bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modern Machine Learning: Partition & Vote
Authors: Priebe Carey E. , Vogelstein Joshua T. , Engert Florian , White Christopher M. 
Published: May 2020

AbstractWe present modern machine learning, focusing on the state-of-the-art classification methods of decision forests and deep networks, as partition and vote schemes. This illustrative presentation allows for both a unified basic understanding of how these methods work from the perspective of classical statistical pattern recognition as well as useful basic insight into their relationship with each other … and potentially with brain functioning.
A novel single-domain Na+-selective voltage-gated channel in photosynthetic eukaryotes
Authors: Helliwell Katherine E. , Chrachri Abdul , Koester Julie , Wharam Susan , Taylor Alison R. , Wheeler Glen L. , Brownlee Colin 
Published: May 2020

AbstractThe evolution of Na+-selective four-domain voltage-gated channels (4D-Navs) in animals allowed rapid Na+-dependent electrical excitability, and enabled the development of sophisticated systems for rapid and long-range signalling. Whilst bacteria encode single-domain Na+-selective voltage-gated channels (BacNav), they typically exhibit much slower kinetics than 4D-Navs, and are not thought to have crossed the prokaryote-eukaryote boundary. As such, the capacity for rapid Na+-selective signalling is considered to be confined to certain animal taxa, and absent from photosynthetic eukaryotes. Certainly, in land plants, such as the Venus Flytrap where fast electrical excitability has been described, this is most likely based on fast anion channels. Here, we report a unique class of eukaryotic Na+-selective single-domain channels (EukCatBs) that are present primarily in haptophyte algae, including the ecologically important calcifying coccolithophores. The EukCatB channels exhibit very rapid voltage-dependent activation and inactivation kinetics, and sensitivity to the highly selective 4D-Nav blocker tetrodotoxin. The results demonstrate that the capacity for rapid Na+-based signalling in eukaryotes is not restricted to animals or to the presence of 4D-Navs. The EukCatB channels therefore represent an independent evolution of fast Na+-based electrical signalling in eukaryotes that likely contribute to sophisticated cellular control mechanisms operating on very short time scales in unicellular algae.One Sentence SummaryThe capacity for rapid Na+-based signalling has evolved in ecologically important coccolithophore species via a novel class of voltage-gated Na+ channels, EukCatBs.
Synthesis runs counter to directional folding of a nascent protein domain
Authors: Chen Xiuqi , Rajasekaran Nandakumar , Liu Kaixian , Kaiser Christian M. 
Published: May 2020

AbstractFolding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observedin vitrofor the majority of proteins relate to co-translational folding remains unclear. Combiningin vivoand single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.
Hugin+neurons link the sleep homeostat to circadian clock neurons
Authors: Schwarz Jessica E. , King Anna N. , Hsu Cynthia T. , Barber Annika F. , Sehgal Amita 
Published: May 2020

AbstractSleep is controlled by homeostatic mechanisms, which drive sleep after wakefulness, and a circadian clock, which confers the 24-hour rhythm of sleep. These processes interact with each other to control the timing of sleep in a daily cycle as well as following sleep deprivation. However, the mechanisms by which they interact are poorly understood. We show here thathugin+ neurons, previously identified as neurons that function downstream of the clock to regulate rhythms of locomotor activity, are also targets of the sleep homeostat. Sleep deprivation decreases activity ofhugin+ neurons, likely to suppress circadian-driven activity during recovery sleep, and manipulations ofhugin+ neurons affect sleep increases generated by activation of the homeostatic sleep locus, the dorsal fanshaped body (dFB). Also, mutations in peptides produced by thehugin+ locus increase recovery sleep following deprivation. Trans-synaptic mapping reveals thathugin+ neurons feed-back onto central clock neurons, which also show decreased activity upon sleep loss, in a Hugin-peptide dependent fashion. We propose thathugin+ neurons integrate circadian and sleep signals to modulate circadian circuitry and regulate the timing of sleep.
Plk4 triggers autonomous de novo centriole biogenesis and maturation
Authors: Nabais Catarina , Pessoa Delphine , de-Carvalho Jorge , van Zanten Thomas , Duarte Paulo , Mayor Satyajit , Carneiro Jorge , Telley Ivo A. , Bettencourt-Dias Mónica 
Published: May 2020

AbstractCentrioles form centrosomes and cilia. In most proliferating cells, centrioles assemble through canonical duplication, which is spatially, temporally and numerically regulated by the cell cycle and the presence of mature centrioles. However, in certain cell-types, centrioles assemble de novo, yet by poorly understood mechanisms. Here, we established a controlled system to investigate de novo centriole biogenesis, usingDrosophila melanogasteregg explants overexpressing Polo-like kinase 4 (Plk4), a trigger for centriole biogenesis. We show that at high Plk4 concentration, centrioles form de novo, mature and duplicate, independently of cell cycle progression and of the presence of other centrioles. Plk4 concentration determines the kinetics of centriole assembly. Moreover, our results suggest Plk4 operates in a switch-like manner to control the onset of de novo centriole formation, and that distinct biochemical kinetics regulate de novo and canonical biogenesis. Finally, we investigated which other factors modulate de novo centriole assembly and reveal that proteins of the pericentriolar matrix (PCM) promote biogenesis, likely by locally concentrating critical components.
Site-specific glycosylation mapping of Fc gamma receptor IIIb from neutrophils of health donors
Authors: Wojcik Iwona , Sénard Thomas , de Graaf Erik L , Janssen George MC , de Ru Arnoud H , Mohammed Yassene , van Veelen Peter A , Vidarsson Gestur , Wuhrer Manfred , Falck David 
Published: May 2020

ABSTRACTFc gamma receptors (FcγR) translate antigen-recognition by immunoglobulin G (IgG) into various immune responses. A better understanding of this key element of immunity promises novel insights into mechanisms of (auto-/allo-)immune diseases and more rationally designed antibody-based drugs. Glycosylation on both IgG and FcγR impacts their interaction dramatically. In this study, we developed a straightforward and comprehensive analytical methodology to map FcγRIIIb glycosylation from primary human material. In contrast to recently published alternatives, we assessed all glycosylation sites in a single LC-MS/MS run and simultaneously determined the donor allotype. Studying FcγRIIIb derived from healthy donor neutrophils, we observed profound differences as compared to the soluble variant and the homologous FcγRIIIa on natural killer cells. This method will allow assessment of FcγRIII glycosylation differences between individuals, cell types, subcellular locations and pathophysiological conditions.
De novo synthesis and salvage pathway coordinately regulates polyamine homeostasis and determines T cell proliferation and function
Authors: Wu Ruohan , Chen Xuyong , Kang Siwen , Wang Tingting , Gnanaprakasam JN Rashida , Yao Yufeng , Liu Lingling , Zheng Song Guo , Fan Gaofeng , Burns Mark R , Wang Ruoning 
Published: May 2020

AbstractRobust and effective T cell-mediated immune responses require proper allocation of metabolic resources through metabolic pathways to sustain the energetically costly immune response. As an essential class of polycationic metabolites ubiquitously present in all living organisms, the polyamine pool is tightly regulated by biosynthesis and salvage pathway. We demonstrated that arginine is a major carbon donor and glutamine is a minor carbon donor for polyamine biosynthesis in T cells. Accordingly, the dependence of T cells can be partially relieved by replenishing the polyamine pool. In response to the blockage of de novo synthesis, T cells can rapidly restore the polyamine pool through a compensatory increase in polyamine uptake from the environment, indicating a layer of metabolic plasticity. Simultaneously blocking synthesis and uptake depletes the intracellular PA pool, inhibits T cell proliferation, suppresses T cell inflammation, indicating the potential therapeutic value of targeting the polyamine for managing inflammatory and autoimmune diseases.
Electron tomography visualization of HIV-1 fusion with target cells using fusion inhibitors to trap the pre-hairpin intermediate
Authors: Ladinsky Mark S. , Gnanapragasam Priyanthi N.P. , Yang Zhi , West Anthony P. , Kay Michael S , Bjorkman Pamela J. 
Published: May 2020

AbstractFusion of HIV-1 with the membrane of its target cell, an obligate first step in virus infectivity, is mediated by binding of the viral envelope (Env) spike protein to its receptors, CD4 and CCR5/CXCR4, on the cell surface. The process of viral fusion appears to be fast compared with viral egress and has not been visualized by electron microscopy (EM). To capture fusion events for EM, the process must be slowed or stopped by trapping Env-receptor binding at an intermediate stage. Here we describe using fusion inhibitors to trap HIV-1 virions attached to target cells by Envs in an extended pre-hairpin intermediate state. Electron tomography revealed HIV-1 virions bound to TZM-bl cells by 2-4 narrow spokes, with slightly more spokes present when evaluated with mutant virions that lacked the Env cytoplasmic tail. These results represent the first direct visualization of the hypothesized pre-hairpin intermediate and improve our understanding of Env-mediated HIV-1 fusion and infection of host cells.
HumanizedDrosophilamodel of the Meier-Gorlin syndrome reveals conserved and divergent features of the Orc6 protein
Authors: Balasov Maxim , Akhmetova Katarina , Chesnokov Igor 
Published: May 2020

AbstractMeier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the subunits of the Origin Recognition Complex (ORC), components of the pre-replicative complex (pre-RC) and replication machinery. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. A mutation in conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. Recently, new mutation in Orc6 was also identified however, it is localized in the N-terminal domain of the protein. In order to study the functions of Orc6 we used human gene to rescue theorc6deletion inDrosophila. Using the “humanized” Orc6-basedDrosophilamodel of the Meier-Gorlin syndrome we discovered that unlike previous Y225S MGS mutation in Orc6, the K23E substitution in the N-terminal TFIIB-like domain of Orc6 disrupts the protein ability to bind DNA. Our studies revealed the importance of evolutionary conserved and variable domains of Orc6 protein and allowed the studies of human protein functions and the analysis of the critical amino acids in live animal heterologous system as well as provided novel insights into the mechanisms underlying MGS pathology.
Atypical response inhibition and error processing in 22q11.2 Deletion Syndrome and Schizophrenia: Towards neuromarkers of disease progression and risk
Authors: Francisco Ana A. , Horsthuis Douwe J. , Popiel Maryann , Foxe John J. , Molholm Sophie 
Published: May 2020

ABSTRACT22q11.2 deletion syndrome (also known as DiGeorge syndrome or velo-cardio-facial syndrome) is characterized by increased vulnerability to neuropsychiatric symptoms, with approximately 30% of individuals with the deletion going on to develop schizophrenia. Clinically, deficits in executive function have been noted in this population, but the underlying neural processes are not well understood. Using a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response (a critical component of executive function) in individuals with 22q11.2DS with and without psychotic symptoms, when compared to individuals with idiopathic schizophrenia and age-matched neurotypical controls. Twenty-eight participants diagnosed with 22q11.2DS (14-35 years old; 14 with at least one psychotic symptom), 15 individuals diagnosed with schizophrenia (18-63 years old) and two neurotypical control groups (one age-matched to the 22q11.2DS sample, the other age-matched to the schizophrenia sample) participated in this study. Analyses focused on the N2 and P3 no-go responses and error-related negativity (Ne) and positivity (Pe). Atypical inhibitory processing was shown behaviorally and by significantly reduced P3, Ne, and Pe responses in 22q11.2DS and schizophrenia. Interestingly, whereas P3 was only reduced in the presence of psychotic symptoms, Ne and Pe were equally reduced in schizophrenia and 22q11.2DS, regardless of the presence of symptoms. We argue that while P3 may be a marker of disease severity, Ne and Pe might be candidate markers of risk.
Invasive freshwater snails form novel microbial relationships
Authors: Bankers L. , Dahan D. , Neiman M. , Adrian-Tucci C. , Frost C. , Hurst G.D.D. , King K.C. 
Published: May 2020

ABSTRACTResident microbes (microbiota) can shape host organismal function and adaptation in the face of environmental change. Invasion of new habitats exposes hosts to novel selection pressures, but little is known about the impact of invasion on microbiota and the host-microbiome relationship after this transition (e.g., how rapidly symbioses are formed, whether microbes influence invasion success). We used high-throughput 16S rRNA sequencing of New Zealand (native) and European (invasive) populations of the freshwater snailPotamopyrgus antipodarumand found that while invaders do carry over some core microbial taxa from New Zealand, most of their microbial community is distinct. This finding highlights that invasions can result in the formation of novel symbioses. We further show that the native microbiome is composed of fewer core microbes than the microbiome of invasive snails, suggesting that the microbiota is streamlined to essential members. Together, our findings demonstrate that microbiota comparisons across native and invasive populations can reveal the impact of a long coevolutionary history and specialization of microbes in the native host range, as well as new associations occurring after invasion. We lay essential groundwork for understanding how microbial relationships affect invasion success and how microbes may be utilized in the control of invasive hosts.
Eliciting OTUD3/RIPK-Dependent Necroptosis to Prevent Epithelial Ovarian Cancer
Authors: Johnson Joshua , Bales Elise C. , Bitler Benjamin G. , Watson Zachary L. 
Published: May 2020

AbstractBackgroundThere is an urgent need for early prevention strategies against high grade serous ovarian carcinoma (HGSOC), the deadliest gynecologic malignancy. Transformed p53-null fallopian tube epithelium (FTE) cells are precursors of HGSOC that may be eliminated by inducing necroptosis, a programmed form of inflammatory cell death. Induction of necroptosis is dependent upon activation of receptor-interacting serine/threonine-protein kinases 1 and 3 (RIPK1/3). TNFα and progesterone (P4) effectively promote necroptosis. In this study, we explore the activation of necroptosis as an approach to inhibit HGSOC progression.MethodsUsing gene ontology sets as a reference, we analyzed publicly available datasets of HGSOC to correlate the expression of necroptosis effectors to clinical outcomes. Usingin vitromodels of HGSOC we evaluated the effect of TNFα, P4, and α-eleostearic acid on necroptosis. In parallel, the necroptosis inhibitor Necrostatin-1 was used to confirm necroptosis-specific cell death.ResultsExpression of the P4 receptor (PGR) was sharply reduced in a HGSOC cohort compared to normal, nonmalignant FTE. However, several genes involved in necroptosis signaling were elevated in HGSOC, includingTNFandRIPK1. Increased expression ofPGR, the necroptosis effectorsTNFandRIPK1/3, as well as ovarian tumor domain-containing deubiquitinase 3 (OTUD3) were associated with higher overall survival in 484 HGSOC cases. HGSOC cells activated necroptosis in response to P4, TNFα, and α-eleostearic acid treatment, while P4 or TNFα treatment of HGSOC cells increasedTNF,RIPK1, andOTUD3expression. OTUD3 is a putative tumor suppressor that stabilizes PTEN and is hypothesized to be functionally similar to the necroptosis inducer, OTUD7B. shRNA knockdown ofOTUD3resulted in decreased PTEN protein and RIPK1 protein.ConclusionsWe conclude that necroptosis activation may be a viable prevention strategy that leads to the elimination of transformed FTE “founder” cells and prevents HGSOC tumorigenesis. Our data indicate that HGSOC cells activate necroptosis in response to P4, TNFα, and α-eleostearic acid, suggesting that established HGSOC cells may also be eliminated by activating necroptosis.
CNCDatabase: a database of non-coding cancer drivers
Authors: Liu Eric Minwei , Martinez-Fundichely Alexander , Bollapragada Rajesh , Spiewack Maurice , Khurana Ekta 
Published: May 2020

ABSTRACTMost mutations in cancer genomes occur in the non-coding regions with unknown impact to tumor development. Although the increase in number of cancer whole-genome sequences has revealed numerous putative non-coding cancer drivers, their information is dispersed across multiple studies and thus it is difficult to bridge the understanding of non-coding alterations, the genes they impact and the supporting evidence for their role in tumorigenesis across multiple cancer types. To address this gap, we have developed CNCDatabase, Cornell Non-Coding Cancer driver Database (https://cncdatabase.med.cornell.edu/) that contains detailed information about predicted non-coding drivers at gene promoters, 5’ and 3’ UTRs (untranslated regions), enhancers, CTCF insulators and non-coding RNAs. CNCDatabase documents 1,111 protein-coding genes and 90 non-coding RNAs with reported drivers in their non-coding regions from 32 cancer types by computational predictions of positive selection in whole-genome sequences; differential gene expression in samples with and without mutations; or another set of experimental validations including luciferase reporter assays and genome editing. The database can be easily modified and scaled as lists of non-coding drivers are revised in the community with larger whole-genome sequencing studies, CRISPR screens and further experimental validations. Overall, CNCDatabase provides a helpful resource for researchers to explore the pathological role of non-coding alterations and their associations with gene expression in human cancers.
Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2
Authors: Korber B , Fischer WM , Gnanakaran S , Yoon H , Theiler J , Abfalterer W , Foley B , Giorgi EE , Bhattacharya T , Parker MD , Partridge DG , Evans CM , Freeman TM , de Silva TI ,   on behalf of the Sheffield COVID-19 Genomics Group, LaBranche CC , Montefiori DC 
Published: May 2020

SummaryWe have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike (S) protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified thirteen mutations in Spike that are accumulating. Mutations are considered in a broader phylogenetic context, geographically, and over time, to provide an early warning system to reveal mutations that may confer selective advantages in transmission or resistance to interventions. Each one is evaluated for evidence of positive selection, and the implications of the mutation are explored through structural modeling. The mutation Spike D614G is of urgent concern; it began spreading in Europe in early February, and when introduced to new regions it rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections. These finding have important implications for SARS-CoV-2 transmission, pathogenesis and immune interventions.
Removing the Gβγ-SNAP25 brake on exocytosis enhances insulin action, promotes adipocyte browning, and protects against diet-induced obesity
Authors: Ceddia Ryan P. , Zurawski Zack , Gray Analisa Thompson , Adegboye Feyisayo , McDonald-Boyer Ainsley , Shi Fubiao , Liu Dianxin , Maldonado Jose , Feng Jiesi , Li Yulong , Alford Simon , Ayala Julio E. , McGuinness Owen P. , Collins Sheila , Hamm Heidi E. 
Published: May 2020

AbstractNegative regulation of exocytosis from secretory cells throughout the body is accomplished through inhibitory signals from Gi/oG protein-coupled receptors by Gβγ subunit inhibition of two common mechanisms: (i) decreased calcium entry and (ii) direct interaction of Gβγ with the SolubleN-ethylmaleimide-sensitive factor Attachment Protein (SNAP) Receptor (SNARE) plasma membrane fusion machinery. We have previously shown that disabling the second mechanism with a truncation of SNAP25 (SNAP25Δ3/Δ3) decreases the affinity of Gβγ for the SNARE complex, leaving exocytotic fusion as well as modulation of calcium entry intact but disabling GPCR inhibition of exocytosis. Here we report significant beneficial metabolic remodeling in mice carrying this mutation. Chow-fed SNAP25Δ3/Δ3mice exhibit enhanced insulin sensitivity and increased beiging of white fat. In response to a high fat diet, the metabolic protection was amplified in SNAP25Δ3/Δ3mice. Glucose homeostasis, whole body insulin action, and insulin-mediated glucose uptake into white adipose tissue were improved along with resistance to diet-induced obesity. This metabolic protection in SNAP25Δ3/Δ3mice occurred without compromising the physiological response to fasting or cold. All metabolic phenotypes were reversed at thermoneutrality, suggesting basal autonomic activity is required. Direct electrode stimulation of sympathetic neurons exocytosis from SNAP25Δ3/Δ3inguinal adipose depot resulted in enhanced and prolonged norepinephrine release. Thus, the Gβγ-SNARE interaction represents a cellular mechanism that deserves further exploration as a new avenue for combatting metabolic disease.GRAPHICAL ABSTRACT