affinity for DREADD receptors, which necessitates high doses for systemic administration applications. New DREADD ligands aim to reduce metabolic and potential off-target effects while maintaining strong efficacy for the designer receptors. Recently a novel DREADD ligand, deschloroclozapine (DCZ), was shown to induce chemogenetic-mediated cellular and behavioral effects in mice and monkeys without detectable side effects. While promising, further testing of DCZ across species and experimental paradigms is warranted. The goal of the present study was to examine the effectiveness of systemic DCZ for DREADD-based chemogenetic manipulations in behavioral and slice electrophysiological applications in rats. We demonstrate that a relatively low dose of DCZ (0.1 mg/kg) supports excitatory DREADD-mediated cFos induction, DREADD-mediated inhibition of a central amygdala-dependent behavior, and DREADD-mediated inhibition of neuronal activity in a slice electrophysiology preparation. In addition, we show that this dose of DCZ does not alter gross locomotor activity or induce a place preference/aversion in control rats without DREADD expression. Together, our findings support the use of systemic DCZ for DREADD-based manipulations in rats, and provide evidence that DCZ is a superior alternative to CNO.


title: Differential momentary reports of stress and affect associated with alcohol consumption in middle-aged versus younger adults

abstract:
ObjectiveStress is a motivator to consume alcohol, a well-documented relapse risk, and is known to differentially affect biological and psychological processes as people age. Because alcohol consumption is known to decrease stress and increase affect, this study examined differences in ratings of stress and affect across the day in middle-aged versus younger adults who regularly consumed alcohol.

MethodsA sample of males and females including younger (n=17) and middle-aged (n=18) drinkers was studied across two experimental periods: a 3-day period of usual drinking and a 3-day period of abstinence from alcohol. We also measured resting levels of respiratory sinus arrhythmia (RSArest), since it is a well-documented biomarker of stress and known to decrease with age. Ecological momentary assessment (EMA) ratings across periods of normal drinking and abstinence were modeled using hierarchical regression to assess differences in stress and affect throughout days of abstinence and normal drinking between the two age groups.

ResultsAs anticipated, middle-aged participants had lower RSArest than those who were younger. Our analyses showed that middle-aged adults experienced a significant reduction in stress following drinking while no such effect was observed in the younger adults. Although the middle-aged adults showed overall lower stress, generally they also expressed higher affect than younger adults.

ConclusionsDespite the mitigating role of alcohol on stress in the middle-aged group and the fact that they had higher affect than the younger adults, their lower levels of RSArest and higher daily reports of stress could pose a risk for chronic alcohol consumption.


title: Natural age-related sleep-wake alterations onset prematurely in the Tg2576 mouse model of Alzheimer disease

abstract: Sleep insufficiency or decreased quality have been associated with Alzheimers disease (AD) already in its preclinical stages. Whether such traits are also present in rodent models of the disease has been poorly addressed, somewhat disabling the preclinical exploration of sleep-based therapeutic interventions for AD. We investigated age-dependent sleep-wake phenotype of a widely used mouse model of AD, the Tg2576 line. We implanted electroencephalography/ electromyography headpieces into 6 months old (plaque-free, n=10) and 11 months old (moderate plaque-burdened, n=10) Tg2576 and age-matched wild-type (WT) mice and recorded vigilance states for 24 hours. Tg2576 mice exhibited significantly increased wakefulness and decreased non-rapid eye movement sleep over a 24-hour period compared to WT mice at 6, but not at 11 months of age. Concomitantly, delta power appeared decreased in 6-month old Tg2576 mice in comparison to age-matched WT controls, yielding a reduced slow-wave energy phenotype in the young mutants. Lack of genotype-related differences over 24 hours in overall sleep-wake phenotype at 11 months of age appears to be the result of the natural aging of WT mice. Therefore, our results indicate that at plaque-free stages of the disease, diminished sleep quality is present in Tg2576 mice which resembles aged healthy controls, suggesting an early-onset of sleep-wake deterioration in murine AD. Whether such disturbances in the natural patterns of sleep could in turn worsen disease progression warrants further exploration.


title: P300 Parameters Over the Lifespan: Validating Target Ranges from an In-Clinic Platform

abstract:
BackgroundEvoked potential (ERP) markers extracted from an EEG exam can provide novel sources of information regarding brain function allowing changes in cognition, from conditions such as concussion or unhealthy aging, to be measured and tracked over time. Age-related targets can provide useful guides for practitioners, trainers, and patients seeking to optimize and track brain function over time. Objective 1: To compare age-related changes in auditory P300 metrics of latencies and amplitudes collected in the course of routine clinical evaluations with published trends from research.
Objective 2: To establish within-person test-retest variances for these P300 metrics.
Objective 3: To validate a method for presenting age-stratified target ranges of P300 metrics.

ParticipantsOne thousand seven-hundred and seventy-eight reference subjects aged 13-90.

MethodsAudio P300 was measured as part of a health screening exam for studies through Colorado University, Childrens Hospital Colorado, Boone Heart Institute, WAVi Co., and various clinics alongside other clinical evaluations.

ResultsThe age-related trends in both the P300 latency and amplitude measured in clinic match the age-related trends from previous research. In particular, the 2 control group endpoints at 20 and 90 years match the linear slopes predicted for age-related decline from early studies, and the inclusion of all ages produces a maturation prediction of a recent meta analysis where metrics peak near 20 years of age. Large between-person variances are observed across all studies but within-person variances remain consistent with previous studies.

ConclusionIn-clinic measures of P300 latency and amplitude corroborate the age-related trends of published research taken over the last several decades. Large between-person variance remains, leaving P300 best suited for within-person comparison.


title: Characterization of dissolved organic matter from temperate wetlands: field dynamics and photoreactivity changes driven by natural inputs and diagenesis along the hydroperiod

abstract: Wetlands store large amounts of C in biomass, sediments and water. A major C fraction is in the dissolved organic matter (DOM) pool and has multiple regulatory functions in the ecosystem. Patagonian wetlands undergo profound changes in their water cycle due to warming and reduced precipitation, causing shorter hydroperiods and reduced landscape connectivity and overall affecting their C budgets. In this study we characterized the DOM pool of a temporary wetland of North Patagonia during a hydroperiod, using optical DOM proxies obtained by absorption and fluorescence spectroscopy. DOM components were modeled through EEM-PARAFAC. DOC varied between [~]4 and [~]9 mg L-1, displaying aromatic signals and terrestrial/sediment fingerprints. The humic components C1 (microbial and/or vegetation derived) and C2 (soil/sediment derived) prevailed in the DOM pool, whereas the non-humic component C3 (derived from aquatic production) showed lower contribution. Along the hydroperiod DOM optical proxies allowed identifying allochthonous inputs, degradation and an increasing contribution of the internal production to the DOM pool. Photodegradation experiments showed that exposure to PAR+UVR produced slight changes in the DOC concentration and a reduction in DOM molecular weight/size. The contribution of humic vs. non-humic components influenced DOM photoreactivity. The prevalence of humic components determined high DOM photorecalcitrance.

category: ecology


title: Genomic analysis of a parasite invasion: colonization of the Americas by the blood fluke, Schistosoma mansoni

abstract: Schistosoma mansoni, a snail-vectored, blood fluke that infects humans, was introduced into the Americas from Africa during the Trans-Atlantic slave trade. As this parasite shows strong specificity to the snail intermediate host, we expected that adaptation to S. American Biomphalaria spp. snails would result in population bottlenecks and strong signatures of selection. We scored 475,081 single nucleotide variants (SNVs) in 143 S. mansoni from the Americas (Brazil, Guadeloupe, and Puerto Rico) and Africa (Cameroon, Niger, Senegal, Tanzania, and Uganda), and used these data to ask: (i) Was there a population bottleneck during colonization? (ii) Can we identify signatures of selection associated with colonization? And (iii) what were the source populations for colonizing parasites? We found a 2.4-2.9-fold reduction in diversity and much slower decay in linkage disequilibrium (LD) in parasites from East to West Africa. However, we observed similar nuclear diversity and LD in West Africa and Brazil, suggesting no strong bottlenecks and limited barriers to colonization. We identified five genome regions showing selection in the Americas, compared with three in West Africa and none in East Africa, which we speculate may reflect adaptation during colonization. Finally, we infer that unsampled African populations from central African regions between Benin and Angola, with contributions from Niger, are likely the major source(s) for Brazilian S. mansoni. The absence of a bottleneck suggests that this is a rare case of a serendipitous invasion, where S. mansoni parasites were preadapted to the Americas and were able to establish with relative ease.


title: Comparative analysis reveals the long-term co-evolutionary history of parvoviruses and vertebrates.

abstract: Parvoviruses (family Parvoviridae) are small DNA viruses that cause numerous diseases of medical, veterinary, and agricultural significance and have important applications in gene and anticancer therapy. DNA sequences derived from ancient parvoviruses are common in animal genomes and analysis of these endogenous parvoviral elements (EPVs) has demonstrated that the family, which includes twelve vertebrate-specific genera, arose in the distant evolutionary past. So far, however, such  paleovirological analysis has only provided glimpses into biology of parvoviruses and their long-term evolutionary interactions with hosts. Here, we comprehensively map EPV diversity in 752 published vertebrate genomes, revealing defining aspects of ecology and evolution within individual parvovirus genera. We identify 364 distinct EPV sequences and show these represent [~]200 unique germline incorporation events, involving at least five distinct parvovirus genera, that took place at points throughout the Cenozoic Era. We use the spatiotemporal and host range calibrations provided by these sequences to infer defining aspects of long-term evolution within individual parvovirus genera, including mammalian vicariance for genus Protoparvovirus, and inter-class transmission for genus Dependoparvovirus. Moreover, our findings support a model of virus evolution in which the long-term co-circulation of multiple parvovirus genera in vertebrates reflects the adaptation of each viral genus to fill a distinct ecological niche. Our discovery that parvovirus diversity can be understood in terms of genus-specific adaptations acquired over millions of years has important implications for their development as therapeutic tools - we show that these endeavours can now be approached from a rational foundation based on comparative evolutionary analysis. To support this, we published our data in the form of an open, extensible, and cross-platform database designed to facilitate the wider utilisation of evolution-related domain knowledge in parvovirus research.


title: Interaction between sperm whales (Physeter macrocephalus) and northern bottlenose whales (Hyperoodon ampullatus) and deep-water trawlers in the Northwest Atlantic

abstract: Interactions between various cetacean species and fisheries are geographically widespread and diverse. Foraging in association with fishing activities may increase prey encounter rates and possibly increase the quantity and the quality of the food consumed. This paper describes interactions between benthic trawlers, targeting mainly Greenland halibut, and two whale species: sperm whales and northern bottlenose whales, in the eastern Grand Banks of the northwest Atlantic. Whale behaviors were compared during four trawling-related activities: preparing/ shooting the net, towing, hauling and transiting between fishing sites. Sperm whales and bottlenose whales were more likely to be observed during hauling. We observed probable feeding behavior of both species close to the surface at the end of hauling which suggests they are taking fish escaping from the cod end of the net when it is close to the surface. It is not clear whether feeding attempts are made during other phases of the trawling cycle. Ten sperm whales were photo-identified and six of these individuals were resighted on different days. Resights of individuals indicated that sperm whales could follow trawlers through several sets over of distances up to 234 km. While some individuals were observed to move between fishing grounds others remained within one fishing area for some time. By contrast, even though twenty-three bottlenose whales were photo-identified, there were no resights of individual whales. While northern bottlenose whales have been studied quite extensively in some adjacent areas, particularly off Nova Scotia, their behaviour and distribution within the Grand Banks fishing areas has not been well described. No matches were found between northern bottlenose whales in this study and photo-identification catalogues for the Scotian Shelf or the Arctic. Whether and how northern bottlenose whales found in this area are connected to other subpopulations remains unclear.

category: animal behavior and cognition


title: Linear Approximate Pattern Matching Algorithm

abstract: Pattern matching is a fundamental process in almost every scientific domain. The problem involves finding the positions of a given pattern (usually of short length) in a reference stream of data (usually of large length). The matching can be as an exact or as an approximate (inexact) matching. Exact matching is to search for the pattern without allowing for mismatches (or insertions and deletions) of one or more characters in the pattern), while approximate matching is the opposite. For exact matching, several data structures that can be built in linear time and space are used and in practice nowadays. For approximate matching, the solutions proposed to solve this matching are non-linear and currently impractical. In this paper, we designed and implemented a structure that can be built in linear time and space and solve the approxi-mate matching problem in [Formula] search costs, where m is the length of the pattern, n is the length of the reference, and k is the number of tolerated mismatches (and insertion and deletions).


title: pH dependence of C·A, G·A and A·A mismatches in the stem of precursor microRNA-31

abstract:
MicroRNAs (miRNAs) are important regulators of post-transcriptional gene expression. Mature miRNAs are generated from longer transcripts (primary, pri- and precursor, pre-miRNAs) through a series of highly coordinated enzymatic processing steps. The sequence and structure of these pri- and pre-miRNAs play important roles in controlling their processing. Both pri- and pre-miRNAs adopt hairpin structures with imperfect base pairing in the helical stem. Here, we investigated the role of three base pair mismatches (A*A, G*A, and C*A) present in pre-miRNA-31. Using a combination of NMR spectroscopy and thermal denaturation, we found that the three base pair mismatches displayed unique structural properties, including varying dynamics and sensitivity to solution pH. These studies deepen our understanding of how the physical and chemical properties of base pair mismatches influence RNA structural stability.

Graphical abstract

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category: biophysics


title: Nelfinavir induces cytotoxicity towards high-grade serous ovarian cancer cells regardless of platinum sensitivity, involving induction of the unfolded protein response, modulation of protein synthesis, DNA damage, lysosomal impairment, and potentiation of toxicity caused by proteasome inhibition

abstract: High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction of HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction of clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of H2AX indicated NFV-mediated DNA damage, which was associated with decreased survival and proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho- eIF2, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.


title: Nelfinavir induces cytotoxicity towards high-grade serous ovarian cancer cells, involving induction of the unfolded protein response, modulation of protein synthesis, DNA damage, lysosomal impairment, and potentiation of toxicity caused by proteasome inhibition


title: SERCA-mediated calcium uptake in the DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy

abstract: The DBA/2J (D2) mdx mouse has emerged as a more severe model of Duchenne muscular dystrophy when compared to the traditional C57BL/10 (C57) mdx mouse. Here, we questioned whether sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) function would differ in muscles from young D2 and C57 mdx mice. In gastrocnemius muscles, both D2- and C57 mdx mice exhibited signs of impaired Ca2+ uptake, however, this was more severe in D2 mdx mice. Maximal SERCA activity was lowered only in D2 mdx gastrocnemius muscles and not C57 mdx muscles. Furthermore, in the left ventricle and diaphragm, Ca2+ uptake was impaired in C57 mdx muscles with lowered rates of Ca2+ uptake compared with C57 WT mice, whereas in muscles from D2 mdx mice, rates of Ca2+ uptake were unattainable due to the severe impairments in their ability to transport Ca2+. Overall, our study demonstrates that SERCA function is drastically impaired in young D2 mdx mice.

category: pathology


title: Sarcoplasmic reticulum calcium handling in young DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy


title: SERCA function is impaired in skeletal and cardiac muscles from young DBA/2J mdx mice


title: Characterization of cardiac pacemaker activity in the primate lemur Microcebus murinus.

abstract:
BackgroundGray mouse lemurs (Microcebus murinus) are one of the smallest and most ancestral primates known. Their size falls in between that of mice and rats, and their genetic proximity to humans makes them an emerging model to study age-related neurodegeneration. Since Microcebus murinus replicates similar senescence processes of humans, it constitutes a useful model also for studying cardiovascular dysfunctions. However, its cardiac physiology is unknown. Thus, we investigated sinoatrial node (SAN) pacemaker activity of mouse lemurs, presenting the first characterization of heart automaticity in nonhuman primates.

Methods and ResultsWe recorded the heart automaticity in freely moving mouse lemurs and in their SAN tissues and pacemaker myocytes. Mouse lemurs have a heart rate (HR) in between those of mice and rats and a similar generation of electrical impulses in the SAN tissue. Conversely, their ventricular depolarization is more similar to large mammals. Mouse lemur SAN myocytes express the main pacemaker currents at densities similar to mice: the hyperpolarization-activated current (If) and the L-type (ICa,L) and T-type (ICa,T) calcium currents. Moreover, mouse lemur SAN myocytes display spontaneous ryanodine receptor (RyR)-dependent Ca2+ transients. Using muscle-derived stem cells (MDSCs) from the Microcebus murinus skeletal muscle, we also differentiated pacemaker-like (PML) cells showing spontaneous automaticity and expressing markers of native SAN myocytes (HCN4 and connexin-45).

ConclusionsIn conclusion, our characterization of heart automaticity in Microcebus murinus provides new opportunities for comparative cardio-physiology studies in primates and with humans, and for pharmacologic testing of molecules that could assist in modulating age-related dysfunctions of automaticity.


title: Mouse lemur, a new primate model to investigate cardiac pacemaker activity.


title: Mouse lemur, a new animal model to investigate cardiac pacemaker activity in primates.


title: Italian universities do not recruit according to proficiency in scientific production

abstract:
We analyzed the files regarding recruitment competitions won by 186 professors of selected bibliometric disciplines in Florence between January 2014 and 30 June 2021. An equal number of professors recruited at other Italian universities and of researchers who never attained professorship in Italy were randomly chosen in the same disciplines as each Florentine professor among individuals possessing National Scientific Qualification, a prerequisite for professorship. The H-indexes at the time of qualification (T1), of the Florence call (T2), and the current (T3) time were obtained from Scopus.

Non-recruited researchers were more likely (Chi-square test) to show a higher H-index than both Florentine (T1 p=0.0005, T2 p=0.0015, T3 p=0.0095) and non-Florentine professors (T1 p=0.0078, T2 p=0.0245, T3 p=0.0500). Fifty-four non-recruited scientists serve in foreign universities, 100 at national/international research centers. The remaining 32 scientists (25 who keep producing despite precarious employment, and seven who have stopped publishing) were, at any rate, as likely as Florentine (T3 p=0.69) and non-Florentine professors (T3 p=0.14) to show a higher H-index.

This study suggests that Italian academia does not recruit professors according to their qualitative/quantitative ability to publish, a detriment to knowledge for the nationwide system and on a global scale.

category: scientific communication and education


title: Zebrafish airinemes optimize their shape between ballistic and diffusive search

abstract: In addition to diffusive signals, cells in tissue also communicate via long, thin cellular protrusions, such as airinemes in zebrafish. Before establishing communication, cellular protrusions must find their target cell. Here we demonstrate that the shape of airinemes in zebrafish are consistent with a finite persistent random walk model. The probability of contacting the target cell is maximized for a balance between ballistic search (straight) and diffusive search (highly curved, random). We find that the curvature of airinemes in zebrafish, extracted from live cell microscopy, is approximately the same value as the optimum in the simple persistent random walk model. We also explore the ability of the target cell to infer direction of the airinemes source, finding that there is a theoretical trade-off between search optimality and directional information. This provides a framework to characterize the shape, and performance objectives, of non-canonical cellular protrusions in general.


title: The social architecture of an in-depth cellular protein interactome

abstract: Nearly all cellular functions are mediated by protein-protein interactions and mapping the interactome provides fundamental insights into the regulation and structure of biological systems. In principle, affinity purification coupled to mass spectrometry (AP-MS) is an ideal and scalable tool, however, it has been difficult to identify low copy number complexes, membrane complexes and those disturbed by protein-tagging. As a result, our current knowledge of the interactome is far from complete, and assessing the reliability of reported interactions is challenging. Here we develop a sensitive, high-throughput, and highly reproducible AP-MS technology combined with a quantitative two-dimensional analysis strategy for comprehensive interactome mapping of Saccharomyces cerevisiae. We reduced required cell culture volumes thousand-fold and employed 96-well formats throughout, allowing replicate analysis of the endogenous green fluorescent protein (GFP) tagged library covering the entire expressed yeast proteome. The 4159 pull-downs generated a highly structured network of 3,909 proteins connected by 29,710 interactions. Compared to previous large-scale studies, we double the number of proteins (nodes in the network) and triple the number of reliable interactions (edges), including very low abundant epigenetic complexes, organellar membrane complexes and non-taggable complexes interfered by abundance correlation. This nearly saturated interactome reveals that the vast majority of yeast proteins are highly connected, with an average of 15 interactors, the majority of them unreported so far. Similar to social networks between humans, the average shortest distance is 4.2 interactions. A web portal (www.yeast-interactome.org) enables exploration of our dataset by the network and biological communities and variations of our AP-MS technology can be employed in any organism or dynamic conditions.


title: On Riemannian Geometries of Visual Space

abstract: AO_SCPLOWBSTRACTC_SCPLOWThis is a study of the phenomenal geometries constructed in the Riemannian geometry framework from simulated iso-disparity conics in the horizontal visual plane of the binocular system with the asymmetric eyes (AEs). For the eyes resting vergence posture, which depends on parameters of the AE, the iso-disparity conics are frontal straight lines in physical space. For all other fixations, the simulated iso-disparity conics consist of families of the ellipses or hyperbolas depending on both the AEs parameters and the bifoveal fixation. However, the iso-disparity conics arcs are perceived in the gaze direction as the frontal lines. Thus, geometries of physical and visual spaces are different. An assumption underlying the relevant architecture of the human visual system is combined with results from simulated iso-disparity straight lines, giving the relative depth as a function of the AEs parameters and the distance. This establishes the metric tensor in binocular space of fixations for the eyes resting vergence posture. The resulting geodesics in the gaze direction, give the distance to the horizon and zero curvature. For all other fixations, only the sign of the curvature may be inferred from the global behavior of the simulated iso-disparity conics.


title: Subtype transcriptomic profiling of myeloid cells in Alzheimer Disease brain illustrates the diversity in active microglia phenotypes

abstract: Microglia-mediated neuroinflammation contributes to disease progression in Alzheimers Disease (AD). Microglia demonstrate heterogeneous states with proposed beneficial, harmful, and disease-specific subtypes. Defining the spectrum of microglia phenotypes is crucially important to the design of neuroinflammation-modulating therapies. We performed single-nucleus RNA-seq on over 120,000 microglia nuclei isolated from dorsolateral prefrontal cortices collected from 12 AD and 10 controls. We detected several previously unrecognized microglia transcriptomic sub-populations, including three with predominant endolysosomal gene expression patterns and heterogeneous metabolic and inflammatory signatures. One endoloysomal subtype is more abundant in AD individuals and uniquely enriched for transcripts involved in nucleic acid detection and interferon signaling. AD individuals also exhibited increased expression of unfolded protein response and inflammatory genes in homeostatic microglia subpopulations. These results highlight the heterogenous nature of the microglia response to AD pathology and inform efforts to target specific subtypes of microglia in the development of novel AD therapies.


title: Transcriptomic profiling of myeloid cells in Alzheimer's Disease brain illustrates heterogeneity of microglia endolysosomal subtypes


title: Deep neural networks and visuo-semantic models explain complementary components of human ventral-stream representational dynamics

abstract: Deep neural networks (DNNs) are promising models of the cortical computations supporting human object recognition. However, despite their ability to explain a significant portion of variance in neural data, the agreement between models and brain representational dynamics is far from perfect. Here, we address this issue by asking which representational features are currently unaccounted for in neural timeseries data, estimated for multiple areas of the human ventral stream via source-reconstructed magnetoencephalography (MEG) data. In particular, we focus on the ability of visuo-semantic models, consisting of human-generated labels of higher-level object features and categories, to explain variance beyond the explanatory power of DNNs alone. We report a gradual transition in the importance of visuo-semantic features from early to higher-level areas along the ventral stream. While early visual areas are better explained by DNN features, higher-level cortical dynamics are best accounted for by visuo-semantic models. These results suggest that current DNNs fail to fully capture the visuo-semantic features represented in higher-level human visual cortex and suggest a path towards more accurate models of ventral stream computations.


title: Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's

abstract: In Alzheimers disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD. Here we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency specific network hyperexcitability. Our findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.


title: Desire and Craving ratings vary significantly for healthy alcohol consumers: Differences in semantic interpretation?

abstract: Craving is a central concept in alcohol, and other substance, research. Beginning in 1955 the World Health Organization outlined a working definition of the term to be used in research and clinical settings. However, the semantic interpretation of "craving" as a concept is not widely agreed upon. Since the publication of this first craving definition, a handful of studies have been conducted to investigate differences in operational definitions of "craving", and have demonstrated a lack of agreement between studies and across research subjects. With this background as evidence, our research group investigated, when left to their own semantic understanding of the terms, if regular alcohol consumers would rate craving for alcohol and desire for alcohol in similar ways using related descriptors. Thirty-nine healthy, non-binging regular alcohol consumers were studied across periods of their typical alcohol consumption and imposed alcohol abstinence, collecting ratings of desire and craving for alcohol approximately every two hours across the two experimental periods, and during neutral and alcohol related imagery viewing. Among these non-binging regular drinkers, ratings of desire and craving for alcohol are consistently different while drinking according to a persons typical routine or abstaining, throughout the day, and when viewing alcohol cue imagery.


title: COVID 19 breakthrough infection risk: a simple physical model describing the dependence on antibody concentration

abstract: The increase of COVID-19 breakthrough infection risk with time since vaccination has a clear relationship to the decrease of antibody concentration with time. The empirically-observed dependence on blood IgG anti-receptor binding domain antibody concentration of SARS-CoV-2 vaccine efficacy against infection has a rational explanation in the statistics of binding of antibody to spike proteins on the virus surface, leading to blocking of binding to the receptor: namely that the probability of infection is the probability that a critical number of the spike proteins protruding from the virus are unblocked. The model is consistent with the observed antibody concentrations required to induce immunity and with the observed dependence of vaccine efficacy on antibody concentration and thus is a useful tool in the development of models to relate, for an individual person, risk of infection given measured antibody concentration. It can be used to relate population breakthrough infection risk to the distribution across the population of antibody concentration, and its variation with time.

category: immunology


title: Statistics of antibody binding to the spike protein explain the dependence of COVID 19 infection risk on antibody concentration and affinity


title: Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

abstract: Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies. The uncontrolled activation of monocytes and the subsequent excessive production of inflammatory factors damage bone-cartilage joints in Juvenile Idiopathic Arthritis (JIA), a childhood rheumatoid arthritis (RA) disease. Inflammatory monocytes also exert a critical role in the cytokine storm induced by SARS-CoV2 infection in severe COVID-19 patients. The moderate beneficial effect of current therapies and clinical trials highlights the need of alternative strategies targeting monocytes to treat RA and COVID-19 pathologies. Here, we show that targeting CXCR4 with small amino compound such as the histamine analogue clobenpropit (CB) inhibits spontaneous and induced-production of a set of key inflammatory cytokines by monocytes isolated from blood and synovial fluids of JIA patients. Moreover, daily intraperitoneal CB treatment of arthritic mice results in significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption leading to reduction of disease progression. Finally, we provide the prime evidence that the exposure of whole blood from hospitalized COVID-19 patients to CB significantly reduces levels of key cytokine-storm-associated factors including TNF-, IL-6 and IL-1{beta}. These overall data show that targeting CXCR4 with CB-like molecules may represent a promising therapeutic option for chronic and viral-induced inflammatory diseases.


title: Cell-extrinsic autophagy in mature adipocytes regulates anti-inflammatory response to intestinal tissue injury through lipid mobilization

abstract:
Autophagy is a critical cellular recycling pathway which is genetically linked to the development of intestinal inflammation in humans. Inflammation drives adipose tissue breakdown and provision of major nutrients such as free fatty acids (FFA). However, the effect of autophagy-mediated FFA release by adipocytes in immune-mediated inflammatory diseases remains unexplored.

In a mouse model of intestinal inflammation, we found that visceral adipocytes upregulate autophagy at peak inflammation. Adipocyte-specific loss of the key autophagy gene Atg7 (Atg7Ad) resulted in the exacerbation of intestinal inflammation. TNF-induced lipolysis was impaired in Atg7-deficient adipocytes leading to the reduced availability of several FFA species, and decreased expression of the FFA transporter CD36 on adipose tissue macrophages (ATMs). Visceral adipose tissues from Atg7Ad mice released less IL-10 resulting in lower levels of circulating IL-10 in colitis. ATMs present the main source of adipose tissue-derived IL-10 during colitis. In vitro assays confirmed that FFA restriction from macrophages reduced CD36 expression and diminished IL-10 production.

Taken together, our study demonstrates that autophagy-mediated FFA release from adipocytes directs anti-inflammatory responses in ATMs, which in turn conveys protective effects for distant intestinal inflammation.