bluuebunny/crossref_metadata_2025_split huggingface dataset:
The N-terminus of YY1 regulates DNA and RNA binding affinity for both the zinc-fingers and an unexpected nucleic acid binding domain
Authors: Elias Jimmy , Rosin Jane J. , Keplinger Amanda J. , Ruthenburg Alexander J. 
Published: October 2024

ABSTRACTTranscription factors (TFs) play central roles in dictating cellular identity and function by regulating gene expression programs. Beyond their well-folded DNA binding domains (DBDs) which recognize cognate DNA elements in the genome, TFs are enriched for intrinsically disordered regions (IDRs), which have a host of proposed functions including facilitating protein-protein interactions, aiding in binding site search, and binding RNA. Defining intrinsic regulatory properties of TFs requires further mechanistic investigation. We chose to investigate the DNA and RNA binding properties of Yin Yang 1 (YY1), a ubiquitously expressed TF directly involved in transcriptional activation, repression and genome architecture. Through systematic in vitro nucleic acid binding experiments we resolve conflicting literature defining the RNA binding interface of YY1, demonstrating that there are two RNA binding domains within YY1: its canonical 4 zinc finger DBD and a previously unannotated nucleic acid binding domain, which we term the REPO-NAB. Furthermore, we discover surprising autoinhibitory properties that the N-terminus of the protein imparts on each of these binding domains. Our results provide a new example of IDR-mediated regulation within TFs and enables future mechanistically precise functional investigations.
ADT-1004: A First-in-Class, Orally Bioavailable Selective pan-RAS Inhibitor for Pancreatic Ductal Adenocarcinoma
Authors: Reddy Bandi Dhana Sekhar , Nagaraju Ganji Purnachandra , Sarvesh Sujith , Carstens Julienne L. , Foote Jeremy B. , Graff Emily C. , Fang Yu-Hua D , Keeton Adam B. , Chen Xi , Berry Kristy L. , Bae Sejong , Akce Mehmet , Gorman Greg , Yoon Karina J. , Manne Upender , Boyd Micheal R. , Buchsbaum Donald J. , Azmi Asfar S. , Maxuitenko Yulia Y. , Piazza Gary A. , El-Rayes Bassel F. 
Published: October 2024

ABSTRACTHere, we evaluatedin vivoantitumor activity, target engagement, selectivity, and tumor specificity of ADT-1004, an orally bioavailable prodrug of ADT-007 having highly potent and selective pan-RAS inhibitory activity. ADT-1004 strongly blocked tumor growth and RAS activation in mouse PDAC models without discernable toxicity. As evidence of target engagement and tumor specificity, ADT-1004 inhibited activated RAS and ERK phosphorylation in PDAC tumors at dosages approximately 10-fold below the maximum tolerated dose and without discernable toxicity. ADT-1004 inhibited ERK phosphorylation in PDAC tumors. In addition, ADT-1004 blocked tumor growth and ERK phosphorylation in PDX PDAC models with KRASG12D, KRASG12V, KRASG12C, or KRASG13Qmutations. ADT-1004 treatment increased CD4+and CD8+T cells in the TME consistent with exhaustion and increased MHCII+M1 macrophage and dendritic cells. ADT-1004 demonstrated superior efficacy over sotorasib and adagrasib in tumor models involving human PDAC cells resistant to these KRASG12Cinhibitors. As evidence of selectivity for tumors from PDAC cells with mutant KRAS, ADT-1004 did not impact the growth of tumors from RASWTPDAC cells. Displaying broad antitumor activity in multiple mouse models of PDAC, along with target engagement and selectivity at dosages that were well tolerated, ADT-1004 warrants further development.SignificanceADT-1004 displayed robust antitumor activity in aggressive and clinically relevant PDAC models with unique tumor specificity to block RAS activation and MAPK signaling in RAS mutant cells. As a pan-RAS inhibitor, ADT-1004 has broad activity and potential efficacy advantages over allele-specific KRAS inhibitors by averting resistance. These findings support clinical trials of ADT-1004 for KRAS mutant PDAC.
Deep Mining of the Human Antibody Repertoire Identifies Frequent and Immunogenetically Diverse CDRH3 Topologies Targetable by Vaccination
Authors: Habib Rumi , Solieva Shahlo O. , Lin Zi Jie , Ghosh Sukanya , Bayruns Kelly , Singh Maya , Agostino Colby J. , Tursi Nicholas J. , Sowers Kirsten J. , Huang Jinwei , Roark Ryan S. , Purwar Mansi , Park Younghoon , Ayyanathan Kasirajan , Li Hui , Carey John W. , Kim Amber , Park Joyce , McCanna Madison E. , Skelly Ashwin N. , Chokkalingam Neethu , Kriete Sinja , Shupin Nicholas , Huynh Alana , Walker Susanne , Laenger Niklas , Du Jianqiu , Cui Jiayan , Hahn Beatrice H. , Patel Ami , Escolano Amelia , Kwong Peter D. , Shapiro Lawrence , Bowman Gregory R. , Shaw George M. , Weiner David B. , Pallesen Jesper , Kulp Daniel W. 
Published: October 2024

AbstractMany vaccination strategies against highly variable pathogens such as HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV-1 Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex ‘axe-like’ CDRH3s in the human repertoire and developing new immunogens capable of selectively engaging them. We determined the frequency and diversity of axe-like CDHR3s in healthy human donors using a series of structural informatics approaches finding these precursors in 86.5% of donors. Axe-targeting immunogens based on the HIV-1 Env Q23.17 were developed and bound axe-like precursors in cryo-EM structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques. These results unveil a new structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies.
A complete account of the behavioral repertoire uncovers principles of larval zebrafish hunting behavior
Authors: Rubinstein Yoav , Moshkovitz Maayan , Ottenheimer Itay , Shapira Sapir , Tiomkin Stas , Avitan Lilach 
Published: October 2024

AbstractIn goal-directed behavior animals select actions from a diverse repertoire of possible movements. Accurately quantifying the complete behavioral repertoire can uncover the underlying rules that guide such goal-directed behavior. However, these movements are usually complex, high-dimensional, and lead to various outcomes, posing a challenge to fully capture the complete repertoire. By tracking freely hunting zebrafish larvae using a highspeed camera and analyzing their movements, we developed a mathematical model that accurately reproduces the complete repertoire. Using the model, we show that fish position and change in heading angle following a movement are coupled, such that the choice of one of them limits the possibilities of the other. This repertoire structure uncovered fundamental principles of movements, showing that fish rotate around an identified rotation point and then move forward or backward along straight lines. From the uncovered movement principles, we identified a new guiding rule for prey interaction: in each movement, fish turn to face the prey and then move forward or backward. This enables decoupling between orientation and distance selections of the fish during the hunt. These results provide a comprehensive and continuous description of the repertoire of movements, reveal underlying algorithmic rules that govern the behavior, and offer insights into the potential neural implementation of the repertoire.
SEXUAL-DIMORPHISM IN VISUALLY GUIDED APPROACH BEHAVIOR EMERGES UNIQUELY DURING ADOLESCENCE
Authors: Gonzalez-Olvera Rocio , Allen Kelsey , Feng Ting , Hoy Jennifer L. 
Published: October 2024

AbstractStudying prey capture behavior in mice offers a fruitful platform for understanding how ecologically relevant visual stimuli are differentially processed by the brain throughout life. For example, specific visual stimuli that indicate prey and that naturally draw appetitive orienting in the adult may be interpreted differently or evoke distinct behaviors during development. What are the neural mechanisms that might allow an animal to flexibly couple the same stimulus information to distinct behavioral outcomes as a function of developmental needs? To begin to address this important question, we quantified visually evoked orienting behaviors between adolescent and adult C57BL6/J mice of both sexes under the natural prey capture context compared to responses in our established virtual motion stimulus paradigm, C-SPOT. Most surprisingly, we discovered that female versus male adolescent mice have opposing innate behavioral biases evoked by the same sweeping motion stimuli which is not present in adulthood. Further, female mice display a robust enhancement of approach towards visual motion over all other groups tested, yet they are the least aggressive in response to live prey. Thus, our work overall revealed that innate approach towards visual motion is robustly dissociated from predatory aggression in female versus male mice specifically during adolescence. This underscores the different natural behavioral goals and physiological states that uniquely apply to female versus male adolescent animals, and reveals that approach towards visual motion is a key sensory-motor process selectively augmented during female adolescence.HighlightsAdolescent mice of both sexes innately approach insects more than adultsAdolescent males versus females have distinct response biases to visual motionAdolescent males display the strongest hunger-related predatory aggression
Parent-offspring brain similarity: Specificities and commonalities across gender combinations - the Transmit Radiant Individuality to Offspring (TRIO) study
Authors: Matsudaira Izumi , Yamaguchi Ryo , Taki Yasuyuki 
Published: October 2024

AbstractResearch suggests that parent-offspring brain similarities may underlie intergenerational transmission of psychopathology. However, most studies have focused on mothers and offspring, with few including fathers. This study aimed to extend understanding of parent-offspring neural similarities by examining parent-offspring trios. The study included 152 Japanese biological parent-offspring trios who participated in the Transmit Radiant Individuality to Offspring (TRIO) study. We analyzed the parent-offspring similarities in brain structural features (cortical thickness, surface area, local gyrification index, and subcortical volume) across different parent-offspring gender combinations (father-son, father-daughter, mother-son, and mother-daughter). Additionally, we investigated the relationship between brain similarities and similarities in intelligence and personality traits in parents and offspring. Our findings confirmed that correlations in brain structural features between father-offspring or mother-offspring dyads were significantly stronger than those between unrelated individuals. Notably, both sons and daughters exhibited brain regions similar to their fathers only, mothers only, both parents, or neither parent. Furthermore, a significant association was observed between similarities in general intelligence and the surface area of auditory regions in both father-offspring and mother-offspring dyads. These results provide valuable insights into the genetic and environmental factors influencing brain development and aging across generations. This study is expected to contribute to future research elucidating the mechanisms underlying the intergenerational transmission of psychiatric disorders.
Transcriptomic Insights into Hypothalamic Aging During Menopause: A Comparative Analysis of Human and Mouse Models
Authors: Bloom Jordana C. B. , Torres Encarnacion , Pereira Sidney A. , Arvizu-Sanchez Liliana , Fontes Audrey N. , Joffe Hadine , Page David C. , Navarro Victor M. 
Published: October 2024

AbstractMenopause significantly impacts women’s health, yet hypothalamic changes during this transition remain poorly understood. We analyzed gene expression in human hypothalamic samples across menopausal stages, revealing significant changes in inflammatory pathways, KNDy neuron signaling, and thermoregulatory genes. This analysis also identified novel central markers of menopause, including AKAP5 and CDKN1A (p21). To further investigate these changes, we developed a novel mouse model based on long-term (4 months) ovariectomy (OVX) that mimics the gonadotropin and temperature fluctuations of menopausal transition. Remarkably, the posterior hypothalamus of 4-month OVX mice closely mirrored the transcriptional changes observed in perimenopausal women. Both species exhibited increased inflammatory signaling and glial activation, alongside altered KNDy neuron activity. Our findings provide new insights into the central mechanisms of menopausal symptoms and offer a valuable preclinical model for testing interventions.
The effect of population size on adaptation to fluctuating temperatures
Authors: Räsänen Emmi , Nieminen Veera , Summanen Pauliina A. M. , Villalba de la Peña Mariana , Makkonen Peetu , Suisto Kaisa , Ketola Tarmo , Kronholm Ilkka 
Published: October 2024

ABSTRACTClimate change exposes populations to more frequent periods of extreme temperatures and faster temperature fluctuations. Theoretical models suggest that different types of adaptations should occur in constant versus fluctuating environments of varying frequency. Furthermore, evolutionary adaptation to one environment may weaken the adaptations to alternative environments due to antagonistically pleiotropic alleles. However, fitness trade-offs are rarely observed in experiments and it has been hypothesized that the number and severity of trade-offs evolving in fluctuating environments might depend on population size. To evaluate whether specific types of adaptations evolve at fluctuating temperatures and how population size affects the evolution of trade-offs, we performed an evolution experiment with fission yeast (Schizosaccharomyces pombe). The small and large populations evolved for 500 generations at constant and fluctuating temperatures, after which the evolved strains competed against ancestral strains in respective selection environments and in alternative environments to detect trade-offs. We observed significant adaptation and maladaptation only to constant heat, but not to fluctuating temperatures. Overall, the population size did not have significant effects on adaptation capacity or trade-offs in alternative environments. Our results suggest that constant extreme temperatures may act as stronger selective pressures than temperature variation and that trade-offs are unlikely to constrain adaptation to fluctuating temperatures.
Co-lethality ofLEU2andBAP2is carbon source dependent and is overcome byBUL1deletion inSaccharomyces cerevisiae
Authors: Maheswaran S , Bhat Paike Jayadeva 
Published: October 2024

AbstractIn a leucine requiringSaccharomyces cerevisiaestrain, deletion ofBAP2, a high affinity leucine permease confers lethality in presence of fermentable sugars, but not other carbon sources. Deletion ofBUL1, an adaptor overcomes this lethality.BUL1deletion augments leucine import through accumulation of Bap3 and Bap2 in the plasma membrane and reduces their turnover. We suspectBUL1as a cognate adaptor for ubiquitylation of these permeases.
Structure and function of the yeast amino acid-sensing SEAC-EGOC supercomplex
Authors: Tafur Lucas , Bonadei Lenny , Zheng Yiqiang , Loewith Robbie 
Published: October 2024

AbstractThe Seh1-associated complex (SEAC) transduces amino acid signals to the Target of Rapamycin Complex 1 (TORC1), a master regulator of cell growth located on the vacuole membrane. The SEAC acts as a GTPase activating protein (GAP) for Gtr1, a small GTPase that forms a heterodimer with Gtr2, and as part of the EGO complex (EGOC), relays nutrient signals to TORC1. The SEAC is composed of two subcomplexes, SEACIT, an inhibitor of TORC1 that contains the GAP activity, and SEACAT, that has been proposed to regulate the activity of SEACIT. However, molecular details of its regulation are unclear. Here, we determined the cryo-electron microscopy structure of the SEAC-EGOC supercomplex and studied its function in TORC1 amino acid signalling. A single SEAC can interact with two EGOC molecules via SEACIT, binding exclusively to the “active” version of the EGOC as their interaction depends on Gtr1 being loaded with GTP. SEACAT does not modulate nor interact with the EGOC. The GAP activity of the SEAC is essential for the regulation of TORC1 by amino acids, and its loss phenocopies the lack of Gtr1-Gtr2, establishing the SEAC-EGOC complex as an amino acid-sensing hub. Despite being located far from the active site, deletion of Sea2, or its N-terminal β-propeller domain, also results in defects in amino acid signalling to TORC1. We propose that the SEAC-EGOC supercomplex integrates coatomer-like mechanisms of regulation via bidirectional feedback between GAP-GTPase (SEACIT-EGOC) and coat (SEACAT) modules that explain the functional interaction between Sea2 and the GAP activity. Given the conservation between the SEAC and its mammalian ortholog GATOR, we envision that this mechanism is similar in different organisms.
Layer 6 corticothalamic neurons induce high gamma oscillations through cortico-cortical and cortico-thalamo-cortical pathways
Authors: Russo S. , Dimwamwa E. D. , Stanley G. B. 
Published: October 2024

ABSTRACTLayer 6 corticothalamic (L6CT) neurons project to both cortex and thalamus, inducing multiple effects including the modulation of cortical and thalamic firing, and the emergence of high gamma oscillations in the cortical local field potential (LFP). We hypothesize that the high gamma oscillations driven by L6CT neuron activation are shaped by the dynamic engagement of intracortical and cortico-thalamo-cortical circuits. To test this, we optogenetically activated L6CT neurons in NTSR1-cre mice expressing channelrhodopsin-2 in L6CT neurons. Leveraging the vibrissal pathway in awake, head-fixed mice, we presented ramp-and-hold light at different intensities while recording neural activity in the primary somatosensory barrel cortex (S1) and the ventral posteromedial nucleus (VPm) of the thalamus using silicon probes. We found that the activation of S1 L6CT neurons induces high-frequency LFP oscillations in S1 that are modulated in frequency, but not in amplitude, across light intensities and over time. To identify which neuronal classes contribute to these oscillations, we examined the temporal evolution of firing rate in S1 and VPm. While most S1 neurons were steadily suppressed, VPm and S1 Layer 4 fast spiking (L4 FS) neurons evolved from being suppressed to facilitated within 500 ms, suggesting differential recruitment of the intracortical vs cortico-thalamo-cortical pathways. Finally, we found that LFP frequency selectively correlates with VPm firing rate. Taken together, our data suggest that L6CT neurons sculpt the frequency of S1 LFP high gamma oscillations through cortico-thalamo-cortical circuits, linking the recurrent interactions mediated by L6CT neurons to the high gamma oscillations observed across physiological and pathological conditions.Significance StatementLayer 6 corticothalamic (L6CT) neurons are strategically positioned to modulate the cortex and the thalamus allowing them to engage distinct, yet interlocked, circuits. Here we show that the activation of L6CT neurons in the mouse primary somatosensory cortex induces fast cortical oscillations through the coordinated engagement of cortico-thalamo-cortical and intracortical pathways. Our work reveals that these two L6CT-mediated pathways exert competing effects: while intracortical connections suppress cortical spiking, the activity of the cortico-thalamo-cortical loop rapidly evolves, facilitating cortical spiking. We demonstrate that the cortico-thalamo-cortical pathway operates on a faster timescale than the intracortical pathway and critically shapes cortical oscillation frequency. These findings reveal how the unique position of corticothalamic neurons allows them to flexibly and dynamically modulate the thalamocortical network.
Leveraging Single-Cell RNA-Seq to Generate Robust Microglia Aging Clocks
Authors: Stanley Natalie , Dhawka Luvna , Jaikumar Sneha , Huang Yu-Chen , Zannas Anthony S 
Published: October 2024

Abstract‘Biological aging clocks’ - composite molecular markers thought to capture an individual’s biological age - have been traditionally developed through bulk-level analyses of mixed cells and tissues. However, recent evidence highlights the importance of gaining single-cell-level insights into the aging process. Microglia are key immune cells in the brain shown to adapt functionally in aging and disease. Recent studies have generated single-cell RNA sequencing (scRNA-seq) datasets that transcriptionally profile microglia during aging and development. Leveraging such datasets, we develop and compare computational approaches for generating transcriptome-wide summaries to establish robust microglia aging clocks. Our results reveal that unsupervised, frequency-based featurization approaches strike a balance in accuracy, interpretability, and computational efficiency. We further extrapolate and demonstrate applicability of such microglia clocks to readily available bulk RNA-seq data with environmental inputs. Single-cell-derived clocks can yield insights into the determinants of brain aging, ultimately promoting interventions that beneficially modulate health and disease trajectories.
A shared code for perceiving and imagining objects in human ventral temporal cortex
Authors: Wadia V. S. , Reed C. M. , Chung J. M. , Bateman L. M. , Mamelak A. N. , Rutishauser U. , Tsao D. Y. 
Published: October 2024

AbstractMental imagery is a remarkable phenomenon that allows us to remember previous experiences and imagine new ones. Animal studies have yielded rich insight into mechanisms for visual perception, but the neural mechanisms for visual imagery remain poorly understood. Here, we first determined that ∼80% of visually responsive single neurons in human ventral temporal cortex (VTC) used a distributed axis code to represent objects. We then used that code to reconstruct objects and generate maximally effective synthetic stimuli. Finally, we recorded responses from the same neural population while subjects imagined specific objects and found that ∼40% of axis-tuned VTC neurons recapitulated the visual code. Our findings reveal that visual imagery is supported by reactivation of the same neurons involved in perception, providing single neuron evidence for existence of a generative model in human VTC.One Sentence SummarySingle neurons in human temporal cortex use feature axes to encode objects, and imagery reactivates this code.