bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dark nanodiscs as a model membrane for evaluating membrane protein thermostability by differential scanning fluorimetry
Authors: Selvasingh Jazlyn A. , McDonald Eli Fritz , Mckinney Jacob R. , Meiler Jens , Ledwitch Kaitlyn V. 
Published: May 2023

AbstractMeasuring protein thermostability provides valuable information on the biophysical rules that govern structure-energy relationships of proteins. However, such measurements remain a challenge for membrane proteins. Here, we introduce a new experimental system to evaluate membrane protein thermostability. This system leverages a recently-developed non-fluorescent membrane scaffold protein (MSP) to reconstitute proteins into nanodiscs and is coupled with a nano-format of differential scanning fluorimetry (nanoDSF). This approach offers a label-free and direct measurement of the intrinsic tryptophan fluorescence of the membrane protein as it unfolds in solution without signal interference from the “dark” nanodisc. In this work, we demonstrate the application of this method using the disulfide bond formation protein B (DsbB) as a test membrane protein. NanoDSF measurements of DsbB reconstituted in dark nanodiscs show a complex biphasic thermal unfolding pattern in the presence of lipids with a minor unfolding transition followed by a major transition. The inflection points of the thermal denaturation curve reveal two distinct unfolding midpoint melting temperatures (Tm) of 70.5 °C and 77.5 °C, consistent with a three-state unfolding model. Further, we show that the catalytically conserved disulfide bond between residues C41 and C130 drives the intermediate state of the unfolding pathway for DsbB in a nanodisc. We introduce this method as a new tool that can be used to understand how compositionally, and biophysically complex lipid environments drive membrane protein stability.
Medication-Invariant Resting Aperiodic and Periodic Neural Activity in Parkinson’s Disease
Authors: McKeown Daniel J , Jones Manon , Pihl Camilla , Finley Anna , Kelley Nicholas , Baumann Oliver , Schinazi Victor R. , Moustafa Ahmed A. , Cavanagh James F. , Angus Douglas J 
Published: May 2023

ABSTRACTParkinson’s Disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open and eyes-closed resting EEG of PD participants (N= 26) on and off medication, and age-matched controls (CTL;N= 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in eyes-open recordings and no reliable differences in beta power were observed. Differences between PD and CTLs in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.
First trimester maternal serum microRNA expression profile differentiates between uncomplicated pregnancies, and pregnancies which develop pre-eclampsia
Authors: Hedley Paula L. , Larsen Severin Olesen , Wøjdemann Karen R. , Shalmi Anne-Cathrine , Placing Sophie , Rode Line , Gjerris Anne Catrine , Sundberg Karin , Tabor Ann , Christiansen Michael 
Published: May 2023

AbstractNumerous circulating microRNAs (miRNAs) have been detected in maternal blood. Initial studies in third trimester demonstrated differential miRNA expression profiles between uncomplicated pregnancies and pregnancies complicated by pre-eclampsia (PE). Recently, studies in first trimester have shown similar differential profiles, however, these studies were often under-powered. We conducted a nested case-control study, in which serum samples, taken between 10-14 weeks gestation, were obtained from 413 singleton pregnant women, 126 of which later developed PE. Total RNAs were purified and a selection of 46 miRNAs plus two miRNA controls were quantitated by real time quantitative PCR. Seven of the miRNAs, hsa-miR-181b-5p, -323a-3p, -518b, -363-3p, -20a-5p, -29a-3p, and -142-3p, could differentiate between uncomplicated pregnancies and pregnancies which develop PE, but only a single miRNA, hsa-miR-363-3p, could differentiate between mild and severe PE. A combination of all seven differentiating miRNAs was the best at discriminating between PE and uncomplicated pregnancies (AUC= 0.879). In conclusion, first trimester maternal serum miRNA expression profile could differentiate between uncomplicated pregnancies and pregnancies complicated by PE. These circulating miRNA markers have the potential to improve risk assessment of PE in the first trimester, weeks before the onset of symptoms.
The New Normal: Delayed Peak SARS-CoV-2 Viral Loads Relative to Symptom Onset and Implications for COVID-19 Testing Programs
Authors: Frediani Jennifer K. , Parsons Richard , McLendon Kaleb B. , Westbrook Adrianna L. , Lam Wilbur , Martin Greg , Pollock Nira R. 
Published: May 2023

AbstractBackgroundEarly in the COVID-19 pandemic, peak viral loads coincided with symptom onset. We hypothesized that in a highly immune population, symptom onset might occur earlier in infection, coinciding with lower viral loads.MethodsWe assessed SARS-CoV-2 and influenza A viral loads relative to symptom duration in recently-tested adults. Symptomatic participants ≥16y presenting to testing sites in Georgia (4/2022-4/2023; Omicron variant predominant) provided symptom duration. Nasal swab samples were tested by the Xpert Xpress SARS-CoV-2/Flu/RSV assay and Ct values recorded. Nucleoprotein concentrations in SARS-CoV-2 PCR-positive samples were measured by Single Molecule Array. To estimate hypothetical antigen rapid diagnostic test (Ag RDT) sensitivity on each day after symptom onset, percentages of individuals with Ct value ≤30 or ≤25 were calculated.ResultsOf 621 SARS-CoV-2 PCR-positive individuals (64.1% women, median 40.9y), 556/621 (89.5%) had a history of vaccination, natural infection, or both. By both Ct value and antigen concentration measurements, median viral loads rose from the day of symptom onset and peaked on the fourth day. Ag RDT sensitivity estimates were 35.7-71.4% on the first day, 63.9-78.7% on the third day, and 78.6-90.6% on the fourth day of symptoms.In 74 influenza A PCR-positive individuals (55.4% women; median 35.0y), median influenza viral loads peaked on the second day of symptoms.ConclusionsIn a highly immune adult population, median SARS-CoV-2 viral loads peaked on the fourth day of symptoms. Influenza A viral loads peaked soon after symptom onset. These findings have implications for ongoing use of Ag RDTs for COVID-19 and influenza.Key PointsIn a highly immune adult population, median SARS-CoV-2 viral loads by cycle threshold and antigen measurements peaked on the fourth day of symptoms, with implications for testing practice. In contrast, viral loads for influenza A peaked soon after symptom onset.
Two-Step Light Gradient Boosted Model to identify human West Nile Virus infection risk factor in Chicago
Authors: Wan Guangya (Wayne) , Allen Joshua , Ge Weihao , Rawlani Shubham , Uelmen John , Mainzer Liudmila Sergeevna , Smith Rebecca Lee 
Published: May 2023

AbstractWest Nile virus (WNV), a flavivirus transmitted by mosquito bites, causes primarily mild symptoms but can also be fatal. Therefore, predicting and controlling the spread of West Nile virus is essential for public health in endemic areas. We hypothesized that socioeconomic factors may influence human risk from WNV. We analyzed a list of weather, land use, mosquito surveillance, and socioeconomic variables for predicting WNV cases in 1-km hexagonal grids across the Chicago metropolitan area. We used a two-stage lightGBM approach to perform the analysis and found that hexagons with incomes above and below the median are influenced by the same top characteristics. We found that weather factors and mosquito infection rates were the strongest common factors. Land use and socioeconomic variables had relatively small contributions in predicting WNV cases. The Light GBM handles unbalanced data sets well and provides meaningful predictions of the risk of epidemic disease outbreaks.
Evidence for a Male Bias in Atlantic Blue Crab Pot-Based Sampling
Authors: Brunson Jeff F. , Sitta Kimberly A. , Kendrick Michael R. , Kingsley-Smith Peter R. 
Published: May 2023

AbstractThe Atlantic Blue CrabCallinectes sapidusis an ecologically- and economically-important species that supports one of the highest valued commercial fisheries in coastal South Carolina, USA. Researchers at the South Carolina Department of Natural Resources conduct multiple surveys to monitor the status of the Atlantic Blue Crab using a variety of gear configurations. Demographic characterizations, however, can often be influenced by sampling gear-related biases. We compared blue crab sex ratios between passive, pot-based, sampling and active, trawl-based, sampling across three estuaries in the fall and for year-round sampling in a single estuary. For fall sampling, the percent of males in pots was 20.1% higher than values observed for trawl-based sampling, while an overall male bias of 22.7% was observed for year-round sampling; however, this bias was only significant in certain months. Our findings suggest that while different sampling gears may offer their own advantages, such as greater suitability to effectively sample specific habitats, the resulting characterizations of population demographics can differ among gear types. Recognizing gear related biases is important for ensuring that field surveys are representative of populations, particularly when sex-specific modeling approaches are used as part of stock assessments to determine population status.
Extreme genome scrambling in crypticOikopleura dioicaspecies
Authors: Plessy Charles , Mansfield Michael J. , Bliznina Aleksandra , Masunaga Aki , West Charlotte , Tan Yongkai , Liu Andrew W. , Grašič Jan , Pisula María Sara del Río , Sánchez-Serna Gaspar , Fabrega-Torrus Marc , Ferrández-Roldán Alfonso , Roncalli Vittoria , Navratilova Pavla , Thompson Eric M. , Onuma Takeshi , Nishida Hiroki , Cañestro Cristian , Luscombe Nicholas M. 
Published: May 2023

SUMMARYGenes are not randomly distributed throughout chromosomes. How gene order evolves and how selective constraints act to preserve or vary gene order, both at the macrosyntenic level of whole chromosomes or microsyntenic level of gene blocks, are central questions of evolutionary biology and genomics that remain largely unsolved. Here, after sequencing several genomes of the appendicularian tunicateOikopleura dioicafrom different locations around the globe, we show an unprecedented amount of genome scrambling in animals with no obvious morphological differences, consistent with cryptic speciation. Our assemblies suggest that all members of this clade possess a common 3-chromosome karyotype, and that different species largely preserve gene content, despite the presence of thousands of rearrangements in gene order. The movements of genes are largely restricted to chromosome arms and sex-specific regions, which appear to be the primary unit of macrosynteny conservation, and examples of these within-arm movements can be seen in theHoxandFgfgene families. Our approach employing whole-genome alignments demonstrates that segments containing protein-coding elements tend to be preserved at the microsyntenic scale, consistent with strong purifying selection, with appreciably less preservation of non-coding elements. Unexpectedly, scrambling did not preserve operon structure across species, suggesting an absence of selective pressure to maintain operon structure. As well, genome scrambling does not occur uniformly across all chromosomes, as short chromosome arms possess shorter genes, smaller operons, more breakpoints, and elevated dN/dS values compared to long chromosome arms. Estimation of divergence times among the crypticO. dioicalineages yielded an estimated breakpoint accumulation rate of 6 to 25 breakpoints per megabase per million years, which is an order of magnitude higher than the rates for other ascidian tunicates orDrosophilaspecies. Therefore,O. dioicaappears to be an attractive animal system to unravel the mechanisms that underlie gene order and synteny conservation, as well as exploring the limits of genome scrambling without an apparent impact on phenotypic evolution.
B-Cell Precursor Acute Lymphoblastic Leukemia elicits an Interferon-α/β response in Bone Marrow-derived Mesenchymal Stroma
Authors: Smeets Mandy W. E. , Steeghs Elisabeth M. P. , Orsel Jan , Stalpers Femke , Vermeeren Myrthe M. P. , Veltman Christina H. J. , Nierkens Stefan , van de Ven Cesca , den Boer Monique L. 
Published: May 2023

SummaryB-cell precursor acute lymphoblastic leukemia (BCP-ALL) can hijack the normal bone marrow microenvironment to create a leukemic niche which facilitates blast cell survival and promotes drug resistance. Bone marrow-derived mesenchymal stromal cells (MSCs) mimic this protective environment inex vivoco-cultures with leukemic cells obtained from children with newly diagnosed BCP-ALL. We examined the potential mechanisms of this protection by RNA sequencing of flow-sorted MSCs after co-culture with BCP-ALL cells. Leukemic cells induced an interferon (IFN)-related gene signature in MSCs, which was partially dependent on cell-cell signaling by tunneling nanotubes. The signature was selectively induced by BCP-ALL cells, most profoundly byETV6-RUNX1positive ALL cells, as co-culture of MSCs with healthy immune cells did not provoke a similar IFN signature. Leukemic cells and MSCs both secreted IFNα and IFNβ, but no IFNγ. In line, the IFN-gene signature was sensitive to blockade of IFNα/β signaling, but less to that of IFNγ. The viability of leukemic cells and level of resistance to three chemotherapeutic agents was not affected by interference with IFN signaling using selective IFNα/β inhibitors or silencing of IFN-related genes. Taken together, our data suggest that the leukemia-induced expression of IFNα/β-related genes by MSCs does not support survival of BCP-ALL cells but may serve a different role in the pathobiology of BCP-ALL.
Unravelling the relationship between isolated bone matrix vesicles and forming mineral at the nanometer scale
Authors: Cruz Marcos A. E. , Rutten Luco , Martens Martijn , Arntz Onno , van de Loo Fons , Macías-Sánchez Elena , Akiva Anat , Ciancaglini Pietro , Ramos Ana P. , Sommerdijk Nico 
Published: May 2023

AbstractMatrix vesicles (MVs) are involved in the initial deposition of hydroxyapatite (HAp) during bone mineralization, but their mechanism of action is not yet fully understood.In vitrostudies propose two pathways by which MVs can trigger HAp precipitation: the first is mediated by their enhanced phosphatase activity, and the second suggested to depend on structural components present in MVs to mediate nucleation directly from soluble ions without the requirement of phosphatase activity. However, the relevance of these two pathways for bone mineralization and the relationship between MVs and forming mineral in suchin vitroexperiments remains unclear. Here, we used near-native cryoTEM nanoscale imaging in combination with bulk characterizations to disentangle the content and action of MVs duringin vitromineralization. We show that MVs isolation by conventional ultracentrifugation results in heterogeneous dispersions containing non-vesicular particles, including collagens and proteoglycans, in addition to bilayered vesicles. The separation of phosphatase-enriched MVs from non-vesicular particles and comparative mineralization experiments demonstrated that the ability of MVs to induce fast mineralization, independently of phosphatase activity, depends on the presence of non-vesicular particles. Therefore, we conclude that the primary pathway by which MVs trigger mineralization is through the action of their resident phosphatase enzymes, with the direct mineral nucleation to be a secondary event consequential of their membrane components. Lastly, we observed mineral formation restricted to the extravesicular space or in close proximity to the membrane interface, suggesting that the relationship between MVs and forming mineral is more intricate than previously understood.
The Pgbd5 DNA transposase is required for mouse cerebral cortex development through DNA double-strand breaks formation
Authors: Simi Alessandro , Ansaloni Federico , Damiani Devid , Codino Azzurra , Mangoni Damiano , Lau Pierre , Vozzi Diego , Pandolfini Luca , Sanges Remo , Gustincich Stefano 
Published: May 2023

AbstractTransposons are conserved mobile genetic elements and one of the major sources of genetic variability during organisms’ evolution. PiggyBac Transposable Element Derived 5 (Pgbd5), an evolutionarily conserved vertebrate DNA transposase-coding gene, is highly expressed in the central nervous system during development and adult life, suggesting it may play a role in neuronal differentiation and maintenance.Here, we show thatPgbd5controls the expression of pro-neuronal and proliferative genes in a cell autonomous manner, leading to a decreased generation of neurons with altered migration. This activity depends on the induction of endogenous DNA double-strand breaks (DSBs).These results positionPgbd5as a crucial regulator of brain development through its endonuclease activity.One-Sentence SummaryPgbd5regulates cerebral cortex neurogenesis through DNA double-strand breaks modulation.
Genome-scale metabolic models reveal determinants of phenotypic differences in non-Saccharomyces yeasts
Authors: Pettersen Jakob P. , Castillo Sandra , Jouhten Paula , Almaas Eivind 
Published: May 2023

AbstractBackgroundUse of alternative non-Saccharomycesyeasts in wine and beer brewing has gained more attention the recent years. This is both due to the desire to obtain a wider variety of flavours in the product and to reduce the final alcohol content. Given the metabolic differences between the yeast species, we wanted to account for some of the differences by usingin silicomodels.ResultsWe created and studied genome-scale metabolic models of five different non-Saccharomycesspecies using an automated processes. These were:Metschnikowia pulcherrima, Lachancea thermotolerans, Hanseniaspora osmophilaandKluyveromyces lactis. Using the models, we predicted thatM. pulcherrima, when compared to the other species, conducts more respiration and thus produces less fermentation products, a finding which agrees with experimental data. Complex I of the electron transport chain was to be present inM. pulcherrima, but absent in the others. The predicted importance of Complex I was diminished when we incorporated constraints on the amount of enzymatic protein, as this shifts the metabolism towards fermentation.ConclusionsOur results suggest that Complex I in the electron transport chain is a key differentiator betweenMetschnikowia pulcherrimaand the other yeasts considered. Yet, more annotations and experimental data have the potential to improve model quality in order to increase fidelity and confidence in these results. Further experiments should be conducted to confirm thein vivoeffect of Complex I inM. pulcherrimaand its respiratory metabolism.
Temporally organized representations of reward and risk in the human brain
Authors: Man Vincent , Cockburn Jeffrey , Flouty Oliver , Gander Phillip E. , Sawada Masahiro , Kovach Christopher K. , Kawasaki Hiroto , Oya Hiroyuki , Howard Matthew A. , O’Doherty John P. 
Published: May 2023

AbstractThe value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.
Altered calcium signaling in Bergmann glia contributes to Spinocerebellar ataxia type-1
Authors: Noriega-Prieto Jose Antonio , Nanclares Carmen , Labrada-Moncada Francisco E. , Cvetanovic Marija , Araque Alfonso , Kofuji Paulo 
Published: May 2023

AbstractSpinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by an abnormal expansion of glutamine (Q) encoding CAG repeats in theATAXIN1(ATXN1) gene and characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. SCA1 shows severe degeneration of cerebellar Purkinje cells (PCs) and activation of Bergmann glia (BG), a type of cerebellar astroglia closely associated with PCs. Using electrophysiological recordings, confocal imaging and chemogenetic approaches, we have investigated the electrical intrinsic and synaptic properties of PCs and the physiological properties of BG in SCA1 mouse model expressing mutant ATXN1 only in PCs. PCs of SCA1 mice displayed lower spontaneous firing rate and larger medium and slow afterhyperpolarization currents (mIAHPand sIAHP) than wildtype mice, whereas the properties of the synaptic inputs were unaffected. BG of SCA1 mice showed higher calcium hyperactivity and gliotransmission, manifested higher frequency of NMDAR-mediated slow inward currents (SICs) in PC. Preventing the BG calcium hyperexcitability of SCA1 mice by loading BG with the calcium chelator BAPTA restored mIAHPand sIAHPand spontaneous firing rate of PCs to similar levels of wildtype mice. Moreover, mimicking the BG hyperactivity by activating BG expressing Gq- DREADDs in wildtype mice reproduced the SCA1 pathological phenotype of PCs, i.e., enhancement of mIAHPand sIAHPand decrease of spontaneous firing rate. These results indicate that the intrinsic electrical properties of PCs, but not their synaptic properties, were altered in SCA1 mice, and that these alterations were associated with the hyperexcitability of BG. Moreover, preventing BG hyperexcitability in SCA1 mice and promoting BG hyperexcitability in wildtype mice prevented and mimicked, respectively, the pathological electrophysiological phenotype of PCs. Therefore, BG plays a relevant role in the dysfunction of the electrical intrinsic properties of PCs in SCA1 mice, suggesting that they may serve as potential targets for therapeutic approaches to treat the spinocerebellar ataxia type 1.