bluuebunny/crossref_metadata_2025 huggingface dataset:
Middle Miocene Intensification of South Asian Monsoonal Rainfall
Authors: Yang Xueping , Groeneveld Jeroen , Jian Zhimin , Steinke Stephan , Giosan Liviu
Published: November 2020

During the middle Miocene, Earth's climate changed from a global warm period (Miocene Climatic Optimum) into a colder one with the expansion of the Antarctic ice sheet. This prominent climate transition was also a period of drastic changes in global atmospheric circulation. The development of the South Asian monsoon is not well understood and mainly derived from proxy records of wind strength. Data for middle Miocene changes in rainfall are virtually non‐existent for India and the Arabian Sea prior to 11 Ma. This study presents planktic foraminiferal trace element (Mg/Ca and Ba/Ca) and stable oxygen isotope records from NGHP‐01 Site 01A off the coast of West India in the Eastern Arabian Sea (EAS) to reconstruct the regional surface hydrography and hydroclimate in the South Asian monsoon (SAM) region during the middle Miocene. The Ba/Ca and local seawater δ18O (δ18Osw) changes reveal a notable gradual increase in SAM rainfall intensity during the middle Miocene. Additionally to this long‐term increase in precipitation, the seawater δ18O is punctuated by a prominent decrease, i.e. freshening, at ~14 Ma contemporary with Antarctic glaciation. This suggests that Southern Ocean Intermediate Waters (SOIW) transmitted Antarctic salinity changes into the Arabian Sea via an “oceanic tunnel” mechanism. The middle Miocene increase in SAM rainfall is consistent with climate model simulations of an overall strengthening Asian monsoon from the Eocene to the middle/late Miocene with a further acceleration after the middle Miocene climate transition.
RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia
Authors: Koschut David , Ray Debleena , Li Zhenhua , Giarin Emanuela , Groet Jürgen , Alić Ivan , Kham Shirley Kow-Yin , Chng Wee Joo , Ariffin Hany , Weinstock David M. , Yeoh Allen Eng-Juh , Basso Giuseppe , Nižetić Dean
Published: November 2020

Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS‐ALL) is characterized by high frequency of CRLF2‐rearrangements, JAK2‐mutations, or RAS‐pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub‐clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS‐ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre‐inhibition of RAS or PTPN11, but not of PI3K or JAK‐signaling, prevented TSLP‐induced RAS‐GTP boost. Cytotoxicity assays on primary clinical DS‐ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS‐inhibitor or PTPN11-inhibitor, but not PI3K/JAK‐inhibitors, suggesting a unified treatment target for up to 80% of DS‐ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein‐activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient‐stratification strategy for precision therapy in high-risk ALL.
Argonaute 2 is a key regulator of maternal mRNA degradation in mouse early embryos
Authors: Zhang Jia-Ming , Hou Wei-Bo , Du Jia-Wei , Zong Ming , Zheng Kai-Lun , Wang Wei-Jia , Wang Jia-Qiang , Zhang Heng , Mu Yan-Shuang , Yin Zhi , Ding Chun-Ming , Sun Qing-Yuan , Liu Zhong-Hua , Kong Qing-Ran
Published: November 2020

In mammalian early embryos, the transition from maternal to embryonic control of gene expression requires timely degradation of a subset of maternal mRNAs (MRD). Recently, zygotic genome activation (ZGA)-dependent MRD has been characterized in mouse 2-cell embryo. However, in early embryos, the dynamics of MRD is still poorly understood, and the maternal factor-mediated MRD before and along with ZGA has not been investigated. Argonaute 2 (Ago2) is highly expressed in mouse oocyte and early embryos. In this study, we showed that Ago2-dependent degradation involving RNA interference (RNAi) and RNA activation (RNAa) pathways contributes to the decay of over half of the maternal mRNAs in mouse early embryos. We demonstrated that AGO2 guided by endogenous small interfering RNAs (endosiRNAs), generated from double-stranded RNAs (dsRNAs) formed by maternal mRNAs with their complementary long noncoding RNAs (CMR-lncRNAs), could target maternal mRNAs and cooperate with P-bodies to promote MRD. In addition, we also showed that AGO2 may interact with small activating RNAs (saRNAs) to activate Yap1 and Tead4, triggering ZGA-dependent MRD. Thus, Ago2-dependent degradation is required for timely elimination of subgroups of maternal mRNAs and facilitates the transition between developmental states.
Semiconductor-free nanoplasmonic photoelectrochemistry of H2O2 over Ag nanowires
Authors: Chen Ying-Chu , Chen Ying-Zhen , Hsu Yu-Kuei
Published: November 2020

Nanoplasmonics is currently experiencing an ongoing renaissance as a result of the booming research interest in LSPR-mediated but semiconductor-free photocatalysis and photoelectrochemistry directly over nanometals with excellent catalytic activity and conductive properties. To shed light on the underlying mechanism, the present study puts forward H2O2 as the probe molecule, with which the electroreduction at the phase boundary with photoexcited Ag nanowires (NWs) was systemically investigated. In particular, the reaction rate depends not only linearly on the illumination intensity but also on the resonant wavelength of the characteristic LSPR of the Ag NWs, evidently illustrating that the photoelectrochemical H2O2 reduction is mediated by the LSPR-induced energetic electrons of the Ag NWs. In addition to the mechanistic insights, the present study further highlights the great promise of such semiconductor-free LSPR-mediated photoelectrochemistry of H2O2 over Ag NWs in the analytical biochemistry field via proof-of-concept solar photoelectrochemical detection of ultradiluted H2O2 in PBS. The Ag NWs deposited on a carbon cloth substrate as the working electrode exhibit excellent sensitivity amounting to 118 μA cm−2 mM−1 under solar illumination, well outperforming that of the electrochemical counterpart measured in the dark by 50%.
Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability
Authors: Khan Amjad , Umair Muhammad , Sharaf Rania Abdulfattah , Khan Muhammad Ismail , Ullah Amir , Abbas Safdar , Shaheen Nargis , Bilal Muhammad , Ahamd Farooq
Published: November 2020

Congenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.
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

Engineering 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

The 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

Elimination 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

In 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

The 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

Sorghum (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

Robustness 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

Catalysis 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

Touch 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

Crystallization 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

Severe 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

The 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

Opportunistic 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

Environmental 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

Vibrio 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

For 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

Antarctic 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

Understanding 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.
Author Correction: Modeling COVID-19 scenarios for the United States
Authors:   IHME COVID-19 Forecasting Team
Published: November 2020

A Correction to this paper has been published: https://doi.org/10.1038/s41591-020-01181-w
Fully integrated Monte Carlo simulation for evaluating radiation induced DNA damage and subsequent repair using Geant4-DNA
Authors: Sakata Dousatsu , Belov Oleg , Bordage Marie-Claude , Emfietzoglou Dimitris , Guatelli Susanna , Inaniwa Taku , Ivanchenko Vladimir , Karamitros Mathieu , Kyriakou Ioanna , Lampe Nathanael , Petrovic Ivan , Ristic-Fira Aleksandra , Shin Wook-Geun , Incerti Sebastien
Published: November 2020

Ionising radiation induced DNA damage and subsequent biological responses to it depend on the radiation’s track-structure and its energy loss distribution pattern. To investigate the underlying biological mechanisms involved in such complex system, there is need of predicting biological response by integrated Monte Carlo (MC) simulations across physics, chemistry and biology. Hence, in this work, we have developed an application using the open source Geant4-DNA toolkit to propose a realistic “fully integrated” MC simulation to calculate both early DNA damage and subsequent biological responses with time. We had previously developed an application allowing simulations of radiation induced early DNA damage on a naked cell nucleus model. In the new version presented in this work, we have developed three additional important features: (1) modeling of a realistic cell geometry, (2) inclusion of a biological repair model, (3) refinement of DNA damage parameters for direct damage and indirect damage scoring. The simulation results are validated with experimental data in terms of Single Strand Break (SSB) yields for plasmid and Double Strand Break (DSB) yields for plasmid/human cell. In addition, the yields of indirect DSBs are compatible with the experimental scavengeable damage fraction. The simulation application also demonstrates agreement with experimental data of $$\gamma$$
γ
-H2AX yields for gamma ray irradiation. Using this application, it is now possible to predict biological response along time through track-structure MC simulations.
Record high Pacific Arctic seawater temperatures and delayed sea ice advance in response to episodic atmospheric blocking
Authors: Kodaira Tsubasa , Waseda Takuji , Nose Takehiko , Inoue Jun
Published: November 2020

Arctic sea ice is rapidly decreasing during the recent period of global warming. One of the significant factors of the Arctic sea ice loss is oceanic heat transport from lower latitudes. For months of sea ice formation, the variations in the sea surface temperature over the Pacific Arctic region were highly correlated with the Pacific Decadal Oscillation (PDO). However, the seasonal sea surface temperatures recorded their highest values in autumn 2018 when the PDO index was neutral. It is shown that the anomalous warm seawater was a rapid ocean response to the southerly winds associated with episodic atmospheric blocking over the Bering Sea in September 2018. This warm seawater was directly observed by the R/V Mirai Arctic Expedition in November 2018 to significantly delay the southward sea ice advance. If the atmospheric blocking forms during the PDO positive phase in the future, the annual maximum Arctic sea ice extent could be dramatically reduced.
Two pursuit strategies for a single sensorimotor control task in blowfly
Authors: Varennes Leandre , Krapp Holger G. , Viollet Stephane
Published: November 2020

Effective visuomotor coordination is a necessary requirement for the survival of many terrestrial, aquatic, and aerial animal species. We studied the kinematics of aerial pursuit in the blowfly Lucilia sericata using an actuated dummy as target for freely flying males. We found that the flies perform target tracking in the horizontal plane and target interception in the vertical plane. Our behavioural data suggest that the flies’ trajectory changes are a controlled combination of target heading angle and of the rate of change of the bearing angle. We implemented control laws in kinematic models and found that the contributions of proportional navigation strategy are negligible. We concluded that the difference between horizontal and vertical control relates to the difference in target heading angle the fly keeps constant: 0° in azimuth and 23° in elevation. Our work suggests that male Lucilia control both horizontal and vertical steerings by employing proportional controllers to the error angles. In horizontal plane, this controller operates at time delays as small as 10 ms, the fastest steering response observed in any flying animal, so far.
The double fascicular variations of the anterior talofibular ligament and the calcaneofibular ligament correlate with interconnections between lateral ankle structures revealed on magnetic resonance imaging
Authors: Szaro Paweł , Ghali Gataa Khaldun , Polaczek Mateusz , Ciszek Bogdan
Published: November 2020

The anterior talofibular ligament and the calcaneofibular ligament are the most commonly injured ankle ligaments. This study aimed to investigate if the double fascicular anterior talofibular ligament and the calcaneofibular ligament are associated with the presence of interconnections between those two ligaments and connections with non-ligamentous structures. A retrospective re-evaluation of 198 magnetic resonance imaging examinations of the ankle joint was conducted. The correlation between the double fascicular anterior talofibular ligament and calcaneofibular ligament and connections with the superior peroneal retinaculum, the peroneal tendon sheath, the tibiofibular ligaments, and the inferior extensor retinaculum was studied. The relationships between the anterior talofibular ligament’s and the calcaneofibular ligament’s diameters with the presence of connections were investigated. Most of the connections were visible in a group of double fascicular ligaments. Most often, one was between the anterior talofibular ligament and calcaneofibular ligament (74.7%). Statistically significant differences between groups of single and double fascicular ligaments were visible in groups of connections between the anterior talofibular ligament and the peroneal tendon sheath (p < 0.001) as well as the calcaneofibular ligament and the posterior tibiofibular ligament (p < 0.05), superior peroneal retinaculum (p < 0.001), and peroneal tendon sheath (p < 0.001). Differences between the thickness of the anterior talofibular ligament and the calcaneofibular ligament (p < 0.001), the diameter of the fibular insertion of the anterior talofibular ligament (p < 0.001), the diameter of calcaneal attachment of the calcaneofibular ligament (p < 0.05), and tibiocalcaneal angle (p < 0.01) were statistically significant. The presence of the double fascicular anterior talofibular ligament and the calcaneofibular ligament fascicles correlate with connections to adjacent structures.
Quantifying the contribution of established risk factors to cardiovascular mortality differences between Russia and Norway
Authors: Trias-Llimós Sergi , Pennells Lisa , Tverdal Aage , Kudryavtsev Alexander V. , Malyutina Sofia , Hopstock Laila A. , Iakunchykova Olena , Nikitin Yuri , Magnus Per , Kaptoge Stephen , Di Angelantonio Emanuele , Leon David A.
Published: November 2020

Surprisingly few attempts have been made to quantify the simultaneous contribution of well-established risk factors to CVD mortality differences between countries. We aimed to develop and critically appraise an approach to doing so, applying it to the substantial CVD mortality gap between Russia and Norway using survey data in three cities and mortality risks from the Emerging Risk Factor Collaboration. We estimated the absolute and relative differences in CVD mortality at ages 40–69 years between countries attributable to the risk factors, under the counterfactual that the age- and sex-specific risk factor profile in Russia was as in Norway, and vice-versa. Under the counterfactual that Russia had the Norwegian risk factor profile, the absolute age-standardized CVD mortality gap would decline by 33.3% (95% CI 25.1–40.1) among men and 22.1% (10.4–31.3) among women. In relative terms, the mortality rate ratio (Russia/Norway) would decline from 9–10 to 7–8. Under the counterfactual that Norway had the Russian risk factor profile, the mortality gap reduced less. Well-established CVD risk factors account for a third of the male and around a quarter of the female CVD mortality gap between Russia and Norway. However, these estimates are based on widely held epidemiological assumptions that deserve further scrutiny.
Increased TRPV4 expression in non-myelinating Schwann cells is associated with demyelination after sciatic nerve injury
Authors: Feng Xiaona , Takayama Yasunori , Ohno Nobuhiko , Kanda Hirosato , Dai Yi , Sokabe Takaaki , Tominaga Makoto
Published: November 2020

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective calcium-permeable cation channel that is widely expressed and activated in various neurons and glial cells in the nervous system. Schwann cells (SCs) are primary glia cells that wrap around axons to form the myelin sheath in the peripheral nervous system. However, whether TRPV4 is expressed and functions in SCs is unclear. Here, we demonstrate functional expression of TRPV4 in mouse SCs and investigated its physiological significance. Deletion of TRPV4 did not affect normal myelin development for SCs in sciatic nerves in mice. However, after sciatic nerve cut injury, TRPV4 expression levels were remarkably increased in SCs following nerve demyelination. Ablation of TRPV4 expression impaired the demyelinating process after nerve injury, resulting in delayed remyelination and functional recovery of sciatic nerves. These results suggest that local activation of TRPV4 could be an attractive pharmacological target for therapeutic intervention after peripheral nerve injury.
Ligand-directed covalent labelling of a GPCR with a fluorescent tag in live cells
Authors: Stoddart Leigh A. , Kindon Nicholas D. , Otun Omolade , Harwood Clare R. , Patera Foteini , Veprintsev Dmitry B. , Woolard Jeanette , Briddon Stephen J. , Franks Hester A. , Hill Stephen J. , Kellam Barrie
Published: November 2020

To study the localisation of G protein-coupled receptors (GPCR) in their native cellular environment requires their visualisation through fluorescent labelling. To overcome the requirement for genetic modification of the receptor or the limitations of dissociable fluorescent ligands, here we describe rational design of a compound that covalently and selectively labels a GPCR in living cells with a fluorescent moiety. We designed a fluorescent antagonist, in which the linker incorporated between pharmacophore (ZM241385) and fluorophore (sulfo-cyanine5) is able to facilitate covalent linking of the fluorophore to the adenosine A2A receptor. We pharmacologically and biochemically demonstrate irreversible fluorescent labelling without impeding access to the orthosteric binding site and demonstrate its use in endogenously expressing systems. This offers a non-invasive and selective approach to study function and localisation of native GPCRs.
An inducible CRISPR interference library for genetic interrogation of Saccharomyces cerevisiae biology
Authors: Momen-Roknabadi Amir , Oikonomou Panos , Zegans Maxwell , Tavazoie Saeed
Published: November 2020

Genome-scale CRISPR interference (CRISPRi) is widely utilized to study cellular processes in a variety of organisms. Despite the dominance of Saccharomyces cerevisiae as a model eukaryote, an inducible genome-wide CRISPRi library in yeast has not yet been presented. Here, we present a genome-wide, inducible CRISPRi library, based on spacer design rules optimized for S. cerevisiae. We have validated this library for genome-wide interrogation of gene function across a variety of applications, including accurate discovery of haploinsufficient genes and identification of enzymatic and regulatory genes involved in adenine and arginine biosynthesis. The comprehensive nature of the library also revealed refined spacer design parameters for transcriptional repression, including location, nucleosome occupancy and nucleotide features. CRISPRi screens using this library can identify genes and pathways with high precision and a low false discovery rate across a variety of experimental conditions, enabling rapid and reliable assessment of genetic function and interactions in S. cerevisiae.
The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects
Authors: Avet Charlotte , Sturino Claudio , Grastilleur Sébastien , Gouill Christian Le , Semache Meriem , Gross Florence , Gendron Louis , Bennani Youssef , Mancini Joseph A. , Sayegh Camil E. , Bouvier Michel
Published: November 2020

Protease-activated receptor-2 (PAR2) is involved in inflammatory responses and pain, therefore representing a promising therapeutic target for the treatment of immune-mediated inflammatory diseases. However, as for other GPCRs, PAR2 can activate multiple signaling pathways and those involved in inflammatory responses remain poorly defined. Here, we describe a new selective and potent PAR2 inhibitor (I-287) that shows functional selectivity by acting as a negative allosteric regulator on Gαq and Gα12/13 activity and their downstream effectors, while having no effect on Gi/o signaling and βarrestin2 engagement. Such selective inhibition of only a subset of the pathways engaged by PAR2 was found to be sufficient to block inflammation in vivo. In addition to unraveling the PAR2 signaling pathways involved in the pro-inflammatory response, our study opens the path toward the development of new functionally selective drugs with reduced liabilities that could arise from blocking all the signaling activities controlled by the receptor.
N-Heterocyclic carbene-catalyzed enantioselective hetero-[10 + 2] annulation
Authors: Peng Qiupeng , Li Shi-Jun , Zhang Bei , Guo Donghui , Lan Yu , Wang Jian
Published: November 2020

Higher-order cycloadditions are a powerful strategy for the construction of polycycles in one step. However, an efficient and concise version for the induction of asymmetry is lacking. N-heterocyclic carbenes are widely used organocatalysts for asymmetric synthesis and could be an ideal choice for enantioselective higher-order cycloadditions. Here, we report an enantioselective [10 + 2] annulation between catalytically formed aza-benzofulvene intermediates and trifluoromethyl ketone derivatives. This protocol exhibits a wide scope, high yields, and good ee values, reflecting a robust and efficient higher-order cycloaddition. Density functional theory calculations provide an accurate prediction of the reaction enantioselectivity, and in-depth insight to the origins of stereocontrol.
Author Correction: Control over the fibrillization yield by varying the oligomeric nucleation propensities of self-assembling peptides
Authors: Lau Chun Yin Jerry , Fontana Federico , Mandemaker Laurens D. B. , Wezendonk Dennie , Vermeer Benjamin , Bonvin Alexandre M. J. J. , de Vries Renko , Zhang Heyang , Remaut Katrien , van den Dikkenberg Joep , Medeiros-Silva João , Hassan Alia , Perrone Barbara , Kuemmerle Rainer , Gelain Fabrizio , Hennink Wim E. , Weingarth Markus , Mastrobattista Enrico
Published: November 2020

A Correction to this paper has been published: https://doi.org/10.1038/s42004-020-00436-4
Colorimetric detection of ciprofloxacin in aqueous solution based on an unmodified aptamer and the aggregation of gold nanoparticles
Authors: Huang Weiwen , Wang Yichen , Wang Lumei , Pan Chaoqiang , Shen Guoqing
Published: November 2020

Sensitive and selective colorimetric detection of ciprofloxacin based on an unmodified aptamer and the aggregation of AuNPs induced by PDDA.
Endothelial cell adhesion and blood response to hemocompatible peptide 1 (HCP-1), REDV, and RGD peptide sequences with free N-terminal amino groups immobilized on a biomedical expanded polytetrafluorethylene surface
Authors: Liu Yihua , Mahara Atsushi , Kambe Yusuke , Hsu Yu-I. , Yamaoka Tetsuji
Published: November 2020

Free N-terminal cell adhesive peptides are assessed from the viewpoint of endothelial cell adhesion and blood response.
The antagonistic effect of magnesium hydroxide particles on vascular endothelial activation induced by acidic PLGA degradation products
Authors: Ko Kyoung-Won , Choi Bogyu , Kang Eun Young , Shin Sang-Woo , Baek Seung-Woon , Han Dong Keun
Published: November 2020

The addition of magnesium hydroxide to a functional drug-eluting stent coated with PLGA can prevent the cellular stress responses against acidic PLGA degradation products and improve endothelial function.