bluuebunny/crossref_metadata_2025 huggingface dataset:
Overcoming thermo-optical dynamics in broadband nanophotonic sensing
Authors: Wang Mingkang , Perez-Morelo Diego J. , Aksyuk Vladimir
Published: July 2021

Advances in integrated photonics open up exciting opportunities for batch-fabricated optical sensors using high-quality-factor nanophotonic cavities to achieve ultrahigh sensitivities and bandwidths. The sensitivity improves with increasing optical power; however, localized absorption and heating within a micrometer-scale mode volume prominently distorts the cavity resonances and strongly couples the sensor response to thermal dynamics, limiting the sensitivity and hindering the measurement of broadband time-dependent signals. Here, we derive a frequency-dependent photonic sensor transfer function that accounts for thermo-optical dynamics and quantitatively describes the measured broadband optomechanical signal from an integrated photonic atomic force microscopy nanomechanical probe. Using this transfer function, the probe can be operated in the high optical power, strongly thermo-optically nonlinear regime, accurately measuring low- and intermediate-frequency components of a dynamic signal while reaching a sensitivity of 0.7 fm/Hz1/2 at high frequencies, an improvement of ≈10× relative to the best performance in the linear regime. Counterintuitively, we discover that a higher transduction gain and sensitivity are achieved with lower quality-factor optical modes for low signal frequencies. Not limited to optomechanical transducers, the derived transfer function is generally valid for describing the small-signal dynamic responses of a broad range of technologically important photonic sensors subject to the thermo-optical effect.
Assessment of suicide attempt and death in bipolar affective disorder: a combined clinical and genetic approach
Authors: Monson Eric T. , Shabalin Andrey A. , Docherty Anna R. , DiBlasi Emily , Bakian Amanda V. , Li Qingqin S. , Gray Douglas , Keeshin Brooks , Crowell Sheila E. , Mullins Niamh , Willour Virginia L. , Coon Hilary
Published: July 2021

Bipolar disorder (BP) suicide death rates are 10–30 times greater than the general population, likely arising from environmental and genetic risk factors. Though suicidal behavior in BP has been investigated, studies have not addressed combined clinical and genetic factors specific to suicide death. To address this gap, a large, harmonized BP cohort was assessed to identify clinical risk factors for suicide death and attempt which then directed testing of underlying polygenic risks. 5901 individuals of European ancestry were assessed: 353 individuals with BP and 2498 without BP who died from suicide (BPS and NBPS, respectively) from a population-derived sample along with a volunteer-derived sample of 799 individuals with BP and a history of suicide attempt (BPSA), 824 individuals with BP and no prior attempts (BPNSA), and 1427 individuals without several common psychiatric illnesses per self-report (C). Clinical and subsequent directed genetic analyses utilized multivariable logistic models accounting for critical covariates and multiple testing. There was overrepresentation of diagnosis of PTSD (OR = 4.9, 95%CI: 3.1–7.6) in BPS versus BPSA, driven by female subjects. PRS assessments showed elevations in BPS including PTSD (OR = 1.3, 95%CI:1.1–1.5, versus C), female-derived ADHD (OR = 1.2, 95%CI:1.1–1.4, versus C), and male insomnia (OR = 1.4, 95%CI: 1.1–1.7, versus BPSA). The results provide support from genetic and clinical standpoints for dysregulated traumatic response particularly increasing risk of suicide death among individuals with BP of Northern European ancestry. Such findings may direct more aggressive treatment and prevention of trauma sequelae within at-risk bipolar individuals.
A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer
Authors: Liu Qian , Guo Lijuan , Qi Hongyan , Lou Meng , Wang Rui , Hai Boning , Xu Kailun , Zhu Lijun , Ding Yongfeng , Li Chen , Xie Lingdan , Shen Jing , Xiang Xueping , Shao Jimin
Published: July 2021

Ribonucleotide reductase (RR) is a unique enzyme for the reduction of NDPs to dNDPs, the building blocks for DNA synthesis and thus essential for cell proliferation. Pan-cancer profiling studies showed that RRM2, the small subunit M2 of RR, is abnormally overexpressed in multiple types of cancers; however, the underlying regulatory mechanisms in cancers are still unclear. In this study, through searching in cancer-omics databases and immunohistochemistry validation with clinical samples, we showed that the expression of MYBL2, a key oncogenic transcriptional factor, was significantly upregulated correlatively with RRM2 in colorectal cancer (CRC). Ectopic expression and knockdown experiments indicated that MYBL2 was essential for CRC cell proliferation, DNA synthesis, and cell cycle progression in an RRM2-dependent manner. Mechanistically, MYBL2 directly bound to the promoter of RRM2 gene and promoted its transcription during S-phase together with TAF15 and MuvB components. Notably, knockdown of MYBL2 sensitized CRC cells to treatment with MK-1775, a clinical trial drug for inhibition of WEE1, which is involved in a degradation pathway of RRM2. Finally, mouse xenograft experiments showed that the combined suppression of MYBL2 and WEE1 synergistically inhibited CRC growth with a low systemic toxicity in vivo. Therefore, we propose a new regulatory mechanism for RRM2 transcription for CRC proliferation, in which MYBL2 functions by constituting a dynamic S-phase transcription complex following the G1/early S-phase E2Fs complex. Doubly targeting the transcription and degradation machines of RRM2 could produce a synthetic inhibitory effect on RRM2 level with a novel potential for CRC treatment.
Exosomes secreted by palmitic acid-treated hepatocytes promote LX-2 cell activation by transferring miRNA-107
Authors: Wang Wei , Li Fangfang , Lai Xiaoyang , Liu Han , Wu Shuting , Han Yunqin , Shen Yunfeng
Published: July 2021

Activation of hepatic stellate cells (HSCs) is a key inducer of liver fibrogenesis in nonalcoholic fatty liver disease (NAFLD). Exosomes play an important role between hepatocytes and HSCs. This study aims to explore the role of exosomes derived from palmitic acid (PA)-treated hepatocytes in regulating HSCs (LX-2 cell) proliferation and activation and the underlying mechanisms. Exosomes were isolated from PA-treated human normal hepatocytes and incubated with LX-2 cells. Cell Counting Kit-8 (CCK-8) was performed to determine LX-2 cell proliferation, and the expression of fibrosis markers α-smooth muscle actin (α-SMA) and collagen type 1 α1 (CoL1A1) were examined to evaluateLX-2 cell activation. PA induced hepatocytes to release more exosomes enriched in miR-107. Mechanically, on the one hand, exosomes from PA-treated hepatocytes shuttled miR-107 to LX-2 cells, where miR-107 activated Wnt signaling by targeting DKK1 and thereby induced LX-2 cell activation; on the other hand, PA-treated hepatocytes derived exosomes also delivered miR-107 to CD4 + T lymphocytes, where miR-107 elevated IL-9 expression by targeting Foxp1, which bound to the IL-9 promoter in CD4 + T cells and suppressed Th9 cell differentiation and reduced IL-9 expression, and thus promoted LX-2 cell activation by activating Raf/MEK/ERK signaling pathway.
Spatial coherence of light inside three-dimensional media
Authors: Leonetti Marco , Pattelli Lorenzo , De Panfilis Simone , Wiersma Diederik S. , Ruocco Giancarlo
Published: July 2021

Speckle is maybe the most fundamental interference effect of light in disordered media, giving rise to fascinating physical phenomena and cutting edge applications. While speckle formed outside a sample is easily measured and analysed, true bulk speckle, as formed inside random media, is difficult to investigate directly due to the obvious issue of physical access. Furthermore, its proper theoretical description poses enormous challenges. Here we report on the first direct measurements of spatially resolved intensity correlations of light inside a disordered medium, using embedded DNA strings decorated with emitters separated by a controlled nanometric distance. Our method provides in situ access to fundamental properties of bulk speckles as their size and polarization degrees of freedom, both of which are found to deviate significantly from theoretical predictions. The deviations are explained, by comparison with rigorous numerical calculations, in terms of correlations among polarization components and non-universal near-field contributions at the nanoscale.
Spectral index-flux relation for investigating the origins of steep decay in γ-ray bursts
Authors: Ronchini Samuele , Oganesyan Gor , Branchesi Marica , Ascenzi Stefano , Bernardini Maria Grazia , Brighenti Francesco , Dall’Osso Simone , D’Avanzo Paolo , Ghirlanda Giancarlo , Ghisellini Gabriele , Ravasio Maria Edvige , Salafia Om Sharan
Published: July 2021

γ-ray bursts (GRBs) are short-lived transients releasing a large amount of energy (1051 − 1053 erg) in the keV-MeV energy range. GRBs are thought to originate from internal dissipation of the energy carried by ultra-relativistic jets launched by the remnant of a massive star’s death or a compact binary coalescence. While thousands of GRBs have been observed over the last thirty years, we still have an incomplete understanding of where and how the radiation is generated in the jet. Here we show a relation between the spectral index and the flux found by investigating the X-ray tails of bright GRB pulses via time-resolved spectral analysis. This relation is incompatible with the long standing scenario which invokes the delayed arrival of photons from high-latitude parts of the jet. While the alternative scenarios cannot be firmly excluded, the adiabatic cooling of the emitting particles is the most plausible explanation for the discovered relation, suggesting a proton-synchrotron origin of the GRB emission.
The molecular basis for SARS-CoV-2 binding to dog ACE2
Authors: Zhang Zengyuan , Zhang Yanfang , Liu Kefang , Li Yan , Lu Qiong , Wang Qingling , Zhang Yuqin , Wang Liang , Liao Hanyi , Zheng Anqi , Ma Sufang , Fan Zheng , Li Huifang , Huang Weijin , Bi Yuhai , Zhao Xin , Wang Qihui , Gao George F. , Xiao Haixia , Tong Zhou , Qi Jianxun , Sun Yeping
Published: July 2021

SARS-CoV-2 can infect many domestic animals, including dogs. Herein, we show that dog angiotensin-converting enzyme 2 (dACE2) can bind to the SARS-CoV-2 spike (S) protein receptor binding domain (RBD), and that both pseudotyped and authentic SARS-CoV-2 can infect dACE2-expressing cells. We solved the crystal structure of RBD in complex with dACE2 and found that the total number of contact residues, contact atoms, hydrogen bonds and salt bridges at the binding interface in this complex are slightly fewer than those in the complex of the RBD and human ACE2 (hACE2). This result is consistent with the fact that the binding affinity of RBD to dACE2 is lower than that of hACE2. We further show that a few important mutations in the RBD binding interface play a pivotal role in the binding affinity of RBD to both dACE2 and hACE2. Our work reveals a molecular basis for cross-species transmission and potential animal spread of SARS-CoV-2, and provides new clues to block the potential transmission chains of this virus.
Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape
Authors: Bruce Jeff P. , To Ka-Fai , Lui Vivian W. Y. , Chung Grace T. Y. , Chan Yuk-Yu , Tsang Chi Man , Yip Kevin Y. , Ma Brigette B. Y. , Woo John K. S. , Hui Edwin P. , Mak Michael K. F. , Lee Sau-Dan , Chow Chit , Velapasamy Sharmila , Or Yvonne Y. Y. , Siu Pui Kei , El Ghamrasni Samah , Prokopec Stephenie , Wu Man , Kwan Johnny S. H. , Liu Yuchen , Chan Jason Y. K. , van Hasselt C. Andrew , Young Lawrence S. , Dawson Christopher W. , Paterson Ian C. , Yap Lee-Fah , Tsao Sai-Wah , Liu Fei-Fei , Chan Anthony T. C. , Pugh Trevor J. , Lo Kwok-Wai
Published: July 2021

Interplay between EBV infection and acquired genetic alterations during nasopharyngeal carcinoma (NPC) development remains vague. Here we report a comprehensive genomic analysis of 70 NPCs, combining whole-genome sequencing (WGS) of microdissected tumor cells with EBV oncogene expression to reveal multiple aspects of cellular-viral co-operation in tumorigenesis. Genomic aberrations along with EBV-encoded LMP1 expression underpin constitutive NF-κB activation in 90% of NPCs. A similar spectrum of somatic aberrations and viral gene expression undermine innate immunity in 79% of cases and adaptive immunity in 47% of cases; mechanisms by which NPC may evade immune surveillance despite its pro-inflammatory phenotype. Additionally, genomic changes impairing TGFBR2 promote oncogenesis and stabilize EBV infection in tumor cells. Fine-mapping of CDKN2A/CDKN2B deletion breakpoints reveals homozygous MTAP deletions in 32-34% of NPCs that confer marked sensitivity to MAT2A inhibition. Our work concludes that NPC is a homogeneously NF-κB-driven and immune-protected, yet potentially druggable, cancer.
Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
Authors: Elleman Anna V. , Devienne Gabrielle , Makinson Christopher D. , Haynes Allison L. , Huguenard John R. , Du Bois J.
Published: July 2021

Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaVs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaVs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial NaV block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.
Atomic-scale regulation of anionic and cationic migration in alkali metal batteries
Authors: Xiong Pan , Zhang Fan , Zhang Xiuyun , Liu Yifan , Wu Yunyan , Wang Shijian , Safaei Javad , Sun Bing , Ma Renzhi , Liu Zongwen , Bando Yoshio , Sasaki Takayoshi , Wang Xin , Zhu Junwu , Wang Guoxiu
Published: July 2021

The regulation of anions and cations at the atomic scale is of great significance in membrane-based separation technologies. Ionic transport regulation techniques could also play a crucial role in developing high-performance alkali metal batteries such as alkali metal-sulfur and alkali metal-selenium batteries, which suffer from the non-uniform transport of alkali metal ions (e.g., Li+ or Na+) and detrimental shuttling effect of polysulfide/polyselenide anions. These drawbacks could cause unfavourable growth of alkali metal depositions at the metal electrode and irreversible consumption of cathode active materials, leading to capacity decay and short cycling life. Herein, we propose the use of a polypropylene separator coated with negatively charged Ti0.87O2 nanosheets with Ti atomic vacancies to tackle these issues. In particular, we demonstrate that the electrostatic interactions between the negatively charged Ti0.87O2 nanosheets and polysulfide/polyselenide anions reduce the shuttling effect. Moreover, the Ti0.87O2-coated separator regulates the migration of alkali ions ensuring a homogeneous ion flux and the Ti vacancies, acting as sub-nanometric pores, promote fast alkali-ion diffusion.
The role of membrane destabilisation and protein dynamics in BAM catalysed OMP folding
Authors: White Paul , Haysom Samuel F. , Iadanza Matthew G. , Higgins Anna J. , Machin Jonathan M. , Whitehouse James M. , Horne Jim E. , Schiffrin Bob , Carpenter-Platt Charlotte , Calabrese Antonio N. , Storek Kelly M. , Rutherford Steven T. , Brockwell David J. , Ranson Neil A. , Radford Sheena E.
Published: July 2021

The folding of β-barrel outer membrane proteins (OMPs) in Gram-negative bacteria is catalysed by the β-barrel assembly machinery (BAM). How lateral opening in the β-barrel of the major subunit BamA assists in OMP folding, and the contribution of membrane disruption to BAM catalysis remain unresolved. Here, we use an anti-BamA monoclonal antibody fragment (Fab1) and two disulphide-crosslinked BAM variants (lid-locked (LL), and POTRA-5-locked (P5L)) to dissect these roles. Despite being lethal in vivo, we show that all complexes catalyse folding in vitro, albeit less efficiently than wild-type BAM. CryoEM reveals that while Fab1 and BAM-P5L trap an open-barrel state, BAM-LL contains a mixture of closed and contorted, partially-open structures. Finally, all three complexes globally destabilise the lipid bilayer, while BamA does not, revealing that the BAM lipoproteins are required for this function. Together the results provide insights into the role of BAM structure and lipid dynamics in OMP folding.
Mapping mutations to the SARS-CoV-2 RBD that escape binding by different classes of antibodies
Authors: Greaney Allison J. , Starr Tyler N. , Barnes Christopher O. , Weisblum Yiska , Schmidt Fabian , Caskey Marina , Gaebler Christian , Cho Alice , Agudelo Marianna , Finkin Shlomo , Wang Zijun , Poston Daniel , Muecksch Frauke , Hatziioannou Theodora , Bieniasz Paul D. , Robbiani Davide F. , Nussenzweig Michel C. , Bjorkman Pamela J. , Bloom Jesse D.
Published: July 2021

Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions of these different antibody classes to the polyclonal response remains unclear. Here we use a yeast-display system to map all mutations to the viral spike receptor-binding domain (RBD) that escape binding by representatives of three potently neutralizing classes of anti-RBD antibodies with high-resolution structures. We compare the antibody-escape maps to similar maps for convalescent polyclonal plasmas, including plasmas from individuals from whom some of the antibodies were isolated. While the binding of polyclonal plasma antibodies are affected by mutations across multiple RBD epitopes, the plasma-escape maps most resemble those of a single class of antibodies that target an epitope on the RBD that includes site E484. Therefore, although the human immune system can produce antibodies that target diverse RBD epitopes, in practice the polyclonal response to infection is skewed towards a single class of antibodies targeting an epitope that is already undergoing rapid evolution.
Chaperone-like protein DAY plays critical roles in photomorphogenesis
Authors: Lee Ho-Seok , Choi Ilyeong , Jeon Young , Ahn Hee-Kyung , Cho Huikyong , Kim JiWoo , Kim Jae-Hee , Lee Jung-Min , Lee SungHee , Bünting Julian , Seo Dong Hye , Lee Tak , Lee Du-Hwa , Lee Insuk , Oh Man-Ho , Kim Tae-Wuk , Belkhadir Youssef , Pai Hyun-Sook
Published: July 2021

Photomorphogenesis, light-mediated development, is an essential feature of all terrestrial plants. While chloroplast development and brassinosteroid (BR) signaling are known players in photomorphogenesis, proteins that regulate both pathways have yet to be identified. Here we report that DE-ETIOLATION IN THE DARKANDYELLOWING IN THE LIGHT (DAY), a membrane protein containing DnaJ-like domain, plays a dual-role in photomorphogenesis by stabilizing the BR receptor, BRI1, as well as a key enzyme in chlorophyll biosynthesis, POR. DAY localizes to both the endomembrane and chloroplasts via its first transmembrane domain and chloroplast transit peptide, respectively, and interacts with BRI1 and POR in their respective subcellular compartments. Using genetic analysis, we show that DAY acts independently on BR signaling and chlorophyll biogenesis. Collectively, this work uncovers DAY as a factor that simultaneously regulates BR signaling and chloroplast development, revealing a key regulator of photomorphogenesis that acts across cell compartments.
A genomic surveillance framework and genotyping tool for Klebsiella pneumoniae and its related species complex
Authors: Lam Margaret M. C. , Wick Ryan R. , Watts Stephen C. , Cerdeira Louise T. , Wyres Kelly L. , Holt Kathryn E.
Published: July 2021

Klebsiella pneumoniae is a leading cause of antimicrobial-resistant (AMR) healthcare-associated infections, neonatal sepsis and community-acquired liver abscess, and is associated with chronic intestinal diseases. Its diversity and complex population structure pose challenges for analysis and interpretation of K. pneumoniae genome data. Here we introduce Kleborate, a tool for analysing genomes of K. pneumoniae and its associated species complex, which consolidates interrogation of key features of proven clinical importance. Kleborate provides a framework to support genomic surveillance and epidemiology in research, clinical and public health settings. To demonstrate its utility we apply Kleborate to analyse publicly available Klebsiella genomes, including clinical isolates from a pan-European study of carbapenemase-producing Klebsiella, highlighting global trends in AMR and virulence as examples of what could be achieved by applying this genomic framework within more systematic genomic surveillance efforts. We also demonstrate the application of Kleborate to detect and type K. pneumoniae from gut metagenomes.
Fractional response analysis reveals logarithmic cytokine responses in cellular populations
Authors: Nienałtowski Karol , Rigby Rachel E. , Walczak Jarosław , Zakrzewska Karolina E. , Głów Edyta , Rehwinkel Jan , Komorowski Michał
Published: July 2021

Although we can now measure single-cell signaling responses with multivariate, high-throughput techniques our ability to interpret such measurements is still limited. Even interpretation of dose–response based on single-cell data is not straightforward: signaling responses can differ significantly between cells, encompass multiple signaling effectors, and have dynamic character. Here, we use probabilistic modeling and information-theory to introduce fractional response analysis (FRA), which quantifies changes in fractions of cells with given response levels. FRA can be universally performed for heterogeneous, multivariate, and dynamic measurements and, as we demonstrate, quantifies otherwise hidden patterns in single-cell data. In particular, we show that fractional responses to type I interferon in human peripheral blood mononuclear cells are very similar across different cell types, despite significant differences in mean or median responses and degrees of cell-to-cell heterogeneity. Further, we demonstrate that fractional responses to cytokines scale linearly with the log of the cytokine dose, which uncovers that heterogeneous cellular populations are sensitive to fold-changes in the dose, as opposed to additive changes.
Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis
Authors: Li Shuo , Noor Zorawar S. , Zeng Weihua , Stackpole Mary L. , Ni Xiaohui , Zhou Yonggang , Yuan Zuyang , Wong Wing Hung , Agopian Vatche G. , Dubinett Steven M. , Alber Frank , Li Wenyuan , Garon Edward B. , Zhou Xianghong Jasmine
Published: July 2021

Cell-free DNA (cfDNA) is attractive for many applications, including detecting cancer, identifying the tissue of origin, and monitoring. A fundamental task underlying these applications is SNV calling from cfDNA, which is hindered by the very low tumor content. Thus sensitive and accurate detection of low-frequency mutations (<5%) remains challenging for existing SNV callers. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this challenge. Furthermore, by leveraging cfDNA’s comprehensive coverage of tumor clonal landscape, cfSNV can profile mutations in subclones. In both simulated and real patient data, cfSNV outperforms existing tools in sensitivity while maintaining high precision. cfSNV enhances the clinical utilities of cfDNA by improving mutation detection performance in medium-depth sequencing data, therefore making Whole-Exome Sequencing a viable option. As an example, we demonstrate that the tumor mutation profile from cfDNA WES data can provide an effective biomarker to predict immunotherapy outcomes.
Improved genetic prediction of complex traits from individual-level data or summary statistics
Authors: Zhang Qianqian , Privé Florian , Vilhjálmsson Bjarni , Speed Doug
Published: July 2021

Most existing tools for constructing genetic prediction models begin with the assumption that all genetic variants contribute equally towards the phenotype. However, this represents a suboptimal model for how heritability is distributed across the genome. Therefore, we develop prediction tools that allow the user to specify the heritability model. We compare individual-level data prediction tools using 14 UK Biobank phenotypes; our new tool LDAK-Bolt-Predict outperforms the existing tools Lasso, BLUP, Bolt-LMM and BayesR for all 14 phenotypes. We compare summary statistic prediction tools using 225 UK Biobank phenotypes; our new tool LDAK-BayesR-SS outperforms the existing tools lassosum, sBLUP, LDpred and SBayesR for 223 of the 225 phenotypes. When we improve the heritability model, the proportion of phenotypic variance explained increases by on average 14%, which is equivalent to increasing the sample size by a quarter.
GapClust is a light-weight approach distinguishing rare cells from voluminous single cell expression profiles
Authors: Fa Botao , Wei Ting , Zhou Yuan , Johnston Luke , Yuan Xin , Ma Yanran , Zhang Yue , Yu Zhangsheng
Published: July 2021

Single cell RNA sequencing (scRNA-seq) is a powerful tool in detailing the cellular landscape within complex tissues. Large-scale single cell transcriptomics provide both opportunities and challenges for identifying rare cells playing crucial roles in development and disease. Here, we develop GapClust, a light-weight algorithm to detect rare cell types from ultra-large scRNA-seq datasets with state-of-the-art speed and memory efficiency. Benchmarking on diverse experimental datasets demonstrates the superior performance of GapClust compared to other recently proposed methods. When applying our algorithm to an intestine and 68 k PBMC datasets, GapClust identifies the tuft cells and a previously unrecognised subtype of monocyte, respectively.
Engineering phase and polarization singularity sheets
Authors: Lim Soon Wei Daniel , Park Joon-Suh , Meretska Maryna L. , Dorrah Ahmed H. , Capasso Federico
Published: July 2021

Optical phase singularities are zeros of a scalar light field. The most systematically studied class of singular fields is vortices: beams with helical wavefronts and a linear (1D) singularity along the optical axis. Beyond these common and stable 1D topologies, we show that a broader family of zero-dimensional (point) and two-dimensional (sheet) singularities can be engineered. We realize sheet singularities by maximizing the field phase gradient at the desired positions. These sheets, owning to their precise alignment requirements, would otherwise only be observed in rare scenarios with high symmetry. Furthermore, by applying an analogous procedure to the full vectorial electric field, we can engineer paraxial transverse polarization singularity sheets. As validation, we experimentally realize phase and polarization singularity sheets with heart-shaped cross-sections using metasurfaces. Singularity engineering of the dark enables new degrees of freedom for light-matter interaction and can inspire similar field topologies beyond optics, from electron beams to acoustics.
Translocation of vaginal microbiota is involved in impairment and protection of uterine health
Authors: Wang Jinfeng , Li Zhanzhan , Ma Xiuling , Du Lifeng , Jia Zhen , Cui Xue , Yu Liqun , Yang Jing , Xiao Liwen , Zhang Bing , Fan Huimin , Zhao Fangqing
Published: July 2021

The vaginal and uterine microbiota play important roles in the health of the female reproductive system. However, the interactions among the microbes in these two niches and their effects on uterine health remain unclear. Here we profile the vaginal and uterine microbial samples of 145 women, and combine with deep mining of public data and animal experiments to characterize the microbial translocation in the female reproductive tract and its role in modulating uterine health. Synchronous variation and increasing convergence of the uterine and vaginal microbiome with advancing age are shown. We also find that transplanting certain strains of vaginal bacteria into the vagina of rats induces or reduces endometritis-like symptoms, and verify the damaging or protective effects of certain vaginal bacteria on endometrium. This study clarifies the interdependent relationship of vaginal bacterial translocation with uterine microecology and endometrial health, which will undoubtedly increase our understanding of female reproductive health.
Energy-saving hydrogen production by chlorine-free hybrid seawater splitting coupling hydrazine degradation
Authors: Sun Fu , Qin Jingshan , Wang Zhiyu , Yu Mengzhou , Wu Xianhong , Sun Xiaoming , Qiu Jieshan
Published: July 2021

Seawater electrolysis represents a potential solution to grid-scale production of carbon-neutral hydrogen energy without reliance on freshwater. However, it is challenged by high energy costs and detrimental chlorine chemistry in complex chemical environments. Here we demonstrate chlorine-free hydrogen production by hybrid seawater splitting coupling hydrazine degradation. It yields hydrogen at a rate of 9.2 mol h–1 gcat–1 on NiCo/MXene-based electrodes with a low electricity expense of 2.75 kWh per m3 H2 at 500 mA cm–2 and 48% lower energy equivalent input relative to commercial alkaline water electrolysis. Chlorine electrochemistry is avoided by low cell voltages without anode protection regardless Cl– crossover. This electrolyzer meanwhile enables fast hydrazine degradation to ~3 ppb residual. Self-powered hybrid seawater electrolysis is realized by integrating low-voltage direct hydrazine fuel cells or solar cells. These findings enable further opportunities for efficient conversion of ocean resources to hydrogen fuel while removing harmful pollutants.
Quantum random number cloud platform
Authors: Huang Leilei , Zhou Hongyi , Feng Kai , Xie Chongjin
Published: July 2021

Randomness lays the foundation for information security. Quantum random number generation based on various quantum principles has been proposed to provide true randomness in the last two decades. We integrate four different types of quantum random number generators on the Alibaba Cloud servers to enhance cybersecurity. Post-processing modules are integrated into the quantum platform to extract true random numbers. We employ improved authentication protocols where original pseudo-random numbers are replaced with quantum ones. Users from the Alibaba Cloud, such as Ant Financial and Smart Access Gateway, request random numbers from the quantum platform for various cryptographic tasks. For cloud services demanding the highest security, such as Alipay at Ant Financial, we combine the random numbers from four quantum devices by XOR the outputs to enhance practical security. The quantum platform has been continuously run for more than a year.
Optimization of catalytic wet oxidating fulvic acid with zero-valent copper chitosan activated carbon ball as the catalyst
Authors: Song Chaofei , Lv Yue , Qin Xia , Guo Chengrui , Cui Jiaxin , Kaghembega Wendkuuni Steve-Harold
Published: July 2021

The degradation efficiency of fulvic acid (FA) was investigated in the catalytic wet oxidation process (CWPO) by zero-valent copper chitosan activated carbon ball (ZVC/CTS-ACB). Characterization of ZVC/CTS-ACB shows that zero-valent copper was loaded successfully on the chitosan activated carbon. Plackett–Buiman (PB) design and response surface methodology (RSM) were employed to determine the influence factors and the optimum processing parameters. The model was well fitted to the actual data and the correlation coefficients of R2 and R2-adj were 0.9359 and 0.9039, respectively. Under the obtained optimum conditions for FA degradation: temperature = 94 °C and pH 3.8, the average FA removal by three replicate experiments was 93.02%, which has a high consistency to the RSM optimal target response of 93.86%. The comparison of catalytic performance showed that the addition of catalyst ZVC/CTS-ACS could increase the removal rate of FA, color number (CN) and TOC by 93.6%, 83.5% and 81.9% respectively. The high TOC removal rate indicated the good performance of the catalyst to FA mineralization. Additionally, the ICP analysis of copper ion leaching was only 0.08 mg/l after 5 repeated recycles of the catalyst, demonstrating the high stability of ZVC/CTS-ACB that is beneficial for the actual application.
Genomic epidemiology of SARS-CoV-2 in the UAE reveals novel virus mutation, patterns of co-infection and tissue specific host immune response
Authors: Liu Rong , Wu Pei , Ogrodzki Pauline , Mahmoud Sally , Liang Ke , Liu Pengjuan , Francis Stephen S. , Khalak Hanif , Liu Denghui , Li Junhua , Ma Tao , Chen Fang , Liu Weibin , Huang Xinyu , He Wenjun , Yuan Zhaorong , Qiao Nan , Meng Xin , Alqarni Budoor , Quilez Javier , Kusuma Vinay , Lin Long , Jin Xin , Yang Chongguang , Anton Xavier , Koshy Ashish , Yang Huanming , Xu Xun , Wang Jian , Xiao Peng , Al Kaabi Nawal , Fasihuddin Mohammed Saifuddin , Selvaraj Francis Amirtharaj , Weber Stefan , Al Hosani Farida Ismail , Liu Siyang , Zaher Walid Abbas
Published: July 2021

To unravel the source of SARS-CoV-2 introduction and the pattern of its spreading and evolution in the United Arab Emirates, we conducted meta-transcriptome sequencing of 1067 nasopharyngeal swab samples collected between May 9th and Jun 29th, 2020 during the first peak of the local COVID-19 epidemic. We identified global clade distribution and eleven novel genetic variants that were almost absent in the rest of the world and that defined five subclades specific to the UAE viral population. Cross-settlement human-to-human transmission was related to the local business activity. Perhaps surprisingly, at least 5% of the population were co-infected by SARS-CoV-2 of multiple clades within the same host. We also discovered an enrichment of cytosine-to-uracil mutation among the viral population collected from the nasopharynx, that is different from the adenosine-to-inosine change previously reported in the bronchoalveolar lavage fluid samples and a previously unidentified upregulation of APOBEC4 expression in nasopharynx among infected patients, indicating the innate immune host response mediated by ADAR and APOBEC gene families could be tissue-specific. The genomic epidemiological and molecular biological knowledge reported here provides new insights for the SARS-CoV-2 evolution and transmission and points out future direction on host–pathogen interaction investigation.
Label-free two-photon imaging of mitochondrial activity in murine macrophages stimulated with bacterial and viral ligands
Authors: Allen Christian Harry , Ahmed Duale , Raiche-Tanner Olivia , Chauhan Vinita , Mostaço-Guidolin Leila , Cassol Edana , Murugkar Sangeeta
Published: July 2021

Mitochondria are the metabolic hub of the cell, playing a central role in regulating immune responses. Dysfunction of mitochondrial reprogramming can occur during bacterial and viral infections compromising hosts’ immune signaling. Comparative evaluation of these alterations in response to bacterial and viral ligands can provide insights into a cell’s ability to mount pathogen-specific responses. In this study, we used two-photon excitation fluorescence (TPEF) imaging to quantify reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) and flavin adenine dinucleotide (FAD) levels in the cell and to calculate the optical redox ratio (ORR), an indicator of mitochondrial dysfunction. Analyses were performed on RAW264.7 cells and murine bone marrow derived macrophages (BMM) stimulated with bacterial (LPS) and viral (Poly(I:C)) ligands. Responses were cell type dependent, with primary cells having significantly higher levels of FAD and higher oxygen consumption rates suggesting BMM may be more dependent on mitochondrial metabolism. Our findings also suggest that FAD-TPEF intensity may be a better predictor of mitochondrial activity and localization since it demonstrates unique mitochondrial clustering patterns in LPS vs. Poly(I:C) stimulated macrophages. Collectively, we demonstrate that TPEF imaging is a powerful label-free approach for quantifying changes in mitochondrial function and organization in macrophages following bacterial and viral stimuli.
Comprehensive assessment of myocardial remodeling in ischemic heart disease by synchrotron propagation based X-ray phase contrast imaging
Authors: Planinc Ivo , Garcia-Canadilla Patricia , Dejea Hector , Ilic Ivana , Guasch Eduard , Zamora Monica , Crispi Fàtima , Stampanoni Marco , Milicic Davor , Bijnens Bart , Bonnin Anne , Cikes Maja
Published: July 2021

Cardiovascular research is in an ongoing quest for a superior imaging method to integrate gross-anatomical information with microanatomy, combined with quantifiable parameters of cardiac structure. In recent years, synchrotron radiation-based X-ray Phase Contrast Imaging (X-PCI) has been extensively used to characterize soft tissue in detail. The objective was to use X-PCI to comprehensively quantify ischemic remodeling of different myocardial structures, from cell to organ level, in a rat model of myocardial infarction. Myocardial infarction-induced remodeling was recreated in a well-established rodent model. Ex vivo rodent hearts were imaged by propagation based X-PCI using two configurations resulting in 5.8 µm and 0.65 µm effective pixel size images. The acquired datasets were used for a comprehensive assessment of macrostructural changes including the whole heart and vascular tree morphology, and quantification of left ventricular myocardial thickness, mass, volume, and organization. On the meso-scale, tissue characteristics were explored and compared with histopathological methods, while microstructural changes were quantified by segmentation of cardiomyocytes and calculation of cross-sectional areas. Propagation based X-PCI provides detailed visualization and quantification of morphological changes on whole organ, tissue, vascular as well as individual cellular level of the ex vivo heart, with a single, non-destructive 3D imaging modality.
Corneal pachymetry by AS-OCT after Descemet’s membrane endothelial keratoplasty
Authors: Heslinga Friso G. , Lucassen Ruben T. , van den Berg Myrthe A. , van der Hoek Luuk , Pluim Josien P. W. , Cabrerizo Javier , Alberti Mark , Veta Mitko
Published: July 2021

Corneal thickness (pachymetry) maps can be used to monitor restoration of corneal endothelial function, for example after Descemet’s membrane endothelial keratoplasty (DMEK). Automated delineation of the corneal interfaces in anterior segment optical coherence tomography (AS-OCT) can be challenging for corneas that are irregularly shaped due to pathology, or as a consequence of surgery, leading to incorrect thickness measurements. In this research, deep learning is used to automatically delineate the corneal interfaces and measure corneal thickness with high accuracy in post-DMEK AS-OCT B-scans. Three different deep learning strategies were developed based on 960 B-scans from 50 patients. On an independent test set of 320 B-scans, corneal thickness could be measured with an error of 13.98 to 15.50 μm for the central 9 mm range, which is less than 3% of the average corneal thickness. The accurate thickness measurements were used to construct detailed pachymetry maps. Moreover, follow-up scans could be registered based on anatomical landmarks to obtain differential pachymetry maps. These maps may enable a more comprehensive understanding of the restoration of the endothelial function after DMEK, where thickness often varies throughout different regions of the cornea, and subsequently contribute to a standardized postoperative regime.
Synergistic protective effects of lycopene and N-acetylcysteine against cisplatin-induced hepatorenal toxicity in rats
Authors: Elsayed Asmaa , Elkomy Ashraf , Elkammar Reda , Youssef Gehan , Abdelhiee Ehab Yahya , Abdo Walied , Fadl Sabreen Ezzat , Soliman Ahmed , Aboubakr Mohamed
Published: July 2021

Cisplatin (CP) is one of the most frequently used chemotherapy agents. The objective of this design was to determine the ameliorative effect of lycopene (LP) and/or N-acetylcysteine (NAC) in rats with hepatic and renal toxicity induced by CP. Rats were divided randomly into 7 groups (7 rats/group): control vehicle group (saline only), the LP group (10 mg/kg, orally), the NAC group (150 mg/kg, orally), the CP group (7.5 mg/kg, IP on day 27), the LP-CP group, the NAC-CP group, and the LP-NAC-CP group. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (APK), and levels of urea, creatinine, and lipids (cholesterol, triglycerides, and low-density lipoprotein-cholesterol) increased after CP injection in the serum. Moreover, CP decreased levels of protein, albumin, and HDL cholesterol. Meanwhile, malondialdehyde significantly increased with a decrease in reduced glutathione, superoxide dismutase, and catalase in the liver and kidney tissues. CP also induced some pathological lesions and increased the expression of caspase-3 in the liver and kidney tissues. Administration of LP and NAC alone or in combinations ameliorated hepatorenal toxicity and apoptosis induced by CP.
User experience analysis of AbC-19 Rapid Test via lateral flow immunoassays for self-administrated SARS-CoV-2 antibody testing
Authors: Jing Min , Bond Raymond , Robertson Louise J. , Moore Julie , Kowalczyk Amanda , Price Ruth , Burns William , Nesbit M. Andrew , McLaughlin James , Moore Tara
Published: July 2021

Lateral flow immunoassays are low cost, rapid and highly efficacious point-of-care devices, which have been used for SARS-CoV-2 antibody testing by professionals. However, there is a lack of understanding about how self-administered tests are used by the general public for mass testing in different environmental settings. The purpose of this study was to assess the user experience (UX) (including usability) of a self-testing kit to identify COVID-19 antibodies used by a representative sample of the public in their cars, which included 1544 participants in Northern Ireland. The results based on 5-point Likert ratings from a post-test questionnaire achieved an average UX score of 96.03% [95% confidence interval (CI) 95.05–97.01%], suggesting a good degree of user experience. The results of the Wilcoxon rank sum tests suggest that UX scores were independent of the user’s age and education level although the confidence in this conclusion could be strengthened by including more participants aged younger than 18 and those with only primary or secondary education. The agreement between the test result as interpreted by the participant and the researcher was 95.85% [95% CI 94.85–96.85%], Kappa score 0.75 [95% CI 0.69–0.81] (indicating substantial agreement). Text analysis via the latent Dirichlet allocation model for the free text responses in the survey suggest that the user experience could be improved for blood-sample collection, by modifying the method of sample transfer to the test device and giving clearer instructions on how to interpret the test results. The overall findings provide an insight into the opportunities for improving the design of SARS-CoV-2 antibody testing kits to be used by the general public and therefore inform protocols for future user experience studies of point-of-care tests.
Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications
Authors: Whitmore L. , Mackay R. I. , van Herk M. , Jones J. K. , Jones R. M.
Published: July 2021

This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.
Navigation of a magnetic micro-robot through a cerebral aneurysm phantom with magnetic particle imaging
Authors: Bakenecker Anna C. , von Gladiss Anselm , Schwenke Hannes , Behrends André , Friedrich Thomas , Lüdtke-Buzug Kerstin , Neumann Alexander , Barkhausen Joerg , Wegner Franz , Buzug Thorsten M.
Published: July 2021

Cerebral aneurysms are potentially life threatening and nowadays treated by a catheter-guided coiling or by a neurosurgical clipping intervention. Here, we propose a helically shaped magnetic micro-robot, which can be steered by magnetic fields in an untethered manner and could be applied for a novel coiling procedure. This is shown by navigating the micro-robot through an additively manufactured phantom of a human cerebral aneurysm. The magnetic fields are applied with a magnetic particle imaging (MPI) scanner, which allows for the navigation and tomographic visualization by the same machine. With MPI the actuation process can be visualized with a localization accuracy of 0.68 mm and an angiogram can be acquired both without any radiation exposure. First in-vitro phantom experiments are presented, showing an idea of a robot conducted treatment of cerebral aneurysms.
Subthreshold electrical stimulation as a low power electrical treatment for stroke rehabilitation
Authors: Kim Kyungsoo , Yoo Seung-Jun , Kim So Yeon , Lee Taeju , Lim Sung-Ho , Jang Jae-Eun , Je Minkyu , Moon Cheil , Choi Ji-Woong
Published: July 2021

As a promising future treatment for stroke rehabilitation, researchers have developed direct brain stimulation to manipulate the neural excitability. However, there has been less interest in energy consumption and unexpected side effect caused by electrical stimulation to bring functional recovery for stroke rehabilitation. In this study, we propose an engineering approach with subthreshold electrical stimulation (STES) to bring functional recovery. Here, we show a low level of electrical stimulation boosted causal excitation in connected neurons and strengthened the synaptic weight in a simulation study. We found that STES with motor training enhanced functional recovery after stroke in vivo. STES was shown to induce neural reconstruction, indicated by higher neurite expression in the stimulated regions and correlated changes in behavioral performance and neural spike firing pattern during the rehabilitation process. This will reduce the energy consumption of implantable devices and the side effects caused by stimulating unwanted brain regions.