bluuebunny/crossref_metadata_2025_split huggingface dataset:
Engineering highly multivalent sperm-binding IgG antibodies for potent non-hormonal female contraception
Authors: Shrestha Bhawana , Schaefer Alison , Saada Jamal , Yong Zhu , Jacobs Timothy M. , Chavez Elizabeth C. , Omsted Stuart S. , Vincent Kathleen , Moench Thomas R. , Lai Samuel K. 
Published: April 2020

AbstractMany women risk unintended pregnancy due to dissatisfaction with available hormonal contraceptive methods. This led us to pursue topical sperm-binding monoclonal antibodies as a strategy for safe, non-hormonal contraception. Motivated by the greater agglutination potencies of polymeric immunoglobulins such as IgM and the exceptional bioprocessing ease in manufacturing IgG, we engineered IgGs possessing 6-10 Fabs against a unique surface antigen universally present on human sperm. These highly multivalent IgGs (HM-IgGs) are at least 10- to 16-fold more potent and faster than the parent IgG at agglutinating sperm, while preserving Fc-mediated trapping of individual spermatozoa in mucus. The increased potencies translate to effective (>99.9%) reduction of progressively motile sperm in the sheep vagina using 33 micrograms of the 10 Fab HM-IgG. HM-IgGs produce at comparable yields and possess identical thermal stability to the parent IgG, with greater homogeneity. HM-IgGs represent not only promising biologics for non-hormonal contraception but also a promising platform for generating potent agglutinating mAb for diverse medical applications.
CeMbio - TheC. elegansmicrobiome resource
Authors: Dirksen Philipp , Assié Adrien , Zimmermann Johannes , Zhang Fan , Tietje Adina-Malin , Marsh Sarah Arnaud , Félix Marie-Anne , Shapira Michael , Kaleta Christoph , Schulenburg Hinrich , Samuel Buck S. 
Published: April 2020

ABSTRACTThe study of microbiomes by sequencing has revealed a plethora of correlations between microbial community composition and various life-history characteristics of the corresponding host species. However, inferring causation from correlation is often hampered by the sheer compositional complexity of microbiomes, even in simple organisms. Synthetic communities offer an effective approach to infer cause-effect relationships in host-microbiome systems. Yet the available communities suffer from several drawbacks, such as artificial (thus non-natural) choice of microbes, microbe-host mismatch (e.g. human microbes in gnotobiotic mice), or hosts lacking genetic tractability. Here we introduce CeMbio, a simplified naturalCaenorhabditis elegansmicrobiota derived from our previous meta-analysis of the natural microbiome of this nematode. The CeMbio resource is amenable to all strengths of theC. elegansmodel system, strains included are readily culturable, they all colonize the worm gut individually, and comprise a robust community that distinctly affects nematode life-history. Several tools have additionally been developed for the CeMbio strains, including diagnostic PCR primers, completely sequenced genomes, and metabolic network models. With CeMbio, we provide a versatile resource and toolbox for the in-depth dissection of naturally relevant host-microbiome interactions inC. elegans.Dataset accession numbersWhole genome sequencing data (PRJNA624308); microbiome sequencing [PRJEB37101 and PRJEB37035]; data supplement on the GSA Figshare Portal.
Differential and sequential immunomodulatory role of neutrophils and Ly6Chiinflammatory monocytes during antiviral antibody therapy
Authors: Lambour Jennifer , Naranjo-Gomez Mar , Boyer-Clavel Myriam , Pelegrin Mireia 
Published: April 2020

AbstractAntiviral monoclonal antibodies (mAbs) can generate protective immunity through Fc-Fcγ Rs interactions. Using a mouse model of retroviral infection, we previously showed a crucial role for immune complexes (ICs) in the enhancement of T-cell responses through FcγR-mediated activation of dendritic cells (DCs). However, IC-FcγR interactions involve different cells of the immune system other than DCs such as neutrophils and monocytes. These two myeloid cell-types are innate effector cells rapidly recruited to sites of infection. In addition to being key cells to fight against invading pathogens, they are also endowed with immunomodulatory properties. While the role of DCs in enhancing antiviral immune responses upon mAb treatment has been addressed in several studies, the role of neutrophils and monocytes has been much less studied. Here we addressed how mAb therapy affects the functional activation of neutrophils and inflammatory monocytes in retrovirus-infected mice. We found that both cell-types activatedin vitroby viral ICs secreted high levels of chemokines able to recruit monocytes and neutrophils themselves. Moreover, inflammatory cytokines potentiated chemokines and cytokines release by IC-activated cells and induced FcγRIV upregulation. Similarly, infection and mAb-treatment upregulated FcγRIV expression on neutrophils and inflammatory monocytes and enhanced their cytokines and chemokines secretion. Notably, upon antibody therapy neutrophils and inflammatory monocytes displayed distinct functional activation states and sequentially modulated the antiviral immune response through the secretion of Th1-type polarizing cytokines and chemokines. Our work provides novel findings on the immunomodulatory role of neutrophils and monocytes in the enhancement of immune responses upon antiviral mAb therapy.
scLM: automatic detection of consensus gene clusters across multiple single-cell datasets
Authors: Song Qianqian , Su Jing , Miller Lance D. , Zhang Wei 
Published: April 2020

AbstractIn gene expression profiling studies, including single-cell RNA-seq (scRNAseq) analyses, the identification and characterization of co-expressed genes provides critical information on cell identity and function. Gene co-expression clustering in scRNA-seq data presents certain challenges. We show that commonly used methods for single cell data are not capable of identifying co-expressed genes accurately, and produce results that substantially limit biological expectations of co-expressed genes. Herein, we present scLM, a gene co-clustering algorithm tailored to single cell data that performs well at detecting gene clusters with significant biologic context. scLM can simultaneously cluster multiple single-cell datasets, i.e. consensus clustering, enabling users to leverage single cell data from multiple sources for novel comparative analysis. scLM takes raw count data as input and preserves biological variations without being influenced by batch effects from multiple datasets. Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy. To illustrate the biological insights of scLM, we apply it to our in-house and public experimental scRNA-seq datasets. scLM identifies novel functional gene modules and refines cell states, which facilitates mechanism discovery and understanding of complex biosystems such as cancers. A user-friendly R package with all the key features of the scLM method is available athttps://github.com/QSong-WF/scLM.
Development of a Novel Class of Self-Assembling dsRNA Cancer Therapeutics: a Proof of Concept Investigation
Authors: Asthana Vishwaratn , Stern Brett S. , Tang Yuqi , Bugga Pallavi , Li Ang , Ferguson Adam , Asthana Anantratn , Bao Gang , Drezek Rebekah A. 
Published: April 2020

AbstractCancer has proven to be an extremely difficult challenge to treat. Several fundamental issues currently underlie cancer treatment including differentiating self from non-self, functional coupling of the recognition and therapeutic components of various therapies, and the propensity of cancerous cells to develop resistance to common treatment modalities via evolutionary pressure. Given these limitations, there is an increasing need to develop an all-encompassing therapeutic that can uniquely target malignant cells, decouple recognition from treatment, and overcome evolutionarily driven cancer resistance. We describe herein, a new class of programmable self-assembling dsRNA-based cancer therapeutics, that uniquely targets aberrant genetic sequences, and in a functionally decoupled manner, undergoes oncogenic RNA activated displacement (ORAD), initiating a therapeutic cascade that induces apoptosis and immune activation. As a proof-of-concept, we show that RNA strands targeting the EWS/Fli1 fusion gene in Ewing Sarcoma cells that are end-blocked with phosphorothioate bonds and additionally sealed with a 2’-U modified DNA protector can be used to induce specific and potent killing of cells containing the target oncogenic sequence, but not wildtype.
Modulation of the vesicle code transmitting the visual signal in the retina
Authors: Moya-Díaz José , James Ben , Lagnado Leon 
Published: April 2020

SummaryMultivesicular release (MVR) allows retinal bipolar cells to transmit visual signals as changes in both the rate and amplitude of synaptic events. How do neuromodulators reguate this vesicle code? By imaging larval zebrafish, we find that the variability of calcium influx is a major source of synaptic noise. Dopamine increases synaptic gain up to 15-fold while Substance P reduces it 7-fold, both by acting on the presynaptic calcium transient to alter the distribution of amplitudes of multivesicular events. An increase in gain is accompanied by a decrease in the temporal precision of transmission and a reduction in the efficiency with which vesicles transfer visual information. The decrease in gain caused by Substance P was also associated with a shift in temporal filtering from band-pass to low-pass. This study demonstrates how neuromodulators act on the synaptic transformation of the visual signal to alter the way information is coded with vesicles.
The ancient fusogen EnvP(b)1 is expressed in human tissues and its structure informs the evolution of gammaretrovirus envelope proteins
Authors: McCarthy Kevin R. , Timpona Joseph L. , Jenni Simon , Brusic Vesna , Johnson Welkin E. , Whelan Sean P.J. , Robinson-McCarthy Lindsey R. 
Published: April 2020

ABSTRACTHost genomes have acquired diversity from viruses through the capture of viral elements, often from endogenous retroviruses (ERVs). These viral elements contribute new transcriptional control elements and new protein encoding genes, and their refinement through evolution can generate novel physiological functions for the host. EnvP(b)1 is an endogenous retroviral envelope gene found in human and other primate genomes. We show that EnvP(b)1 arose very early in the evolution of primates, i.e. at least 40-47 million years ago, but has nevertheless retained its ability to fuse primate cells. We have detected similar sequences in the genome of a lemur species, suggesting that a progenitor virus may have circulated 55+ million years ago. We demonstrate that EnvP(b)1 protein is expressed in multiple human tissues and is fully processed, rendering it competent to fuse cells. This activated fusogen is expressed in multiple healthy human tissues and is under purifying selection, suggesting that its expression is selectively advantageous. We determined a structure of the inferred receptor binding domain of human EnvP(b)1, revealing close structural similarities between this Env protein and those of currently circulating leukemia viruses, despite poor sequence conservation. This observation highlights a common scaffold from which novel receptor binding specificities have evolved. The evolutionary plasticity of this domain may underlie the diversity of related Envs in circulating viruses and coopted elements alike. The function of EnvP(b)1 in primates remains unknown.SIGNIFICANCE STATEMENTOrganisms can access genetic and functional novelty by capturing viral elements within their genomes, where they can evolve to drive new cellular or organismal processes. We demonstrate that a retrovirus envelope gene, EnvP(b)1, has been maintained as a functional protein for 40 to ≥55 million years and is expressed as a protein in multiple healthy human tissues. We believe it has an unknown function in primates. We determined the structure of its inferred receptor binding domain and compared it with the same domain in modern viruses. We find a common conserved architecture that underlies the varied receptor binding activity of divergent Env genes. The modularity and versatility of this domain may underpin the evolutionary success of this clade of fusogens.
Autonomic/Central Coupling Boosts Working Memory in Healthy Young Adults
Authors: Chen Pin-Chun , Whitehurst Lauren N. , Naji Mohsen , Mednick Sara C. 
Published: April 2020

AbstractWorking memory (WM) is an executive function that can improve with training. However, the precise mechanism for this improvement is not known. Studies have shown greater WM gains after a period of sleep than a similar period of wake (Kuriyama et al. 2008a; Zinke, Noack, and Born 2018), with WM improvement correlated with slow wave activity (SWA; 0.5-1Hz) during slow wave sleep (SWS) (Sattari et al. 2019; Pugin et al. 2015; Ferrarelli et al. 2019). A different body of literature has suggested an important role for autonomic activity during wake for WM (Hansen et al. 2004; Mosley, Laborde, and Kavanagh 2018). A recent study from our group reported that the temporal coupling of autonomic and central events (ACEs) during sleep was associated with memory consolidation (Naji et al. 2019). We found that heart rate bursts (HR bursts) during non-rapid eye movement (NREM) sleep are accompanied by increases in SWA and sigma (12-15Hz) power, as well as increases in the high-frequency (HF) component of the RR interval, reflecting vagal rebound. In addition, ACEs predict long-term, episodic memory improvement. Building on these previous results, we examined whether ACEs may also contribute to gains in WM. We tested 104 young adults in an operation span task (OSPAN) in the morning and evening, with either a nap (with electroencephalography (EEG) and electrocardiography (ECG)) or wake between testing sessions. We identified HR bursts in the ECG and replicated the increases in SWA and sigma prior to peak of the HR burst, as well as vagal rebound after the peak. Furthermore, we showed sleep-dependent WM improvement, which was predicted by ACE activity. Using regression analyses, we discovered that significantly more variance in WM improvement could be explained with ACE variables than with overall sleep activity not time-locked with ECG. These results provide the first evidence that coordinated autonomic and central events play a significant role in sleep-related WM improvement and implicate the potential of autonomic interventions during sleep for cognitive enhancement.
Gray matter networks associated with cognitive deficit in ADHD across adolescence and adulthood
Authors: Liu Jingyu , Duan Kuaikuai , Jiang Wenhao , Rootes-Murdy Kelly , Schoenmacker Gido , Buitelaar Jan K. , Hoogman Martine , Oosterlaan Jaap , Hoekstra Pieter J. , Heslenfeld Dirk J. , Hartman Catharina A. , Calhoun Vince D. , Arias-Vasquez Alejandro , Turner Jessica A. 
Published: April 2020

AbstractAttention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disorder, and its existence in adulthood is well established. Beyond symptoms of inattention and hyperactivity/impulsivity, patients commonly present with impairments in cognition. How neuronal underpinnings of symptoms and cognitive deficits differ across adolescence and adulthood is not clear. In this cross sectional study, we investigated gray matter of two cohorts, 486 adults and 508 adolescents, each including participants with ADHD and healthy controls. Independent component analysis was applied to the gray matter of each cohort, separately, to extract cohort specific networks. Then, we identified gray matter networks associated with symptoms, working memory and/or diagnosis in each cohort, and projected them onto the other cohort for comparison. Two components in the inferior, middle/superior frontal regions identified in adults and one component in the insula and inferior frontal region identified in adolescents were significantly associated with working memory deficits in both cohorts. One component in bilateral cerebellar tonsil and culmen identified in adults and one component in left cerebellar region identified in adolescents were significantly associated with inattentive symptoms in both cohorts. All these components presented significant or nominal level of gray matter reduction for ADHD patients in adolescents, but only one showed nominal reduction for patients in adults. Our findings suggest gray matter reduction may not be a sensitive marker for persist ADHD. However, the patterns of certain brain regions are associated with deficits in working memory or attention persistently from childhood into adulthood, which might help understand the mechanism of disease persistence.
Genome-wide study of the effect of blood collection tubes on the cell-free DNA methylome
Authors: Van Paemel Ruben , De Koker Andries , Caggiano Christa , Morlion Annelien , Mestdagh Pieter , De Wilde Bram , Vandesompele Jo , De Preter Katleen 
Published: April 2020

AbstractBackgroundThe methylation pattern of cfDNA, isolated from liquid biopsies, is gaining substantial interest for diagnosis and monitoring of diseases. We have evaluated the impact of type of blood collection tube and time delay between blood draw and plasma preparation on bisulfite-based cfDNA methylation profiling.Methods15 tubes of blood were drawn from three healthy volunteer subjects (BD Vacutainer K2E EDTA spray tubes, Streck Cell-Free DNA BCT tubes, PAXgene Blood ccfDNA tubes, Roche Cell-Free DNA Collection tubes and Biomatrica LBgard blood tubes in triplicate). Samples were either immediately processed or stored at room temperature for 24 or 72 hours before plasma preparation. DNA fragment size was evaluated by capillary electrophoresis. Reduced representation bisulfite sequencing was performed on the cell-free DNA isolated from these plasma samples. We evaluated the impact of blood tube and time delay on several quality control metrics.ResultsAll preservation tubes performed similar on the quality metrics that were evaluated. Furthermore, a considerable increase in cfDNA concentration and the fraction of it derived from NK cells was observed after a 72-hour time delay in EDTA tubes.ConclusionThe methylation pattern of cfDNA is robust and reproducible in between the different preservation tubes. EDTA tubes processed as soon as possible, preferably within 24 hours, are the most cost effective. If immediate processing is not possible, preservation tubes are valid alternatives.
Mapping the Immunodominance Landscape of SARS-CoV-2 Spike Protein for the Design of Vaccines against COVID-19
Authors: Zhang Bao-zhong , Hu Ye-fan , Chen Lin-lei , Tong Yi-gang , Hu Jing-chu , Cai Jian-piao , Chan Kwok-Hung , Dou Ying , Deng Jian , Gong Hua-rui , Kuwentrai Chaiyaporn , Li Wenjun , Wang Xiao-lei , Chu Hin , Su Cai-hui , Hung Ivan Fan-Ngai , Cheung Yau Thomas Chung , To Kelvin Kai-Wang , Yuen Kwok Yung , Huang Jian-Dong 
Published: April 2020

AbstractThe ongoing coronavirus disease 2019 (COVID-19) pandemic is a serious threat to global public health, and imposes severe burdens on the entire human society. The severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) can cause severe respiratory illness and death. Currently, there are no specific antiviral drugs that can treat COVID-19. Several vaccines against SARS-CoV-2 are being actively developed by research groups around the world. The surface S (spike) protein and the highly expressed internal N (nucleocapsid) protein of SARS-CoV-2 are widely considered as promising candidates for vaccines. In order to guide the design of an effective vaccine, we need experimental data on these potential epitope candidates. In this study, we mapped the immunodominant (ID) sites of S protein using sera samples collected from recently discharged COVID-19 patients. The SARS-CoV-2 S protein-specific antibody levels in the sera of recovered COVID-19 patients were strongly correlated with the neutralising antibody titres. We used epitope mapping to determine the landscape of ID sites of S protein, which identified nine linearized B cell ID sites. Four out of the nine ID sites were found in the receptor-binding domain (RBD). Further analysis showed that these ID sites are potential high-affinity SARS-CoV-2 antibody binding sites. Peptides containing two out of the nine sites were tested as vaccine candidates against SARS-CoV-2 in a mouse model. We detected epitope-specific antibodies and SARS-CoV-2-neutralising activity in the immunised mice. This study for the first time provides human serological data for the design of vaccines against COVID-19.
Arabidopsis O-fucosyltransferase SPINDLY regulates root hair patterning independently of gibberellin signalling
Authors: Mutanwad Krishna Vasant , Zangl Isabella , Lucyshyn Doris 
Published: April 2020

AbstractRoot hairs are able to sense soil composition and play an important role for water and nutrient uptake. InArabidopsis thaliana, root hairs are distributed in the epidermis in a specific pattern, regularly alternating with non-root hair cells in continuous cell files. This patterning is regulated by internal factors such as a number of hormones, as well as external factors like nutrient availability. Thus, root-hair patterning is an excellent model for studying the plasticity of cell fate determination in response to environmental changes. Here, we report that loss-of-function mutants in the Protein O-Fucosyltransferase SPINDLY (SPY) form ectopic root hairs. Using a number of transcriptional reporters, we show that patterning inspy-22is affected upstream of the central regulators GLABRA2 (GL2) and WEREWOLF (WER). O-fucosylation of nuclear and cytosolic proteins is an important post-translational modification that is still not very well understood. So far, SPY is best characterized for its role in gibberellin signalling via fucosylation of the growth-repressing DELLA protein REPRESSOR OF GA (RGA). Our data suggest that the formation of ectopic root hairs inspy-22is independent of RGA and gibberellin signalling.
Targeted CRM1-inhibition perturbs leukemogenic NUP214 fusion proteins and exerts anti-cancer effects in leukemia cell lines withNUP214rearrangements
Authors: Mendes Adélia , Jühlen Ramona , Martinelli Valérie , Fahrenkrog Birthe 
Published: April 2020

AbstractChromosomal translocations fusing the locus of nucleoporinNUP214each with the proto-oncogenesSETandDEKare recurrent in, largely intractable, acute leukemias. The molecular basis underlying the pathogenesis of SET-NUP214 and DEK-NUP214 are still poorly understood, but both chimeras inhibit protein nuclear export mediated by the ß-karyopherin CRM1. In this report, we show that SET-NUP214 and DEK-NUP214 both disturb the localization of proteins essential for nucleocytoplasmic transport, in particular for CRM1-mediated protein export. Endogenous and exogenous SET-NUP214 and DEK-NUP214 form nuclear bodies. These nuclear bodies disperse upon targeted inhibition of CRM1 and the two fusion proteins re-localize throughout the nucleoplasm. Moreover, SET-NUP214 and DEK-NUP214 nuclear bodies reestablish shortly after removal of CRM1 inhibitors. Likewise, cell viability, metabolism, and proliferation of leukemia cell lines harboring SET-NUP214 and DEK-NUP214 are compromised by CRM1 inhibition, which is even sustained after clearance from CRM1 antagonists. Our results indicate CRM1 as a possible therapeutic target in NUP214-related leukemia. This is especially important, since no specific or targeted treatment options for NUP214 driven leukemia are available yet.