bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human USP18 protects diverse cancer lineages from Type I Interferon independently of its canonical catalytic function
Authors: Jové Veronica , Wheeler Heather , Lee Chiachin Wilson , Healy David R. , Levine Kymberly , Ralph Erik C. , Yang Bing , Giddabasappa Anand , Loria Paula , Yamaguchi Masaya , Casimiro-Garcia Agustin , Kessler Benedikt M. , Pinto-Fernández Adán , Frattini Véronique , Wes Paul D. , Wang Feng 
Published: March 2023

ABSTRACTPrecise temporal regulation of Type I interferon signaling is imperative to effectively fight infections and cancerous cells without triggering autoimmunity. The key negative regulator of Type I interferon signaling is ubiquitin-specific protease 18 (USP18). USP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and directly inhibits interferon receptor signaling through its scaffold role.USP18loss-of-function dramatically impacts autoimmune disease, viral susceptibility, and cancer cell survival. However, the relative contribution of catalytic versus scaffold function is unresolved and must be determined to design effective therapeutics targeting USP18. To precisely delineate individual contribution, we evaluated the functional impact of single amino acid mutations that disrupt catalytic or scaffold activity. Here we demonstrate catalytic activity does not contribute to cell autonomous Type I interferon sensitivity across multiple cancer cell lineages. Furthermore, introducing a patient-derived mutation that disrupts scaffold function is sufficient to inhibit cancer growth. These findings establish a fundamental mechanistic basis for USP18 therapeutic design across diseases.OVERVIEWUSP18 is the key negative regulator of Type I interferon signaling in humans, mediating autoimmune disease, viral susceptibility, and cancer cell survival.USP18 cleaves interferon-inducible ubiquitin-like modifications through its canonical catalytic function and attenuates interferon receptor signaling through its scaffold role.Delineating the contribution of each function is critical to resolve the mechanistic basis of interferon regulation and enable the development of therapeutics targeting USP18.We demonstrate that cell intrinsic interferon sensitivity is not mediated by loss of catalytic activity. However, disruption of scaffold function by a patient-specific mutation inhibits cancer cell growth.Furthermore, we discovered that canonical catalytic activity is surprisingly inefficient in human cells.These results clarify a fundamental mechanism of immune regulation and cancer cell survival in humans.Abstract Figure
MutationExplorer- a webserver for mutation of proteins and 3D visualization of energetic impacts
Authors: Philipp Michelle , Moth Christopher W. , Ristic Nikola , Tiemann Johanna K.S. , Seufert Florian , Panfilova Aleksandra , Meiler Jens , Hildebrand Peter W. , Stein Amelie , Wiegreffe Daniel , Staritzbichler René 
Published: March 2023

AbstractThe possible effects of mutations on stability and function of a protein can only be understood in the context of protein 3D structure. The MutationExplorerwebserver maps sequence changes onto protein structures and allows users to study variation by inputting sequence changes. As the user enters variants, the 3D model evolves, and estimated changes in energy are highlighted. In addition to a basic per-residue input format, MutationExplorercan also upload an entire replacement sequence. Previously the purview of desktop applications, such an upload can back-mutate PDB structures to wildtype sequence in a single step. Another supported variation source is human single nucelotide polymorphisms (SNPs), genomic coordinates input in VCF format.Structures are flexibly colorable, not only by energetic differences, but also by hydrophobicity, sequence conservation, or other biochemical profiling. Coloring by interface score reveals mutation impacts on binding surfaces.MutationExplorerstrives for efficiency in user experience. For example, we have prepared 45,000 PDB depositions for instant retrieval and initial display. All modeling steps are performed by Rosetta. Visualizations leverage MDsrv/Mol*. MutationExploreris available at:http://proteinformatics.org/mutation_explorer/
High versatility to meet conservation targets for biodiversity and hydrological services at the Riviera Maya, Quintana Roo, Mexico
Authors: Aguilar-Sánchez Juan Alberto , Kolb Melanie 
Published: March 2023

AbstractThe ecosystem services (ES) framework has been proposed as an alternative to face the multiple challenges presented by biodiversity conservation, but the spatial conservation priorities of ES have been found to show low concordance levels with areas of high importance for biodiversity, which can lead to conflict during reserve design. To address this problem, the use of quantitative methods derived from systematic conservation planning has been proposed to identify spatial solutions that achieve the simultaneous representation of both elements in a spatially efficient manner. The aim of this study is to evaluate the differences between priority sites for biodiversity and hydrological ecosystem services (HES) using spatial prioritization models and to identify opportunities for co-benefits that allow an efficient conservation planning proposal, using as a case study the Riviera Maya, Mexico. The following hypothesis were tested by comparing models based on the prioritization algorithm Marxan: (1) Priority sites for biodiversity and HES are different, (2) HES priority sites adequately represent biodiversity conservation targets, and (3) integrating HES and biodiversity into one model is more efficient for representing conservation targets than combining the individual models for both elements. The results confirm: (1) Biodiversity and HES priority sites have different spatial patterns, sharing only 24% of priority sites, (2) HES priority sites achieve a high percentage (95%) of biodiversity conservation targets, showing that they can potentially be used for biodiversity representation, and (3) integrating HES and biodiversity into one model is more efficient to represent conservation targets than considering both elements individually (46% vs 66% of the study area). As there are no irreplaceable sites for biodiversity conservation, and less than 8% of the study area is covered by protected areas, there are clearly opportunities to align biodiversity and HES conservation actions at the Riviera Maya, Mexico. Despite the high context dependency of the spatial distribution of priority sites for biodiversity and HES, this study shows that the integration of conservation targets of both in the planning process can provide a solution to represent a high number of biodiversity and HES conservation targets.
Stability of brain-behavior correlation patterns across measures of social support
Authors: Merritt Haily , Faskowitz Joshua , Gonzalez Marlen Z. , Betzel Richard F. 
Published: March 2023

AbstractThe social environment has a critical influence on human development, cognition, and health. By using network approaches to map and analyze the connectivity between all pairs of brain regions simultaneously, we can clarify how relationships between brain regions (e.g. connectivity) change as a function of social relationships. Here we apply multilayer modeling and modularity maximization–both established tools in network neuroscience–to jointly cluster patterns of brain-behavior associations for seven social support measures. Our analyses build on both neuroecological findings and network neuroscientific approaches. In particular we find that subcortical and control systems are especially sensitive to different constructs of perceived social support. Network nodes in these systems are highly flexible; their community affiliations, which reflect groups of nodes with similar patterns of brain behavior associations, differ across social support measures. The multilayer approach used here enables direct comparison of the roles of all regions of the brain across all social support measures included. Additionally, our application of multilayer modeling to patterns of brainbehavior correlations, as opposed to just functional connectivity, represents an innovation in how multilayer models are used in. More than that, it offers a generalizable technique for studying the stability brain-behavior correlations.
Multi-Scale Spiking Network Model of Human Cerebral Cortex
Authors: Pronold Jari , van Meegen Alexander , Vollenbröker Hannah , Shimoura Renan O. , Senden Mario , Hilgetag Claus C. , Bakker Rembrandt , van Albada Sacha J. 
Published: March 2023

AbstractAlthough the structure of cortical networks provides the necessary substrate for their neuronal activity, the structure alone does not suffice to understand it. Leveraging the increasing availability of human data, we developed a multi-scale, spiking network model of human cortex to investigate the relationship between structure and dynamics. In this model, each area in one hemisphere of the Desikan-Killiany parcellation is represented by a 1 mm2column with a layered structure. The model aggregates data across multiple modalities, including electron microscopy, electrophysiology, morphological reconstructions, and DTI, into a coherent framework. It predicts activity on all scales from the single-neuron spiking activity to the area-level functional connectivity. We compared the model activity against human electrophysiological data and human resting-state fMRI data. This comparison reveals that the model can reproduce aspects of both spiking statistics and fMRI correlations if the cortico-cortical connections are sufficiently strong. Furthermore, we show that a single-spike perturbation propagates through the network within a time close to the limit imposed by the delays.
CDH1 loss promotes diffuse-type gastric cancer tumorigenesis via epigenetic reprogramming and immune evasion
Authors: Zou Gengyi , Huang Yuanjian , Zhang Shengzhe , Ko Kyung-Pil , Kim Bongjun , Zhang Jie , Venkatesan Vishwa , Pizzi Melissa P. , Fan Yibo , Jun Sohee , Niu Na , Wang Huamin , Song Shumei , Ajani Jaffer A. , Park Jae-Il 
Published: March 2023

SummaryThis study investigates diffuse-type gastric adenocarcinoma (DGAC), a deadly and treatment-resistant cancer. It reveals that CDH1 inactivation occurs in a subset of DGAC patient tumors, leading to the identification of two distinct DGAC subtypes. The findings emphasize the importance of understanding DGAC’s molecular diversity for personalized medicine in patients with CDH1 inactivation.
Western diet dampens T regulatory cell function to fuel hepatic inflammation in nonalcoholic fatty liver disease
Authors: Chaudhary Sudrishti , Rai Ravi , Pal Pabitra B. , Tedesco Dana , Singhi Aatur D. , Monga Satdarshan P. , Grakoui Arash , Iyer Smita S. , Raeman Reben 
Published: March 2023

ABSTRACTBackground and aimsThe immunosuppressive T regulatory cells (Tregs) regulate immune responses and maintain immune homeostasis, yet their functions in nonalcoholic fatty liver disease (NAFLD) pathogenesis remains controversial.MethodsMice were fed a normal diet (ND) or a western diet (WD) for 16 weeks to induce NAFLD. Diphtheria toxin injection to deplete Tregs in Foxp3DTRmice or Treg induction therapy in WT mice to augment Treg numbers was initiated at twelve and eight weeks, respectively. Liver tissues from mice and NASH human subjects were analyzed by histology, confocal imaging, and qRT-PCR.ResultsWD triggered accumulation of adaptive immune cells, including Tregs and effector T cells, within the liver parenchyma. This pattern was also observed in NASH patients, where an increase in intrahepatic Tregs was noted. In the absence of adaptive immune cells in Rag1 KO mice, WD promoted accumulation of intrahepatic neutrophils and macrophages and exacerbated hepatic inflammation and fibrosis. Similarly, targeted Treg depletion exacerbated WD-induced hepatic inflammation and fibrosis. In Treg-depleted mice, hepatic injury was associated with increased accumulation of neutrophils, macrophages, and activated T cells within the liver. Conversely, induction of Tregs using recombinant IL2/αIL2 mAb cocktail reduced hepatic steatosis, inflammation, and fibrosis in WD-fed mice. Analysis of intrahepatic Tregs from WD-fed mice revealed a phenotypic signature of impaired Treg function in NAFLD.Ex vivofunctional studies showed that glucose and palmitate, but not fructose, impaired the immunosuppressive ability of Treg cells.ConclusionsOur findings indicate that the liver microenvironment in NAFLD impairs ability of Tregs to suppress effector immune cell activation, thus perpetuating chronic inflammation and driving NAFLD progression. These data suggest that targeted approaches aimed at restoring Treg function may represent a potential therapeutic strategy for treating NAFLD.Lay summaryIn this study, we elucidate the mechanisms contributing to the perpetuation of chronic hepatic inflammation in nonalcoholic fatty liver disease (NAFLD). We show that dietary sugar and fatty acids promote chronic hepatic inflammation in NAFLD by impairing immunosuppressive function of regulatory T cells. Finally, our preclinical data suggest that targeted approaches aimed at restoring T regulatory cell function have the potential to treat NAFLD.
TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy
Authors: Edwards George A. , Wood Caleb A. , Nguyen Quynh , Kim Peter J. , Gomez-Gutierrez Ruben , Park Kyung-Won , Zurhellen Cody , Al-Ramahi Ismael , Jankowsky Joanna L. 
Published: March 2023

AbstractTMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimer’s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation.
Poly(A) tail length regulation by mRNA deadenylases is critical for suppression of transposable elements
Authors: Wang Ling , Li Hui , Lei Zhen , Yan Mengxiao , Wang Yuqin , Zhao Jiamin , Wang Hongxia , Yang Jun , Cho Jungnam 
Published: March 2023

AbstractTransposons are mobile genetic elements that can impair the host genome stability and integrity. In plants, suppression of transposons is thought to be mediated mainly by small RNAs; however, the role of RNA decay in posttranscriptional repression of transposons is unknown. Here we show that RNA deadenylation is critical for controlling transposons inArabidopsis. Previously, we demonstrated that transposon RNAs often harbor structural aberrancy owing to its inherently suboptimal codon usage and ribosome stalling. Such RNA aberrancy is monitored and resolved by RNA decay which is initiated by removal of poly(A) tail or deadenylation. The CCR4-NOT complex is a primary RNA deadenylase inArabidopsis, and we found that it is required for stable repression of transposons. Intriguingly, RNA deadenylation controls transposons that are not targeted by cytoplasmic secondary small RNAs, which implies a target-specific regulation of transposon by the host. Our study suggests a previously unknown mechanism for transposon repression mediated by RNA deadenylation and unveils a complex nature of the host’s strategy to maintain the genome integrity.
Glycosylation-modified antigens as a tolerance-inducing vaccine platform prevent anaphylaxis in a pre-clinical model of food allergy
Authors: Cao Shijie , Maulloo Chitavi D. , Raczy Michal M. , Sabados Matthew , Slezak Anna J. , Nguyen Mindy , Solanki Ani , Wallace Rachel P. , Shim Ha-Na , Wilson D. Scott , Hubbell Jeffrey A. 
Published: March 2023

SummaryThe only FDA-approved oral immunotherapy for a food allergy provides protection against accidental exposure to peanuts. However, this therapy often causes discomfort or side effects and requires long-term commitment. Better preventive and therapeutic solutions are urgently needed. We have developed a tolerance-inducing vaccine technology that utilizes glycosylation-modified antigens to induce antigen-specific non-responsiveness. The glycosylation-modified antigens were administered intravenously (i.v.) or subcutaneously (s.c.) and were found to traffic to the liver or lymph nodes, respectively, leading to preferential internalization by antigen-presenting cells, educating the immune system to respond in an innocuous way. In a mouse model of cow’s milk allergy, treatment with glycosylation-modified β- lactoglobulin (BLG) was effective in preventing the onset of allergy. In addition, s.c. administration of glycosylation-modified BLG showed superior safety and potential in treating existing allergies in combination with an anti-CD20 co-therapy. This platform may provide an antigen-specific immunomodulatory strategy to prevent and treat food allergies.
Developmental exposure to polychlorinated biphenyls prevents recovery from noise-induced hearing loss and disrupts the functional organization of the inferior colliculus
Authors: Ibrahim Baher A. , Louie Jeremy , Shinagawa Yoshitaka , Xiao Gang , Asilador Alexander R. , Sable Helen J. K. , Schantz Susan L. , Llano Daniel A. 
Published: March 2023

AbstractExposure to combinations of environmental toxins is growing in prevalence, and therefore understanding their interactions is of increasing societal importance. Here, we examined the mechanisms by which two environmental toxins – polychlorinated biphenyls (PCBs) and high-amplitude acoustic noise – interact to produce dysfunction in central auditory processing. PCBs are well-established to impose negative developmental impacts on hearing. However, it is not known if developmental exposure to this ototoxin alters the sensitivity to other ototoxic exposures later in life. Here, male mice were exposed to PCBs in utero, and later as adults were exposed to 45 minutes of high-intensity noise. We then examined the impacts of the two exposures on hearing and the organization of the auditory midbrain using two-photon imaging and analysis of the expression of mediators of oxidative stress. We observed that developmental exposure to PCBs blocked hearing recovery from acoustic trauma. In vivo two-photon imaging of the inferior colliculus revealed that this lack of recovery was associated with disruption of the tonotopic organization and reduction of inhibition in the auditory midbrain. In addition, expression analysis in the inferior colliculus revealed that reduced GABAergic inhibition was more prominent in animals with a lower capacity to mitigate oxidative stress. These data suggest that combined PCBs and noise exposure act nonlinearly to damage hearing and that this damage is associated with synaptic reorganization, and reduced capacity to limit oxidative stress. In addition, this work provides a new paradigm by which to understand nonlinear interactions between combinations of environmental toxins.Significance statementExposure to common environmental toxins is a large and growing problem in the population. This work provides a new mechanistic understanding of how the pre-and postnatal developmental changes induced by polychlorinated biphenyls could negatively impact the resilience of the brain to noise-induced hearing loss later in adulthood. The use of state-of-the-art tools, including in vivo multiphoton microscopy of the midbrain helped in identifying the long-term central changes in the auditory system after the peripheral hearing damage induced by such environmental toxins. In addition, the novel combination of methods employed in this study will lead to additional advances in our understanding of mechanisms of central hearing loss in other contexts.
Atomistic molecular simulations of Aβ-Zn conformational ensembles
Authors: Aduriz-Arrizabalaga Julen , Lopez Xabier , De Sancho David 
Published: March 2023

AbstractThe amyloid-forming Aβpeptide is able to interact with metal cations to form very stable complexes that influence fibril formation and contribute to the onset of Alzheimer’s disease. Multiple structures of peptides derived from Aβin complex with different metals have been resolved experimentally to provide an atomic-level description of the metal-protein interactions. However, Aβis intrinsically disordered, and hence more amenable to an ensemble description. Molecular dynamics simulations can now reach the timescales needed to generate ensembles for this type of complexes. However, this requires accurate force fields both for the protein and the protein-metal interactions. Here we use state-of-the-art methods to generate force field parameters for the Zn(II) cations in a set of Aβcomplexes and combine them with the Amber99SB⋆-ILDN optimized force field. Upon comparison of NMR experiments with the simulation results, further optimized with a Bayesian/Maximum entropy approach, we provide an accurate description of the molecular ensembles for most Aβ-metal complexes. We find that the resulting conformational ensembles are more heterogeneous than the NMR models deposited in the Protein Data Bank.
Forecasting dynamics of a recolonizing wolf population under different management strategies
Authors: Petracca Lisanne S. , Gardner Beth , Maletzke Benjamin T. , Converse Sarah J. 
Published: March 2023

ABSTRACTSpecies recovery can be influenced by a wide variety of factors, such that predicting the spatiotemporal dynamics of recovering species can be exceedingly difficult. These predictions, however, are valuable for decision makers tasked with managing species and determining their legal status. We applied a novel spatially explicit projection model to estimate population viability of gray wolves (Canis lupus) from 2021-2070 in Washington State, USA, where wolves have been naturally recolonizing since the establishment of the first resident pack in 2008. Using this model, we predicted the effects of 12 scenarios of interest relating to management actions (e.g., lethal removals, translocation, harvest) and system uncertainties (e.g., immigration from out of state, disease) on the probability of meeting Washington’s wolf recovery goals, along with other metrics related to population status. Population recovery was defined under Washington’s Wolf Conservation and Management Plan as four breeding pairs in each of three recovery regions and three additional breeding pairs anywhere in the state. The baseline, translocation, and 50% immigration scenarios indicated a high (>60%) probability of wolf recovery in Washington over the next 50 years, but scenarios related to harvest mortality (removal of 5% of the population every six months), increased lethal removals (removal of 30% of the population every four years), and cessation of immigration from out of state resulted in low probabilities (0.07, 0.12, and 0.12, respectively) of meeting recovery goals across all years (2021-2070). All but one management scenarios exhibited a geometric mean of population growth that was ≥1, indicating long-term population stability or growth, depending on the scenario. Our results suggest that wolves will continue to recolonize Washington and that recovery goals will be met so long as harvest and lethal removals are not at unsustainable levels and adjacent populations support immigration into Washington.