bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of B cells in immune cell activation in polycystic ovary syndrome
Authors: Ascani Angelo , Torstensson Sara , Risal Sanjiv , Lu Haojiang , Eriksson Gustaw , Li Congru , Teshl Sabrina , Menezes Joana , Sandor Katalin , Ohlsson Claes , Svensson Camilla I , Karlsson Mikael C.I. , Stradner Martin Helmut , Obermayer-Pietsch Barbara , Stener-Victorin Elisabet
Published: January 2023

Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knock-out mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.

Androgen receptor activation alters B cell frequencies and functionality as the transfer of human PCOS IgG increase weight in female mice. Lack of B cells does not protect from the development of a PCOS phenotype, suggesting an unrecognized role for B cells in PCOS autoimmune comorbidities.

Graphical Abstract
Heterogeneous responsiveness to environmental stimuli*
Authors: Cavailles Jerome , Kuzmics Christoph , Grube Martin
Published: January 2023

Individuals of a species cope with environmental variability through behavioral adjustments driven by individuals’ responsiveness to environmental stimuli. Three key empirical observations have been made for many animal species: Thecoexistenceof different degrees of responsiveness within one species; theconsistencyof an individual’s degree of responsiveness across time; and thecorrelationof an individual’s degree of responsiveness across contexts. Taking up key elements of existing approaches, we provide one unifying explanation for all three observations, by identifying a unique evolutionarily stable strategy of an appropriately defined game within a stochastic environment that has all three features. Coexistence is explained by a form of negative frequency dependence. Consistency and correlation is explained through potentially small, individual, differences of states animals have and the resulting differential advantages they can get from it. Our results allow us to identify a variety of testable implications.
The Spread of Interferon-γ in Melanomas is Highly Spatially Confined, Driving Non-Genetic Variability in Tumor Cells
Authors: Centofanti Edoardo , Wang Chad , Iyer Sandhya , Krichevsky Oleg , Oyler-Yaniv Alon , Oyler-Yaniv Jennifer
Published: January 2023

Interferon-γ (IFNγ) is a critical anti-tumor cytokine that has varied effects on different cell types. The global effect of IFNγ in the tumor depends on which cells it acts upon and the spatial extent of its spread. Reported measurements of IFNγ spread vary dramatically in different contexts, ranging from nearest-neighbor signaling to perfusion throughout the entire tumor. Here, we apply theoretical considerations to experiments bothin vitroandin vivoto study the spread of IFNγ in melanomas. We observe spatially confined niches of IFNγ signaling in 3-D mouse melanoma cultures and human tumors that generate cellular heterogeneity in gene expression and alter the susceptibility of affected cells to T cell killing. Widespread IFNγ signaling only occurs when niches overlap due to high local densities of IFNγ-producing T cells. We measured length scales of ∼30-40μm for IFNγ spread in B16 mouse melanoma cultures and human primary cutaneous melanoma. Our results are consistent with IFNγ spread being governed by a simple diffusion-consumption model, and offer insight into how the spatial organization of T cells contributes to intra-tumor heterogeneity in inflammatory signaling, gene expression, and immune-mediated clearance. Solid tumors are often viewed as collections of diverse cellular “neighborhoods”: our work provides a general explanation for such non-genetic cellular variability due to confinement in the spread of immune mediators.
Addressing the Southeast Asian snaring crisis: impact of 11 years of snare removal in a biodiversity hotspot
Authors: Tilker Andrew , Niedballa Jürgen , Viet Hung Luong , Abrams Jesse F. , Marescot Lucile , Wilkinson Nicholas , Rawson Benjamin M. , Sollmann Rahel , Wilting Andreas
Published: January 2023

Unsustainable snaring is causing biodiversity declines across tropical protected areas, resulting in species extinctions and jeopardizing the health of forest ecosystems. Here, we used 11 years of ranger collected data to assess the impact of intensive snare removal on snaring levels in two protected areas in Viet Nam. Snare removal resulted in significant declines in snare occupancy (36.9, 95% BCI [4.6, 59.0] reduction in percent area occupied), but snaring levels nonetheless remained high (31.4, [23.6, 40.8] percent area occupied), and came with a substantial financial cost. Our results indicate that snare removal remains an important component of efforts to protect tropical protected areas, but by itself, is likely insufficient to address this threat. To stop snaring in protected areas, a multifaceted approach will be necessary that combines short-term reactive snare removal with long-term proactive programs that address the underlying drivers behind snaring.
Biventricular interaction during acute left ventricular ischemia in mice: a combined in-vivo and in-silico approach
Authors: Colebank M. J. , Taylor R. , Hacker T. A. , Chesler N.C.
Published: January 2023

Computational models provide an efficient paradigm for integrating and linking multiple spatial and temporal scales. However, these models are difficult to parameterize and match to experimental data. Recent advances in both data collection and model analyses have helped overcome this limitation. Here, we combine a multiscale, biventricular interaction model with mouse data before and after left ventricular (LV) ischemia. Sensitivity analyses are used to identify the most influential parameters on pressure and volume predictions. The subset of influential model parameters are calibrated to biventricular pressure-volume loop data (n=3) at baseline. Each mouse underwent left anterior descending coronary artery ligation, during which changes in fractional shortening and RV pressure-volume dynamics were recorded. Using the calibrated model, we simulate acute LV ischemia and contrast outputs at baseline and in simulated ischemia. Our baseline simulations align with the LV and RV data, and our predictions during ischemia complement recorded RV data and prior studies on LV function during myocardial infarction. We show that a model with both biventricular mechanical interaction and systems level cardiovascular dynamics can quantitatively reproducein-vivodata and qualitatively match prior findings from animal studies on LV ischemia.
A flexible loop in the paxillin LIM3 domain mediates direct binding to integrin β3
Authors: Baade Timo , Michaelis Marcus , Prestel Andreas , Paone Christoph , Klishin Nikolai , Scheinost Laura , Nedielkov Ruslan , Hauck Christof R. , Möller Heiko M.
Published: January 2023

Integrins are fundamental for cell adhesion and the formation of focal adhesions (FA). Accordingly, these receptors guide embryonic development, tissue maintenance and haemostasis, but are also involved in cancer invasion and metastasis. A detailed understanding of the molecular interactions that drive integrin activation, focal adhesion assembly, and downstream signalling cascades is critical. Here, we reveal a direct association of paxillin, a marker protein of focal adhesion sites, with the cytoplasmic tails of the integrin β1 and β3 subunits. The binding interface resides in paxillin’s LIM3 domain, where based on the NMR structure and functional analyses a flexible, seven amino acid loop engages the unstructured part of the integrin cytoplasmic tail. Genetic manipulation of the involved residues in either paxillin or integrin β3 compromises cell adhesion and motility. This direct interaction between paxillin and the integrin cytoplasmic domain identifies an alternative, kindlin-independent mode of integrin outside-in signalling particularly important for integrin β3 function.
Scientific civility and academic performance
Authors: Camacho Emma , Dragotakes Quigly , Hartshorn Isabella , Casadevall Arturo , Buccino Daniel L
Published: January 2023

In modern science, interdisciplinary and collaborative research is encouraged among scientists to solve complex problems. However, when the time comes to measure an individual’s academic productivity, collaborative efforts are hard to conceptualize and quantify. In this study, we hypothesized that a social behavior coined “scientific civility”, which encompasses civility, collaboration, cooperation, or a combination of these, enhances an individual’s productivity influencing their academic performance. To facilitate recognition of this unique attribute within the scientific environment, we developed a new indicator: theCscore. We examined publicly available data from 1000 academic scientists at the individual-level, focusing on their scholarly output and collaborative networks as a function of geographic distribution and time. Our findings strongly suggest that theCscore gauges academic performance from an integral perspective based on a synergistic interaction between productivity and collaborative networks, prevailing over institutionally limited economic resources and minimizing inequalities related to the length of individual’s academic career, field of investigation, and gender.

Author Summary

The increased connectivity between fields and specialties of science is undeniable. We propose a new indicator, theCscore, to assess the value of collaborative efforts and research output to a scientist’s academic performance. This indicator reflects collaborative and interdisciplinary efforts and provides a measure of “scientific civility” and teamwork. TheCscore may be used as a decision-making tool to track career advancement within the academic environment. Along with other indicators such as thehindex, theCscore supports a more integrative and holistic assessment of an individual’s academic performance.
The mineralocorticoid receptor forms higher order oligomers upon DNA binding
Authors: Fettweis Gregory , Johnson Thomas A. , Almeida-Prieto Brian , Presman Diego M. , Hager Gordon L. , de la Rosa Diego Alvarez
Published: January 2023

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.
Multivariate models of animal sex: breaking binaries leads to a better understanding of ecology and evolution
Authors: McLaughlin J. F. , Brock Kinsey M. , Gates Isabella , Pethkar Anisha , Piattoni Marcus , Rossi Alexis , Lipshutz Sara E.
Published: January 2023

‘Sex’ is often used to describe a suite of phenotypic and genotypic traits of an organism related to reproduction. However, these traits – gamete type, chromosomal inheritance, physiology, morphology, behavior, etc. – are not necessarily coupled, and the rhetorical collapse of variation into a single term elides much of the complexity inherent in sexual phenotypes. We argue that consideration of ‘sex’ as a constructed category operating at multiple biological levels opens up new avenues for inquiry in our study of biological variation. We apply this framework to three case studies that illustrate the diversity of sex variation, from decoupling sexual phenotypes to the evolutionary and ecological consequences of intrasexual polymorphisms. We argue that instead of assuming binary sex in these systems, some may be better categorized as multivariate and nonbinary. Finally, we conduct a meta-analysis of terms used to describe diversity in sexual phenotypes in the scientific literature to highlight how a multivariate model of sex can clarify, rather than cloud, studies of sexual diversity within and across species. We argue that such an expanded framework of ‘sex’ better equips us to understand evolutionary processes, and that as biologists it is incumbent upon us to push back against misunderstandings of the biology of sexual phenotypes that enact harm on marginalized communities.
Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/-mouse model of inflammatory bowel disease
Authors: Armstrong Heather , Rahbari Mandana , Park Heekuk , Sharon David , Thiesen Aducio , Hotte Naomi , Sun Ning , Syed Hussain , Abofayed Hiatem , Wang Weiwei , Madsen Karen , Wine Eytan , Mason Andrew
Published: January 2023

Background

Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-I0-/-) model derived from the SvEv mouse, had evidence of increased mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wildtype. MMTV is endemic in several mouse strains as an endogenously encoded betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/-model.

Results

Viral preparations extracted from IL-10-/-weanling stomachs revealed augmented MMTV load compared to the SvEv wildtype. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4% - 97.3% identity with themtv-1endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTVsaggene cloned from IL-10-/-spleen encoded the MTV-9 superantigen that preferentially activates T cell receptor Vβ-12 subsets, which were expanded in the IL-10-/-versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/-splenocytes with amplified interferon-γ production versus the SvEv wildtype. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12 weeks treatment versus placebo. The combination anti-retroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL10-/-mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis.

Conclusions

This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.
Pooled CRISPR screening of high-content cellular phenotypes by ghost cytometry
Authors: Tsubouchi Asako , An Yuri , Kawamura Yoko , Yanagihashi Yuichi , Murata Yuri , Teranishi Kazuki , Ishiguro Soh , Aburatani Hiroyuki , Yachie Nozomu , Ota Sadao
Published: January 2023

Fast enrichment of cells based on morphological information remains a challenge, limiting genome-wide perturbation screening for diverse high-content phenotypes of cells. Here we show that multi-modal ghost cytometry-based cell sorting is applicable to fast pooled CRISPR screening for both fluorescence and label-free high-content phenotypes of millions of cells. By employing the high-content cell sorter in the fluorescence mode, we enabled the genome-wide CRISPR screening of genes that affect NF-κB nuclear translocation. Furthermore, by employing the multi-parametric, label-free mode, we performed the large-scale screening to identify a gene involved in macrophage polarization. Especially the label-free platform can enrich target phenotypes without invasive staining, preserving untouched cells for downstream assays and unlocking the potential to screen for the cellular phenotypes even when suitable markers are lacking.

One-Sentence Summary

Machine vision-based cell sorter enabled genome-wide perturbation screens for high-content cell phenotypes even without labeling
Neural tuning instantiates prior expectations in the human visual system
Authors: Harrison William J , Bays Paul M , Rideaux Reuben
Published: January 2023

Perception is often modelled as a process of active inference, whereby prior expectations are combined with noisy sensory measurements to estimate the structure of the world. This mathematical framework has proven critical to understanding perception, cognition, motor control, and social interaction. While theoretical work has shown how priors can be computed from environmental statistics, their neural instantiation could be realised through multiple competing encoding schemes. Using a data-driven approach, here we extract the brain’s representation of visual orientation and compare this with simulations from different sensory coding schemes. We found that the tuning of the human visual system is highly conditional on stimulus-specific variations in a way that is not predicted by previous proposals. We further show that the adopted encoding scheme effectively embeds an environmental prior for natural image statistics within the sensory measurement, providing the functional architecture necessary for optimal inference in the earliest stages of cortical processing.
COVID-19-related burnout reduces COVID-19 vaccination intention in cardiac patients: a cross-sectional study in Greece
Authors: Galanis Petros , Katsiroumpa Aglaia , Vraka Irene , Siskou Olga , Konstantakopoulou Olympia , Kaitelidou Daphne
Published: January 2023

Background

New SARS-CoV-2 variants have emerged and COVID-19 is still a public health issue, especially for vulnerable groups such as people with chronic medical conditions.

Objective

To investigate the impact of COVID-19-related burnout on COVID-19 vaccination intention in cardiac patients. Moreover, we investigated other possible demographic and psychological predictors of vaccination intention in cardiac patients.

Methods

We conducted a cross-sectional study in Greece using a convenience sample. Data collection was performed from 20 November 2022 to 10 January 2023. We measured demographic data, COVID-19-related burnout, anxiety, depression, social support, and resilience. We used the following valid tools: COVID-19 burnout scale, Patient Health Questionnaire-4, Multidimensional Scale of Perceived Social Support, and Brief Resilience Scale.

Results

Among patients, 45.8% were willing to accept a COVID-19 booster dose, 25.3% were hesitant, and 28.9% were unwilling. Patients experienced moderate levels of COVID-19-related burnout. After multivariable linear regression analysis, we found that increased age and decreased emotional exhaustion due to COVID-19 were associated with increased vaccination intention. Moreover, patients who have already received a booster dose had also a greater willingness to accept a new booster dose.

Conclusions

Identification of factors that influence patients’ decision to accept a COVID-19 booster dose is crucial to maintain a high vaccination coverage rate among them in order to avoid COVID-19-related outcomes. Since a COVID-19 booster dose on an annual basis seems to be necessary policy makers should develop and implement vaccination programmes tailored for patients.
Waves in time, but not in space – An analysis of pandemic severity of COVID-19 in Germany based on spatio-temporal clustering
Authors: Kuebart Andreas , Stabler Martin
Published: January 2023

While pandemic waves are often studied on the national scale, they typically are not distributed evenly within countries. This paper employs a novel approach to analyze the tempo-spatial dynamics of the COVID-19 pandemic in Germany. First, we base the analysis on a composite indicator of pandemic severity to gain a more robust understanding of the temporal dynamics of the pandemic. Second, we subdivide the pandemic during the years 2020 and 2021 into fifteen phases, each with a coherent trend of pandemic severity. Third, we analyze the patterns of spatial association during each phase. Fourth, similar types of trajectories of pandemic severity among all German counties were identified through hierarchical clustering. The results imply that the hotspots and cold spots of the first four waves of the pandemic were relatively stationary in space so that the pandemic moved in time but less in space.
Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD
Authors: Park Se-Hyung , Helsley Robert N. , Fadhul Taghreed , Willoughby Jennifer L.S. , Noetzli Leila , Tu Ho-Chou , Solheim Marie H. , Fujisaka Shiho , Pan Hui , Dreyfuss Jonathan M. , Bons Joanna , Rose Jacob , King Christina D. , Schilling Birgit , Lusis Aldons J. , Pan Calvin , Gupta Manoj , Kulkarni Rohit N. , Fitzgerald Kevin , Kern Philip A. , Divanovic Senad , Kahn C. Ronald , Softic Samir
Published: January 2023

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform increases endoplasmic reticulum (ER) stress in a dose dependent fashion, so when fructose is coupled with a HFD intake it leads to unresolved ER stress. Conversely, a liver-specific knockdown of KHK in C57BL/6J male mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and exert a profound effect on the hepatic transcriptome. Overexpression of KHK-C in cultured hepatocytes is sufficient to induce ER stress in fructose free media. Upregulation of KHK-C is also observed in genetically obesity ob/ob, db/db and lipodystrophic FIRKO male mice, whereas KHK knockdown in these mice improves metabolic function. Additionally, in over 100 inbred strains of male or female mice hepatic KHK expression correlates positively with adiposity, insulin resistance, and liver triglycerides. Similarly, in 241 human subjects and their controls, hepaticKhkexpression is upregulated in early, but not late stages of NAFLD. In summary, we describe a novel role of KHK-C in triggering ER stress, which offers a mechanistic understanding of how the combined intake of fructose and a HFD propagates the development of metabolic complications.
Efficient image analysis for large-scale next generation histopathology using pAPRica
Authors: Scholler Jules , Jonsson Joel , Jordá-Siquier Tomás , Gantar Ivana , Batti Laura , Cheeseman Bevan L. , Pagès Stéphane , Sbalzarini Ivo F. , Lamy Christophe M.
Published: January 2023

The large size of imaging datasets generated by next-generation histology methods limits the adoption of those approaches in research and the clinic. We propose pAPRica (pipelines for Adaptive Particle Representation image compositing and analysis), a framework based on the Adaptive Particle Representation (APR) to enable efficient analysis of large microscopy datasets, scalable up to petascale on a regular workstation. pAPRica includes stitching, merging, segmentation, registration, and mapping to an atlas as well as visualization of the large 3D image data, achieving 100+ fold speedup in computation and commensurate data-size reduction.
Iron Regulatory Protein 1 is Required for the Propagation of Inflammation in Inflammatory Bowel Disease
Authors: Fahoum L. , Belisowski S. , Ghatpande N. , Guttmann-Raviv N. , Zhang W. , Li K. , Tong W-H. , Nyska A. , Waterman M. , Weisshof R. , Zuckerman A. , Meyron-Holtz E.G.
Published: January 2023

Objective

Inflammatory bowel diseases (IBD) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation are known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution and that this in turn perpetuates the inflammation.

Design

This study analyzed human biopsies, animal models and cellular systems to decipher the role of iron homeostasis in IBD.

Results

We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP)1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular co-culture model was established, that replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation.

Conclusion

These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

What is already known on this topic

Inflammatory bowel diseases (IBD) are chronic conditions that cause inflammation in the digestive tract. Iron accumulation is a common feature of IBD, but the mechanism of accumulation and its implications for the course of inflammation are not fully understood.

What this study adds

This study reveals an inflammatory intestinal iron distribution-pattern, that has not been described previously involving iron accumulation in immune cells and iron deficiency in epithelial cells. We show that an inflammation mediated activation of the Iron Regulatory Protein (IRP)1 is responsible for this inflammatory iron pattern and that this drives the propagation of the inflammation in IBD. Moreover, targeted deletion of IRP1 completely abolished the intestinal inflammation.

How this study might affect research, practice or policy

These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa in IBD. This might lead to the development of novel treatment approaches for IBD focused on modulating IRP1 activity.
Mitotic heritability of DNA methylation at intermediately methylated sites is imprecise
Authors: Hay Amir D. , Kessler Noah J. , Gebert Daniel , Takahashi Nozomi , Tavares Hugo , Teixeira Felipe K. , Ferguson-Smith Anne C.
Published: January 2023

DNA methylation is considered a stable epigenetic mark due to its presumed long-term inheritance through cell divisions. Here, we perform high-throughput bisulfite sequencing on clonally derived cell lines to quantitatively measure mitotic methylation inheritance at the nucleotide level. We find that although DNA methylation is generally faithfully maintained at hypo- and hypermethylated sites, this is not the case at intermediately methylated CpGs. Low fidelity intermediate methylation is interspersed throughout the genome and within genes with no or low transcriptional activity. Moreover, we determine that the probabilistic changes that occur at intermediately methylated sites are due to DNMT1 rather than DNMT3A/3B activity. The observed lack of clonal inheritance at intermediately methylated sites challenges the concept of DNA methylation as a consistently stable epigenetic mark.
The fission yeast methyl phosphate capping enzyme Bmc1 guides 2’-O-methylation of the U6 snRNA
Authors: Porat Jennifer , Slat Viktor A. , Rader Stephen D. , Bayfield Mark A.
Published: January 2023

Splicing requires the tight coordination of dynamic spliceosomal RNAs and proteins. U6 is the only spliceosomal RNA transcribed by RNA Polymerase III and undergoes an extensive maturation process. In humans and fission yeast, this includes addition of a 5’ γ-monomethyl phosphate cap by members of the Bin3/MePCE family. Previously, we have shown that the Bin3/MePCE homolog Bmc1 is recruited to theS. pombetelomerase holoenzyme by the LARP7 family protein Pof8, where it acts in a catalytic-independent manner to protect the telomerase RNA and facilitate holoenzyme assembly. Here, we show that Bmc1 and Pof8 also interact in a U6-containing snRNP. We demonstrate that Bmc1 and Pof8 promote 2’-O-methylation of U6 and identify and characterize a non-canonical snoRNA that guides this methylation. Further, we show that fission yeast strains deleted of Bmc1 or Pof8 show altered U6 snRNP assembly patterns, supporting a more general role for these factors in guiding noncoding RNP assembly beyond the telomerase RNP. These results are thus consistent with a novel role for Bmc1/MePCE family members in stimulating U6 post-transcriptional modifications.
Power Series Template Matching Model for Pitch Perception
Authors: Takahashi Jun-ichi
Published: January 2023

The problem of pitch perception has been the subject of a long debate between place theory and time theory. Here, we propose a Power Series Template (PoST) model to answer the problem of how and why pitch perception comes about. The sensitive measurement of acoustic signals requires efficient Sound Amplification, which inevitably accompanies mode coupling due to the perturbative non-linearities. Under reinforcement learning for Sound Localization with the second- and third-order modes as default teacher signals, a chain of coincidence is generated. After learning in Sound Localization is completed, two power series templates of 2nand 3mare generated, and the 2f1−f2coupling of the elements contained therein fills the blanks of matchable harmonics up to N=10 in the template, providing the well-known harmonic template. When complex tones containing multiple harmonics are input into the trained network, two power series are evoked from each harmonic, and from their intersection, the brain acquires the fundamental of the complex tone as the pitch. Based on this template model, consistent explanations are given for the problems of missing fundamental, pitch shift, pitch and chroma, and resolvability jump without the help of time theory.
Exploring Replay
Authors: Antonov Georgy , Dayan Peter
Published: January 2023

Exploration is vital for animals and artificial agents who face uncertainty about their environments due to initial ignorance or subsequent changes. Their choices need to balance exploitation of the knowledge already acquired, with exploration to resolve uncertainty [1, 2]. However, the exact algorithmic structure of exploratory choices in the brain still remains largely elusive. A venerable idea in reinforcement learning is that agents can plan appropriate exploratory choices offline, during the equivalent of quiet wakefulness or sleep. Although offline processing in humans and other animals, in the form of hippocampal replay and preplay, has recently been the subject of highly successful modelling [3–5], existing methods only apply to known environments. Thus, they cannot predict exploratory replay choices during learning and/or behaviour in dynamic environments. Here, we extend the theory of Mattar & Daw [3] to examine the potential role of replay in approximately optimal exploration, deriving testable predictions for the patterns of exploratory replay choices in a paradigmatic spatial navigation task. Our modelling provides a normative interpretation of the available experimental data suggestive of exploratory replay. Furthermore, we highlight the importance of sequence replay, and license a range of new experimental paradigms that should further our understanding of offline processing.
Phylogenetics and phylogeography ofEuphorbia canariensisreveal an extreme Canarian-Asian disjunction and limited inter-island colonization
Authors: Coello Alberto J. , Vargas Pablo , Cano Emilio , Riina Ricarda , Fernández-Mazuecos Mario
Published: January 2023

Euphorbia canariensisis an iconic endemic species of the Canary Islands and one of the most characteristic species of lowland xerophytic communities known, in Spanish, as ‘cardonal-tabaibal’. This species is widely distributed in the archipelago, which contrasts with the theoretically low dispersal abilities suggested by its unspecialized diasporas. Furthermore, the phylogenetic relationships of this species are unclear, although it is thought to be related to the IndianE. epiphylloidesand not to other cactus-likeEuphorbiaof the Canary Islands (E. handiensis) and Africa. Here we aimed to reconstruct the evolutionary history ofE. canariensisat two levels: (i) a phylogenetic approach aimed at unravelling relationships of this species and large-scale biogeographic patterns, and (ii) a phylogeographic approach focused on the history of colonization between islands of the Canarian archipelago in relation to habitat availability for this species through time. Based on previous phylogenetic studies ofEuphorbia, we sequenced the ITS region forE. canariensisand several potentially related species to build a phylogenetic framework. We also sequenced two cpDNA regions for 92 individuals from 29 populations ofE. canariensisrepresenting its distribution range. We estimated the number of inter-island colonization events using PAICE, a recently developed method that includes a sampling effort correction. Additionally, we used species distribution modelling (SDM) to project current habitat availability forE. canariensisto past periods. Phylogenetic results supported the CanarianE. canariensisas closely related to the Southeast AsianE. epiphylloidesandE. sessiliflora. In the Canarian archipelago,E. canariensisdisplayed a surprising west-to-east colonization pattern. The estimated number of inter-island colonization events was c. 20 – 50, and SDM suggested an increase in habitat availability in recent times. In summary, in this study we confirmed an extreme biogeographic disjunction between Macaronesia and Southeast Asia, described only for a small number of plant species, and estimated relatively low dispersal capabilities forE. canariensis, with a west-to-east colonization pattern in the Canary Islands.

Highlights

The CanarianEuphorbia canariensisis sister to Southeast Asian species.

This lineage shows one of the widest disjunctions affecting Macaronesian plants.

The lack of intermediate relatives could be the result of extinction events.

E. canariensisdisplays low colonization ability in the Canarian archipelago.
Characterization of the zebrafishgabra1sa43718/sa43718germline loss of function allele confirms a function for Gabra1 in motility and nervous system development
Authors: Paz David , Reyes-Nava Nayeli G. , Pinales Briana E. , Perez Isaiah , Gil Claudia B. , Gonzales Annalise V. , Grajeda Brian , Estevao Igor L. , Ellis Cameron C. , Castro Victoria L. , Quintana Anita M.
Published: January 2023

Mutation of theGABRA1gene is associated with neurodevelopmental defects and epilepsy.GABRA1encodes for the α1 subunit of the gamma-aminobutyric acid type A receptor (GABAAR), which regulates the fast inhibitory impulses of the nervous system. Multiple model systems have previously been developed to understand the function ofGABRA1during development, but these models have produced complex and at times incongruent data. Thus, additional model systems are required to validate and substantiate previously published results. We investigated the behavioral swim patterns associated with a nonsense mutation of the zebrafishgabra1(sa43718allele) gene. Thesa43718allele causes a decrease ingabra1mRNA expression, which is associated with light induced hypermotility, one phenotype associated with seizure like behavior in zebrafish. Mutation ofgabra1was accompanied by decreased mRNA expression ofgabra2, gabra3, and gabra5,indicating a reduction in the expression of additional alpha sub-units of the GABAAR. Although multiple sub-units were decreased in total expression, larvae continued to respond to pentylenetetrazole (PTZ) indicating that a residual GABAAR exists in thesa43718allele. Proteomics analysis demonstrated that nonsense mutation ofgabra1is associated with abnormal expression of proteins that regulate proton transport, ion homeostasis, vesicle transport, and mitochondrial protein complexes. These data support previous studies performed in a zebrafish nonsense allele created by CRISPR/Cas9 and validate that loss of function mutations in thegabra1gene result in seizure like phenotypes with abnormal function of inhibitory synapses.
Anillin Related Mid1 as an Adaptive and Multimodal Contractile Ring Anchoring Protein: A Simulation Study
Authors: Hall Aaron R. , Choi Yeol Kyo , Im Wonpil , Vavylonis Dimitrios
Published: January 2023

The organization of the cytokinetic ring at the cell equator of dividing animal and fungi cells depends crucially on the anillin scaffold proteins. In fission yeast, anillin related Mid1 binds to the plasma membrane and helps anchor and organize a medial broad band of cytokinetic nodes, which are the precursors of the contractile ring. Similar to other anillins, Mid1 contains a C terminal globular domain with two potential regions for membrane binding, the Pleckstrin Homology (PH) and C2 domains, and an N terminal intrinsically disordered region that is strongly regulated by phosphorylation. Previous studies have shown that both PH and C2 domains can associate with the membrane, preferring phosphatidylinositol-(4,5)-bisphosphate (PIP2) lipids. However, it is unclear if they can simultaneously bind to the membrane in a way that allows dimerization or oligomerization of Mid1, and if one domain plays a dominant role. To elucidate Mid1’s membrane binding mechanism, we used the available structural information of the C terminal region of Mid1 in all-atom molecular dynamics (MD) near a membrane with a lipid composition based on experimental measurements (including PIP2lipids). The disordered L3 loop of C2, as well as the PH domain, separately bind the membrane through charged lipid contacts. In simulations with the full C terminal region started away from the membrane, Mid1 binds through the L3 loop and is stabilized in a vertical orientation with the PH domain away from the membrane. However, a configuration with both C2 and PH initially bound to the membrane remains associated with the membrane. These multiple modes of binding may reflect Mid1’s multiple interactions with membranes and other node proteins, and ability to sustain mechanical forces.
Dysregulated CD38 expression in blood and skin immune cells of patients with hidradenitis suppurativa
Authors: Dimitrion Peter , Hamzavi Iltefat , Yin Congcong , Loveless Ian , Toor Jugmohit , Subedi Kalpana , Khalasawi Namir , Miller Angela , Huggins Richard , Adrianto Indra , Veenstra Jesse , Vellaichamy Gautham , Hans Aakash , Daveluy Steven , Athar Mohammad , Liao Wilson , Lim Henry , Ozog David , Zhou Li , Mi Qing-Sheng
Published: January 2023

2.

Background

Hidradenitis suppurativa (HS) is a multifactorial, inflammatory skin disease. Increased systemic inflammatory comorbidities and serum cytokines highlight systemic inflammation as a feature of HS. However, the specific immune cell subsets contributing to systemic and cutaneous inflammation have not been resolved.

Objective

Identify features of peripheral and cutaneous immune dysregulation.

Methods

Here, we generated whole-blood immunomes by mass cytometry. We performed a meta-analysis of RNA-seq data, immunohistochemistry, and imaging mass cytometry to characterize the immunological landscape of skin lesions and perilesions from patients with HS.

Results

Blood from patients with HS exhibited lower frequencies of natural killer cells, dendritic cells, and classical (CD14+CD16-) and nonclassical (CD14-CD16+) monocytes, as well as higher frequencies of Th17 cells and intermediate (CD14+CD16+) monocytes than blood from healthy controls. Classical and intermediate monocytes from patients with HS had increased expression of skin-homing chemokine receptors. Furthermore, we identified a CD38+ intermediate monocyte subpopulation that was more abundant in the immunome of blood from patients with HS. Meta-analysis of RNA-seq data found higher CD38 expression in lesional HS skin than in perilesional skin, and markers of classical monocyte infiltration. Imaging mass cytometry showed that CD38+ classical monocytes and CD38+ monocyte-derived macrophages were more abundant in lesional HS skin.

Conclusion

Overall, we report targeting CD38 may be worth pursuing in clinical trials.

3.

Key Messages

Monocyte subsets express markers of activation in circulation and HS lesions

Targeting CD38 may be a viable strategy for treating systemic and cutaneous inflammation in patients with HS

4.

Capsule Summary

Dysregulated immune cells in patients with HS express CD38 and may be targeting by anti-CD38 immunotherapy.
Joint tensor modeling of single cell 3D genome and epigenetic data with Muscle
Authors: Park Kwangmoon , Keleş Sündüz
Published: January 2023

Emerging single cell technologies that simultaneously capture long-range interactions of genomic loci together with their DNA methylation levels are advancing our understanding of three-dimensional genome structure and its interplay with the epigenome at the single cell level. While methods to analyze data from single cell high throughput chromatin conformation capture (scHi-C) experiments are maturing, methods that can jointly analyze multiple single cell modalities with scHi-C data are lacking. Here, we introduce Muscle, a semi-nonnegative joint decomposition ofMultiplesinglecelltensors, to jointly analyze 3D conformation and DNA methylation data at the single cell level. Muscle takes advantage of the inherent tensor structure of the scHi-C data, and integrates this modality with DNA methylation. We developed an alternating least squares algorithm for estimating Muscle parameters and established its optimality properties. Parameters estimated by Muscle directly align with the key components of the downstream analysis of scHi-C data in a cell type specific manner. Evaluations with data-driven experiments and simulations demonstrate the advantages of the joint modeling framework of Muscle over single modality modeling or a baseline multi modality modeling for cell type delineation and elucidating associations between modalities. Muscle is publicly available athttps://github.com/keleslab/muscle.
Pleistocene dispersion supports a unique native diversity in the Colombian avocado germplasm
Authors: Berdugo-Cely J.A. , Cortés A.J. , López-Hernández F. , Delgadillo P. , Cerón-Souza I. , Reyes-Herrera P. , Navas A. , Yockteng R
Published: January 2023

Genomic characterization of ex-situ collections optimizes the utilization of genetic resources, identifies redundancies among accessions, captures cryptic variation, establishes reference collections, and ultimately assists pre-breeding and breeding efforts. However, the integration of population genomic analyses is often lacking when studying the biodiversity of crop gene pools. Here, we present modern classification and machine learning approaches to characterize and harness the genebank of an agrobiodiversity hotspot onPersea americanaMill., an iconic American fruit tree crop that has seen an unprecedented expansion worldwide. We selected 144 accessions from the Colombian National genebank and 240 materials from local plantations in the Colombian Northwest Andes. We genotyped them using a strategy based on reduced representation sequencing. We included available sequences of genotypes from known avocado races, Mexican, Guatemalan, and West Indian, to discover SNPs, analyze the population structure and identify possible new genetic groups in Colombian germplasm. We detected a population structure suggestive of a new fourth race in Colombia, with a possible genetic substructure related to geographical origin (Andean and Caribbean). Hybrid determination and ABC modeling suggested rampant inter-race geneflow. They supported the hypothesis of the high mobility of native avocado trees from Central America to Northern South America starting in the Pleistocene. Our study supports that Colombia might be a new diversity center forP. americana.Genotypes of the two newly identified Colombian groups can be used as parents in plant breeding strategies to generate cultivars adapted to specific ecogeographical regions of Colombia.