bluuebunny/crossref_metadata_2025 huggingface dataset:
A set of codes for numerical convection and geodynamo calculations
Authors: Gibbons Steven J , Willis Ashley P , Davies Chris , Gubbins David
Published: September 2023

We present a set of codes for calculating and displaying solutions to diverse problems within thermal convection and magnetic field generation in rotating fluid-filled spheres and spherical shells. There are diverse programs for the kinematic dynamo problem, the onset of thermal convection, and boundary-locked thermal convection, and time-stepping codes for non-magnetic convection and the dynamo with either homogeneous or spatially varying thermal boundary conditions. Where possible, all programs have been benchmarked against other codes and tested by reproducing previously published results. Each program comes with the complete source code, a pdf instruction manual, and at least one example run with a sample input file and all necessary files for describing an initial condition. The only prerequisite for running most of the codes is a FORTRAN compiler. The plotting programs require in addition the PGPLOT graphics library. All source code, examples, input files, solutions, and instructions are available for download from github and Zenodo.
Scalp and hippocampal sleep correlates of memory function in drug-resistant temporal lobe epilepsy
Authors: Latreille Véronique , Avigdor Tamir , Thomas John , Crane Joelle , Sziklas Viviane , Jones-Gotman Marilyn , Frauscher Birgit
Published: September 2023

Seminal animal studies demonstrated the role of sleep oscillations such as cortical slow waves, thalamocortical spindles, and hippocampal ripples in memory consolidation. In humans, whether ripples are involved in sleep-related memory processes is less clear. Here, we explored the interactions between sleep oscillations (measured as traits) and general episodic memory abilities in 26 adults with drug-resistant temporal lobe epilepsy who performed scalp-intracranial electroencephalographic recordings and neuropsychological testing, including two analogous hippocampal-dependent verbal and nonverbal memory tasks. We explored the relationships between hemispheric scalp (spindles, slow waves) and hippocampal physiological and pathological oscillations (spindles, slow waves, ripples, and epileptic spikes) and material-specific memory function. To differentiate physiological from pathological ripples, we used multiple unbiased data-driven clustering approaches. At the individual level, we found material-specific cerebral lateralization effects (left-verbal memory, right-nonverbal memory) for all scalp spindles (rs > 0.51, ps < 0.01) and fast spindles (rs > 0.61, ps < 0.002). Hippocampal epileptic spikes and short pathological ripples, but not physiological oscillations, were negatively (rs > −0.59, ps < 0.01) associated with verbal learning and retention scores, with left lateralizing and antero-posterior effects. However, data-driven clustering failed to separate the ripple events into defined clusters. Correlation analyses with the resulting clusters revealed no meaningful or significant associations with the memory scores. Our results corroborate the role of scalp spindles in memory processes in patients with drug-resistant temporal lobe epilepsy. Yet, physiological and pathological ripples were not separable when using data-driven clustering, and thus our findings do not provide support for a role of sleep ripples as trait-like characteristics of general memory abilities in epilepsy.
Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study
Authors: Chen Daniel M , Taporoski Tâmara P , Alexandria Shaina J , Aaby David A , Beijamini Felipe , Krieger José E , von Schantz Malcolm , Pereira Alexandre C , Knutson Kristen L
Published: September 2023

Study Objectives

People with diabetes and prediabetes are more likely to have sleep-disordered breathing (SDB), but few studies examined sleep architecture in people with diabetes or prediabetes in the absence of moderate-severe SDB, which was the aim of our cross-sectional study.

Methods

This cross-sectional sample is from the Baependi Heart Study, a family-based cohort of adults in Brazil. About 1074 participants underwent at-home polysomnography (PSG). Diabetes was defined as fasting glucose >125 mg/dL or HbA1c > 6.4 mmol/mol or taking diabetic medication, and prediabetes was defined as HbA1c ≥ 5.7 & <6.5 mmol/mol or fasting glucose ≥ 100 & ≤125 mg/dl. We excluded participants with an apnea-hypopnea index (AHI) ≥ 30 in primary analyses and ≥ 15 in secondary analysis. We compared sleep stages among the 3 diabetes groups (prediabetes, diabetes, neither).

Results

Compared to those without diabetes, we found shorter REM duration for participants with diabetes (−6.7 min, 95%CI −13.2, −0.1) and prediabetes (−5.9 min, 95%CI −10.5, −1.3), even after adjusting for age, gender, BMI, and AHI. Diabetes was also associated with lower total sleep time (−13.7 min, 95%CI −26.8, −0.6), longer slow-wave sleep (N3) duration (+7.6 min, 95%CI 0.6, 14.6) and higher N3 percentage (+2.4%, 95%CI 0.6, 4.2), compared to those without diabetes. Results were similar when restricting to AHI < 15.

Conclusions

People with diabetes and prediabetes had less REM sleep than people without either condition. People with diabetes also had more N3 sleep. These results suggest that diabetes and prediabetes are associated with differences in sleep architecture, even in the absence of moderate-severe sleep apnea.
Mesenchymal Stem Cells Promote Polarization of M2 Macrophages in Mice with Acute-On-Chronic Liver Failure via Mertk/JAK1/STAT6 Signaling
Authors: Li Zhi-Hui , Chen Jun-Feng , Zhang Jing , Lei Zi-Ying , Wu Li-Li , Meng Shi-Bo , Wang Jia-Lei , Xiong Jing , Lin Deng-Na , Wang Jun-Yi , Gao Zhi-Liang , Lin Bing-Liang
Published: September 2023

Acute-on-chronic liver failure (ACLF) is a severe disease with a high mortality. Macrophage-related inflammation plays a crucial role in ACLF development. Mesenchymal stem cells (MSCs) treatment was demonstrated to be beneficial in ACLF in our previous study; however, the underlying mechanisms remain unknown. Therefore, mouse bone marrow-derived MSCs were used to treat an ACLF mouse model or cocultured with RAW264.7/J774A.1 macrophages that were stimulated with LPS. Histological and serological parameters and survival were analyzed to evaluate efficacy. We detected changes of Mer tyrosine kinase (Mertk), JAK1/STAT6, inflammatory cytokines, and markers of macrophage polarization in vitro and in vivo. In ACLF mice, MSCs improved liver function and 48-h survival of ACLF mice and alleviated inflammatory injury by promoting M2 macrophage polarization and elevated Mertk expression levels in macrophages. This is significant, as Mertk regulates M2 macrophage polarization via the JAK1/STAT6 signaling pathway.
Detection and characterization of resting state functional networks in squirrel monkey brain
Authors: Sengupta Anirban , Wang Feng , Mishra Arabinda , Reed Jamie L , Chen Li Min , Gore John C
Published: September 2023

Resting-state fMRI based on analyzing BOLD signals is widely used to derive functional networks in the brain and how they alter during disease or injury conditions. Resting-state networks can also be used to study brain functional connectomes across species, which provides insights into brain evolution. The squirrel monkey (SM) is a non-human primate (NHP) that is widely used as a preclinical model for experimental manipulations to understand the organization and functioning of the brain. We derived resting-state networks from the whole brain of anesthetized SMs using Independent Component Analysis of BOLD acquisitions. We detected 15 anatomically constrained resting-state networks localized in the cortical and subcortical regions as well as in the white-matter. Networks encompassing visual, somatosensory, executive control, sensorimotor, salience and default mode regions, and subcortical networks including the Hippocampus-Amygdala, thalamus, basal-ganglia and brainstem region correspond well with previously detected networks in humans and NHPs. The connectivity pattern between the networks also agrees well with previously reported seed-based resting-state connectivity of SM brain. This study demonstrates that SMs share remarkable homologous network organization with humans and other NHPs, thereby providing strong support for their suitability as a translational animal model for research and additional insight into brain evolution across species.
VData: Temporally annotated data manipulation and storage
Authors: Bouvier Matteo , Bonnaffoux Arnaud
Published: September 2023

Background

Recent advances in both single-cell sequencing technologies and gene expression simulation algorithms have led to the production of increasingly large datasets. Larger datasets (tens or hundreds of Gigabytes) can no longer fit on regular computers’ RAM and thus pose important challenges for storage and manipulation. Existing solutions offer partial solutions but do not explicitly handle the temporal dimension of simulated data and still require large amounts of RAM to run.

Results

VData is a Python extension to the widely used AnnData format that solves these issues by extending 2D dataframes to 3 dimensions (cells, genes and time). VData is built on top of Ch5mpy, a custom built Python library for easily working with hdf5 files and which allows to reduce the memory footprint to the minimum.

Conclusions

VData allows to store and manipulate very large datasets of (empirical or simulated) time-stamped data. Since it follows the original Ann-Data format, it is compatible with the scverse tools and AnnData users will find it easy to use.
A unified open-source platform for multimodal neural recording and perturbation during naturalistic behavior
Authors: Newman Jonathan P. , Zhang Jie , Cuevas-López Aarón , Miller Nicholas J. , Honda Takato , van der Goes Marie-Sophie H. , Leighton Alexandra H. , Carvalho Filipe , Lopes Gonçalo , Lakunina Anna , Siegle Joshua H. , Harnett Mark T. , Wilson Matthew A. , Voigts Jakob
Published: September 2023

Behavioral neuroscience faces two conflicting demands: long-duration recordings from large neural populations and unimpeded animal behavior. To meet this challenge, we developed ONIX, an open-source data acquisition system with high data throughput (2GB/sec) and low closed-loop latencies (<1ms) that uses a novel 0.3 mm thin tether to minimize behavioral impact. Head position and rotation are tracked in 3D and used to drive active commutation without torque measurements. ONIX can acquire from combinations of passive electrodes, Neuropixels probes, head-mounted microscopes, cameras, 3D-trackers, and other data sources. We used ONIX to perform uninterrupted, long (∼7 hours) neural recordings in mice as they traversed complex 3-dimensional terrain. ONIX allowed exploration with similar mobility as non-implanted animals, in contrast to conventional tethered systems which restricted movement. By combining long recordings with full mobility, our technology will enable new progress on questions that require high-quality neural recordings during ethologically grounded behaviors.
Dual role of Vascular Endothelial Growth Factor-C (VEGF-C) in post-stroke recovery
Authors: Choi Yun Hwa , Hsu Martin , Laaker Collin , Herbath Melinda , Yang Heeyoon , Cismaru Peter , Johnson Alexis M. , Spellman Bailey , Wigand Kelsey , Sandor Matyas , Fabry Zsuzsanna
Published: September 2023

Using a mouse model of ischemic stroke, this study characterizes stroke-induced lymphangiogenesis at the cribriform plate (CP). While blocking CP lymphangiogenesis with a VEGFR-3 inhibitor improves stroke outcome, administration of VEGF-C induced larger brain infarcts.

Cerebrospinal fluid (CSF), antigens, and antigen-presenting cells drain from the central nervous system (CNS) into lymphatic vessels near the cribriform plate and dural meningeal lymphatics. However, the pathological roles of these lymphatic vessels surrounding the CNS during stroke are not well understood. Using a mouse model of ischemic stroke, transient middle cerebral artery occlusion (tMCAO), we show that stroke induces lymphangiogenesis near the cribriform plate. Interestingly, lymphangiogenesis is restricted to lymphatic vessels at the cribriform plate and downstream cervical lymph nodes, without affecting the conserved network of lymphatic vessels in the dura. Cribriform plate lymphangiogenesis peaks at day 7 and regresses by day 14 following tMCAO and is regulated by VEGF-C/VEGFR-3. These newly developed lymphangiogenic vessels transport CSF and immune cells to the cervical lymph nodes. Inhibition of VEGF-C/VEGFR-3 signaling using a blocker of VEGFR-3 prevented lymphangiogenesis and led to improved stroke outcomes at earlier time points but had no effects at later time points following stroke. Administration of VEGF-C after tMCAO did not further increase post-stroke lymphangiogenesis, but instead induced larger brain infarcts. The differential roles for VEGFR-3 inhibition and VEGF-C in regulating stroke pathology call into question recent suggestions to use VEGF-C therapeutically for stroke.
Effects of optogenetic silencing the Anterior Cingulate Cortex in a delayed non-match to trajectory task
Authors: Cruz Ana S , Cruz Sara , Remondes Miguel
Published: September 2023

Working memory is a fundamental cognitive ability, allowing us to keep information in memory for the time needed to perform a given task. A complex neural circuit fulfills these functions, among which is the anterior cingulate cortex (CG). Functionally and anatomically connected to the medial prefrontal, retrosplenial, midcingulate and hippocampus, as well as motor cortices, CG has been implicated in retrieving appropriate information when needed to select and control appropriate behavior. The role of cingulate cortex in working memory-guided behaviors remains unclear due to the lack of studies reversibly interfering with its activity during specific epochs of working memory. We used light to activate eNpHR3.0 and thus silence cingulate neurons while animals perform a standard delayed non-match to trajectory task. We found that, while not causing an impairment in eNpHR3.0+ animals when compared to eNpHR3.0-CTRL animals, silencing cingulate neurons during retrieval decreases the mean performance if compared to silencing during encoding. Such retrieval-associated changes are accompanied by longer delays in control animals, consistent with an adaptive recruitment of additional cognitive resources.
Vitamin D promotes DNase1L3 to degrade ecDNA and inhibit the malignant progression of hepatocellular carcinoma
Authors: Zhang Heng , Qin Lu-ning , Li Qing-qing , Wu Ting , Zhang Lei , Wang Kai-wen , Cheng Shan-bin , Shi Yue , Feng Yi-qian , Han Jing-xia , Li Yi-nan , Li Zhi-yang , Liu Hui-juan , Sun Tao
Published: September 2023

Extrachromosomal DNA (ecDNA) is an important carrier of oncogene amplification. However, the degradation mechanism of ecDNA is not well understood. We found that endogenous natural molecular vitamin D (VD) reduces ecDNA and inhibits the progression of hepatocellular carcinoma (HCC). VD reduces ecDNA depending on its transporter GC, which interacts with the endonuclease DNase1L3 and stabilize its protein level. DNase1L3 with its lipophilic region on N-terminus exhibiting an affinity towards lipid droplets (LDs) demonstrates direct degradation effect on ecDNA. Intranuclear LDs are abundantly distributed around ecDNA, DNase1L3 therefore shows an affinity for ecDNA owing to its lipophilic region. VD, as a lipid-soluble molecule, can increase the size of LDs and improve the degradation of DNase1L3 on ecDNA. Consequently, we designed two mRNA-based therapeutics, DNase1L3 and GC-DNase, both of which had an anti-tumor effect on PDX models. The above results showed that treatments targeting ecDNA in cancer are prospective in clinical practice.
Discovering optimal kinetic pathways for self-assembly using automatic differentiation
Authors: Jhaveri Adip , Loggia Spencer , Qian Yian , Johnson Margaret E.
Published: September 2023

During self-assembly of macromolecules ranging from ribosomes to viral capsids, the formation of long-lived intermediates or kinetic traps can dramatically reduce yield of the functional products. Understanding biological mechanisms for avoiding traps and efficiently assembling is essential for designing synthetic assembly systems, but learning optimal solutions requires numerical searches in high-dimensional parameter spaces. Here, we exploit powerful automatic differentiation algorithms commonly employed by deep learning frameworks to optimize physical models of reversible self-assembly, discovering diverse solutions in the space of rate constants for 3-7 subunit complexes. We define two biologically-inspired protocols that prevent kinetic trapping through either internal design of subunit binding kinetics or external design of subunit titration in time. Our third protocol acts to recycle intermediates, mimicking energy-consuming enzymes. Preventative solutions via interface design are the most efficient and scale better with more subunits, but external control via titration or recycling are effective even for poorly evolved binding kinetics. Whilst all protocols can produce good solutions, diverse subunits always helps; these complexes access more efficient solutions when following external control protocols, and are simpler to design for internal control, as molecular interfaces do not need modification during assembly given sufficient variation in dimerization rates. Our results identify universal scaling in the cost of kinetic trapping, and provide multiple strategies for eliminating trapping and maximizing assembly yield across large parameter spaces.

SIGNIFICANCE

Macromolecular complexes are frequently composed of diverse subunits. While evolution may favor repeated subunits and symmetry, we show how diversity in subunits generates an expansive parameter space that naturally improves the ‘expressivity’ of self-assembly, much like a deeper neural network. By using automatic differentiation algorithms commonly used in deep learning, we searched these parameter spaces to identify classes of kinetic protocols that mimic biological solutions for productive self-assembly. Our results reveal how high-yield complexes that easily become kinetically trapped in incomplete intermediates can instead be steered by internal design of rate constants or external and active control of subunits to efficiently assemble, exploiting nonequilibrium control of these ubiquitous dynamical systems.
Acid-sensing ion channel 1a contributes to the prefrontal cortex ischemia-enhanced neuronal activities in the amygdala
Authors: Park Gyeongah , Ge Qian , Jin Zhen , Du Jianyang
Published: September 2023

Following a stroke, the emergence of amygdala-related disorders poses a significant challenge, with severe implications for post-stroke mental health, including conditions such as anxiety and depression. These disorders not only hinder post-stroke recovery but also elevate mortality rates. Despite their profound impact, the precise origins of aberrant amygdala function after stroke remain elusive. As a target of reduced brain pH in ischemia, acid-sensing ion channels (ASICs) have been implicated in synaptic transmission after ischemia, hinting at their potential role in reshaping neural circuits following a stroke. This study delves into the intriguing relationship between post-stroke alterations and ASICs, specifically focusing on postsynaptic ASIC1a enhancement in the amygdala following prefrontal cortex (PFC) ischemia induced by endothelin-1 (ET-1) injection. Our findings intriguingly illustrate that mPFC ischemia not only accentuates the PFC to amygdala circuit but also implicates ASIC1a in fostering augmented synaptic plasticity after ischemia. In contrast, the absence of ASIC1a impairs the heightened induction of long-term potentiation (LTP) in the amygdala induced by ischemia. This pivotal research introduces a novel concept with the potential to inaugurate an entirely new avenue of inquiry, thereby significantly enhancing our comprehension of the intricate mechanisms underlying post-stroke neural circuit reconfiguration. Importantly, these revelations hold the promise of paving the way for groundbreaking therapeutic interventions.
The small G-protein Rac1 in the dorsomedial striatum promotes alcohol-dependent structural plasticity and goal-directed learning in mice
Authors: Hoisington Zachary W. , Salvi Alexandra , Laguesse Sophie , Ehinger Yann , Shukla Chhavi , Phamluong Khanhky , Ron Dorit
Published: September 2023

The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice, or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an AAV expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning.

Significance Statement

Addiction, including alcohol use disorder, is characterized by molecular and cellular adaptations that promote maladaptive behaviors. We found that Rac1 was activated by alcohol in the dorsomedial striatum (DMS) of male mice. We show that alcohol-mediated Rac1 signaling is responsible for alterations in actin dynamics and neuronal morphology. We also present data to suggest that Rac1 is important for alcohol-associated learning processes. These results suggest that Rac1 in the DMS is an important contributor to adaptations that promote alcohol use disorder.
FindingCandida aurisin public metagenomic repositories
Authors: Mario-Vasquez Jorge E. , Bagal Ujwal R. , Lowe Elijah , Morgulis Aleksandr , Phan John , Sexton D. Joseph , Shiryev Sergey , Slatkevičius Rytis , Welsh Rory , Litvintseva Anastasia P. , Blumberg Matthew , Agarwala Richa , Chow Nancy A.
Published: September 2023

Candida aurisis a newly emerged multidrug-resistant fungus capable of causing invasive infections with high mortality. Despite intense efforts to understand how this pathogen rapidly emerged and spread worldwide, its environmental reservoirs are poorly understood. Here, we present a collaborative effort between the U.S. Centers for Disease Control and Prevention, the National Center for Biotechnology Information, and GridRepublic (a volunteer computing platform) to identifyC. aurissequences in publicly available metagenomic datasets. We developed the MetaNISH pipeline that uses SRPRISM to align sequences to a set of reference genomes and computes a score for each reference genome. We used MetaNISH to scan ∼300,000 SRA metagenomic runs from 2010 onwards and identified five datasets containingC. aurisreads. Finally, GridRepublic has implemented a prospectiveC. aurismolecular monitoring system using MetaNISH and volunteer computing.
Sperm competition intensity shapes divergence in both sperm morphology and reproductive genes across murine rodents
Authors: Kopania Emily E. K. , Thomas Gregg W. C. , Hutter Carl R. , Mortimer Sebastian M. E. , Callahan Colin M. , Roycroft Emily , Achmadi Anang S. , Breed William G. , Clark Nathan L. , Esselstyn Jacob A. , Rowe Kevin C. , Good Jeffrey M.
Published: September 2023

It remains unclear how variation in the intensity of sperm competition shapes phenotypic and molecular evolution across clades. Mice and rats in the subfamily Murinae are a rapid radiation exhibiting incredible diversity in sperm morphology and production. We combined phenotypic and genomic data to perform phylogenetic comparisons of male reproductive traits and genes across 78 murine species. We identified several shifts towards smaller relative testes mass, presumably reflecting reduced sperm competition. Several sperm traits were associated with relative testes mass, suggesting that mating system evolution selects for convergent suites of traits related to sperm competitive ability. We predicted that sperm competition would also drive more rapid molecular divergence in species with large testes. Contrary to this, we found that many spermatogenesis genes evolved more rapidly in species with smaller relative testes mass due to relaxed purifying selection. While some reproductive genes evolved rapidly under recurrent positive selection, relaxed selection played a greater role in underlying rapid evolution in small testes species. Our work demonstrates that postcopulatory sexual selection can impose strong purifying selection shaping the evolution of male reproduction, and that broad patterns of molecular evolution may help identify genes that contribute to male fertility.
Gigantic Animal Cells Suggest Organellar Scaling Mechanisms Across a 50-fold Range in Cell Volume
Authors: Adams Alexander Nichols , Smith Bradford Julian , Raad Thomas John , Mueller Rachel Lockridge
Published: September 2023

Across the tree of life, cell size varies by orders of magnitude, and organelles scale to maintain cell function. Depending on their shape, organelles can scale by increasing volume, length, or number. Scaling may also reflect demands placed on organelles by increased cell size. The 8,653 species of amphibians exhibit diverse cell sizes, providing a powerful system to investigate organellar scaling. Using transmission electron microscopy and stereology, we analyzed three frog and salamander species whose enterocyte cell volumes range from 228 to 10,593 μm3. We show that the nucleus increases in radius while the mitochondria increase in total network length; the endoplasmic reticulum and Golgi apparatus, with their complex shapes, are intermediate. Notably, all four organelles increase in volume proportionate to cell volume. This pattern suggests that protein concentrations are the same across amphibian species that differ 50-fold in cell size, and that organellar building blocks are incorporated into more or larger organelles following the same “rules” across cell sizes, despite variation in metabolic and transport demands. This conclusion contradicts results from experimental cell size increases, which produce severe proteome dilution. We hypothesize that salamanders have evolved the biosynthetic capacity to maintain a functional proteome despite a huge cell volume.
Mating system and environment predict the direction and extent of introgression between incipientClarkiaspecies
Authors: Sianta Shelley A. , Moeller David A. , Brandvain Yaniv
Published: September 2023

Introgression is pervasive across the tree of life, varying across taxa, geography, and genomes. However, we are only beginning to understand the factors that modulate this variation and how they may be affected by global change. Here, we used 200 genomes and a 15-year site-specific environmental dataset to investigate the effect of mating system divergence and environmental variation on the magnitude of introgression between two recently diverged annual plants. Two subspecies ofClarkia xantianadiverged ca. 65k years ago and subsequently came into secondary sympatry where they form replicated contact zones. We found that introgression is asymmetric between taxa, with substantially more introgression from the self-fertilizing taxon to the outcrossing taxon. This asymmetry is caused by a bias in the direction of initial F1 hybrid formation and subsequent backcrossing. We also found extensive variation in the outcrosser’s admixture proportion among contact zones, which is predicted nearly entirely by interannual variance in spring precipitation. Greater fluctuations in spring precipitation result in higher admixture proportions, likely mediated by the effects of spring precipitation on the expression of traits that determine premating reproductive isolation. Climate-driven hybridization dynamics may be particularly affected by global change, potentially reshaping species boundaries and adaptation to novel environments.
Chromatin Profiling of CBFA2T3-GLIS2 AMLs Identifies Key Transcription Factor Dependencies and BRG1 Inhibition as a Novel Therapeutic Strategy
Authors: Kaonis Samantha , Smith Jenny L. , Katiyar Neerja , Merrill Morgan , Hyelkma Tiffany , Namciu Stephanie , Le Quy , Babaeva Ekaterina , Ishida Takashi , Morris Shelli M. , Girard Emily , Furuyama Suzanne , Ries Rhonda , Bernstein Irwin , Meshinchi Soheil , Henikoff Steven , Meers Michael , Hadland Brandon , Sarthy Jay F.
Published: September 2023

Oncogenic fusions involving transcription factors are present in the majority of pediatric leukemias; however, the context-specific mechanisms they employ to drive cancer remain poorly understood. CBFA2T3-GLIS2 (C/G) fusions occur in treatment-refractory acute myeloid leukemias and are restricted to young children. To understand how the C/G fusion drives oncogenesis we applied CUT&RUN chromatin profiling to an umbilical cord blood/endothelial cell (EC) co-culture model of C/G AML that recapitulates the biology of this malignancy. We find C/G fusion binding is mediated by its zinc finger domains. Integration of fusion binding sites in C/G- transduced cells with Polycomb Repressive Complex 2 (PRC2) sites in control cord blood cells identifiesMYCN, ZFPM1, ZBTB16 and LMO2as direct C/G targets. Transcriptomic analysis of a large pediatric AML cohort shows that these genes are upregulated in C/G patient samples. Single cell RNA-sequencing of umbilical cord blood identifies a population of megakaryocyte precursors that already express many of these genes despite lacking the fusion. By integrating CUT&RUN data with CRISPR dependency screens we identifyBRG1/SMARCA4as a vulnerability in C/G AML. BRG1 profiling in C/G patient-derived cell lines shows that theCBFA2T3locus is a binding site, and treatment with clinically-available BRG1 inhibitors reduces fusion levels and downstream C/G targets including N-MYC, resulting in C/G leukemia cell death and extending survival in a murine xenograft model.
Learning induced neuronal identity switch in the superficial layers of the primary somatosensory cortex
Authors: Dai Jiaman , Sun Qian-Quan
Published: September 2023

During learning, multi-dimensional inputs are integrated within the sensory cortices. However, the strategies by which the sensory cortex employs to achieve learning remains poorly understood. We studied the sensory cortical neuronal coding of trace eyeblink conditioning (TEC) in head-fixed, freely running mice, where whisker deflection was used as a conditioned stimulus (CS) and an air puff to the cornea delivered after an interval was used as unconditioned stimulus (US). After training, mice learned the task with a set of stereotypical behavioral changes, most prominent ones include prolonged closure of eyelids, and increased reverse running between CS and US onset. The local blockade of the primary somatosensory cortex (S1) activities with muscimol abolished the behavior learning suggesting that S1 is required for the TEC. In naive animals, based on the response properties to the CS and US, identities of the small proportion (∼20%) of responsive primary neurons (PNs) were divided into two subtypes: CR (i.e. CS-responsive) and UR neurons (i.e. US-responsive). After animals learned the task, identity of CR and UR neurons changed: while the CR neurons are less responsive to CS, UR neurons gain responsiveness to CS, a new phenomenon we defined as ‘learning induced neuronal identity switch (LINIS)’. To explore the potential mechanisms underlying LINIS, we found that systemic and local (i.e. in S1) administration of the nicotinic receptor antagonist during TEC training blocked the LINIS, and concomitantly disrupted the behavior learning. Additionally, we monitored responses of two types of cortical interneurons (INs) and observed that the responses of the somatostatin-expressing (SST), but not parvalbumin-expressing (PV) INs are negatively correlated with the learning performance, suggesting that SST-INs contribute to the LINIS. Thus, we conclude that L2/3 PNs in S1 encode perceptual learning by LINIS like mechanisms, and cholinergic pathways and cortical SST interneurons are involved in the formation of LINIS.
Chemical Tools for Profiling the Intracellular ADP-ribosylated Proteome
Authors: Draganov Simeon D. , Gruet Michael J. , Conole Daniel , Balcells Cristina , Siskos Alexandros P. , Keun Hector C. , Haskard Dorian O. , Tate Edward W.
Published: September 2023

The post-translational modification (PTM) ADP-ribosylation plays an important role in cell signaling and regulating protein function and has been implicated in the development of multiple diseases, including breast and ovarian cancers. Studying the underlying mechanisms through which this PTM contributes towards disease development, however, has been hampered by the lack of appropriate tools for reliable identification of physiologically relevant ADP-ribosylated proteins in a live-cell environment. Herein, we explore the applications of an alkyne-tagged proprobe, 6Yn-ProTide-Ad (6Yn-Pro) as a chemical tool for the identification of intracellular ADP-ribosylated proteins through metabolic labelling. We applied targeted metabolomics and chemical proteomics in HEK293T cells treated with 6Yn-Pro to demonstrate intracellular metabolic conversion of the probe into ADP-ribosylation cofactor 6Yn-NAD+, and subsequent labelling and enrichment of PARP1 and multiple known ADP-ribosylated proteins in cells under hydrogen peroxide-induced stress. We anticipate that the approach and methodology described here will be useful for future identification of novel intracellular ADP-ribosylated proteins.

Abstract Figure
Pathological brain states in Alzheimer’s disease
Authors: Adams Jenna N. , Kark Sarah M. , Chappel-Farley Miranda G. , Escalante Yuritza , Stith Lea A. , Rapp Paul E. , Yassa Michael A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

Dynamic and rapid reconfigurations of neural activation patterns, known as brain states, support cognition. Recent analytic advances applied to functional magnetic resonance imaging now enable the quantification of brain states, which offers a substantial methodological improvement in characterizing spatiotemporal dynamics of activation over previous functional connectivity methods. Dysfunction to the persistence and temporal transitions between discrete brain states may be proximal factors reflecting neurophysiological disruptions in Alzheimer’s disease, although this has not yet been established. Here, we identified six distinct brain states, representing spatiotemporal trajectories of coactivation at single time points, in older adults across the Alzheimer’s disease continuum. Critically, we identified a pathological brain state that reflects coactivation within limbic regions. Higher persistence within and transitions to this limbic state, at the expense of other brain states, is associated with an increased likelihood of a clinically impaired diagnosis, worse cognitive performance, greater Alzheimer’s pathology, and neurodegeneration. Together, our results provide compelling evidence that neural activity settling into a pathological limbic state reflects the progression to Alzheimer’s disease. As brain states have recently been shown to be modifiable targets, this work may inform the development of novel neuromodulation techniques to reduce limbic state persistence. This application would be an innovative clinical approach to rescue cognitive decline in the early stages of Alzheimer’s disease.
Rapid measurement and statistical ranking of leaf drought tolerance capacity in cotton
Authors: Dong Xuejun , Mott Dale A. , Garg Jhanvi , Zhou Quan , Sunoj V. S. John , McKnight Benjamin M.
Published: September 2023

Recent progress in ecological remote sensing calls for a more rapid measurement and a closer assessment of crop drought tolerance traits under field conditions. This study addresses three main questions: (1) If leaf dry matter content (LDMC) is equally effective in indicating cotton drought tolerance as leaf osmotic potential at full turgor (πo); (2) if drought tolerance is inversely related to fiber yield/quality in line with the leaf economics spectrum; and (3) if a reliable statistical model can be developed to rank cotton drought tolerance. The values ofπo, along with those of LDMC, of 2736 leaves obtained from cotton variety trials conducted during 2020-2022 in both dryland and irrigated regimes were measured using osmometry. The relationships betweenπoand LDMC, as well as those between traits and lint yield and fiber quality indices, were investigated using regression analysis. A Bayesian hierarchical linear model was developed to rank cotton drought tolerance based on differences (or adjustments) inπoand LDMC between dryland and irrigated sites. LDMC was not only shown to be an alternate and equally effective drought tolerance trait compared withπoobtained from the widely accepted osmometry method, its use is also estimated to lead to a tenfold increase in measuring speed. A stronger drought tolerance capacity of the tested cotton varieties correlated with a lower lint yield and quality, which is generally consistent with the prediction of the leaf economics spectrum. The drought tolerance rankings using the Bayesian hierarchical model help divide the selected 17 cotton varieties into three groups: (a) more-drought tolerant, (b) less-drought tolerant, and (c) intermediate. The ranking results are interpreted using field-measured data of root distribution and diurnal leaf gas exchange from selected cotton varieties. Our work provides new opportunities for a more rapid measurement and an unambiguous ranking of drought tolerance capacity for crop genotypes under various management regimes.
Propagating population activity patterns during spontaneous slow waves in the thalamus of rodents
Authors: Horváth Csaba , Ulbert István , Fiáth Richárd
Published: September 2023

Slow waves (SWs) represent the most prominent electrophysiological events in the thalamocortical system under anesthesia and during deep sleep. Recent studies have revealed that SWs have complex spatiotemporal dynamics and propagate across neocortical regions. However, it is still unclear whether neuronal activity in the thalamus exhibits similar propagation properties during SWs. Here, we report propagating population activity in the thalamus of ketamine/xylazine-anesthetized rats and mice visualized by high-density silicon probe recordings. In both rodent species, propagation of spontaneous thalamic activity during up-states was most frequently observed in dorsal thalamic nuclei such as the higher order posterior (Po), lateral posterior (LP) or laterodorsal (LD) nuclei. The preferred direction of thalamic activity spreading was along the dorsoventral axis, with over half of the up-states exhibiting a gradual propagation in the ventral-to-dorsal direction. Furthermore, simultaneous neocortical and thalamic recordings demonstrated that there is a weak but noticeable interrelation between propagation patterns observed during cortical up-states and those displayed by thalamic population activity. In addition, using chronically implanted silicon probes, we detected propagating activity patterns in the thalamus of naturally sleeping rats during slow-wave sleep. However, in comparison to propagating up-states observed under anesthesia, these propagating patterns were characterized by a reduced rate of occurrence and a faster propagation speed. Our findings suggest that the propagation of spontaneous population activity is an intrinsic property of the thalamocortical network during synchronized brain states such as deep sleep or anesthesia. Additionally, our data implies that the neocortex may have partial control over the formation of propagation patterns within the dorsal thalamus.
ZBTB24 is a conserved multifaceted transcription factor at genes and centromeres that governs the DNA methylation state and expression of satellite repeats
Authors: Grillo Giacomo , Boyarchuk Ekaterina , Mihic Seed , Ivkovic Ivana , Bertrand Mathilde , Jouneau Alice , Dahlet Thomas , Dumas Michael , Weber Michael , Velasco Guillaume , Francastel Claire
Published: September 2023

Since its discovery as an Immunodeficiency with Centromeric instability and Facial anomalies syndrome-causative gene, ZBTB24 has emerged as a key player in DNA methylation, immunity and development. By extensively analyzing ZBTB24 genomic functions in ICF-relevant mouse and human cellular models, we revealed here its multiple facets as a transcription factor, with key roles in immune response-related genes expression and also in early embryonic development. Using a constitutiveZbtb24ICF-like mutant and an auxin-inducible degron system in mouse embryonic stem cells, we showed that ZBTB24 is recruited to centromeric satellite DNA where it is required to establish the correct DNA methylation patterns through the recruitment of DNMT3B. Thus, our results further revealed an essential role for ZBTB24 at human and mouse centromeric satellite arrays, as a transcriptional repressor. Together, we unveiled unprecedented functions of ZBTB24 at human and mouse centromeres by directly controlling DNA methylation and transcription of the underlying tandem satellite repeats.
Transcriptomic Response to Nitrogen Availability Highlights Signatures of Adaptive Plasticity During Tetraploid Wheat Domestication
Authors: Pieri Alice , Beleggia Romina , Gioia Tania , Tong Hao , Vittori Valerio di , Frascarelli Giulia , Bitocchi Elena , Nanni Laura , Bellucci Elisa , Fiorani Fabio , Pecchioni Nicola , Quattro Concetta De , Limongi Antonina Rita , Vita Pasquale De , Rossato Marzia , Schurr Ulrich , David Jacques L. , Nikoloski Zoran , Papa Roberto
Published: September 2023

The domestication of crops, with the development of the agroecosystems, is associated with major environmental changes and represent a model to test the role of phenotypic plasticity. Here we investigated 32 genotypes representing key stages of tetraploid wheat domestication. We developed a dedicated pipeline combining RNA-Seq data, estimates of evolvability andQSTto characterize the plasticity of gene expression and identify signatures of selection under different nitrogen conditions. The analysis of gene expression diversity showed contrasting results between primary and secondary domestication in relation to nitrogen availability. Indeed, nitrogen triggered the expression of twice the number of genes in durum wheat compared to emmer and wild emmer.QSTdistributions andQST–FSTcomparisons revealed distinct selection signatures at each domestication stage. While primary domestication affected the expression of genes involved in biotic interactions, secondary domestication was associated with changes in expression of genes involved in metabolism of amino acids, particularly lysine. Selection signatures were found also in differentially expressed genes, specifically involved in nitrogen metabolism, such asglutamate dehydrogenase. Overall, our findings show that nitrogen availability had a pivotal role during the domestication and adaptive responses of a major food crop, with varying effects across different traits and growth conditions.
SIDERITE: Unveiling Hidden Siderophore Diversity in the Chemical Space Through Digital Exploration
Authors: He Ruolin , Gu Shaohua , Xu Jiazheng , Li Xuejian , Chen Haoran , Shao Zhengying , Wang Fanhao , Shao Jiqi , Yin Wen-Bing , Qian Long , Wei Zhong , Li Zhiyuan
Published: September 2023

Siderophores, a highly diverse family of secondary metabolites, play a crucial role in facilitating the acquisition of the essential iron. However, the current discovery of siderophore relies largely on manual approaches. In this work, we introduced SIDERTE, a digitized siderophore information database containing 872 siderophore records with 649 unique structures. Leveraging this digitalized dataset, we gained a systematic overview of siderophores by their clustering patterns in the chemical space. Building upon this, we developed a functional group-based method for predicting new iron-binding molecules. Applying this method to 4,314 natural product molecules from TargetMol’s Natural Product Library for high throughput screening, we experimentally confirmed that 40 out of the 48 molecules predicted as siderophore candidates possessed iron-binding abilities. Expanding our approach to the COCONUT natural product database, we predicted a staggering 3,199 siderophore candidates, showcasing remarkable structure diversity that are largely unexplored. Our study provides a valuable resource for accelerating the discovery of novel iron-binding molecules and advancing our understanding towards siderophores.
Single-cell RNA sequencing identifies SLC6A3 as a biomarker and prognostic marker in clear cell renal cell carcinoma
Authors: Narayanan Sathiya Pandi , Gopal Ramani , Jenifer Sebastian Arockia , Masoodi Tariq Ahmad
Published: September 2023

Background

The SLC6A3 gene encodes dopamine protein and is a member of the sodium and chloride-dependent neurotransmitter transporter family. While the role of SLC6A3 in Parkinson’s disease is well established, its function in cancer, especially in clear cell renal cell carcinoma (ccRCC), remains unclear.

Methods

To investigate the expression and function of SLC6A3 in ccRCC, we conducted a study using single-cell transcriptomics and bulk RNA sequencing data. We analyzed advanced ccRCC single-cell RNA sequencing profiles, bulk RNA sequencing, and microarray data to assess the expression of SLC6A3 in tumor cells, benign kidney tubule cells, and immune cells.

Results

Our analysis showed that SLC6A3 expression is specific to ccRCC tumor cells and is not present in benign kidney tubule cells or immune cells of benign kidney and kidney tumors. Further, we found an elevated expression of SLC6A3 in ccRCC tumors compared to the benign kidney. Receiver operating characteristics analysis suggests that SLC6A3 is highly sensitive and specific to ccRCC. Additionally, we found a correlation between HNF4A signaling and SLC6A3 expression in two independent mRNA expression profiles. Interestingly, elevated expression of SLC6A3 is a predictor of better overall and progression-free survival of ccRCC patients.

Conclusions

Our findings suggest that SLC6A3 is a potential diagnostic and prognostic marker for ccRCC. The study highlights the importance of understanding the role of SLC6A3 in cancer and provides new insights into ccRCC diagnosis and treatment.