bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential effects of intra-modal and cross-modal reward value on visual perception: ERP evidence
Authors: Vakhrushev Roman , Cheng Felicia , Schacht Annekathrin , Pooresmaeili Arezoo
Published: October 2021

Stimuli associated with high reward modulate perception and such value-driven effects have been shown to originate from the modulation of the earliest stages of sensory processing in the brain. In natural environments objects comprise multiple features (imagine a rolling soccer ball, with its black and white patches and the swishing sound made during its motion), where each feature may signal different associations with previously encountered rewards. How perception of such an object is affected by the value associations of its constituent parts is unknown. The present study compares intra- and cross-modal value-driven effects on behavioral and electrophysiological correlates of visual perception. Human participants first learned the reward associations of visual and auditory cues. Subsequently, they performed a visual orientation discrimination task in the presence of previously rewarded visual or auditory cues (intra- and cross-modal cues, respectively) that were concurrently presented with the target stimulus. During the conditioning phase, when reward associations were learned and reward cues were the target of the task, reward value of both modalities enhanced the electrophysiological correlates of sensory processing in visual cortex. During the post-conditioning phase, when reward delivery was halted and previously rewarded stimuli were task-irrelevant, cross-modal value-enhanced behavioral measures of visual sensitivity whereas intra-modal value led to a trend for suppression. A similar pattern of modulations was found in the simultaneously recorded event-related potentials (ERPs) of posterior electrodes. We found an early (90-120 ms) suppression of ERPs evoked by high-value, intra-modal stimuli. Cross-modal cues led to a later value-driven modulation, with an enhancement of response positivity for high-compared to low-value stimuli starting at the N1 window (180-250 ms) and extending to the P3 (300-600 ms) responses of the posterior electrodes. These results indicate that visual cortex is modulated by the reward value of visual as well as auditory cues. Previously rewarded, task-irrelevant cues from the same or different sensory modality have a different effect on visual perception, as intra-modal high-value cues may interfere with the target processing, whereas cross-modal high-value cues boost the perception of the target.
A preclinical randomized multicenter trial of anti-IL-17A treatment for acute ischemic stroke
Authors: Gelderblom Mathias , Koch Simon , Strecker Jan-Kolja , Jørgensen Carina , Garcia-Bonilla Lidia , Ludewig Peter , Bernreuther Christian , Pinnschmidt Hans , Arumugam Thiruma V. , Thomalla Goetz , Faber Cornelius , Sedlacik Jan , Gerloff Christian , Minnerup Jens , Clausen Bettina H. , Anrather Josef , Magnus Tim
Published: October 2021

Multiple consensus statements have called for preclinical randomized controlled trials (pRCT) to improve translation in stroke research. Here, we investigated the efficacy of IL-17A neutralizing antibodies in a multicentric pRCT using a murine stroke model. C57/Bl.6 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Mice were randomly allocated (1:1). Either anti-IL-17A (500 µg) or isotype antibody (500 µg) were administered 1 h after tMCAO. Primary analysis of infarct volumes was done by MRI after three days. Secondary analysis included mortality, neurological score, neutrophil infiltration and the impact of the gut microbiome on treatment effects. Out of 136 mice, 109 mice were included in the analysis. Mixed model analysis revealed that the IL-17A neutralization significantly reduced infarct sizes (anti IL-17A: 61.77 ± 31.04 mm3; IgG control: 75.66 ± 34.79 mm3; p=0.01). Secondary outcome measures showed a decrease in mortality (Hazard Ratio=3.43, 95% CI = 1.157 - 10.18; p=0.04) and neutrophil invasion into ischemic cortices. There was no difference in the neurological score. The analysis of the gut microbiome showed significant differences between centers. Taken together, this is the first positive pRCT in an ischemia reperfusion model. It suggests IL-17A neutralization as a potential target in stroke.
Bromodomain factor 5 is an essential transcriptional regulator of the Leishmania genome
Authors: Jones Nathaniel G. , Geoghegan Vincent , Moore Gareth , Carnielli Juliana B. T. , Newling Katherine , Calderón Félix , Gabarró Raquel , Martín Julio , Prinjha Rab , Rioja Inmaculada , Wilkinson Anthony J. , Mottram Jeremy C.
Published: October 2021

Leishmania are unicellular parasites that cause human and animal disease. Alongside other organisms in kinetoplastida, they have evolved an unusual genome architecture that requires all RNA polymerase II transcribed genes to be expressed constitutively, with transcriptional start regions denoted by histone variants and histone lysine acetylation. However, the way these chromatin marks are interpreted by the cell is not understood. Seven predicted bromodomain factors (BDF1-7), the reader modules for acetyl-lysine, were identified across Leishmania genomes. Using L. mexicana as a model, Cas9-driven gene deletions indicate that BDF1-5 are essential for promastigote survival, whilst DiCre inducible gene deletion of the dual bromodomain factor BDF5 identified it to be essential for both promastigotes and amastigotes. ChIP-seq assessment of BDF5s genomic distribution revealed it as highly enriched at transcriptional start sites. Using an optimised proximity proteomic and phosphoproteomic technique, XL-BioID, we defined the BDF5-proximal environment to be enriched for other bromodomain factors, histone acetyltransferase 2, and proteins essential for transcriptional activity and RNA processing. Inducible deletion of BDF5, led to a disruption of pol II transcriptional activity and global defects in gene expression. Our results indicate the requirement of Leishmania to interpret histone acetylation marks for normal levels of gene expression and thus cellular viability.
A systematic evaluation of 41 DNA methylation predictors across 101 data preprocessing and normalization strategies highlights considerable variation in algorithm performance
Authors: Ori Anil P.S. , Lu Ake T , Horvath Steve , Ophoff Roel A
Published: October 2021

Background

DNA methylation (DNAm) based predictors hold great promise to serve as clinical tools for health interventions and disease management. While these algorithms often have high prediction accuracy and are associated with many disease-related phenotypes, the reliability of their performance remains to be determined. We therefore conducted a systematic evaluation across 101 different data processing strategies that preprocess and normalize DNAm data and assessed how each analytical strategy affects the reliability and prediction accuracy of 41 DNAm-based predictors.

Results

Our analyses were conducted in a large EPIC DNAm sample of the Jackson Heart Study (N=2,053) that included 146 pairs of technical replicate samples. By estimating the average absolute agreement between replicate pairs, we show that 32 out of 41 predictors (78%) demonstrate excellent test-retest reliability when appropriate data processing and normalization steps are implemented. Across all pairs of predictors, we find a moderate correlation in performance across analytical strategies (mean rho=0.40, SD=0.27), highlighting significant heterogeneity in performance across algorithms within a choice of an analytical pipeline. (Un)successful removal of technical variation furthermore significantly impacts downstream phenotypic association analysis, such as all-cause mortality risk associations.

Conclusions

We show that DNAm-based algorithms are sensitive to technical variation. The right choice of data processing and normalization pipeline is important to achieve reproducible estimates and improve prediction accuracy in downstream phenotypic association analyses. For each of the 41 DNAm predictors, we report its test-retest reliability and provide the best performing analytical strategy as a guideline for the research community. As DNAm-based predictors become more and more widely used, both for research purposes as well as for clinic applications, our work helps improve their performance and standardize their implementation.
Quantifying mediation between omics layers and complex traits
Authors: Sadler Marie C. , Auwerx Chiara , Porcu Eleonora , Kutalik Zoltán
Published: October 2021

Background

High-dimensional omics datasets provide valuable resources to determine the causal role of molecular traits in mediating the path from genotype to phenotype. Making use of quantitative trait loci (QTL) and genome-wide association studies (GWASs) summary statistics, we developed a multivariable Mendelian randomization (MVMR) framework to quantify the connectivity between three omics layers (DNA methylome (DNAm), transcriptome and proteome) and their cascading causal impact on complex traits and diseases.

Results

Evaluating 50 complex traits, we found that on average 37.8% (95% CI: [36.0%-39.5%]) of DNAm-to-trait effects were mediated through transcripts in thecis-region, while only 15.8% (95% CI: [11.9%-19.6%]) are mediated through proteins incis. DNAm sites typically regulate multiple transcripts, and while found to predominantly decrease gene expression, this was only the case for 53.4% across ≈ 47,000 significant DNAm-transcript pairs. The average mediation proportion for transcript-to-trait effects through proteins (encoded for by the assessed transcript or located intrans) was estimated to be 5.27% (95%CI: [4.11%-6.43%]). Notable differences in the transcript and protein QTL architectures were detected with only 22% of protein levels being causally driven by their corresponding transcript levels. Several regulatory mechanisms were hypothesized including an example where cg10385390 (chr1:8’022’505) increases the risk of irritable bowel disease by reducingPARK7transcript and protein expression.

Conclusions

The proposed integrative framework identified putative causal chains through omics layers providing a powerful tool to map GWAS signals. Quantification of causal effects between successive layers indicated that molecular mechanisms can be more complex than what the central dogma of biology would suggest.
Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation
Authors: Thompson Alex F. , Blackburn Patrick R. , Arons Noah S. , Stevens Sarah N. , Babovic-Vuksanovic Dusica , Lian Jane B. , Klee Eric W. , Stumpff Jason K.
Published: October 2021

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the α2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22’s functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest the motor domain α2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of α2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.
Integrated Regulation of PKA by Fast and Slow Neurotransmission in the Nucleus Accumbens Controls Plasticity and Stress Responses
Authors: Thomas Rachel , Hernandez Adan , Benavides David R. , Li Wei , Tan Chunfeng , Plattner Florian , Chakraborti Ayanabha , Pozzo-Miller Lucas , Taylor Susan S. , Bibb James A.
Published: October 2021

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. We find that glutamate-dependent reduction in Cdk5-dependent RIIβ phosphorylation alters the PKA holoenzyme auto-inhibitory state to increase PKA signaling in response to dopamine. Disruption of RIIβ phosphorylation by Cdk5, consequently, enhances cortico-ventral striatal synaptic plasticity. Acute and chronic stress in rats inversely modulate RIIβ phosphorylation and ventral striatal infusion of a small interfering peptide that selectively targets RIIβ regulation by Cdk5 improves behavioral response to stress. This new signaling mechanism integrating ventral striatal glutamate and dopamine neurotransmission is likely important to brain function, may contribute to neuropsychiatric conditions, and serves as a possible target for the development of novel therapeutics for stress-related disorders.
A genome-wide genetic screen uncovers novel determinants of human pigmentation
Authors: Bajpai Vivek K. , Swigut Tomek , Mohammed Jaaved , Tycko Josh , Naqvi Sahin , Arreola Martin , Kim Tayne C. , Arora Neha , Pritchard Jonathan K. , Bassik Michael C. , Wysocka Joanna
Published: October 2021

The skin color is one of the most diverse human traits and is determined by the quantity, type and distribution of melanin. Here, we leverage light scattering properties of melanin to conduct a genome-wide CRISPR-Cas9 screen for novel regulators of melanogenesis. We identify functionally diverse genes converging on melanosome biogenesis, endosomal transport and transcriptional/posttranscriptional gene regulation, most of which represent novel associations with pigmentation. A survey of transcriptomes from diversely pigmented individuals reveals that the majority of genes discovered in our screen are upregulated in dark skin melanocytes, in agreement with their melanin-promoting function and potential contribution to skin color variation. This association is further buttressed by the significant skin color heritability enrichment in the vicinity of these genes. Taken together, our study presents a novel approach to assay pigmentation and uncovers a plethora of melanogenesis regulators, with broad implications for human variation, cell biology and medicine.

One Sentence Summary

Genetic screen uncovers genes involved in human melanogenesis, many of which are differentially expressed in individuals of diverse skin color.
Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane hunter-horticulturalists
Authors: Schneider-Crease India , Blackwell Aaron D. , Kraft Thomas S. , Thompson Melissa Emery , Suarez Ivan Maldonado , Cummings Daniel K. , Stieglitz Jonathan , Snyder-Mackler Noah , Gurven Michael , Kaplan Hillard , Trumble Benjamin C.
Published: October 2021

Background

Soil-transmitted helminth (STH) infections can catalyze immunological changes that affect the response to subsequent infections, particularly those that elicit strong inflammatory responses. As globalization heightens the risk that remote communities with high STH prevalence will encounter novel pathogens, understanding how STHs shape immune responses to these downstream infections becomes increasingly crucial.

Methodology

We worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels—most likely indicative of infection in this population—are associated with dampened immune responses toin vitrostimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (interferon gamma [INF-γ], interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, Granulocyte-macrophage colony-stimulating factor [GM-CSF], and Tumor necrosis factor-alpha [TNF-α]). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation.

Results

Infection withAscaris lumbricoideswas significantly (p ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men.

Conclusions and implications

We find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens, and suggest that this mitigation of host-induced damage may reduce the incidence of cytokine storms in populations with high STH prevalence.
Assessing extracellular vesicles from bovine mammary gland epithelial cells cultured in FBS-free medium
Authors: Silvestrelli G. , Ulbrich S.E. , Saenz-de-Juano M.D.
Published: October 2021

Aim

Mammary gland extracellular vesicles (EVs) are found in both human and livestock milk. Our knowledge of the role of EVs in the mammary gland development, breast cancer and mastitis derives mainly from in vitro cell culture models. However, a commonly shared limitation is the use of foetal bovine serum (FBS) as a supplement, which naturally contains EVs. For this reason, the purpose of the study is to establish a novel tool to investigate mammary gland EVs in vitro and in an FBS-free system.

Methods

Primary bovine mammary epithelial cells (pbMECs) and a mammary gland alveolar epithelial cell line (MAC-T) were cultured in a chemically defined EV-free medium. To find a reliable EVs isolation protocol from a starting cell conditioned medium (10 mL), we compared eight different methodologies by combining ultracentrifugation (UC), chemical precipitation (CP), size exclusion chromatography (SEC), and ultrafiltration (UF).

Results

The medium formula sustained both pbMECs and MAC-T cell growth and did not alter MAC-T cell identity. Transmission electron microscopy revealed that we obtained EV-like particles in five out of eight protocols. The cleanest samples with the highest particles amount and detectable amounts of RNA were obtained by using UF-SEC-UC and UC-SEC-UC.

Conclusion

Our chemically defined, EV-free medium sustains the growth of both pbMECs and MAC-T and allows the isolation of EVs that are free from any contamination by UF-SEC-UC and UC-SEC-UC. In conclusion, we propose a new culture system and EVs isolation protocols for further research on mammary epithelial EVs.
Spatially resolved whole transcriptome profiling in human and mouse tissue using Digital Spatial Profiling
Authors: Zimmerman Stephanie M. , Fropf Robin , Kulasekara Bridget R. , Griswold Maddy , Appelbe Oliver , Bahrami Arya , Boykin Rich , Buhr Derek L. , Fuhrman Kit , Hoang Margaret L. , Huynh Quoc , Isgur Lesley , Klock Andrew , Kutchma Alecksandr , Lasley Alexa E. , Liang Yan , McKay-Fleisch Jill , Nelson Jeffrey S. , Nguyen Karen , Piazza Erin , Rininger Aric , Zollinger Daniel R. , Rhodes Michael , Beechem Joseph M.
Published: October 2021

Emerging spatial profiling technology has enabled high-plex molecular profiling in biological tissues, preserving the spatial and morphological context of gene expression. Here we describe expanding the chemistry for the Digital Spatial Profiling platform to quantify whole transcriptomes in human and mouse tissues using a wide range of spatial profiling strategies and sample types. We designed multiplexed in situ hybridization probe pools targeting the protein-coding genes in the human and mouse transcriptomes, hereafter referred to as the human or mouse Whole Transcriptome Atlas (WTA). We validated the human and mouse WTA using cell lines to demonstrate concordance with orthogonal gene expression profiling methods in profiled region sizes ranging from ~10-500 cells. By benchmarking against bulk RNAseq and fluorescence in situ hybridization, we demonstrate robust transcript detection possible down to ~100 transcripts per region. To assess the performance of WTA across tissue and sample types, we applied WTA to biological questions in cancer, molecular pathology, and developmental biology. We show that spatial profiling with WTA can detect expected spatial gene expression differences between tumor and tumor microenvironment, identify spatial disease-specific heterogeneity in gene expression in histological structures of the human kidney, and comprehensively map transcriptional programs in anatomical substructures of nine organs in the developing mouse embryo. Digital Spatial Profiling technology with the WTA assays provides a flexible method for spatial whole transcriptome profiling applicable to diverse tissue types and biological contexts.
Sexual and temporal variation in New Zealand bellbird song repertoires
Authors: Roper Michelle M. , Webb Wesley H. , Fukuzawa Yukio , Evans Christine , Harmer Aaron M.T. , Brunton Dianne H.
Published: October 2021

How song repertoires vary within species and change over time is well studied in male songbirds. However, variation in female song repertoires remains largely unstudied despite female song being much more common and complex than once assumed. We investigated the song syllable repertoire of the New Zealand bellbird (Anthornis melanura), a species where both sexes have complex but sexually dimorphic song. We compared songs at individual and population levels to investigate sex and temporal variation of syllable repertoires. We detected 96 syllable types in the population over four years, of which 58% were unique to males, 32% unique to females and 9% were shared between the sexes. The population syllable repertoire of both sexes changed substantially across years with similar turnover rates (Jaccard’s similarity coefficients; female 52.9–69.0%; male 58.6–73.7%). Furthermore, many syllable types, unique to each sex, varied in prevalence within the population across years. The syllable repertoire sizes of individuals were higher for males than females (13-32, n = 7 and 6-16, n = 8, respectively). Although these sample sizes were low, the temporal variation in syllable prevalence and turnover for individuals were similar to patterns at the population level. Overall, male and female bellbirds exhibited similarities in temporal patterns of yearly repertoire composition, with rapid changes in syllable prevalence, but females had fewer syllable types than males. We suggest that these similarities and differences are consistent with male and female song repertoires being driven by similar but not identical selection pressures.
Structural basis for the absence of low-energy chlorophylls responsible for photoprotection from a primitive cyanobacterial PSI
Authors: Kato Koji , Hamaguchi Tasuku , Nagao Ryo , Kawakami Keisuke , Ueno Yoshifumi , Suzuki Takehiro , Uchida Hiroko , Murakami Akio , Nakajima Yoshiki , Yokono Makio , Akimoto Seiji , Dohmae Naoshi , Yonekura Koji , Shen Jian-Ren
Published: October 2021

Photosystem I (PSI) of photosynthetic organisms is a multi-subunit pigment-protein complex and functions in light harvesting and photochemical charge-separation reactions, followed by reduction of NADP to NADPH required for CO2 fixation. PSI from different photosynthetic organisms has a variety of chlorophylls (Chls), some of which are at lower-energy levels than its reaction center P700, a special pair of Chls, and are called low-energy Chls. However, the site of low-energy Chls is still under debate. Here, we solved a 2.04-Å resolution structure of a PSI trimer by cryo-electron microscopy from a primitive cyanobacterium Gloeobacter violaceus PCC 7421, which has no low-energy Chls. The structure showed absence of some subunits commonly found in other cyanobacteria, confirming the primitive nature of this cyanobacterium. Comparison with the known structures of PSI from other cyanobacteria and eukaryotic organisms reveals that one dimeric and one trimeric Chls are lacking in the Gloeobacter PSI. The dimeric and trimeric Chls are named Low1 and Low2, respectively. Low2 does not exist in some cyanobacterial and eukaryotic PSIs, whereas Low1 is absent only in Gloeobacter. Since Gloeobacter is susceptible to light, this indicates that Low1 serves as a main photoprotection site in most oxyphototrophs, whereas Low2 is involved in either energy transfer or energy quenching in some of the oxyphototrophs. Thus, these findings provide insights into not only the functional significance of low-energy Chls in PSI, but also the evolutionary changes of low-energy Chls responsible for the photoprotection machinery from photosynthetic prokaryotes to eukaryotes.
Optogenetic EB1 inactivation shortens metaphase spindles by disrupting cortical force-producing interactions with astral microtubules
Authors: Dema Alessandro , van Haren Jeffrey , Wittmann Torsten
Published: October 2021

Chromosome segregation is accomplished by the mitotic spindle, a bipolar micromachine built primarily from microtubules. Different microtubule populations contribute to spindle function: Kinetochore microtubules attach and transmit forces to chromosomes, antiparallel interpolar microtubules support spindle structure, and astral microtubules connect spindle poles to the cell cortex [1,2]. In mammalian cells, End Binding (EB) proteins associate with all growing microtubule plus ends throughout the cell cycle and serve as adaptors for a diverse group of +TIPs that control microtubule dynamics and interactions with other intracellular structures [3]. Because binding of many +TIPs to EB1 and thus microtubule-end association is switched off by mitotic phosphorylation [4–6] the mitotic function of EBs remains poorly understood. To analyze how EB1 and associated +TIPs on different spindle microtubule populations contribute to mitotic spindle dynamics, we use a light sensitive EB1 variant, π-EB1, that allows local, acute and reversible inactivation of +TIP association with growing microtubule ends in live cells [7]. We find that acute π-EB1 photoinactivation results in rapid and reversible metaphase spindle shortening and transient relaxation of tension across the central spindle. However, in contrast to interphase, π-EB1 photoinactivation does not inhibit microtubule growth in metaphase, but instead increases astral microtubule length and number. Yet, in the absence of EB1 activity astral microtubules fail to engage the cortical dynein/dynactin machinery and spindle poles move away from regions of π-EB1 photoinactivation. In conclusion, our optogenetic approach reveals mitotic EB1 functions that remain hidden in genetic experiments likely due to compensatory molecular systems regulating vertebrate spindle dynamics.
The perceptual categorization of multidimensional stimuli is hierarchically organized
Authors: Chen Chi , de Hoz Livia
Published: October 2021

As we interact with our surroundings, we encounter the same or similar objects from different perspectives and are compelled to generalize. For example, we recognize dog barks as a distinct class of sound, despite the variety of individual barks. While we have some understanding of how generalization is done along a single stimulus dimension, such as frequency or color, natural stimuli are identifiable by a combination of dimensions. To understand perception, measuring the interaction across stimulus dimensions is essential. For example, when identifying a sound, does our brain focus on a specific dimension or a combination, such as its frequency and duration? Furthermore, does the relative relevance of each dimension reflect its contribution to the natural sensory environment? Using a 2- dimension discrimination task for mice we tested untrained generalization across several pairs of auditory dimensions in a naturalistic and automatized behavioral paradigm. We uncovered a perceptual hierarchy over the tested dimensions that was dominated by the sound’s spectral composition. This hierarchy could reflect the relevance of the different dimensions in natural stimuli and their potentially associated differential shaping of neuronal tuning. Mice could learn to pay more attention to dimensions low in the hierarchy, but this learning was more rigid and did not generalize as flexibly. Stimuli are thus not perceived as a whole but as a combination of their features, each of which weights differently on the dentification of the stimulus according to an established hierarchy.
Odor motion sensing enables complex plume navigation
Authors: Kadakia Nirag , Demir Mahmut , Michaelis Brenden T. , Reidenbach Matthew A. , Clark Damon A. , Emonet Thierry
Published: October 2021

Studies dating back a century (Flügge, 1934) have stressed the critical role of the wind as the primary directional cue in odor plume navigation. Here, we show that Drosophila shape their navigational decisions using a second directional cue – the direction of motion of odors – which they detect from the temporal correlations of the odor signal between their two antennae. Using a high-resolution virtual reality paradigm to deliver spatiotemporally complex fictive odors to freely-walking flies, we demonstrate that such odor direction sensing is computationally equivalent to motion detection algorithms underlying motion detection in vision. Simulations and theoretical analysis of turbulent plumes reveal that odor motion contains valuable directional information absent from the airflow; indeed, this information is used by both Drosophila and virtual agents to navigate naturalistic odor environments. The generality of our findings suggests that odor direction sensing is likely used throughout the animal kingdom, and could significantly improve olfactory robot navigation in harsh chemical environments.
Roles of PKCdelta in Photoperiod and Circadian Regulations in Drosophila melanogaster
Authors: Khaira Harjit , Patro Somya , Lee Kwangwon
Published: October 2021

Many organisms are known to regulate seasonal behaviors and physiological processes in response to day length changes through photoperiodism. Extreme changes in photoperiods have detrimental effects on human health, which can impair development and serve as the origin of adult diseases. Since the seminal work by Bünning in 1936, there are studies supporting the view that organisms can measure the day length through an endogenous 24-hour cellular circadian clock. However, the mechanisms involved in measuring seasonal or day-length changes are not understood. In the current study, we performed a genome-wide association study (GWAS) on photoperiodism using the Drosophila Genetic Reference Panel. The GWAS identified 4 top candidate genes responsible for photoperiodic regulations. The knockout mutants of the four candidate genes (Protein Kinase C delta (Pkcdelta), Glucuronyltransferase-P (GlcAT-P), Brain-specific homeobox (Bsh), and Diuretic hormone 31 Receptor (Dh31-R1)) were analyzed for their photoperiod and circadian period phenotypes. PKCdelta and GlcAT-P mutants show a significantly different photoperiod response compared to that of the wild type strain, and also had an altered circadian period phenotype. Further molecular characterization revealed two independent mutant alleles of PKCdelta with a defective catalytic domain had distinct photoperiod responses. Taken these data together, we concluded that there is overlap between the circadian clock and photoperiodic regulations in Drosophila, and PKCdelta is a component that is involved in both circadian and photoperiodic regulations. By identifying novel molecular components of photoperiod, the current study provides new insights into the genetic mechanisms of determining the seasonal changes.

Author Summary

Extreme changes in photoperiods have detrimental effects on human health, which can impair development and serve as the origin of adult diseases. The molecular and genetic mechanisms of how an organism interprets and adapts to seasonal environmental changes are not well understood. Drosophila Genetic Reference Panel (DGRP) is a community resource of 205 inbred lines created for studying population genomics and quantitative traits. Using DGRP we performed a genome-wide association study (GWAS) to find potential photoperiod candidate genes. PKCdelta, a candidate gene from the GWAS study was identified to have both photoperiod and circadian effects. This data supports the view that circadian clock and photoperiodism have a shared regulatory circuit. Our study sheds light onto potential genes that could be further studied to characterize the mechanisms of photoperiodism, and its relationship to the circadian clock.
Variation in the response to malaria in Diversity Outbred mice
Authors: Gupta Avni S. , Chevée Victoria , Kirosingh Adam S. , Davis Nicole M. , Schneider David S.
Published: October 2021

We infected Diversity Outbred mice with Plasmodium chabaudi to better understand how the host response to infection can vary and to try to identify genetic loci responsible for this variation. We identified two loci correlating with binary traits: one on chromosome two was linked to undetectable parasite loads and another on chromosome ten which was linked to death. Though we tested many variable traits, none of those reached statistical significance using the 489 mice we tested.
Drivers and Determinants of Strain Dynamics Following Faecal Microbiota Transplantation
Authors: Schmidt Thomas SB , Li Simone S , Maistrenko Oleksandr M , Akanni Wasiu , Coelho Luis Pedro , Dolai Sibasish , Fullam Anthony , Glazek Anna M , Hercog Rajna , Herrema Hilde , Jung Ferris , Kandels Stefanie , Orakov Askarbek , Van Rossum Thea , Benes Vladimir , Borody Thomas J , de Vos Willem M , Ponsioen Cyriel Y , Nieuwdorp Max , Bork Peer
Published: October 2021

Faecal microbiota transplantation (FMT) is an efficacious therapeutic intervention, but its clinical mode of action and underlying microbiome dynamics remain poorly understood. Here, we analysed the metagenomes associated with 142 FMTs, in a time series-based meta-study across five disease indications. We quantified strain-level dynamics of 1,089 microbial species based on their pangenome, complemented with 47,548 newly constructed metagenome-assembled genomes. Using subsets of procedural-, host- and microbiome-based variables, LASSO-regularised regression models accurately predicted the colonisation and resilience of donor and recipient microbes, as well as turnover of individual species. Linking this to putative ecological mechanisms, we found these sets of variables to be informative of the underlying processes that shape the post-FMT gut microbiome. Recipient factors and complementarity of donor and recipient microbiomes, encompassing entire communities to individual strains, were the main determinants of individual strain population dynamics, and mostly independent of clinical outcomes. Recipient community state and the degree of residual strain depletion provided a neutral baseline for donor strain colonisation success, in addition to inhibitive priority effects between species and conspecific strains, as well as putatively adaptive processes. Our results suggest promising tunable parameters to enhance donor flora colonisation or recipient flora displacement in clinical practice, towards the development of more targeted and personalised therapies.
The unforeseen intracellular lifestyle of Enterococcus faecalis in hepatocytes
Authors: Nunez Natalia , Derré-Bobillot Aurélie , Lakisic Goran , Lecomte Alexandre , Mercier-Nomé Françoise , Cassard Anne-Marie , Bierne Hélène , Serror Pascale , Archambaud Cristel
Published: October 2021

Enterococcus faecalis is a bacterial species present at a sub-dominant level in the human gut microbiota. This commensal turns into an opportunistic pathogen under specific conditions involving dysbiosis and host immune deficiency. E. faecalis is also the only intestinal pathobiont identified to date as contributing to liver damage in alcoholic liver disease. We have previously observed that E. faecalis is internalized in hepatocytes. Here, the survival and fate of E. faecalis was examined in hepatocytes, the main epithelial cell type in the liver. Although referred to as an extracellular pathogen, we demonstrate that E. faecalis is able to survive and divide in hepatocytes, and form intracellular clusters in two distinct hepatocyte cell lines, in primary mouse hepatocytes, as well as in vivo. This novel process extends to kidney cells. Unravelling the intracellular lifestyle of E. faecalis, our findings contribute to the understanding of pathobiont-driven diseases.
An Evolutionarily Conserved Regulatory Pathway of Muscle Mitochondrial Network Organization
Authors: Katti Prasanna , Ajayi Peter T. , Aponte Angel , Bleck Christopher K.E. , Glancy Brian
Published: October 2021

Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial network-type separately from contractile fiber-type remain unclear. Here, we show that natural energetic demands placed onDrosophila melanogastermuscles yield native cell-types among which contractile and mitochondrial network-types are regulated independently. Proteomic analyses of indirect flight, jump, and leg muscles together with muscles misexpressing known fiber-type specification factorsalmidentified transcription factorsH15andcutas potential mitochondrial network regulators. We demonstrateH15operates downstream ofsalmregulating flight muscle contractile and mitochondrial network-type. Conversely,H15regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find thatcutregulatessalmexpression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization separately from contractile type, mitochondrial content, and mitochondrial size through an evolutionarily conserved pathway involvingcut, salm, andH15.
Structures of core eukaryotic protein complexes
Authors: Humphreys Ian R. , Pei Jimin , Baek Minkyung , Krishnakumar Aditya , Anishchenko Ivan , Ovchinnikov Sergey , Zhang Jing , Ness Travis J. , Banjade Sudeep , Bagde Saket , Stancheva Viktoriya G. , Li Xiao-Han , Liu Kaixian , Zheng Zhi , Barrero Daniel J. , Roy Upasana , Fernández Israel S. , Szakal Barnabas , Branzei Dana , Greene Eric C. , Biggins Sue , Keeney Scott , Miller Elizabeth A. , Fromme J. Christopher , Hendrickson Tamara L. , Cong Qian , Baker David
Published: October 2021

Protein-protein interactions play critical roles in biology, but despite decades of effort, the structures of many eukaryotic protein complexes are unknown, and there are likely many interactions that have not yet been identified. Here, we take advantage of recent advances in proteome-wide amino acid coevolution analysis and deep-learning-based structure modeling to systematically identify and build accurate models of core eukaryotic protein complexes, as represented within the Saccharomyces cerevisiae proteome. We use a combination of RoseTTAFold and AlphaFold to screen through paired multiple sequence alignments for 8.3 million pairs of S. cerevisiae proteins and build models for strongly predicted protein assemblies with two to five components. Comparison to existing interaction and structural data suggests that these predictions are likely to be quite accurate. We provide structure models spanning almost all key processes in Eukaryotic cells for 104 protein assemblies which have not been previously identified, and 608 which have not been structurally characterized.

One-sentence summary

We take advantage of recent advances in proteome-wide amino acid coevolution analysis and deep-learning-based structure modeling to systematically identify and build accurate models of core eukaryotic protein complexes.
Combined Lineage Tracing and scRNA-seq Reveals Unexpected First Heart Field Predominance of Human iPSC Differentiation
Authors: Galdos Francisco X. , Lee Carissa , Lee Soah , Goodyer William , Paige Sharon , Escobar Gabriela V. , Darsha Adrija , Beck Aimee , Xu Sidra , Bak Rasmus O. , Porteus Matthew , Wu Sean M.
Published: October 2021

During mammalian development, the left and right ventricles arise from early populations of cardiac progenitors known as the first and second heart fields, respectively. While these populations have been extensively studied in non-human model systems, their identification and studyin vivohuman tissues have been limited due to the ethical and technical limitations of accessing gastrulation stage human embryos. Human induced pluripotent stem cells (hiPSCs) present an exciting alternative for modeling early human embryogenesis due to their well-established ability to differentiate into all embryonic germ layers. Here, we describe the development of a TBX5/MYL2 lineage tracing reporter system that allows for the identification of FHF-progenitors and their descendants including left ventricular cardiomyocytes.

Furthermore, using single cell RNA sequencing (scRNA-seq) with oligonucleotide-based sample multiplexing, we extensively profiled differentiating hiPSCs across 12 timepoints in two independent iPSC lines. Surprisingly, our reporter system and scRNA-seq analysis revealed a predominance of FHF differentiation using the small molecule Wnt-based 2D differentiation protocol. We compared this data with existing murine and 3D cardiac organoid scRNA-seq data and confirmed the dominance of left ventricular cardiomyocytes (>90%) in our hiPSC-derived progeny. Together, our work provides the scientific community with a powerful new genetic lineage tracing approach as well as a single cell transcriptomic atlas of hiPSCs undergoing cardiac differentiation.
Revisiting colorectal cancer tumorigenesis with spatially-resolved gene expression profiling
Authors: Roelands Jessica , van der Ploeg Manon , Dang Hao , Boonstra Jurjen J. , Hardwick James C.H. , Hawinkels Lukas J.A.C. , Morreau Hans , de Miranda Noel F.C.C.
Published: October 2021

Early detection and treatment are paramount to the clinical outcome of patients with colorectal cancer (CRC). Deciphering the dynamic interactions that occur between epithelial cells and stromal cells during tumorigenesis requires in-depth analyses of early-stage CRC lesions in spatial context. Here we employed spatially-resolved gene expression profiling to dissect molecular processes that associate with malignant transformation in CRC. We provide the transcriptional landscapes of colorectal cancer tumorigenesis from healthy mucosa, through different degrees of dysplasia, to cancer. The complementary examination of epithelial and stromal fractions allowed us to define whether specific oncogenic processes involved cancer cells, stromal cells, or the tumor microenvironment as a whole. We identified several genes that were consistently deregulated during CRC onset that could serve as clinical biomarkers for early-stage CRC. Furthermore, we uncovered an essential role for the innate immune system during CRC tumorigenesis.

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A nuclear function for an oncogenic microRNA as a modulator of snRNA and splicing
Authors: Fatimy Rachid EI , Zhang Yanhong , Deforzh Evgeny , Ramadas Mahalakshmi , Saravanan Harini , Wei Zhiyun , Rabinovsky Rosalia , Teplyuk Nadiya M. , Uhlmann Erik J. , Krichevsky Anna M.
Published: October 2021

miRNAs are regulatory transcripts established as repressors of mRNA stability and translation. Here we demonstrate that a key onco-miRNA, miR-10b, binds to U6 snRNA, a core component of the spliceosomal machinery. We provide evidence of direct binding between miR-10b and U6, in situ visualizations of miR-10b and U6 co-localization in glioma cells and patient-derived tumor tissues, and biochemical co-isolation of miR-10b with the components of the spliceosome. We further demonstrate that miR-10b modulates U6 N-6-adenosine methylation and pseudouridylation, U6 binding to splicing factors SART3 and PRPF8, and regulates U6 stability, conformation, and levels. These effects on U6 result in splicing alterations, illustrated by the altered ratio of the isoforms of a small GTPase CDC42, reduced overall CDC42 levels, and downstream CDC42 -mediated effects on cell viability. We, therefore, present an unexpected intersection of the miRNA and splicing machineries and a new nuclear function for a major cancer-associated miRNA.
arakno - An R Package for Effective Spider Nomenclature, Distribution and Trait Data Retrieval from Online Resources
Authors: Cardoso Pedro , Pekar Stano
Published: October 2021

Online open databases are increasing in number, usefulness, and ease of use. There are currently two main global databases exclusive for spiders, the World Spider Catalogue (WSC) and the World Spider Trait (WST) database. Both are regularly used by thousands of researchers. Computational tools that allow effective processing of large data are now part of the workflow of any researcher and R is becoming ade factostandard for data manipulation, analysis, and presentation. Here we present an R package,arakno, that allows interface with the two databases. Implemented tools include checking species names against nomenclature of the WSC, obtaining and mapping data on distribution of species from both WST and the Global Biodiversity Information Facility (GBIF), and downloading trait data from the WST. A set of tools are also provided to prepare data for further statistical analysis.
Identification of CD73 as the antigen of an antigen-unknown monoclonal antibody established by exosome immunization, and its antibody-drug conjugate exerts an antitumor effect on glioblastoma cell lines
Authors: anzai Takahiro , Saijou Shinji , Takashima Hiroki , Hara Misato , Hanaoka Shingo , Matsumura Yasuhiro , Yasunaga Masahiro
Published: October 2021

Development of antibodies against the native structure of membrane proteins with multiple transmembrane domains is challenging because it is difficult to prepare antigens with native structures. Previously, we successfully developed a monoclonal antibody against multi-pass membrane protein TMEM180 by exosome immunization in rats. This approach yielded antibod-ies that recognized cancer-specific antigens on the exosome. In this study, we performed im-munoprecipitation using magnetic beads to identify the antigen of one of the rat antibody clones, 0614, as CD73. We then converted antibody 0614 to human chimeric antibody 0614-5 and found that the humanized antibody did not inhibit CD73 enzymatic activity. Glioblastoma (GB) was the cancer type with the highest expression of CD73 in the tumor relative to healthy tissue. An antibody–drug conjugate (ADC) of 0614-5 exerted an antitumor effect on GB cell lines according to expression of CD73. The 0614-5-ADC could be used to treat cancers with high CD73 expression. In addition, our strategy could be used to determine the antigen of any antibody produced by exosome immunization.