bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo
Authors: Parayath N. N. , Stephan S. B. , Koehne A. L. , Nelson P. S. , Stephan M. T. 
Published: November 2020

AbstractEngineering chimeric antigen receptors (CAR) or T cell receptors (TCR) helps create disease-specific T cells for targeted therapy, but the cost and rigor associated with manufacturing engineered T cells ex vivo can be prohibitive, so programing T cells in vivo may be a viable alternative. Here we report an injectable nanocarrier that delivers in vitro-transcribed (IVT) CAR or TCR mRNA for transiently reprograming of circulating T cells to recognize disease-relevant antigens. In mouse models of human leukemia, prostate cancer and hepatitis B-induced hepatocellular carcinoma, repeated infusions of these polymer nanocarriers induce sufficient host T cells expressing tumor-specific CARs or virus-specific TCRs to cause disease regression at levels similar to bolus infusions of ex vivo engineered lymphocytes. Given their ease of manufacturing, distribution and administration, these nanocarriers, and the associated platforms, could become a therapeutic for a wide range of diseases.
Plasma N-terminal tau fragment levels predict future cognitive decline and neurodegeneration in healthy elderly individuals
Authors: Chhatwal Jasmeer P. , Schultz Aaron P. , Dang Yifan , Ostaszewski Beth , Liu Lei , Yang Hyun-Sik , Johnson Keith A. , Sperling Reisa A. , Selkoe Dennis J. 
Published: November 2020

AbstractThe availability of blood-based assays detecting Alzheimer’s disease (AD) pathology should greatly accelerate AD therapeutic development and improve clinical care. This is especially true for markers that capture the risk of decline in pre-symptomatic stages of AD, as this would allow one to focus interventions on participants maximally at risk and at a stage prior to widespread synapse loss and neurodegeneration. Here we quantify plasma concentrations of an N-terminal fragment of tau (NT1) in a large, well-characterized cohort of clinically normal elderly who were followed longitudinally. Plasma NT1 levels at study entry (when all participants were unimpaired) were highly predictive of future cognitive decline, pathological tau accumulation, neurodegeneration, and transition to a diagnosis of MCI/AD. These predictive effects were particularly strong in participants with even modestly elevated brain β-amyloid burden at study entry, suggesting plasma NT1 levels capture very early cognitive, pathologic and neurodegenerative changes along the AD trajectory.
CRISPR based editing of SIV proviral DNA in ART treated non-human primates
Authors: Mancuso Pietro , Chen Chen , Kaminski Rafal , Gordon Jennifer , Liao Shuren , Robinson Jake A. , Smith Mandy D. , Liu Hong , Sariyer Ilker K. , Sariyer Rahsan , Peterson Tiffany A. , Donadoni Martina , Williams Jaclyn B. , Siddiqui Summer , Bunnell Bruce A. , Ling Binhua , MacLean Andrew G. , Burdo Tricia H. , Khalili Kamel 
Published: November 2020

AbstractElimination of HIV DNA from infected individuals remains a challenge in medicine. Here, we demonstrate that intravenous inoculation of SIV-infected macaques, a well-accepted non-human primate model of HIV infection, with adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct designed for eliminating proviral SIV DNA, leads to broad distribution of editing molecules and precise cleavage and removal of fragments of the integrated proviral DNA from the genome of infected blood cells and tissues known to be viral reservoirs including lymph nodes, spleen, bone marrow, and brain among others. Accordingly, AAV9-CRISPR treatment results in a reduction in the percent of proviral DNA in blood and tissues. These proof-of-concept observations offer a promising step toward the elimination of HIV reservoirs in the clinic.
Dispersal-induced instability in complex ecosystems
Authors: Baron Joseph W. , Galla Tobias 
Published: November 2020

AbstractIn his seminal work in the 1970s, Robert May suggested that there is an upper limit to the number of species that can be sustained in stable equilibrium by an ecosystem. This deduction was at odds with both intuition and the observed complexity of many natural ecosystems. The so-called stability-diversity debate ensued, and the discussion about the factors contributing to ecosystem stability or instability continues to this day. We show in this work that dispersal can be a destabilising influence. To do this, we combine ideas from Alan Turing’s work on pattern formation with May’s random-matrix approach. We demonstrate how a stable equilibrium in a complex ecosystem with trophic structure can become unstable with the introduction of dispersal in space, and we discuss the factors which contribute to this effect. Our work highlights that adding more details to the model of May can give rise to more ways for an ecosystem to become unstable. Making May’s simple model more realistic is therefore unlikely to entirely remove the upper bound on complexity.
Designer spin order in diradical nanographenes
Authors: Zheng Yuqiang , Li Can , Xu Chengyang , Beyer Doreen , Yue Xinlei , Zhao Yan , Wang Guanyong , Guan Dandan , Li Yaoyi , Zheng Hao , Liu Canhua , Liu Junzhi , Wang Xiaoqun , Luo Weidong , Feng Xinliang , Wang Shiyong , Jia Jinfeng 
Published: November 2020

AbstractThe magnetic properties of carbon materials are at present the focus of intense research effort in physics, chemistry and materials science due to their potential applications in spintronics and quantum computing. Although the presence of spins in open-shell nanographenes has recently been confirmed, the ability to control magnetic coupling sign has remained elusive but highly desirable. Here, we demonstrate an effective approach of engineering magnetic ground states in atomically precise open-shell bipartite/nonbipartite nanographenes using combined scanning probe techniques and mean-field Hubbard model calculations. The magnetic coupling sign between two spins was controlled via breaking bipartite lattice symmetry of nanographenes. In addition, the exchange-interaction strength between two spins has been widely tuned by finely tailoring their spin density overlap, realizing a large exchange-interaction strength of 42 meV. Our demonstrated method provides ample opportunities for designer above-room-temperature magnetic phases and functionalities in graphene nanomaterials.
A grass-specific cellulose–xylan interaction dominates in sorghum secondary cell walls
Authors: Gao Yu , Lipton Andrew S. , Wittmer Yuuki , Murray Dylan T. , Mortimer Jenny C. 
Published: November 2020

AbstractSorghum (Sorghum bicolorL. Moench) is a promising source of lignocellulosic biomass for the production of renewable fuels and chemicals, as well as for forage. Understanding secondary cell wall architecture is key to understanding recalcitrance i.e. identifying features which prevent the efficient conversion of complex biomass to simple carbon units. Here, we use multi-dimensional magic angle spinning solid-state NMR to characterize the sorghum secondary cell wall. We show that xylan is mainly in a three-fold screw conformation due to dense arabinosyl substitutions, with close proximity to cellulose. We also show that sorghum secondary cell walls present a high ratio of amorphous to crystalline cellulose as compared to dicots. We propose a model of sorghum cell wall architecture which is dominated by interactions between three-fold screw xylan and amorphous cellulose. This work will aid the design of low-recalcitrance biomass crops, a requirement for a sustainable bioeconomy.
Robustness and lethality in multilayer biological molecular networks
Authors: Liu Xueming , Maiorino Enrico , Halu Arda , Glass Kimberly , Prasad Rashmi B. , Loscalzo Joseph , Gao Jianxi , Sharma Amitabh 
Published: November 2020

AbstractRobustness is a prominent feature of most biological systems. Most previous related studies have been focused on homogeneous molecular networks. Here we propose a comprehensive framework for understanding how the interactions between genes, proteins and metabolites contribute to the determinants of robustness in a heterogeneous biological network. We integrate heterogeneous sources of data to construct a multilayer interaction network composed of a gene regulatory layer, a protein–protein interaction layer, and a metabolic layer. We design a simulated perturbation process to characterize the contribution of each gene to the overall system’s robustness, and find that influential genes are enriched in essential and cancer genes. We show that the proposed mechanism predicts a higher vulnerability of the metabolic layer to perturbations applied to genes associated with metabolic diseases. Furthermore, we find that the real network is comparably or more robust than expected in multiple random realizations. Finally, we analytically derive the expected robustness of multilayer biological networks starting from the degree distributions within and between layers. These results provide insights into the non-trivial dynamics occurring in the cell after a genetic perturbation is applied, confirming the importance of including the coupling between different layers of interaction in models of complex biological systems.
Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war
Authors: Favretto Filippo , Flores David , Baker Jeremy D. , Strohäker Timo , Andreas Loren B. , Blair Laura J. , Becker Stefan , Zweckstetter Markus 
Published: November 2020

AbstractCatalysis of cis/trans isomerization of prolines is important for the activity and misfolding of intrinsically disordered proteins. Catalysis is achieved by peptidylprolyl isomerases, a superfamily of molecular chaperones. Here, we provide atomic insight into a tug-of-war between cis/trans isomerization and molecular chaperone activity. Catalysis of proline isomerization by cyclophilin A lowers the energy barrier for α-synuclein misfolding, while isomerase-binding to a separate, disease-associated protein region opposes aggregation. We further show that cis/trans isomerization outpowers the holding activity of cyclophilin A. Removal of the proline isomerization barrier through posttranslational truncation of α-synuclein reverses the action of the proline isomerase and turns it into a potent molecular chaperone that inhibits protein misfolding. The data reveal a conserved mechanism of dual functionality in cis/trans isomerases and define its molecular determinants acting on intrinsically disordered proteins.
Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis
Authors: Wang Chi , Liu Hui , Li Kun , Wu Zhen-Zhen , Wu Chen , Yu Jing-Ying , Gong Qian , Fang Ping , Wang Xing-Xing , Duan Shu-Min , Wang Hao , Gu Yan , Hu Ji , Pan Bing-Xing , Schmidt Mathias V. , Liu Yi-Jun , Wang Xiao-Dong 
Published: November 2020

AbstractTouch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.
Feedback regulation of crystal growth by buffering monomer concentration
Authors: Schaffter Samuel W. , Scalise Dominic , Murphy Terence M. , Patel Anusha , Schulman Rebecca 
Published: November 2020

AbstractCrystallization is a ubiquitous means of self-assembly that can organize matter over length scales orders of magnitude larger than those of the monomer units. Yet crystallization is notoriously difficult to control because it is exquisitely sensitive to monomer concentration, which changes as monomers are depleted during growth. Living cells control crystallization using chemical reaction networks that offset depletion by synthesizing or activating monomers to regulate monomer concentration, stabilizing growth conditions even as depletion rates change, and thus reliably yielding desired products. Using DNA nanotubes as a model system, here we show that coupling a generic reversible bimolecular monomer buffering reaction to a crystallization process leads to reliable growth of large, uniformly sized crystals even when crystal growth rates change over time. Buffering could be applied broadly as a simple means to regulate and sustain batch crystallization and could facilitate the self-assembly of complex, hierarchical synthetic structures.
SARS-CoV-2 genomic and subgenomic RNAs in diagnostic samples are not an indicator of active replication
Authors: Alexandersen Soren , Chamings Anthony , Bhatta Tarka Raj 
Published: November 2020

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was first detected in late December 2019 and has spread worldwide. Coronaviruses are enveloped, positive sense, single-stranded RNA viruses and employ a complicated pattern of virus genome length RNA replication as well as transcription of genome length and leader containing subgenomic RNAs. Although not fully understood, both replication and transcription are thought to take place in so-called double-membrane vesicles in the cytoplasm of infected cells. Here we show detection of SARS-CoV-2 subgenomic RNAs in diagnostic samples up to 17 days after initial detection of infection and provide evidence for their nuclease resistance and protection by cellular membranes suggesting that detection of subgenomic RNAs in such samples may not be a suitable indicator of active coronavirus replication/infection.
Yeast Nup84-Nup133 complex structure details flexibility and reveals conservation of the membrane anchoring ALPS motif
Authors: Nordeen Sarah A. , Turman Daniel L. , Schwartz Thomas U. 
Published: November 2020

AbstractThe hallmark of the eukaryotic cell is the complex endomembrane system that compartmentalizes cellular functions. Transport into and out of the nucleus occurs through the nuclear pore complex (NPC). The heptameric Nup84 or Y complex is an essential scaffolding component of the NPC. Here we report two nanobody-bound structures: the full-length Nup84-Nup133 C-terminal domain complex and the Nup133 N-terminal domain, both from S. cerevisiae. Together with previously published structures, this work enables the structural description of the entire 575 kDa Y complex from one species. The structure of Nup84-Nup133CTD details the high flexibility of this dimeric unit of the Y complex. Further, the Nup133NTD contains a structurally conserved amphipathic lipid packing sensor motif, confirmed by liposome interaction studies. The presented structures reveal important details about the function of the Y complex that affect our understanding of NPC structure and assembly.
Mechanism and inhibition of Streptococcus pneumoniae IgA1 protease
Authors: Wang Zhiming , Rahkola Jeremy , Redzic Jasmina S. , Chi Ying-Chih , Tran Norman , Holyoak Todd , Zheng Hongjin , Janoff Edward , Eisenmesser Elan 
Published: November 2020

AbstractOpportunistic pathogens such as Streptococcus pneumoniae secrete a giant metalloprotease virulence factor responsible for cleaving host IgA1, yet the molecular mechanism has remained unknown since their discovery nearly 30 years ago despite the potential for developing vaccines that target these enzymes to block infection. Here we show through a series of cryo-electron microscopy single particle reconstructions how the Streptococcus pneumoniae IgA1 protease facilitates IgA1 substrate recognition and how this can be inhibited. Specifically, the Streptococcus pneumoniae IgA1 protease subscribes to an active-site-gated mechanism where a domain undergoes a 10.0 Å movement to facilitate cleavage. Monoclonal antibody binding inhibits this conformational change, providing a direct means to block infection at the host interface. These structural studies explain decades of biological and biochemical studies and provides a general strategy to block Streptococcus pneumoniae IgA1 protease activity to potentially prevent infection.
A systematic comprehensive longitudinal evaluation of dietary factors associated with acute myocardial infarction and fatal coronary heart disease
Authors: Milanlouei Soodabeh , Menichetti Giulia , Li Yanping , Loscalzo Joseph , Willett Walter C. , Barabási Albert-László 
Published: November 2020

AbstractEnvironmental factors, and in particular diet, are known to play a key role in the development of Coronary Heart Disease. Many of these factors were unveiled by detailed nutritional epidemiology studies, focusing on the role of a single nutrient or food at a time. Here, we apply an Environment-Wide Association Study approach to Nurses’ Health Study data to explore comprehensively and agnostically the association of 257 nutrients and 117 foods with coronary heart disease risk (acute myocardial infarction and fatal coronary heart disease). After accounting for multiple testing, we identify 16 food items and 37 nutrients that show statistically significant association – while adjusting for potential confounding and control variables such as physical activity, smoking, calorie intake, and medication use – among which 38 associations were validated in Nurses’ Health Study II. Our implementation of Environment-Wide Association Study successfully reproduces prior knowledge of diet-coronary heart disease associations in the epidemiological literature, and helps us detect new associations that were only marginally studied, opening potential avenues for further extensive experimental validation. We also show that Environment-Wide Association Study allows us to identify a bipartite food-nutrient network, highlighting which foods drive the associations of specific nutrients with coronary heart disease risk.
RNA-mediated control of cell shape modulates antibiotic resistance in Vibrio cholerae
Authors: Peschek Nikolai , Herzog Roman , Singh Praveen K. , Sprenger Marcel , Meyer Fabian , Fröhlich Kathrin S. , Schröger Luise , Bramkamp Marc , Drescher Knut , Papenfort Kai 
Published: November 2020

AbstractVibrio cholerae, the cause of cholera disease, exhibits a characteristic curved rod morphology, which promotes infectivity and motility in dense hydrogels. Periplasmic protein CrvA determines cell curvature in V. cholerae, yet the regulatory factors controlling CrvA are unknown. Here, we discover the VadR small RNA (sRNA) as a post-transcriptional inhibitor of the crvA mRNA. Mutation of vadR increases cell curvature, whereas overexpression has the inverse effect. We show that vadR transcription is activated by the VxrAB two-component system and triggered by cell-wall-targeting antibiotics. V. cholerae cells failing to repress crvA by VadR display decreased survival upon challenge with penicillin G indicating that cell shape maintenance by the sRNA is critical for antibiotic resistance. VadR also blocks the expression of various key biofilm genes and thereby inhibits biofilm formation in V. cholerae. Thus, VadR is an important regulator for synchronizing peptidoglycan integrity, cell shape, and biofilm formation in V. cholerae.
Hollow core optical fibres with comparable attenuation to silica fibres between 600 and 1100 nm
Authors: Sakr Hesham , Chen Yong , Jasion Gregory T. , Bradley Thomas D. , Hayes John R. , Mulvad Hans Christian H. , Davidson Ian A. , Numkam Fokoua Eric , Poletti Francesco 
Published: November 2020

AbstractFor over 50 years, pure or doped silica glass optical fibres have been an unrivalled platform for the transmission of laser light and optical data at wavelengths from the visible to the near infra-red. Rayleigh scattering, arising from frozen-in density fluctuations in the glass, fundamentally limits the minimum attenuation of these fibres and hence restricts their application, especially at shorter wavelengths. Guiding light in hollow (air) core fibres offers a potential way to overcome this insurmountable attenuation limit set by the glass’s scattering, but requires reduction of all the other loss-inducing mechanisms. Here we report hollow core fibres, of nested antiresonant design, with losses comparable or lower than achievable in solid glass fibres around technologically relevant wavelengths of 660, 850, and 1060 nm. Their lower than Rayleigh scattering loss in an air-guiding structure offers the potential for advances in quantum communications, data transmission, and laser power delivery.
Continuous moulting by Antarctic krill drives major pulses of carbon export in the north Scotia Sea, Southern Ocean
Authors: Manno C. , Fielding S. , Stowasser G. , Murphy E. J. , Thorpe S. E. , Tarling G. A. 
Published: November 2020

AbstractAntarctic krill play an important role in biogeochemical cycles and can potentially generate high-particulate organic carbon (POC) fluxes to the deep ocean. They also have an unusual trait of moulting continuously throughout their life-cycle. We determine the krill seasonal contribution to POC flux in terms of faecal pellets (FP), exuviae and carcasses from sediment trap samples collected in the Southern Ocean. We found that krill moulting generated an exuviae flux of similar order to that of FP, together accounting for 87% of an annual POC flux (22.8 g m−2 y−1). Using an inverse modelling approach, we determined the krill population size necessary to generate this flux peaked at 261 g m−2. This study shows the important role of krill exuviae as a vector for POC flux. Since krill moulting cycle depends on temperature, our results highlight the sensitivity of POC flux to rapid regional environmental change.
Cellular events of acute, resolving or progressive COVID-19 in SARS-CoV-2 infected non-human primates
Authors: Fahlberg M. D. , Blair R. V. , Doyle-Meyers L. A. , Midkiff C. C. , Zenere G. , Russell-Lodrigue K. E. , Monjure C. J. , Haupt E. H. , Penney T. P. , Lehmicke G. , Threeton B. M. , Golden N. , Datta P. K. , Roy C. J. , Bohm R. P. , Maness N. J. , Fischer T. , Rappaport J. , Vaccari M. 
Published: November 2020

AbstractUnderstanding SARS-CoV-2 associated immune pathology is crucial to develop pan-effective vaccines and treatments. Here we investigate the immune events from the acute state up to four weeks post SARS-CoV-2 infection, in non-human primates (NHP) with heterogeneous pulmonary pathology. We show a robust migration of CD16 expressing monocytes to the lungs occurring during the acute phase, and we describe two subsets of interstitial macrophages (HLA-DR+CD206−): a transitional CD11c+CD16+ cell population directly associated with IL-6 levels in plasma, and a long-lasting CD11b+CD16+ cell population. Trafficking of monocytes is mediated by TARC (CCL17) and associates with viral load measured in bronchial brushes. We also describe associations between disease outcomes and high levels of cell infiltration in lungs including CD11b+CD16hi macrophages and CD11b+ neutrophils. Accumulation of macrophages is long-lasting and detectable even in animals with mild or no signs of disease. Interestingly, animals with anti-inflammatory responses including high IL-10:IL-6 and kynurenine to tryptophan ratios show less severe illness. Our results unravel cellular mechanisms of COVID-19 and suggest that NHP may be appropriate models to test immune therapies.