bluuebunny/crossref_metadata_2025 huggingface dataset:
ERnet: a tool for the semantic segmentation and quantitative analysis of endoplasmic reticulum topology for video-rate super-resolution imaging
Authors: Lu Meng , Christensen Charles N. , Weber Jana M. , Konno Tasuku , Läubli Nino F. , Scherer Katharina M. , Avezov Edward , Lio Pietro , Lapkin Alexei A. , Kaminski Schierle Gabriele S. , Kaminski Clemens F.
Published: May 2022

The topology of endoplasmic reticulum (ER) network is highly regulated by various cellular and environmental stimuli and affects major functions such as protein quality control and the cell’s response to metabolic changes. The ability to quantify the dynamical changes of the ER structures in response to cellular perturbations is crucial for the development of novel therapeutic approaches against ER associated diseases, such as hereditary spastic paraplegias and Niemann Pick Disease type C. However, the rapid movement and small spatial dimension of ER networks make this task challenging. Here, we combine video-rate super-resolution imaging with a state-of-the-art semantic segmentation method capable of automatically classifying sheet and tubular ER domains inside individual cells. Data are skeletonised and represented by connectivity graphs to enable the precise and efficient quantification and comparison of the network connectivity from different complex ER phenotypes. The method, called ERnet, is powered by a Vision Transformer architecture, and integrates multi-head self-attention and channel attention into the model for adaptive weighting of frames in the time domain. We validated the performance of ERnet by measuring different ER morphology changes in response to genetic or metabolic manipulations. Finally, as a means to test the applicability and versatility of ERnet, we showed that ERnet can be applied to images from different cell types and also taken from different imaging setups. Our method can be deployed in an automatic, high-throughput, and unbiased fashion to identify subtle changes in cellular phenotypes that can be used as potential diagnostics for propensity to ER mediated disease, for disease progression, and for response to therapy.
Mathematical Characterization of Private and Public Immune Repertoire Sequences
Authors: Böttcher Lucas , Wald Sascha , Chou Tom
Published: May 2022

Diverse T and B cell repertoires play an important role in mounting effective immune responses against a wide range of pathogens and malignant cells. The number of unique T and B cell clones is characterized by T and B cell receptors (TCRs and BCRs), respectively. Although receptor sequences are generated probabilistically by recombination processes, clinical studies found a high degree of sharing of TCRs and BCRs among different individuals. In this work, we formulate a mathematical and statistical framework to quantify receptor distributions. We define information-theoretic metrics for comparing the frequency of sampled sequences observed across different individuals. Using synthetic and empirical TCR amino acid sequence data, we perform simulations to compare theoretical predictions of this clonal commonality across individuals with corresponding observations. Thus, we quantify the concept of “publicness” or “privateness” of T cell and B cell clones. Our methods can also be used to study the effect of different sampling protocols on the expected commonality of clones and on the confidence levels of this overlap. We also quantify the information loss associated with grouping together certain receptor sequences, as is done in spectratyping.
Prenatal valproic acid-induced autism marmoset model exhibits higher salivary cortisol levels
Authors: Nakamura Madoka , Nakagami Akiko , Nakagaki Keiko , Yasue Miyuki , Kawai Nobuyuki , Ichinohe Noritaka
Published: May 2022

Individuals with autism spectrum disorder (ASD) are exposed to a variety of stressors owing to their behavioral traits. Cortisol is a hormone typically associated with stress, and its concentration and response to stress are higher in individuals with ASD than in controls. The mechanisms underlying cortisol dysregulation in ASD have been explored in rodents. Although rodent models have successfully replicated the major symptoms of autism (i.e., impaired vocal communication, social interaction deficits, and restricted/repetitive patterns of behavior), evidence suggests that the hypothalamic-pituitary-adrenal (HPA) axis system differs between rodents and primates. We developed an ASD model in the common marmoset (Callithrix jacchus), a New World monkey, utilizing prenatal exposure to valproic acid (VPA). In this study, we collected the salivary cortisol levels in VPA-exposed and unexposed marmosets in the morning and afternoon. Our results revealed that both VPA-exposed and unexposed marmosets showed similar diurnal changes in cortisol levels, which were lower in the afternoon than in the morning. However, heightened cortisol levels were observed in VPA-exposed marmosets in the morning, but not in the afternoon. These results are consistent with those of ASD in humans. Our results suggest that VPA-exposed marmosets show similarities not only in their behavioral patterns and brain pathologies, which we have reported previously but also in hormonal regulation, validating the usefulness of VPA-exposed marmosets also as a tool for ASD stress research.
Interplay between cell height variations and planar pulsations in epithelial monolayers
Authors: Thiagarajan Raghavan , Inamdar Mandar M. , Riveline Daniel
Published: May 2022

Biological tissues change their shapes through collective interactions of cells. This coordination sets length and time scales for dynamics where precision is essential, in particular during morphogenetic events. However, how these scales emerge remains unclear. Here we address this question using the pulsatile domains observed in confluent epithelial MDCK monolayers where cells exhibit synchronous contraction and extension cycles of ≈5 hours duration and ≈200 μm length scale. We report that the monolayer thickness changes gradually in space and time by more than two folds in order to counterbalance the contraction and extension of the incompressible cytoplasm. We recapitulate these pulsatile dynamics using a continuum model and show that incorporation of cell stiffness dependent height variations is critical both for generating temporal pulsations and establishing the domain size. We propose that this feedback between height and mechanics could be important in coordinating the length scales of tissue dynamics.
Thermopriming-associated proteome and sugar content responses in Pinus radiata embryogenic tissue
Authors: Castander-Olarieta Ander , Pereira Cátia , Mendes Vera M. , Correia Sandra , Manadas Bruno , Canhoto Jorge , Montalbán Itziar A. , Moncaleán Paloma
Published: May 2022

Improving the capacity of plants to face adverse environmental conditions requires a deep understanding of the molecular mechanisms governing stress response and adaptation. Proteomics, combined with metabolic analyses, offers a wide resource of information to be used in plant breeding programs. Previous studies have shown that somatic embryogenesis in Pinus spp. is a suitable tool not only to investigate stress response processes but also to modulate the behaviour of somatic plants. Based on this, the objective of this study was to analyse the protein and soluble sugar profiles of Pinus radiata embryonal masses after the application of high temperatures to unravel the mechanisms involved in thermopriming and memory acquisition at early stages of the somatic embryogenesis process. Results confirmed that heat provokes deep readjustments in the life-cycle of proteins, together with a significant reduction in the carbon-flux of central-metabolism pathways. Heat-priming also promotes the accumulation of proteins involved in oxidative stress defence, in the synthesis of specific amino acids such as isoleucine, influences cell division, the organization of the cytoskeleton and cell-walls, and modifies the levels of free soluble sugars like glucose or fructose. All this seems to be regulated by proteins linked with epigenetic, transcriptional and post-transcriptional mechanisms.
Immunomodulatory Extracellular Matrix Hydrogel Mitigates Scar Formation in a Model of Tongue Fibrosis
Authors: Zelus EI , Panduro A , Alperin M , Vahabzadeh-Hagh AM , Christman KL
Published: May 2022

Background

While head and neck cancer treatment regimens, including surgical resection, irradiation, and chemotherapy, are effective at removing tumors, they lead to muscle atrophy, denervation, and fibrosis, contributing to the pathogenesis of tongue dysphagia – difficulty swallowing. Current standard of care is ineffective; we propose an alternative approach utilizing an acellular and minimally invasive biomaterial to preserve muscle content and reduce fibrosis of the tongue after injury. Here, we investigate a decellularized extracellular matrix hydrogel for the treatment of tongue fibrosis in a partial glossectomy injury model.

Methods

Skeletal muscle extracellular matrix (SKM) hydrogel was fabricated by decellularizing porcine skeletal muscle tissue through established protocols. A partial glossectomy injury in the rat was used as a model of tongue fibrois, and SKM hydrogels along with saline controls were injected to the site of scarring two weeks after injury. Tissues were harvested at 3 and 7 days post-injection for gene expression analysis of immune and myogenic pathways, and at 4 weeks post-injection to evaluate histomorphological changes in skeletal muscle and scar formation.

Results

SKM hydrogel reduced scar formation and improved muscle fiber cross-sectional area in the region of injury compared to saline controls. SKM upregulated pro-regenerative immune response while downregulating pro-inflammatory response and further promoted angiogenic gene expression.

Conclusion

This study demonstrates the immunomodulatory and tissue-regenerative capacity of an acellular and minimally invasive biomaterial in a rodent model of tongue fibrosis.
Assessing PDB Macromolecular Crystal Structure Confidence at the Individual Amino Acid Residue Level
Authors: Shao Chenghua , Wang Sijian , Burley Stephen K.
Published: May 2022

Approximately 87% of the more than 190,000 atomic-level, (three-dimensional) 3D biostructures in the Protein Data Bank (PDB) were determined using macromolecular crystallography (MX). Agreement between 3D atomic coordinates and experimental data for >100 million individual amino acid residues occurring within ∼150,000 PDB MX structures was analyzed in detail. The Real-Space-Correlation-Coefficient (RSCC) calculated using the 3D atomic coordinates for each residue and experimental electron density enables outlier detection of unreliable atomic coordinates (particularly important for poorly-resolved sidechain atoms) and ready evaluation of local structure quality by PDB users. For human protein MX structures in PDB, comparisons of per-residue RSCC experimental-agreement metric with AlphaFold2 computed structure model confidence (pLDDT-predicted local distance difference test) document (i) that RSCC values and pLDDT scores are correlated (median correlation coefficient∼0.41), and (ii) that experimentally-determined MX structures (3.5 Å resolution or better) are more reliable than AlphaFold2 computed structure models and should be used preferentially whenever possible.
Cosmopolitan Scolytinae: strong common drivers but too many singularities for accurate prediction
Authors: Grégoire Jean-Claude , Jactel Hervé , Hulcr Jiri , Battisti Andrea , Inward Daegan , Petter Françoise , Grousset Fabienne
Published: May 2022

Aim

Many scolytine beetle species have been expanding their range in new territories across geographic barriers, traveling with wood, wood products and plants for planting, sometimes with a high impact on plant health. Here we attempt to quantify the mobility of these cosmopolitan species and to identify the biological drivers of mobility and impact.

Location

World

Major taxa studied

Coleoptera; Curculionidae; Scolytinae

Methods

Mobility was estimated by counting the numbers of landmasses (contiguous pieces of land, surrounded by ocean or sea) colonized by each species. A series of potential drivers (taxonomic tribes; feeding habits; polyphagy; reproductive strategy; host taxa; pheromones and primary attractants) as well as impact on host health were recorded.

Results

163 species were identified, out of 5546 counted in the whole subfamily. Four tribes (Xyleborini; Ipini; Crypturgini; Hylastini) were significantly over-represented, and two others (Corthylini; Hexacolini) were under-represented. 53% of the 163 species are inbreeding, a very significant excess as compared to the whole subfamily (29%). The inbreeders colonized more landmasses than the outbreeders. There is a significant relationship between the number of host families attacked by a species and the number of colonized landmasses. Species restricted to conifers colonized fewer landmasses than hardwood generalists. Species attacking both types of hosts are the most mobile. Most of the invasive species respond to host primary attractants, only one quarter respond to pheromones. All very mobile species respond to primary attractants, and none responds to pheromones. Very mobile species are all associated with a high or moderate impact.

Main conclusions

The most mobile species belong for a large part to a limited number of subtribes. They are often inbreeding, polyphagous and respond to primary attractants but do not produce pheromones. However, many species that do not, or only partly, belong to these categories, have established in several landmasses, sometimes with a high impact. For example, the outbreeding Scolytus multistriatus, that attacks only 3 host families and produces aggregation pheromones, has established in thirteen landmasses, with a high impact. Therefore, risk prediction needs to assess diversity of species-specific biological traits beyond the few routinely analyzed in literature.
Striosomes constrain locomotor vigor with respect to an innate valence differential
Authors: Hawes Sarah , Liang Bo , Oldham Braden , Song Bin , Chang Lisa , Lin Da-Ting , Cai Huaibin
Published: May 2022

Survival demands that safe and unsafe contexts are met with different locomotor profiles, yet whether striatal microcircuitry links contextual valence to spontaneous locomotor vigor is unresolved. Here we test for striosome contributions to spontaneous locomotion using ablation, calcium imaging and chemogenetics in the context of a modified Light/Dark box test. We found that locomotor speed reflects the unlearned, external valence differential present in this test, and that striosomes gate valence-oriented speed selection. Our data suggest that striosomes dampen motor vigor associated with lesser valence, or elevated anxiety.

Highlights

Mice explore the light and dark zones in Light/Dark box with different walk speed

Striosome ablation reduces restful slowing and elevates speed relative to zone

Many striosome neurons exhibit light-zone preference and speed related activity

Striosome enhancement slows mice and blunts zone discrimination by speed
Highly Dynamic Gene Family Evolution Suggests Changing Roles for PON Genes Within Metazoa
Authors: Lucas Sarah A.M. , Graham Allie M , Presnell Jason S , Clark Nathan L
Published: May 2022

Change in gene family size has been shown to facilitate adaptation to different selective pressures. This includes gene duplication to increase dosage or diversification of enzymatic substrates and gene deletion due to relaxed selection. We recently found that the PON1 gene, an enzyme with arylesterase and lactonase activity, was lost repeatedly in different aquatic mammalian lineages, suggesting that the PON gene family is responsive to environmental change. We further investigated if these fluctuations in gene family size were restricted to mammals and approximately when this gene family was expanded within mammals. Using 112 metazoan protein models, we explored the evolutionary history of the PON family to characterize the dynamic evolution of this gene family. We found that there have been multiple, independent expansion events in tardigrades, cephalochordates, and echinoderms. In addition, there have been partial gene loss events in monotremes and sea cucumbers and what appears to be complete loss in arthropods, urochordates, platyhelminths, ctenophores, and placozoans. In addition, we show the mammalian expansion to three PON paralogs occurred in the ancestor of all mammals after the divergence of sauropsida but before the divergence of monotremes from therians. We also provide evidence of a novel PON expansion within the brushtail possum. In the face of repeated expansions and deletions in the context of changing environments, we suggest a range of selective pressures, including pathogen infection and mitigation of oxidative damage, are likely influencing the diversification of this dynamic gene family across metazoa.
Microglia maintain homeostatic conditions in the developing rostral migratory stream
Authors: Meller Sarah J. , Hernandez Lexie , Martin-Lopez Eduardo , Liberia Teresa , Greer Charles A.
Published: May 2022

Microglia invade the neuroblast migratory corridor of the rostral migratory stream (RMS) early in development. This work examines how microglia maintain the homeostatic conditions permissive to neuroblast migration in the RMS during the early postnatal period. GFP labeled microglia in CX3CR-1GFP/+ mice assemble primarily along the outer borders of the RMS during the first postnatal week, where they exhibit predominantly an ameboid morphology and associate with migrating neuroblasts. Microglia ablation for 3 days postnatally does not impact the density of pulse labeled BrdU+ neuroblasts nor the distance migrated by tdTomato electroporated neuroblasts in the RMS. However, microglia wrap DsRed-labeled neuroblasts in the RMS of P7 CX3CR-1GFP/+;DCXDsRed/+ mice and express the phagocytic markers CD68, CLEC7A and MERTK, suggesting active phagocytosis of neuroblasts in the developing RMS. Microglia depletion for 14 days postnatally further induced an accumulation of DCX+ neuroblasts and CC3+ apoptotic cells in the RMS, a wider RMS and extended patency of the lateral ventricle extension in the olfactory bulb. These findings illustrate the importance of microglia phagocytosis in maintaining the homeostasis of the early postnatal RMS.

SIGNIFICANCE STATEMENT

Microglia are brain-resident immune cells responsible for both maintaining homeostatic conditions necessary for normal neurodevelopment as well as orchestrating the brain’s response to environmental insults. The effects of microglia-mediated immune response during development may be of special relevance to the olfactory system, which is unique in both its vulnerability to environmental insults as well as its extended period of neurogenesis and neuronal migration. The work presented here examines how microglia maintain homeostatic conditions in the neuroblast migratory corridor of the rostral migratory stream (RMS) in the olfactory system during early postnatal development. Our findings illustrate the importance of microglia phagocytosis in the early postnatal RMS and provides insights into microglia function during periods of neurogenesis and neuronal migration.
Inferring Neural Activity Before Plasticity: A Foundation for Learning Beyond Backpropagation
Authors: Song Yuhang , Millidge Beren , Salvatori Tommaso , Lukasiewicz Thomas , Xu Zhenghua , Bogacz Rafal
Published: May 2022

For both humans and machines, the essence of learning is to pinpoint which components in its information processing pipeline are responsible for an error in its output — a challenge that is known ascredit assignment. How the brain solves credit assignment is a key question in neuroscience, and also of significant importance for artificial intelligence. It has long been assumed that credit assignment is best solved by backpropagation, which is also the foundation of modern machine learning. However, it has been questioned whether it is possible for the brain to implement backpropagation and learning in the brain may actually be more efficient and effective than backpropagation. Here, we set out a fundamentally different principle on credit assignment, calledprospective configuration. In prospective configuration, the network first infers the pattern of neural activity that should result from learning, and then the synaptic weights are modified to consolidate the change in neural activity. We demonstrate that this distinct mechanism, in contrast to backpropagation, (1) underlies learning in a well-established family of models of cortical circuits, (2) enables learning that is more efficient and effective in many contexts faced by biological organisms, and (3) reproduces surprising patterns of neural activity and behaviour observed in diverse human and animal learning experiments. Our findings establish a new foundation for learning beyond backpropagation, for both understanding biological learning and building artificial intelligence.
Fruitful female fecundity after feedingGryllodes sigillatusroyal jelly
Authors: Muzzatti MJ , McConnell E , Neave S , MacMillan HA , Bertram SM
Published: May 2022

Dietary honey bee royal jelly increases insect growth rates and adult body size. Royal jelly could enhance mass insect production as a dietary supplement, but it is costly to produce. The mechanisms underlying the effects of royal jelly on growth remain unclear, and so it is valuable to understand the effects of royal jelly on a mass reared model species to try and augment body size in a more cost-effective manner. To determine the effect of royal jelly on a cricket species (Gryllodes sigillatus) farmed on mass for human consumption, we ran two experiments. In one experiment we tested the dose-dependent response ofGryllodes sigillatusto royal jelly using a range of diets across 0-30% w/w royal jelly. In another experiment we measured the individual-level life history responses ofGryllodes sigillatusto royal jelly over time by individually rearing freshly-hatchedGryllodes sigillatuson two separate diets: half were fed a commercially available cricket diet, while the other half were fed the same diet mixed with 15% w/w fresh royal jelly. Body size and mass measurements were recorded weekly for five weeks. We found the effects of royal jelly to be sex-dependent within crickets: females fed the royal jelly diet grew to be 30% heavier, and this effect was driven by significantly longer abdomens containing 67% more eggs compared to those fed the basal diet. There was a higher probability of crickets reaching adulthood after 35 days when fed royal jelly, and female mass was optimised at approximately 17% w/w royal jelly. Our results reveal that while a royal jelly dietary supplement can increase the yield of mass-reared insects, the life-history responses are species- and sex-specific.
Plasticity of threespine stickleback nuptial signals: laboratory manipulation of ambient light causes a shift in male reflectance patterns
Authors: Scott Robert J.
Published: May 2022

I caught courting male threespine stickleback (Gasterosteus aculeatus) in Hotel Lake, BC, Canada, and transferred them to one of three experimental lighting environments. Male signal reflectance was measured upon capture from the lake, at one-day post transfer to the experimental light, and at onset of courtship behaviour under artificial light. Male signals responded rapidly to the change in lighting environment following transfer from the wild to the artificial lighting environments and in different ways dependent upon the artificial light composition. Males under red-shifted light had higher signal reflectance in the short wavelength range of the spectrum and less reflectance in the medium and long wavelength range of the spectrum relative to the males in blue-green shifted and full-spectrum lighting. Given the relative prominence of the male stickleback nuptial signal in the behavioural ecology literature, the increasing evidence for the signal’s ambient light dependent expression, and the large body of literature based on experiments conducted under artificial light, it would be prudent to repeat some of the classic mate choice experiments under more realistic lighting conditions.
Pdx1 expression in hematopoietic cells activates Kras-mutation to drive leukemia in KC (Pdx1-Cre ; LSL-KrasG12D/+) mice
Authors: Walcheck Morgan T. , Nukaya Manabu , Ranheim Erik A. , Matkowskyj Kristina A. , Ronnekleiv-Kelly Sean
Published: May 2022

Background

Pdx1 expression in pancreatic lineage cells underlies the utility of the KC mouse model (Pdx1-Cre; LSL-KrasG12D/+) for understanding how KrasG12D-mutation drives formation of pancreas cancer precursor lesions and carcinoma. The highly utilized KC model has a reported mortality rate of about 30%, which has been attributed to pancreas cancer, despite lack of substantive evidence. This study describes a novel cause of the early deaths, in which KC mice develop Kras-driven T-cell acute lymphoblastic leukemia (T-ALL).

Methods

KC mice and control mice underwent histopathologic examination including thymus, liver, spleen, bone marrow and pancreas, and immunohistochemistry (IHC) was used to confirm leukemia development. A reporter strain (Ai14) was used to identify location of Pdx1-Cre expression and concomitant mutant-Kras activation, which was confirmed using flow cytometry, IHC, immunofluorescence, mRNA analysis, and bone marrow transplant studies.

Results

Pdx1 expression in the hematopoietic compartment of KC mice resulted in Cre-recombinase mediated excision of lox-stop and activation of mutant-Kras gene (KrasG12D/+) in the multipotent progenitor cells (MPP), and subsequent development of Kras-mutant T-ALL creating thymic tumors in a subset of mice. Overall, 20% (5/25) of KC mice developed a large thymic tumor due to T-ALL by 9 months of age. Moreover, through isolation and transplantation of pooled bone marrow from KC mice into CD45 congenic mice, 100% of recipient mice were found to develop T-ALL. These results further confirm mutant-Kras expression in the hematologic compartment is driving the development of T-ALL in the KC mouse model.

Conclusions

These results are an essential consideration for investigators while utilizing this model in pancreas cancer studies, particularly when evaluating factors that may coincidentally enhance the formation of KrasG12D-driven T-ALL (e.g. transcription factors impacting hematopoietic cells). Finally, the lower penetrance of T-ALL development in KC mice (compared to existing leukemia models) suggest that the KC mouse could be considered as an alternative research model to evaluate onset and factors that exacerbate development of T-ALL.
Physical Obstacles Constrain Behavioral Parameter Space of Successful Localization in Honey Bee Swarms
Authors: Nguyen Dieu My T. , Iuzzolino Michael L. , Peleg Orit
Published: May 2022

Honey bees (Apis mellifera L.) localize the queen and aggregate into a swarm by forming a collective scenting network to directionally propagate volatile pheromone signals. Previous experiments show the robustness of this communication strategy in the presence of physical obstacles that partially block pheromone flow and the path to the queen. Specifically, there is a delay in the formation of the scenting network and aggregation compared to a simple environment without perturbations. To better understand the effect of obstacles beyond temporal dynamics, we use the experimental results as inspiration to explore how the behavioral parameter space of collective scenting responds to obstacle. We extend an agent-based model previously developed for a simple environment to account for the presence of physical obstacles. We study how individual agents with simple behavioral rules for scenting and following concentration gradients can give rise to collective localization and swarming. We show that the bees are capable of navigating the more complex environment with a physical obstacle to localize the queen and aggregate around her, but their range of behavioral parameters is more limited and less flexible as a result of the spatial density heterogeneity in the bees imposed by the obstacle.
Bacteroides muris sp. nov. isolated from the cecum of wild-derived house mice
Authors: Fokt Hanna , Unni Rahul , Repnik Urska , Schmitz Ruth A , Bramkamp Marc , Baines John F. , Unterweger Daniel
Published: May 2022

Two bacterial strains, KH365_2T and KH569_7, were isolated from the cecum contents of wild-derived house mice. The strains were characterized as Gram-negative, rod-shaped, strictly anaerobic, and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences revealed that both strains were most closely related to Bacteroides uniformis ATCC 8492T. Whole genome sequences of KH365_2T and KH569_7 strains have a DNA G+C content of 46.02% and 46.03% mol, respectively. Most morphological and biochemical characteristics did not differ between the newly isolated strains and classified Bacteroides strains. However, the average nucleotide identity (ANI) and dDNA-DNA hybridization (dDDH) values clearly distinguished the two strains from described members of the genus Bacteroides. Here, we present the phylogeny, morphology, and physiology of a novel species of the genus Bacteroides and propose the name Bacteroides muris sp. nov., with KH365_2T (DSM XXX = CCUG XXX) as type strain.
Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice
Authors: Engler-Chiurazzi EB , Russel AE , Povroznik JM , McDonald K , Porter K , Wang DS , Billig BK , Felton CC , Hammock J , Schreurs BG , O’Callaghan JD , Zwezdaryk KJ , Simpkins JW
Published: May 2022

Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections is emerging as a potential driver of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented. Yet, the brain aging impacts of repeated, intermittent inflammatory challenges are less well studied. To extend the emerging literature assessing the impact of infection burden on cognitive function among normally aging mice, here, we repeatedly exposed adult mice to intermittent LPS challenges during the aging period. Male 10-month-old C57BL6 mice were systemically administered escalating doses of LPS once every two weeks for 2.5 months. We evaluated cognitive consequences using the non-spatial step-through inhibitory avoidance task and both spatial working and reference memory versions of the Morris water maze. We also probed several potential mechanisms, including cortical and hippocampal cytokine/chemokine gene expression as well as hippocampal neuronal function via extracellular field potential recordings. Though there was limited evidence for an ongoing inflammatory state in cortex and hippocampus, we observed impaired learning and memory and a disruption of hippocampal long-term potentiation. These data suggest that a history of intermittent exposure to LPS-induced inflammation is associated with a subtle but significantly accelerated trajectory of cognitive decline. The broader impact of these findings may have important implications for standard of care involving infections in aging individuals or populations at-risk for dementia.
COInr and mkCOInr: Building and customizing a non-redundant barcoding reference database from BOLD and NCBI using a lightweight pipeline
Authors: Meglécz Emese
Published: May 2022

The taxonomic assignment of metabarcoding data strongly depends on the taxonomic coverage of the reference database. Therefore, it is fundamental to access and pool data from the two major sources of COI sequences, the BOLD and the NCBI nucleotide databases, and enrich them with custom COI data, when available.

The COInr database is a freely available, easy-to-access database of COI reference sequences extracted from the BOLD and NCBI nucleotide databases. It is a comprehensive database: not limited to a taxon, a gene region, or a taxonomic resolution; therefore, it is a good starting point for creating custom databases. Sequences are dereplicated between databases and within taxa. Each taxon has a unique taxonomic Identifier (taxID), fundamental to avoid ambiguous associations of homonyms and synonyms in the source database. TaxIDs form a coherent hierarchical system fully compatible with the NCBI taxIDs allowing to create their full or ranked linages.

The mkCOInr tool is a series of Perl scripts necessary to download sequences from BOLD and NCBI, build the COInr database and customize it according to the users’ needs. It is possible to select or eliminate sequences for a list of taxa, select a specific gene region, select for minimum taxonomic resolution, add new custom sequences, and format the database for BLAST, QIIME, RDP classifier.

The COInr database can be downloaded from https://doi.org/10.5281/zenodo.6555985 and mkCOInr and the full documentation is available at https://github.com/meglecz/mkCOInr.
Interplay between Polycomb PCGF protein interactomes revealed by screening under endogenous conditions
Authors: Munawar Nayla , Wynne Kieran , Oliviero Giorgio
Published: May 2022

The six PCGF proteins (PCGF1-6) define the biochemical identity of Polycomb Repressor Complex 1 (PRC1) subcomplexes. While structural and functional studies of PRC1 subcomplexes have revealed specialized roles in distinct aspects of epigenetic regulation, our understanding of variation in protein interaction networks between the PCGF subunits is incomplete. We carried out an affinity purification mass spectrometry (AP-MS) screen of subunits PCGF1 (NSPC1), PCGF2 (MEL18), and PCGF4 (BMI1), using an immunoprecipitation approach that replicated endogenous cellular conditions in a cell line capable of differentiation programs. Over 200 interactions were found, including 83 that had not been described previously. Bioinformatic analysis found that these interacting proteins covered a range of functional pathways, often focused on cell biology and chromatin regulation. We found evidence of mutual regulation (at mRNA and protein level) between distinct PCGF subunits. Furthermore, we confirmed that disruption of each subunit using shRNA results in reduced proliferation ability. Overall, our work adds to understanding of the role of PCGF proteins within the wider cellular network.
Comprehensive analysis of pathways in Coronavirus 2019 (COVID-19) using an unsupervised machine learning method
Authors: Taheri Golnaz , Habibi Mahnaz
Published: May 2022

The World Health Organization (WHO) introduced “Coronavirus disease 19” or “COVID-19” as a novel coronavirus in March 2020. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the fast discovery of effective treatments to fight this worldwide crisis. Artificial intelligence and bioinformatics analysis pipelines can assist with finding biomarkers, explanations, and cures. Artificial intelligence and machine learning methods provide powerful infrastructures for interpreting and understanding the available data. On the other hand, pathway enrichment analysis, as a dominant tool, could help researchers discover potential key targets present in biological pathways of host cells that are targeted by SARS-CoV-2. In this work, we propose a two-stage machine learning approach for pathway analysis. During the first stage, four informative gene sets that can represent important COVID-19 related pathways are selected. These “representative genes” are associated with the COVID-19 pathology. Then, two distinctive networks were constructed for COVID-19 related signaling and disease pathways. In the second stage, the pathways of each network are ranked with respect to some unsupervised scorning method based on our defined informative features. Finally, we present a comprehensive analysis of the top important pathways in both networks. Materials and implementations are available at: https://github.com/MahnazHabibi/Pathway.
Using unsupervised learning algorithms to identify essential genes associated with SARS-CoV-2 as potential therapeutic targets for COVID-19
Authors: Taheri Golnaz , Habibi Mahnaz
Published: May 2022

Motivation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires the fast discovery of effective treatments to fight this worldwide concern. Several genes associated with the SARS-CoV-2, which are essential for its functionality, pathogenesis, and survival, have been identified. These genes, which play crucial roles in SARS-CoV-2 infection, are considered potential therapeutic targets. Developing drugs against these essential genes to inhibit their regular functions could be a good approach for COVID-19 treatment. Artificial intelligence and machine learning methods provide powerful infrastructures for interpreting and understanding the available data and can assist in finding fast explanations and cures.

Results

We propose a method to highlight the essential genes that play crucial roles in SARS-CoV-2 pathogenesis. For this purpose, we define eleven informative topological and biological features for the biological and PPI networks constructed on gene sets that correspond to COVID-19. Then, we use three different unsupervised learning algorithms with different approaches to rank the important genes with respect to our defined informative features. Finally, we present a set of 18 important genes related to COVID-19.

Availability

Materials and implementations are available at: https://github.com/MahnazHabibi/Gene_analysis.

Contact

m_habibi@qiau.ac.ir

Supplementary information

Supplementary data are available at Bioinformatics online.
An evolutionary paradigm favoring crosstalk between bacterial two-component signaling systems
Authors: Vemparala Bharadwaj , Parambathu Arjun Valiya , Saini Deepak Kumar , Dixit Narendra M
Published: May 2022

The prevalent paradigm governing bacterial two-component signaling systems (TCSs) is specificity, wherein the histidine kinase (HK) of a TCS exclusively activates its cognate response regulator (RR). Crosstalk, where HKs activate noncognate RRs, is considered evolutionarily disadvantageous because it can compromise adaptive responses by leaking signals. Yet, crosstalk is observed in several bacteria. Here, to resolve this paradox, we propose an alternative paradigm where crosstalk can be advantageous. We envisioned ‘programmed’ environments, wherein signals appear in predefined sequences. In such environments, crosstalk that primes bacteria to upcoming signals may improve adaptive responses and confer evolutionary benefits. To test this hypothesis, we employed mathematical modeling of TCS signaling networks and stochastic evolutionary dynamics simulations. We considered the comprehensive set of bacterial phenotypes, comprising thousands of distinct crosstalk patterns, competing in varied signaling environments. Our simulations predicted that in programmed environments phenotypes with crosstalk facilitating priming would outcompete phenotypes without crosstalk. In environments where signals appear randomly, bacteria without crosstalk would dominate, explaining the specificity widely seen. Additionally, a testable prediction was that the phenotypes selected in programmed environments would display ‘one-way’ crosstalk, ensuring priming to ‘future’ signals. Interestingly, the crosstalk networks we deduced from available data on TCSs of Mycobacterium tuberculosis all displayed one-way crosstalk, offering strong support to our predictions. Our study thus identifies potential evolutionary underpinnings of crosstalk in bacterial TCSs, suggests a reconciliation of specificity and crosstalk, makes testable predictions of the nature of crosstalk patterns selected, and has implications for understanding bacterial adaptation and the response to interventions.

IMPORTANCE

Bacteria use two-component signaling systems (TCSs) to sense and respond to environmental changes. The prevalent paradigm governing TCSs is specificity, where signal flow through TCSs is insulated; leakage to other TCSs is considered evolutionarily disadvantageous. Yet, crosstalk between TCSs is observed in many bacteria. Here, we present a potential resolution of this paradox. We envision programmed environments, wherein stimuli appear in predefined sequences. Crosstalk that primes bacteria to upcoming stimuli could then confer evolutionary benefits. We demonstrate this benefit using mathematical modeling and evolutionary simulations. Interestingly, we found signatures of predicted crosstalk patterns in Mycobacterium tuberculosis. Furthermore, specificity was selected in environments where stimuli occurred randomly, thus reconciling specificity and crosstalk. Implications follow for understanding bacterial evolution and for interventions.
Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation
Authors: Pizzoni Alejandro , Zhang Xuefeng , Naim Nyla , Altschuler Daniel L
Published: May 2022

cAMP is a key player in many physiological processes. Classically considered to originate solely from the plasma membrane, this view was recently challenged by observations showing that GPCRs can sustain cAMP signaling from intracellular compartments associated with nuclear PKA translocation and activation of transcriptional events. In this report we show that neither PKA translocation nor cAMP diffusion, but rather nuclear sAC activation represents the only source of nuclear cAMP accumulation, PKA activation, and CREB phosphorylation. Both pharmacological and genetic sAC inhibition, that did not affect the cytosolic cAMP levels, completed blunted nuclear cAMP accumulation, PKA activation and proliferation, while an increase in sAC nuclear expression significantly enhanced cell proliferation. Moreover, utilizing novel compartment-specific optogenetic actuators we showed that light-dependent nuclear cAMP synthesis can stimulate PKA, CREB and trigger cell proliferation. Thus, our results show that sAC-mediated nuclear accumulation is not only necessary but sufficient and rate-limiting for cAMP-dependent proliferation.
Cellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma
Authors: Salam Rana , Saliou Alexa , Bielle Franck , Bertrand Mathilde , Antoniewski Christophe , Carpentier Catherine , Alentorn Agusti , Capelle Laurent , Sanson Marc , Huillard Emmanuelle , Bellenger Léa , Guégan Justine , Le Roux Isabelle
Published: May 2022

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells were identified in patient and mouse GBMs. Partial removal of p16Ink4a-expressing malignant senescent cells, which make up less than 7 % of the tumor, modified the tumor ecosystem and improved the survival of GBM-bearing mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identified the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.
Sparse RNNs can support high-capacity classification
Authors: Turcu Denis , Abbott L. F.
Published: May 2022

Feedforward network models performing classification tasks rely on highly convergent output units that collect the information passed on by preceding layers. Although convergent output-unit like neurons may exist in some biological neural circuits, notably the cerebellar cortex, neocortical circuits do not exhibit any obvious candidates for this role; instead they are highly recurrent. We investigate whether a sparsely connected recurrent neural network (RNN) can perform classification in a distributed manner without ever bringing all of the relevant information to a single convergence site. Our model is based on a sparse RNN that performs classification dynamically. Specifically, the interconnections of the RNN are trained to resonantly amplify the magnitude of responses to some external inputs but not others. The amplified and non-amplified responses then form the basis for binary classification. Furthermore, the network acts as an evidence accumulator and maintains its decision even after the input is turned off. Despite highly sparse connectivity, learned recurrent connections allow input information to flow to every neuron of the RNN, providing the basis for distributed computation. In this arrangement, the minimum number of synapses per neuron required to reach maximum memory capacity scales only logarithmically with network size. The model is robust to various types of noise, works with different activation and loss functions and with both backpropagation- and Hebbian-based learning rules. The RNN can also be constructed with a split excitation-inhibition architecture with little reduction in performance.
Neural learning rules for generating flexible predictions and computing the successor representation
Authors: Fang Ching , Aronov Dmitriy , Abbott L.F. , Mackevicius Emily
Published: May 2022

The predictive nature of the hippocampus is thought to be useful for memory-guided cognitive behaviors. Inspired by the reinforcement learning literature, this notion has been formalized as a predictive map called the successor representation (SR). The SR captures a number of observations about hippocampal activity. However, the algorithm does not provide a neural mechanism for how such representations arise. Here, we show the dynamics of a recurrent neural network naturally calculate the SR when the synaptic weights match the transition probability matrix. Interestingly, the predictive horizon can be flexibly modulated simply by changing the network gain. We derive simple, biologically plausible learning rules to learn the SR in a recurrent network. We test our model with realistic inputs and match hippocampal data recorded during random foraging. Taken together, our results suggest that the SR is more accessible in neural circuits than previously thought and can support a broad range of cognitive functions.