bluuebunny/crossref_metadata_2025_split huggingface dataset:
Birth weight is associated with brain tissue volumes seven decades later, but not with age-associated changes to brain structure
Authors: Wheater Emily N. W. , Shenkin Susan D. , Maniega Susana Muñoz , Hernández Maria Valdés , Wardlaw Joanna M. , Deary Ian J. , Bastin Mark E. , Boardman James P. , Cox Simon R. 
Published: August 2020

AbstractBirth weight, an indicator of fetal growth, is associated with cognitive outcomes in early life and risk of metabolic and cardiovascular disease across the life course. Cognitive ability in early life is predictive of cognitive ability in later life. Brain health in older age, defined by MRI features, is associated with cognitive performance. However, little is known about how variation in normal birth weight impacts on brain structure in later life. In a community dwelling cohort of participants in their early seventies we tested the hypothesis that birthweight is associated with the following MRI features: total brain (TB), grey matter (GM) and normal appearing white matter (NAWM) volumes; whiter matter hyperintensity (WMH) volume; a general factor of fractional anisotropy (gFA) and peak width skeletonised mean diffusivity (PSMD) across the white matter skeleton. We also investigated the associations of birthweight with cortical surface area, volume and thickness. Birthweight was positively associated with TB, GM and NAWM volumes in later life (β ≥ 0.194), and with regional cortical surface area but not gFA, PSMD, WMH volume, or cortical volume or thickness. These positive relationships appear to be explained by larger intracranial volume rather than by age-related tissue atrophy, and are independent of body height and weight in adulthood. This suggests that larger birthweight is linked to increased brain tissue reserve in older life, rather than a resilience to age-related changes in brain structure, such as tissue atrophy or WMH volume.Significance StatementCognitive brain ageing carries a high personal, societal and financial cost and understanding its developmental origins is important for identifying possible preventative strategies. In a sample of older participants from the Lothian Birth Cohort 1936 we were able to explore the neurobiological correlates of birth weight, which is indicative of the fetal experience. We find that higher birth weight is related to larger brain tissue volumes in later life, but does not modify the trajectory of age-related change. This suggests that early life growth confers preserved differentiation, rather than differential preservation with regards to brain reserve. That these effects are detectable into later life indicates that this variable may be valuable biomarker in the epidemiology of ageing.
Hyperbolic geometry of gene expression
Authors: Zhou Yuansheng , Sharpee Tatyana 
Published: August 2020

AbstractUnderstanding the patterns of gene expression is key to elucidating the differences between cell types and across disease conditions. The overwhelmingly large number of genes involved generally makes this problem intractable. Yet, we find that gene expression patterns in five different data datasets can all be described using a small number of variables. These variables describe differences between cells according to a hyperbolic metric. We reach this conclusion by developing methods that, starting with an initial assumption of a Euclidean geometry, can detect the presence of other geometries in the data. The Euclidean metric is used in most of current studies of gene expression, primarily because it is difficult to use other non-linear metrics in high dimensional spaces. The hyperbolic metric is much more suitable for describing data produced by a hierarchically organized network, which is relevant for many biological processes. We find that the hyperbolic effects, but not the space dimensionality, increase with the number of genes that are taken into account. The hyperbolic curvature was the smallest for mouse embryonic stem cells, stronger for mouse kidney, lung and brain cells, and reached the largest value in a set of human cells integrated from multiple sources. We show that taking into account hyperbolic geometry strongly improves the visualization of gene expression data compared to leading visualization methods. These results demonstrate the advantages of knowing the underlying geometry when analyzing high-dimensional data.
PIEZO ion channel is required for root mechanotransduction inArabidopsis thaliana
Authors: Mousavi Seyed A. R. , Dubin Adrienne E , Zeng Wei-Zheng , Coombs Adam M. , Do Khai , Ghadiri Darian A. , Ge Chennan , Zhao Yunde , Patapoutian Ardem 
Published: August 2020

SummaryPlant roots adapt to the mechanical constraints of the soil to grow and absorb water and nutrients. As in animal species, mechanosensitive ion channels in plants are proposed to transduce external mechanical forces into biological signals. However, the identity of these plant root ion channels remains unknown. Here, we show thatArabidopsis thalianaPIEZO (AtPIEZO) has preserved the function of its animal relatives and acts as an ion channel. We present evidence that plant PIEZO is highly expressed in the columella and lateral root cap cells of the root tip which experience robust mechanical strain during root growth. Deleting PIEZO from the whole plant significantly reduced the ability of its roots to penetrate denser barriers compared to wild type plants.piezomutant root tips exhibited diminished calcium transients in response to mechanical stimulation, supporting a role of AtPIEZO in root mechanotransduction. Finally, a chimeric PIEZO channel that includes the C-terminal half of AtPIEZO containing the putative pore region was functional and mechanosensitive when expressed in naive mammalian cells. Collectively, our data suggest thatArabidopsisPIEZO plays an important role in root mechanotransduction and establishes PIEZOs as physiologically relevant mechanosensitive ion channels across animal and plant kingdoms.
Transcriptomic response during wasp parasitism in theDrosophila-Spiroplasmainteraction
Authors: Higareda-Alvear Victor M. , Mateos Mariana , Quezada Diego Cortez , Tamborindeguy Cecilia , Martínez-Romero Esperanza 
Published: August 2020

AbstractSeveral facultative bacterial symbionts of insects protect their hosts against natural enemies.Spiroplasma poulsoniistrainsMel, a male-killing heritable symbiont ofDrosophila melanogaster, confers protection against some species of parasitic wasps. Several lines of evidence suggest thatSpiroplasma-encoded ribosome inactivating proteins (RIPs) are involved in the protection mechanism, but the potential contribution of the fly-encoded functions has not been deeply explored. Here we used RNA-seq to evaluate the response ofD. melanogasterto infection bySpiroplasmaand parasitism by theSpiroplasma-susceptible waspLeptopilina heterotoma, and theSpiroplasma-resistant waspGanaspis hookeri. In the absence ofSpiroplasmainfection, we found evidence ofDrosophilaimmune activation byG. hookeri, but not byL. heterotoma, which in turn negatively influenced functions associated with male gonad development. As expected for a symbiont that kills males, we detected extensive downregulation in theSpiroplasma-infected treatments of genes known to have male-biased expression. We detected very few genes whose expression was influenced by theSpiroplasma-L. heterotomainteraction, and they do not appear to be related to immune response. For most of them, parasitism byL. heterotoma(in the absence ofSpiroplasma) caused an expression change that was at least partly reversed whenSpiroplasmawas also present. It is unclear whether such genes are involved in theSpiroplasma-mediated mechanism that leads to wasp death or fly rescue. Nonetheless, the expression pattern of some of these genes, which reportedly undergo expression shifts during the larva-to-pupa transition, is suggestive of an influence ofSpiroplasmaon the development time ofL. heterotoma-parasitized flies. In addition, we used the RNAseq data and quantitative (q)PCR to evaluate the transcript levels of theSpiroplasma-encoded RIP genes. One of the five RIP genes (RIP2) was consistently highly expressed independently of wasp parasitism, in two substrains ofsMel. Finally, the RNAseq data revealed evidence consistent with RIP-induced damage in the ribosomal (r)RNA of theSpiroplasma-susceptible, but not theSpiroplasma-resistant, wasp. We conclude that immune priming is unlikely to contribute to theSpiroplasma-mediated protection against wasps, and that the mechanism by whichG. hookeriresists/toleratesSpiroplasmadoes not involve inhibition of RIP transcription.
Twin studies with unmet assumptions are biased towards genetic heritability
Authors: Dalmaijer Edwin S. 
Published: August 2020

SummaryFor a century [1,2], studies of monozygotic and dizygotic twins have yielded estimates of trait heritability. The clever logic behind them is that while both types of twins share environments, their genetic overlap is different. Hence, larger trait correlations between monozygotic compared to dizygotic twins indicate heritability (nature), whereas similar correlations indicate shared environmental influences (nurture), and low correlations indicate shaping through non-shared environments (external influences and measurement error). While many have written on the assumptions that both types of twins share equal environments [3–5], and that parental genetics and environment are independent [6,7]; fewer have put their data where their mouth is. Here, the impacts of unmet assumptions were investigated using a generative mixture model of twin phenotypes. The results indicated that violations of the equal environments assumption yielded large overestimations of heritability and underestimations of shared environmental influences. On the other hand, when parental genetics shaped twins’ shared environments, only minor non-linear biases against heritability emerged. Finally, realistic levels of measurement error uniformly depressed estimates for genetic and shared environmental factors. In sum, twin studies are particularly susceptible to overestimation of genetic and non-shared environmental influences. This bias could explain why some traits, such as attitudes towards property taxes [8], show suspiciously high heritability without a biologically plausible mechanism. Particularly in the context of traits with convincing mechanisms of cultural transmission [9–11] and complex gene-environment interactions [6], researchers should not allow biases in twin studies to overestimate heritability.
The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat
Authors: Montefiori David C. , Filsinger Interrante Maria V. , Bell Benjamin N. , Rubio Adonis A. , Joyce Joseph G. , Shiver John W. , LaBranche Celia C. , Kim Peter S. 
Published: August 2020

AbstractThe HIV-1 gp41 N-heptad repeat (NHR) region of the pre-hairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the FDA-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1-infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared to those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1-infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.
Long Period Modeling SARS-CoV-2 Infection of in Vitro Cultured Polarized Human Airway Epithelium
Authors: Hao Siyuan , Ning Kang , Kuz Cagla Aksu , Vorhies Kai , Yan Ziying , Qiu Jianming 
Published: August 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. However, previous studies only characterized short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7-10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed Zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of 2.5 × 105virions per cm2of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2.
Immune response to vaccine candidates based on different types of nanoscaffolded RBD domain of the SARS-CoV-2 spike protein
Authors: Lainšček Duško , Fink Tina , Forstnerič Vida , Hafner-Bratkovič Iva , Orehek Sara , Strmšek Žiga , Manček-Keber Mateja , Pečan Peter , Esih Hana , Malenšek Špela , Aupič Jana , Dekleva Petra , Plaper Tjaša , Vidmar Sara , Kadunc Lucija , Benčina Mojca , Omersa Neža , Anderluh Gregor , Pojer Florence , Lau Kelvin , Hacker David , Correia Bruno , Peterhoff David , Wagner Ralf , Jerala Roman 
Published: August 2020

AbstractEffective and safe vaccines against SARS-CoV-2 are highly desirable to prevent casualties and societal cost caused by Covid-19 pandemic. The receptor binding domain (RBD) of the surface-exposed spike protein of SARS-CoV-2 represents a suitable target for the induction of neutralizing antibodies upon vaccination. Small protein antigens typically induce weak immune response while particles measuring tens of nanometers are efficiently presented to B cell follicles and subsequently to follicular germinal center B cells in draining lymph nodes, where B cell proliferation and affinity maturation occurs. Here we prepared and analyzed the response to several DNA vaccines based on genetic fusions of RBD to four different scaffolding domains, namely to the foldon peptide, ferritin, lumazine synthase and β-annulus peptide, presenting from 6 to 60 copies of the RBD on each particle. Scaffolding strongly augmented the immune response with production of neutralizing antibodies and T cell response including cytotoxic lymphocytes in mice upon immunization with DNA plasmids. The most potent response was observed for the 24-residue β-annulus peptide scaffold that forms large soluble assemblies, that has the advantage of low immunogenicity in comparison to larger scaffolds. Our results support the advancement of this vaccine platform towards clinical trials.
Resolvin D1 and D2 reduce SARS-Cov-2-induced inflammation in cystic fibrosis macrophages
Authors: Recchiuti Antonio , Patruno Sara , Mattoscio Domenico , Isopi Elisa , Pomilio Antonella , Lamolinara Alessia , Iezzi Manuela , Pecce Romina , Romano Mario 
Published: August 2020

AbstractResolvins (Rv) are endogenous lipid autacoids that mediate resolution of inflammation and bacterial infections. Their roles in SARS-CoV-2 and COVID-19 are of considerable interest in the context of cystic fibrosis (CF) given the paucity of data regarding the effect of this virus on immune cells from individuals with CF. Here, we provide evidence for Rv biosynthesis and regulatory actions on CF macrophage inflammatory responses.
MCART1 is required for mitochondrial NAD transport
Authors: Kory Nora , uit de Bos Jelmi , van der Rijt Sanne , Jankovic Nevena , Güra Miriam , Arp Nicholas , Pena Izabella A. , Prakash Gyan , Chan Sze Ham , Kunchok Tenzin , Lewis Caroline A. , Sabatini David M. 
Published: August 2020

AbstractThe nicotinamide adenine dinucleotide (NAD+/NADH) pair is a cofactor in redox reactions and is particularly critical in mitochondria as it connects substrate oxidation by the tricarboxylic acid (TCA) cycle to ATP generation by the electron transport chain (ETC) and oxidative phosphorylation. While a mitochondrial NAD+transporter has been identified in yeast, how NAD enters mitochondria in higher eukaryotes is unknown. Here, we mine gene essentiality data from human cell lines to identifyMCART1(SLC25A51) as co-essential with ETC components.MCART1-null cells have large decreases in TCA cycle flux, mitochondrial respiration, ETC complex I activity, and mitochondrial levels of NAD+and NADH. Isolated mitochondria from cells lacking or overexpressingMCART1have greatly decreased or increased NAD uptake in vitro, respectively. Moreover,MCART1andNDT1, a yeast mitochondrial NAD+transporter, can functionally complement for each other. Thus, we propose that MCART1 is the long sought mitochondrial transporter for NAD in human cells.
Breadth and function of antibody response to acute SARS-CoV-2 infection in humans
Authors: Huang Kuan-Ying A. , Tan Tiong Kit , Chen Ting-Hua , Huang Chung-Guei , Harvey Ruth , Hussain Saira , Chen Cheng-Pin , Harding Adam , Gilbert-Jaramillo Javier , Liu Xu , Knight Michael , Schimanski Lisa , Shih Shin-Ru , Lin Yi-Chun , Cheng Chien-Yu , Cheng Shu-Hsing , Huang Yhu-Chering , Lin Tzou-Yien , Jan Jia-Tsrong , Ma Che , James William , Daniels Rodney S. , McCauley John W. , Rijal Pramila , Townsend Alain R. 
Published: August 2020

AbstractSerological and plasmablast responses and plasmablast-derived IgG monoclonal antibodies (MAbs) have been analysed in three COVID-19 patients with different clinical severities. Potent humoral responses were detected within 3 weeks of onset of illness in all patients and the serological titre was elicited soon after or concomitantly with peripheral plasmablast response. An average of 13.7% and 13.0% of plasmablast-derived MAbs were reactive with virus spike glycoprotein or nucleocapsid, respectively. A subset of anti-spike (10 of 32) and over half of anti-nucleocapsid (19 of 35) antibodies cross-reacted with other betacoronaviruses tested and harboured extensive somatic mutations, indicative of an expansion of memory B cells upon SARS-CoV-2 infection. Fourteen of 32 anti-spike MAbs, including five anti-RBD, three anti-non-RBD S1 and six anti-S2, neutralised wild-type SARS-CoV-2 in independent assays. Anti-RBD MAbs were further grouped into four cross-inhibiting clusters, of which six antibodies from three separate clusters blocked the binding of RBD to ACE2 and five were neutralising. All ACE2-blocking anti-RBD antibodies were isolated from two patients with prolonged fever, which is compatible with substantial ACE2-blocking response in their sera. At last, the identification of non-competing pairs of neutralising antibodies would offer potential templates for the development of prophylactic and therapeutic agents against SARS-CoV-2.
A PCR amplicon–based SARS-CoV-2 replicon for antiviral screening
Authors: Kotaki Tomohiro , Xie Xuping , Shi Pei-Yong , Kameoka Masanori 
Published: August 2020

AbstractThe development of specific antiviral compounds to SARS-CoV-2 is an urgent task. One of the obstacles for the antiviral development is the requirement of biocontainment because infectious SARS-CoV-2 must be handled in a biosafety level-3 laboratory. Replicon, a non-infectious self-replicative viral RNA, could be a safe and effective tool for antiviral screening; however, SARS-CoV-2 replicon has not been reported yet. Herein, we generated a PCR-based SARS-CoV-2 replicon. Eight fragments covering the entire SARS-CoV-2 genome except S, E, and M genes were amplified with HiBiT-tag sequence by PCR. The amplicons were ligated andin vitrotranscribed to RNA. The cells electroporated with the replicon RNA showed more than 3,000 times higher luminescence than MOCK control cells at 24 hours post-electroporation, indicating robust viral translation and RNA replication. The replication was drastically inhibited by remdesivir, an RNA polymerase inhibitor for SARS-CoV-2. The IC50of remdesivir in this study was 0.29 μM, generally consistent to the IC50obtained using infectious SARS-CoV-2 in a previous study (0.77 μM). Taken together, this system could be applied to the safe and effective antiviral screening without using infectious SARS-CoV-2. Because this is a transient replicon, further improvement including the establishment of stable cell line must be achieved.
A SARS-CoV-2 BioID-based virus-host membrane protein interactome and virus peptide compendium: new proteomics resources for COVID-19 research
Authors: St-Germain Jonathan R. , Astori Audrey , Samavarchi-Tehrani Payman , Abdouni Hala , Macwan Vinitha , Kim Dae-Kyum , Knapp Jennifer J. , Roth Frederick P. , Gingras Anne-Claude , Raught Brian 
Published: August 2020

SummaryKey steps of viral replication take place at host cell membranes, but the detection of membrane-associated protein-protein interactions using standard affinity-based approaches (e.g. immunoprecipitation coupled with mass spectrometry, IP-MS) is challenging. To learn more about SARS-CoV-2 - host protein interactions that take place at membranes, we utilized a complementary technique, proximity-dependent biotin labeling (BioID). This approach uncovered a virus-host topology network comprising 3566 proximity interactions amongst 1010 host proteins, highlighting extensive virus protein crosstalk with: (i) host protein folding and modification machinery; (ii) membrane-bound vesicles and organelles, and; (iii) lipid trafficking pathways and ER-organelle membrane contact sites. The design and implementation of sensitive mass spectrometric approaches for the analysis of complex biological samples is also important for both clinical and basic research proteomics focused on the study of COVID-19. To this end, we conducted a mass spectrometry-based characterization of the SARS-CoV-2 virion and infected cell lysates, identifying 189 unique high-confidence virus tryptic peptides derived from 17 different virus proteins, to create a high quality resource for use in targeted proteomics approaches. Together, these datasets comprise a valuable resource for MS-based SARS-CoV-2 research, and identify novel virus-host protein interactions that could be targeted in COVID-19 therapeutics.