bluuebunny/crossref_metadata_2025_split huggingface dataset:
Propofol Mediated Unconsciousness Disrupts Progression of Sensory Signals through the Cortical Hierarchy
Authors: Tauber John M. , Brincat Scott L. , Stephen Emily P. , Donaghue Jacob A. , Kozachkov Leo , Brown Emery N. , Miller Earl K. 
Published: June 2023

AbstractA critical component of anesthesia is the loss sensory perception. Propofol is the most widely used drug for general anesthesia, but the neural mechanisms of how and when it disrupts sensory processing are not fully understood. We analyzed local field potential (LFP) and spiking recorded from Utah arrays in auditory cortex, associative cortex, and cognitive cortex of non-human primates before and during propofol mediated unconsciousness. Sensory stimuli elicited robust and decodable stimulus responses and triggered periods of stimulus-induced coherence between brain areas in the LFP of awake animals. By contrast, propofol mediated unconsciousness eliminated stimulus-induced coherence and drastically weakened stimulus responses and information in all brain areas except for auditory cortex, where responses and information persisted. However, we found stimuli occurring during spiking Up states triggered weaker spiking responses than in awake animals in auditory cortex, and little or no spiking responses in higher order areas. These results suggest that propofol’s effect on sensory processing is not just due to asynchronous down states. Rather, both Down states and Up states reflect disrupted dynamics.
Demographic disequilibrium and growth-mortality asymmetry of forests across climate gradients
Authors: Zhou Jian 
Published: June 2023

AbstractForests are commonly believed to adapt themselves to environment and ultimately converge to demographic equilibrium characterized by a fixed size-structure. The expectation, however, has been lacking in mathematical rigor and been debating for evidential solidity. Here, by giving a general time-dynamic solution to the forest demographic model and verifying the prediction with worldwide forest inventory data, we show the inherent disequilibrium of forest demography with oscillations of forest-size-structure. Forests adapt to environment in a way of asymmetric growth-mortality tradeoff along climate gradients, which generates divergence to convergence oscillations of size-structure with rising temperature and precipitation. The demographic disequilibrium framework can provide a general basis for elucidating the variability of forest-size-structure with implications on intrinsic ecosystem instability, and for improving the Earth system modeling.
Late reproduction is associated with extended female survival but not with familial longevity
Authors: de Kat Annelien C , Roelofs Femke , Slagboom P. Eline , Broekmans Frank JM , Beekman Marian , van den Berg Niels 
Published: June 2023

AbstractObjectiveFemale reproductive health comprises adequate oocyte quality and quantity, normal fecundability, a normal course of pregnancy, and the delivery of healthy offspring. General aging patterns and the maintenance of somatic health have been associated with female reproductive health. However, it is unknown whether better long-term somatic maintenance is directly related to reproductive outcomes, and whether there is a shared genetic predisposition underlying both somatic and reproductive aging. Here we investigate whether reproductive health is related to female lifespan or familial longevity.DesignObservational studySubjects10,255 female members of a multigenerational historical cohort (1812-1910), the LINKing System for historical family reconstruction (LINKS) and 1,258 females from 651 long-lived families in the Leiden Longevity Study.Main outcome measuresThe association between reproductive characteristics and longevity was studied both on an individual and familial level. Individual survival was studied in relation to age at last childbirth and total number of children. Familial longevity was studied through parental survival and related to age at last childbirth, total number of children and a polygenic risk score (PRS) for age at menopause.ResultsFemales giving birth to their last child at a higher age lived longer: for each year increase in the age of the birth of the last child, a woman’s lifespan increased with 0.06 years (22 days) (p<0.005). Females who lived to be in the top 10% survivors of their birth cohort (n=2,241, 21.9%) on average gave birth to their last child at a 1% later age than the remaining cohort (IRR=1.01, p<0.005).Females with 1 or 2 long-lived parents did not have a higher mean age of last childbirth. There was neither a significant association between an increasing number of long-lived ancestral family members (familial longevity), nor the PRS.ConclusionFemale reproductive health associates with a longer lifespan and with survival to more extreme ages (longevity). The heritable component in familial longevity, however, does not associate to extended reproductive health and the PRS underlying age at menopause does not explain familial longevity. Other factors in somatic maintenance that support a longer lifespan are likely to have an impact on reproductive health.
EPIC-TRACE: predicting TCR binding to unseen epitopes using attention and contextualized embeddings
Authors: Korpela Dani , Jokinen Emmi , Dumitrescu Alexandru , Huuhtanen Jani , Mustjoki Satu , Lähdesmäki Harri 
Published: June 2023

AbstractT cells play an essential role in adaptive immune system to fight pathogens and cancer but may also give rise to autoimmune diseases. The recognition of a peptide-MHC (pMHC) complex by a T cell receptor (TCR) is required to elicit an immune response. Many machine learning models have been developed to predict the binding, but generalizing predictions to pMHCs outside the training data remains challenging.We have developed a new machine learning model that utilizes information about the TCR from bothαandβchains, epitope sequence, and MHC. Our method uses ProtBERT embeddings for the amino acid sequences of both chains and the epitope, as well as convolution and multi-head attention architectures. We show the importance of each input feature as well as the benefit of including epitopes with only a few TCRs to the training data. We evaluate our model on existing databases and show that it compares favorably against other state-of-the-art models.
Freeze dehydration vs. supercooling in tree stems: physical and physiological modelling
Authors: Bozonnet Cyril , Saudreau Marc , Badel Eric , Améglio Thierry , Charrier Guillaume 
Published: June 2023

AbstractFrost resistance is the major factor affecting the distribution of plant species at high latitude and elevation. The main effects of freeze-thaw cycles are damage to living cells and formation of gas embolism in tree xylem vessels. Lethal intracellular freezing can be prevented in living cells by two mechanisms: dehydration and deep supercooling. We developed a multiphysics numerical model coupling water flow, heat transfer, and phase change, considering different cell types in plant tissues, to study the dynamics and extent of cell dehydration, xylem pressure changes, and stem diameter changes in response to freezing and thawing. Results were validated using experimental data for stem diameter changes of walnut trees. The effect of cell mechanical properties was found to be negligible as long as the intracellular tension developed during dehydration was sufficiently low compared to the ice induced cryostatic suction. The model was finally used to explore the coupled effects of relevant physiological parameters (initial water and sugar content) and environmental conditions (air temperature variations) on the dynamics and extent of dehydration. It revealed configurations where cell dehydration could be sufficient to protect cells from intracellular freezing, and situations where supercooling was necessary. This model, freely available with this paper, could easily be extended to explore different anatomical structures, different species and more complex physical processes.
Oligomerization-dependent and synergistic regulation of Cdc42 GTPase cycling by a GEF and a GAP
Authors: Tschirpke Sophie , Daalman Werner K-G. , van Opstal Frank , Laan Liedewij 
Published: June 2023

AbstractCell polarity is a crucial biological process essential for cell division, directed growth, and motility. InSaccharomyces cerevisiae, polarity establishment centers around the small Rho-type GTPase Cdc42, which cycles between GTP-bound and GDP-bound states, regulated by GEFs like Cdc24 and GAPs such as Rga2. To dissect the dynamic regulation of Cdc42, we employedin vitroGTPase assays, revealing inverse concentration-dependent profiles for Cdc24 and Rga2: with increasing concentration, Cdc24’s GEF activity is non-linear and oligomerization-dependent, which is possibly linked to the relief of its self-inhibition. In contrast, Rga2’s GAP activity saturates, likely due to self-inhibition upon oligomerization. Together, Cdc24 and Rga2 exhibit a strong synergy driven by weak Cdc24-Rga2 binding. We propose that the synergy stems from Cdc24 alleviating the self-inhibition of oligomeric Rga2. We believe this synergy contributes to efficient regulation of Cdc42’s GTPase cycle over a wide range of cycling rates, enabling cells to resourcefully establish polarity. As Cdc42 is highly conserved among eukaryotes, we propose the GEF-GAP synergy to be a general regulatory property in other eukaryotes.
Zero-mode waveguide nanowells for single-molecule detection in living cells
Authors: Yang Sora , Klughammer Nils , Barth Anders , Tanenbaum Marvin E. , Dekker Cees 
Published: June 2023

AbstractSingle-molecule fluorescence imaging experiments generally require sub-nanomolar protein concentrations to isolate single protein molecules, which makes such experiments challenging in live cells due to high intracellular protein concentrations. Here, we show that single-molecule observations can be achieved in live cells through a drastic reduction in the observation volume using overmilled zero-mode waveguides (ZMWs - subwavelength-size holes in a metal film). Overmilling of the ZMW in a palladium film creates a nanowell of tunable size in the glass layer below the aperture, which cells can penetrate. We present a thorough theoretical and experimental characterization of the optical properties of these nanowells over a wide range of ZMW diameters and overmilling depths, showing an excellent signal confinement and a five-fold fluorescence enhancement of fluorescent molecules inside nanowells. ZMW nanowells facilitate live-cell imaging, as cells form stable protrusions into the nanowells. Importantly, the nanowells greatly reduce cytoplasmic background fluorescence, enabling detection of individual membrane-bound fluorophores in the presence of high cytoplasmic expression levels, which could not be achieved with TIRF microscopy. Zero-mode waveguide nanowells thus provide great potential to study individual proteins in living cells.Graphical abstract
Proteomic profiling identifies Serpin B9 as mediator of resistance to CAR T-cell and bispecific antibody treatment in B-cell lymphoma
Authors: Brinkmann Berit J. , Capraz Tümay , Roider Tobias , Knoll Mareike , Kolb Carolin , Liu Yi , Angeli-Terzidou Antonia-Eugenia , Paramasivam Nagarajan , Chapuy Björn , Eckstein Volker , Sauer Tim , Schmitt Michael , Rosenwald Andreas , Müller-Tidow Carsten , Huber Wolfgang , Dietrich Sascha 
Published: June 2023

AbstractAlthough T-cell-engaging therapies are highly effective in patients with relapsed and/or refractory B-cell non-Hodgkin lymphoma (B-NHL), responses are often not durable. To identify tumor-intrinsic drivers of resistance, we quantifiedin-vitroresponse to CD19-directed chimeric antigen receptor T-cells (CD19-CAR) and bispecific antibodies (BsAb) across 46 B-NHL cell lines and measured their proteomic profiles at baseline. Among the proteins associated with poorin-vitroresponse was Serpin B9, an endogenous granzyme B inhibitor. Knock-out ofSERPINB9in cell lines with high intrinsic expression rendered them more susceptible to CD19-CAR and CD19-BsAb. Overexpression in cell lines with low intrinsic expression attenuated responses. Polatuzumab, vorinostat, lenalidomide, or checkpoint inhibitors improved response to CD19-CAR, although independently of Serpin B9 expression. Besides providing an important resource of therapy response and proteomic profiles, this study refines our understanding of resistance in T-cell engaging therapies, and suggests clinically relevant combination regimes.
Engineeringin vitromodels of cystic fibrosis lung disease using neutrophil extracellular trap inspired biomaterials
Authors: Boboltz Allison M. , Yang Sydney , Duncan Gregg A. 
Published: June 2023

AbstractCystic fibrosis (CF) is a muco-obstructive lung disease where inflammatory responses due to chronic infection result in the accumulation of neutrophil extracellular traps (NETs) in the airways. NETs are web-like complexes comprised mainly of decondensed chromatin that function to capture and kill bacteria. Prior studies have established excess release of NETs in CF airways increases viscoelasticity of mucus secretions and reduces mucociliary clearance. Despite the pivotal role of NETs in CF disease pathogenesis, currentin vitromodels of this disease do not account for their contribution. Motivated by this, we developed a new approach to study the pathobiological effects of NETs in CF by combining synthetic NET-like biomaterials, composed of DNA and histones, with anin vitrohuman airway epithelial cell culture model. To determine the impact of synthetic NETs on airway clearance function, we incorporated synthetic NETs into mucin hydrogels and cell culture derived airway mucus to assess their rheological and transport properties. We found that the addition of synthetic NETs significantly increases mucin hydrogel and native mucus viscoelasticity. As a result, mucociliary transportin vitrowas significantly reduced with the addition of mucus containing synthetic NETs. Given the prevalence of bacterial infection in the CF lung, we also evaluated the growth ofPseudomonas aeruginosain mucus with or without synthetic NETs. We found mucus containing synthetic NETs promoted microcolony growth and prolonged bacterial survival. Together, this work establishes a new biomaterial enabled approach to study innate immunity mediated airway dysfunction in CF.
Piroplasm parasites (Apicomplexa: Piroplasmida) in northeastern populations of the invasive Asian longhorned tick,Haemaphysalis longicornisNeumann (Ixodida: Ixodidae), in the United States
Authors: Herb H , Ferreira FC , Gonzalez J , Fonseca DM 
Published: June 2023

AbstractPiroplasms, which include the agents of cattle fever and human and dog babesiosis, are a diverse group of blood parasites of significant veterinary and medical importance. The invasive Asian longhorned tick,Haemaphysalis longicornis, is a known vector of piroplasms in its native range in east Asia and invasive range in Australasia. In the US state of Virginia,H. longicornishas been associated withTheileria orientalisIkeda outbreaks that caused cattle mortality. We examined 667H. longicorniscollected in 2021 from three sites in New Brunswick, New Jersey, the US state where established populations of this species were first detected in 2017. We used primers targeting the 18S small subunit rRNA and the cytochrome b oxidase loci and unveiled the presence of DNA from an unidentifiedTheileriaspecies (in 1 nymph) andTheileria cervitype F (1 adult, 5 nymphs). In addition, we sequenced a 130 bp fragment of the cytochrome oxidase b locus fromOdocoileus virginianus, the white-tailed deer, in a partially engorged questingH. longicornis, supporting the association of this tick species with deer. We also detected DNA from an undescribedBabesiasensu stricto (‘true’Babesia, 2 adults, 2 nymphs) as well asBabesiasp. Coco (1 adult, 1 nymph). Finally, we detected DNA fromBabesia microtiS837 (1 adult, 4 nymphs).Babesia microtiS837 has been sequenced from striped skunks,Mephitis mephitis, and is closely related to the human pathogenB. microtiUS-type. The five parasites we are associating withH. longicornisrepresent a diverse assemblage spanning three clades in the piroplasm phylogeny, two undescribed, raising concerns of transmission amplification of veterinary pathogens as well as spillover of pathogens from wildlife to humans.
Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor
Authors: Jablonowski Carolyn , Quarni Waise , Singh Shivendra , Tan Haiyan , Bostanthirige Dhanushka Hewa , Jin Hongjian , Fang Jie , Chang Ti-Cheng , Finkelstein David , Cho Ji-Hoon , Hu Dongli , Pagala Vishwajeeth , Sakurada Sadie Miki , Pruett-Miller Shondra M. , Wang Ruoning , Murphy Andrew , Freeman Kevin , Peng Junmin , Davidoff Andrew M , Wu Gang , Yang Jun 
Published: June 2023

AbstractDysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that Jumonji Domain Containing 6, Arginine Demethylase and Lysine Hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a “molecular glue” that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.
Influence of DNA extraction methods on microbiome and resistome analysis in activated sludge
Authors: Calderón-Franco David , Kok Dana , Dukker Renzo , Abbas Ben , Abreu-Silva Joana , Rocha Jaqueline , Lopez Marin Marco Antonio , Vega Rebeca Pallarés , Gajdos Stanislav , Ananth Mythili , Apoorva Seeram , Karpisek Ivan , Solcova Milada , Leal Lucia Hernández , Bartacek Jan , Manaia Célia , Purkrtova Sabina , Weissbrodt David G. 
Published: June 2023

AbstractAmplicon sequencing, metagenomics, and quantitative polymerase chain reaction (qPCR) are commonly used techniques to analyse microorganisms and antibiotic resistance genes (ARGs) in activated sludge from wastewater treatment plants (WWTPs). However, the lack of workflow harmonisation poses challenges in comparing measurements across studies and research groups. To address this issue, we examined the impact of DNA extraction procedures on 16S rRNA gene amplicon sequencing, shotgun metagenomics, and qPCR analyses of activated sludge by combining two widely used DNA extraction kits (PowerSoil and FastDNA) and two commonly employed disruption instruments (bead-beater and vortex) through a 2×2 factorial experimental design involving four groups of three analysts performing DNA extractions in triplicates. Our findings revealed significant differences in DNA yield, purity, and reproducibility of amplicon sequencing profiles among the extraction kits. Operator variability also influenced the results. We compared microbiome profiles obtained by amplicon sequencing and metagenomics and observed that bead-beating introduced more variability among triplicates compared to vortexing. The combinations of extraction kits and disruption instruments impacted the relative abundances of specific phyla such asActinobacteriota,Bacteroidota, andNitrospirota. For resistome analysis, we employed metagenomics for high-resolution profiling and qPCR for high-sensitivity detection of ARGs. The compositions and diversities of resistome datasets were not significantly affected by the choice of extraction kits and disruption instruments. Although using the same method is ideal for accurate comparisons, our results suggest that acceptable reproducibility can still be achieved when using different methods. This finding encourages the implementation of ARG monitoring in wastewater treatment processes. However, it is important to consider biases introduced by DNA extraction workflows when designing analytical studies, interpreting their results, and comparing their findings. Striving for more harmonised molecular workflows is crucial in the field of wastewater microbiology and engineering.Abstract FigureGraphical abstract
Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism
Authors: Yazdi Zhinous Shahidzadeh , Streeten Elizabeth A. , Whitlatch Hilary B. , Montasser May E. , Beitelshees Amber L. , Taylor Simeon I. 
Published: June 2023

ABSTRACTContextThe body has evolved homeostatic mechanisms to maintain free levels of Ca+2and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis.ObjectiveTo investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.DesignCrossover clinical trial studying participants before and after VitD3-supplementation.SettingCommunity.Participants11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL).InterventionsVitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL.ResultsVitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3).ConclusionsSuppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity – thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.