bluuebunny/crossref_metadata_2025 huggingface dataset:
The airborne transmission of viruses causes tight transmission bottlenecks
Authors: Sinclair Patrick , Zhao Lei , Beggs Clive , Illingworth Christopher J. R.
Published: April 2023

The transmission bottleneck describes the number of viral particles that found an infection in a new host. Previous studies have used genome sequence data to suggest that transmission bottlenecks for influenza and SARS-CoV-2 involve few viral particles, but the general principles underlying these bottlenecks are not fully understood. Here we show that, across a broad range of circumstances, tight transmission bottlenecks arise as a consequence of the physical process underlying airborne viral transmission. We use a mathematical model to describe the process of infectious particles being emitted by an infected individual and inhaled by others nearby. The extent to which exposure to particles translates into infection is determined by an effective viral load, which is calculated as a function of the epidemiological parameter R0. Across multiple scenarios, including those present at a superspreading event, our model suggests that the great majority of transmission bottlenecks involve few viral particles, with a high proportion of infections being caused by a single viral particle. Our results provide a physical explanation for previous inferences of bottleneck size and predict that tight transmission bottlenecks prevail more generally in respiratory virus transmission.
Y-linked copy number polymorphism of target of rapamycin (TOR) is associated with sexual size dimorphism in seed beetles
Authors: Kaufmann Philipp , Wiberg R. Axel W. , Papachristos Konstantinos , Scofield Douglas G. , Tellgren-Roth Christian , Immonen Elina
Published: April 2023

The Y chromosome is theorized to facilitate evolution of sexual dimorphism by accumulating sexually antagonistic loci, but empirical support is scarce. Due to the lack of recombination Y chromosomes are prone to degenerative processes, which poses a constraint on their adaptive potential. Yet, in the seed beetleCallosobruchus maculatussegregating Y linked variation affects male body size and thereby sexual size dimorphism (SSD). Here we assembleC. maculatussex chromosome sequences and identify molecular differences associated with Y-linked SSD variation. The assembled Y chromosome is largely euchromatic and contains over 400 genes, many of which are ampliconic with a mixed autosomal and X chromosome ancestry. Functional annotation suggests that the Y chromosome plays important roles in males beyond primary reproductive functions. Crucially, we find that, besides an autosomal copy of the genetarget of rapamycin(TOR), males carry an additionalTORcopy on the Y chromosome. TOR is a conserved regulator of growth across taxa, and our results suggest that a Y-linkedTORprovides a male specific opportunity to alter body size. A comparison of Y haplotypes associated with male size difference uncovers a copy number variation forTOR, where the haplotype associated with decreased male size, and thereby increased sexual dimorphism, has two additionalTORcopies. This suggests that sexual conflict over growth has been mitigated by autosome to Y translocation ofTORfollowed by gene duplications. Our results reveal that despite of suppressed recombination, the Y chromosome can harbour adaptive potential as a male-limited supergene.
Impact of prenatal synthetic glucocorticoid exposure on the adolescent brain
Authors: Magalhães Ricardo , Gonçalves Nuno , Sousa Rui , Coelho Ana , Soares-Cunha Carina , Moreira Pedro , Marques Paulo , Tuulari Jetro J , Scheinin Nora M , Karlsson Linnea , Karlsson Hasse , Sousa Nuno , Rodrigues Ana João
Published: April 2023

Synthetic Glucocorticoids (sGC) are commonly prescribed in preterm risk pregnancies in order to improve fetal organ maturation. This administration greatly reduces perinatal and neonatal mortality and respiratory distress syndrome associated with prematurity, but preclinical evidence warns for an adverse effect of sGC in the developing brain.

In this work we evaluated the long-term effects of prenatal exposure to sGC in the brain of 17 years-old adolescents using multimodal MRI. From 4607 birth registrations from Hospital de Braga - Portugal, we selected participants that were born with similar gestational age, but that were either exposed during pregnancy to sGC (n=21) or non-exposed (n=24). After obtaining a detailed clinical history, participants were subjected to an extensive neuropsychological evaluation, followed by structural and functional MRI.

No differences were found in the performance on neuropsychological tests between sGC-exposed and non-exposed participants. Moreover, no differences were found in regional brain volumes. However, the sGC-exposed group presented reduced functional connectivity at rest in a network involving primarily sub-cortical, cerebellar and frontal nodes in comparison to the non-exposed group, even after controlling for confounding factors such as gestational age at birth, birth weight, and sex.

Our results suggest that prenatal sGC-exposed adolescents present no significant deviations in neuropsychological performance in the dimensions that we evaluated, although they presented altered functional connectivity, highlighting the need for additional studies to understand the impact of these changes in brain functioning and in behavior.

Highlights

Prenatal synthetic glucocorticoid exposure does not lead to structural changes in the adolescent brain.

Adolescents prenatally exposed to synthetic glucocorticoids present altered resting state network.
Optimized husbandry and targeted gene-editing for the cnidarianNematostella vectensis
Authors: Carvalho João E. , Burtin Maxence , Detournay Olivier , Amiel Aldine R. , Röttinger Eric
Published: April 2023

Optimized laboratory conditions for research models are crucial for the success of scientific projects. This includes the control of the entire life cycle, access to all developmental stages and maintaining stable physiological conditions. Reducing the life cycle of a research model can also enhance the access to biological material and speed up genetic tool development. Thus, we optimized the rearing conditions for the sea anemoneNematostella vectensis, a cnidarian research model to study embryonic and post-metamorphic processes, such as regeneration.

We adopted a semi-automated aquaculture system forN. vectensisand developed a dietary protocol optimized for the different life stages. Thereby, we increased spawning efficiencies and post-spawning survival rates, and considerably reduced the overall life cycle down to two months. To further improve the obtention of CRISPR-Cas9 mutants, we optimized the design of sgRNAs leading to full KO animals in F0 polyps using a single sgRNA. Finally, we show that NHEJ-mediated transgene insertion is possible inN. vectensis. In sum our study provides additional resources for the scientific community that uses or will useN. vectensisas a research model.

Summary statement

Optimized life cycle, in combination with efficient gene-editing approaches facilitates the establishment of genetic tools inN. vectensis, an emerging model for environmental stress response, regeneration, and longevity.
The Major Histocompatibility Complex modulatesBatrachochytrium dendrobatidisandRanavirusinfections in three amphibian species
Authors: Cortazar-Chinarro M , Richter-Boix A , Halvarsson P , Palomar G , Bosch J
Published: April 2023

Genetic variation of immune genes is an important component of genetic diversity. Major histocompatibility complex (MHC) genes have been put forward as a model for studying how genetic diversity is maintained and geographically distributed in wild populations. Pathogen-mediated selection processes (i.e., heterozygosity advantage, rare-allele advantage or fluctuating selection) and demography are believed to generate and maintain the extreme diversity of MHC genes observed. However, establishing the relative importance of the different proposed mechanisms has proved extremely difficult, but heterozygote advantage is expected to be more detectable when multiple pathogens are considered simultaneously. Here, we test whether MHC diversity in three amphibian species (Ichthyosaura alpestris, Pleurodeles waltl,andPelophylax perezi) is driven by pathogen-mediated selection. We examined the relationship between the individual MHC class II exon variability with individual infection status (infected or not), infection intensity, and co-infection of two main amphibian pathogens:Batrachochytrium dendrobatidis(Bd) andRanavirussp. (Rv). We found higher MHC class II exon 2 allelic diversity inI.alpestrisandP. perezithan inP.waltlbut no significant differences in allele frequencies between infection groups. We also observed significant differences inBdinfection intensity betweenBdinfected individuals and co-infected individuals depending on the number of MHC loci that an individual carries. ForI. alpestris, we show stronger evidence for MHC associations with infection intensity and status when individuals carry specific alleles and supertypes. Our results suggest that studying the association between MHC genes and single and co-infected individuals might provide new insights into host-parasite evolution and a better understanding of evolutionary mechanisms driven by MHC diversity.
The ‘Stem’ and the ‘Workers’ of the mtDNA population of the cell. Evidence from mutational analysis
Authors: Cote-L’Heureu Auden , Franco Melissa , Maithania Yogesh N. K. , Popadin Konstantin , Woods Dori , Tilly Jonathan , Khrapko Konstantin
Published: April 2023

Every cell in our body contains a vibrant population of mitochondria, or, more precisely, of mitochondrial DNA molecules (mtDNAs). Just like members of any population mtDNAs multiply (by replication) and ‘die’ (i.e., are removed, either by degradation or by distribution into the sister cell in mitosis). An intriguing question is whether all mitochondria in this population are equal, especially whether some are responsible primarily for reproduction and some - for empowering the various jobs of the mitochondrion, oxidative phosphorylation in the first place. Importantly, because mtDNA is highly damaged such a separation of responsibilities could help greatly reduce the conversion of DNA damage into real inheritable mutations. An unexpected twist in the resolution of this problem has been brought about by a recent high-precision analysis of mtDNA mutations (Sanchez-Contreras et al. 2023). They discovered that certain transversion mutations, unlike more common transitions, are not accumulating with age in mice. We argue that this observation requires the existence of a permanent replicating subpopulation/lineage of mtDNA molecules, which are protected from DNA damage, a.k.a. the ‘stem’ mtDNA. This also implies the existence of its antipode i.e., the ‘worker’ mtDNA, which empowers OSPHOS, sustains damage and rarely replicates. The analysis of long HiFi reads of mtDNA performed by PacBio closed circular sequencing confirms this assertion.
Engineering Nme2Cas9 Adenine Base Editors with Improved Activity and Targeting Scope
Authors: Bamidele Nathan , Zhang Han , Dong Xiaolong , Gaston Nicholas , Cheng Haoyang , Kelly Karen , Watts Jonathan K. , Xie Jun , Gao Guangping , Sontheimer Erik J.
Published: April 2023

Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we have engineered Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first used domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex. These domain-inlaid Nme2Cas9 variants exhibited shifted editing windows and increased activity in comparison to the N-terminally fused Nme2-ABE. We next expanded the editing scope by swapping the Nme2Cas9 PAM-interacting domain with that of SmuCas9, which we had previously defined as recognizing a single-cytidine PAM. We used these enhancements to correct two commonMECP2mutations associated with Rett syndrome with little or no bystander editing. Finally, we validated domain-inlaid Nme2-ABEs for single-AAV deliveryin vivo.
DifferentiatingBacillus subtilisincorporates valine and methionine carbon into the backbone of specific fatty acids
Authors: Rowe Gerald E. , Perreault Jonathan
Published: April 2023

Sporulation inBacillus subtilishas long been a model of cellular differentiation, many aspects of which are well understood. The early stage of this process is of particular interest, especially the interrelationship of regulatory processes with metabolism in response to environmental changes. We analyzed cellular fatty acids as their methyl esters using capillary gas chromatography coupled to mass spectrometry during the transition from vegetative growth to early sporulation phase. Measurement of changes in the content of heavy fatty acid analogs in cultures supplemented with deuterium-labeled valine or methionine, or13C-labeld valine, showed that label was incorporated into the backbone of 12-methyltridecanoic and 14-methylpentadecanoic acid, in both sporulating andΔspo0Acultures. These fatty acids were formed starting with isobutyryl-CoA apparently originating only fromL-valine-d8in cultures so supplemented. Our observations indicate that following vegetative growth a pathway exists from certain amino acids into fatty acid methylene groups, evidently passing through propionyl-CoA. This finding has the potential to deepen understanding of the metabolic basis of cellular differentiation and identify new targets for antibiotics. We also observed a significant, continuous increase in the proportion of 13-methyltetradecanoic acid in fatty acids during the same period in which the pre-spore membrane would be formed.

Graphical abstract:

Abbreviated Summary

Early in at least someBacillus subtilisdifferentiation scenarios, a straight-chain metabolite derived from propionyl-CoA is incorporated into fatty acids primed with isobutyryl-CoA possibly derived from cellular protein valine. Concurrently a leucine related fatty acid increases significantly, potentially comprising the predominant pre-spore septum fatty acid component. These processes occur in conjunction with the onset of fatty acid β-oxidation and bulk protein turnover.
A cell-type-specific nitric oxide-cGMP pathway regulates proprioceptor morphology
Authors: Cohn Raphael , Kolba Natalie , Picache Jaqueline A. , Lin Nancy , Saleem Aisha , Grueber Wesley B.
Published: April 2023

Neurons show remarkable morphological diversity facilitated by transcriptional regulation during development and fitting with their connectivity and function. Second messenger pathways mediated by cyclic 3’,5’ adenosine or guanosine monophosphate (cAMP or cGMP) may serve to integrate extrinsic signals and regulate branching and growth of neurites. We investigated the regulation of cGMP signaling in neuronal morphogenesis inDrosophilasomatosensory neurons and found cell type-specificity in expression of the enzyme soluble guanylate cyclase (sGC) in different sensory neuron classes. sGC is responsible for the production of cGMP in response to the diffusible free radical messenger nitric oxide (NO) such that different levels of sGC impart cell type-specific sensitivity to NO. Supporting a role for the NO-cGMP pathway in neuronal morphogenesis, we find that knockout of sGC or nitric oxide synthase (NOS) impacts the morphology of multidendritic proprioceptors. The homeodomain transcription factor Cut shows different levels of expression in different somatosensory neuron types and we find that Cut regulates the level of cGMP signaling via repression of sGC expression. Thus, transcription factor levels contribute to cell type diversification by regulating levels of a signaling pathway to mediate somatosensory neuron morphogenesis.
A rapid ELISA platform with no sample preparation requirement
Authors: Maganzini Nicolò , Reschke Agnes , Cartwright Alyssa , Gidi Yasser , Thompson Ian A. P. , Hariri Amani , Dory Constantin , Rosenberg-Hasson Yael , Pan Jing , Eisenstein Michael , Cornell Timothy Thomas , Soh Hyongsok Tom
Published: April 2023

Since its invention in the 1970’s, the enzyme-linked immunosorbent assay (ELISA) has served as the “gold-standard” for blood and plasma protein biomarker quantification. However, ELISAs require significant amounts of sample preparation entailing multiple reagent additions, incubations, and washing steps, limiting their clinical usefulness in the context of diagnosis and prognosis of rapidly evolving medical conditions. In this work, we describe the ‘instant ELISA’ biosensor platform, a probe that can be exposed directly to blood or other biological samples and quantifies protein biomarkers within 15 minutes. The sensor leverages a novel affinity reagent termed ‘monolithic dual-antibody clamp’ (MDAC) which preserves the specificity, sensitivity, and generalizability of ELISA while also enabling rapid analysis of unprocessed blood and other complex matrices. Using MDAC in chicken media, we demonstrate picomolar quantification of the inflammatory marker tumor necrosis factor alpha (TNFα), as well as monocyte chemotactic protein (MCP)-1, a useful prognostic indicator of cytokine release syndrome (CRS) during chimeric antigen receptor (CAR) T-cell immunotherapy. Finally, we demonstrate MCP-1 quantification in plasma samples from patients who had undergone CAR T-cell treatment.
SPADE: Spatial Deconvolution for Domain Specific Cell-type Estimation
Authors: Lu Yingying , Chen Qin , An Lingling
Published: April 2023

The advent of spatial transcriptomics technology has allowed for the acquisition of gene expression profiles with multi-cellular resolution in a spatially resolved manner, presenting a new milestone in the field of genomics. However, the aggregate gene expression from heterogeneous cell types obtained by these technologies poses a significant challenge for a comprehensive delineation of cell type-specific spatial patterns. Here, we propose SPADE (SPAtial DEconvolution), an in-silico method designed to address this challenge by incorporating spatial patterns during cell type decomposition. SPADE utilizes a combination of single-cell RNA sequencing data, spatial location information, and histological information to computationally estimate the proportion of cell types present at each spatial location. In our study, we showcased the effectiveness of SPADE by conducting analyses on synthetic data. Our results indicated that SPADE was able to successfully identify cell type-specific spatial patterns that were not previously identified by existing deconvolution methods. Furthermore, we applied SPADE to a real-world dataset analyzing the developmental chicken heart, where we observed that SPADE was able to accurately capture the intricate processes of cellular differentiation and morphogenesis within the heart. Specifically, we were able to reliably estimate changes in cell type compositions over time, which is a critical aspect of understanding the underlying mechanisms of complex biological systems. These findings underscore the potential of SPADE as a valuable tool for analyzing complex biological systems and shedding light on their underlying mechanisms. Taken together, our results suggest that SPADE represents a significant advancement in the field of spatial transcriptomics, providing a powerful tool for characterizing complex spatial gene expression patterns in heterogeneous tissues.
Sensory neurons couple arousal and foraging decisions inC. elegans
Authors: Scheer Elias , Bargmann Cornelia I.
Published: April 2023

Foraging animals optimize feeding decisions by adjusting both common and rare behavioral patterns. Here, we characterize the relationship between an animal’s arousal state and a rare decision to leave a patch of bacterial food. Using long-term tracking and behavioral state classification, we find that food leaving decisions inC. elegansare coupled to arousal states across multiple timescales. Leaving emerges probabilistically over minutes from the high arousal roaming state, but is suppressed during the low arousal dwelling state. Immediately before leaving, animals have a brief acceleration in speed that appears as a characteristic signature of this behavioral motif. Neuromodulatory mutants and optogenetic manipulations that increase roaming have a coupled increase in leaving rates, and similarly acute manipulations that inhibit feeding induce both roaming and leaving. By contrast, inactivating a set of chemosensory neurons that depend on the cGMP-gated transduction channel TAX-4 uncouples roaming and leaving dynamics. In addition,tax-4-expressing sensory neurons promote lawn-leaving behaviors that are elicited by feeding inhibition. Our results indicate that sensory neurons responsive to both internal and external cues play an integrative role in arousal and foraging decisions.
Transcriptomic analysis during fruit development of the oil palm revealed specific isozymes related to starch metabolism that control oil yield
Authors: Apriyanto Ardha , Compart Julia , Fettke Joerg
Published: April 2023

The oil palm (Elaeis guineensisJacq.) produces a large amount of oil from the fruit. A recent study has shown that starch metabolism is essential for oil synthesis in fruit-producing species. Therefore, we detected gene expression changes related to starch metabolism genes throughout the maturity stages of oil palm fruit with different oil yields. Gene expression profiles were examined with three different oil yields (low, medium, and high) at six fruit development phases (4, 8, 12, 16, 20, and 22 weeks after pollination). Using RNA-seq analysis, we successfully identified and analyzed differentially expressed genes in oil palm mesocarps during development. The results showed that the transcriptome profile for each developmental phase was unique. Additionally, we found that starch synthesis and degradation occurred during fruit development and influenced oil production. Sucrose flux to the mesocarp tissue, rapid starch turnover, and high glycolytic activity have been identified as critical factors for oil production in oil palms. For starch metabolism and the glycolytic pathway, we identified specific enzyme isoforms (isozymes) that may control the oil production. This study provides valuable information for creating new high-oil-yielding palm varieties via breeding programs or genome editing approaches.
Nociception in chicken embryos, Part II: Embryonal development of electroencephalic neuronal activityin ovoas a prerequisite for nociception
Authors: Kollmansperger Sandra , Anders Malte , Werner Julia , Saller Anna M. , Weiss Larissa , Süß Stephanie C. , Reiser Judith , Schneider Gerhard , Schusser Benjamin , Baumgartner Christine , Fenzl Thomas
Published: April 2023

Chicken culling is forbidden in Germany since 2022, male/female selection and male elimination must be brought to an embryonic status prior to the onset of nociception. The present study evaluated the ontogenetic point when noxious stimuli potentially could be perceived/processed in the brainin ovo.

EEG-recordings from randomized hyperpallial brain sites were recordedin ovoand noxious stimuli were applied. Temporal and spectral analyses of the EEG were performed.

The onset of physiological neuronal signals could be determined at developmental day 13. ERP/ERSP/ITC analysis did not reveal phase-locked nociceptive responses.

Although no central nociceptive responses were documented, adequate EEG-responses to noxious stimuli from other brain areas cannot be excluded. The extreme stress impact on the embryo during the recording may overwrite the perception of noniceptive stimuli. The results suggest developmental day 13 as the earliest embryonal stage being able to receive and process nociceptive stimuli.
All-in-one AAV-delivered epigenome-editing platform:proof-of-conceptand therapeutic implications for neurodegenerative disorders
Authors: Kantor Boris , Odonovan Bernadette , Rittiner Joseph , Hodgson Dellila , Lindner Nicholas , Guerrero Sophia , Dong Wendy , Zhang Austin , Chiba-Falek Ornit
Published: April 2023

Safely and efficiently controlling gene expression is a long-standing goal of biomedical research, and the recently discovered bacterial CRISPR/Cas system can be harnessed to create powerful tools for epigenetic editing. Current state-of-the-art systems consist of a deactivated-Cas9 nuclease (dCas9) fused to one of several epigenetic effector motifs/domains, along with a guide RNA (gRNA) which defines the genomic target. Such systems have been used to safely and effectively silence or activate a specific gene target under a variety of circumstances. Adeno-associated vectors (AAVs) are the therapeutic platform of choice for the delivery of genetic cargo; however, their small packaging capacity is not suitable for delivery of large constructs, which includes most CRISPR/dCas9-effector systems. To circumvent this, many AAV-based CRISPR/Cas tools are delivered in two pieces, from two separate viral cassettes. However, this approach requires higher viral payloads and usually is less efficient. Here we develop a compact dCas9-based repressor system packaged within a single, optimized AAV vector. The system uses a smaller dCas9 variant derived fromStaphylococcus aureus(Sa). A novel repressor was engineered by fusing the small transcription repression domain (TRD) from MeCP2 with the KRAB repression domain. The final dSaCas9-KRAB-MeCP2(TRD) construct can be efficiently packaged, along with its associated gRNA, into AAV particles. Using reporter assays, we demonstrate that the platform is capable of robustly and sustainably repressing the expression of multiple genes-of-interest, bothin vitroandin vivo. Moreover, we successfully reduced the expression of ApoE, the stronger genetic risk factor for late onset Alzheimer’s disease (LOAD). This new platform will broaden the CRISPR/dCas9 toolset available for transcriptional manipulation of gene expression in research and therapeutic settings.
Multiple behavioural mechanisms shape development in a highly social cichlid fish
Authors: Harmon Isabela P. , McCabe Emily A. , Vergun Madeleine R. , Weinstein Julia , Graves Hannah L. , Bradley Deijah D. , Boldt Clare M. , Lee June , Maurice Jessica M. , Solomon-Lane Tessa K.
Published: April 2023

Early-life social experiences shape adult phenotype, yet the underlying behavioural mechanisms remain poorly understood. We manipulated early-life social experience in the highly social African cichlid fishAstatotilapia burtonito investigate the effects on behaviour and neuroendocrine stress axis function. Juveniles experienced different numbers of early-life social partners in stable pairs (1 partner), stable groups (6 fish; 5 partners), and socialized pairs (a novel fish was exchanged every 5 days; 5 partners). Treatments differed in group size (groups vs. pairs) and stability (stable vs. socialized). We then measured behaviour in multiple contexts and collected water-borne cortisol. We found effects of treatment on behaviour across all assays: open field exploration, social cue investigation, dominant behaviour, and subordinate behaviour. Cortisol did not differ across treatments. Principal components (PC) analysis revealed robust co- variation of behaviour across contexts, including with cortisol, to form behavioural syndromes sensitive to early-life social experience. PC1 (25.1%) differed by numbers of social partners: juveniles with more social partners were more active during the social cue investigation, spent less time in the territory, and were more interactive as dominants. Differences in PC5 (8.5%) were based on stability: socialized pairs were more dominant, spent less time in and around the territory, were more socially investigative, and had lower cortisol than stable groups or pairs. Behaviour observations in the home tanks provided further insights into the behavioural mechanisms underlying these effects. These results contribute to our understanding of how early- life social experiences are accrued and exert strong, lasting effects on adult phenotype.
Modeling synaptic integration of bursty and beta oscillatory inputs in ventromedial motor thalamic neurons in normal and parkinsonian states
Authors: Cavarretta Francesco , Jaeger Dieter
Published: April 2023

The Ventromedial Motor Thalamus (VM) is implicated in multiple motor functions and occupies a central position in the cortico-basal ganglia-thalamocortical loop. It integrates glutamatergic inputs from motor cortex (MC) and motor-related subcortical areas, and it is a major recipient of inhibition from basal ganglia. Previous experiments in vitro showed that dopamine depletion enhances the excitability of thalamocortical cells (TC) in VM due to reduced M-type potassium currents. To understand how these excitability changes impact synaptic integration in vivo, we constructed biophysically detailed VM TC models fit to normal and dopamine-depleted conditions, using the NEURON simulator. These models allowed us to assess the influence of excitability changes with dopamine depletion on the integration of synaptic inputs expected in vivo. We found that VM TCs in the dopamine-depleted state showed increased firing rates with the same synaptic inputs. Synchronous bursting in inhibitory input from the substantia nigra pars reticulata (SNR), as observed in parkinsonian conditions, evoked a post-inhibitory firing rate increase with a longer duration in dopamine-depleted than control conditions, due to different M-type potassium channel densities. With beta oscillations in the inhibitory inputs from SNR and the excitatory inputs from drivers and modulators, we observed spike-phase locking in the activity of the models in normal and dopamine-depleted states, which relayed and amplified the oscillations of the inputs, suggesting that the increased beta oscillations observed in VM of parkinsonian animals are predominantly a consequence of changes in the presynaptic activity rather than changes in intrinsic properties.

Significance Statement

The Ventromedial Motor Thalamus is implicated in multiple motor functions. Experiments in vitro showed this area undergoes homeostatic changes following dopamine depletion (parkinsonian state). Here we studied the impact of these changes in vivo, using biophysically detailed modeling. We found that dopamine depletion increased firing rate in the ventromedial thalamocortical neurons and changed their responses to synchronous inhibitory inputs from substantia nigra reticulata. All thalamocortical neuron models relayed and amplified beta oscillations from substantia nigra reticulata and cortical/subcortical inputs, suggesting that increased beta oscillations observed in parkinsonian animals predominantly reflect changes in presynaptic activity.
Stromal netrin-1 coordinates renal arteriogenesis and mural cell differentiation
Authors: Luo Peter M. , Gu Xiaowu , Chaney Christopher , Carroll Thomas , Cleaver Ondine
Published: April 2023

The kidney vasculature has a uniquely complex architecture that is essential to proper renal function. Little is known about the molecular mechanisms that direct where and when blood vessels form during kidney development. We identified a regionally-restricted, stroma-derived signaling molecule, netrin-1 (Ntn1), as a putative regulator of vascular patterning. We generated a stromal progenitor-specific knockout of netrin-1 (Ntn1SPKO) that resulted in smaller postnatal kidneys with altered epithelial development and profound defects in arterial and capillary architecture. We also found significant loss of arterial vascular smooth muscle cell (vSMC) coverage and ectopic smooth muscle cell deposition at the kidney cortex. Transcriptomic analysis ofNtn1SPKOkidneys revealed downregulation of Klf4, which we find expressed in stromal progenitors. Deletion of Klf4 in the stroma largely phenocopies loss of Ntn1, and expression of Klf4 inNtn1SPKOkidneys rescues ectopic vSMC deposition. Vascular defects observed inNtn1SPKOare transient, as both arterial and smooth muscle coverage defects resolve late in development, however ectopic peripheral smooth muscle perdures perinatally. These data suggest a stromal-intrinsic Ntn1-Klf4 axis acting as an essential mediator of stromal crosstalk and vascular progenitor differentiation.
Computational Models Suggest that Human Memory Judgments Exhibit Interference due to the Use of Distributed Representations
Authors: Huffman Derek J. , Guan Ruijia
Published: April 2023

Episodic memory is a core function that allows us to remember the events of our lives. Given that many events in our life contain overlapping elements (e.g., similar people and places), it is critical to understand how well we can remember the specific events of our lives vs. how susceptible we are to interference between similar memories. Several prominent theories converged on the notion that pattern separation in the hippocampus causes it to play a greater role in processes such as recollection, associative memory, and memory for specific details, while distributed representations in the neocortex cause it to play a stronger role in domain-specific memory. We propose that studying memory performance on tasks with targets and similar lures provides a critical testbed for comparing the extent to which human memory is driven by hippocampal pattern separation vs. more distributed representations (e.g., neocortex) vs. a blend thereof. We generated predictions from several computational models and then tested these predictions in a large sample of human participants. We found a linear relationship between memory performance and target-lure pattern similarity within a neural network simulation of area IT, an object-processing region of the brain. We also observed strong effects of test format on performance and consistent relationships between test formats. Altogether, our results were better accounted for by distributed memory models than the pattern-separated representations of the hippocampus; therefore, our results provide important insight into prominent memory theories by suggesting that memory performance is primarily driven by distributed representations (e.g., neocortex).
Discovery of novel multi-functional peptides by using protein language models and graph-based deep learning
Authors: Luo Jiawei , Zhao Kejuan , Chen Junjie , Yang Caihua , Qu Fuchuan , Yan Ke , Zhang Yang , Liu Bin
Published: April 2023

Functional peptides are one kind of short protein fragments that have a wide range of beneficial functions for living organisms. The majority of previous research focused on mono-functional peptides, but a growing number of multi-functional peptides have been discovered. Although enormous experimental efforts endeavor to assay multi-functional peptides, only a small fraction of millions of known peptides have been explored. Effective and precise techniques for identifying multi-functional peptides can facilitate their discovery and mechanistic understanding. In this article, we presented a novel method, called iMFP-LG, for identifying multi-functional peptides based on protein language models (pLMs) and graph attention networks (GATs). Comparison results showed iMFP-LG significantly outperforms state-of-the-art methods on both multifunctional bioactive peptides and multi-functional therapeutic peptides datasets. The interpretability of iMFP-LG was also illustrated by visualizing attention patterns in pLMs and GATs. Regarding to the outstanding performance of iMFP-LG on the identification of multi-functional peptides, we employed iMFP-LG to screen novel candidate peptides with both ACP and AMP functions from millions of known peptides in the UniRef90. As a result, 8 candidate peptides were identified, and 1 candidate that exhibits significant antibacterial and anticancer effect was confirmed through molecular structure alignment and biological experiments. We anticipate iMFP-LG can assist in the discovery of multi-functional peptides and contribute to the advancement of peptide drug design.

Availability and implementation

The models and associated code are available at:https://github.com/chen-bioinfo/iMFP-LG.

Supplementary information

Supplementary data are available online.
Early-life stress and ovarian hormones alter transcriptional regulation in the nucleus accumbens resulting in sex-specific responses to cocaine
Authors: Rocks Devin , Jaric Ivana , Bellia Fabio , Cham Heining , Greally John M. , Suzuki Masako , Kundakovic Marija
Published: April 2023

Early-life stress and ovarian hormones contribute to increased female vulnerability to cocaine addiction. Here we reveal molecular substrates in the key reward area, the nucleus accumbens, through which these female-specific factors affect immediate and conditioning responses to cocaine in mice. We find shared involvement of X chromosome and estrogen signaling gene regulation in enhanced conditioning responses seen after early-life stress and during the low-estrogenic state in females. During the low-estrogenic state, females respond to acute cocaine exposure by increasing the accessibility of neuronal chromatin enriched for the binding sites of ΔFosB, a transcription factor implicated in chronic cocaine response and addiction. Conversely, high-estrogenic females respond to cocaine by preferential closing of neuronal chromatin, providing a mechanism for limiting cocaine-driven chromatin and synaptic plasticity. We find that physiological estrogen withdrawal, exposure to early-life stress, and absence of the second X chromosome all nullify the protective effect of high-estrogenic state on cocaine conditioning in females. Our findings offer a molecular framework to understand sex-specific neuronal mechanisms underlying cocaine use disorder.
Longitudinal Survey of Astrovirus infection in different bat species in Zimbabwe: Evidence of high genetic Astrovirus diversity
Authors: Vimbiso Chidoti , Hélène De Nys , Malika Abdi , Getrude Mashura , Valérie Pinarello , Ngoni Chiweshe , Gift Matope , Laure Guerrini , Davies Pfukenyi , Julien Cappelle , Ellen Mwandiringana , Dorothée Missé , Elizabeth Gori , Mathieu Bourgarel , Florian Liégeois
Published: April 2023

Astroviruses (AstVs) have been discovered in over 80 animal species including diverse bat species and avian species. A study on Astrovirus circulation and diversity in different insectivorous and frugivorous chiropteran species roosting in trees, caves and building basements was carried out at 11 different sites across Zimbabwe. Pooled and individual faecal sampling methods were used for this study, with collection dates ranging from June 2016 to July 2021. In two sites, Magweto and Chirundu, sampling was carried out at monthly intervals from August 2020 to July 2021. Astroviruses and bat mitochondrial genes were amplified using pan-AstVs and CytB /12S RNA PCR systems respectively. Phylogenetic analysis of theRdRpAstrovirus sequences revealed a high genetic diversity of astroviruses. All the bat astroviruses tested in this study clustered with theMamastrovirusgenus. Two distinct groups of amplified sequences were identified. One group was comprised of sequences isolated fromHipposideros, RhinolophusandEidolon helvumspp. clustered with Human Astrovirus strains:HuAstVtypes1-6,HuAstV-MLB1-3 andHuAstV-VA-1. The second group comprising the majority of the sequences clustered with different strains of Bat AstVs. Results from the longitudinal study at Magweto and Chirundu showed an overall AstV prevalence of 13.7% and 10.4% respectively. Peaks of AstV infection at Chirundu coincided with the period when juveniles are 4-6 months old. By combining data from our previous work on Coronaviruses, we also anaylzed co-infection of bats with Coronaviruses and Astroviruses at Magweto and Chirundu sites for which the prevalence of co-infection was 2.6% and 3.5% respectively.
There and back again: when and how the world’s richest snake family (Dipsadidae) dispersed and speciated across the Neotropical region
Authors: Serrano Filipe C. , Pontes-Nogueira Matheus , Sawaya Ricardo J. , Alencar Laura R.V. , Nogueira Cristiano C. , Grazziotin Felipe G.
Published: April 2023

Aim

The widespread megadiverse Neotropical snake family Dipsadidae occurs in a large range of diverse habitats. Thus it represents an excellent model to study the diversification of Neotropical biota. Herein, by generating a time-calibrated species-level phylogeny, we investigate the origin and historical biogeography of Dipsadidae and test if its two main Neotropical subfamilies, Xenodontinae and Dipsadinae, have different geographical origins.

Location

Neotropical region.

Taxon

Dipsadidae (Serpentes).

Methods

We generated a new Bayesian time-calibrated phylogeny including sequences from six genes for 344 species, including 287 species of Dipsadidae. We subsequently estimated ancestral areas of distribution by comparing models in BioGeoBEARS: DEC (subset sympatry, narrow vicariance), DIVALIKE (narrow and wide vicariance), BAYAREALIKE (no vicariance and widespread sympatry), also testing jump dispersal.

Results

The best models show that Dipsadidae likely originated approximately 50 million years ago (mya) in Asia. Dispersal was a fundamental process in its historical biogeography. The DEC model with jump dispersal indicated that this family underwent a range extension from Asia and posterior vicariance of North and Central America ancestors. Both Xenodontinae and Dipsadinae originated in Central America and dispersed to South America during Middle Eocene, but did so to different regions (cis and trans-Andean South America, respectively). Xenodontinae entered cis-Andean South America around 39 mya and jump dispersed to the West Indies around 33 mya, while Dipsadinae entered trans-Andean South America multiple times 20 – 38 mya.

Main conclusions

Our results show that Dipsadidae has an Asian origin and that the two main Neotropical subfamilies originated in Central America, later dispersing to South America in different time periods. The current biogeographical patterns of the family Dipsadidae, the most species-rich snake family in the world, have likely been shaped by complex evolutionary and geological processes such as Eocene land bridges, Andean uplift and the formation of the Panama isthmus.
Temporal Effects of Galactose and Manganese Supplementation on Monoclonal Antibody N-Linked Glycosylation in Fed-Batch and Perfusion Bioreactor Operation
Authors: Gyorgypal Aron , Fratz-Berilla Erica , Kohnhorst Casey , Powers David N. , Chundawat Shishir P. S.
Published: April 2023

Monoclonal antibodies (mAbs) represent a majority of biotherapeutics on the market today. These glycoproteins undergo post-translational modifications, such as N-linked glycosylation, that influence the structural & functional characteristics of the antibody. Glycosylation is a heterogenous post-translational modification that may influence therapeutic glycoprotein stability and clinical efficacy, which is why it is often considered a critical quality attribute (CQA) of the mAb product. While much is known about the glycosylation pathways of Chinese Hamster Ovary (CHO) cells and how cell culture chemical modifiers may influence the N-glycosylation profile of the final product, this knowledge is often based on the final cumulative glycan profile at the end of the batch process. Building a temporal understanding of N-glycosylation and how mAb glycoform composition responds to real-time changes in the biomanufacturing process will help build integrated process models that may allow for glycosylation control to produce a more homogenous product. Here, we look at the effect of specific nutrient feed media additives (e.g., galactose, manganese) and feeding times on the N-glycosylation pathway to modulate N-glycosylation of a Herceptin biosimilar mAb (i.e., Trastuzumab). We deploy the N-GLYcanyzer process analytical technology (PAT) to monitor glycoforms in near real-time for bench-scale bioprocesses operated in both fed-batch and perfusion modes to build an understanding of how temporal changes in mAb N-glycosylation are dependent on specific media additives. We find that Trastuzumab terminal galactosylation is sensitive to media feeding times and intracellular nucleotide sugar pools. Temporal analysis reveals an increased desirable production of single and double galactose-occupied glycoforms over time under glucose-starved fed-batch cultures. Comparable galactosylation profiles were also observed between fed-batch (nutrient-limited) and perfusion (non-nutrient-limited) bioprocess conditions. In summary, our results demonstrate the utility of real-time monitoring of mAb glycoforms and feeding critical cell culture nutrients under fed-batch and perfusion bioprocessing conditions to produce higher-quality biologics.
Sterile Soil as Prebiotics Mitigate Intergenerational Loss of Gut Microbial Diversity and Anxiety-Like Behavior Induced by Antibiotics in mice
Authors: Li Na , Xiao Xiaoao , Zhang Honglin , Bai Zhimao , Li Mengjie , Sun Jia , Dong Yangyang , Zhu Wenyong , Fei Zhongjie , Sun Xiao , Xiao Pengfeng , Gao Yuanqing , Zhou Dongrui
Published: April 2023

The decline in gut microbial diversity of modern human is closely associated with the rising prevalence of various diseases. It is imperative to investigate the underlying causes of gut microbial loss and the rescue measures. Although the impact of non-perinatal antibiotic use on gut microbiota has been recognized, its intergenerational effects remain unexplored. Our previous research has highlighted soil in the farm environment as a key prebiotic for gut microbiome health by restoring gut microbial diversity and balance. In this study, we investigated the intergenerational consequences of antibiotic exposure and the therapeutic potential of soil prebiotics. We treated mice with vancomycin and streptomycin for 2 weeks continuously, followed by 4-8 weeks of withdrawal period before breeding. The process was repeated across 3 generations. Half of the mice in each generation received an oral soil prebiotic intervention. We assessed gut microbial diversity, anxiety behavior, microglia reactivity, and gut barrier integrity across generations. The antibiotics exposure led to a decrease in gut microbial diversity over generations, along with aggravated anxiety behavior, microglia abnormalityies, and altered intestinal tight junction protein expression. Notably, the third generation of male mice exhibited impaired reproductive capacity. Oral sterile soil intervention restored gut microbial diversity in adult mice across generations, concomitantly rescuing abnormalities in behavior, microglia activity, and intestinal barrier integrity. In conclusion, this study simulated an important process of the progressive loss gut microbiota diversity in modern human and demonstrated the potential of sterile soil as a prebiotic to reverse this process. The study provides a theoretical and experimental basis for the research and therapeutic interventions targeting multiple modern chronic diseases related to intestinal microorganisms.