bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down-regulation of AKT proteins slows the growth of mutant-KRAS pancreatic tumors
Authors: Chen Chuankai , Jiang Ya-Ping , You Inchul , Gray Nathanael S. , Lin Richard Z. 
Published: May 2024

ABSTRACTSerine/threonine kinase AKT isoforms play a well-established role in cell metabolism and growth. Most pancreatic adenocarcinoma (PDAC) harbors activation mutations of KRAS, which activates the PI3K/AKT signaling pathway. However, AKT inhibitors are not effective in the treatment of pancreatic cancer. To better understand the role of AKT signaling in mutant-KRAS pancreatic tumors, this study utilizes proteolysis-targeting chimeras (PROTACs) and CRISPR-Cas9-genome editing to investigate AKT proteins. PROTAC down-regulation of AKT proteins markedly slowed the growth of three pancreatic tumor cell lines harboring mutant KRAS. In contrast, inhibition of AKT kinase activity alone had very little effect on the growth of these cell lines. Concurrent genetic deletion of all AKT isoforms (AKT1, AKT2, and AKT3) in the KPC (KrasG12D;Trp53R172H;Pdx1-Cre) pancreatic cancer cell line also dramatically slowed its growthin vitroand when orthotopically implanted in syngeneic mice. Surprisingly, insulin-like growth factor-1 (IGF-1), but not epidermal growth factor (EGF), restored KPC cell growth in serum-deprived conditions and the IGF-1 growth stimulation effect was AKT dependent. RNA-seq analysis of AKT1/2/3-deficient KPC cells suggested that reduced cholesterol synthesis may be responsible for the decreased response to IGF-1 stimulation. These results indicate that the presence of all three AKT isoforms supports pancreatic tumor cell growth and pharmacological degradation of AKT proteins may be more effective than AKT catalytic inhibitors for treating pancreatic cancer.
Host-derived Interleukin 1α induces an immunosuppressive tumor microenvironment via regulating monocyte-to-macrophage differentiation
Authors: Keerthi Raja Manikanda Raja , Gupta Gourab , Atkinson Grace , Kathrein Katie , Armstrong Alissa , Gower Michael , Roninson Igor , Broude Eugenia , Chen Menqiang , Ji Hao , Lim Chang-uk , Wang Hongjun , Fan Daping , Xu Peisheng , Li Jie , Zhou Gang , Chen Hexin 
Published: May 2024

AbstractTumor-associated macrophages exhibit high heterogeneity and contribute to the establishment of an immunosuppressive tumor microenvironment (TME). Although numerous studies have demonstrated that extracellular factors promote macrophage proliferation and polarization, the regulatory mechanisms governing the differentiation process to generate phenotypically, and functionally diverse macrophage subpopulations remain largely unexplored. In this study, we examined the influence of interleukin 1α (IL-1α) on the development of an immunosuppressive TME using orthotopic transplantation murine models of breast cancer. Deletion of host Il1α led to the rejection of inoculated congenic tumors. Single-cell sequencing analysis revealed that CX3CR1+ macrophage cells were the primary sources of IL-1α in the TME. The absence of IL-1α reprogrammed the monocyte-to-macrophage differentiation process within the TME, characterized by a notable decrease in the subset of CX3CR+ ductal-like macrophages and an increase in iNOS-expressing inflammatory cells. Comparative analysis of gene signatures in both human and mouse macrophage subsets suggested that IL-1α deficiency shifted the macrophage polarization from M2 to M1 phenotypes, leading to enhanced cytotoxic T lymphocyte activity in the TME. Importantly, elevated levels of IL-1α in human cancers were associated with worse prognosis following immunotherapy. These findings underscore the pivotal role of IL-1α in shaping an immune-suppressive TME through the regulation of macrophage differentiation and activity, highlighting IL-1α as a potential target for breast cancer treatment.TeaserInterleukin 1α dictates macrophage behavior, influencing an immunosuppressive microenvironment in breast cancer, suggesting it as a treatment target.
Cardiovascular responses to natural and auditory evoked slow waves predict post-sleep cardiac function
Authors: Alessandrelli Giulia , Huwiler Stephanie , Bernardi Giulio , Carro-Domínguez Manuel , Stich Fabia , Sala Rossella , Aziri Florent , Trippel Anna , Markendorf Susanne , Niederseer David , Bohm Philipp , Cerveri Pietro , Siclari Francesca , Huber Reto , Wenderoth Nicole , Schmied Christian , Lustenberger Caroline 
Published: May 2024

AbstractThe interplay between slow-wave sleep and cardiovascular health is increasingly recognized. Our prior research showed that auditory-enhanced slow waves can boost cardiac function, yet the mechanisms behind this remain unclear. Advancing these findings, our current analysis dissected the effects of two slow wave types on cardiovascular function, using data from 18 middle-aged men across three nights. We found that the strength of heart rate and blood pressure responses concurrent with slow waves predicts cardiac function post-sleep. Notably, we identified that highly synchronized type I slow waves, as opposed to lower-amplitude type II slow waves, primarily co-occur with these cardiovascular pulsations. While auditory stimulation enhances both types of slow waves, they exhibit distinct temporal dynamics, pointing to different underlying biological mechanisms. This study crucially addresses how distinct slow wave types can affect cardiovascular function, implying that targeted slow wave stimulation could be a strategic approach to improve heart health.
Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism
Authors: New Lauryn E. , Wang Niannian , Khan Shabbir , Griffiths Joanne C. , Hains Ryan , Johnston Jamie , Filippi Beatrice M. 
Published: May 2024

AbstractThe central nervous system (CNS) plays a key role in regulating metabolic functions, but conditions like obesity and diabetes can disrupt this balance. Within the CNS, the nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) controls glucose metabolism and feeding behaviour. In rodents, the NTS senses insulin and communicates with the liver to regulate glucose production. Even short-term exposure to a high-fat diet (HFD) can lead to insulin resistance and impair NTS function. However, we still know little about which cells in the NTS are sensitive to insulin. Our study aimed to identify these insulin-sensitive cells and understand how they affect glucose metabolism.We found that insulin receptors in astrocytes are crucial for the NTS’s ability to regulate glucose production in the liver. Insulin evokes the release of endozepines from astrocytes, and injecting endozepines into the NTS reduces glucose production. The effect of endozepines within the NTS is mimicked by GABAA antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABAA receptor activity, ultimately reducing glucose production in the liver.Our study is the first to show that insulin–dependent release of endozepines from NTS- astrocytes is fundamental to control blood glucose levels, providing valuable insights into the mechanisms underlying insulin function within this specific region of the CNS.
Salmonids elicit an acute behavioral response to heterothermal environments
Authors: Naudascher Robert , Brizzolara Stefano , Slomka Jonasz , Boes Robert M. , Holzner Markus , Silva Luiz G. M. , Stocker Roman 
Published: May 2024

AbstractMost fish species are ectothermic and rely on behavioral strategies to control their body temperature in heterothermal environments. Both thermotaxis and thermokinesis have been suggested as important underlying mechanisms. However, to what extent these behaviors allow fish to respond to rapid (timescales of minutes) and strong thermal disturbances, like those caused by anthropogenic water releases into natural freshwater systems, is poorly understood. Here, we quantify this response for a salmonid species with a novel laboratory approach coupled with image-based tracking. We exposed brown trout parr (Salmo trutta), acclimated to 12 °C, to rapidly forming cold- and warm-water interfaces with temperatures ranging from 4 to 20 °C. We found that fish actively avoided colder water (≤8 °C) through a rapid response that combined thermotaxis and thermokinesis. In contrast, fish did not avoid warmer water and frequently crossed interfaces having temperature contrasts of up to 8 °C. This study shows that brown trout parr swiftly deploy multiple behavioral strategies to minimize exposure to cold water and take advantage of warm water, illustrating their capability to cope with rapidly occurring thermal alterations.
HER4 is a high affinity dimerization partner for all EGFR/HER/ErbB-family proteins
Authors: Singh Pradeep Kumar , Kim Soyeon , Smith Adam W. 
Published: May 2024

AbstractHuman epidermal growth factor receptors (HER) – also known as EGFR or ErbB receptors – are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis through cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line studied with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER-family proteins in live cells with a time-resolved fluorescence technique called pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring protein expression levels and diffusion coefficients. Our PIE-FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4-specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.
Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas
Authors: Kazansky Yaniv , Mueller Helen S. , Cameron Daniel , Demarest Phillip , Zaffaroni Nadia , Arrighetti Noemi , Zuco Valentina , Mundi Prabhjot S. , Kuwahara Yasumichi , Somwar Romel , Qu Rui , Califano Andrea , de Stanchina Elisa , Dela Cruz Filemon S. , Kung Andrew L. , Gounder Mrinal M. , Kentsis Alex 
Published: May 2024

AbstractDespite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment ofSMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and loss of SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference fromSMARCB1-deficient tumor cells, we nominate the DNA damage repair kinase ATR as a target for rational combination EZH2 epigenetic therapy. We show that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of the transposase-derived PGBD5. We leverage this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR but not CHK1 using elimusertib. Consequently, combined EZH2 and ATR inhibition improves therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumorsin vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.
Does standard adjustment for genomic population structure capture direct genetic effects?
Authors: Sotoudeh Ramina , Trejo Sam , Harpak Arbel , Conley Dalton 
Published: May 2024

AbstractContemporary genomic studies of complex traits, such as genome-wide association studies (GWASs) and polygenic index (PGI) analyses, often use the principal components of the genotype matrix (PCs) to adjust for population stratification. In this paper, we explore the extent to which we may be discounting direct genetic effects by adjusting for PCs. Using family-based models that control for parental genotype (obtained via Mendelian imputation), we test whether PCs have a direct genetic effect on nine complex phenotypes in the White British subsample of the UK Biobank. Further, we assess the extent to which estimates of polygenic effects meaningfully change when adjusting for PCs in within-family models. Across the nine traits, within-family effects of the top 40 PCs are highly similar to their population effects, suggesting that standard PC adjustments diminish, albeit to a small degree, detectable signals of direct genetic effects. Within family models also confirm that PCs have significant marginal effects on a few traits, most consistently, height and educational attainment. Nonetheless, the variance explained by the effects of PCs is modest, and adjusting for PCs does not appear to affect the magnitude and significance of PGI effects in within-family models.
Efficient and durable gene activation by Cas9-mediated epigenome editing in vivo
Authors: Qin Yuanbo , Akbulut Talha , Mandraju Rajakumar , Connolly Keith , Bechill John , Assadian Farzaneh , Shottek Alison , Levy Seth , Benoit Jamie , Yamagata Tetsuya 
Published: May 2024

AbstractEpigenome editing technology holds great promise for treating diverse genetic disorders. While a series of advances has been made on epigenetic silencing using programmable editors, little progress has been made in leveraging epigenetic activation for therapeutic application. Here we demonstrate epigenetic activation of the LAMA1 gene for the treatment of LAMA2-CMD, a severe congenital muscle dystrophy (CMD) caused by biallelic mutations in the LAMA2 gene. LAMA1 is a sister homologue that is known to compensate for the function of LAMA2. However, supplementing LAMA1 or LAMA2 gene via viral platform is not feasible due to the large size of their coding sequences. Through a single administration of our (Adeno-associated virus) AAV vector encoding all the necessary elements for epigenetic activation, a platform termed CRISPR guide-nucleotide directed modulation (GNDM), we observed significant LAMA1 gene upregulation and phenotype improvements in DyW mice, a severe disease model of LAMA2-CMD. Notably, sustained expression of the GNDM gene and subsequent activation of the LAMA1 gene persisted beyond analyzed period of one year despite immune recognition of the GNDM protein by the host immune system. Regulatory T (Treg) cells appeared to facilitate tolerance to GNDM in the transduced muscle tissue. The muscle-tropic AAV capsid exhibited desired vector biodistribution and promising pharmacodynamics with good safety profiles in adult non-human primates (NHPs). Moreover, administration to juvenile NHPs demonstrated superior pharmacodynamics compared to adults, even at half the adult dose, suggesting safer and more effective therapeutic outcomes in mostly pediatric LAMA2-CMD patients. Our approach holds broad applicability for a range of loss-of-function genetic disorders and could offer a therapeutic breakthrough where active epigenome brings clinical benefit.
Postnatal hearing development limits early parent-to-offspring vocal communication and gates sensorimotor learning in the zebra finch
Authors: Anttonen Tommi , Christensen-Dalsgaard Jakob , Elemans Coen P. H. 
Published: May 2024

ABSTRACTHearing is critical for vocal communication, and in birds its onset is linked to egg hatching. Hearing develops after hatching in early hatching (altricial) species, while already functional in the egg in later hatching (precocial) species. Recent work suggests that altricial zebra finches exhibit parent-to-embryo acoustic communication, requiring functional, high-frequency hearing already in the egg. Yet, the early postnatal development of their auditory sensitivity remains unknown. By measuring hearing and vibration-detection capacity during postnatal development in zebra finches, we show that zebra finch hatchlings are deaf even to loud, broadband sounds. Auditory nerve sensitivity develops gradually in a low-to-high frequency manner. Auditory nerve responses show adult-like properties only after 20 days from hatching. Our data provide evidence against the plausibility of early parent-to-offspring acoustic communication in zebra finches and suggest that hearing functionality may set the onset of vocal learning in zebra finches.
Estropausal gut microbiota transplant improves measures of ovarian function in adult mice
Authors: Kim Minhoo , Wang Justin , Pilley Steven E. , Lu Ryan J. , Xu Alan , Kim Younggyun , Liu Minying , Fu Xueyan , Booth Sarah L. , Mullen Peter J. , Benayoun Bérénice A. 
Published: May 2024

AbstractDecline in ovarian function with age not only affects fertility but is also linked to a higher risk of age-related diseases in women (e.g. osteoporosis, dementia). Intriguingly, earlier menopause is linked to shorter lifespan; however, the underlying molecular mechanisms of ovarian aging are not well understood. Recent evidence suggests the gut microbiota may influence ovarian health. In this study, we characterized ovarian aging associated microbial profiles in mice and investigated the effect of the gut microbiome from young and estropausal female mice on ovarian health through fecal microbiota transplantation. We demonstrate that the ovarian transcriptome can be broadly remodeled after heterochronic microbiota transplantation, with a reduction in inflammation-related gene expression and trends consistent with transcriptional rejuvenation. Consistently, these mice exhibited enhanced ovarian health and increased fertility. Using metagenomics-based causal mediation analyses and serum untargeted metabolomics, we identified candidate microbial species and metabolites that may contribute to the observed effects of fecal microbiota transplantation. Our findings reveal a direct link between the gut microbiota and ovarian health.
Pred-AHCP: Robust feature selection enabled Sequence-Specific Prediction of Anti-Hepatitis C Peptides via Machine Learning
Authors: Saraswat Akash , Sharma Utsav , Gandotra Aryan , Wasan Lakshit , Artham Sainithin , Maitra Arijit , Singh Bipin 
Published: May 2024

AbstractEvery year, an estimated 1.5 million people worldwide contract Hepatitis C (HepC), a significant contributor to liver disease. Although many studies have explored machine learning’s potential to predict antiviral peptides, very few have addressed predicting peptides against specific viruses such as Hepatitis C. In this study, we demonstrate the use of machine learning (ML) algorithms to predict peptides that are effective against HepC. We developed an explainable ML model that harnesses the amino acid sequence of a peptide to predict its potential as an anti-HepC (AHC) agent. Specifically, features were computed based on sequence and physicochemical properties, with feature selection performed utilizing a combined scheme of mutual information and variance inflation factor. This facilitated the removal of redundant and multicollinear features from the sequence data, enhancing the model’s generalizability in predicting AHCPs. The model using therandom forestalgorithm produced the best performance with an accuracy of about 90%. The feature selection analysis highlights that the distribution of hydrophobicity and polarizability, as well as the frequencies of glycine residues and di-peptide motifs—YXL, LXK, VXXXF, VL, LV, CC, RR, TXXXV, VXXA, CXXXC—emerged as the key predictors for identifying AHCPs targeting different components of the HepC virus. The model developed can be accessed through the Pred-AHCP web server, provided athttp://tinyurl.com/web-Pred-AHCP. This resource facilitates the prediction and re-engineering of AHCPs for designing peptide-based therapeutics while also proposing an exploration of similar strategies for designing peptide inhibitors effective against other viruses.
Theoretical analyses for the evolution of biogenic volatile organic compounds (BVOCs) emission strategy
Authors: Hirose Sotaro , Satake Akiko 
Published: May 2024

AbstractPlants emit biogenic volatile organic compounds (BVOCs) as signaling molecules, playing a crucial role in inducing resistance against herbivores. Neighboring plants that eavesdrop on BVOC signals can also increase defenses against herbivores or alter growth patterns to respond to potential risks of herbivore damage. Despite the significance of BVOC emissions, the evolutionary rationales behind their release and the factors contributing to the diversity in such emissions remain poorly understood. To unravel the conditions for the evolution of BVOC emission, we developed a spatially-explicit model that formalizes the evolutionary dynamics of BVOC emission and non-emission strategies. Our model considered two effects of BVOC signaling that impact the fitness of plants: intra-individual communication, which mitigates herbivore damage through the plant’s own BVOC signaling incurring emission costs, and inter-individual communication, which alters the influence of herbivory based on BVOC signals from other individuals without incurring emission costs. Employing two mathematical models—the lattice model and the random distribution model—we investigated how intra-individual communication, inter-individual communication, and spatial structure influenced the evolution of BVOC emission strategies. Our analysis revealed that the increase in intra-individual communication promotes the evolution of the BVOC emission strategy. In contrast, the increase in inter-individual communication effect favors cheaters who benefit from the BVOCs released from neighboring plants without bearing the costs associated with BVOC emission. Our analysis also demonstrated that the narrower the spatial scale of BVOC signaling, the higher the likelihood of BVOC evolution. This research sheds light on the intricate dynamics governing the evolution of BVOC emissions and their implications for plant-plant communication.
Genetic Inactivation of the β1 adrenergic receptor prevents Cerebral Cavernous Malformations in zebrafish
Authors: Li Wenqing , McCurdy Sara , Lopez-Ramirez Miguel A. , Lee Ho-sup , Ginsberg Mark H. 
Published: May 2024

AbstractPropranolol reduces experimental murine cerebral cavernous malformations (CCMs) and prevents embryonic caudal venous plexus (CVP) lesions in zebrafish that follow mosaic inactivation ofccm2. Because morpholino silencing of the β1 adrenergic receptor (adrb1) prevents the embryonic CVP lesion, we proposed thatadrb1plays a role in CCM pathogenesis. Here we report thatadrb1−/-zebrafish exhibited 86% fewer CVP lesions and 87% reduction of CCM lesion volume relative to wild type brood mates at 2dpf and 8-10 weeks stage, respectively. Treatment with metoprolol, a β1 selective antagonist, yielded a similar reduction in CCM lesion volume.Adrb1−/-zebrafish embryos exhibited reduced heart rate and contractility and reduced CVP blood flow. Similarly, slowing the heart and eliminating the blood flow in CVP by administration of 2,3-BDM suppressed the CVP lesion. In sum, our findings provide genetic and pharmacological evidence that the therapeutic effect of propranolol on CCM is achieved through β1 receptor antagonism.