bluuebunny/crossref_metadata_2025 huggingface dataset:
scCODA is a Bayesian model for compositional single-cell data analysis
Authors: Büttner M. , Ostner J. , Müller C. L. , Theis F. J. , Schubert B.
Published: November 2021

Compositional changes of cell types are main drivers of biological processes. Their detection through single-cell experiments is difficult due to the compositionality of the data and low sample sizes. We introduce scCODA (https://github.com/theislab/scCODA), a Bayesian model addressing these issues enabling the study of complex cell type effects in disease, and other stimuli. scCODA demonstrated excellent detection performance, while reliably controlling for false discoveries, and identified experimentally verified cell type changes that were missed in original analyses.
Initiation of cytosolic plant purine nucleotide catabolism involves a monospecific xanthosine monophosphate phosphatase
Authors: Heinemann Katharina J. , Yang Sun-Young , Straube Henryk , Medina-Escobar Nieves , Varbanova-Herde Marina , Herde Marco , Rhee Sangkee , Witte Claus-Peter
Published: November 2021

In plants, guanosine monophosphate (GMP) is synthesized from adenosine monophosphate via inosine monophosphate and xanthosine monophosphate (XMP) in the cytosol. It has been shown recently that the catabolic route for adenylate-derived nucleotides bifurcates at XMP from this biosynthetic route. Dephosphorylation of XMP and GMP by as yet unknown phosphatases can initiate cytosolic purine nucleotide catabolism. Here we show that Arabidopsis thaliana possesses a highly XMP-specific phosphatase (XMPP) which is conserved in vascular plants. We demonstrate that XMPP catalyzes the irreversible entry reaction of adenylate-derived nucleotides into purine nucleotide catabolism in vivo, whereas the guanylates enter catabolism via an unidentified GMP phosphatase and guanosine deaminase which are important to maintain purine nucleotide homeostasis. We also present a crystal structure and mutational analysis of XMPP providing a rationale for its exceptionally high substrate specificity, which is likely required for the efficient catalysis of the very small XMP pool in vivo.
Plant LHC-like proteins show robust folding and static non-photochemical quenching
Authors: Skotnicová Petra , Staleva-Musto Hristina , Kuznetsova Valentyna , Bína David , Konert Minna M. , Lu Shan , Polívka Tomáš , Sobotka Roman
Published: November 2021

Life on Earth depends on photosynthesis, the conversion of light energy into chemical energy. Plants collect photons by light harvesting complexes (LHC)—abundant membrane proteins containing chlorophyll and xanthophyll molecules. LHC-like proteins are similar in their amino acid sequence to true LHC antennae, however, they rather serve a photoprotective function. How pigments associated with LHC-like proteins are organised and how they contribute to protein function has not yet been determined. Here, we characterize plant LHC-like proteins (LIL3 and ELIP2) produced in the cyanobacterium Synechocystis sp. PCC 6803 (hereafter Synechocystis). Both proteins were associated with chlorophyll a (Chl) and zeaxanthin and LIL3 was shown to be capable of quenching Chl fluorescence via direct energy transfer from the Chl Qy state to zeaxanthin S1 state. Interestingly, the ability of the ELIP2 protein to quench can be acquired by modifying its N-terminal sequence. By employing Synechocystis carotenoid mutants and site-directed mutagenesis we demonstrate that, although LIL3 does not need pigments for folding, pigments stabilize the LIL3 dimer.
SARS-CoV-2 transmission across age groups in France and implications for control
Authors: Tran Kiem Cécile , Bosetti Paolo , Paireau Juliette , Crépey Pascal , Salje Henrik , Lefrancq Noémie , Fontanet Arnaud , Benamouzig Daniel , Boëlle Pierre-Yves , Desenclos Jean-Claude , Opatowski Lulla , Cauchemez Simon
Published: November 2021

The shielding of older individuals has been proposed to limit COVID-19 hospitalizations while relaxing general social distancing in the absence of vaccines. Evaluating such approaches requires a deep understanding of transmission dynamics across ages. Here, we use detailed age-specific case and hospitalization data to model the rebound in the French epidemic in summer 2020, characterize age-specific transmission dynamics and critically evaluate different age-targeted intervention measures in the absence of vaccines. We find that while the rebound started in young adults, it reached individuals aged ≥80 y.o. after 4 weeks, despite substantial contact reductions, indicating substantial transmission flows across ages. We derive the contribution of each age group to transmission. While shielding older individuals reduces mortality, it is insufficient to allow major relaxations of social distancing. When the epidemic remains manageable (R close to 1), targeting those most contributing to transmission is better than shielding at-risk individuals. Pandemic control requires an effort from all age groups.
Volcanic activity and hazard in the East African Rift Zone
Authors: Biggs Juliet , Ayele Atalay , Fischer Tobias P. , Fontijn Karen , Hutchison William , Kazimoto Emmanuel , Whaler Kathy , Wright Tim J.
Published: November 2021

Over the past two decades, multidisciplinary studies have unearthed a rich history of volcanic activity and unrest in the densely-populated East African Rift System, providing new insights into the influence of rift dynamics on magmatism, the characteristics of the volcanic plumbing systems and the foundation for hazard assessments. The raised awareness of volcanic hazards is driving a shift from crisis response to reducing disaster risks, but a lack of institutional and human capacity in sub-Saharan Africa means baseline data are sparse and mitigating geohazards remains challenging.
Cell-fate transition and determination analysis of mouse male germ cells throughout development
Authors: Zhao Jiexiang , Lu Ping , Wan Cong , Huang Yaping , Cui Manman , Yang Xinyan , Hu Yuqiong , Zheng Yi , Dong Ji , Wang Mei , Zhang Shu , Liu Zhaoting , Bian Shuhui , Wang Xiaoman , Wang Rui , Ren Shaofang , Wang Dazhuang , Yao Zhaokai , Chang Gang , Tang Fuchou , Zhao Xiao-Yang
Published: November 2021

Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells’ identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
A supergene underlies linked variation in color and morphology in a Holarctic songbird
Authors: Funk Erik R. , Mason Nicholas A. , Pálsson Snæbjörn , Albrecht Tomáš , Johnson Jeff A. , Taylor Scott A.
Published: November 2021

The genetic architecture of a phenotype can have considerable effects on the evolution of a trait or species. Characterizing genetic architecture provides insight into the complexity of a given phenotype and, potentially, the role of the phenotype in evolutionary processes like speciation. We use genome sequences to investigate the genetic basis of phenotypic variation in redpoll finches (Acanthis spp.). We demonstrate that variation in redpoll phenotype is broadly controlled by a ~55-Mb chromosomal inversion. Within this inversion, we find multiple candidate genes related to melanogenesis, carotenoid coloration, and bill shape, suggesting the inversion acts as a supergene controlling multiple linked traits. A latitudinal gradient in ecotype distribution suggests supergene driven variation in color and bill morphology are likely under environmental selection, maintaining supergene haplotypes as a balanced polymorphism. Our results provide a mechanism for the maintenance of ecotype variation in redpolls despite a genome largely homogenized by gene flow.
Architecture of the outer-membrane core complex from a conjugative type IV secretion system
Authors: Amin Himani , Ilangovan Aravindan , Costa Tiago R. D.
Published: November 2021

Conjugation is one of the most important processes that bacteria utilize to spread antibiotic resistance genes among bacterial populations. Interbacterial DNA transfer requires a large double membrane-spanning nanomachine called the type 4 secretion system (T4SS) made up of the inner-membrane complex (IMC), the outer-membrane core complex (OMCC) and the conjugative pilus. The iconic F plasmid-encoded T4SS has been central in understanding conjugation for several decades, however atomic details of its structure are not known. Here, we report the structure of a complete conjugative OMCC encoded by the pED208 plasmid from E. coli, solved by cryo-electron microscopy at 3.3 Å resolution. This 2.1 MDa complex has a unique arrangement with two radial concentric rings, each having a different symmetry eventually contributing to remarkable differences in protein stoichiometry and flexibility in comparison to other OMCCs. Our structure suggests that F-OMCC is a highly dynamic complex, with implications for pilus extension and retraction during conjugation.
Defect engineering on V2O3 cathode for long-cycling aqueous zinc metal batteries
Authors: Zhu Kefu , Wei Shiqiang , Shou Hongwei , Shen Feiran , Chen Shuangming , Zhang Pengjun , Wang Changda , Cao Yuyang , Guo Xin , Luo Mi , Zhang Hongjun , Ye Bangjiao , Wu Xiaojun , He Lunhua , Song Li
Published: November 2021

Defect engineering is a strategy that is attracting widespread attention for the possibility of modifying battery active materials in order to improve the cycling stability of the electrodes. However, accurate investigation and quantification of the effect of the defects on the electrochemical energy storage performance of the cell are not trivial tasks. Herein, we report the quantification of vanadium-defective clusters (i.e., up to 5.7%) in the V2O3 lattice via neutron and X-ray powder diffraction measurements, positron annihilation lifetime spectroscopy, and synchrotron-based X-ray analysis. When the vanadium-defective V2O3 is employed as cathode active material in an aqueous Zn coin cell configuration, capacity retention of about 81% after 30,000 cycles at 5 A g−1 is achieved. Density functional theory calculations indicate that the vanadium-defective clusters can provide favorable sites for reversible Zn-ion storage. Moreover, the vanadium-defective clusters allow the storage of Zn ions in V2O3, which reduces the electrostatic interaction between the host material and the multivalent ions.
Hematopoiesis under telomere attrition at the single-cell resolution
Authors: Thongon Natthakan , Ma Feiyang , Santoni Andrea , Marchesini Matteo , Fiorini Elena , Rose Ashley , Adema Vera , Ganan-Gomez Irene , Groarke Emma M. , Gutierrez-Rodrigues Fernanda , Chen Shuaitong , Lockyer Pamela , Schneider Sarah , Bueso-Ramos Carlos , Montalban-Bravo Guillermo , Class Caleb A. , Soltysiak Kelly A. , Pellegrini Matteo , Sahin Ergun , Bertuch Alison A. , DiNardo Courtney D. , Garcia-Manero Guillermo , Young Neal S. , Dwyer Karen , Colla Simona
Published: November 2021

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance.
Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
Authors: Lv Dongwen , Pal Pratik , Liu Xingui , Jia Yannan , Thummuri Dinesh , Zhang Peiyi , Hu Wanyi , Pei Jing , Zhang Qi , Zhou Shuo , Khan Sajid , Zhang Xuan , Hua Nan , Yang Qingping , Arango Sebastian , Zhang Weizhou , Nayak Digant , Olsen Shaun K. , Weintraub Susan T. , Hromas Robert , Konopleva Marina , Yuan Yaxia , Zheng Guangrong , Zhou Daohong
Published: November 2021

PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRLVHL)/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs.
Species richness and identity both determine the biomass of global reef fish communities
Authors: Lefcheck Jonathan S. , Edgar Graham J. , Stuart-Smith Rick D. , Bates Amanda E. , Waldock Conor , Brandl Simon J. , Kininmonth Stuart , Ling Scott D. , Duffy J. Emmett , Rasher Douglas B. , Agrawal Aneil F.
Published: November 2021

Changing biodiversity alters ecosystem functioning in nature, but the degree to which this relationship depends on the taxonomic identities rather than the number of species remains untested at broad scales. Here, we partition the effects of declining species richness and changing community composition on fish community biomass across >3000 coral and rocky reef sites globally. We find that high biodiversity is 5.7x more important in maximizing biomass than the remaining influence of other ecological and environmental factors. Differences in fish community biomass across space are equally driven by both reductions in the total number of species and the disproportionate loss of larger-than-average species, which is exacerbated at sites impacted by humans. Our results confirm that sustaining biomass and associated ecosystem functions requires protecting diversity, most importantly of multiple large-bodied species in areas subject to strong human influences.
6 nm super-resolution optical transmission and scattering spectroscopic imaging of carbon nanotubes using a nanometer-scale white light source
Authors: Ma Xuezhi , Liu Qiushi , Yu Ning , Xu Da , Kim Sanggon , Liu Zebin , Jiang Kaili , Wong Bryan M. , Yan Ruoxue , Liu Ming
Published: November 2021

Optical transmission and scattering spectroscopic microscopy at the visible and adjacent wavelengths denote one of the most informative and inclusive characterization methods in material research. Unfortunately, restricted by the diffraction limit of light, it cannot resolve the nanoscale variation in light absorption and scattering, diagnostics of the local inhomogeneity in material structure and properties. Moreover, a large quantity of nanomaterials has anisotropic optical properties that are appealing yet hard to characterize through conventional optical methods. There is an increasing demand to extend the optical hyperspectral imaging into the nanometer length scale. In this work, we report a super-resolution hyperspectral imaging technique that uses a nanoscale white light source generated by superfocusing the light from a tungsten-halogen lamp to simultaneously obtain optical transmission and scattering spectroscopic images. A 6-nm spatial resolution in the visible to near-infrared wavelength regime (415–980 nm) is demonstrated on an individual single-walled carbon nanotube (SW-CNT). Both the longitudinal and transverse optical electronic transitions are measured, and the SW-CNT chiral indices can be identified. The band structure modulation in a SW-CNT through strain engineering is mapped.
Self-activating anti-infection implant
Authors: Fu Jieni , Zhu Weidong , Liu Xiangmei , Liang Chunyong , Zheng Yufeng , Li Zhaoyang , Liang Yanqin , Zheng Dong , Zhu Shengli , Cui Zhenduo , Wu Shuilin
Published: November 2021

Clinically, it is difficult to endow implants with excellent osteogenic ability and antibacterial activity simultaneously. Herein, the self-activating implants modified with hydroxyapatite (HA)/MoS2 coating are designed to prevent Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections and accelerate bone regeneration simultaneously. The electron transfer between bacteria and HA/MoS2 is triggered when bacteria contacted with the material. RNA sequencing data reveals that the expression level of anaerobic respiration–related genes is up-regulated and the expression level of aerobic respiration–related genes is down-regulated when bacteria adhere to the implants. HA/MoS2 presents a highly effective antibacterial efficacy against both S. aureus and E. coli because of bacterial respiration–activated metabolic pathway changes. Meanwhile, this coating promotes the osteoblastic differentiation of mesenchymal stem cells by altering the potentials of cell membrane and mitochondrial membrane. The proposed strategy exhibits great potential to endow implants with self-activating anti-infection performance and osteogenic ability simultaneously.
Light helicity detector based on 2D magnetic semiconductor CrI3
Authors: Cheng Xing , Cheng Zhixuan , Wang Cong , Li Minglai , Gu Pingfan , Yang Shiqi , Li Yanping , Watanabe Kenji , Taniguchi Takashi , Ji Wei , Dai Lun
Published: November 2021

Two-dimensional magnetic semiconductors provide a platform for studying physical phenomena at atomically thin limit, and promise magneto-optoelectronic devices application. Here, we report light helicity detectors based on graphene-CrI3-graphene vdW heterostructures. We investigate the circularly polarized light excited current and reflective magnetic circular dichroism (RMCD) under various magnetic fields in both monolayer and multilayer CrI3 devices. The devices exhibit clear helicity-selective photoresponse behavior determined by the magnetic state of CrI3. We also find abnormal negative photocurrents at higher bias in both monolayer and multilayer CrI3. A possible explanation is proposed for this phenomenon. Our work reveals the interplay between magnetic and optoelectronic properties in CrI3 and paves the way to developing spin-optoelectronic devices.
Reprogramming microbial populations using a programmed lysis system to improve chemical production
Authors: Diao Wenwen , Guo Liang , Ding Qiang , Gao Cong , Hu Guipeng , Chen Xiulai , Li Yang , Zhang Linpei , Chen Wei , Chen Jian , Liu Liming
Published: November 2021

Microbial populations are a promising model for achieving microbial cooperation to produce valuable chemicals. However, regulating the phenotypic structure of microbial populations remains challenging. In this study, a programmed lysis system (PLS) is developed to reprogram microbial cooperation to enhance chemical production. First, a colicin M -based lysis unit is constructed to lyse Escherichia coli. Then, a programmed switch, based on proteases, is designed to regulate the effective lysis unit time. Next, a PLS is constructed for chemical production by combining the lysis unit with a programmed switch. As a result, poly (lactate-co-3-hydroxybutyrate) production is switched from PLH synthesis to PLH release, and the content of free PLH is increased by 283%. Furthermore, butyrate production with E. coli consortia is switched from E. coli BUT003 to E. coli BUT004, thereby increasing butyrate production to 41.61 g/L. These results indicate the applicability of engineered microbial populations for improving the metabolic division of labor to increase the efficiency of microbial cell factories.
Recent changes to Arctic river discharge
Authors: Feng Dongmei , Gleason Colin J. , Lin Peirong , Yang Xiao , Pan Ming , Ishitsuka Yuta
Published: November 2021

Arctic rivers drain ~15% of the global land surface and significantly influence local communities and economies, freshwater and marine ecosystems, and global climate. However, trusted and public knowledge of pan-Arctic rivers is inadequate, especially for small rivers and across Eurasia, inhibiting understanding of the Arctic response to climate change. Here, we calculate daily streamflow in 486,493 pan-Arctic river reaches from 1984-2018 by assimilating 9.18 million river discharge estimates made from 155,710 satellite images into hydrologic model simulations. We reveal larger and more heterogenous total water export (3-17% greater) and water export acceleration (factor of 1.2-3.3 larger) than previously reported, with substantial differences across basins, ecoregions, stream orders, human regulation, and permafrost regimes. We also find significant changes in the spring freshet and summer stream intermittency. Ultimately, our results represent an updated, publicly available, and more accurate daily understanding of Arctic rivers uniquely enabled by recent advances in hydrologic modeling and remote sensing.
Engineering transient dynamics of artificial cells by stochastic distribution of enzymes
Authors: Song Shidong , Mason Alexander F. , Post Richard A. J. , De Corato Marco , Mestre Rafael , Yewdall N. Amy , Cao Shoupeng , van der Hofstad Remco W. , Sanchez Samuel , Abdelmohsen Loai K. E. A. , van Hest Jan C. M.
Published: November 2021

Random fluctuations are inherent to all complex molecular systems. Although nature has evolved mechanisms to control stochastic events to achieve the desired biological output, reproducing this in synthetic systems represents a significant challenge. Here we present an artificial platform that enables us to exploit stochasticity to direct motile behavior. We found that enzymes, when confined to the fluidic polymer membrane of a core-shell coacervate, were distributed stochastically in time and space. This resulted in a transient, asymmetric configuration of propulsive units, which imparted motility to such coacervates in presence of substrate. This mechanism was confirmed by stochastic modelling and simulations in silico. Furthermore, we showed that a deeper understanding of the mechanism of stochasticity could be utilized to modulate the motion output. Conceptually, this work represents a leap in design philosophy in the construction of synthetic systems with life-like behaviors.
The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3
Authors: Zhang Qing , Yao Deqiang , Rao Bing , Jian Liyan , Chen Yang , Hu Kexin , Xia Ying , Li Shaobai , Shen Yafeng , Qin An , Zhao Jie , Zhou Lu , Lei Ming , Jiang Xian-Cheng , Cao Yu
Published: November 2021

As the major component of cell membranes, phosphatidylcholine (PC) is synthesized de novo in the Kennedy pathway and then undergoes extensive deacylation-reacylation remodeling via Lands’ cycle. The re-acylation is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT) and among the four LPCAT members in human, the LPCAT3 preferentially introduces polyunsaturated acyl onto the sn-2 position of lysophosphatidylcholine, thereby modulating the membrane fluidity and membrane protein functions therein. Combining the x-ray crystallography and the cryo-electron microscopy, we determined the structures of LPCAT3 in apo-, acyl donor-bound, and acyl receptor-bound states. A reaction chamber was revealed in the LPCAT3 structure where the lysophosphatidylcholine and arachidonoyl-CoA were positioned in two tunnels connected near to the catalytic center. A side pocket was found expanding the tunnel for the arachidonoyl CoA and holding the main body of arachidonoyl. The structural and functional analysis provides the basis for the re-acylation of lysophosphatidylcholine and the substrate preference during the reactions.
NogoA-expressing astrocytes limit peripheral macrophage infiltration after ischemic brain injury in primates
Authors: Boghdadi Anthony G. , Spurrier Joshua , Teo Leon , Li Mingfeng , Skarica Mario , Cao Benjamin , Kwan William C. , Merson Tobias D. , Nilsson Susan K. , Sestan Nenad , Strittmatter Stephen M. , Bourne James A.
Published: November 2021

Astrocytes play critical roles after brain injury, but their precise function is poorly defined. Utilizing single-nuclei transcriptomics to characterize astrocytes after ischemic stroke in the visual cortex of the marmoset monkey, we observed nearly complete segregation between stroke and control astrocyte clusters. Screening for the top 30 differentially expressed genes that might limit stroke recovery, we discovered that a majority of astrocytes expressed RTN4A/ NogoA, a neurite-outgrowth inhibitory protein previously only associated with oligodendrocytes. NogoA upregulation on reactive astrocytes post-stroke was significant in both the marmoset and human brain, whereas only a marginal change was observed in mice. We determined that NogoA mediated an anti-inflammatory response which likely contributes to limiting the infiltration of peripheral macrophages into the surviving parenchyma.
Real-time ultrafast oscilloscope with a relativistic electron bunch train
Authors: Baek In Hyung , Kim Hyun Woo , Bark Hyeon Sang , Jang Kyu-Ha , Park Sunjeong , Shin Junho , Kim Young Chan , Kim Mihye , Oang Key Young , Lee Kitae , Rotermund Fabian , Vinokurov Nikolay A. , Jeong Young Uk
Published: November 2021

The deflection of charged particles is an intuitive way to visualize an electromagnetic oscillation of coherent light. Here, we present a real-time ultrafast oscilloscope for time-frozen visualization of a terahertz (THz) optical wave by probing light-driven motion of relativistic electrons. We found the unique condition of subwavelength metal slit waveguide for preserving the distortion-free optical waveform during its propagation. Momentary stamping of the wave, transversely travelling inside a metal slit, on an ultrashort wide electron bunch enables the single-shot recording of an ultrafast optical waveform. As a proof-of-concept experiment, we successfully demonstrated to capture the entire field oscillation of a THz pulse with a sampling rate of 75.7 TS/s. Owing to the use of transversely-wide and longitudinally-short electron bunch and transversely travelling wave, the proposed “single-shot oscilloscope” will open up new avenue for developing the real-time petahertz (PHz) metrology.
Assessing population exposure to coastal flooding due to sea level rise
Authors: Hauer Mathew E. , Hardy Dean , Kulp Scott A. , Mueller Valerie , Wrathall David J. , Clark Peter U.
Published: November 2021

The exposure of populations to sea-level rise (SLR) is a leading indicator assessing the impact of future climate change on coastal regions. SLR exposes coastal populations to a spectrum of impacts with broad spatial and temporal heterogeneity, but exposure assessments often narrowly define the spatial zone of flooding. Here we show how choice of zone results in differential exposure estimates across space and time. Further, we apply a spatio-temporal flood-modeling approach that integrates across these spatial zones to assess the annual probability of population exposure. We apply our model to the coastal United States to demonstrate a more robust assessment of population exposure to flooding from SLR in any given year. Our results suggest that more explicit decisions regarding spatial zone (and associated temporal implication) will improve adaptation planning and policies by indicating the relative chance and magnitude of coastal populations to be affected by future SLR.
Dietary essential amino acids restore liver metabolism in ovariectomized mice via hepatic estrogen receptor α
Authors: Della Torre Sara , Benedusi Valeria , Pepe Giovanna , Meda Clara , Rizzi Nicoletta , Uhlenhaut Nina Henriette , Maggi Adriana
Published: November 2021

In female mammals, the cessation of ovarian functions is associated with significant metabolic alterations, weight gain, and increased susceptibility to a number of pathologies associated with ageing. The molecular mechanisms triggering these systemic events are unknown because most tissues are responsive to lowered circulating sex steroids. As it has been demonstrated that isoform alpha of the estrogen receptor (ERα) may be activated by both estrogens and amino acids, we test the metabolic effects of a diet enriched in specific amino acids in ovariectomized (OVX) mice. This diet is able to block the OVX-induced weight gain and fat deposition in the liver. The use of liver-specific ERα KO mice demonstrates that the hepatic ERα, through the control of liver lipid metabolism, has a key role in the systemic response to OVX. The study suggests that the liver ERα might be a valuable target for dietary treatments for the post-menopause.
Analog programing of conducting-polymer dendritic interconnections and control of their morphology
Authors: Janzakova Kamila , Kumar Ankush , Ghazal Mahdi , Susloparova Anna , Coffinier Yannick , Alibart Fabien , Pecqueur Sébastien
Published: November 2021

Although materials and processes are different from biological cells’, brain mimicries led to tremendous achievements in parallel information processing via neuromorphic engineering. Inexistent in electronics, we emulate dendritic morphogenesis by electropolymerization in water, aiming in operando material modification for hardware learning. Systematic study of applied voltage-pulse parameters details on tuning independently morphological aspects of micrometric dendrites’: fractal number, branching degree, asymmetry, density or length. Growths time-lapse image processing shows spatial features to be dynamically dependent, and expand distinctively before and after conductive bridging with two electro-generated dendrites. Circuit-element analysis and impedance spectroscopy confirms their morphological control in temporal windows where growth kinetics is finely perturbed by the input frequency and duty cycle. By the emulation of one’s most preponderant mechanisms for brain’s long-term memory, its implementation in vicinity of sensing arrays, neural probes or biochips shall greatly optimize computational costs and recognition required to classify high-dimensional patterns from complex environments.
Efficacy and safety of next-generation tick transcriptome-derived direct thrombin inhibitors
Authors: Koh Cho Yeow , Shih Norrapat , Yip Christina Y. C. , Li Aaron Wei Liang , Chen Weiming , Amran Fathiah S. , Leong Esther Jia En , Iyer Janaki Krishnamoorthy , Croft Grace , Mazlan Muhammad Ibrahim Bin , Chee Yen-Lin , Yap Eng-Soo , Monroe Dougald M. , Hoffman Maureane , Becker Richard C. , de Kleijn Dominique P. V. , Verma Vaishali , Gupta Amita , Chaudhary Vijay K. , Richards A. Mark , Kini R. Manjunatha , Chan Mark Y.
Published: November 2021

Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.
AGPAT2 interaction with CDP-diacylglycerol synthases promotes the flux of fatty acids through the CDP-diacylglycerol pathway
Authors: Mak Hoi Yin , Ouyang Qian , Tumanov Sergey , Xu Jiesi , Rong Ping , Dong Feitong , Lam Sin Man , Wang Xiaowei , Lukmantara Ivan , Du Ximing , Gao Mingming , Brown Andrew J. , Gong Xin , Shui Guanghou , Stocker Roland , Huang Xun , Chen Shuai , Yang Hongyuan
Published: November 2021

AGPATs (1-acylglycerol-3-phosphate O-acyltransferases) catalyze the acylation of lysophosphatidic acid to form phosphatidic acid (PA), a key step in the glycerol-3-phosphate pathway for the synthesis of phospholipids and triacylglycerols. AGPAT2 is the only AGPAT isoform whose loss-of-function mutations cause a severe form of human congenital generalized lipodystrophy. Paradoxically, AGPAT2 deficiency is known to dramatically increase the level of its product, PA. Here, we find that AGPAT2 deficiency impairs the biogenesis and growth of lipid droplets. We show that AGPAT2 deficiency compromises the stability of CDP-diacylglycerol (DAG) synthases (CDSs) and decreases CDS activity in both cell lines and mouse liver. Moreover, AGPAT2 and CDS1/2 can directly interact and form functional complexes, which promote the metabolism of PA along the CDP-DAG pathway of phospholipid synthesis. Our results provide key insights into the regulation of metabolic flux during lipid synthesis and suggest substrate channelling at a major branch point of the glycerol-3-phosphate pathway.
Giant single-crystal-to-single-crystal transformations associated with chiral interconversion induced by elimination of chelating ligands
Authors: Li Yun , Zhao Bo , Xue Jin-Peng , Xie Jing , Yao Zi-Shuo , Tao Jun
Published: November 2021

Numerous single crystals that exhibit single-crystal-to-single-crystal (SCSC) transformations have been reported, and some of them show great promise for application to advanced adsorption materials, magnetic switches, and smart actuators. However, the development of single crystals with super-adaptive crystal lattices capable of huge and reversible structural change remains a great challenge. In this study, we report a ZnII complex that undergoes giant SCSC transformation induced by a two-step thermal elimination of ethylene glycol chelating ligands. Although the structural change is exceptionally large (50% volume shrinkage and 36% weight loss), the single-crystal nature of the complex persists because of the multiple strong hydrogen bonds between the constituent molecules. This allows the reversible zero-dimensional to one-dimension and further to three-dimensional structural changes to be fully characterized by single-crystal X-ray diffraction analyses. The elimination of chelating ligands induces a chiral interconversion in the molecules that manifests as a centric-chiral-polar symmetric variation of the single crystal. The study not only presents a unique material, featuring both a periodic crystal lattice and gel-like super-ductility, but also reveals a possible solid-state reaction method for preparing chiral compounds via the elimination of chelating ligands.
The barley immune receptor Mla recognizes multiple pathogens and contributes to host range dynamics
Authors: Bettgenhaeuser Jan , Hernández-Pinzón Inmaculada , Dawson Andrew M. , Gardiner Matthew , Green Phon , Taylor Jodie , Smoker Matthew , Ferguson John N. , Emmrich Peter , Hubbard Amelia , Bayles Rosemary , Waugh Robbie , Steffenson Brian J. , Wulff Brande B. H. , Dreiseitl Antonín , Ward Eric R. , Moscou Matthew J.
Published: November 2021

Crop losses caused by plant pathogens are a primary threat to stable food production. Stripe rust (Puccinia striiformis) is a fungal pathogen of cereal crops that causes significant, persistent yield loss. Stripe rust exhibits host species specificity, with lineages that have adapted to infect wheat and barley. While wheat stripe rust and barley stripe rust are commonly restricted to their corresponding hosts, the genes underlying this host specificity remain unknown. Here, we show that three resistance genes,Rps6,Rps7, andRps8, contribute to immunity in barley to wheat stripe rust.Rps7cosegregates with barley powdery mildew resistance at theMlalocus. Using transgenic complementation of differentMlaalleles, we confirm allele-specific recognition of wheat stripe rust byMla. Our results show that major resistance genes contribute to the host species specificity of wheat stripe rust on barley and that a shared genetic architecture underlies resistance to the adapted pathogen barley powdery mildew and non-adapted pathogen wheat stripe rust.
Engineering a PAM-flexible SpdCas9 variant as a universal gene repressor
Authors: Wang Jian , Teng Yuxi , Zhang Ruihua , Wu Yifei , Lou Lei , Zou Yusong , Li Michelle , Xie Zhong-Ru , Yan Yajun
Published: November 2021

The RNA-guided CRISPR-associated Cas9 proteins have been widely applied in programmable genome recombination, base editing or gene regulation in both prokaryotes and eukaryotes. SpCas9 from Streptococcus pyogenes is the most extensively engineered Cas9 with robust and manifold functionalities. However, one inherent limitation of SpCas9 is its stringent 5′-NGG-3′ PAM requirement that significantly restricts its DNA target range. Here, to repurpose SpCas9 as a universal gene repressor, we generate and screen variants of the deactivated SpCas9 (SpdCas9) with relaxed 5′-CAT-3′ PAM compatibility that can bind to the start codon ATG of almost any gene. Stepwise structure-guided mutations of the PAM-interacting residues and auxiliary PAM-proximal residues of the SpdNG (5′-NG-3′ PAM) create a PAM-flexible variant SpdNG-LWQT that preferentially accommodates 5′-NRN-3′ PAMs. SpdNG-LWQT is demonstrated to be effective in gene repression with the advantage of customizable sgRNA design in both Escherichia coli and Saccharomyces cerevisiae. This work validates the feasibility of purposeful PAM expansion of Cas9 towards signature PAMs and establishes a universal SpdCas9-based gene repressor.
Cholinesterase inhibitors for gait, balance, and fall in Parkinson disease: a meta-analysis
Authors: Chen Jia-Hung , Huang Tsai-Wei , Hong Chien-Tai
Published: November 2021

Gait disturbance and imbalance are the major symptoms of Parkinson disease (PD), with fall being the most undesirable consequence. However, few effective evidence-based treatments are available for alleviating these symptoms and preventing falls. Cholinesterase inhibitors (ChEIs) are a well-established treatment for PD dementia with possible impacts on gait, balance, and fall reduction. The present study involved a meta-analysis of randomized controlled trials (RCTs) to investigate the effects of ChEIs on gait, balance, and fall in patients with PD. We searched for studies using the PubMed, Embase, and Web of Science databases. The major outcomes were effects on gait parameters, balance, and fall. This study was registered with PROSPERO (CRD42021254733). Five RCTs were included in the present meta-analysis. ChEIs did not significantly increase gait speed in PD patients (mean difference [MD]: 0.03 m/s, 95% confidence interval [CI]: −0.02 to 0.07, p = 0.29). However, ChEI treatment significantly decreased step or stride variability during the single task (standard MD: −0.43, 95% CI = −0.79 to −0.06, p = 0.02). Regarding fall and balance, trending but nonsignificant beneficial effects were observed with ChEI treatment. In conclusion, although ChEI treatment did not significantly improve gait speed and reduce fall, it can significantly reduce step or stride variability. Considering that gait disorder is a challenging issue in patients with PD and that ChEIs are generally tolerable, the present meta-analysis may provide more evidence for the benefit of ChEIs on PD gait disturbance as an alternative treatment consideration.
Precise, fast and comprehensive analysis of intact glycopeptides and modified glycans with pGlyco3
Authors: Zeng Wen-Feng , Cao Wei-Qian , Liu Ming-Qi , He Si-Min , Yang Peng-Yuan
Published: November 2021

Great advances have been made in mass spectrometric data interpretation for intact glycopeptide analysis. However, accurate identification of intact glycopeptides and modified saccharide units at the site-specific level and with fast speed remains challenging. Here, we present a glycan-first glycopeptide search engine, pGlyco3, to comprehensively analyze intact N- and O-glycopeptides, including glycopeptides with modified saccharide units. A glycan ion-indexing algorithm developed for glycan-first search makes pGlyco3 5–40 times faster than other glycoproteomic search engines without decreasing accuracy or sensitivity. By combining electron-based dissociation spectra, pGlyco3 integrates a dynamic programming-based algorithm termed pGlycoSite for site-specific glycan localization. Our evaluation shows that the site-specific glycan localization probabilities estimated by pGlycoSite are suitable to localize site-specific glycans. With pGlyco3, we confidently identified N-glycopeptides and O-mannose glycopeptides that were extensively modified by ammonia adducts in yeast samples. The freely available pGlyco3 is an accurate and flexible tool that can be used to identify glycopeptides and modified saccharide units.
China material stocks and flows account for 1978–2018
Authors: Song Lulu , Han Ji , Li Nan , Huang Yuanyi , Hao Min , Dai Min , Chen Wei-Qiang
Published: November 2021

As the world’s top material consumer, China has created intense pressure on national or global demand for natural resources. Building an accurate material stocks and flows account of China is a prerequisite for promoting sustainable resource management. However, there is no annually, officially published material stocks and flows data in China. Existing material stocks and flows estimates conducted by scholars exhibit great discrepancies. In this study, we create the Provincial Material Stocks and Flows Database (PMSFD) for China and its 31 provinces. This dataset describes 13 materials’ stocks, demand, and scrap supply in five end-use sectors in each province during 1978–2018. PMSFD is the first version of material stocks and flows inventories in China, and its uniform estimation structure and formatted inventories offer a comprehensive foundation for future accumulation, modification, and enhancement. PMSFD contributes insight into the material metabolism, which is an important database for sustainable development as well as circular economy policy-making in China. This dataset will be updated annually.
Chromosome-scale genome assembly of the high royal jelly-producing honeybees
Authors: Cao Lianfei , Zhao Xiaomeng , Chen Yanping , Sun Cheng
Published: November 2021

A high royal jelly-producing strain of honeybees (HRJHB) has been obtained by successive artificial selection of Italian honeybees (Apis mellifera ligustica) in China. The HRJHB can produce amounts of royal jelly that are dozens of times greater than their original counterparts, which has promoted China to be the largest producer of royal jelly in the world. In this study, we generated a chromosome-scale of the genome sequence for the HRJHB using PacBio long reads and Hi-C technique. The genome consists of 16 pseudo-chromosomes that contain 222 Mb of sequence, with a scaffold N50 of 13.6 Mb. BUSCO analysis yielded a completeness score of 99.3%. The genome has 12,288 predicted protein-coding genes and a rate of 8.11% of repetitive sequences. One chromosome inversion was identified between the HRJHB and the closely related Italian honeybees through whole-genome alignment analysis. The HRJHB’s genome sequence will be an important resource for understanding the genetic basis of high levels of royal jelly production, which may also shed light on the evolution of domesticated insects.
Differences in characteristics between people with tinnitus that seek help and that do not
Authors: Rademaker M. M. , Stegeman I. , Brabers A. E. M. , de Jong J. D. , Stokroos R. J. , Smit A. L.
Published: November 2021

Knowledge on characteristics of people that seek help for tinnitus is scarce. The primary objective of this study was to describe differences in characteristics between people with tinnitus that seek help compared to those who do not seek help. Next, we described differences in characteristics between those with and without tinnitus. In this cross-sectional study, we sent a questionnaire on characteristics in different domains; demographic, tinnitus-specific, general- and psychological health, auditory and noise- and substance behaviour. We assessed if participants had sought help or planned to seek help for tinnitus. Tinnitus distress was defined with the Tinnitus Functional Index. Differences between groups (help seeking: yes/no, tinnitus: yes/no) were described. 932 people took part in our survey. Two hundred and sixteen participants were defined as having tinnitus (23.2%). Seventy-three of those sought or planned to seek help. A constant tinnitus pattern, a varying tinnitus loudness, and hearing loss, were described more frequently in help seekers. Help seekers reported higher TFI scores. Differences between help seekers and people not seeking help were mainly identified in tinnitus- and audiological characteristics. These outcomes might function as a foundation to explore the heterogeneity in tinnitus patients.