bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbial methane cycling in a landfill on a decadal time scale
Authors: Grégoire Daniel S. , George Nikhil A. , Hug Laura A. 
Published: January 2023

AbstractLandfills generate outsized environmental footprints due to microbial degradation of organic matter in municipal solid waste, which produces the potent greenhouse gas methane. With global solid waste production predicted to increase 69% by the year 2050, there is a pressing need to better understand the biogeochemical processes that control microbial methane cycling in landfills. In this study, we had the rare opportunity to characterize the microbial community responsible for methane cycling in landfill waste covering a 39-year timeframe. We coupled long term geochemical analyses to whole-community DNA (i.e., metagenomic) sequencing and identified key features that shape methane cycling communities over the course of a landfill’s lifecycle. Anaerobic methanogenic microbes are more abundant, diverse, and metabolically versatile in newer waste, fueling rapid methane production early in a landfill’s lifecycle. Aerobic methanotrophs were repeatedly found in leachate where low levels of oxygen were present and exhibited adaptations that aid survival under steep redox gradients in landfills. The potential for anaerobic methane oxidation, which has historically been overlooked despite anoxic habitats dominating landfills, was prevalent in a 26-year-old landfill cell which was in a state of slow methanogenesis. Finally, we identified the metabolic potential for methane oxidation in lineages that are widespread in aquatic and terrestrial habitats, whose capacity to metabolize methane remains poorly characterized. Ultimately, this work expands the diversity of methane cycling guilds in landfills and outlines how these communities can curb methane emissions from municipal solid waste.SignificanceMicrobes are major contributors to methane emissions from solid waste however the temporal dynamics of methane cycling communities in landfills remain poorly understood. We addressed this gap by using whole-community DNA (i.e., metagenomic) approaches to characterize microbial methane cycling in waste covering a 39-year timeframe. We show that methane-producing microbes are more abundant, diverse, and metabolically versatile in new waste compared to old waste. We highlight that methane oxidation in the absence of oxygen is overlooked in landfill biogeochemical models and that novel lineages can potentially contribute to methane sinks across a broad range of habitats. These findings can strengthen predictive models for methane cycling in landfills and inform sustainable waste management strategies to curb methane emissions from solid waste.
Dasatinib Resensitizes MAPK Inhibitor Efficacy in Standard-of-Care Relapsed Melanomas
Authors: Rebecca Vito W. , Xiao Min , Kossenkov Andrew , Godok Tetiana , Brown Gregory Schuyler , Fingerman Dylan , Alicea Gretchen M. , Wei Meihan , Ji Hongkai , Bravo Jeremy , Chen Yeqing , Fane Mitchell E. , Villanueva Jessie , Nathanson Katherine , Liu Qin , Gopal Y. N. Vashisht , Davies Michael A. , Herlyn Meenhard 
Published: January 2023

AbstractResistance to combination BRAF/MEK inhibitor (BRAFi/MEKi) therapy arises in nearly every patient withBRAFV600E/Kmelanoma, despite promising initial responses. Achieving cures in this expanding BRAFi/MEKi-resistant cohort represents one of the greatest challenges to the field; few experience additional durable benefit from immunotherapy and no alternative therapies exist. To better personalize therapy in cancer patients to address therapy relapse, umbrella trials have been initiated whereby genomic sequencing of a panel of potentially actionable targets guide therapy selection for patients; however, the superior efficacy of such approaches remains to be seen. We here test the robustness of the umbrella trial rationale by analyzing relationships between genomic status of a gene and the downstream consequences at the protein level of related pathway, which find poor relationships between mutations, copy number amplification, and protein level. To profile candidate therapeutic strategies that may offer clinical benefit in the context of acquired BRAFi/MEKi resistance, we established a repository ofpatient-derivedxenograft models from heavily pretreated patients with resistance to BRAFi/MEKi and/or immunotherapy (R-PDX). With these R-PDXs, we executedin vivocompound repurposing screens using 11 FDA-approved agents from an NCI-portfolio with pan-RTK, non-RTK and/or PI3K-mTOR specificity. We identify dasatinib as capable of restoring BRAFi/MEKi antitumor efficacy in ∼70% of R-PDX tested. A systems-biology analysis indicates elevated baseline protein expression of canonical drivers of therapy resistance (e.g., AXL, YAP, HSP70, phospho-AKT) as predictive of MAPKi/dasatinib sensitivity. We therefore propose that dasatinib-based MAPKi therapy may restore antitumor efficacy in patients that have relapsed to standard-of-care therapy by broadly targeting proteins critical in melanoma therapy escape. Further, we submit that this experimental PDX paradigm could potentially improve preclinical evaluation of therapeutic modalities and augment our ability to identify biomarker-defined patient subsets that may respond to a given clinical trial.SINGLE SENTENCE SUMMARYBroad target inhibition effective as a salvage strategy in BRAF/MEK inhibitor-acquired resistance PDX
The impact of selected abiotic factors on zooplankton hatching process through real-time, in-situ observation
Authors: Dey Preyojon , Bradley Terence M. , Boymelgreen Alicia 
Published: January 2023

AbstractCurrent studies on abiotic impacts on marine microorganisms often focus on endpoint analysis (e.g., hatching rates, survival). Here, we demonstrate that a mechanistic understanding can be obtained through real-time measurement of respiration and morphology in controlled microenvironments over extended time periods. As a demonstration, temperature and salinity are chosen to represent critical abiotic parameters that are also threatened by climate change and a target species ofArtemia, a prominent zooplankton whose reproduction can affect the marine food pyramid. Different temperatures (20, 35, and 30ºC) and salinities (0, 25, 50, and 75 ppt) are shown to significantly alter the duration of hatching stages, metabolic rates, and hatchability. Higher temperatures and moderate salinity boosted metabolic reactivation of latent cysts, while higher temperatures alone sped up the process. Hatchability is inversely related to the duration of the differentiation stage of hatching, which persisted longer at lower temperatures and salinities. Initial oxygen availability affects respiration but not hatchability owing to temperature and salinity interactions.Graphical abstract
mini-MEndR: A 96-well mixed species culture assay to co-evaluate human and mouse Pax7+cell-mediated skeletal muscle repair
Authors: Gulati Nitya , Davoudi Sadegh , Xu Bin , Rjaibi Saifedine T. , Jacques Erik , Pham Justin , Fard Amir , McGuigan Alison P. , Gilbert Penney M. 
Published: January 2023

AbstractFunctional evaluation of molecules that are predicted to promote stem cell mediated endogenous repair often requiresin vivotransplant studies that are low throughput and hinder the rate of discovery. Here, we offer a strategy to rapidly test and prioritize molecules for functional validation studies. We miniaturized, simplified and expanded the functionality of a previously developed muscle endogenous repair (MEndR)in vitroassay that was shown to capture significant events of the first week of thein vivomuscle endogenous repair process. The new “mini-MEndR assay” consists of miniaturized cellulose scaffolds designed to fit in 96-well plates. The scaffold pores are infiltrated with myoblasts encapsulated in a fibrin-based hydrogel to form thin, engineered skeletal muscle tissues. By evaluating multiple commercially available human primary myoblast lines in 2D and 3D culture, we establish quality assurance metrics for cell line selection that standardize myotube template quality. Pre-adsorbing thrombin to the cellulose scaffolds facilitatesin situtissue polymerization, a critical modification that enables users proficient in myoblast culture to rapidly acquire myotube template fabrication expertise. Following the generation of the 3D myotube template, muscle stem cells (MuSCs), enriched from digested mouse skeletal muscle tissue using an improved magnetic-activated cell sorting protocol, are engrafted onto the engineered human muscle template. A regenerative milieu is then introduced by injuring the muscle tissue with a myotoxin. Addition of a known modulator of MuSC mediated repair recapitulates thein vivooutcomes (enhanced muscle production and Pax7+cell expansion), but only in the presence of both the stem cells and the regenerative milieu. By fluorescently labeling the mouse MuSCs, we demonstrate the feasibility of co-evaluating human and mouse Pax7+cell responses to drug treatment, thereby expanding the utility of the assay. Importantly, phenotypic data is collected with a high-content imaging system and is analyzed using CellProfiler-based image analysis pipelines. The miniaturized predictive assay offers a simple, scaled platform with which to co-investigate human and mouse skeletal muscle endogenous repair molecular modulators, and thus is a promising strategy to accelerate the muscle endogenous repair discovery pipeline.
A new Karyopherin-β2 binding PY-NLS epitope of HNRNPH2 is linked to neurodevelopmental disorders
Authors: Gonzalez Abner , Kim Hong Joo , Freibaum Brian D. , Joyce Fung Ho Yee , Brautigam Chad A. , Taylor J. Paul , Chook Yuh Min 
Published: January 2023

AbstractThe normally nuclear HNRNPH2 is mutated inHNRNPH2-related X-linked neurodevelopmental disorder causing the protein to accumulate in the cytoplasm. Interactions of HNRNPH2 with its importin Karyopherin–β2 (Transportin-1) had not been studied. We present a structure that shows Karyopherin-β2 binding HNRNPH2 residues 204-215, a proline-tyrosine nuclear localization signal or PY-NLS that contains a typical R-X2-4-P-Y motif,206RPGPY210, followed a new Karyopherin-β2 binding epitope at211DRP213that make many interactions with Karyopherin-β2 W373. Mutations at each of these sites decrease Karyopherin-β2 binding affinities by 70-100 fold, explaining aberrant accumulation in cells and emphasizing the role of nuclear import defects in the disease. Sequence/structure analysis suggests that the new epitope C-terminal of the PY-motif, which binds Karyopherin-β2 W373, is rare and thus far limited to close paralogs HNRNPH2, HNRNPH1 and HNRNPF. Karyopherin-β2 W373, a HNRNPH2-binding hotspot, corresponds to W370 of close paralog Transportin-2, a site of pathological variants in patients with neurodevelopmental abnormalities, suggesting that Transportin-2-HNRNPH2/H1/F interactions may be compromised in the abnormalities.SummaryHNRNPH2 variants inHNRNPH2-related X-linked neurodevelopmental disorder aberrantly accumulate in the cytoplasm. A structure of Karyopherin-β2•HNRNPH2 explains nuclear import defects of the variants, reveals a new NLS epitope that suggests mechanistic changes in pathological variants of Karyopherin-β2 paralog Transportin-2.
Sex and estrous cycle stage shape left-right asymmetry in chronic hippocampal seizures in mice
Authors: Cutia Cathryn A. , Leverton Leanna K. , Christian-Hinman Catherine A. 
Published: January 2023

AbstractLateralization of hippocampal function is indicated by varied outcomes of patients with neurological disorders that selectively affect one hemisphere of this structure, such as temporal lobe epilepsy (TLE). The intrahippocampal kainic acid (IHKA) injection model of TLE allows for targeted damage to the left or right hippocampus, enabling systematic comparison of effects of left-right asymmetry on seizure and non-seizure outcomes. Although varying non-seizure phenotypic outcomes based on injection side in dorsal hippocampus were recently evaluated in this model, differences in chronic seizure patterns in left- (IHKA-L) vs. right-injected (IHKA-R) IHKA animals have yet to be evaluated. Here, we evaluated hippocampal seizure incidence in male and female IHKA-L and IHKA-R mice. Females displayed increased electrographic seizure activity compared to males at both 2 months and 4 months post-injection (mpi). In addition, IHKA-L females showed higher seizure frequency than IHKA-R on diestrus and estrus at 2 mpi, but seizure duration and time in seizures were only higher in IHKA-L females on diestrus. These cycle stage-associated changes, however, did not persist to 4 mpi. Furthermore, this lateralized difference in seizure burden was not observed in males. These results indicate for the first time that the side of IHKA injection can shape chronic electrographic seizure burden. Overall, these results demonstrate a female-specific left-right asymmetry in hippocampal function can interact with estrous cycle stage to shape chronic seizures in mice with epilepsy, with implications for neural activity and behavior in both normal and disease states.
Threat and reward imminence processing in the human brain
Authors: Murty Dinavahi V. P. S. , Song Songtao , Surampudi Srinivas Govinda , Pessoa Luiz 
Published: January 2023

AbstractIn the human brain, aversive and appetitive processing have been studied with controlled stimuli in rather static settings. In addition, the extent to which aversive- and appetitive-related processing engage distinct or overlapping circuits remains poorly understood. Here, we sought to investigate the dynamics of aversive and appetitive processing while male and female participants engaged in comparable trials involving threat-avoidance or reward-seeking. A central goal was to characterize the temporal evolution of responses during periods ofthreat or reward imminence. For example, in the aversive domain, we predicted that the bed nucleus of the stria terminalis (BST), but not the amygdala, would exhibit anticipatory responses given the role of the former in anxious apprehension. We also predicted that the periaqueductal gray (PAG) would exhibit threat-proximity responses based on its involvement in proximal-threat processes, and that the ventral striatum would exhibit threat-imminence responses given its role in threat escape in rodents. Overall, we uncovered imminence-related temporally increasing (“ramping”) responses in multiple brain regions, including the BST, PAG, and ventral striatum, subcortically, and dorsal anterior insula and anterior midcingulate, cortically. Whereas the ventral striatum generated anticipatory responses in the proximity of reward as expected, it also exhibited threat-related imminence responses. In fact, across multiple brain regions, we observed a main effect of arousal. In other words, we uncovered extensive temporally-evolving, imminence-related processing in both the aversive and appetitive domain, suggesting that distributed brain circuits are dynamically engaged during the processing of biologically relevant information irrespective of valence, findings further supported by network analysis.Significance StatementIn the human brain, aversive and appetitive processing have been studied with controlled stimuli in rather static settings. Here, we sought to investigate the dynamics of aversive/appetitive processing while participants engaged in trials involving threat-avoidance or reward-seeking. A central goal was to characterize the temporal evolution of responses during periods ofthreat or reward imminence. We uncovered imminence-related temporally increasing (“ramping”) responses in multiple brain regions, including the bed nucleus of the stria terminalis, periaqueductal gray, and ventral striatum, subcortically, and dorsal anterior insula and anterior midcingulate, cortically. Overall, we uncovered extensive temporally-evolving, imminence-related processing in both the aversive and appetitive domain, suggesting that distributed brain circuits are dynamically engaged during the processing of biologically relevant information irrespective of valence.
Genome-wide association analysis of plasma lipidome identifies 495 genetic associations
Authors: Ottensmann Linda , Tabassum Rubina , Ruotsalainen Sanni E. , Gerl Mathias J. , Klose Christian , Widén Elisabeth , FinnGen  , Simons Kai , Ripatti Samuli , Pirinen Matti 
Published: January 2023

AbstractHuman plasma lipidome captures risk for cardio-metabolic diseases. To discover new lipid-associated variants and understand link between lipid species and cardiometabolic disorders, we performed univariate and multivariate genome-wide analyses of 179 lipid species in 7,174 Finnish individuals. We further fine-mapped the associated loci, prioritized genes, and examined their disease links in 377,277 FinnGen participants. We identified 495 genome-trait associations in 56 genetic loci including 9 novel loci, with a considerable boost provided by multivariate analysis. For 26 loci, fine-mapping identified variants with a high causal probability, including 14 coding variants indicating likely causal genes. Phenome-wide analysis across 953 disease endpoints in FinnGen revealed disease associations for 40 lipid loci. For 11 known coronary artery disease risk variants, we detected strong associations with lipid species. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomics data and reveals genetic links between diseases and detailed lipid measures beyond standard lipids.
Increased AGE-RAGE axis stress in methamphetamine (MA) abuse and MA-induced psychosis: associations with oxidative stress and increased atherogenicity
Authors: Al-Hakeim Hussein Kadhem , Altufaili Mazin Fadhil , Alhaideri Amer Fadhil , Almulla Abbas F. , Moustafa Shatha Rouf , Maes Michael 
Published: January 2023

AbstractBackground and aimsMethamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defenses. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGE). There are no data on whether MA use may cause AGE-RAGE stress, and whether the latter is associated with MIP.MethodsThis case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defenses (ANTIOX), magnesium, copper, atherogenicity, and AGE, soluble RAGE (sRAGE), and computed a composite reflecting AGE-RAGE axis activity.FindingsMA dependence and use were accompanied by increased AGE, sRAGE, AGE-RAGE, OSTOX/ANTIOX, Castelli risk index 1 and atherogenic index of plasma, indicating that MA causes AGE-RAGE axis stress, oxidative damage, and atherogenicity. The severity of dependence and MA dose were strongly correlated with increased sRAGE concentrations. Increased AGE-RAGE stress was strongly associated with OSTOX, OSTOX/ANTIOX, and MA-induced intoxication symptoms, psychosis, hostility, excitation, and formal thought disorders. We found that 54.8% of the variance in MIP symptoms was explained by the regression on AGE-RAGE, the OSTOX/ANTIOX ratio, lowered magnesium, and increased copper, and that these biomarkers mediated the effects of increasing MA doses on MIP symptoms. We found that 36.0% of the variance in the atherogenicity indices was explained by OSTOX/ANTIOX, AGE-RAGE, and lowered magnesium.ConclusionsMA use causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.
Development and qualification of a high-yield recombinant human Erythropoietin biosimilar
Authors: Nag Kakon , Islam Md. Jikrul , Rahman Khan Md. Maksudur , Rahman Chowdhury Md. Mashfiqur , Haq Sarker Md. Enamul , Kumar Samir , Khan Habiba , Chakraborty Sourav , Roy Rony , Roy Raton , Kaunain Oli Md. Shamsul , Barman Uttam , Hasan Bappi Md. Emrul , Biswas Bipul Kumar , Mohiuddin Mohammad , Sultana Naznin 
Published: January 2023

ABSTRACTRecombinant human erythropoietin (rhEPO) has been saving millions of lives worldwide as a potent and safe treatment for the lack of erythrocyte, which is caused by chronic kidney disease (CKD) and other issues. Several biosimilars of rhEPO have been approved since the expiry of the relevant patents to provide cost-effective options but the price of rhEPO is still high for the affordability of global community. Therefore, development of biosimilar of rhEPO at a lower price is highly necessary. Here we report the development and characterization of a biosimilar of rhEPO with high-yield satisfying regulatory requirements. The hEPO-expressing cDNA was stably expressed in CHO cells with successive transfection. The master cell bank (MCB) and working cell bank (WCB) were established from the best selected clone and characterized for 50 passages. The rhEPO was expressed from the WCB in single-use suspension culture system with a high-titer (1.24±0.16 g/L). To the best of our knowledge this is the highest reported rhEPO titer to date. The rhEPO was purified using a series of validated chromatography unit processes including virus inactivation and filtration. The purified EPO was formulated in serum-free buffer, sterile filtered, and analyzed as the biosimilar of reference product Eprex®. Physicochemical analysis strongly suggested similarities between the developed rhEPO (GBPD002) and the reference. Thein vitroandin vivofunctional assays confirmed the similar biofunctionality of the GBPD002 and Eprex®. GBPD002 could provide a less-expensive solution to the needful communities as an effective and safe biosimilar where rhEPO treatment is necessary.
Sensitized piRNA reporter identifies multiple RNA processing factors involved in piRNA-mediated gene silencing
Authors: Brown Jordan , Zhang Donglei , Chen Wenjun , Lee Heng-Chi 
Published: January 2023

AbstractMetazoans guard their germlines against transposons and other foreign transcripts with PIWI-interacting RNAs (piRNAs). Due to the robust heritability of the silencing initiated by piRNAs inC.elegans, previous screens usingCaenorhabditis eleganswere strongly biased to uncover members of this pathway in the maintenance process but not in the initiation process. To identify novel piRNA pathway members, we have utilized a sensitized reporter strain which detects defects in initiation, amplification, or regulation of piRNA silencing. Using our reporter, we have identified Integrator complex subunits, nuclear pore components, protein import components, and pre-mRNA splicing factors as essential for piRNA-mediated gene silencing. We found the snRNA processing cellular machine termed the Integrator complex is required for both type I and type II piRNA production. Notably, we identified a role for nuclear pore and nucleolar components in promoting the perinuclear localization of anti-silencing CSR-1 Argonaute, as well as a role for Importin factor IMA-3 in nuclear localization of silencing Argonaute HRDE-1. Together, we have shown that piRNA silencing is dependent on evolutionarily ancient RNA processing machinery that has been co-opted to function in the piRNA mediated genome surveillance pathway.