bluuebunny/crossref_metadata_2025_split huggingface dataset:
Individual variability in the relationship between physiological and resting-state fMRI metrics
Authors: Moia Stefano , Chen Gang , Uruñuela Eneko , Stickland Rachael C. , Termenon Maite , Caballero-Gaudes César , Bright Molly G. 
Published: May 2024

AbstractCerebrovascular Reactivity (CVR), the brain’s vascular response to a vasodilatory stimulus, can be measured using fMRI during breathing challenges that modulate arterial CO2levels. CVR is an important indicator of cerebrovascular health, although its estimation can be challenging due to the extra experimental setup and/or the subject compliance required. To overcome these limitations, summary metrics based on resting state fluctuations (RSF), such as the (fractional) amplitude of low frequency fluctuations (f/ALFF) and the resting state fluctuation amplitude (RSFA), have been proposed as alternative estimates of CVR, as they are frequently associated with vascular and physiological factors. Previous studies have reported a significant relationship between CVR estimates obtained by means of respiratory paradigms and RSF metrics. However, the total sample sizes, considering both subjects and sessions, are typically small, and not all studies agree on the degree of the relationship. Furthermore, to our knowledge, these studies have only reported cross-sectional analyses, whereas intra-subject longitudinal relationships between CVR estimates and RSF metrics are unknown. Leveraging a unique dense sampling dataset in which resting state and breath-hold multi-echo fMRI were collected in 7 subjects with 10 sessions each, we provide evidence of high individual variability in the inter-session (i.e. intra-subject) relationship between RSF metrics and CVR. These results indicate that RSF metrics might not be a suitable proxy of CVR in clinical settings or for BOLD signal calibration as they may not properly account for intra-individual physiological variations in BOLD fMRI data.
Vestibular Modulation by Stimulant Derivatives in a Pentameric Ligand-Gated Ion Channel
Authors: Karlsson Emelia , Andén Olivia , Fan Chen , Fourati Zaineb , Haouz Ahmed , Zhuang Yuxuan , Howard Rebecca J , Delarue Marc , Lindahl Erik 
Published: May 2024

AbstractAllosteric modulation of pentameric ligand-gated ion channels (pLGICs) is critical to the action of neurotransmitters and many psychoactive drugs. However, details of their modulatory mechanisms remain unclear, especially beyond the orthosteric neurotransmitter-binding sites. The recently reported prokaryotic channel sTeLIC, a pH-gated homolog of eukaryotic receptors in the pLGIC family, is thought to be modulated by aromatic compounds via a relatively uncharacterized modulatory site in the extracellular vestibule. Here, we show that sTeLIC is sensitive to potentiation by psychostimulant derivatives. By determining new cryo-EM and X-ray structures in closed and open states, and testing the impact of targeted mutations on electrophysiological behavior, we show that several amphiphilic compounds preferentially bind a vestibular pocket in the contracted open-state extracellular domain. This work provides a detailed structure-function mechanism for allosteric potentiation via a noncanonical lig- and site, with potential conservation in eukaryotic pentameric ligand-gated ion channels.
Perinatal maternal undernutrition in baboons modulates hepatic mitochondrial function but not metabolites in aging offspring
Authors: Adekunbi Daniel A. , Yang Bowen , Huber Hillary F. , Riojas Angelica M. , Moody Alexander J. , Li Cun , Olivier Michael , Nathanielsz Peter W. , Clarke Geoffery D. , Cox Laura A. , Salmon Adam B. 
Published: May 2024

AbstractWe previously demonstrated in baboons that maternal undernutrition (MUN), achieved by 70 % of control nutrition, impairs fetal liver function, but long-term changes associated with aging in this model remain unexplored. Here, we assessed clinical phenotypes of liver function, mitochondrial bioenergetics, and protein abundance in adult male and female baboons exposed to MUN during pregnancy and lactation and their control counterparts. Plasma liver enzymes were assessed enzymatically. Liver glycogen, choline, and lipid concentrations were quantified by magnetic resonance spectroscopy. Mitochondrial respiration in primary hepatocytes under standard culture conditions and in response to metabolic (1 mM glucose) and oxidative (100 µM H2O2) stress were assessed with Seahorse XFe96. Hepatocyte mitochondrial membrane potential (MMP) and protein abundance were determined by tetramethylrhodamine ethyl ester staining and immunoblotting, respectively. Liver enzymes and metabolite concentrations were largely unaffected by MUN, except for higher aspartate aminotransferase levels in MUN offspring when male and female data were combined. Oxygen consumption rate, extracellular acidification rate, and MMP were significantly higher in male MUN offspring relative to control animals under standard culture. However, in females, cellular respiration was similar in control and MUN offspring. In response to low glucose challenge, only control male hepatocytes were resistant to low glucose-stimulated increase in basal and ATP-linked respiration. H2O2did not affect hepatocyte mitochondrial respiration. Protein markers of mitochondrial respiratory chain subunits, biogenesis, dynamics, and antioxidant enzymes were unchanged. Male-specific increases in mitochondrial bioenergetics in MUN offspring may be associated with increased energy demand in these animals. The similarity in systemic liver parameters suggests that changes in hepatocyte bioenergetics capacity precede detectable circulatory hepatic defects in MUN offspring and that the mitochondria may be an orchestrator of liver programming outcome.
In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood
Authors: Wang Xizhe , Tazearslan Cagdas , Kim Seungsoo , Guo Qinghua , Contreras Daniela , Yang Jiping , Hudgins Adam D. , Suh Yousin 
Published: May 2024

AbstractSeveral decades of heterochronic parabiosis (HCPB) studies have demonstrated the restorative impact of young blood, and deleterious influence of aged blood, on physiological function and homeostasis across tissues, although few of the factors responsible for these observations have been identified. Here we develop an in vitro HCPB system to identify these circulating factors, using replicative lifespan (RLS) of primary human fibroblasts as an endpoint of cellular health. We find that RLS is inversely correlated with serum donor age and sensitive to the presence or absence of specific serum components. Through in vitro HCPB, we identify the secreted protein pigment epithelium-derived factor (PEDF) as a circulating factor that extends RLS of primary human fibroblasts and declines with age in mammals. Systemic administration of PEDF to aged mice reverses age-related functional decline and pathology across several tissues, improving cognitive function and reducing hepatic fibrosis and renal lipid accumulation. Together, our data supports PEDF as a systemic mediator of the effect of young blood on organismal health and homeostasis and establishes our in vitro HCPB system as a valuable screening platform for the identification of candidate circulating factors involved in aging and rejuvenation.
QuAPPro: An R/shiny app for Quantification and Alignment of Polysome Profiles
Authors: Schiller Chiara , Reitter Sonja , Lehmann Janina A. , Fenzl Kai , Schott Johanna 
Published: May 2024

AbstractPolysome profiling is a powerful technique to study mRNA translation. After separation of ribosomal subunits from monosomes and polysomes by ultracentrifugation on sucrose density gradients, a UV absorbance profile is recorded during elution. This profile can be used to assess global translational activity, or reveal changes in ribosome biogenesis or translation elongation. In parallel to UV absorbance profiles, it is also possible to record fluorescence to measure the association of fluorescently tagged proteins with ribosomes or polysomes. To this end, the area under subsections of the UV/fluorescence profiles needs to be quantified carefully. In addition, alignment of profiles in one graph helps to visualize differences. With QuAPPro, we present the first interactive web app that allows quantification and alignment of polysome profiles, independently of the device or software that was used to generate the profiles. This user-friendly tool does not only speed up the analysis of polysome profiles but also facilitates reproducibility and documentation of the process.
High-Resolution Epitope Mapping for Glycosylated Antigens: Pembrolizumab-PD1 as a Case Study
Authors: Zhang Sara , Simmons Calvin , Young Mike , Pan Jason 
Published: May 2024

AbstractHigh-resolution epitope mapping is important for in-depth activity assessment of antibodies and understanding of their functions, however, glycosylated antigens are challenging for many methods including crystallography. PD1 is a highly glycosylated antigen, and with the traditional HDX-MS method, only 51% sequence coverage could be obtained with multiple epitope residues undetected for Pembrolizumab (Keytruda). By implementing glyco-peptide detection, subzero temperature LC-MS and electron based MSMS fragmentation, the FineMapping methodology enabled 100% sequence coverage and complete epitope characterization for the Pembrolizumab-PD1 system, with amino acid level resolution. As 50% to 70% of proteins in the cell are glycosylated, the middle-down HDX-MS based FineMapping technology presented here should find its wide application on these protein targets. Also, FineMapping detects antibody epitopes directly in solution, without any mutation or modification to either the antigen or the antibody. And its amino acid level resolution combined with its low cost, minimal sample consumption, fast turnaround time, and no need of mutant library or crystallization makes it a competitive methodology for high-resolution epitope mapping.
Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations
Authors: Malone Samantha G. , Davis Christal N. , Piserchia Zachary , Setzer Michael R. , Toikumo Sylvanus , Zhou Hang , Winterlind Emma L. , Gelernter Joel , Justice Amy , Leggio Lorenzo , Rentsch Christopher T. , Kranzler Henry R. , Gray Joshua C. 
Published: May 2024

AbstractDespite neurobiological overlap, alcohol use disorder (AUD) and body mass index (BMI) show minimal genetic correlation (rg), possibly due to mixed directions of shared variants. We applied MiXeR to investigate shared genetic architecture between AUD and BMI, conjunctional false discovery rate (conjFDR) to detect shared loci and their directional effect, Local Analysis of (co)Variant Association (LAVA) for local rg, Functional Mapping and Annotation (FUMA) to identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) to examine tissue enrichment, and BrainXcan to assess associations with brain phenotypes. MiXeR indicated 82.2% polygenic overlap, despite a rgof −.03. ConjFDR identified 132 shared lead SNPs, with 53 novel, showing both concordant and discordant effects. GTEx analyses identified overexpression in multiple brain regions. Amygdala and caudate nucleus volumes were associated with AUD and BMI. Opposing variant effects explain the minimal rg between AUD and BMI, with implicated brain regions involved in executive function and reward, clarifying their polygenic overlap and neurobiological mechanisms.
Molecular identification of whole squids and calamari at fairs and markets in regions of Latin America
Authors: Paiva Bianca Lima , Souza Rodrigues Alan Erik , de Freitas Almeida Igor Oliveira , Haimovici Manuel , Markaida Unai , Charvet Patricia , Faria Vicente Vieira , Batista Bruno B. , Gomes Tomás Acácio Ribeiro , da Silva Rodrigues-Filho Luis Fernando , Ready Jonathan Stuart , de Luna Sales João Bráullio 
Published: May 2024

AbstractIn recent decades, the commercial importance of cephalopods has increased considerably, being an important fishing resource around the world. However, during the preparation for commercialization of those species, especially those sold in markets, they suffer the process known as“calamari”which includes removing and separating the head, arm, skin or even having the body structure cut into rings, which ends up making it difficult or often prevents the identification of the species, which can lead to replacements. In this sense, the present study aimed to use the large ribosomal region, rrnL (also known as 16S rDNA) to genetically identify cephalopod species sold in markets and fairs in Latin America. Whole and processed samples were collected from supermarkets and directly from local fishers the approximate collection location. Each generated sequence was submitted to the websiteGenbankfor molecular comparison and included in the database for subsequent genetic identification. Comparison of sequences using theBlastnrevealed the presence of eight species that are widely traded in the Latin American region. Our results indicate labeling errors in samples from the State of Pará that contained the speciesDosidicus gigas(d’ Orbigny, 1823) found only in the Pacific Ocean and were generically labeled as “National Lula”. No type of substitution was found among the samples that were being sold at fairs and markets, only labeling errors. Thus, our results demonstrate the effectiveness of the rrnL for identifying species and evaluating labeling errors.
Eco-evolutionary dynamics of anthelmintic resistance in soil-transmitted helminths
Authors: Patel Swati , Lyberger Kelsey , Vegvari Carolin , Gulbudak Hayriye 
Published: May 2024

AbstractAnthelmintic resistance (AR) of helminth parasites against the most widely available drugs is an ongoing concern for both human and livestock-infecting species. Indeed, there has been substantial evidence of AR in livestock but less in humans, which may be due to a variety of reasons. In this paper, we develop an eco-evolutionary model that couples the life cycle of these parasites with their underlying evolution in a single biallelic genetic locus that confers resistance to treatment drugs. We determine the critical treatment frequency needed to effectively eliminate the population, for a fixed drug efficacy (without evolution) and use this to classify three qualitative distinct behaviors of the eco-evolutionary model. Then, we describe how aspects of the life cycle influence which qualitative outcome is achieved and the spread of the resistance allele, comparing across parameterized models of human- and livestock-infecting species. For all but one species, we find that lower fecundity rates and lower contact rates speed the spread of resistance, while lower larval death slows it down. The life cycle parameters ofAncylostoma duodenaleandOstertagia circumcinctaare associated with the fastest and slowest spread of resistance, respectively. We discuss the mechanistic reason for these results.
Viral overexpression of human alpha-synuclein in mouse substantia nigra dopamine neurons results in hyperdopaminergia but no neurodegeneration
Authors: Moreno Sofia Ines Garcia , Limani Fabian , Ludwig Iina , Gilbert Catherine , Pifl Christian , Hnasko Thomas S. , Steinkellner Thomas 
Published: May 2024

AbstractLoss of select neuronal populations such as midbrain dopamine (DA) neurons is a pathological hallmark of Parkinson’s disease (PD). The small neuronal protein α-synuclein has been related both genetically and neuropathologically to PD, yet how it contributes to selective vulnerability remains elusive. Here, we describe the generation of a novel adeno-associated viral vector (AAV) for Cre-dependent overexpression of wild-type human α-synuclein. Our strategy allows us to restrict α-synuclein to select neuronal populations and hence investigate the cell-autonomous effects of elevated α-synuclein in genetically-defined cell types. Since DA neurons in the substantia nigrapars compacta(SNc) are particularly vulnerable in PD, we investigated in more detail the effects of increased α-synuclein in these cells. AAV-mediated overexpression of wildtype human α-synuclein in SNc DA neurons increased the levels of α-synuclein within these cells and augmented phosphorylation of α-synuclein at serine-129, which is considered a pathological feature of PD and other synucleinopathies. However, despite abundant α-synuclein overexpression and hyperphosphorylation we did not observe any DA neurodegeneration up to 90 days post virus infusion. In contrast, we noticed that overexpression of α-synuclein resulted in increased locomotor activity and elevated striatal DA levels suggesting that α-synuclein enhanced dopaminergic activity. We therefore conclude that cell-autonomous effects of elevated α-synuclein are not sufficient to trigger acute DA neurodegeneration.
Insect abundance and richness response to ecological reclamation on well pads 5-12 years into succession in a semi-arid natural gas field
Authors: Curran Michael F. , Allison Jasmine , Robinson Timothy J. , Robertson Blair L. , Knudson Alexander H. , Bott Bee M.M. , Bower Steven , Saleh Bobby M. 
Published: May 2024

AbstractNatural gas extraction is a critical driver of the economy in western North America. Ecological reclamation is important to ensure surface disturbance impacts associated with natural gas development are not permanent and to assist native biota. Previous studies in semi-arid natural gas fields within Sublette County, Wyoming, USA have shown insects respond favorably to 1-3-year-old well pads undergoing reclamation compared to older successional, reference vegetation communities dominated by Wyoming big sagebrush (Artemisia tridentaspp.Wyomingensis). Here we examined well pads which were initially seeded between 5, 8, 10, 11, and 12 prior to our study. We used a free, image-based software called SamplePoint to quantify vegetation on these well pads and adjacent reference areas from high-resolution cell phone camera pictures. Insects were collected with a sweep net and identified to the family and morphospecies level. Statistical analyses were conducted to compare both vegetation and insect communities between reclamation sites and their paired reference area. We found little statistical difference between vegetation communities across our study, but found significantly more insect abundance in 3 of 5 years and significantly higher family and species richness in 4 of 5 years. Our results suggest reclamation of natural gas well pads within an old successional stand of sagebrush continues to support higher levels of insect biodiversity and abundance for at least 12 years. As insects are the most diverse group of animals on Earth and because they provide a wide array of ecosystem services, our findings suggest ecological reclamation plays an important role in returning biodiversity and ecosystem functionality to a semi-arid and old successional sagebrush-steppe ecosystem.
Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases
Authors: Huang Shih-Wen , Lai Yein-Gei , Liao Hao-Ting , Chang Chin-Ling , Ma Ruo-Yu , Chen Yung-Hsiang , Liou Yae-Huei , Wu Zhen-Qi , Wu Yu-Chen , Liu Ko-Jiunn , Huang Yen-Tsung , Yang Jen-Lung , Dai Ming-Shen , Liao Nan-Shih 
Published: May 2024

AbstractNatural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3−CD4+T cells and stem cell-like CD8+T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+tumor cells by activating the cDC-T cell axis at metastatic sites.
Incorporation of Epstein-Barr viral variation implicates significance of LMP1 in survival prediction and prognostic subgrouping in Burkitt lymphoma
Authors: Kim Isaac E. , Oduor Cliff , Stamp Julian , Luftig Micah A. , Moormann Ann M. , Crawford Lorin , Bailey Jeffrey A. 
Published: May 2024

ABSTRACTWhile Epstein-Barr virus (EBV) plays a role in Burkitt lymphoma (BL) tumorigenesis, it is unclear if EBV genetic variation impacts clinical outcomes. From 130 publicly available whole-genome tumor sequences of EBV-positive BL patients, we used least absolute shrinkage and selection operator (LASSO) regression and Bayesian variable selection models within a Cox proportional hazards framework to select the top EBV variants, putative driver genes, and clinical features associated with patient survival time. These features were incorporated into survival prediction and prognostic subgrouping models. Our model yielded 22 EBV variants including seven in LMP1 as most associated with patient survival time. Using the top EBV variants, driver genes, and clinical features, we defined three prognostic subgroups that demonstrated differential survival rates, laying the foundation for incorporating EBV variants such as those in LMP1 as predictive biomarker candidates in future studies.
Protein S-glutathionylation confers cell resistance to ferroptosis
Authors: Ju Yi , Zhang Yuting , Qiao Yiming , Tian Xiaolin , Zheng Yufan , Yang Tao , Niu Baolin , Li Xiaoyun , Yu Liu , Liu Zhuolin , Wu Yixuan , Zhi Yang , Dong Yinuo , Xu Qingling , Wang Xuening , Wang Xiaokai , Mao Yimin , Li Xiaobo 
Published: May 2024

ABSTRACTFerroptosis is a type of cell death that is strongly associated with the cellular redox state. Glutathione is the key to buffering lipid peroxidation in ferroptosis and can also modify proteins by S-glutathionylation under oxidative stress. Here, we showed that the strong associations among glutathione pools, protein S-glutathionylation, and susceptibility to ferroptosis existed broadly in ferroptosis induced by erastin or acetaminophen. Deficiency of CHAC1, a glutathione-degrading enzyme, led to decreased glutathione pools and reduced protein S-glutathionylation, improved liver function and attenuated hepatocyte ferroptosis upon acetaminophen challenge, which could be retarded by CHAC1 overexpression. We conducted quantitative redox proteomics in primary mouse hepatocytes to identify glutathione pool-sensitive S-glutathionylated proteins and found that S-glutathionylation is required to maintain the function of ADP-ribosylation factor 6 (ARF6). Our data suggest that aberrant ARF6 S-glutathionylation increases the labile iron pool by delaying the recycling of transferrin receptors, thereby promoting ferroptosis. Our study reveals the importance of protein S-glutathionylation in conferring cell resistance to ferroptosis.HIGHLIGHTSHighly upregulated CHAC1 decreases glutathione pools and protein S-glutathionylation.Reduced protein S-glutathionylation associated with decreased glutathione pools promotes ferroptosis.S-glutathionylation of ARF6 at Cys90 promotes ARF6 activation.Reduced S-glutathionylation of ARF6 provides a labile iron pool to drive ferroptosis.