bluuebunny/crossref_metadata_2025_split huggingface dataset:
In search of a unifying theory of white matter aging: improving the understanding of tract-wise degeneration using multi-parametric signatures of morphometry and microstructure
Authors: Robinson Tyler D. , Sun Yutong L. , Chang Paul T. H. , Chen J. Jean 
Published: March 2023

ABSTRACTWhile tract-wise differences in volume and microstructure are common targets of investigation in age-related changes in the white matter (WM), there has been relatively little exploration into other attributes of tract morphometry or its relation to microstructure in vivo, and limited understanding on how they jointly inform the interpretation of the WM aging trajectory. This study examines ten WM tracts for tract-wise differences in morphometry (i.e. volume, length, and volume-to-length ratio) and microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) using diffusion MRI data from the Human Connectome Project in Aging (HCP-A) with the goal of laying the foundation for a unified model of age-related WM microstructure-morphometry trajectories with a special focus on sex differences. Results indicated widely heterogeneous patterns of decline and morphometry-microstructural associations across tracts. Multi-parametric signatures of decline suggest stages or mechanisms of degeneration that differ between sexes. This work highlights the value of integrating microstructural and morphometric measures of WM health instead of observing them separately, suggesting multiple modes of WM degeneration.
Rational design of immune gene therapy combinations viain vivoCRISPR activation screen of tumor microenvironment modulators
Authors: Wang Guangchuan , Zhang Feifei , Chow Ryan D. , He Emily , Zhu Lvyun , Han Qin , Chen Sidi 
Published: March 2023

AbstractThe hostile tumor microenvironment (TME) is major challenge for cancer immunotherapies. Here, we design and perform TME-targetedin vivoCRISPR activation (CRISPRa) screens to uncover factors that promote anti-tumor immunity, culminating in rationally designed immune gene therapy combinations. Through adeno-associated virus (AAV) delivery, multiplexed activation of pooled immunoregulatory genes encodingantigenpresentation,cytokine, and co-stimulationmolecules (APCM) leads to enhanced anti-tumor immunity. APCM screen in metastatic tumors identifiesCd80, Tnfsf14, Cxcl10, Tnfsf18, Tnfsf9, andIfngas the top immunostimulatory candidates. AAV-mediated delivery of these factors individually or in combination shows anti-tumor efficacy across different cancer models. Further optimization pinpointsIfng+Tnfsf9+Il12b(Il12/Il23)as a potent therapeutic combination, leading to increased IFN-γ+CD8+and tissue-resident memory T cells. APCM therapy synergizes with CAR-T cell therapy against human solid tumorsin vivo. APCM-based CRISPRa screen and gene activation systems can thus be leveraged for the rapid generation of off-the-shelf immune gene therapies against solid tumors.
Multiplexed inhibition of immunosuppressive genes with Cas13d for on-demand combinatorial cancer immunotherapy
Authors: Zhang Feifei , Guangchuan Wang , Chow Ryan , He Emily , Majety Medha , Zhang Yueqi , Chen Sidi 
Published: March 2023

AbstractCheckpoint blockade immunotherapy is a potent class of cancer treatment, however, the complex immunosuppressive tumor microenvironment (TME) often requires multi-agent combinations to be effective. Current cancer immunotherapy combination approaches are cumbersome, usually involving one-drug-at-a-time scheme. Here, we devise Multiplex Universal Combinatorial Immunotherapy via Gene-silencing (MUCIG), as a versatile approach for combinatorial cancer immunotherapy. We harness CRISPR-Cas13d to efficiently target multiple endogenous immunosuppressive genes on demand, allowing us to silence various combinations of multiple immunosuppressive factors in the TME. Intratumoral AAV-mediated administration of MUCIG (AAV-MUCIG) elicits significant anti-tumor activity with several Cas13d gRNA compositions. TME target expression analysis driven optimization led to a simplified off-the-shelf MUCIG targeting a four gene combination (PGGC:Pdl1, Galectin9, Galectin3andCd47). AAV-PGGC shows significantin vivoefficacy in syngeneic tumor models. Single cell and flow profiling revealed that AAV-PGGC remodeled the TME by increasing CD8+T cell infiltration and reducing myeloid-derived immunosuppressive cells (MDSCs). MUCIG thus serves as a universal method to silence multiple immune genesin vivo,and can be delivered via AAV as a therapeutic approach.
Divergent roles for caspase-8 and MLKL in high-fat diet induced obesity and NAFLD in mice
Authors: Tye Hazel , Conos Stephanie A. , Djajawi Tirta M. , Abdoulkader Nasteho , Kong Isabella Y. , Kammoun Helene L. , Narayana Vinod K. , Speir Mary , Gottschalk Timothy A. , Emery Jack , Simpson Daniel S. , Hall Cathrine , Vince Angelina J. , Russo Sophia , Crawley Rhiannan , Rashidi Maryam , Hildebrand Joanne M. , Murphy James M. , Whitehead Lachlan , De Souza David P. , Masters Seth L. , Hawkins Edwin D. , Murphy Andrew J. , Vince James E. , Lawlor Kate E. 
Published: March 2023

AbstractCell death frequently occurs in the pathogenesis of obesity and non-alcoholic fatty liver disease (NAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we showviathe direct comparison of mice genetically deficient in apoptotic caspase-8 in myeloid cells, or the essential necroptotic regulators, Receptor-interacting protein kinase-3 (RIPK3) and Mixed lineage kinase domain-like (MLKL), that RIPK3-caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and NAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and NAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport and metabolism and, congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease.
A brief real-time fNIRS-informed neurofeedback training of the prefrontal cortex changes brain activity and connectivity during subsequent working memory challenge
Authors: Yang Xi , Zeng Yixu , Jiao Guojuan , Gan Xianyang , Linden David , Hernaus Dennis , Zhu Chaozhe , Li Keshuang , Yao Dezhong , Yao Shuxia , Jiang Yihan , Becker Benjamin 
Published: March 2023

AbstractWorking memory (WM) represents a building-block of higher cognitive functions and a wide range of mental disorders are associated with WM impairments. Initial studies have shown that several sessions of functional nearinfrared spectroscopy (fNIRS) informed real-time neurofeedback (NF) allow healthy individuals to volitionally increase activity in the dorsolateral prefrontal cortex (DLPFC), a region critically involved in WM. For the translation to therapeutic or neuroenhancement applications, however, it is critical to assess whether fNIRS-NF success transfers into neural and behavioral WM enhancement in the absence of feedback. We therefore combined single-session fNIRS-NF of the left DLPFC with a randomized sham-controlled design (N = 62 participants) and a subsequent WM challenge with concomitant functional MRI. Over four runs of fNIRS-NF, the left DLPFC NF training group demonstrated enhanced neural activity in this region, reflecting successful acquisition of neural selfregulation. During the subsequent WM challenge, we observed no evidence for performance differences between the training and the sham group. Importantly, however, examination of the fMRI data revealed that - compared to the sham group - the training group exhibited significantly increased regional activity in the bilateral DLPFC and decreased left DLPFC - left anterior insula functional connectivity during the WM challenge. Exploratory analyses revealed a negative association between DLPFC activity and WM reaction times in the NF group. Together, these findings indicate that healthy individuals can learn to volitionally increase left DLPFC activity in a single training session and that the training success translates into WM-related neural activation and connectivity changes in the absence of feedback. This renders fNIRS-NF as a promising and scalable WM intervention approach that could be applied to various mental disorders.
TheRalstonia pseudosolanacearumeffector RipE1 is recognized at the plasma membrane byNbPtr1, Nicotiana benthamianahomolog ofPseudomonas tomato race 1
Authors: Kim Boyoung , Kim Injae , Yu Wenjia , Kim Haseong , Ahn Ye Jin , Sohn Kee Hoon , Macho Alberto P. , Segonzac Cécile 
Published: March 2023

AbstractThe bacterial wilt disease caused by soil-borne bacteria of theRalstonia solanacearumspecies complex (RSSC) threatens important crops worldwide. Only a few immune receptors conferring resistance to this devastating disease are known so far. Individual RSSC strains deliver around 70 different type III secretion system effectors into host cells to manipulate the plant physiology and dampen immune responses. RipE1 is an effector conserved across RSSC isolated from diverse plant species and triggers immune responses in the model SolanaceaeNicotiana benthamiana. Here, we used multiplexed virus-induced gene silencing of the nucleotide-binding and leucine-rich repeat receptor family to identify the genetic basis of RipE1 recognition inN. benthamiana. Specific silencing of theN. benthamianahomolog ofSolanum lycopersicoides Pseudomonas tomato race 1gene (NbPtr1) completely abolished RipE1-induced hypersensitive response and immunity toRalstonia pseudosolanacearum. In Nb-ptr1knock-out plants, expression of the nativeNbPtr1coding sequence was sufficient to restore RipE1 recognition. In addition to the putative catalytic triad Cys-His-Asp, RipE1 association with the host cell plasma membrane was found necessary for NbPtr1-dependent recognition. Furthermore, we found that NbPtr1-dependent recognition of RipE1 natural variants is polymorphic suggesting the coevolutionary nature of this interaction. This work hence provides an additional evidence for the indirect mode of activation of NbPtr1 and supports NbPtr1 relevance for resistance to bacterial wilt disease in Solanaceae.
Clonality-Related Traits Add Independent Specialization Axes to Herbs’ Trait Strategies
Authors: Chelli Stefano , Klimešová Jitka , Tsakalos James Lee , Puglielli Giacomo 
Published: March 2023

AbstractThe functional diversity of vascular plants is remarkable. Yet, previous studies showed that trait trade-offs constrain aboveground or fine-root trait variation. How do neglected functions such as resprouting and clonal growth, key for fitness maintenance in some plant groups, integrate in these trait frameworks? By using an extensive dataset (> 2000 species) spanning aboveground, fine-root and clonality-related traits of herbs, we asked whether clonal traits relate to species positioning in the aboveground or fine-root trait spaces. Clonal and non-clonal herbs were undistinguishable in the aboveground or fine-root trait spaces. Clonality-related traits were also weakly coordinated with the other trait dimensions. Altogether, these results suggest that clonality-related traits add independent functional specialization axes to plants’ trait strategies. We identified two potential specialization axes in clonal traits. The first axis summarizes the positive scaling between bud bank size and persistence of clonal connections, reflecting species specialization for on-spot persistence and tolerance to disturbance (persistenceaxis). The second axis, summarizes the positive scaling between multiplication rate and lateral spread, reflecting specialization for clonal multiplication and acquiring new space in horizontal dimension (clonal multiplicationaxis). We call for integrating these axes in existing strategy schemes to fully elucidate the multidimensional trait strategies of plants.
Limits to the adaptation of herbivorous spider mites to metal accumulation in homogeneous and heterogeneous environments
Authors: Godinho Diogo P. , Fragata Inês , Majer Agnieszka , Rodrigues Leonor R. , Magalhães Sara 
Published: March 2023

AbstractMetal accumulation is used by some plants as a defence against herbivores. Yet, herbivores may adapt to these defences, becoming less susceptible. Moreover, ecosystems often contain plants that do and do not accumulate metals, and such heterogeneity may affect herbivore adaptation. Surprisingly, few studies have tested this. Tomato plants accumulate cadmium, affecting the performance of the herbivorous spider miteTetranychus evansi. Here, we performed experimental evolution to test whether these mites adapt to plants with high cadmium concentrations, in homogeneous (plants with cadmium) or heterogeneous (plants with and without cadmium) environments. We measured fecundity, hatching rate and the number of adult offspring after 12 and 33 generations and habitat choice after 14 and 51 generations, detecting no trait change, which implies absence of adaptation. We then tested whether this absence of adaptation was due to a lack of genetic variation in the traits measured and, indeed, additive genetic variance was low for the measured traits. Possibly, we did not measure the traits that contributed to population persistence on plants with cadmium. Interestingly, despite no signs of adaptation we observed a decrease in fecundity and number of adult offspring produced in cadmium-free plants, in the populations evolving in environments with cadmium. Being this the case, evolving in environments with cadmium may reduce the growth rate of spider mite populations on non-accumulating plants as well. Nevertheless, adaptation to metal accumulation may occur via herbivore traits not commonly measured, which calls for broader studies on this topic.
What Strengthens Protein-Protein Interactions: Analysis and Applications of Residue Correlation Networks
Authors: Hung Ta I , Hsieh Yun-Jung , Lu Wei-Lin , Wu Kuen-Phon , Chang Chia-en A. 
Published: March 2023

AbstractIdentifying critical residues in protein-protein binding and efficiently designing stable and specific protein binders is challenging. In addition to direct contacts in a protein-protein binding interface, our study employs computation modeling to reveal the essential network of residue interaction and dihedral angle correlation critical in protein-protein recognition. We propose that mutating residues regions exhibited highly correlated motions within the interaction network can efficiently optimize protein-protein interactions to create tight and selective protein binders. We validated our strategy using ubiquitin (Ub) and MERS coronaviral papain-like protease (PLpro) complexes, where Ub is one central player in many cellular functions and PLpro is an antiviral drug target. Our designed UbV with 3 mutated residues resulted in a ∼3,500-fold increase in functional inhibition, compared with the wild-type Ub. Further optimization by incorporating 2 more residues within the network, the 5-point mutant achieved a KDof 1.5 nM and IC50of 9.7 nM. The modification led to a 27,500-fold and 5,500-fold enhancements in affinity and potency, respectively, as well as improved selectivity, without destabilizing the UbV structure. Our study highlights residue correlation and interaction networks in protein-protein interaction, introduces an effective approach to design high affinity protein binders for cell biology and future therapeutics solutions.
Uptake of plant-derived carbon and proximity to the root determine differences in temporal and spatial stability among microbial groups
Authors: Lange Markus , Azizi-Rad Mina , Dittmann Georg , Lange Dan Frederik , Orme Alice May , Schroeter Simon Andreas , Simon Carsten , Gleixner Gerd 
Published: March 2023

AbstractThe interactions between plants and soil microorganisms are fundamental for ecosystem functioning. However, it remains unclear if seasonality of plant growth impacts plant-microbial interactions, such as by inducing shifts in the microbial community composition, their biomass, or changes in the microbial uptake of plant-derived carbon. Here, we investigate the stability of microbial biomass of different functional groups and their net assimilation of plant-derived carbon over an entire growing season. Using a C3-C4 vegetation change experiment, and taking advantage of natural abundances of13C, we measured the plant-derived carbon in lipid biomarkers of soil microorganisms in rhizosphere and non-rhizosphere soil. We found that temporal and spatial stability was higher in bacterial than in fungal biomass, while the high temporal stability of all bacterial groups even increased in close proximity to roots. Moreover, differences in the association to plants, i.e., symbionts vs. free-living microorganisms, tend to determine the stability in the uptake of plant-derived carbon. Our results indicate, the inputs of plant-derived carbon over the growing season did not result in a shift in the microbial community composition, but instead, functional groups that are not in obligate symbiosis with plants showed a varying use of soil- and plant-derived carbon.
The search for CDK4/6 inhibitor biomarkers has been hampered by inappropriate proliferation assays
Authors: Foy Reece , Lew Kah Xin , Saurin Adrian T 
Published: March 2023

SUMMARYCDK4/6 inhibitors arrest the cell cycle in G1 and are used in combination with hormone therapy to treat advanced HR+/HER- breast cancer. To allow more effective use of these drugs in breast cancer, and to facilitate their use in other tumour types, biomarkers that can predict response are urgently needed. We demonstrate here that previous large-scale screens designed to identify the most sensitive tumour types and genotypes have misrepresented the responsive cell lines because of a reliance on ATP-based proliferation assays. When cells arrest in G1 following CDK4/6 inhibition, they continue to grow in size, producing more mitochondria and ATP. This cellular overgrowth masks an efficient arrest using metabolic ATP-based assays, but not if DNA-based assays are used instead. By comparing tumour cells using different assay types, we demonstrate that the lymphoma lines previously identified as the most responsive cell types, simply appear to respond the best because they fail to overgrow during the G1 arrest. Similarly, the CDK4/6 inhibitor abemaciclib appears to inhibit proliferation better than palbociclib, but this is because it also inhibits cell overgrowth through off-target effects. DepMap analysis of previous screening data using only the reliable assay types, demonstrates that palbociclib-sensitivity is associated with sensitivity to Cyclin D1, CDK4 and CDK6 knockout/knockdown, and resistance is associated with sensitivity to Cyclin E1, CDK2 and SKP2 knockout/knockdown. Furthermore, potential biomarkers of palbociclib-sensitivity are increased expression of Cyclin D1 (CCND1) and RB1, and reduced expression of Cyclin E1 (CCNE1) and CDKN2A. None of these associations are present when analysing DepMap using similar data from metabolic assays. This reinforces the importance of new screens to assess CDK4/6 inhibitors, and potentially other anti-cancer drugs, against a wide range of cell types using an appropriate proliferation assay. This would help to better inform clinical trials and to identify much needed biomarkers of response.
Ontogenetic modifications produce similar phenotypes in distantly related click beetles (Coleoptera: Elateridae)
Authors: Kusy Dominik , Motyka Michal , Bocak Ladislav 
Published: March 2023

AbstractThe study analyzes the relationships of click beetles (Elateridae)PaulusiellaLöbl, 2007, andAnalestesaLeach, 1824 (=CebriognathusChobaut, 1899), both incapable of jumping, with soft-bodied habitus, and unknown females. Due to divergent morphology, their positions have been an uncertain issue. We use mitochondrial genomes to test their current placement in Cebrionini (=Cebriognathini) and Elaterinaeincertae sedis, respectively. We recoverPaulusiellaas a sister toHemiopsLaporte, 1838 (Hemiopinae) andAnalestesaas one of the serially splitting branches in Cardiophorinae, both with robust support. Paulusiellinaesubfam. nov. is proposed forPaulusiella. Analestesais transferred to Cardiophorinae, and Cebriognathini Paulus, 1981, an earlier synonym of Elaterinae: Cebrionini, is a synonym of Cardiophorinae Candèze, 1859. The click beetles affected by ontogenetic modifications converge to similar forms lacking derived states. As a result, their phylogenetic position cannot be reliably inferred by morphological analyses and needs to be validated by molecular data. Paulusiellinae andAnalestesarepresent two additional cases of the shift to incomplete sclerotization in elaterids raising the total number to six. The present transfers of extant taxa between subfamilies call for a cautious interpretation of morphology in other soft-bodied groups, including the taxa described from amber deposits.
A mathematical model of the disruption of glucose homeostasis in cancer patients
Authors: Salentine Noah , Doria Jonathan , Nguyen Chinh , Pinter Gabriella , Wang Shizhen Emily , Hinow Peter 
Published: March 2023

AbstractIn this paper we investigate the disruption of the glucose homeostasis at the whole-body level by the presence of cancer disease. Of particular interest are the potentially different responses of patients with or without hyperglycemia (including Diabetes Mellitus) to the cancer challenge, and how tumor growth, in turn, responds to hyperglycemia and its medical management. We propose a mathematical model that describes the competition between cancer cells and glucosedependent healthy cells for a shared glucose resource. We also include the metabolic reprogramming of healthy cells by cancer-cell-initiated mechanism to reflect the interplay between the two cell populations. We parametrize this model and carry out numerical simulations of various scenarios, with growth of tumor mass and loss of healthy body mass as endpoints. We report sets of cancer characteristics that show plausible disease histories. We investigate parameters that change cancer cells’ aggressiveness, and we exhibit differing responses in diabetic and non-diabetic, in the absence or presence of glycemic control. Our model predictions are in line with observations of weight loss in cancer patients and the increased growth (or earlier onset) of tumor in diabetic individuals. The model will also aid future studies on countermeasures such as the reduction of circulating glucose in cancer patients.