bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein fusion strategies for a multi-component Rieske oxygenase
Authors: Runda Michael E. , Miao Hui , Schmidt Sandy 
Published: June 2024

ABSTRACTRieske oxygenases (ROs) are enzyme systems involved in microbial biodegradation or late-stage modifications during natural product biosynthesis. A major obstacle to working with ROs is their dependence on multi-component electron transfer chains (ETCs). Thereby, electrons from NAD(P)H are shuttled directly via a reductase (Red) or indirectly via an additional ferredoxin (Fd) to a terminal oxygenase (Oxy) for oxygen activation and subsequent substrate conversion. The present work evaluates potential fusion strategies to simplify the ETC of the three-component cumene dioxygenase (CDO) fromPseudomonas fluorescence. Inin vitroreactions, the fusion of CDO-Red to CDO-Fd is the most suitable for activation of CDO-Oxy with product formation of approximately 22 mM (72 % conversion). Furthermore, protein fusion to CDO-Oxy was found to be feasible, highlighting the versatility of the redox partner fusion approach. Overall, this study aims to contribute to the research field of ROs by providing a promising strategy to simplify their multi-component nature.
Gangliosides in neural stem cell fate determination and nerve cell specification--preparation and administration
Authors: Itokazu Yutaka , Ariga Toshio , Fuchigami Takahiro , Li Dongpei 
Published: June 2024

AbstractGangliosides are sialylated glycosphingolipids with essential but enigmatic functions in healthy and disease brains. GD3 is the predominant species in neural stem cells (NSCs) and GD3-synthase (sialyltransferase II;St8Sia1) knockout (GD3S-KO) revealed reduction of postnatal NSC pools with severe behavioral deficits including cognitive impairment, depression-like phenotypes, and olfactory dysfunction. Exogenous administration of GD3 significantly restored the NSC pools and enhanced the stemness of NSCs with multipotency and self-renewal, followed by restored neuronal functions. Our group discovered that GD3 is involved in the maintenance of NSC fate determination by interacting with epidermal growth factor receptors (EGFRs), by modulating expression of cyclin-dependent kinase (CDK) inhibitors p27 and p21, and by regulating mitochondrial dynamics via associating a mitochondrial fission protein, the dynamin-related protein-1 (Drp1). Furthermore, we discovered that nuclear GM1 promotes neuronal differentiation by an epigenetic regulatory mechanism. GM1 binds with acetylated histones on the promoter ofN-acetylgalactosaminyltransferase (GalNAcT; GM2 synthase (GM2S); B4galnt1)as well as on theNeuroD1in differentiated neurons. In addition, epigenetic activation of the GM2S gene was detected as accompanied by an apparent induction of neuronal differentiation in NSCs responding to an exogenous supplement of GM1. Interestingly, GM1 induced epigenetic activation of thetyrosine hydroxylase (TH)gene, with recruitment of Nurr1 and PITX3, dopaminergic neuron-associated transcription factors, to theTHpromoter region. In this way, GM1 epigenetically regulates dopaminergic neuron specific gene expression, and it would modify Parkinson’s disease. Multifunctional gangliosides significantly modulate lipid microdomains to regulate functions of important molecules on multiple sites: the plasma membrane, mitochondrial membrane, and nuclear membrane. Versatile gangliosides regulate functional neurons as well as sustain NSC functions via modulating protein and gene activities on ganglioside microdomains. Maintaining proper ganglioside microdomains benefits healthy neuronal development and millions of senior citizens with neurodegenerative diseases.Here, we introduce how to isolate GD3 and GM1 and how to administer them into the mouse brain to investigate their functions on NSC fate determination and nerve cell specification.
Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events
Authors: Middha Pooja , Thummalapalli Rohit , Quandt Zoe , Balaratnam Karmugi , Cardenas Eduardo , Falcon Christina J. ,   Princess Margaret Lung Group, Gubens Matthew A. , Huntsman Scott , Khan Khaleeq , Li Min , Lovly Christine M. , Patel Devalben , Zhan Luna Jia , Liu Geoffrey , Aldrich Melinda C. , Schoenfeld Adam J. , Ziv Elad 
Published: June 2024

AbstractIntroductionImmune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.MethodsUsing Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSADand cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage.ResultsWe found an association between PRSADand ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 – 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSADhad 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSADhad an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04).ConclusionsWe demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.
Optimization of an adult immunization program in Canada
Authors: Locke Nathan , Paulden Mike , MacDonald Shannon E. , Montesanti Stephanie , Tuite Ashleigh , Hempel Karsten , McDonald Wade , Rafferty Ellen 
Published: June 2024

AbstractBackgroundProvincial decisions to fund a new immunization program are generally made on a case-by-case basis, without systematic consideration of how the new immunization program may fit within the larger provincial immunization portfolio.AimThe goal of this study was to develop evidence and tools to guide policy-makers in making fiscally and ethically responsible decisions on which adult immunization programs to include in their portfolio under various constrained budgetary scenarios.MethodsUsing previously published infectious disease models, cost-utility data was estimated for adult pneumococcal, influenza, pertussis, and shingles immunization programs. This data was then inputted into a newly developed constrained optimization model to determine portfolios of immunization programs that maximize either population health or incremental net monetary benefit, subject to a budget constraint. Sensitivity analyses were conducted on model parameters such as vaccine costs, cost-effectiveness thresholds, and the budget constraint.ResultsOptimized solutions changed dramatically based on the number of immunization programs included, total budget, what was optimized for (i.e., population health or incremental net monetary benefit), the cost-effectiveness threshold and the assumed vaccine prices. Maximal health gains and budget spending was achieved when optimizing based on population health. Reductions in health gains and budget spending were observed at a CAN$50,000 cost-effectiveness threshold, and at a CAN$30,000 threshold, the budget was significantly underutilized and health gains were noticeably reduced.ConclusionIf budgets for the adult immunization portfolio are fixed, then shifting to more expensive programs that offer large health benefits may be preferable. However, if budgets can be spread across various public health programs (i.e., childhood immunization, well-baby programs), it may make more sense to optimize based on cost-effectiveness. Constrained optimization tools could improve goals-based decision-making and allow for transparent and effective methods to make allocation decisions.HighlightsOptimized solutions changed dramatically based on the number of immunization programs available, total budget, and the cost-effectiveness threshold.If budgets for the adult immunization portfolio are fixed, then shifting to more expensive programs that offer large health benefits may be preferable.If budgets can be spread across various public health programs, it may make more sense to optimize based on cost-effectiveness.Constrained optimization tools could improve goals-based decision-making and allow for transparent and effective methods to make allocation decisions.
Differential effects of theta-gamma tACS on motor skill acquisition in young individuals and stroke survivors: a double-blind, randomized, sham-controlled study
Authors: Grigutsch L.S. , Haverland B. , Timmsen L. S. , Asmussen L. , Braaß H. , Wolf S. , Luu T. V. , Stagg C.J. , Schulz R. , Quandt F. , Schwab B.C. 
Published: June 2024

AbstractBackgroundTheta-gamma transcranial alternating current stimulation (tACS) was recently found to enhance thumb acceleration in young, healthy participants, suggesting a potential role in facilitating motor skill acquisition. Given the relevance of motor skill acquisition in stroke rehabilitation, theta-gamma tACS may hold potential for treating stroke survivors.ObjectiveWe aimed to examine the effects of theta-gamma tACS on motor skill acquisition in young, healthy participants and stroke survivors.MethodsIn a pre-registered, double-blind, randomized, sham-controlled study, 78 young, healthy participants received either theta-gamma peak-coupled (TGP) tACS, theta-gamma trough-coupled (TGT) tACS or sham stimulation. 20 individuals with a chronic stroke received either TGP or sham. TACS was applied over motor cortical areas while participants performed an acceleration-dependent thumb movement task. Stroke survivors were characterized using standardized testing, with a subgroup receiving additional anatomical brain imaging.ResultsNeither TGP nor TGT tACS significantly modified general motor skill acquisition in the young, healthy cohort. In contrast, in the stroke cohort, TGP diminished motor skill acquisition compared to sham. Exploratory analyses revealed that, independent of general motor skill acquisition, healthy participants receiving TGP or TGT exhibited greater peak thumb acceleration than those receiving sham.ConclusionAlthough theta-gamma tACS increased thumb acceleration in young, healthy participants, consistent with previous reports, it did not enhance overall motor skill acquisition in a more complex motor task. Furthermore, it even had detrimental effects on motor skill acquisition in stroke survivors.
The Microbiome and Metatranscriptome of a Panel from theSarraceniaMapping Population Reveal Complex Assembly and Function Involving Host Influence
Authors: Cai Jiazhang , Mohsin Iqra , Rogers Willie , Zhang Mengrui , Jiang Lin , Malmberg Russell , Alabady Magdy 
Published: June 2024

AbstractSarraceniaprovide an optimal system for deciphering the host-microbiome interactions at various levels. We analyzed the pitcher microbiomes and metatranscriptomes of the parental species, and F1 and F2 generations from the mapping population (Sarracenia purpureaXSarracenia psittacina) utilizing high-throughput sequencing methods. This study aimed to examine the host influences on the microbiome structure and function and to identify the key microbiome traits. Our quality datasets included 8,892,553 full-length bacterial 16s rRNA gene sequences and 65,578 assembled metatranscripts with microbial protein annotations. The correlation network of the bacterial microbiome revealed the presence of 3-7 distinct community clusters, with 8 hub and 19 connector genera. The entire microbiome consisted of viruses, bacterial, archaea, and fungi. The richness and diversity of the microbiome varied among the parental species and offspring genotypes despite being under the same greenhouse environmental conditions. We have discovered certain microbial taxa that are genotype-enriched, including the community hub and connector genera. Nevertheless, there were no significant differences observed in the functional enrichment analysis of the metatranscriptomes across the different genotypes, suggesting a functional convergence of the microbiome. Our results revealed that the pitcher microcosm harbors both rhizosphere and phyllosphere microbiomes within its boundaries, resulting in a structurally diverse and functionally complex microbiome community. A total of 50,424 microbial metatranscripts were linked to plant growth-promoting microbial proteins. We show that this complex pitcher microbiome possesses various functions that contribute to plant growth promotion, such as biofertilization, bioremediation, phytohormone signaling, stress regulation, and immune response stimulation. Additionally, the pitcher microbiome exhibits traits related to microbe-microbe interactions, such as colonization of plant systems, biofilm formation, and microbial competitive exclusion. In summary, the demonstrated taxonomical divergence and functionally convergence of the pitcher microbiome are impacted by the host genetics, making it an excellent system for discovering novel beneficial microbiome traits.
Retinoid X Receptor as a Novel Drug Target to Treat Neurological Disorders Associated with α- Synucleinopathies
Authors: Zhylkibayev Assylbek , Starr Christopher R. , Atigadda Venkatram , Grant Maria B. , Gorbatyuk Marina S. , Gorbatyuk Oleg S. 
Published: June 2024

AbstractThe pathology of Parkinson’s Disease (PD) is multifaceted, with chronic neuroinflammation associated with glial cell activation standing out as a hallmark of PD pathophysiology. While a few treatments exist to interfere with inflammation, a breakthrough therapy based on innovative molecular mechanisms and targets is still awaited. The nuclear retinoid X receptor (RXR) is of particular interest for therapeutic intervention due to its ability to bind and activate permissive partners, NURR1 and PPARs, which have been shown to be dysfunctional in PD brains. Therefore, the goal of this study was to validate RXR-based therapy to slow down PD pathogenesis. Adult C57BL6 male mice were used in the study. PD-like pathology was triggered by co-delivery of AAV expressing α-Syn and PFF (AAV/PFF) to the substantia nigra pars compacta. The therapeutic potential of RXR activation was evaluated using AAV-mediated gene transport. Unbiased stereology, immunohistochemical analysis, LC/MS, and western blotting were employed to assess the therapeutic effect. At 8 weeks post-injection—elevated GFAP and Iba1 levels, associated with accumulated LB-like aggregates, pronounced loss of TH neuronal cells, and diminished dopamine (DA) levels—were observed in affected brains. Moreover, PPAR and NURR1 protein levels were also reduced in these brains. Conversely, RXR overexpression resulted in an increase in PPAR and NURR1 levels, a reduction in GFAP and Iba1 levels, and a decrease in the number and distribution of LB-like aggregates. These phenomena were also accompanied by the prevention of tyrosine hydroxylase (TH)+cell loss and the DA deficit in the treated brains. Therefore, our data provide direct evidence of the therapeutic potential of RXR-based therapy and highlight RXR as a novel drug target for PD.
Systemic and targeted activation of Nrf2 reverses doxorubicin-induced cognitive impairments and sensorimotor deficits in mice
Authors: Singh Anand Kumar , Ruiz David , Ur Rasheed Mohd Sami , Avery Thomas D. , Turner Dion J. L. , Abell Andrew D. , Grace Peter M. 
Published: June 2024

AbstractWhile cancer survivorship has increased due to advances in treatments, chemotherapy often carries long-lived neurotoxic side effects which reduce quality of life. Commonly affected domains include memory, executive function, attention, processing speed and sensorimotor function, colloquially known as chemotherapy-induced cognitive impairment (CICI) or “chemobrain”. Oxidative stress and neuroimmune signaling in the brain have been mechanistically linked to the deleterious effects of chemotherapy on cognition and sensorimotor function. With this in mind, we tested if activation of the master regulator of antioxidant response nuclear factor E2-related factor 2 (Nrf2) alleviates cognitive and sensorimotor impairments induced by doxorubicin. The FDA-approved systemic Nrf2 activator, diroximel fumarate (DRF) was used, along with our recently developed prodrug1cwhich has the advantage of specifically releasing monomethyl fumarate at sites of oxidative stress. DRF and1cboth reversed doxorubicin-induced deficits in executive function, spatial and working memory, as well as decrements in fine motor coordination and grip strength, across both male and female mice. Both treatments reversed doxorubicin-induced loss of synaptic proteins and microglia phenotypic transition in the hippocampus. Doxorubicin-induced myelin damage in the corpus callosum was reversed by both Nrf2 activators. These results demonstrate the therapeutic potential of Nrf2 activators to reverse doxorubicin-induced cognitive impairments, motor incoordination, and associated structural and phenotypic changes in the brain. The localized release of monomethyl fumarate by1chas the potential to diminish unwanted effects of fumarates while retaining efficacy.
Neural correlates of retrieval success and precision: an fMRI study
Authors: Hou Mingzhu , Hill Paul F. , Aktas Ayse N. Z. , Ekstrom Arne D. , Rugg Michael D. 
Published: June 2024

AbstractPrior studies examining the neural mechanisms underlying retrieval success and precision have yielded inconsistent results. Here, their neural correlates were examined using a memory task that assessed precision for spatial location. A sample of healthy young adults underwent fMRI scanning during a single study-test cycle. At study, participants viewed a series of object images, each placed at a randomly selected location on an imaginary circle. At test, studied images were intermixed with new images and presented to the participants. The requirement was to move a cursor to the location of the studied image, guessing if necessary. Participants then signaled whether the presented image as having been studied. Memory precision was quantified as the angle between the studied location and the location selected by the participant. A precision effect was evident in the left angular gyrus, where BOLD activity covaried across trials with location accuracy. Multi-voxel pattern analysis also revealed a significant item-level reinstatement effect for high-precision trials. There was no evidence of a retrieval success effect in the angular gyrus. BOLD activity in the hippocampus was insensitive to both success and precision. These findings are partially consistent with prior evidence that success and precision are dissociable features of memory retrieval.
Biochemical characterization of extended-spectrum β-lactamases fromAkkermansiagenus
Authors: Lin Jiafu , Wang Tiantian , Zhou Yaliang , Sha Jingzhou , Chen Xueke , Wang Wenjie , Zhang Chuan , Xie Feng , Chu Yiwen , Wang Xinrong , Luo Dan , Song Tao 
Published: June 2024

AbstractAkkermansia muciniphila, a member of theVerrucomicrobiotaphylum, is recognized as a key gut microbe and has emerged as a potential next-generation probiotic. Assessment of antibiotic resistance in probiotics is a prerequisite for their therapeutic application, while very few is known inAkkermansiaspecies. Firstly, we screened eight representative class A β-lactamases (36.90%-41.30% identity with known β-lactamases) from theAkkermansiaspecies, which could increase the minimum inhibitory concentration (MIC) ofEscherichia colitoβ-lactams. Secondly, fourβ-lactamases were purified and identified as extended-spectrum β-lactamase because they exhibited hydrolase activity against 19 β-lactam antibiotics from penicillin, cephalosporins, and monobactam classes. Based on sequence alignment, three-dimensional structure, and binding pocket information, we hypothesized and validated that serine at 51 position was catalytic amino acid. Thirdly, the genomic context analysis revealed the absence of mobile genetic elements or other antibiotic resistance genes surrounding β-lactamase genes, suggesting that the β-lactamases fromAkkermansiaspecies may not be transferable. The finding and biochemical characterization of β-lactamase fromAkkermansiaspecies provide a foundational basis for the safety evaluation ofAkkermansiaspecies as probiotics.
Leveraging Artificial Intelligence to Mitigate Adolescent Risky Behaviors: A Scoping Review Protocol
Authors: Sadeghsalehi Hamidreza , Joulaei Hassan 
Published: June 2024

Adolescents are particularly vulnerable to engaging in risky behaviors such as violence, unprotected sex, and substance abuse, which have significant negative impacts on their health and development. Recent advancements in artificial intelligence (AI) offer innovative solutions to address these behaviors, yet the evidence regarding the efficacy and implementation of AI-based interventions remains fragmented. This scoping review aims to systematically explore and map the literature on AI-based interventions designed to reduce risky behaviors among adolescents.This review will follow the methodological frameworks outlined by Arksey and O’Malley (2005) and improved by Levac, Colquhoun, and O’Brien (2010), in line with the Joanna Briggs Institute guidelines. The PRISMA Extension for Scoping Reviews (PRISMA-ScR) will guide the reporting. The search strategy will be executed across PubMed, Scopus, Web of Science Core Collection, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials, Embase, SID, and Magiran, focusing on articles published up to June 2024 in English and Farsi. Titles and abstracts will be screened by two independent reviewers using Rayyan, followed by full-text screening of relevant studies. Data will be charted using a standardized form, and discrepancies will be resolved through discussion or by consulting a third reviewer. Data will be synthesized descriptively and presented in tables, figures, and diagrams.