bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic Control of Eye-Head Gaze Shifts by a Spiking Neural Network Model of the Superior Colliculus
Authors: Alizadeh Arezoo , Van Opstal A. John 
Published: August 2022

AbstractTo reorient gaze (the eye in space) towards a target can be achieved by infinitely many combinations of eye- and head movements. However, behavioral measurements show that the primate gaze-control system selects specific contributions of eye- and head to the saccade, which depend on the initial eye-in-head orientation. Single-unit recordings in the primate superior colliculus (SC) during head-unrestrained gaze shifts have further suggested that cells may encode the instantaneous trajectory of a desired straight gaze path in a feedforward way by the total cumulative number of spikes in the neural population, and that the instantaneous gaze kinematics are determined by the neural firing rates. The recordings also indicated that the latter depended strongly on the initial eye position as well. We recently proposed a conceptual model that accounts for many of the observed properties of eye-head gaze shifts and on the potential role of the SC. Here, we extend and test the model by incorporating a spiking neural network of the SC motor map, the output of which drives the eye-head motor control circuitry by linear cumulative summation of individual spike effects of each recruited SC neuron. We propose a simple neural mechanism on SC cells that explains the modulatory influence of feedback from an initial eye-in-head position signal on their spiking activity. The same signal also determines the onset delay of the head movement with respect to the eye. The downstream eye- and head burst generators were taken to be linear, as our earlier work had suggested that much of the nonlinear kinematics of saccadic eye movements may be due to neural encoding at the collicular level, rather than at the brainstem. We show that the spiking activity of the SC population drives gaze to the intended target location within a dynamic local gaze-velocity feedback circuit that yields realistic eye- and head-movement kinematics and dynamic SC gaze-movement fields.
Normalized LST is an efficient biomarker for homologous recombination deficiency and Olaparib response in ovarian carcinoma
Authors: Christinat Yann , Ho Liza , Clément Sophie , Genestie Catherine , Sehouli Jalid , Martin Antonio Gonzalez , Denison Ursula , Fujiwara Keiichi , Vergote Ignace , Tognon Germana , Hietanen Sakari , Ray-Coquard Isabelle , Pujade-Lauraine Eric , McKee Thomas A. 
Published: August 2022

AbstractBACKGROUNDThe efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide use of PARP inhibitors has been demonstrated in several phase III trials. However its high failure rate and limited accessibility establish a need for a clinically validated laboratory developed test.PATIENTS AND METHODSA novel biomarker to identify HRD was developed using TCGA data and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 phase 3 trial using the OncoScan™ CNV Assay. Results were compared to the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the Olaparib+Bevacizumab and placebo+Bevacizumab arms.RESULTSAnalysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions (nLST) by the number of whole genome doubling events allows a better separation and classification of HRD samples than the GIS. The Oncoscan+nLST test yielded a lower failure rate on the 469 PAOLA-1 samples (10/469 vs 59/469 inconclusive results) and positive and negative agreement values of 96% (204/213) and, 81% (159/197) respectively. In nLST-positive samples, the hazard ratio (HR) was 0.40 (95% CI: 0.28-0.57) compared with 0.35 for Myriad GIS. In tumors that were BRCA wild-type and nLST-positive, the HR was 0.53 (Myriad: 0.41). In this subpopulation the nLST test and the Myriad myChoice test yielded a similar 1-year PFS (87% and 88%) but a different 2-year PFS (52% vs 60%) upon Olaparib+ Bevacizumab treatment.CONCLUSIONThe proposed test is a viable alternative to the Myriad myChoice HRD test and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the commercial test but its lower failure rate allows a 10% increase in the number of patients who will receive a conclusive laboratory result.Highlights-A novel laboratory-developed test that increased HRD scoring accessibility for ovarian cancer patients-Clinically validated on 469 samples from the PAOLA-1 trial within the ENGOT HRD European Initiative-A similar performance as the Myriad myChoice Dx HRD test but at a lower failure rate
A35R and H3L are Serological and B Cell Markers for Monkeypox Infection
Authors: Yefet Ron , Friedel Nadav , Tamir Hadas , Polonsky Ksenia , Mor Michael , Hagin David , Sprecher Eli , Israely Tomer , Freund Natalia T 
Published: August 2022

AbstractMonkeypox virus (MPXV) resides in two forms, mature and enveloped virions, and depending on it, distinct proteins are displayed on the viral surface. We expressed in mammalian cells two MPXV antigens from the mature form and two MPXV antigens from the enveloped form and tested their reactivity to sera of 11 MPXV convalescent donors diagnosed in Israel during May-June 2022 and collected 33-62 days post infection. While only 4 out of 11 donors neutralized the related Vaccinia Lister strain, all MPXV recoverees demonstrated a strong serological response to a 124-amino acid truncation of the A35R antigen, and to a 276-amino acid truncation of the H3L antigen. Moreover, A35R- and H3L-specific B cells ranging from 0.03-0.5% and 0.01-0.35% of IgG+CD19+ cells, respectively, were detected in all 11 MPXV donors (A35R), and in 8 out of 11 donors (H3L). Therefore, A35R and H3L represent MPXV immune targets, and can be used in a simple heat-inactivated serological enzyme-linked immunosorbent assay for the identification of recent MPXV infection.
BNIP3 regulates Chikungunya virus infection independently of autophagy and cell death
Authors: Echavarria-Consuegra Liliana , Kumar Nilima Dinesh , Mauthe Mario , Van de Pol Denise , Reggiori Fulvio , Smit Jolanda M. 
Published: August 2022

AbstractChikungunya virus (CHIKV) is a human pathogen causing outbreaks of febrile illness for which vaccines and specific treatments remain unavailable. Autophagy-related (ATG) proteins and autophagy receptors are a set of host factors that participate in autophagy, but have also shown to function in other unrelated cellular pathways. Although autophagy is reported to both inhibit and enhance CHIKV replication, the specific role of individual ATG proteins remains largely unknown. Here, a siRNA screen was performed to evaluate the importance of the ATG proteome and autophagy receptors in controlling CHIKV infection. We observed that 7 out of 50 ATG proteins impact the replication of CHIKV. Among those, depletion of the mitochondrial protein and autophagy receptor BCL2 Interacting Protein 3 (BNIP3) increased CHIKV infection. Interestingly, BNIP3 controls CHIKV independently of autophagy and cell death. Detailed analysis of the CHIKV viral cycle revealed that BNIP3 interferes with the early stages of infection. Moreover, the antiviral role of BNIP3 was found conserved across two distinct CHIKV genotypes and the closely related Semliki Forest virus. Altogether, this study describes a novel and previously unknown function of the mitochondrial protein BNIP3 in the control of the early stages of the alphavirus viral cycle.
An outbreak of SARS-CoV-2 in big hairy armadillos (Chaetophractus villosus) associated with Gamma variant in Argentina three months after being undetectable in humans
Authors: Arteaga Franco Lucero , Jodar Mercedes Nabaes , Mondino Mariela , Portu Ana , Boeris Monica , Joly Ana , Jar Ana , Mundo Silvia , Castro Eliana , Alvarez Diego , Torres Carolina , Viegas Mariana , Bratanich Ana 
Published: August 2022

AbstractThe present pandemic produced by SARS-CoV-2 and its variants represents an example of the one health concept in which humans and animals are components of the same epidemiologic chain. Animal reservoirs of these viruses are thus the focus of surveillance programs to monitor their circulation and evolution in potentially new hosts and reservoirs. In this work, we report the detection of SARS-CoV-2 Gamma variant infection in four specimens of Chaetophractus villosus (big hairy armadillo/armadillo peludo) in Argentina. In addition to the finding of a new wildlife species susceptible to SARS-CoV-2 infection, the identification of the Gamma variant three months after its last detection in humans is a noteworthy result, raising the question of potential unidentified viral reservoirs.
A modular CRISPR screen identifies individual and combination pathways contributing to HIV-1 latency
Authors: Hsieh Emily , Janssens Derek H , Paddison Patrick J , Browne Edward P , Henikoff Steve , OhAinle Molly , Emerman Michael 
Published: August 2022

AbstractTranscriptional silencing of latent HIV-1 proviruses entails complex and overlapping mechanisms that pose a major barrier toin vivoelimination of HIV-1. We developed a new latency CRISPR screening strategy, called Latency HIV-CRISPR, which uses the packaging of guideRNA-encoding lentiviral vector genomes into the supernatant of budding virions as a direct readout of factors involved in the maintenance of HIV-1 latency. We developed a custom guideRNA library targeting epigenetic regulatory genes and paired the screen with and without a latency reversal agent – AZD5582, an activator of the non-canonical NFκB pathway – to examine a combination of mechanisms controlling HIV-1 latency. A component of the Nucleosome Acetyltransferase of H4 histone acetylation (NuA4 HAT) complex, ING3, acts in concert with AZD5582 to activate proviruses in J-Lat cell lines and in a primary CD4+ T cell model of HIV-1 latency. We found that the knockout ofING3reduces acetylation of the H4 histone tail and BRD4 occupancy on the HIV-1 LTR, and only in the combination ofING3knockout with the activation of non-canonical NFκB via AZD5582 is there dramatic increase in initiation and elongation of RNA Polymerase II on the HIV-1 provirus in a manner that is nearly unique among all cellular promoters.
Engineering of NEMO as calcium indicators with large dynamics and high sensitivity
Authors: Li Jia , Shang Ziwei , Chen Jia-Hui , Gu Wenjia , Yao Li , Yang Xin , Sun Xiaowen , Wang Liuqing , Wang Tianlu , Liu Siyao , Li Jiajing , Hou Tingting , Xing Dajun , Gill Donald L. , Li Jiejie , Wang Shi-Qiang , Hou Lijuan , Zhou Yubin , Tang Ai-Hui , Zhang Xiaohui , Wang Youjun 
Published: August 2022

AbstractGenetically-encoded calcium indicators (GECI) are indispensable tools for real-time monitoring of intracellular calcium signals and cellular activities in living organisms. Current GECIs face the challenge of sub-optimal peak signal-to-baseline-ratio (SBR) with limited resolution for reporting subtle calcium transients. We report herein the development of a suite of calcium sensors, designated NEMO, with fast kinetics and wide dynamic ranges (>100-fold). NEMO indicators report Ca2+transients with peak SBRs ~20-fold larger than the top-of-the-range GCaMP series. NEMO sensors further enable the quantification of absolution calcium concentration with ratiometric or photochromic imaging. Compared to GCaMPs, NEMOs could detect single action potentials in neurons with a peak SBR two times higher and a median peak SBR four times largerin vivo, thereby outperforming most existing state-of-the-art GECIs. Given their high sensitivity and resolution to report intracellular Ca2+signals, NEMO sensors may find broad applications in monitoring neuronal activities and other Ca2+-modulated physiological processes in both mammals and plants.
Deep proteome profiling of white adipose tissue reveals marked conservation and distinct features between different anatomical depots
Authors: Madsen Søren , Nelson Marin E. , Deshpande Vinita , Humphrey Sean J. , Cooke Kristen C. , Howell Anna , Diaz-Vegas Alexis , Burchfield James G. , Stöckli Jacqueline , James David E. 
Published: August 2022

ABSTRACTWhite adipose tissue is deposited mainly as subcutaneous adipose tissue (SAT), often associated with metabolic protection, and abdominal/visceral adipose tissue (VAT), which contributes to metabolic disease. To investigate the molecular underpinnings of these differences, we conducted comprehensive proteomics profiling of whole tissue and isolated adipocytes from these two depots across two diets from C57Bl/6J mice. The adipocyte proteomes from lean mice were highly conserved between depots, with the major depot-specific differences encoded by just 3% of the proteome. Adipocytes from SAT (SAdi) were enriched in pathways related to mitochondrial complex I and beiging, whereas visceral adipocytes (VAdi) were enriched in structural proteins and positive regulators of mTOR presumably to promote nutrient storage and cellular expansion. This indicates that SAdi are geared toward higher catabolic activity, while VAdi are more suited for lipid storage.By comparing adipocytes from mice fed chow or Western diet (WD), we define a core adaptive proteomics signature consisting of increased extracellular matrix proteins and decreased fatty acid metabolism and mitochondrial Coenzyme Q biosynthesis. Relative to SAdi, VAdi displayed greater changes with WD including a pronounced decrease in mitochondrial proteins concomitant with upregulation of apoptotic signaling and decreased mitophagy, indicating pervasive mitochondrial stress. Furthermore, WD caused reduction in lipid handling and glucose uptake pathways particularly in VAdi, consistent with adipocyte de-differentiation. By overlaying the proteomics changes with diet in whole adipose tissue and isolated adipocytes, we uncovered concordance between adipocytes and tissue only in the VAT, indicating a unique tissue-specific adaptation to sustained WD in SAT.Finally, an in-depth comparison of isolated adipocytes and 3T3-L1 proteomes revealed a high degree of overlap, supporting the utility of the 3T3-L1 adipocyte model. These deep proteomes provide an invaluable resource highlighting differences between white adipose depots that may fine-tune their unique functions and adaptation to an obesogenic environment.
Data-Driven Design of Protein-Derived Peptide Multiplexes for Biomimetic Detection of Exhaled Breath VOC Profiles
Authors: Nakano-Baker Oliver , Fong Hanson , Shukla Shalabh , Lee Richard , Cai Le , Godin Dennis , Hennig Tatum , Rath Siddharth , Novosselov Igor , Dogan Sami , Sarikaya Mehmet , MacKenzie J. Devin 
Published: August 2022

AbstractExhaled human breath contains a rich mixture of volatile organic compounds (VOCs) whose concentration can vary in response to disease or other stressors. Using simulated odorant-binding proteins (OBPs) and machine learning methods, we designed a multiplex of short VOC- and carbon-binding peptide probes that detect the characteristic “VOC fingerprint”. Specifically, we target VOCs associated with COVID-19 in a compact, molecular sensor array that directly transduces vapor composition into multi-channel electrical signals. Rapidly synthesizable, chimeric VOC- and solid-binding peptides were derived from selected OBPs using multi-sequence alignment with protein database structures. Selective peptide binding to targeted VOCs and sensor surfaces was validated using surface plasmon resonance spectroscopy and quartz crystal microbalance. VOC sensing was demonstrated by peptide-sensitized, exposed-channel carbon nanotube transistors. The data-to-device pipeline enables the development of novel devices for non-invasive monitoring, diagnostics of diseases, and environmental exposures assessment.
Cryo-EM structure and functional landscape of an RNA polymerase ribozyme
Authors: McRae Ewan K.S. , Wan Christopher J.K. , Kristoffersen Emil L. , Hansen Kalinka , Gianni Edoardo , Gallego Isaac , Curran Joseph F. , Attwater James , Holliger Philipp , Andersen Ebbe S. 
Published: August 2022

AbstractThe emergence of an RNA replicase capable of self-replication is considered an important stage in the origin of life. RNA polymerase ribozymes (PR) including a variant that uses trinucleotide triphosphates (triplets) as substrates have been created byin vitroevolution and are the closest functional analogues of the replicase but the structural basis for their function is poorly understood. Here, we leverage single-particle cryo-EM and high-throughput mutation analysis to obtain the structure of a triplet polymerase ribozyme (TPR) apoenzyme and map its functional landscape. The TPR cryo-EM structure at 5-Å resolution reveals an RNA heterodimer comprising a catalytic and an inactive accessory subunit, where the complex resembles a left hand with thumb and fingers at a 70° angle. The two subunits are connected by two distinct kissing-loop (KL) interactions that are essential for polymerase function. Our combined structural and functional data suggest a model for templated RNA synthesis by the TPR holoenzyme whereby heterodimer formation and KL interactions preorganize the TPR for optimal template binding and templated RNA synthesis activity. These results provide a foundation for a better understanding RNA’s potential for self-replication.
New C3H KitN824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance
Authors: Klein-Rodewald Tanja , Micklich Kateryna , Sanz-Moreno Adrián , Calzada-Wack Julia , Tost Monica , Adler Thure , Klaften Matthias , Sabrautzki Sibylle , Aigner Bernhard , Kraiger Markus , Gailus-Durner Valerie , Fuchs Helmut ,   German Mouse Clinic Consortium, Gründer Albert , Pahl Heike , Wolf Eckhard , de Angelis Martin Hrabe , Rathkolb Birgit 
Published: August 2022

AbstractGastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT-mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT-variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous KIT-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.
Pathogen-specific structural features of two key players in Candida albicans morphogenetic switch
Authors: Manso José A , Carabias Arturo , Sárkány Zsuzsa , de Pereda José M , Pereira Pedro José Barbosa , Macedo-Ribeiro Sandra 
Published: August 2022

AbstractRas-like protein 1 (CaRas1) is a key regulator of the switch between the yeast and hyphal forms of Candida albicans, a feature associated with pathogenesis. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its highly conserved GTP-binding domain (G-domain). An important function in hyphal growth has also been proposed for the long hypervariable region downstream of the G-domain of CaRas1, whose unusual content of polyQ stretches and Q/N repeats make CaRas1 unique within Ras-family proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 displays an elongated shape and that its hypervariable region contains helical structural elements with intramolecular coiled-coil propensity and limited conformational flexibility. Functional assays revealed that CaRas1 activation by CaCdc25 is highly efficient, with 5-to 2000-fold higher activity levels than reported for human GEFs. In addition, the threedimensional structure of the catalytic region of CaCdc25, together with the structural characterization of CaRas1/CaCdc25 complexes, unveiled a specific region located in the α-helical hairpin of CaCdc25, critical for CaRas1 activation, where negatively charged substitutions reduce its activity. The unique structural features of the low complexity region of CaRas1 and the distinctive properties of CaRas1 activation by CaCdc25, common in the homologous proteins from CTG-clade species, uncover novel strategies to target key virulence factors in human-infecting fungal pathogens.
Oxidative reactions catalyzed by hydrogen peroxide produced byStreptococcus pneumoniaeand other Streptococci Cause the Release and Degradation of Heme from Hemoglobin
Authors: Alibayov Babek , Scasny Anna , Khan Faidad , Creel Aidan , Smith Perriann , Jop Vidal Ana G. , Fitisemanu Fa’alataitaua M. , Padilla-Benavides Teresita , Weiser Jeffrey , Vidal Jorge E. 
Published: August 2022

AbstractStreptococcus pneumoniae(Spn) strains cause pneumonia that kills millions every year worldwide. Spn produces Ply, a hemolysin that lyses erythrocytes releasing hemoglobin and also produces the pro-oxidant hydrogen peroxide (Spn-H2O2) during growth. The hallmark of the pathophysiology of hemolytic diseases is the oxidation of hemoglobin but oxidative reactions catalyzed by Spn-H2O2has been poorly studied. We characterized the oxidation of hemoglobin by Spn-H2O2. We prepared a series of single (ΔspxB, or ΔlctO), double mutant (ΔspxBΔlctO) and complemented strains in TIGR4, D39 and EF3030. We then utilized anin vitromodel with oxy-hemoglobin to demonstrate that oxy-hemoglobin was oxidized rapidly, within 30 min of incubation, by Spn-H2O2to met-hemoglobin and that the main source of Spn-H2O2was pyruvate oxidase (SpxB). Moreover, extended incubation caused the release and the degradation of heme. We then assessed oxidation of hemoglobin and heme degradation by other bacteria inhabitants of the respiratory tract. All hydrogen peroxide-producing streptococci tested caused the oxidation of hemoglobin and heme degradation whereas those bacterial species that produce <1 μM H2O2, neither oxidized hemoglobin nor degraded heme. Anex vivobacteremia model confirmed that oxidation of hemoglobin and heme degradation occurred concurrently with hemoglobin that was released from erythrocytes by Ply. Finally, gene expression studies demonstrated that heme, but not red blood cells or hemoglobin induced an upregulated transcription of thespxBgene. Oxidation of hemoglobin may be important for pathogenesis and for the symbiosis of hydrogen peroxide-producing bacteria with other species by providing nutrients such as iron.