bluuebunny/crossref_metadata_2025_split huggingface dataset:
6Economic Criticism
Authors: Stallings Camille L 
Published: June 2023

Abstract
This essay reviews recent work in economic history, covering critical topics that span the history of inequality, the violence of primitive accumulation, and the Ukraine–Russia war. Following the introduction, this chapter has two sections: 1. Thomas Piketty and the Great Redistribution (1914–1980), and 2. Helen Thompson and Twenty-First Century Disorder. The conclusion considers sections 1 and 2 in the context of both Marx’s language of cyclical overaccumulation and overproduction and Alison Shonkwiler and Leigh Claire La Berge’s theoretical concept of ‘capitalist realism’.
Two different isoforms of osteopontin modulate myelination and axonal integrity
Authors: Nilsson Gisela , Mottahedin Amin , Zelco Aura , Lauschke Volker M. , Ek C. Joakim , Song Juan , Ardalan Maryam , Hua Sha , Zhang Xiaoli , Mallard Carina , Hagberg Henrik , Leavenworth Jianmei W. , Wang Xiaoyang 
Published: June 2023

AbstractAbnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform‐specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN‐KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs‐iOPN‐KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN‐KO mice compared to control mice. Accordingly, adult OPN‐KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin‐related proteins. In contrast, neonatal oligodendrocytes from OLs‐iOPN‐KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs‐iOPN‐KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform‐specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
The pentameric complex is not required for vertical transmission of cytomegalovirus in seronegative pregnant rhesus macaques
Authors: Wang Hsuan-Yuan , Taher Husam , Kreklywich Craig N. , Schmidt Kimberli A. , Scheef Elizabeth A. , Barfield Richard , Otero Claire E. , Valencia Sarah M. , Crooks Chelsea M. , Mirza Anne , Woods Kelsey , Burgt Nathan Vande , Kowalik Timothy F. , Barry Peter A. , Hansen Scott G. , Tarantal Alice F. , Chan Cliburn , Streblow Daniel N. , Picker Louis J. , Kaur Amitinder , Früh Klaus , Permar Sallie R. , Malouli Daniel 
Published: June 2023

AbstractCongenital cytomegalovirus (cCMV) infection is the leading infectious cause of neonatal neurological impairment but essential virological determinants of transplacental CMV transmission remain unclear. The pentameric complex (PC), composed of five subunits, glycoproteins H (gH), gL, UL128, UL130, and UL131A, is essential for efficient entry into non-fibroblast cellsin vitro. Based on this role in cell tropism, the PC is considered a possible target for CMV vaccines and immunotherapies to prevent cCMV. To determine the role of the PC in transplacental CMV transmission in a non-human primate model of cCMV, we constructed a PC-deficient rhesus CMV (RhCMV) by deleting the homologues of the HCMV PC subunits UL128 and UL130 and compared congenital transmission to PC-intact RhCMV in CD4+ T cell-depleted or immunocompetent RhCMV-seronegative, pregnant rhesus macaques (RM). Surprisingly, we found that the transplacental transmission rate was similar for PC-intact and PC-deleted RhCMV based on viral genomic DNA detection in amniotic fluid. Moreover, PC-deleted and PC-intact RhCMV acute infection led to similar peak maternal plasma viremia. However, there was less viral shedding in maternal urine and saliva and less viral dissemination in fetal tissues in the PC-deleted group. As expected, dams inoculated with PC-deleted RhCMV demonstrated lower plasma IgG binding to PC-intact RhCMV virions and soluble PC, as well as reduced neutralization of PC-dependent entry of the PC-intact RhCMV isolate UCD52 into epithelial cells. In contrast, binding to gH expressed on the cell surface and neutralization of entry into fibroblasts by the PC-intact RhCMV was higher for dams infected with PC-deleted RhCMV compared to those infected with PC-intact RhCMV. Our data demonstrates that the PC is dispensable for transplacental CMV infection in our non-human primate model.One Sentence SummaryCongenital CMV transmission frequency in seronegative rhesus macaques is not affected by the deletion of the viral pentameric complex.
Cdc48 and its co-factor Ufd1 segregate CENP-A from centromeric chromatin and can induce chromosome elimination in the fission yeastSchizosaccharomyces pombe
Authors: Nakase Yukiko , Murakami Hiroaki , Suma Michiko , Nagano Kaho , Wakuda Airi , Kitagawa Teppei , Matsumoto Tomohiro 
Published: June 2023

AbstractCENP-A, a variant of histone H3, determines the identity of the centromere, a chromosome locus at which a microtubule attachment site termed kinetochore is assembled. Because the position and size of the centromere and its number per chromosome must be maintained for the faithful segregation of chromosomes, the distribution of CENP-A is strictly regulated. In this study, we have aimed to understand mechanisms to regulate the distribution of CENP-A by a genetic approach in the fission yeastSchizosaccharomyces pombe. A mutant of theufd1+gene (ufd1-73) encoding a cofactor of Cdc48 ATPase is sensitive to CENP-A expressed at a high level and allows mislocalization of CENP-A. ChIP analysis has revealed that the level of CENP-A in centromeric chromatin is increased in theufd1-73mutant even when CENP-A is expressed at a normal level. A preexisting mutant of thecdc48+gene (cdc48-353) phenocopies theufd1-73mutant. We have also shown that Cdc48 and Ufd1 proteins physically interact with centromeric chromatin. Finally, Cdc48 ATPase with Ufd1 artificially recruited to the centromere of a mini-chromosome (Ch16) induce a loss of CENP-A fromCh16, resulting in an increased rate of chromosome loss. It appears that Cdc48 ATPase, together with its cofactor Ufd1 segregates excess CENP-A from chromatin, likely in a direct manner, to maintain proper distribution of CENP-A. This mechanism may play an important role in centromere disassembly, a process to eliminate CENP-A massively to inactivate the kinetochore function during development, differentiation, and stress response in other organisms.Significance statementMaintaining the proper distribution of CENP-A is crucial for centromere identity. This process involves accurate positioning of CENP-A and removal of excess CENP-A from chromatin. The Cdc48-Ufd1 complex is essential for this regulation as it acts as a segregase that directly eliminates surplus CENP-A from chromatin. These findings have therapeutic significance as targeting the Cdc48 complex can potentially correct abnormal karyotypes in disomic embryos and prevent trisomic disorders like Down syndrome. This research advances our understanding of centromeric chromatin regulation and its potential therapeutic applications.
Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning
Authors: Castillo Hair Sebastian , Fedak Stephen , Wang Ban , Linder Johannes , Havens Kyle , Certo Michael , Seelig Georg 
Published: June 2023

AbstractmRNA therapeutics are revolutionizing the pharmaceutical industry, but methods to optimize the primary sequence for increased expression are still lacking. Here, we design 5’UTRs for efficient mRNA translation using deep learning. We perform polysome profiling of fully or partially randomized 5’UTR libraries in three cell types and find that UTR performance is highly correlated across cell types. We train models on all our datasets and use them to guide the design of high-performing 5’UTRs using gradient descent and generative neural networks. We experimentally test designed 5’UTRs with mRNA encoding megaTALTM gene editing enzymes for two different gene targets and in two different cell lines. We find that the designed 5’UTRs support strong gene editing activity. Editing efficiency is correlated between cell types and gene targets, although the best performing UTR was specific to one cargo and cell type. Our results highlight the potential of model-based sequence design for mRNA therapeutics.
Low gH/gL (sub)species-specific antibody levels indicate elephants at risk of fatal elephant endotheliotropic herpesvirus hemorrhagic disease
Authors: Hoornweg Tabitha E. , Schaftenaar Willem , Rutten Victor P.M.G. , de Haan Cornelis A.M. 
Published: June 2023

AbstractElephant endotheliotropic herpesviruses (EEHVs), of which seven species and multiple subspecies are currently distinguished, naturally infect either Asian (Elephas maximus) or African elephants (Loxodontaspecies). While all adult elephants are latently infected with at least one EEHV (sub)species, EEHV infections in young elephants may lead to acute, fatal hemorrhagic disease (EEHV-HD). The disease is primarily observed in calves with low to non-detectable EEHV-specific antibodies, suggesting it is the result of an uncontrolled primary infection. Yet, young elephants showing high antibody levels in serological assays based on EEHV(1A) gB, which detect antibodies against multiple EEHV (sub)species, are not necessarily protected against EEHV-HD. To better determine which animals are at risk of EEHV-HD, we developed gB and gH/gL ELISAs for all Asian elephant EEHV (sub)species and assessed their specificity using 396 sera from 164 Asian elephants kept in Europeans zoos. Antibody levels measured against gB of different EEHV (sub)species correlated strongly with one another, indicating gB-specific antibodies are highly cross-reactive. In contrast, antibody responses towards gH/gL of different EEHV (sub)species were far less correlated and could be used to distinguish between infections with different (sub)species. Subsequently, antibody responses in sera of 23 EEHV-HD fatalities were analyzed. Whereas high antibody levels against gB could be detected in sera of multiple EEHV-HD fatalities, all fatalities had low antibody levels against gH/gL of the EEHV (sub)species they succumbed to. Overall, our data indicate that (sub)species-specific gH/gL ELISAs may be used to identify animals at risk of developing EEHV-HD upon infection with a particular EEHV (sub)species.
HSP90 inhibitor NVP-HSP990 alleviates rotavirus infection
Authors: Cao Yi , Zhu Qingmin , Wu Xiaoping , Xie Zhunyi , Yang Chengying , Guo Yanyan , Meng Dongwei , Zhou Xinyuan , Wu Yuzhang , Li Jintao , He Haiyang 
Published: June 2023

AbstractRotavirus (RV) infection is a significant cause of hospitalization and mortality in infants and young children. Although conventional symptomatic treatments usually appear effective, tens of thousands of infants and young children still die each year due to the absence of safe and effective anti-RV drugs. Heat shock protein 90 (HSP90) is usually required for efficient viral infection; however, due to unsatisfactory antiviral efficacy and toxicity, there has been no HSP90-targeting agents applied for clinical antiviral therapy currently. Here, we demonstrated that NVP-HSP990, a novel small-molecule HSP90 inhibitor with excellent oral bioavailability and brain penetration, was a potent inhibitor of RV infection with much bigger selectivity index (SI) than traditional HSP990 inhibitors. NVP-HSP990 potently inhibited RV replicationin vitrowithout blocking infection establishment. NVP-HSP990 remarkably restored gene expressions of most KEGG pathways disturbed by RV infection in intestinal cells, except some inflammatory pathways (IL-17, TNF, etc.). To be noted, NVP-HSP990 significantly altered gene expressions in MAPK signaling pathway and inhibited RV-induced activation of MAPK as well as disruption of tight junctions in Caco-2 cells. More importantly, NVP-HSP990 effectively alleviated RV diarrhea, competently inhibited RV replication, and obviously prevented pathological lesions of intestine in BALB/c suckling mice. Therefore, our results suggested that NVP-HSP990 can be a promising antiviral drug candidate against RV infection.
DNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
Authors: Bjarnason Sveinn , McIvor Jordan A.P. , Prestel Andreas , Demény Kinga S. , Bullerjahn Jakob T. , Kragelund Birthe B. , Mercadante Davide , Heidarsson Pétur O. 
Published: June 2023

AbstractMore than 1600 human transcription factors orchestrate the transcriptional machinery to control gene expression and cell fate. Their function is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains but lacking quantitative structural ensemble models prevents their mechanistic decoding. Here we integrate single-molecule FRET and NMR spectroscopy with molecular simulations showing that DNA binding can lead to complex changes in the IDR ensemble and accessibility. The C-terminal IDR of pioneer factor Sox2 is highly disordered but its conformational dynamics are guided by weak and dynamic charge interactions with the folded DNA binding domain. Both DNA and nucleosome binding induce major rearrangements in the IDR ensemble without affecting DNA binding affinity. Remarkably, interdomain interactions are redistributed in complex with DNA leading to variable exposure of two activation domains critical for transcription. Charged intramolecular interactions allowing for dynamic redistributions may be common in transcription factors and necessary for sensitive tuning of structural ensembles.
A scalable platform for efficient CRISPR-Cas9 chemical-genetic screens of DNA damage-inducing compounds
Authors: Lin Kevin , Chang Ya-Chu , Billmann Maximilian , Ward Henry N. , Le Khoi , Hassan Arshia , Bhojoo Urvi , Chan Katherine , Costanzo Michael , Moffat Jason , Boone Charles , Bielinsky Anja-Katrin , Myers Chad L. 
Published: June 2023

AbstractCurrent approaches to define chemical-genetic interactions (CGIs) in human cell lines are resource-intensive. We designed a scalable chemical-genetic screen platform by generating a DNA damage response (DDR)-focused custom sgRNA library. We performed five proof-of-principle compound screens and found that the compounds’ known modes-of-action (MoA) were enriched among the compounds’ CGIs. These scalable screens recapitulated expected CGIs at a comparable signal-to-noise ratio (SNR) relative to genome-wide screens. Furthermore, time-resolved CGIs, captured by sequencing screens at various time points, suggested an unexpected, late time point interstrand-crosslinking (ICL) repair pathway response to camptothecin-induced DNA damage. Our approach can facilitate screening compounds at scale and produce biologically informative CGI profiles.
Screening for variable drug responses using human iPSC cohorts
Authors: Platani Melpomeni , Jiang Hao , Davidson Lindsay , Hariharan Santosh , Doyonnas Regis , Lamond Angus I. , Swedlow Jason R. 
Published: June 2023

ABSTRACTWe have developed a laboratory-based drug screening platform that uses a cohort of human induced pluripotent stem cell (hiPSC) lines, derived from different donors, to predict variable drug responses of potential clinical relevance. This builds on recent findings that pluripotent hiPSC lines express a broad repertoire of gene transcripts and proteins, whose expression levels reflect the genetic identity of the donor. We demonstrate that a cohort of hiPSC lines from different donors can be screened efficiently in their pluripotent state, using high-throughput Cell Painting assays. Variable phenotypic responses between hiPSC lines were detected with a wide range of clinically approved drugs, in use across multiple disease areas. Furthermore, information on mechanisms of drug-cell interactions underlying the observed variable responses was derived by using quantitative proteomic analysis to compare sets of hiPSC lines that had been stratified objectively, based upon variable response, Cell Painting data. We propose that information derived from comparative drug screening, using curated libraries of hiPSC lines from different donors, can help to improve the delivery of safe new drugs suitable for a broad range of genetic backgrounds and sexual diversity within human populations.
Supraclavicular brown adipocytes originate fromTbx1+myoprogenitors
Authors: Huang Zan , Gu Chenxin , Zhang Zengdi , Arianti Rini , Swaminathan Aneesh , Tran Kevin , Battist Alex , Kristóf Endre , Ruan Hai-Bin 
Published: June 2023

SUMMARYBrown adipose tissue (BAT) dissipates energy as heat, contributing to temperature control, energy expenditure, and systemic homeostasis. In adult humans, BAT mainly exists in supraclavicular areas and its prevalence is associated with cardiometabolic health. However, the developmental origin of supraclavicular BAT remains unknown. Here, using genetic fate mapping in mice, we demonstrate that supraclavicular brown adipocytes do not develop from thePax3+/Myf5+epaxial dermomyotome that gives rises to interscapular BAT. Instead, theTbx1+lineage that specifies the pharyngeal mesoderm marks the majority of supraclavicular brown adipocytes.Tbx1Cre-mediated ablation of peroxisome proliferator-activated receptor gamma (PPARγ) or PR/SET Domain 16 (PRDM16), components of the transcriptional complex for brown fat determination, leads to supraclavicular BAT paucity or dysfunction, thus rendering mice more sensitive to cold exposure. Moreover, human deep neck BAT expresses higher levels of theTBX1gene than subcutaneous neck white adipocytes. Taken together, our observations reveal location-specific developmental origins of BAT depots and call attention toTbx1+lineage cells when investigating human relevant supraclavicular BAT.
Cochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
Authors: Vollmar Leonie , Schimpf Julia , Hermann Bianca , Hugel Thorsten 
Published: June 2023

AbstractThe molecular chaperone and heat shock protein Hsp90 is part of many protein complexes in eukaryotic cells. Together with its cochaperones, Hsp90 is responsible for the maturation of hundreds of clients. Although having been investigated for decades, it still is largely unknown which components are necessary for a functional complex and how the energy of ATP hydrolysis is used to enable cyclic operation. Here we use single-molecule FRET to show how cochaperones introduce directionality into Hsp90’s conformational changes during its interaction with the client kinase Ste11. Most interestingly, three cochaperones are needed to couple ATP turnover to these conformational changes. All three are therefore essential for a functional cyclic operation, which requires coupling to an energy source. Finally, our findings show how the formation of sub-complexes in equilibrium followed by a directed selection of the functional complex can be the most energy efficient pathway for kinase maturation.
Borrelia PeptideAtlas: A proteome resource of commonBorrelia burgdorferiisolates for Lyme research
Authors: Reddy Panga Jaipal. , Sun Zhi , Wippel Helisa H. , Baxter David , Swearingen Kristian , Shteynberg David D. , Midha Mukul K. , Caimano Melissa J. , Strle Klemen , Choi Yongwook , Chan Agnes P. , Schork Nicholas J. , Moritz Robert L. 
Published: June 2023

AbstractLyme disease, caused by an infection with the spirocheteBorrelia burgdorferi, is the most common vector-borne disease in North America.B. burgdorferistrains harbor extensive genomic and proteomic variability and further comparison is key to understanding the spirochetes infectivity and biological impacts of identified sequence variants. To achieve this goal, both transcript and mass spectrometry (MS)-based proteomics was applied to assemble peptide datasets of laboratory strains B31, MM1, B31-ML23, infective isolates B31-5A4, B31-A3, and 297, and other public datasets, to provide a publicly available Borrelia PeptideAtlas (http://www.peptideatlas.org/builds/borrelia/). Included is information on total proteome, secretome, and membrane proteome of theseB. burgdorferistrains. Proteomic data collected from 35 different experiment datasets, with a total of 855 mass spectrometry runs, identified 76,936 distinct peptides at a 0.1% peptide false-discovery-rate, which map to 1,221 canonical proteins (924 core canonical and 297 noncore canonical) and covers 86% of the total base B31 proteome. The diverse proteomic information from multiple isolates with credible data presented by the Borrelia PeptideAtlas can be useful to pinpoint potential protein targets which are common to infective isolates and may be key in the infection process.
Inhibition of the Notch signal transducer CSL by Pkc53E-mediated phosphorylation to fend off parasitic immune challenge inDrosophila
Authors: Deichsel Sebastian , Frankenreiter Lisa , Fechner Johannes , Gahr Bernd M. , Zimmermann Mirjam , Mastel Helena , Preis Irina , Preiss Anette , Nagel Anja C. 
Published: June 2023

AbstractNotch signalling activity regulates hematopoiesis inDrosophilaand vertebrates alike. Parasitoid wasp infestation ofDrosophilalarvae, however, requires a timely downregulation of Notch activity to allow the formation of encapsulation-active blood cells. Here we show that theDrosophilaCSL transcription factor Suppressor of Hairless [Su(H)] is phosphorylated at Serine 269 in response to parasitoid wasp infestation. As this phosphorylation interferes with the DNA-binding of Su(H), it reversibly precludes its activity. Accordingly, phospho-deficientSu(H)S269Amutants are immune compromised. A screen for kinases involved in Su(H) phosphorylation identified Pkc53E, required for normal hematopoiesis as well as for parasitoid immune response. Genetic and molecular interactions support the specificity of the Su(H)-Pkc53E relationship. Moreover, phorbol ester treatment inhibits Su(H) activityin vivoand in human cell culture. We conclude that Pkc53E targets Su(H) during parasitic wasp infestation, thereby remodeling the blood cell population required for wasp egg encapsulation.