bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune landscape of tertiary lymphoid structures in hepatocellular carcinoma (HCC) treated with neoadjuvant immune checkpoint blockade
Authors: Shu Daniel H. , Ho Won Jin , Kagohara Luciane T. , Girgis Alexander , Shin Sarah M. , Danilova Ludmila , Lee Jae W. , Sidiropoulos Dimitrios N. , Mitchell Sarah , Munjal Kabeer , Howe Kathryn , Bendinelli Kayla J. , Qi Hanfei , Mo Guanglan , Montagne Janelle , Leatherman James M. , Lopez-Vidal Tamara Y. , Zhu Qingfeng , Huff Amanda L. , Yuan Xuan , Hernandez Alexei , Coyne Erin M. , Zaidi Neeha , Zabransky Daniel J. , Engle Logan L. , Ogurtsova Aleksandra , Baretti Marina , Laheru Daniel , Durham Jennifer N. , Wang Hao , Anders Robert , Jaffee Elizabeth M. , Fertig Elana J. , Yarchoan Mark 
Published: October 2023

ABSTRACTNeoadjuvant immunotherapy is thought to produce long-term remissions through induction of antitumor immune responses before removal of the primary tumor. Tertiary lymphoid structures (TLS), germinal center-like structures that can arise within tumors, may contribute to the establishment of immunological memory in this setting, but understanding of their role remains limited. Here, we investigated the contribution of TLS to antitumor immunity in hepatocellular carcinoma (HCC) treated with neoadjuvant immunotherapy. We found that neoadjuvant immunotherapy induced the formation of TLS, which were associated with superior pathologic response, improved relapse free survival, and expansion of the intratumoral T and B cell repertoire. While TLS in viable tumor displayed a highly active mature morphology, in areas of tumor regression we identified an involuted TLS morphology, which was characterized by dispersion of the B cell follicle and persistence of a T cell zone enriched for ongoing antigen presentation and T cell-mature dendritic cell interactions. Involuted TLS showed increased expression of T cell memory markers and expansion of CD8+cytotoxic and tissue resident memory clonotypes. Collectively, these data reveal the circumstances of TLS dissolution and suggest a functional role for late-stage TLS as sites of T cell memory formation after elimination of viable tumor.Graphical AbstractHighlightsIn patients with hepatocellular carcinoma (HCC), tertiary lymphoid structures (TLS) are induced by neoadjuvant immunotherapy and are associated with favorable clinical outcomes.TLS within the same tumor demonstrate extensive sharing of expanded granzyme K and granzyme B-expressing CD8+T effector memory clonotypes, but the B cell repertoires of individual TLS are almost wholly distinct, consistent with independent germinal center reactions.Within areas of viable tumor, mature TLS are characterized by high expression of CD21 and CD23, BCL6+germinal center B cells, and close interactions between DCLAMP+mature dendritic cells and CXCR5-CXCR3+CD4 T peripheral helper cells within a T cell zone adjacent to the B cell follicle.Within areas of tumor regression, an involuted TLS morphology is identified that is notable for dissolution of the B cell germinal center, retention of the T cell zone, and increased T cell memory.
Vicious cycle of hemodynamic perturbation and endothelial injury in development and progression of pulmonary arterial hypertension
Authors: Deng Yupu , Chaudhary Ketul R. , Yang Anli , Kesavan Kirishani , Wang Liyuan , Chathely Kevin , Stewart Duncan J. 
Published: October 2023

AbstractBackgroundPulmonary arterial hypertension (PAH) is a devastating disease caused by loss of effective lung microvasculature for which there is no curative treatment. Evidence from preclinical models and human disease-causing genetic mutations point to endothelial cell (EC) injury and apoptosis as a central trigger for the initiation of PAH. However, how EC apoptosis leads to pulmonary hypertension (PH) and complex arteriolar remodeling is uncertain.MethodsRats were subjected to SU5416-hypoxia (SUHx) and EC apoptosis, pulmonary vascular remodeling and arterial volume was assessed by immunohistochemistry, histology and microCT, respectively. Left pulmonary artery banding (LPAB) was performed, either 1 week before (prevention) or 5 weeks after SU injection (reversal), to study the effect of hemodynamic offloading.ResultsIn the SUHx model, EC apoptosis was markedly increased as early as 3 days post-SU, persisting through PAH development, and this was associated with a profound arterial pruning with reduction in lung arterial volume (∼80%). LPAB abrogated lung EC apoptosis in the banded left lung and prevented as well as reversed arteriolar pruning. Moreover, in the reversal protocol, removal of the band at 10 weeks resulted in improvement in pulmonary hemodynamics and RV function at 13 weeks.ConclusionThese data demonstrate that perturbed hemodynamic factors triggered by lung microvascular arteriolar loss play a requisite role in perpetuating endothelial injury in experimental PAH, leading to persistent arterial EC injury and disease progression. Importantly, vascular loss, arterial remodeling and PH are reversible once the cycle of perturbed hemodynamics and EC injury is broken by unilateral lung banding.
Neuroinflammation increases oxygen extraction in a mouse model of Alzheimer’s disease
Authors: Liu Chang , Cardenas-Rivera Alfredo , Teitelbaum Shayna , Birmingham Austin , Alfadhel Mohammed , Yaseen Mohammad A. 
Published: October 2023

AbstractNeuroinflammation, impaired metabolism, and hypoperfusion are fundamental pathological hallmarks of early Alzheimer’s disease (AD). Numerous studies have asserted a close association between neuroinflammation and disrupted cerebral energetics. During AD progression and other neurodegenerative disorders, a persistent state of chronic neuroinflammation reportedly exacerbates cytotoxicity and potentiates neuronal death. Here, we assessed the impact of a neuroinflammatory challenge on metabolic demand and microvascular hemodynamics in the somatosensory cortex of an AD mouse model. We utilized in vivo 2-photon microscopy and the phosphorescent oxygen sensor Oxyphor 2P to measure partial pressure of oxygen (pO2) and capillary red blood cell flux in cortical microvessels of awake mice. Intravascular pO2 and capillary RBC flux measurements were performed in 8-month-old APPswe/PS1dE9 mice and wildtype littermates on days 0, 7, and 14 of a 14-day period of lipopolysaccaride-induced neuroinflammation. Before the induced inflammatory challenge, AD mice demonstrated reduced metabolic demand but similar capillary red blood cell flux as their wild type counterparts. Neuroinflammation provoked significant reductions in cerebral intravascular oxygen levels and elevated oxygen extraction in both animal groups, without significantly altering red blood cell flux in capillaries. This study provides evidence that neuroinflammation alters cerebral oxygen demand at the early stages of AD without substantially altering vascular oxygen supply. The results will guide our understanding of neuroinflammation’s influence on neuroimaging biomarkers for early AD diagnosis.
A Bond-Anchored Network Structure Alignment (BANSA) Method for Graphical Analysis of Protein-Protein Interfacial Regions
Authors: Tam Justin , Chen Brian Y. 
Published: October 2023

AbstractWe introduce a method to analyze and compare intermolecular bonds formed between protein-protein interactions. Utilizing the DiffBond software, we calculate potential intermolecular bonds, such as ionic bonds, hydrogen bonds, and salt bridges, based on amino acid structural and spatial parameters. This results in a graphical representation of bonds termed a bond network for each protein pair interaction. We then introduce an innovative strategy, the Bond-anchored Network Structural Alignment (BANSA), to align these networks using bond formation as anchor points. This alignment process uses the Root Mean Square Deviation (RMSD) to quantitatively assess the similarity between molecular structures. We validate the BANSA approach using several forms of analysis including a heatmap analysis, which provides a consolidated view of the entire bond network as well as a thorough comparison with existing literature. The results highlight the method’s potential to offer insights into molecular interactions across various protein pairs without a need for direct modelling of protein-protein interactions.
Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation
Authors: Prabakaran Ashok Daniel , McFarland Kevin , Miz Karen , Durumutla Hima Bindu , Piczer Kevin , Soussi Fadoua El Abdellaoui , Latimer Hannah , Werbrich Cole , Blair N. Scott , Millay Douglas P , Prideaux Brendan , Finck Brian N , Quattrocelli Mattia 
Published: October 2023

AbstractSarcopenia burdens the elderly population through loss of muscle energy and mass, yet treatments to functionally rescue both parameters are missing. The glucocorticoid prednisone remodels muscle metabolism based on frequency of intake, but its mechanisms in sarcopenia are unknown. We found that once-weekly intermittent prednisone rescued muscle quality in aged 24-month-old mice to levels comparable to young 4-month-old mice. We discovered an age- and sex-independent glucocorticoid receptor transactivation program in muscle encompassing PGC1alpha and its co-factor Lipin1. Treatment coordinately improved mitochondrial abundance through isoform 1 and muscle mass through isoform 4 of the myocyte-specific PGC1alpha, which was required for the treatment-driven increase in carbon shuttling from glucose oxidation to amino acid biogenesis. We also probed the myocyte-specific Lipin1 as non-redundant factor coaxing PGC1alpha upregulation to the stimulation of both oxidative and anabolic capacities. Our study unveils an aging-resistant druggable program in myocytes to coordinately rescue energy and mass in sarcopenia.
Root Ions Fluxes and Osmolarity Changes in Grass Species Differing in Salinity Tolerance
Authors: Wang Liping , Elzenga Theo , Staal Marten 
Published: October 2023

AbstractAgricultural areas are increasingly being affected by salt due to irrigation practices and rising levels of salty groundwater. Different plant species have varying degrees of sensitivity to salinity and employ distinct mechanisms to avoid severe damage caused by salt stress. We compared three grass species with different ecological backgrounds, namelyLolium perenne, Festuca rubra, andPuccinellia maritima, in terms of their ability to maintain growth when exposed to salt stress, the extent of Na+-induced K+efflux, and the accumulation of salts in their shoots. Our results demonstrate that the changes in K+and H+fluxes at the root tip induced by NaCl exposure are correlated with the salt tolerance characteristics of these grass species. Specifically,L. perenneexhibited the highest leakage of K+from its roots, the highest accumulation of Na+in its shoots, and the lowest shoot growth under salt stress. On the other hand,P. maritimashowed minimal changes in ion fluxes in response to salinity stress.P. maritimamaintained the lowest contribution of Na+to the total osmolarity in its shoots and exhibited the least detrimental effect of salt on shoot dry matter. The root cortex including the exodermis and endodermis could be one of the benefit barriers that help defense against salts. In conclusion, root ions fluxes and osmolarity changes in grass species have different salinity tolerance of plants from various habitats. The salt resistance plants restrict leakage of K and exclude Na more effectively. Overall, these results broadened our knowledge of salt resistance in grass species.
Healthy ageing influences how the shape of alpha and beta oscillations change during reaction time tasks
Authors: Opie George M , Hughes James M , Puri Rohan 
Published: October 2023

AbstractAge-related changes to the power and frequency of the brains oscillatory activity have been reported by an extensive literature. In contrast, the influence of advancing age on theshapeof oscillation waveforms, a characteristic with increasingly recognised physiological and functional relevance, has not been previously investigated. To address this, we examined the shape of alpha and beta band oscillations from electroencephalography (EEG) data recorded during performance of simple and go/no-go reaction time tasks in 33 young (23.3 ± 2.9 years, 27 females) and 27 older (60.0 ± 5.2 years, 23 females) adults. The shape of individual cycles was characterised using instantaneous frequency, and then decomposed into waveform motifs using principal component analysis. This analysis identified four principal components (one from the alpha band, 3 from the beta band) that were uniquely influenced by the different motor tasks and/or age. These each described different dimensions of shape and tended to be modulated during the reaction phase of each task. However, the way in which each facet of shape varied during the task was unrelated to motor performance, indexed via reaction time, in either group or band. Our results suggest that although oscillation shape is task-dependent, the nature of this effect is altered by advancing age. While these outcomes demonstrate the utility of this approach for understanding the neurophysiological effects of ageing, future work that more clearly links these outcomes with function will be critical.
Life history traits mediate elevational adaptation in a perennial alpine plant
Authors: Pålsson Aksel , Walther Ursina , Fior Simone , Widmer Alex 
Published: October 2023

SummarySpatially divergent natural selection drives adaptation to contrasting environments and the evolution of ecotypes. Understanding this process in perennial plants is challenging because natural selection acts on multiple life history traits linked by fitness trade-offs.In a multi-year reciprocal transplant experiment of high and low elevation populations of the alpine carnationDianthus carthusianorumin the Central Alps, we tested how different stages of the life cycle contribute to adaptation. Moreover, we used matrix population models to infer the specific contributions of individual life stages to fitness, coupled with trade-off analyses.We found genotype x environment interactions consistent with elevational adaptation both in single fitness components linked to reproduction and survival, and in integrative fitness estimates. Adaptation at low elevation is driven by early reproduction, in contrast to an opposite strategy at high elevation. Adaptive life-history differences between populations originating from low and high elevations are mediated by environmental effects on plant growth and trade-offs between reproduction and survival.Our work reveals elevational ecotypes of the perennial alpine plantD. carthusianorumthat express alternative life history strategies in response to climatic differences shaping resource allocation.
Discarded sequencing reads uncover natural variation in pest resistance inThlaspi arvense
Authors: Galanti Dario , Jung Jun Hee , Müller Caroline , Bossdorf Oliver 
Published: October 2023

AbstractUnderstanding the genomic basis of natural variation in plant pest resistance is an important goal in plant science, but it usually requires large and labour-intensive phenotyping experiments. Here, we explored the possibility that non-target reads from plant DNA sequencing can serve as phenotyping proxies for addressing such questions. We used data from a whole-genome and -epigenome sequencing study of 207 natural lines of field pennycress (Thlaspi arvense) that were grown in a common environment and spontaneously colonized by aphids, mildew and other microbes. We found that the numbers of non-target reads assigned to the pest species differed between populations, had significant SNP-based heritability, and were associated with climate of origin and baseline glucosinolates content. Specifically, pennycress lines from cold and thermally fluctuating habitats, presumably less favorable to aphids, showed higher aphid DNA load, i.e. decreased aphid resistance. Genome-wide association analyses identified genetic variants at known defense genes but also novel genomic regions associated with variation in aphid and mildew DNA load. Moreover, we found several differentially methylated regions associated with pathogen loads, in particular differential methylation at transposons and hypomethylation in the promoter of a gene involved in stomatal closure, likely induced by pathogens. Our study provides first insights into the defense mechanisms ofThlaspi arvense, a rising crop and model species, and demonstrates that non-target whole genome sequencing reads, usually discarded, can be leveraged to estimate intensities of plant biotic interactions. With rapidly increasing numbers of large sequencing datasets worldwide, this approach should have broad application in fundamental and applied research.
An “alert state” ribosome population acts as a master regulator of cytokine-mediated processes
Authors: Dopler Anna , Alkan Ferhat , Malka Yuval , Hoefakker Kelly , Isaeva Olga I. , Kerkhoff Mandy , Gangaev Anastasia , Silva Joana , Ramalho Sofia , Hoekman Liesbeth , Altelaar Maarten , van der Kammen Rob , Yewdell Jonathan Wilson , Kvistborg Pia , Faller William James 
Published: October 2023

AbstractInflammatory cytokines are pivotal to immune responses. Upon cytokine exposure, cells enter an “alert-state” that enhances their visibility to the immune system. Here, we identified an “alert-state” subpopulation of ribosomes (ASRs) defined by the presence of the P-stalk. We show that ASRs are formed in response to cytokines linked to tumor immunity, and are involved in the preferential translation of mRNAs vital for the cytokine response.Mechanistically, ASRs are required for the efficient translation of transmembrane domains of receptor molecules involved in cytokine-mediated processes. Importantly, loss of the ASR prevents CD8+ T cell recognition and killing, and inhibitory cytokines like TGFβ hinder ASR formation, suggesting that the ASR is a central regulatory hub upon which multiple signals converge. Thus, the ASR is an essential mediator of the cellular rewiring that occurs following cytokine exposure, via the translational regulation of this process.
Measuring age-dependent viscoelastic properties of organelles, cells and organisms via Time-Shared Optical Tweezer Microrheology
Authors: Català-Castro Frederic , Ortiz-Vásquez Santiago , Martínez-Fernández Carmen , Pezzano Fabio , Garcia-Cabau Carla , Fernández-Campo Martín , Sanfeliu-Cerdán Neus , Jiménez-Delgado Senda , Salvatella Xavier , Ruprecht Verena , Frigeri Paolo-Antonio , Krieg Michael 
Published: October 2023

AbstractRecording the mechanical response of biological samples, the cell’s interior and complex fluids in general, would enable deeper understanding of cellular differentiation, ageing and drug discovery. Here, we present a time-shared optical tweezer microrheology (TimSOM) pipeline to determine the frequency- and age-dependent viscoelastic properties of biological materials. Our approach consists in splitting a single laser beam into two near-instantaneous time-shared optical traps to carry out simultaneous force and displacement measurements with sub-nanometer and sub-picoNewton accuracy during sinusoidal perturbations. Leveraging numerical and analytical models, we find solutions to commonly encountered deviations, to build a practical and robust nanorheometer. We demonstrate the versatility of the technique by 1) measuring the phase transitions of an ageing biomolecular condensate, 2) quantifying the complex viscoelastic properties of three intracellular compartments of zebrafish progenitor cells, and, 3) usingCaenorhabditis elegans, we uncover how mutations causing nuclear envelopathies soften the cytosol of intestinal cells during organismal age. Together, our advances afford rapid phenotyping of material properties inside cells and proteins blends, opening avenues for biomedical and drug screening applications.
Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs
Authors: Schmidlin  , Apodaca  , Newell  , Sastokas  , Kinsler  , Geiler-Samerotte  
Published: October 2023

AbstractThere is growing interest in designing multidrug therapies that leverage tradeoffs to combat resistance. Tradeoffs are common in evolution and occur when, for example, resistance to one drug results in sensitivity to another. Major questions remain about the extent to which tradeoffs are reliable, specifically, whether the mutants that provide resistance to a given drug all suffer similar tradeoffs. This question is difficult because the drug-resistant mutants observed in the clinic, and even those evolved in controlled laboratory settings, are often biased towards those that provide large fitness benefits. Thus, the mutations (and mechanisms) that provide drug resistance may be more diverse than current data suggests. Here, we perform evolution experiments utilizing lineage-tracking to capture a fuller spectrum of mutations that give yeast cells a fitness advantage in fluconazole, a common antifungal drug. We then quantify fitness tradeoffs for each of 774 evolved mutants across 12 environments, finding these mutants group into 6 classes with characteristically different tradeoffs. Their unique tradeoffs may imply that each group of mutants affects fitness through different underlying mechanisms. Some of the groupings we find are surprising. For example, we find some mutants that resist single drugs do not resist their combination, while others do. And some mutants to the same gene have different tradeoffs than others. These findings, on one hand, demonstrate the difficulty in relying on consistent or intuitive tradeoffs when designing multidrug treatments. On the other hand, by demonstrating that hundreds of adaptive mutations can be reduced to a few groups with characteristic tradeoffs, our findings may yet empower multidrug strategies that leverage tradeoffs to combat resistance. More generally speaking, by grouping mutants that likely affect fitness through similar underlying mechanisms, our work guides efforts to map the phenotypic effects of mutation.
A deep learning model embedded framework to distinguish DNA and RNA mutations directly from RNA-seq
Authors: Fu Zhi-Can , Gao Bao-Qing , Nan Fang , Ma Xu-Kai , Yang Li 
Published: October 2023

AbstractWe develop a stepwise computational framework, called DEMINING, to directlydetectexpressed DNA and RNAmutations in RNA deep sequencingdata. DEMINING incorporates a deep learning model named DeepDDR, which facilitates the separation of expressed DNA mutations from RNA mutations after RNA-seq read mapping and pileup. When applied in RNA-seq of acute myeloid leukemia patients, DEMINING uncovered previously-underappreciated DNA and RNA mutations, some associated with the upregulated expression of host genes or the production of neoantigens. Finally, we demonstrate that DEMINING could precisely classify DNA and RNA mutations in RNA-seq data from non-primate species through the utilization of transfer learning.