bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-responsive, multifunctional CAR-NK cells cooperate with impaired autophagy to infiltrate and target glioblastoma
Authors: Wang Jiao , Toregrosa-Allen Sandra , Elzey Bennett D. , Utturkar Sagar , Lanman Nadia Atallah , Bernal-Crespo Victor , Behymer Matthew M. , Knipp Gregory T. , Yun Yeonhee , Veronesi Michael C. , Sinn Anthony L. , Pollok Karen E. , Brutkiewicz Randy R. , Nevel Kathryn S. , Matosevic Sandro 
Published: October 2020

AbstractTumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking have rendered glioblastoma (GBM) highly resistant to therapy. As a result, GBM immunotherapies have failed to demonstrate sustained clinical improvements in patient overall survival (OS). To overcome these obstacles, here we describe a novel, sophisticated combinatorial platform for GBM: the first multifunctional immunotherapy based on genetically-engineered, human NK cells bearing multiple anti-tumor functions, including local tumor responsiveness, that addresses key drivers of GBM resistance to therapy: antigen escape, poor immune cell homing, and immunometabolic reprogramming of immune responses. We engineered dual-specific CAR-NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally-released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site specific activity in the tissue and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells, but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising new NK cell-based combinatorial strategy that can target multiple clinically-recognized mechanisms of GBM progression simultaneously.
Action potential-coupled Rho GTPase signaling drives presynaptic plasticity
Authors: Dube Shataakshi , Rácz Bence , Brown Walter E. , Gao Yudong , Soderblom Erik J. , Yasuda Ryohei , Soderling Scott H. 
Published: October 2020

ABSTRACTIn contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix usingin vivobiotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with presynaptic vesicle membranes and negatively regulate synaptic vesicle replenishment at both excitatory and inhibitory synapses. Using optogenetics and fluorescence lifetime imaging, we show this pathway bidirectionally sculpts short-term synaptic depression and that its presynaptic activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study provides a new proteomic framework for understanding presynaptic physiology and uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across cell types.
FARCI: Fast and Robust Connectome Inference
Authors: Meamardoost Saber , Bhattacharya Mahasweta , Hwang EunJung , Komiyama Takaki , Mewes Claudia , Wang Linbing , Zhang Ying , Gunawan Rudiyanto 
Published: October 2020

AbstractThe inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using gold standard datasets from the Neural Connectomics Challenge (NCC) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison to the best performing algorithm in the NCC, FARCI produces more accurate networks over different network sizes and subsampling, while providing over two orders of magnitude faster computational speed.
EFFECT OF CONVALESCENT PLASMA ON MORTALITY IN PATIENTS WITH COVID-19 PNEUMONIA
Authors: Salazar Martín R. , González Soledad E. , Regairaz Lorena , Ferrando Noelia S. , González Martínez Veronica V. , Carrera Ramos Patricia M. , Muñoz Laura , Pesci Santiago A. , Vidal Juan M. , Kreplak Nicolas , Estenssoro Elisa 
Published: October 2020

AbstractBackgroundConvalescent plasma, widely utilized in viral infections that induce neutralizing antibodies, has been proposed for COVID-19, and preliminary evidence shows that it might have beneficial effect. Our objective was to compare epidemiological characteristics and outcomes between patients who received convalescent plasma for COVID-19 and those who did not, admitted to hospitals in Buenos Aires Province, Argentina, throughout the pandemic.MethodsThis is a multicenter, retrospective cohort study of 2-month duration beginning on June 1, 2020, including unselected, consecutive adult patients with diagnosed COVID-19, admitted to 215 hospitals with pneumonia. Epidemiological and clinical variables were registered in the Provincial Hospital Bed Management System. Convalescent plasma was supplied as part of a centralized, expanded access program.ResultsWe analyzed 3,529 patients with pneumonia, predominantly male, aged 62±17, with arterial hypertension and diabetes as main comorbidities; 51.4% were admitted to the ward, 27.1% to the Intensive Care Unit (ICU), and 21.7% to the ICU with mechanical ventilation requirement (ICU-MV). 28-day mortality was 34.9%; and was 26.3%, 30.1% and 61.4% for ward, ICU and ICU-MV patients. Convalescent plasma was administered to 868 patients (24.6%); their 28-day mortality was significantly lower (25.5% vs. 38.0%, p<0.001). No major adverse effects occurred.Logistic regression analysis identified age, ICU admission with and without MV requirement, diabetes and preexistent cardiovascular disease as independent predictors of 28-day mortality, whereas convalescent plasma administration acted as a protective factor.ConclusionsOur study suggests that the administration of convalescent plasma in COVID-19 pneumonia admitted to the hospital might be associated with decreased mortality.Key PointsPreliminary evidence showed that convalescent plasma might be beneficial in COVID-19.In a cohort of 3,529 patients with pneumonia due to COVID-19, convalescent plasma was administered to 868 patients, without major adverse effects.Convalescent plasma was independently associated with decreased mortality.
Phosphoproteomics identifies PI3K inhibitor-selective adaptive responses in pancreatic cancer cell therapy and resistance
Authors: Cintas C , Douche T , Dantes Z , Mouton-Barbosa E , Bousquet MP , Cayron C , Therville N , Pont F , Ramos-Delgado F , Guyon C , Garmy-Susini B , Cappello P , Burlet-Schiltz O , Hirsch E , Gomez-Brouchet A , Thibault B , Reichert M , Guillermet-Guibert J 
Published: October 2020

AbstractThe PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform-selectivity towards PI3Kα, PI3Kβ or PI3Kγ (namely A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced re-activation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.Graphical abstractSignificanceHalf of all human cancers show increased PI3K activity but the mutational pattern of the PI3K pathway is not sufficient to predict sensitivity to PI3K inhibitors. By identifying for the first time specific signaling induced by PI3K inhibitors with different isoform-selectivity patterns, we provide insight in how to handle heterogeneity of PI3K expression in tumor samples for the choice of available PI3K-targetting drugs. Our work provides a roadmap to target the PI3K pathway, balancing the use of isoform-selective PI3K inhibitors with personalized information extending beyond the specific mutational status.
Statistical validation verifies that enantiomorphic states of cell chirality are determinant dictating the left- or right-handed direction of the hindgut rotation inDrosophila
Authors: Ishibashi Tomoki , Inaki Mikiko , Matsuno Kenji 
Published: October 2020

AbstractIn the left-right (LR) asymmetric development of invertebrates, chirality of cells (cell chirality) plays crucial roles. Left- or right-handed structure of cells consequently directs the morphogenesis with corresponding LR asymmetry. InDrosophila, it has been suggested that cell chirality drives the LR-asymmetric development of various organs including the embryonic hindgut. However, this hypothesis is supported only by apparent concordance between these two events and by computer simulations connecting them[1–5]. Therefore, here, we mathematically evaluated the causal relationship between the cell chirality of the hindgut epithelial cells and the LR-directional rotation of the hindgut, which was previously postulated. Our logistic model obtained from various genetic backgrounds significantly explained the correlation between the enantiomorphic states of cell chirality and the LR directionality of hindgut rotation. This model also significantly explained the correlation between cell chirality stochastically formed in advance in each living embryo and the LR-directionality of the following rotation, suggesting the irrelevance of modes how cell chirality is formed. This analysis also showed that the cell chirality is not only sufficient but also required for the rotation. Considering the chronological order of these events, our study validated that cell chirality causally defines the LR asymmetry of the hindgut rotation.
DNAJB chaperones inhibit aggregation of destabilised proteins via a C-terminal region distinct from that used to prevent amyloid formation
Authors: McMahon Shannon , Bergink Steven , Kampinga Harm H. , Ecroyd Heath 
Published: October 2020

AbstractDisturbances to protein homeostasis (proteostasis) can lead to protein aggregation and inclusion formation, processes associated with a variety of neurodegenerative disorders. DNAJBs are molecular chaperones previously identified as potent suppressors of disease-related protein aggregation. In this work, we over-expressed a destabilised isoform of firefly luciferase (R188Q/R261Q Fluc; FlucDM) in cells to assess the capacity of DNAJBs to inhibit inclusion formation. Co-expression of all DNAJBs tested significantly inhibited the intracellular aggregation of FlucDM. Moreover, we show that DNAJBs suppress aggregation by supporting the Hsp70-dependent degradation of FlucDMvia the proteasome. The serine-rich stretch in DNAJB6 and DNAJB8, essential for preventing fibrillar aggregation, is not involved in the suppression of FlucDMinclusion formation. Conversely, deletion of the C-terminal TTK-LKS region in DNAJB8, a region not required to suppress polyQ aggregation, abolished its ability to inhibit inclusion formation by FlucDM. Thus, our data suggest that DNAJB6 and DNAJB8 possess two distinct domains involved in the inhibition of protein aggregation, one responsible for binding to β-hairpins that form during amyloid formation and another that mediates the degradation of destabilised client proteins via the proteasome.Summary statementSpecialised DNAJB molecular chaperones are potent suppressors of protein aggregation and interact with different types of client proteins via distinct C-terminal regions
CD73 maintains hepatocyte metabolic integrity and mouse liver homeostasis in a sex-dependent manner
Authors: Alcedo Karel P. , Rouse Morgan A. , Jung Gloria S. , Fu Dong , Minor Marquet , Willcockson Helen H. , Greene Kevin G. , Snider Natasha T. 
Published: October 2020

AbstractBackground & AimsMetabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. One promising target is CD73, the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. In normal liver, CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. The aim of this study was to determine if CD73 has non-redundant hepatoprotective functions.Approach & ResultsWe generated mice with a targeted deletion of the CD73-encoding gene (Nt5e) in hepatocytes (CD73-LKO). Deletion of hepatocyteNt5eresulted in approximately 70% reduction in total liver CD73 protein (p<0.0001). Male and female CD73-LKO mice developed normally during the first 21 weeks, without significant liver phenotypes. Between 21-42 weeks, the CD73-LKO mice developed spontaneous onset liver disease with significant severity in male mice. Notably, middle-aged male CD73-LKO mice displayed hepatocyte swelling and ballooning (p<0.05), inflammation (p<0.01) and variable steatosis. Female CD73-LKO mice had lower serum albumin (p<0.05) and elevated inflammatory markers (p<0.01), but did not exhibit the spectrum of histopathologic changes characteristic of the male mice, potentially due to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice revealed significant metabolic imbalance, with elevated blood urea nitrogen (p<0.0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypo-phosphorylation in AMPK substrate in CD73-LKO livers (p<0.0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (p<0.001).ConclusionsHepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.
Raptor: A fast and space-efficient pre-filter for querying very large collections of nucleotide sequences
Authors: Seiler Enrico , Mehringer Svenja , Darvish Mitra , Turc Etienne , Reinert Knut 
Published: October 2020

AbstractWe present Raptor, a tool for approximately searching many queries in large collections of nucleotide sequences. In comparison with similar tools like Mantis and COBS, Raptor is 12-144 times faster and uses up to 30 times less memory. Raptor uses winnowing minimizers to define a set of representativek-mers, an extension of the Interleaved Bloom Filters (IBF) as a set membership data structure, and probabilistic thresholding for minimizers. Our approach allows compression and a partitioning of the IBF to enable the effective use of secondary memory.
Isolation and characterization of lumpy skin disease virus from cattle in India
Authors: Kumar Naveen , Chander Yogesh , Kumar Ram , Khandelwal Nitin , Riyesh Thachamvally , Chaudhary Khushboo , Shanmugasundaram Karuppusamy , Kumar Sanjit , Kumar Anand , Gupta Madhurendu K. , Pal Yash , Barua Sanjay , Tripathi Bhupendra N. 
Published: October 2020

ABSTRACTLumpy skin disease (LSD) has devastating economic impact. During the last decade, LSD had spread to climatically new and previously disease-free countries, which also includes its recent emergence in the Indian subcontinent (2019). This study deals with the LSD outbreak(s) from cattle in Ranchi (India). Virus was isolated from the scabs (skin lesions) in the primary goat kidney cells. Phylogenetic analysis based on nucleotide sequencing of LSD virus (LSDV) ORF011, ORF012 and ORF036 suggested that the isolated virus (LSDV/Bos taurus-tc/India/2019/Ranchi) is closely related to Kenyan LSDV strains. Further, we adapted the isolated virus in Vero cells, an alternative cell line that was found suitable for LSDV propagation. In addition, kinetics of viral DNA synthesis and one-step growth curve analysis suggested that LSDV initiates synthesizing its genome at ∼24 hours post-infection (hpi) with a peak level at ∼96 hpi whereas evidence of progeny virus particles was observed at 36-48 hours (h) with a peak titre at ∼120 h. This study reports the first successful isolation of LSDV in India, besides describing alternative cells for virus isolation (primary goat kidney cells) andin vitropropagation (Vero cells) as well as providing some insights on LSDV life cycle.Author SummaryThis study describes the first successful isolation of LSDV in India. Nucleotide sequencing of LSDV ORF011, ORF012 and ORF036 suggested that the isolated virus is closely related to Kenyan LSDV strains. This is in accordance with the previous (only) study, thereby suggesting that a single LSDV strain is circulating in India. For the first time, we employed primary goat kidney (PGK) cells for the isolation of LSDV, where PGK cells were found more sensitive for LSDV isolation as compared to the primary lamb testicle (PLT) and primary goat testicle (PGT) cells. We also adapted the isolated virus in Vero cells and demonstrated that Vero cells are also suitable forin vitropropagation of LSDV. Besides, we also provide some insights on the LSDV life cycle.
Whole-genome SNP analysis elucidates the genetic population structure and diversity of Acrocomia species
Authors: Díaz Brenda G. , Zucchi Maria I. , Alves-Pereira Alessandro. , de Almeida Caléo P. , Moraes Aline C. L. , Vianna Suelen A. , Azevedo-Filho Joaquim A. , Colombo Carlos A 
Published: October 2020

AbstractAcrocomia (Arecaceae) is a genus widely distributed in tropical and subtropical America that has been achieving economic interest due to the great potential of oil production of some of its species. In particularA. aculeata, due to its vocation to supply oil with the same productive capacity as the oil palm even in areas with water deficit. Although eight species are recognized in the genus, the taxonomic classification based on morphology and geographic distribution is still controversial. Knowledge about the genetic diversity and population structure of the species is limited, which has limited the understanding of the genetic relationships and the orientation of management, conservation, and genetic improvement activities of species of the genus. In the present study, we analyzed the genomic diversity and population structure of seven species of Acrocomia including 117 samples ofA. aculeatacovering a wide geographical area of occurrence, using single nucleotide Polymorphism (SNP) markers originated from Genotyping By Sequencing (GBS). The genetic structure of the Acrocomia species were partially congruent with the current taxonomic classification based on morphological characters, recovering the separation of the speciesA. aculeata, A. totai, A. crispaandA. intumescensas distinct taxonomic groups. However, the species A. media was attributed to the cluster ofA. aculeatawhileA. hassleriandA. glauscescenswere grouped together withA. totai. The species that showed the highest and lowest genetic diversity were A. totai and A. media, respectively. When analyzed separately, the species A.aculeatashowed a strong genetic structure, forming two genetic groups, the first represented mainly by genotypes from Brazil and the second by accessions from Central and North American countries. Greater genetic diversity was found in Brazil when compared to the other countries. Our results on the genetic diversity of the genus are unprecedented, as is also establishes new insights on the genomic relationships between Acrocomia species. It is also the first study to provide a more global view of the genomic diversity ofA. aculeata. We also highlight the applicability of genomic data as a reference for future studies on genetic diversity, taxonomy, evolution and phylogeny of the Acrocomia genus, as well as to support strategies for the conservation, exploration and breeding of Acrocomia species and in particularA. aculeata.
Biting and resting preferences of malaria vectors in The Gambia
Authors: Hamid-Adiamoh Majidah , Nwakanma Davis , Assogba Benoit Sessinou , Ndiath Mamadou Ousmane , D’Alessandro Umberto , Afrane Yaw A. , Amambua-Ngwa Alfred 
Published: October 2020

AbstractBackgroundThe scale-up of indoor residual spraying and long-lasting insecticidal nets, together with other interventions have considerably reduced the malaria burden in The Gambia. This study examined the biting and resting preferences of the local insecticide-resistant vector populations few years following scale-up of anti-vector interventions.MethodIndoor and outdoor-restingAnopheles gambiaemosquitoes were collected between July and October 2019 from ten villages in five regions in The Gambia using pyrethrum spray collection (indoor) and prokopack aspirator from pit traps (outdoor). Polymerase chain reaction assays were performed to identify molecular species, insecticide resistance mutations,Plasmodiuminfection rate and host blood meal.ResultsA total of 844 mosquitoes were collected both indoors (421, 49.9%) and outdoors (423, 50.1%). Four main vector species were identified, includingAn. arabiensis(indoor: 15%, outdoor: 26%);An. coluzzii(indoor: 19%, outdoor: 6%),An. gambiae s.s. (indoor: 11%, outdoor: 16%),An. melas(indoor: 2%, outdoor: 0.1%) and hybrids ofAn. coluzzii-An. gambiae(indoors: 3%, outdoors: 2%). A significant preference for outdoor resting was observed inAn. arabiensis(PearsonX2=22.7, df=4, P<0.001) and for indoor resting inAn. coluzzii(PearsonX2=55.0, df=4, P<0.001). Prevalence of the voltage-gated sodium channel (Vgsc)-1014Swas higher in the indoor-resting (allele freq. = 0.96, 95%CI: 0.78–1) than outdoor-resting (allele freq. = 0.82, 95%CI: 0.76–0.87)An. arabiensispopulation. ForAn. coluzzii, the prevalence of most mutation markers were higher in the outdoor (allele freq. = 0.92, 95%CI: 0.81–0.98) than indoor-resting (allele freq. = 0.78, 95%CI: 0.56–0.86) mosquitoes. Sporozoite positivity rate was 1.3% (95% CI: 0.5–2%). Indoor-restingAn. coluzziihad mainly fed on human blood while indoor-restingAn. arabiensis, animal blood.ConclusionThe indoor-resting behavior ofAn. arabiensisthat preferred animal blood and had low sporozoite rates, may be determined by theVgsc-1014Smutation. Control interventions may include complementary vector control approaches such as zooprophylaxis.