bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endogenous opioid receptor system mediates costly altruism in the human brain
Authors: Chen Jinglu , Putkinen Vesa , Seppälä Kerttu , Hirvonen Jussi , Ioumpa Kalliopi , Gazzola Valeria , Keysers Christian , Nummenmaa Lauri 
Published: December 2023

AbstractFunctional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behaviour. The neuromolecular basis of individual differences in vicarious pain and helping, however, have remain poorly understood. Here we investigated the role of the endogenous μ-opioid receptor (MOR) system – known for its role in analgesia and sociability – in altruistic costly helping. MOR density was measured with high-affinity agonist radioligand [11C]carfentanil. In a separate fMRI experiment, participants could choose to donate money to reduce the pain of the confederate who was subjected to electric shocks of varying intensity. We found that subjects were in general willing to engage in costly helping, and haemodynamic activity in amydala, anterior insula, anterior cingulate cortex, striatum, primary motor cortex, primary somatosensory cortex, and thalamus increased when participants witnessed the pain of others. These haemodynamic responses were negatively associated with MORs availability in the striatolimbic and cortical emotion circuits. In turn, haemodynamic responses during helping were positively associated with MOR availability in the anterior cingulate cortex and hippocampus. Altogether these data suggest that the endogenous MOR system modulates the processing of altruistic behaviour and costly helping in the human brain.
Integrating Multiplexed Imaging and Multiscale Modeling Identifies Tumor Phenotype Transformation as a Critical Component of Therapeutic T Cell Efficacy
Authors: Hickey John W. , Agmon Eran , Horowitz Nina , Lamore Matthew , Sunwoo John , Covert Markus , Nolan Garry P. 
Published: December 2023

SUMMARYCancer progression is a complex process involving interactions that unfold across molecular, cellular, and tissue scales. These multiscale interactions have been difficult to measure and to simulate. Here we integrated CODEX multiplexed tissue imaging with multiscale modeling software, to model key action points that influence the outcome of T cell therapies with cancer. The initial phenotype of therapeutic T cells influences the ability of T cells to convert tumor cells to an inflammatory, anti-proliferative phenotype. This T cell phenotype could be preserved by structural reprogramming to facilitate continual tumor phenotype conversion and killing. One takeaway is that controlling the rate of cancer phenotype conversion is critical for control of tumor growth. The results suggest new design criteria and patient selection metrics for T cell therapies, call for a rethinking of T cell therapeutic implementation, and provide a foundation for synergistically integrating multiplexed imaging data with multiscale modeling of the cancer-immune interface.
In vivo proximity proteomics uncovers palmdelphin (PALMD) as a Z-line-associated mitigator of isoproterenol-induced cardiac injury
Authors: Guo Congting , Jardin Blake D. , Lin Junsen , Ambroise Rachelle L. , Wang Ze , Yang Luzi , Mazumdar Neil , Lu Fujian , Ma Qing , Cao Yangpo , Liu Canzhao , Liu Xujie , Lan Feng , Zhao Mingming , Xiao Han , Dong Erdan , Pu William T. , Guo Yuxuan 
Published: December 2023

SummaryZ-lines are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-line-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-line proteome in vivo. We found palmdelphin (PALMD) as a novel Z-line-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specificpalmdknockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed transverse tubules (T-tubules) and their association with sarcoplasmic reticulum, which formed the Z-line-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with disrupted localization of T-tubule markers caveolin-3 (CAV3) and junctophilin-2 (JPH2) and the reduction of nexilin (NEXN) protein, a crucial Z-line-associated protein that is essential for both Z-line and JMC structures and functions. PALMD was found to interact with NEXN and enhance its protein stability while theNexnmRNA level was not affected. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.HighlightsIn vivo proximity proteomics uncover novel Z-line components that are undetected in in vitro proximity proteomics in cardiomyocytes.PALMD is a novel Z-line-associated protein that is dispensable for baseline cardiomyocyte function in vivo.PALMD mitigates cardiac dysfunction and myocardial injury after repeated isoproterenol insults.PALMD stabilizes NEXN, an essential Z-line-associated regulator of the junctional membrane complex and cardiac systolic function.
The Molecular Logic of Gtr1/2 and Pib2 Dependent TORC1 Regulation in Budding Yeast
Authors: Cecil Jacob H. , Padilla Cristina M. , Lipinski Austin A. , Langlais Paul R. , Luo Xiangxia , Capaldi Andrew P. 
Published: December 2023

ABSTRACTThe Target of Rapamycin kinase Complex I (TORC1) regulates cell growth and metabolism in eukaryotes. Previous studies have shown that, inSaccharomyces cerevisiae, nitrogen and amino acid signals activate TORC1 via the highly conserved small GTPases, Gtr1/2, and the phosphatidylinositol 3-phosphate binding protein, Pib2. However, it was unclear if/how Gtr1/2 and Pib2 cooperate to control TORC1. Here we report that this dual regulator system pushes TORC1 into three distinct signaling states: (i) a Gtr1/2 on, Pib2 on, rapid growth state in nutrient replete conditions; (ii) a Gtr1/2 off, Pib2 on, adaptive/slow growth state in poor-quality growth medium; and (iii) a Gtr1/2 off, Pib2 off, quiescent state in starvation conditions. We suggest that other signaling pathways work in a similar way, to drive a multi-level response via a single kinase, but the behavior has been overlooked since most studies follow signaling to a single reporter protein.
Garden, greenhouse or climate chamber? Experimental conditions influence whether genetic differences are phenotypically expressed
Authors: Karitter Pascal , March-Salas Martí , Ensslin Andreas , Rauschkolb Robert , Godefroid Sandrine , Poorter Hendrik , Scheepens Johannes F. 
Published: December 2023

AbstractCommon-environment experiments are important to study genetically-based phenotypic variation within and among plant populations. Such experiments can be performed in an experimental garden, greenhouse or climate chamber. However, phenotypic expression may be strongly affected by the environmental conditions and influenced by parental and storage effects. Hence, it is unclear if results from common-environment experiments are reproducible across multiple experimental setups.In this study, we assessed the effects of three different growth facilities – outdoor garden, greenhouse, and climate chamber –, on phenotypic expression. We compared ancestral and descendant genotypes of the same population ofLeontodon hispidus. We also evaluated differences in phenotypic expression between plants grown after one (F1) vs. two (F2) intermediate generations.We observed strong differences among plants growing in different growth facilities. Furthermore, we found that descendants had larger rosettes than ancestors only in the greenhouse and they flowered later than ancestors exclusively in the climate chamber. We did not find significant differences between intermediate generations within the growth facilities.Overall, our study demonstrates that environmental variation among growth facilities can dictate the presence and magnitude of phenotypic differences. This implies that absence of evidence for phenotypic differences is not evidence of absence. Experimental systems should be carefully designed to provide meaningful conditions related to the research question. Finally, growing a second intermediate generation did not impact the genetic differences of ancestors and descendants within the facilities, supporting that only one intermediate generation may be sufficient to reduce detectable parental and storage effects.
Causal inference for multiple risk factors and diseases from genomics data
Authors: Machnik Nick , Mahmoudi Mahdi , Borczyk Malgorzata , Krätschmer Ilse , Bauer Markus J. , Robinson Matthew R. 
Published: December 2023

AbstractStatistical causal learning in genomics relies on the instrumental variable method of Mendelian Randomization (MR). Currently, an overwhelming number of MR studies purport to show causal relationships among a wide range of risk factors and outcomes. Here, we show that selecting instrument variables from genome-wide association study estimates leads to high false discovery rates for many MR approaches, which can be greatly reduced by employing a graphical inference approach which: (i) explicitly tests instrumental variable assumptions; (ii) distinguishes direct from indirect factors in very high-dimensional data; (iii) discriminates pleiotropic from trait-specific markers, controlling for LD genome-wide; (iv) accommodates rare variants and binary outcomes in a principled way; and (v) identifies potential unobserved latent confounding. For 17 traits and 8.4M variants recorded for 458,747 individuals in the UK Biobank, we show that standard MR analysis gives an abundance of findings that disappear under stringent assumption checks, with many relationships reflecting potential unmeasured confounding. This implies that mixtures of temporal precedence and potential for reverse-causality prohibit understanding the underlying nature of phenotypic and genetic correlations in biobank data. We propose that well-curated longitudinal records are likely needed and that our approach provides a first-step toward robust principled screening for potential causal links.
Reduced Survival Expectancy Weakens Reproductive Isolation Between Annual FishesGarcialebias reichertiandG. charrua
Authors: Rivas-Ortiz Noelle , Passos Carlos 
Published: December 2023

ABSTRACTHybridization depends on reproductive isolation, which can be impacted by mate choice. Mate choice may vary temporally, as it is modulated by several factors, including survival expectancy and future opportunities for reproduction.Garcialebias reichertiandG. charruaare annual fishes with parapatric distributions that hybridize in the overlapping area of their distributions. They inhabit temporary ponds that flood during the autumn and dry out during the spring, resulting in decreased survival expectancy and future opportunities for reproduction during the breeding season. We predicted that a decrease in survival expectancy would promote reproduction and reduce reproductive isolation betweenG. reichertiandG charrua. By simulating desiccation in the early and late breeding season, we investigated the effects of the desiccation risk and the phase of the breeding season on reproductive isolation and reproductive effort of these species. As expected, our findings reveal that decreased survival expectancy influences both reproductive isolation betweenG. reichertiand G. charrua, and their reproductive effort. Notably, reproductive isolation between these species decreased under a high desiccation risk and in the late breeding season. Additionally, we observed an increase in the frequency of mating and courtship events and aggressive behaviours in the late breeding season. Our study suggests that reproductive isolation betweenG. reichertiandG. charruaand their reproductive effort can change rapidly within a short period of time, emphasizing the influence of survival expectancy on the temporal dynamics of reproductive isolation and hybridization.
Doxycycline Levofloxacin or Moxifloxacin are superior to ciprofloxacin in treating anthrax meningitis in rabbits
Authors: Ben-Shmuel Amir , Glinert Itai , Sittner Assa , Bar-David Elad , Schlomovitz Josef , Levy Haim , Weiss Shay 
Published: December 2023

AbstractEfficient treatment of anthrax related meningitis in patients poses a significant therapeutic challenge. Previously we demonstrated in our anthrax meningitis rabbit model that ciprofloxacin treatment in ineffective with most of the treated animals succumbing to the infection. Herein we tested the efficacy of Doxycycline in our rabbit model and found it highly effective. To test whether the low efficacy of Ciprofloxacin is an example of low efficacy of all fluoroquinolones or only this substance, we treated rabbits that were inoculated intra cisterna magna (ICM) with Levofloxacin or Moxifloxacin. We found that in contrast to Ciprofloxacin, Levofloxacin and Moxifloxacin were highly efficient in treating lethal anthrax related meningitis in rabbits. We demonstrated (in naïve rabbits) that this deference probably results from variances in blood brain barrier (BBB) penetration of the different fluoroquinolones. The combined treatment of doxycycline and any one of the tested fluoroquinolones was highly effective in the rabbit CNS infection model. The combined treatment of doxycycline and levofloxacin was effective in inhalation rabbit model, as good as the doxycycline monotherapy. These findings imply that while Ciprofloxacin is highly effective as a post exposure prophylactic drug, using this drug to treat symptomatic patients should be reconsidered.
A new efficacious Mcl-1 inhibitor maximizes bortezomib and venetoclax responsiveness in resistant multiple myeloma cells
Authors: Al-Odat Omar S. , Gowda Krishne , Srivastava Sandeep K. , Amin Shantu G , Jonnalagadda Subash C. , Budak-Alpdogan Tulin , Pandey Manoj K. 
Published: December 2023

ABSTRACTDespite a record number of clinical studies investigating various anti-cancer drugs, the 5-year survival rate for multiple myeloma (MM) patients in the United States is only 55%, and nearly all patients relapse. Poor patient outcomes demonstrate that myeloma cells are “born to survive,” which means they can adapt and evolve following treatment. As a result, new therapeutic approaches to combat this survival mechanism and target treatment-resistant malignant cells are required. Mcl-1, an anti-apoptotic protein, is required for the development of MM and resistance to therapy. This study looks at the possibility of KS18, a Mcl-1 inhibitor derived from pyoluteorin, to treat resistant MM. We show that KS18 inhibits Mcl-1 selectively and promotes post-translational modifications, resulting in UPS-dependent Mcl-1 degradation. Our findings show that KS18-induced Mcl-1 degradation results in caspase-dependent apoptosis. Importantly, KS18 triggered apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. Furthermore, KS18 inhibits colony formation in bortezomib-resistant cells. KS18 treated NSG mice displayed significant tumor shrinkage without significant toxicity after four weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.Key pointsGiven that KS18 is a robust Mcl-1 inhibitor that targets Mcl-1 efficiently, it has the potential to be a novel treatment for multiple myeloma.KS18 has shown promise in re-sensitizing myeloma cells to chemotherapy as well as in overcoming resistance to bortezomib, venetoclax, and ABT-737.
Dietary restriction of individual amino acids stimulates unique molecular responses in mouse liver
Authors: Haws Spencer A. , Liu Yang , Green Cara L. , Babygirija Reji , Armstrong Eric A. , Mehendale Anusha T. , Lamming Dudley W. , Denu John M. 
Published: December 2023

AbstractDietary protein and essential amino acid (EAA) restriction promotes favorable metabolic reprogramming, ultimately resulting in improvements to both health and lifespan. However, as individual EAAs have distinct catabolites and engage diverse downstream signaling pathways, it remains unclear to what extent shared or AA-specific molecular mechanisms promote diet-associated phenotypes. Here, we investigated the physiological and molecular effects of restricting either dietary methionine, leucine, or isoleucine (Met-R, Leu-R, and Ile-R) for 3 weeks in C57BL/6J male mice. While all 3 AA-depleted diets promoted fat and lean mass loss and slightly improved glucose tolerance, the molecular responses were more diverse; while hepatic metabolites altered by Met-R and Leu-R were highly similar, Ile-R led to dramatic changes in metabolites, including a 3-fold reduction in the oncometabolite 2-hydroxyglutarate. Pathways regulated in an EAA-specific manner included glycolysis, the pentose phosphate pathway (PPP), nucleotide metabolism, the TCA cycle and amino acid metabolism. Transcriptiome analysis and global profiling of histone post-translational modifications (PTMs) revealed different patterns of responses to each diet, although Met-R and Leu-R again shared similar transcriptional responses. While the pattern of global histone PTMs were largely unique for each dietary intervention, Met-R and Ile-R had similar changes in histone-3 methylation/acetylation PTMs at lysine-9. Few similarities were observed between the physiological or molecular responses to EAA restriction and treatment with rapamycin, an inhibitor of the mTORC1 AA-responsive protein kinase, indicating the response to EAA restriction may be largely independent of mTORC1. Together, these results demonstrate that dietary restriction of individual EAAs has unique, EAA-specific effects on the hepatic metabolome, epigenome, and transcriptome, and suggests that the specific EAAs present in dietary protein may play a key role at regulating health at the molecular level.
The evolutionary dynamics of locally adaptive chromosome inversions inMimulus guttatus
Authors: Kollar Leslie M. , Stanley Lauren E. , Kenchanmane Raju Sunil K. , Lowry David B. , Niederhuth Chad E. 
Published: December 2023

AbstractChromosomal inversion polymorphisms are ubiquitous across the diversity of diploid organisms and play a significant role in the evolution of adaptations in those species. Inversions are thought to operate as supergenes by trapping adaptive alleles at multiple linked loci through the suppression of recombination. While there is now considerable support for the supergene mechanism of inversion evolution, the extent to which inversions trap pre-existing adaptive genetic variation versus accumulate new adaptive variants over time remains unclear. In this study, we report new insights into the evolutionary dynamics of a locally adaptive chromosomal inversion polymorphism (inv_chr8A), which contributes to the evolutionary divergence between coastal perennial and inland annual ecotypes of the yellow monkeyflower,Mimulus guttatus. This research was enabled by the sequencing, assembly, and annotation of new annual and perennial genomes ofM. guttatususing Oxford Nanopore long-read sequencing technology. In addition to the adaptive inv_chr8A inversion, we identified three other large inversion polymorphisms, including a previously unknown large inversion (inv_chr8B) nested within the inv_chr8A. Through population genomic analyses and comparative genomics, we determined that the nested inv_chr8B inversion is significantly older than the larger chromosomal inversion in which it resides. We also evaluated key candidate genes involved in gibberellin biosynthesis and anthocyanin regulation, which we hypothesize to underlie the adaptive phenotypic effects of the inv_chr8A inversion. Although little evidence was found to suggest that inversion breakpoint mutations drive adaptive phenotypic effects, our findings support the supergene mechanism of adaptive evolution as a dynamic and continuous process.
Hyper-specialized primates possess a reduced suite of xenobiotic-metabolizing cytochrome P450 genes
Authors: Chaney Morgan E. , Tosi Anthony J. , Bergey Christina M. 
Published: December 2023

AbstractSubfamilies of cytochrome P450 proteins have been strongly linked to the metabolism of physiologically disruptive compounds such as alkaloids, terpenoids, and other xenobiotics. Consistent with this function, these genes have adaptively evolved in response to environmental pressures exerted on animals, such as herbivores, that consume elevated amounts of toxic xenobiotics or plant secondary metabolites (PSMs). Theory on evolutionary tradeoffs predicts that highly specialized herbivores should exhibit a relatively narrow toolkit of adaptations to accommodate the concomitantly narrow arrays of PSMs in their diets. The bamboo lemurs of Madagascar (generaProlemurandHapalemur) represent an interesting test case for this theory because of their dietary hyper-specialization, as these lemurs consume bamboo and grasses at rates otherwise unseen in the order Primates. To test whether the hyper-specialized folivory of these primates is reflected in a similarly specialized and narrow P450 gene suite, we assembled a dataset of confidently assembledCYP1-3genes for two species of bamboo lemur as well as additional lemur species. We tested the predictions that bamboo lemurs would exhibit, first, greater rates of gene loss for xenobiotic-metabolizing P450s and, second, relaxed selection on xenobiotic-metabolizing P450 subfamilies relative to lemurs without such dietary hyper-specialization. We found support for the first prediction, related to gene loss, in theCYP2B, CYP2C, CYP2D, CYP2J,andCYP3Asubfamilies, all of which encode xenobiotic metabolizers. We additionally inferred relaxation of selection for theCYP2FandCYP2Jsubfamilies. The evolution of the P450 genes in bamboo lemurs provides support for the evolutionary tradeoff hypothesis, and we further hypothesize that, rather than adapting to a general array of PSMs, bamboo lemurs have instead adapted to the primary toxin in their diet, the highly potent poison cyanide.HighlightsSome of the most specialized diets among primates are those of bamboo lemurs.Bamboo lemurs have fewer xenobiotic-metabolizing P450 genes than other lemurs.Natural selection has relaxed on theCYP2FandCYP2Jsubfamilies in bamboo lemurs.
Single Amplified Genome Catalog Reveals the Dynamics of Mobilome and Resistome in the Human Microbiome
Authors: Kawano-Sugaya Tetsuro , Arikawa Koji , Saeki Tatsuya , Endoh Taruho , Kamata Kazuma , Matsuhashi Ayumi , Hosokawa Masahito 
Published: December 2023

AbstractThe increase in metagenome-assembled genomes (MAGs) has significantly advanced our understanding of the functional characterization and taxonomic assignment within the human microbiome. However, MAGs, as population consensus genomes, often mask heterogeneity among species and strains, thereby obfuscating the precise relationships between microbial hosts and mobile genetic elements (MGEs). In contrast, single amplified genomes (SAGs) derived via single-cell genome sequencing can capture individual genomic content, including MGEs. We present the bbsag20 dataset, which encompasses 17,202 human-associated prokaryotic SAGs and 869 MAGs, spanning 647 gut and 312 oral bacterial species. The SAGs revealed diverse bacterial lineages and MGEs with a broad host range that were absent in the MAGs and traced the translocation of oral bacteria to the gut. Importantly, our SAGs linked individual mobilomes to resistomes and meticulously charted a dynamic network of antibiotic resistance genes (ARGs) on MGEs, pinpointing potential ARG reservoirs in the microbial community.