bluuebunny/crossref_metadata_2025 huggingface dataset:
Interspecies blastocyst complementation generates functional rat cell-derived forebrain tissues in mice
Authors: Huang Jia , He Bingbing , Yang Xiali , Long Xin , Wei Yinghui , Gao Yanxia , Fang Yuan , Ying Wenqin , Wang Zikang , Li Chao , Zhou Yingsi , Li Shuaishuai , Shi Linyu , Guo Fan , Zhou Haibo , Yang Hui , Wu Jun
Published: April 2023

Interspecies organogenesis via blastocyst complementation provides a unique platform to study development in an evolutionarily context and holds potential to overcome world-wide organ shortages1. By using this technique, rat pancreas, thymus, heart, and eye tissues have been generated in mice2–4. To date, however, xeno-generation of brain tissues has not been achieved through blastocyst complementation. Here, we developed an optimized one-step blastocyst complementation strategy based on C-CRISPR5, which facilitated rapid screening of candidate genes to support blastocyst complementation. Among the seven WNT pathway-related genes selected for targeting, onlyDkk1orHesx1deficiency supported forebrain complementation by blastocyst injection of mouse embryonic stem cells (mESCs). Further, injecting rat ESCs (rESCs) into mouse blastocysts deficient forHesx1but notDkk1supported the development of adult chimeric forebrains comprised a large proportion of rat cells that were structurally and functionally similar to the mouse forebrains. Our analysis revealed that the rESC-derived forebrains developed along the spatial-temporal trajectory with the mouse forebrains rather than rat forebrains, but gene expression profiles of rESC-derived nerve cells surprisingly maintained the characteristics of the rat cells. We noted that the chimeric rate gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late prenatal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRIPSR based IBC strategy developed here holds great potential to broaden the study and application of interspecies organogenesis.
Sex biased human thymic architecture guides T cell development through spatially defined niches
Authors: Stankiewicz Laura N , Salim Kevin , Flaschner Emily A , Wang Yu Xin , Edgar John M , Lin Bruce ZB , Bingham Grace C , Major Matthew C , Jones Ross D , Blau Helen M , Rideout Elizabeth J , Levings Megan K , Zandstra Peter W , Rossi Fabio MV
Published: April 2023

Within the thymus, regulation of the cellular cross-talk directing T cell development is dependent on spatial interactions within specialized niches. To create a holistic, spatially defined map of tissue niches guiding postnatal T cell development we employed the multidimensional imaging platform CO-detection by indEXing (CODEX), as well as CITE-seq and ATAC-seq. We generated age-matched 4–5-month-old postnatal thymus datasets for male and female donors, and identify significant sex differences in both T cell and thymus biology. We demonstrate a crucial role for JAG ligands in directing thymic-like dendritic cell development, reveal important functions of a novel population of ECM-fibroblasts, and characterize the medullary niches surrounding Hassall’s corpuscles. Together, these data represent a unique age-matched spatial multiomic resource to investigate how sex-based differences in thymus regulation and T cell development arise, and provide an essential resource to understand the mechanisms underlying immune function and dysfunction in males and females.
Evidence for the role of selection for reproductively advantageous alleles in human aging
Authors: Long Erping , Zhang Jianzhi
Published: April 2023

The antagonistic pleiotropy hypothesis posits that natural selection for pleiotropic mutations that confer earlier or more reproduction but impair the post-reproductive life causes aging. This hypothesis of the evolutionary origin of aging is supported by case studies but lacks unambiguous genomic evidence. Here we genomically test this hypothesis using the genotypes, reproductive phenotypes, and death registry of 276,406 UK Biobank participants. We observe a strong, negative genetic correlation between reproductive traits and lifespan. Individuals with higher polygenetic scores for reproduction (PGSR) have lower survivorships to age 76 (SV76), andPGSRincreased over birth cohorts from 1940 to 1969. Similar trends are found from individual genetic variants examined.PGSRandSV76remain negatively correlated upon the control of the offspring number, revealing horizontal pleiotropy between reproduction and lifespan. Intriguingly, regardless ofPGSR, having two children maximizesSV76. These and other findings strongly support the antagonistic pleiotropy hypothesis of aging in humans.
Plasma cells are formed in waning germinal centers via an affinity-independent process
Authors: Sutton Henry J. , Parker Brian J. , Lofgren Mariah , Dacon Cherrelle , Chatterjee Deepyan , Gao Xin , Kelly Hannah G. , Seder Robert A. , Tan Joshua , Idris Azza H. , Neeman Teresa , Cockburn Ian A.
Published: April 2023

Long-lived plasma cells (PCs) secrete antibodies that can provide sustained immunity against infection. It has been proposed that high affinity cells are preferentially selected into this compartment, potentiating the immune response. Here we used single cell RNA-seq to track the development of Ighg2A10cells, specific for thePlasmodium falciparumcircumsporozoite protein (PfCSP) within the germinal center (GC). We identified cells differentiating into memory B cells (MBC) or PCs and estimated their affinity by V(D)J sequencing. While pre-memory cells were of lower affinity than GC B cells generally, the affinity of pre-PC cells was indistinguishable. Rather, a larger proportion of cells differentiated into PCs in waning GCs. These later emigrants replaced early arrivals in the bone marrow allowing the development of a high affinity PC compartment.
A Randomised Controlled Trial of Nasal Immunisation with Live Virulence AttenuatedStreptococcus pneumoniaeStrains using Human Infection Challenge
Authors: Hill H , Mitsi E , Nikolaou E , Blizard A , Pojar S , Howard A , Hyder-Wright A , Devin Jack , Reiné J , Robinson R , Solórzano C , Jochems S , Kenny-Nyazika T , Ramos-Sevillano E , Weight CM , Myerscough C , McLennan D , Morton B , Gibbons E , Farrar M , Randles V , Burhan H , Chen T , Shandling AD , Campo JJ , Heyderman R , Gordon SB , Brown J , Collins AM , Ferreira DM
Published: April 2023

Rationale

Pneumococcal pneumonia remains a global health problem. Pneumococcal colonisation increases local and systemic protective immunity, suggesting nasal administration of live attenuatedS. pneumoniaestrains could help prevent infections.

Objectives

We used a controlled human infection model to investigate whether nasopharyngeal colonisation with attenuatedS. pneumoniaestrains protected against re-colonisation with wild-type (WT)S. pneumoniae(Spn).

Methods

Healthy adults aged 18-50 years were randomised (1:1:1:1) for nasal administration twice (two weeks interval) with saline, WT Spn6B (BHN418) or one of two genetically modified Spn6B strains - SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against re-colonisation (Stage II).

Measurements and Main Results

125 participants completed both study stages as per intention to treat. No Serious Adverse Events were reported. In Stage I, colonisation rates were similar amongst groups: SpnWT 58.1% (18/31), SpnA1 60% (18/30) and SpnA3 59.4% (19/32). Anti-Spn nasal IgG levels post-colonisation were similar in all groups whilst serum IgG responses were higher in the SpnWT and SpnA1 groups than the SpnA3 group. In colonised individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 but not SpnA3 in phase 1 were partially protected against re-colonisation with SpnWT (recolonisation rates of 29% versus 30% respectively).

Conclusion

Nasal colonisation with genetically modified live attenuated Spn was safe and induced protection against recolonisation, suggesting nasal adminstration of live attenuated Spn could be an effective stategy for preventing pneumococcal infections.
Participant characteristics and exclusion from trials: a meta-analysis of individual participant-level data from phase 3/4 industry-funded trials in chronic medical conditions
Authors: Lees Jennifer S , Crowther Jamie , Hanlon Peter , Butterly Elaine , Wild Sarah H , Mair Frances S , Guthrie Bruce , Gillies Katie , Dias Sofia , Welton Nicky J , Katikireddi Srinivasa Vittal , McAllister David A
Published: April 2023

Objectives

Trials often do not represent their target populations, threatening external validity. The aim was to assess whether age, sex, comorbidity count and/or race/ethnicity are associated with likelihood of screen failure (i.e., failure to be randomised to the trial for any reason) among potential trial participants.

Design

Bayesian meta-analysis of individual participant-level data (IPD).

Setting

Industry-funded phase 3/4 trials in chronic medical conditions. Participants were identified as “randomised” or “screen failure” using trial IPD.

Participants

Data were available for 52 trials involving 72,178 screened individuals of whom 24,733 (34%) failed screening.

Main outcome measures

For each trial, logistic regression models were constructed to assess likelihood of screen failure, regressed on age (per 10-year increment), sex (male versus female), comorbidity count (per one additional comorbidity) and race/ethnicity. Trial-level analyses were combined in Bayesian hierarchical models with pooling across condition.

Results

In age- and sex-adjusted models, neither age nor sex was associated with increased odds of screen failure, though weak associations were detected after additionally adjusting for comorbidity (age, per 10-year increment: odds ratio [OR] 1.02; 95% credibility interval [CI] 1.01 to 1.04 and male sex: OR 0.95; 95% CI 0.91 to 1.00). Comorbidity count was weakly associated with screen failure, but in an unexpected direction (OR 0.97 per additional comorbidity, 95% CI 0.94 to 1.00, adjusted for age and sex). Those who self-reported as Black were slightly more likely to fail screening (OR 1.04; 95% CI 0.99 to 1.09); an effect which persisted after adjustment for age, sex and comorbidity count (OR 1.05; 95% CI 0.98 to 1.12).

Conclusions

Age, sex, comorbidity count and Black race/ethnicity were not strongly associated with increased likelihood of screen failure. Proportionate increases in screening these underserved populations may improve representation in trials.

Trial registration

Relevant trials in chronic medical conditions were identified according to pre-specified criteria (PROSPERO CRD42018048202).
Longitudinal sequencing and variant detection of SARS-CoV-2 across Southern California wastewater from April 2020 – August 2021
Authors: Rothman Jason A. , Saghir Andrew , Zimmer-Faust Amity G. , Langlois Kylie , Steele Joshua A. , Griffith John F. , Whiteson Katrine L.
Published: April 2023

Wastewater based epidemiology (WBE) is a useful method to detect pathogen prevalence and may serve to effectively monitor diseases at a broad scale. WBE has been used throughout the COVID-19 pandemic to track localized and population-level disease burden through the quantification of SARS-CoV-2 RNA present in wastewater. Aside from case load estimation, WBE is being used to assay viral genomic diversity and the emergence of potential SARS-CoV-2 variants.

Here, we present a study in which we sequenced RNA extracted from sewage influent samples obtained from eight wastewater treatment plants representing 16 million people in Southern California over April 2020 – August 2021. We sequenced SARS-CoV-2 with two methods: Illumina Respiratory Virus Enrichment and metatranscriptomic sequencing (N = 269), and QIAseq SARS-CoV-2 tiled amplicon sequencing (N = 95). We were able to classify SARS-CoV-2 reads into lineages and sublineages that approximated several named variants across a full year, and we identified a diversity of single nucleotide variants (SNVs) of which many are putatively novel SNVs, and SNVs of unknown potential function and prevalence. Through our retrospective study, we also show that several sublineages of SARS-CoV-2 were detected in wastewater up to several months before clinical detection, which may assist in the prediction of future Variants of Concern. Lastly, we show that sublineage diversity was similar between wastewater treatment plants across Southern California, and that diversity changed by sampling month indicating that WBE is effective across megaregions.

As the COVID-19 pandemic moves to new phases, and additional SARS-CoV-2 variants emerge, the ongoing monitoring of wastewater is important to understand local and population-level dynamics of the virus. Our study shows the potential of WBE to detect SARS-CoV-2 variants throughout Southern California’s wastewater and track the diversity of viral SNVs and strains in urban and suburban locations. These results will aid in our ability to monitor the evolutionary potential of SARS-CoV-2 and help understand circulating SNVs to further combat COVID-19.
A New Vaccination Assessment Method and Strategy for COVID-19
Authors: Michaelson James
Published: April 2023

Optimizing vaccination to reduceCOVID-19death remains a challenge. A new method,Gompertzian Analysis, examines numbers of infectious disease cases and deaths, by age, on log graphs, capturingCOVID-19Lethality(Deaths/Cases) by theGompertz Mortality Equation.Gompertzian Analysisrevealed that each of the first 4Vaccination Events(primary and boosters) led to a ∼1/3rdreduction inCOVID-19Lethality. These vaccination reductions inCOVID-19Lethalitywere cumulative, persistent, and undiminished by variants, while vaccination’s impact onCOVID-19Infectivity(Cases/Population) was fleeting. Primary vaccination and 3 boosters gave an ∼85% reduction inCOVID-19Lethality, with projections suggesting ∼68% fewer deaths (∼267,000 to ∼85,000). Projections also suggest that 6 boosters may offer a ∼96% reduction inCOVID-19Lethality, to the familiar level of influenza, with a ∼91% reduction inCOVID-19deaths, to ∼25,000, fewer than automobile deaths.Gompertzian Analysisprovides rational vaccination guidelines by age.Gompertzian Analysispoints to a strategy molded by multiple vaccinations reducingCOVID-19Lethality, which is persistent, rather than focusing on reducingCOVID-19Infectivity, which is fleeting. Such a strategy, based on accumulating the necessary number of vaccinations (∼7), and possibly no more, would accept vaccination’s limited ability to prevent infection in exchange for its power to prevent death.
Circulating tumor extracellular vesicles to monitor metastatic prostate cancer genomics and transcriptomic evolution
Authors: Casanova-Salas Irene , Cordoba-Terreros Sarai , Aguilar Daniel , Agundez Laura , Brandariz Julian , Herranz Nicolas , Gonzalez Macarena , Morales-Barrera Rafael , Sierra Alexandre , Soriano-Navarro Mario , Cresta Pablo , Simonetti Sara , Rodrigues Gonçalo , Arce-Gallego Sara , Delgado-Soriano Luisa , Agustí Irene , Castellano-Sanz Elena , Mast Richard , Albert Matias de , Celma Ana , Santamaria Anna , Gonzalez Lucila , Castro Natalia , Suanes Maria del Mar , Hernández-Losa Javier , Nonell Lara , Peinado Hector , Carles Joan , Mateo Joaquin
Published: April 2023

Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for interrogating the molecular features of tumors through multi-omic profiling remains widely unexplored. Genomic and transcriptomic profiling of circulating EV-DNA and EV-RNA isolated from a range ofin-vitroandin-vivomodels of metastatic prostate cancer (mPC) revealed a high contribution of tumor material to EV-loaded DNA/RNA. Findings were validated in a cohort of longitudinal plasma samples collected from mPC patients during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA genomic features recapitulated matched-patient biopsies and associated with clinical progression. We developed a novel approach to enable the transcriptomic profiling of EV-RNA (RExCuE). We report how the transcriptomic profile in mPC EV-RNA is enriched for tumor-associated transcripts when compared to same patient blood RNA and healthy individuals EV-RNA, and reflect early on-therapy tumor adaptation changes. Altogether, we show that EV profiling enables longitudinal transcriptomic and genomic profiling of mPC in liquid biopsy.
No general effects of advancing male age on ejaculates: a meta-analysis across the animal kingdom
Authors: Sanghvi Krish , Vega-Trejo Regina , Nakagawa Shinichi , Gascoigne Samuel J.L. , Johnson Sheri , Salguero-Gómez Roberto , Pizzari Tommaso , Sepil Irem
Published: April 2023

Senescence, the deterioration of organismal function with advancing age, is a puzzling biological phenomenon. While actuarial senescence (i.e., age-dependent increases in mortality rates) is well described across some taxa, reproductive senescence (i.e.age- dependent declines in reproduction) is less understood, especially in males, with mixed patterns reported across studies. To examine the evidence for male reproductive senescence, we investigated how advancing male age affects ejaculate traits across non-human animals via a meta-analysis yielding 1814 effect sizes from 379 studies. We found no evidence for a general pattern of reproductive senescence. Instead, we found high heterogeneity for how reproduction changes with male age across animals. Some of this heterogeneity (>10%) was associated with biological factors. For example, there were taxonomical differences for some ejaculate traits — sperm motility declined with male age in lab rodents and fish, whereas ejaculate size improved with male age in bulls, fish, and insects. Some methodological factors were also important in explaining this heterogeneity: studies sampling a larger proportion of a species’ lifespan were more likely to detect senescence in ejaculate traits, emphasising the need to examine the full life cycle of species to document senescence. Contrary to predictions, we reveal that the evidence for senescence in ejaculate traits is sporadic. Our findings will help generate novel hypotheses and identify more effective methodological approaches for studying male reproductive senescence.
Deep flanking sequence engineering for efficient promoter design
Authors: Zhang Pengcheng , Wang Haochen , Xu Hanwen , Wei Lei , Hu Zhirui , Wang Xiaowo
Published: April 2023

Human experts are good at summarizing explicit strong patterns from small samples, while deep learning models can learn implicit weak patterns from big data. Biologists have traditionally described the sequence patterns of promoters via transcription factor binding sites (TFBSs), while the flanking sequences among TFBSs, which can also significantly influence promoter activity and function, remain largely uncharacterized. Thus, current synthetic promoters are mainly designed by the manipulation of TFBSs, while the flanking sequence is often chosen arbitrarily or by previous experience due to a lack of well-summarized optimization criteria. Here, we introduced an AI-aided promoter design framework, DeepSEED, that employs expert knowledge and deep learning methods to efficiently design synthetic promoters that have various desirable functions. DeepSEED incorporates the user-defined cis-regulatory sequences as ‘seeds’ and generates flanking sequences that match the ‘seeds’. We showed that DeepSEED can automatically capture k-mer frequencies and DNA shape features from active promoters in the training set and efficiently optimize the flanking sequences to better match desired properties in synthetic promoters. We validated the effectiveness of this framework for diverse synthetic promoter design tasks in both prokaryotic and eukaryotic cells. DeepSEED successfully designedE. coliconstitutive, isopropyl-beta-D-1-thiogalactopyranoside (IPTG)-inducible, and mammalian cell doxycycline (Dox)-inducible promoters with significant performance improvements, suggesting that DeepSEED has potential as an efficient AI-aided flanking sequence optimization approach for promoter design that may be of great benefit in synthetic biology applications.

Availability

https://github.com/WangLabTHU/deepseed
Investigating the role of lipid genes in liver disease using fatty liver models of alcohol and high fat in zebrafish (Danio rerio)
Authors: Shihana Fathima , Cholan Pradeep Manuneedhi , Fraser Stuart , Oehlers Stefan H , Seth Devanshi
Published: April 2023

Background

Accumulation of lipid in the liver is the first hallmark of both alcohol-related liver disease (ALD) and non-alcohol-related fatty liver disease (NAFLD). Recent studies indicate that specific mutations in lipid genes confer risk and might influence disease progression to irreversible liver cirrhosis. This study aimed to understand the function/s of lipid risk genes driving disease development in zebrafish genetic models of alcohol- and non-alcohol related fatty liver.

Methods

We used zebrafish larvae to investigate the effect of alcohol and high fat to model fatty liver and tested the utility of this model to study lipid risk gene functions. CRISPR/Cas9 gene editing was used to create knockdowns in 5 days post-fertilization zebrafish larvae for the available orthologs of human cirrhosis risk genes (pnpla3, faf2, tm6sf2). To establish fatty liver models, larvae were exposed to ethanol and a high fat diet (HFD) consisting of chicken egg yolk. Changes in morphology (imaging), survival, liver injury (biochemical tests, histopathology), gene expression (qPCR) and lipid accumulation (dye specific live imaging) were analysed across treatment groups to test the functions of these genes.

Results

Exposure of 5-day post-fertilization (dpf) WT larvae to 2% ethanol or HFD for 48 hours developed measurable hepatic steatosis. CRISPR-Cas9 genome editing depletedpnpla3, faf2andtm6sf2gene expression in these CRISPR knockdown larvae (crispants). Knockdown significantly increased effects of ethanol and HFD toxicity by increasing hepatic steatosis and hepatic neutrophil recruitment ≥2-fold in all three crispants. Furthermore, ethanol or HFD exposure significantly altered the expression of genes associated with ethanol metabolism (cyp2y3) and lipid metabolism-related gene expression, includingatgl(triglyceride hydrolysis),axox1, echs1(fatty acid β-oxidation),fabp10a(transport),hmgcra(metabolism),notch1(signaling) andsrebp1(lipid synthesis), in all threepnpla3, faf2andtm6sf2crispants. Nile Red staining in all three crispants revealed significantly increased lipid droplet size and triglyceride accumulation in the livers following exposure to ethanol or HFD.

Conclusions

We identified roles forpnpla3, faf2andtm6sf2genes in triglyceride accumulation and fatty acid oxidation pathways in a zebrafish larvae model of fatty liver.
The herbicide acetochlor causes lipid peroxidation by inhibition of glutathione peroxidase 4
Authors: Mesmar Fahmi , Muhsen Maram , Tourigny Jason P. , Tennessen Jason M. , Bondesson Maria
Published: April 2023

Obesity is increasing worldwide, particularly in rural communities, where people are likely exposed to high levels of pesticides. We here investigated whether six commonly used agricultural pesticides on corn and soy fields have adipogenic activity and act as obesogens. Exposure to two pesticides, the herbicides acetochlor and metolachlor, induced adipogenesisin vitroin mouse 3T3-L1 preadipocytes. The most potent compound, acetochlor, was selected for further studies in zebrafish. Acetochlor exposure caused morphological malformations and lethality in zebrafish larvae with an EC50of 7.8 µM and an LC50of 12 µM. Acetochlor exposure also resulted in lipid accumulation is zebrafish larvae when simultaneously fed a high cholesterol diet. To decipher the molecular mechanisms behind acetochlor action, we preformed transcriptomic and targeted lipidomic analysis of exposed animals. The combined omics results suggested that acetochlor exposure increased Nrf2 activity in response to reactive oxygen species, as well as induced lipid peroxidation and ferroptosis. We further discovered that acetochlor structurally shares a chloroacetamide group with known inhibitors of glutathione peroxidase 4 (GPX4). Computational docking analysis suggested that acetochlor covalently binds to the active site of GPX4. Consequently, Gpx4 activity was efficiently repressed by acetochlor, and lipid peroxidation was increased in zebrafish. We propose that acetochlor disrupts lipid homeostasis by inhibiting Gpx4, resulting in accumulation of lipid peroxidation, 4-hydroxynonenal, and reactive oxygen species in the cells, which in turn activate Nrf2. Because metolachlor, among other acetanilide herbicides, also contain the chloroacetamide group, inhibition of Gpx4 activity may represent a novel, common molecular initiating event of obesogens.

Synopsis

Rural populations have a high prevalence of metabolic disease and are highly exposed to pesticides. This study reports that the herbicide acetochlor, heavily used on soy and corn fields, inhibits an enzyme that protects from oxidation of lipids in the cell membrane, oxidative stress and a type of cell death called ferroptosis, features that are linked to metabolic disruption and obesity.
Evolution of chemosensory tissues and cells across ecologically diverseDrosophilids
Authors: Bontonou Gwénaëlle , Saint-Leandre Bastien , Kafle Tane , Baticle Tess , Hassan Afrah , Sánchez-Alcañiz Juan Antonio , Arguello Roman J.
Published: April 2023

Chemosensory systems display exceptional variation between species, but little is known about how the evolution of gene expression and cell types contribute to this diversity. We have generated transcriptomes for five chemosensory tissues across six ecologically diverseDrosophilaspecies and integrated their analyses with single-cell datasets to address these questions. The evolution of chemosensory transcriptomes has been predominantly shaped by stabilizing selection, but several thousand genes have nevertheless evolved expression changes in each tissue. Phylogenetic analyses of differentially expressed genes revealed strong evidence that their expression changes have been driven by a combination ofcis-regulatory and cell composition evolution. We have also found that chemosensory-related gene families have undergone pervasive expression level changes and numerous species-specific expression gains/losses. Follow-up experiments revealed several chemoreceptors that evolved novel patterns of tissue and cellular expression that likely contribute to sensory differences. Finally, analyses of the genes that are differentially expressed between sexes uncovered extensive species-specific differences. Among these rapid changes, we discovered aD. melanogaster-specific excess of male-biased gene expression in its forelegs and identified sensory and muscle cells as the primary source of this dimorphism. Together, our analyses provide new insights for understanding evolutionary changes in ecologically key tissues at both global and individual gene levels.
Identification of multiple transcription factor genes potentially involved in the development of electrosensory versus mechanosensory lateral line organs
Authors: Minařík Martin , Modrell Melinda S. , Andrew Gillis J. , Campbell Alexander S. , Fuller Isobel , Lyne Rachel , Micklem Gos , Gela David , Pšenička Martin , Baker Clare V. H.
Published: April 2023

In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well as mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and mechanosensory hair cell development and that electroreceptors evolved as a transcriptionally related ’sister cell type’ to hair cells. We previously identified only one transcription factor gene,Neurod4, as ampullary organ-restricted in the developing lateral line system of a chondrostean ray-finned fish, the Mississippi paddlefish (Polyodon spathula). The other 16 transcription factor genes we previously validated in paddlefish were expressed in both ampullary organs and neuromasts. Here, we used our published lateral line organ-enriched gene-set (arising from differential bulk RNA-seq in late-larval paddlefish), together with a candidate gene approach, to identify 23 transcription factor genes expressed in the developing lateral line system of a more experimentally tractable chondrostean, the sterlet (Acipenser ruthenus, a small sturgeon), and/or that of paddlefish. Twelve are expressed in both ampullary organs and neuromasts, consistent with conservation of molecular mechanisms. Six are electrosensory-restricted on the head(Irx5,Insm1,Sp5,Satb2,MafAandRorc), and five are the first-reported mechanosensory-restricted transcription factor genes (Foxg1,Sox8,Isl1,Hmx2andRorb). However, as previously reported,Sox8is expressed in ampullary organs as well as neuromasts in a shark (Scyliorhinus canicula), suggesting the existence of lineage-specific differences between cartilaginous and ray-finned fishes. Overall, our results support the hypothesis that ampullary organs and neuromasts develop via largely conserved transcriptional mechanisms, and identify multiple transcription factors potentially involved in the formation of electrosensory versus mechanosensory lateral line organs.
Ultrastructure of the brain waste-clearance pathway
Authors: Grubb Søren
Published: April 2023

Efficient metabolic waste clearance is essential for optimal brain function. Waste accumulation can cause inflammation, tissue damage, and potentially lead to dementia and other neurological disorders. The primary waste exit route is debated, with evidence suggesting the lymphatic system or arachnoid villi/granulations as possible pathways.

This study uses an ultrastructural dataset to emphasize the potential underestimation of macrophages and arachnoid villi/granulations in waste removal.

Based on brain surface ultrastructure analysis of the MICrONS dataset, waste clearance may occur through a transcellular route involving astrocytes to the perivascular space. Waste is then either phagocytosed by perivascular macrophages or directed to the subarachnoid space for meningeal macrophage phagocytosis.

Evidence is provided that macrophages transport non-degradable waste in lysosomes to arachnoid villi for exocytosis into the villus lumen and venous system routing. Additionally, the study investigates fibroblast-macrophage interactions via primary cilia, potentially optimizing waste clearance. The role of astrocytes in brain water homeostasis and GFAP’s potential significance in water filtration are also examined. This study offers valuable insights into waste clearance mechanisms in the brain, potentially aiding dementia understanding and treatment.
Declining food availability and habitat shifts drive community responses to marine hypoxia
Authors: Duskey E , Casini M , Limburg KE , Gårdmark A
Published: April 2023

Worsening marine hypoxia has had severe negative consequences for fish communities across the globe. While individual­ and population­level impacts of deoxygenation have been identified, it is unknown how they interact to drive changes in food webs. To address this, we incorporated several major impacts of hypoxia, including declines in benthic re­ sources, habitat shifts, increasing mortality, and changes to rates of feeding, assimilation, and reproductive efficiency, into an existing size spectrum food web modeling framework. We used this structure to ask the following questions: which of these direct effects are most critical to capturing population and community dynamics in a representative hypoxic system, how do they interact to result in community responses to deoxygenation, and what are the potential consequences of these effects in the context of accelerating deoxygenation? We tested the effect of different combinations of oxygen­dependent processes, driven by observed oxygen levels, on the food web model’s ability to explain time series of observed somatic growth, diets, biomass, and fishery yields of commercially relevant species in the Baltic Sea. Model results suggest that food availability is most critical to capturing observed dynamics. There is also some evidence for oxygen­dependent habitat use and physological rates as drivers of observed dynamics. Deoxygenation results in declining growth both of benthic and benthopelagic fish species, as the latter are unable to compensate for the loss of benthic resources by consuming more pelagic fish and resources. Analysis of scenarios of ideal, declining, and degraded oxygen conditions show that deoxygenation results in a decline in somatic growth of predators, an altered habitat occupancy resulting in changing species interactions, and a shift in energy flow to benthopelagic predators from benthic to pelagic resources. This may have important implications for management as oxygen declines or improves.
ANP rescues the preeclamptic symptoms inAxlknockout mice by improving trophoblast function ANP rescues the preeclamptic symptoms
Authors: Zhou Chan , Zhu Yunqing , Zhang Liang , Li Xuexiang , Yao Jiatong , Zhao Miaomiao , Chen Zi-jiang , Zhang Cong
Published: April 2023

Pre-eclampsia (PE) is characterized by maternal hypertension and/or proteinuria after 20 weeks of gestation. Shallow trophoblast invasion into spiral artery (SpA) and defective decidualization have been implicated in the pathogenesis of PE. However, the underlying mechanisms remain unclear. AXL receptor tyrosine kinase is a biomarker and therapeutic target for a variety of metastatic cancers while tumorigenesis and placentation share many features. In this study, a new function of AXL in promoting SpA remodeling and trophoblast invasion were demonstrated. The pregnantAxlknockout (Axl−/−) mice exhibited typical PE symptoms, including increased blood pressure and proteinuria. Artificially induced decidualization experiments showed that appeared normal, however, RNA-seq results ofAxl−/−deciduoma revealed abnormal expression of a number of transcripts, includingCorin, which encodes a cardiac protease that activates atrial natriuretic peptide (ANP). Treatment with ANP reversed the PE symptoms. Moreover, in decidua from women afflicted with PE, AXL level was significantly lower than that in normal pregnancies. These data show that the abnormality of decidua-derived AXL-CORIN-ANP affects maternal-fetal crosstalk and contributes to PE.
Spt5 interacts genetically with Myc and is limiting for brain tumor growth in Drosophila
Authors: Hofstetter Julia , Ogunleye Ayoola , Kutschke André , Buchholz Lisa Marie , Wolf Elmar , Raabe Thomas , Gallant Peter
Published: April 2023

The transcription factor SPT5 physically interacts with MYC oncoproteins and is essential for efficient transcriptional activation of MYC targets in cultured cells. Here we useDrosophilato address the relevance of this interaction in a living organism. Spt5 displays moderate synergy with Myc in fast proliferating young imaginal disc cells. During later development, Spt5-knockdown has no detectable consequences on its own, but strongly enhances eye defects caused by Myc-overexpression. Similarly, Spt5-knockdown in larval type 2 neuroblasts has only mild effects on brain development and survival of control flies, but dramatically shrinks the volumes of experimentally induced neuroblast tumors and significantly extends the lifespan of tumor-bearing animals. This beneficial effect is still observed when Spt5 is knocked down systemically and after tumor initiation, highlighting SPT5 as a potential drug target in human oncology.
Migratory herbivorous waterfowl track multiple resource waves during spring migration
Authors: Xu Fei , Wu Wei , Wei Jie , Xin Qinchuan , Wielstra Ben , La Sorte Frank A. , Ma Zhijun , Lei Guangchun , Lei Jialin , Wu Wenzhao , Yang Yongchuan , Gong Peng , Xu Bing , Si Yali
Published: April 2023

East Asian herbivorous waterfowl intensively use farmland in spring, next to their natural habitat. Accordingly, they might have expanded their migration strategy from merely tracking the green wave of newly emerging vegetation to also incorporating the availability of post-harvest agricultural seeds (here dubbed the seed wave). However, if and how waterfowl use multiple food resources to time their seasonal migration is still unknown. We test this migration strategy using 167 spring migration tracks of five East Asian herbivorous waterfowl species and mixed-effect resource selection function models. We find all study species arrive at their core stopover sites in the Northeast China Plain after agricultural seeds become available, extend their stay after spring vegetation emerges, and arrive at breeding sites around the emergence of vegetation. Moreover, the cue used in exploiting the availability of both food resources varies in different regions and among species. At the core stopover sites, larger-bodied species use the seed wave and smaller-bodied ones adopt the green wave. At the breeding sites, the former follow the green wave, and the latter track the snow-free time. Our findings suggest that waterfowl track multiple resource waves to finetune their migration, highlighting new opportunities for conservation.
Honeybee flight dynamics and pair separation in windy conditions near the hive entrance
Authors: Hejazi Bardia , Antigny Hugo , Huellstrunk Sophia , Bodenschatz Eberhard
Published: April 2023

Animals and living organisms are continuously adapting to changes in their environment. How do animals, especially those that are critical to their ecosystem, respond to rapidly changing conditions in their environment? Here, we report on the three-dimensional trajectories of flying honeybees under calm and windy conditions in front of the hive entrance. We also investigate the pitch and yaw in our experiments. We find that the mean velocities, accelerations and angular velocities of honeybees increase with increasing wind speeds. We observed that pair separation between honeybees is highly controlled and independent of wind speeds. Our results on the coordination used by honeybees may have potential applications for coordinated flight of unmanned aerial vehicles.
Production of sterile Atlantic salmon by germ cell ablation with antisense oligonucleotides
Authors: Tveiten Helge , Andersen Øivind , Swain Jaya Kumari , Johnsen Hanne , Mommens Maren , Slanchev Krasimir
Published: April 2023

Cultivation of sterile-only fish in aquaculture offers multiple benefits of environmental, economical, and social value. A reliable method for efficient sterilization without affecting fish welfare and performance traits would have significant impact on fish production practices. Here, we demonstrate sterilization of Atlantic salmon embryos by targeting thedead endgene with antisense oligonucleotides. Successful gene knock down and sterilization was achieved only when using Gapmer oligonucleotides and not with morpholino oligos. Germ cell-depleted embryos developed into morphologically normal male and female salmon with rudimentary gonads devoid of gametes.
Cross-subject Mapping of Neural Activity with Restricted Boltzmann Machines
Authors: Yang Haoming , Angjelichinoski Marko , Wu Suya , Putney Joy , Sponberg Simon , Tarokh Vahid
Published: April 2023

Subject-to-subject variability is a common challenge in generalizing neural data models across subjects. While many methods exist that map one subject to another, it remains challenging to combine many subjects in a computationally efficient manner, especially with features that are highly non-linear such as when considering populations of spiking neurons or motor units. Our objective is to transfer data from one or more target subjects to the data space of one or more source subject(s) such that the neural decoder of the source subject can directly decode the target data when the source(s) is not available during test time. We propose to use the Gaussian-Bernoulli Restricted Boltzmann Machine (RBM); once trained over the entire set of subjects, the RBM allows the mapping of target features on source feature spaces using Gibbs sampling. We also consider a novel computationally efficient training technique for RBMs based on the minimization of the Fisher divergence, which allows the gradients of the RBM to be computed in closed form, in contrast to the more traditional contrastive divergence. We apply our methods to decode turning behaviors from a comprehensive spike-resolved motor program – neuromuscular recordings of spike trains from the ten muscles that control wing motion in an agile flying Manduca sexta. The dataset consists of the comprehensive motor program recorded from nine subjects driven by six discrete visual stimuli. The evaluations show that the target features can be decoded using the source classifier with an accuracy of up to 95% when mapped using an RBM trained by Fisher divergence.

Significant Statement

In this study, we address the variability of neural data across subjects, which is a significant obstacle in developing models that can generalize across subjects. Our objective is to create a task-specific representation of the target subject signal in the feature space of the source subject. Our proposed RBM architectures achieve highly flexible and accurate cross-subject mapping with few assumptions. Our Fisher RBM improved the previous state of the art method by 300%. Our methods show promise in generalizing features of complex neural datasets across individuals, tuning neural interfaces to subject-specific features, and leveraging data across multiple subjects when experiments are limited in time or completeness.
Arabidopsis NF-YCs interact with CRY2 and PIF4/5 to repress blue light-mediated hypocotyl growth
Authors: Wang Wei , Gao Lin , Zhao Tianliang , Chen Jiamei , Chen Ting , Lin Wenxiong
Published: April 2023

Plants can not move automatically, thus they have to perceive the changing environment (light, temperate and so on) by developing the adapted phenotypes. Light-induced hypocotyl length is an ideal phenotype for studying how plants response to light. So far, many signaling components in light-induced hypocotyl growth have been reported. Here, we focused on identifying transcription factors (TFs) involved in blue light-induced hypocotyl growth by constructing Arabidopsis TFs overexpressing lines and screening blue light-induced hypocotyl length. Finally, we found that three NF-YC proteins, NF-YC7, NF-YC5 and NF-YC8 (NF-YCs as short name), develop longer hypocotyls than the wild type under blue light. While deficient mutants,nf-yc5nf-yc7andnf-yc7nf-yc8, fail to promote the hypocotyl elongation under blue light.

NF-YCs physically interacted with CRY2 and PIF4/5, while the NF-YCs-PIF4/5 interactions were repressed by CRY2. Moreover, overexpression of CRY2 or deficiency of PIF4/5 repressed the hypocotyl elongation induced by NF-YC7 under blue light. Further investigation revealed that NF-YC7 increased the blue light-induced CRY2 degradation and regulated the activities of PIF4/5.

Taking together, this study provided a new insight into that NF-YCs function as CRY2-and PIF4/5-interacting proteins and modulate their stabilization to repress the blue light-mediated hypocotyl growth.

Author Summary

Light is an essential environmental factor for plants growth and development. Plants response to light signaling by displaying short hypocotyls, green leaves, and so on. The mechanisms of light responding to light have aroused extensive attention. In this study, we clarified that NF-YC family members NF-YC5/7/8 interact with CRY2, PIF4/5 and modulate their stabilization to repress the blue light-mediated hypocotyl growth. It was the first time for reporting NF-Y family members function as CRY2-and PIF4/5-interacting proteins. Therefore, this study provides a novel understanding how plants adapt to light.
Stochastic characterization of navigation strategies in an automated variant of the Barnes maze
Authors: Lee Ju-Young , Jung Dahee , Royer Sébastien
Published: April 2023

Animals can use a repertoire of strategies to navigate in an environment, and it remains an intriguing question how these strategies are selected based on the nature and familiarity of environments. To investigate this question, we developed a fully automated variant of the Barnes maze, characterized by 24 vestibules distributed along the periphery of a circular arena, and monitored the trajectories of mice over 15 days as they learned to navigate towards a goal vestibule from a random start vestibule. We show that the patterns of vestibule visits can be reproduced by the combination of three stochastic processes reminiscent of random, serial and spatial strategies. The processes randomly selected vestibules based on either uniform (random) or biased (serial and spatial) probability distributions. They closely matched experimental data across a range of statistical distributions characterizing the length, distribution, step size, direction, and stereotypy of vestibule sequences, revealing a shift from random to spatial and serial strategies over time, with a strategy switch occurring approximately every six vestibule visits. Our study provides a novel apparatus and analysis toolset for tracking the repertoire of navigation strategies and demonstrates that a set of stochastic processes can largely account for exploration patterns in the Barnes maze.
Assessing the quality of comparative genomics data and results with thecogeqcR/Bioconductor package
Authors: Almeida-Silva Fabricio , Van de Peer Yves
Published: April 2023

Comparative genomics has become an indispensable part of modern biology due to the advancements in high-throughput sequencing technologies and the accumulation of genomic data in public databases. However, the quality of genomic data and the choice of parameters used in software tools used for comparative genomics can greatly impact the accuracy of results. To address these issues, we presentcogeqc, an R/Bioconductor package that provides researchers with a toolkit to assess genome assembly and annotation quality, orthogroup inference, and synteny detection. The package offers context-guided assessments of assembly and annotation statistics by comparing observed statistics to those of closely-related species on NCBI. To assess orthogroup inference,cogeqccalculates a protein domain-aware orthogroup score that aims at maximizing the number of shared protein domains within the same orthogroup. The assessment of synteny detection consists in representing anchor gene pairs as a synteny network and analyzing its graph properties, such as clustering coefficient, node count, and scale-free topology fit. The application of cogeqc to real data sets allowed for an evaluation of multiple parameter combinations for orthogroup inference and synteny detection, providing researchers with guidelines to aid in the selection of the most appropriate tools and parameters for their specific data.