bluuebunny/crossref_metadata_2025 huggingface dataset:
TEORIE DELLA TRANSIZIONE E ANALISI DEL SISTEMA POLITICO: IL CASO ITALIANO
Authors: Pasquino Gianfranco
Published: January 2021

Reviewing the book devoted by Sergio Fabbrini to the Italian transition, the author makes three major criticisms. The first is that the book does not provide a precise formulation of what a transition really is and, therefore, does not satisfactorily identify the beginning of the Italian transition. The second criticism is that there is no attempt to utilize some of the existing theories to explain the Italian case. The reviewer strongly suggests that Easton's systems analysis might be a useful starting point. In fact, in the Italian as well as in several other transitions, the three major components of the political system: the political community, the regime, and the authorities, are significantly affected. Fabbrini does not refer to Easton's systems analysis and makes little use of the theory of the veto players as articulated by Tsebelis. The third criticism refers to the very episodical comparison between the Italian transition and the French transition that led to the Fifth Republic. On the one hand, the reviewer points to the fact that the Fourth French Republic was the most similar case to the First Italian Republic and, on the other hand, strongly suggests, contrary to Fabbrini's conclusion, that the French semipresidential solution might satisfactorily work in Italy as well. In the end, this review article underlines the need for the cumulation of knowledge, for the reliance on existing theories, and for the comparison of whole political systems in order to obtain a better understanding of the transitions to democracy.
Dysfunction of Shh signaling activates autophagy to inhibit trophoblast motility in recurrent miscarriage
Authors: Pan Yibin , Yan Lili , Chen Qiaoqiao , Wei Cheng , Dai Yongdong , Tong Xiaomei , Zhu Haiyan , Lu Meifei , Zhang Yanling , Jin Xiaoying , Zhang Tai , Lin Xiaona , Zhou Feng , Zhang Songying
Published: January 2021

In early pregnancy, the placenta anchors the conceptus and supports embryonic development and survival. This study aimed to investigate the underlying functions of Shh signaling in recurrent miscarriage (RM), a serious disorder of pregnancy. In the present study, Shh and Gli2 were mainly observed in cytotrophoblasts (CTBs), Ptch was mainly observed in syncytiotrophoblasts (STBs), and Smo and Gli3 were expressed in both CTBs and STBs. Shh signaling was significantly impaired in human placenta tissue from recurrent miscarriage patients compared to that of gestational age-matched normal controls. VEGF-A and CD31 protein levels were also significantly decreased in recurrent miscarriage patients. Furthermore, inhibition of Shh signaling impaired the motility of JAR cells by regulating the expression of Gli2 and Gli3. Intriguingly, inhibition of Shh signaling also triggered autophagy and autolysosome accumulation. Additionally, knockdown of BECN1 reversed Gant61-induced motility inhibition. In conclusion, our results showed that dysfunction of Shh signaling activated autophagy to inhibit trophoblast motility, which suggests the Shh pathway and autophagy as potential targets for RM therapy.
Inhibition of interferon-signalling halts cancer-associated fibroblast-dependent protection of breast cancer cells from chemotherapy
Authors: Broad Robyn V. , Jones Stacey J. , Teske Melina C. , Wastall Laura M. , Hanby Andrew M. , Thorne James L. , Hughes Thomas A.
Published: January 2021

Background

Triple negative breast cancers (TNBC) have poor prognoses despite aggressive treatment with cytotoxic chemotherapy. Cancer-associated fibroblasts (CAFs) are prominent in tumour stroma. Our hypothesis was that CAFs modulate chemotherapy sensitivity.

Methods

TNBC cells and breast fibroblasts were cultured; survival after chemotherapeutics was assessed using luciferase or clonogenic assays. Signalling was investigated using transcriptomics, reporters, recombinant proteins and blocking antibodies. Clinical relevance was investigated using immunohistochemistry.

Results

Breast CAFs dose-dependently protected TNBC cell lines MDA-MB-231 and MDA-MB-157, but not MDA-MB-468s, from chemotherapy. CAF-induced protection was associated with interferon (IFN) activation. CAFs were induced to express IFNβ1 by chemotherapy and TNBC co-culture, leading to paracrine activation in cancer cells. Recombinant IFNs were sufficient to protect MDA-MB-231 and MDA-MB-157 but not MDA-MB-468 cells. In TNBC patients, IFNβ1 expression in CAFs correlated with cancer cell expression of MX1, a marker of activated IFN signalling. High expression of IFNβ1 (CAFs) or MX1 (tumour cells) correlated with reduced survival after chemotherapy, especially in claudin-low tumours (which MDA-MB-231 and MDA-MB-157 cells represent). Antibodies that block IFN receptors reduced CAF-dependent chemoprotection.

Conclusions

CAF-induced activation of IFN signalling in claudin-low TNBCs results in chemoresistance. Inhibition of this pathway represents a novel method to improve breast cancer outcomes.
Metallic surface doping of metal halide perovskites
Authors: Lin Yuze , Shao Yuchuan , Dai Jun , Li Tao , Liu Ye , Dai Xuezeng , Xiao Xun , Deng Yehao , Gruverman Alexei , Zeng Xiao Cheng , Huang Jinsong
Published: January 2021

Intentional doping is the core of semiconductor technologies to tune electrical and optical properties of semiconductors for electronic devices, however, it has shown to be a grand challenge for halide perovskites. Here, we show that some metal ions, such as silver, strontium, cerium ions, which exist in the precursors of halide perovskites as impurities, can n-dope the surface of perovskites from being intrinsic to metallic. The low solubility of these ions in halide perovskite crystals excludes the metal impurities to perovskite surfaces, leaving the interior of perovskite crystals intrinsic. Computation shows these metal ions introduce many electronic states close to the conduction band minimum of perovskites and induce n-doping, which is in striking contrast to passivating ions such as potassium and rubidium ion. The discovery of metallic surface doping of perovskites enables new device and material designs that combine the intrinsic interior and heavily doped surface of perovskites.
Non-resonant power-efficient directional Nd:YAG ceramic laser using a scattering cavity
Authors: Lee KyeoReh , Ma Ho Jin , Rotermund Fabian , Kim Do Kyung , Park YongKeun
Published: January 2021

Non-resonant lasers exhibit the potential for stable and consistent narrowband light sources. Furthermore, non-resonant lasers do not require well-defined optics, and thus has considerably diversified the available types of laser gain materials including powders, films, and turbid ceramics. Despite these intrinsic advantages, the practical applications of non-resonant lasers have been limited so far, mainly because of their low power efficiency and omnidirectional emission. To overcome these limitations, here we propose a light trap design for non-resonant lasers based on a spherical scattering cavity with a small entrance. Using a porous Nd3+:YAG ceramic, directional laser emission could be observed with significant enhancements in the slope efficiency and linewidth (down to 32 pm). A theoretical model is also developed to describe and predict the operation characteristics of proposed non-resonant laser.
Shielded goethite catalyst that enables fast water dissociation in bipolar membranes
Authors: Shehzad Muhammad A. , Yasmin Aqsa , Ge Xiaolin , Ge Zijuan , Zhang Kaiyu , Liang Xian , Zhang Jianjun , Li Geng , Xiao Xinle , Jiang Bin , Wu Liang , Xu Tongwen
Published: January 2021

Optimal pH conditions for efficient artificial photosynthesis, hydrogen/oxygen evolution reactions, and photoreduction of carbon dioxide are now successfully achievable with catalytic bipolar membranes-integrated water dissociation and in-situ acid-base generations. However, inefficiency and instability are severe issues in state-of-the-art membranes, which need to urgently resolve with systematic membrane designs and innovative, inexpensive junctional catalysts. Here we show a shielding and in-situ formation strategy of fully-interconnected earth-abundant goethite Fe+3O(OH) catalyst, which lowers the activation energy barrier from 5.15 to 1.06 eV per HO − H bond and fabricates energy-efficient, cost-effective, and durable shielded catalytic bipolar membranes. Small water dissociation voltages at limiting current density (ULCD: 0.8 V) and 100 mA cm−2 (U100: 1.1 V), outstanding cyclic stability at 637 mA cm−2, long-time electro-stability, and fast acid-base generations (H2SO4: 3.9 ± 0.19 and NaOH: 4.4 ± 0.21 M m−2 min−1 at 100 mA cm−2) infer confident potential use of the novel bipolar membranes in emerging sustainable technologies.
Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients
Authors: Zhang Yongliang , Yao Yu , Xu Yaping , Li Lifeng , Gong Yan , Zhang Kai , Zhang Meng , Guan Yanfang , Chang Lianpeng , Xia Xuefeng , Li Lin , Jia Shuqin , Zeng Qiang
Published: January 2021

Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient’s genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R2 = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.
Oxygen-rich interface enables reversible stibium stripping/plating chemistry in aqueous alkaline batteries
Authors: Zhang Haozhe , Liu Qiyu , Zheng Dezhou , Yang Fan , Liu Xiaoqing , Lu Xihong
Published: January 2021

Aqueous alkaline batteries see bright future in renewable energy storage and utilization, but their practical application is greatly challenged by the unsatisfactory performance of anode materials. Herein, we demonstrate a latent Sb stripping/plating chemistry by constructing an oxygen-rich interface on carbon substrate, thus providing a decent anode candidate. The functional interface effectively lowers the nucleation overpotential of Sb and strengthens the absorption capability of the charge carriers (SbO2− ions). These two advantageous properties inhibit the occurrence of side reactions and thus enable highly reversible Sb stripping/plating. Consequently, the Sb anode delivers theoretical-value-close specific capacity (627.1 mA h g−1), high depth of discharge (95.0%) and maintains 92.4% coulombic efficiency over 1000 cycles. A robust aqueous NiCo2O4//Sb device with high energy density and prominent durability is also demonstrated. This work provides a train of thoughts for the development of aqueous alkaline batteries based on Sb chemistry.
A new hypothesis for the origin of Amazonian Dark Earths
Authors: Silva Lucas C. R. , Corrêa Rodrigo Studart , Wright Jamie L. , Bomfim Barbara , Hendricks Lauren , Gavin Daniel G. , Muniz Aleksander Westphal , Martins Gilvan Coimbra , Motta Antônio Carlos Vargas , Barbosa Julierme Zimmer , Melo Vander de Freitas , Young Scott D. , Broadley Martin R. , Santos Roberto Ventura
Published: January 2021

Amazonian Dark Earths (ADEs) are unusually fertile soils characterised by elevated concentrations of microscopic charcoal particles, which confer their distinctive colouration. Frequent occurrences of pre-Columbian artefacts at ADE sites led to their ubiquitous classification as Anthrosols (soils of anthropic origin). However, it remains unclear how indigenous peoples created areas of high fertility in one of the most nutrient-impoverished environments on Earth. Here, we report new data from a well-studied ADE site in the Brazilian Amazon, which compel us to reconsider its anthropic origin. The amounts of phosphorus and calcium—two of the least abundant macronutrients in the region—are orders of magnitude higher in ADE profiles than in the surrounding soil. The elevated levels of phosphorus and calcium, which are often interpreted as evidence of human activity at other sites, correlate spatially with trace elements that indicate exogenous mineral sources rather than in situ deposition. Stable isotope ratios of neodymium, strontium, and radiocarbon activity of microcharcoal particles also indicate exogenous inputs from alluvial deposition of carbon and mineral elements to ADE profiles,  beginning several thousands of years before the earliest evidence of soil management for plant cultivation in the region. Our data suggest that indigenous peoples harnessed natural processes of landscape formation, which led to the unique properties of ADEs, but were not responsible for their genesis. If corroborated elsewhere, this hypothesis would transform our understanding of human influence in Amazonia, opening new frontiers for the sustainable use of tropical landscapes going forward.
p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response
Authors: Kageyama Shun , Gudmundsson Sigurdur Runar , Sou Yu-Shin , Ichimura Yoshinobu , Tamura Naoki , Kazuno Saiko , Ueno Takashi , Miura Yoshiki , Noshiro Daisuke , Abe Manabu , Mizushima Tsunehiro , Miura Nobuaki , Okuda Shujiro , Motohashi Hozumi , Lee Jin-A , Sakimura Kenji , Ohe Tomoyuki , Noda Nobuo N. , Waguri Satoshi , Eskelinen Eeva-Liisa , Komatsu Masaaki
Published: January 2021

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress.
Structural basis for nuclear import selectivity of pioneer transcription factor SOX2
Authors: Jagga Bikshapathi , Edwards Megan , Pagin Miriam , Wagstaff Kylie M. , Aragão David , Roman Noelia , Nanson Jeffrey D. , Raidal Shane R. , Dominado Nicole , Stewart Murray , Jans David A. , Hime Gary R. , Nicolis Silvia K. , Basler Christopher F. , Forwood Jade K.
Published: January 2021

SOX (SRY-related HMG-box) transcription factors perform critical functions in development and cell differentiation. These roles depend on precise nuclear trafficking, with mutations in the nuclear targeting regions causing developmental diseases and a range of cancers. SOX protein nuclear localization is proposed to be mediated by two nuclear localization signals (NLSs) positioned within the extremities of the DNA-binding HMG-box domain and, although mutations within either cause disease, the mechanistic basis has remained unclear. Unexpectedly, we find here that these two distantly positioned NLSs of SOX2 contribute to a contiguous interface spanning 9 of the 10 ARM domains on the nuclear import adapter IMPα3. We identify key binding determinants and show this interface is critical for neural stem cell maintenance and for Drosophila development. Moreover, we identify a structural basis for the preference of SOX2 binding to IMPα3. In addition to defining the structural basis for SOX protein localization, these results provide a platform for understanding how mutations and post-translational modifications within these regions may modulate nuclear localization and result in clinical disease, and also how other proteins containing multiple NLSs may bind IMPα through an extended recognition interface.
Long-read metagenomics using PromethION uncovers oral bacteriophages and their interaction with host bacteria
Authors: Yahara Koji , Suzuki Masato , Hirabayashi Aki , Suda Wataru , Hattori Masahira , Suzuki Yutaka , Okazaki Yusuke
Published: January 2021

Bacteriophages (phages), or bacterial viruses, are very diverse and highly abundant worldwide, including as a part of the human microbiomes. Although a few metagenomic studies have focused on oral phages, they relied on short-read sequencing. Here, we conduct a long-read metagenomic study of human saliva using PromethION. Our analyses, which integrate both PromethION and HiSeq data of >30 Gb per sample with low human DNA contamination, identify hundreds of viral contigs; 0–43.8% and 12.5–56.3% of the confidently predicted phages and prophages, respectively, do not cluster with those reported previously. Our analyses demonstrate enhanced scaffolding, and the ability to place a prophage in its host genomic context and enable its taxonomic classification. Our analyses also identify a Streptococcus phage/prophage group and nine jumbo phages/prophages. 86% of the phage/prophage group and 67% of the jumbo phages/prophages contain remote homologs of antimicrobial resistance genes. Pan-genome analysis of the phages/prophages reveals remarkable diversity, identifying 0.3% and 86.4% of the genes as core and singletons, respectively. Furthermore, our study suggests that oral phages present in human saliva are under selective pressure to escape CRISPR immunity. Our study demonstrates the power of long-read metagenomics utilizing PromethION in uncovering bacteriophages and their interaction with host bacteria.
The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation
Authors: Fan Guangjian , Sun Lianhui , Meng Ling , Hu Chen , Wang Xing , Shi Zhan , Hu Congli , Han Yang , Yang Qingqing , Cao Liu , Zhang Xiaohong , Zhang Yan , Song Xianmin , Xia Shujie , He Baokun , Zhang Shengping , Wang Chuangui
Published: January 2021

Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.
Effectively modulating thermal activated charge transport in organic semiconductors by precise potential barrier engineering
Authors: Huang Yinan , Gong Xue , Meng Yancheng , Wang Zhongwu , Chen Xiaosong , Li Jie , Ji Deyang , Wei Zhongming , Li Liqiang , Hu Wenping
Published: January 2021

The temperature dependence of charge transport dramatically affects and even determines the properties and applications of organic semiconductors, but is challenging to effectively modulate. Here, we develop a strategy to circumvent this challenge through precisely tuning the effective height of the potential barrier of the grain boundary (i.e., potential barrier engineering). This strategy shows that the charge transport exhibits strong temperature dependence when effective potential barrier height reaches maximum at a grain size near to twice the Debye length, and that larger or smaller grain sizes both reduce effective potential barrier height, rendering devices relatively thermostable. Significantly, through this strategy a traditional thermo-stable organic semiconductor (dinaphtho[2,3-b:2′,3′-f]thieno[3,2-b]thiophene, DNTT) achieves a high thermo-sensitivity (relative current change) of 155, which is far larger than what is expected from a standard thermally-activated carrier transport. As demonstrations, we show that thermo-sensitive OFETs perform as highly sensitive temperature sensors.
Analysing the mechanism of mitochondrial oxidation-induced cell death using a multifunctional iridium(III) photosensitiser
Authors: Lee Chaiheon , Nam Jung Seung , Lee Chae Gyu , Park Mingyu , Yoo Chang-Mo , Rhee Hyun-Woo , Seo Jeong Kon , Kwon Tae-Hyuk
Published: January 2021

Mitochondrial oxidation-induced cell death, a physiological process triggered by various cancer therapeutics to induce oxidative stress on tumours, has been challenging to investigate owing to the difficulties in generating mitochondria-specific oxidative stress and monitoring mitochondrial responses simultaneously. Accordingly, to the best of our knowledge, the relationship between mitochondrial protein oxidation via oxidative stress and the subsequent cell death-related biological phenomena has not been defined. Here, we developed a multifunctional iridium(III) photosensitiser, Ir-OA, capable of inducing substantial mitochondrial oxidative stress and monitoring the corresponding change in viscosity, polarity, and morphology. Photoactivation of Ir-OA triggers chemical modifications in mitochondrial protein-crosslinking and oxidation (i.e., oxidative phosphorylation complexes and channel and translocase proteins), leading to microenvironment changes, such as increased microviscosity and depolarisation. These changes are strongly related to cell death by inducing mitochondrial swelling with excessive fission and fusion. We suggest a potential mechanism from mitochondrial oxidative stress to cell death based on proteomic analyses and phenomenological observations.
Psychological characteristics associated with COVID-19 vaccine hesitancy and resistance in Ireland and the United Kingdom
Authors: Murphy Jamie , Vallières Frédérique , Bentall Richard P. , Shevlin Mark , McBride Orla , Hartman Todd K. , McKay Ryan , Bennett Kate , Mason Liam , Gibson-Miller Jilly , Levita Liat , Martinez Anton P. , Stocks Thomas V. A. , Karatzias Thanos , Hyland Philip
Published: January 2021

Identifying and understanding COVID-19 vaccine hesitancy within distinct populations may aid future public health messaging. Using nationally representative data from the general adult populations of Ireland (N = 1041) and the United Kingdom (UK; N = 2025), we found that vaccine hesitancy/resistance was evident for 35% and 31% of these populations respectively. Vaccine hesitant/resistant respondents in Ireland and the UK differed on a number of sociodemographic and health-related variables but were similar across a broad array of psychological constructs. In both populations, those resistant to a COVID-19 vaccine were less likely to obtain information about the pandemic from traditional and authoritative sources and had similar levels of mistrust in these sources compared to vaccine accepting respondents. Given the geographical proximity and socio-economic similarity of the populations studied, it is not possible to generalize findings to other populations, however, the methodology employed here may be useful to those wishing to understand COVID-19 vaccine hesitancy elsewhere.
Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex
Authors: Jamann Nora , Dannehl Dominik , Lehmann Nadja , Wagener Robin , Thielemann Corinna , Schultz Christian , Staiger Jochen , Kole Maarten H. P. , Engelhardt Maren
Published: January 2021

The axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when network states change, whether it acts in vivo as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using the mouse whisker-to-barrel pathway as a model system in combination with immunofluorescence, confocal analysis and electrophysiological recordings, we observed bidirectional AIS plasticity in cortical pyramidal neurons. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: Long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapid AIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal input-output relations.
Biomimetic caged platinum catalyst for hydrosilylation reaction with high site selectivity
Authors: Pan Ganghuo , Hu Chunhua , Hong Song , Li Huaping , Yu Dongdong , Cui Chengqian , Li Qiaosheng , Liang Nianjie , Jiang Ying , Zheng Lirong , Jiang Lei , Liu Yuzhou
Published: January 2021

Natural enzymes exhibit unparalleled selectivity due to the microenvironment around the active sites, but how to design artificial catalysts to achieve similar performance is a formidable challenge for the catalysis community. Herein, we report that a less selective platinum catalyst becomes highly active and selective for industrially relevant hydrosilylation of a broad range of substrates when a porous cage ligand is used for confinement around the catalytic active site. The catalyst is more than ten times more active than Karstedt’s catalyst while being recyclable. Properties such as size-selective catalysis and Michaelis-Menten kinetics support the proposed enzyme-like model. This biomimetic catalyst exhibits remarkable site-selectivity through the cage’s confining effect, which amplifies small steric differences into dramatic reactivity changes for similar functional groups within a molecule.
Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease
Authors: Zhang Fen , Zuo Tao , Yeoh Yun Kit , Cheng Frankie W. T. , Liu Qin , Tang Whitney , Cheung Kitty C. Y. , Yang Keli , Cheung Chun Pan , Mo Chow Chung , Hui Mamie , Chan Francis K. L. , Li Chi-Kong , Chan Paul K. S. , Ng Siew C.
Published: January 2021

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.
Neutralizing antibody titres in SARS-CoV-2 infections
Authors: Lau Eric H. Y. , Tsang Owen T. Y. , Hui David S. C. , Kwan Mike Y. W. , Chan Wai-hung , Chiu Susan S. , Ko Ronald L. W. , Chan Kin H. , Cheng Samuel M. S. , Perera Ranawaka A. P. M. , Cowling Benjamin J. , Poon Leo L. M. , Peiris Malik
Published: January 2021

The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT90) and 50% (PRNT50) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT50 titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT50 antibody titres to decrease by half (T1/2) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT90 and PRNT50 antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.
Multi-domain translation between single-cell imaging and sequencing data using autoencoders
Authors: Yang Karren Dai , Belyaeva Anastasiya , Venkatachalapathy Saradha , Damodaran Karthik , Katcoff Abigail , Radhakrishnan Adityanarayanan , Shivashankar G. V. , Uhler Caroline
Published: January 2021

The development of single-cell methods for capturing different data modalities including imaging and sequencing has revolutionized our ability to identify heterogeneous cell states. Different data modalities provide different perspectives on a population of cells, and their integration is critical for studying cellular heterogeneity and its function. While various methods have been proposed to integrate different sequencing data modalities, coupling imaging and sequencing has been an open challenge. We here present an approach for integrating vastly different modalities by learning a probabilistic coupling between the different data modalities using autoencoders to map to a shared latent space. We validate this approach by integrating single-cell RNA-seq and chromatin images to identify distinct subpopulations of human naive CD4+ T-cells that are poised for activation. Collectively, our approach provides a framework to integrate and translate between data modalities that cannot yet be measured within the same cell for diverse applications in biomedical discovery.
Strain-stabilized superconductivity
Authors: Ruf J. P. , Paik H. , Schreiber N. J. , Nair H. P. , Miao L. , Kawasaki J. K. , Nelson J. N. , Faeth B. D. , Lee Y. , Goodge B. H. , Pamuk B. , Fennie C. J. , Kourkoutis L. F. , Schlom D. G. , Shen K. M.
Published: January 2021

Superconductivity is among the most fascinating and well-studied quantum states of matter. Despite over 100 years of research, a detailed understanding of how features of the normal-state electronic structure determine superconducting properties has remained elusive. For instance, the ability to deterministically enhance the superconducting transition temperature by design, rather than by serendipity, has been a long sought-after goal in condensed matter physics and materials science, but achieving this objective may require new tools, techniques and approaches. Here, we report the transmutation of a normal metal into a superconductor through the application of epitaxial strain. We demonstrate that synthesizing RuO2 thin films on (110)-oriented TiO2 substrates enhances the density of states near the Fermi level, which stabilizes superconductivity under strain, and suggests that a promising strategy to create new transition-metal superconductors is to apply judiciously chosen anisotropic strains that redistribute carriers within the low-energy manifold of d orbitals.
A RAC-GEF network critical for early intestinal tumourigenesis
Authors: Pickering K. A. , Gilroy K. , Cassidy J. W. , Fey S. K. , Najumudeen A. K. , Zeiger L. B. , Vincent D. F. , Gay D. M. , Johansson J. , Fordham R. P. , Miller B. , Clark W. , Hedley A. , Unal E. B. , Kiel C. , McGhee E. , Machesky L. M. , Nixon C. , Johnsson A. E. , Bain M. , Strathdee D. , van Hoof S. R. , Medema J. P. , Anderson K. I. , Brachmann S. M. , Stucke V. M. , Malliri A. , Drysdale M. , Turner M. , Serrano L. , Myant K. , Campbell A. D. , Sansom O. J.
Published: January 2021

RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor geneApcin the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling ofApcdeficient intestinal tissue identifiedVav3andTiam1as key targets. Deletion of these indicated that while TIAM1 deficiency could suppressApc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation ofVav2, with subsequent targeting of all three (Vav2−/−Vav3−/−Tiam1−/−), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia
Authors: Lei Hu , Xu Han-Zhang , Shan Hui-Zhuang , Liu Meng , Lu Ying , Fang Zhi-Xiao , Jin Jin , Jing Bo , Xiao Xin-Hua , Gao Shen-Meng , Gao Feng-Hou , Xia Li , Yang Li , Liu Li-Gen , Wang Wei-Wei , Liu Chuan-Xu , Tong Yin , Wu Yun-Zhao , Zheng Jun-Ke , Chen Guo-Qiang , Zhou Li , Wu Ying-Li
Published: January 2021

Identifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.
Rapid parallel adaptation despite gene flow in silent crickets
Authors: Zhang Xiao , Rayner Jack G. , Blaxter Mark , Bailey Nathan W.
Published: January 2021

Gene flow is predicted to impede parallel adaptation via de novo mutation, because it can introduce pre-existing adaptive alleles from population to population. We test this using Hawaiian crickets (Teleogryllus oceanicus) in which ‘flatwing’ males that lack sound-producing wing structures recently arose and spread under selection from an acoustically-orienting parasitoid. Morphometric and genetic comparisons identify distinct flatwing phenotypes in populations on three islands, localized to different loci. Nevertheless, we detect strong, recent and ongoing gene flow among the populations. Using genome scans and gene expression analysis we find that parallel evolution of flatwing on different islands is associated with shared genomic hotspots of adaptation that contain the genedoublesex, but the form of selection differs among islands and corresponds to known flatwing demographics in the wild. We thus show how parallel adaptation can occur on contemporary timescales despite gene flow, indicating that it could be less constrained than previously appreciated.
Synthesis of bio-based methylcyclopentadiene via direct hydrodeoxygenation of 3-methylcyclopent-2-enone derived from cellulose
Authors: Liu Yanting , Wang Ran , Qi Haifeng , Liu Xiao Yan , Li Guangyi , Wang Aiqin , Wang Xiaodong , Cong Yu , Zhang Tao , Li Ning
Published: January 2021

The exploration of highly efficient processes to convert renewable biomass to fuels and value-added chemicals is stimulated by the energy and environment problems. Herein, we describe an innovative route for the production of methylcyclopentadiene (MCPD) with cellulose, involving the transformation of cellulose into 3-methylcyclopent-2-enone (MCP) and subsequent selective hydrodeoxygenation to MCPD over a zinc-molybdenum oxide catalyst. The excellent performance of the zinc-molybdenum oxide catalyst is attributed to the formation of ZnMoO3 species during the reduction of ZnMoO4. Experiments reveal that preferential interaction of ZnMoO3 sites with the C=O bond instead of C=C bond in vapor-phase hydrodeoxygenation of MCP leads to highly selective formations of MCPD (with a carbon yield of 70%).
Three-phase electric power driven electroluminescent devices
Authors: Ji Junpeng , Perepichka Igor F. , Bai Junwu , Hu Dan , Xu Xiuru , Liu Ming , Wang Tao , Zhao Changbin , Meng Hong , Huang Wei
Published: January 2021

Current power supply networks across the world are mostly based on three-phase electrical systems as an efficient and economical way for generation, transmission and distribution of electricity. Now, many electrically driven devices are relying on direct current or single-phase alternating current power supply that complicates utilization of three-phase power supply by requiring additional elements and costly switching mechanisms in the circuits. For example, light-emitting devices, which are now widely used for displays, solid-state lighting etc. typically operate with direct current power sources, although single-phase alternating current driven light-emitting devices have also gained significant attention in the recent years. Yet, light-emitting devices directly driven by a three-phase electric power has never been reported before. Benefiting from our precious work on coplanar electrodes structured light-emitting devices, in this article we demonstrate proof of a concept that light-emitting components can be driven by three-phase electric power without utilizing intricate back-end circuits and can compose state detection sensors and pixel units in a single device inspiring from three primary colors. Here we report a three-phase electric power driven electroluminescent devices fabricated featuring of flexibility and multi-functions. The design consists of three coplanar electrodes with dielectric layer(s) and light emission layer(s) coated on a top of input electrodes. It does not require transparent electrodes for electrical input and the light emission occurs when the top light-emitting layers are connected through a polar bridge. We demonstrate some applications of our three-phase electric power driven electroluminescent devices to realize pixel units, interactive rewritable displays and optical-output sensors. Furthermore, we also demonstrate the applicability of three-phase electrical power source to drive organic light-emitting devices with red, green and blue-emitting pixels and have shown high luminance (up to 6601 cd/m2) and current efficiency (up to 16.2 cd/A) from fabricated three-phase organic light-emitting devices. This novel geometry and driving method for electroluminescent devices is scalable and can be utilized even in a wider range of other types of light-emitting devices and special units.
Nanoelectromechanical modulation of a strongly-coupled plasmonic dimer
Authors: Song Jung-Hwan , Raza Søren , van de Groep Jorik , Kang Ju-Hyung , Li Qitong , Kik Pieter G. , Brongersma Mark L.
Published: January 2021

The ability of two nearly-touching plasmonic nanoparticles to squeeze light into a nanometer gap has provided a myriad of fundamental insights into light–matter interaction. In this work, we construct a nanoelectromechanical system (NEMS) that capitalizes on the unique, singular behavior that arises at sub-nanometer particle-spacings to create an electro-optical modulator. Using in situ electron energy loss spectroscopy in a transmission electron microscope, we map the spectral and spatial changes in the plasmonic modes as they hybridize and evolve from a weak to a strong coupling regime. In the strongly-coupled regime, we observe a very large mechanical tunability (~250 meV/nm) of the bonding-dipole plasmon resonance of the dimer at ~1 nm gap spacing, right before detrimental quantum effects set in. We leverage our findings to realize a prototype NEMS light-intensity modulator operating at ~10 MHz and with a power consumption of only 4 fJ/bit.
Unified divergent strategy towards the total synthesis of the three sub-classes of hasubanan alkaloids
Authors: Li Guang , Wang Qian , Zhu Jieping
Published: January 2021

Elegant asymmetric synthesis of hasubanan alkaloids have been developed over the past decades. However, a divergent approach leading to all three sub-classes of this family of natural products remains unknown. We report herein the realization of such an endeavor by accomplishing enantioselective total syntheses of four representative members. The synthesis is characterized by catalytic enantioselective construction of the tricyclic compounds from which three different intramolecular C-N bond forming processes leading to three topologically different hasubanan alkaloids are developed. An aza-Michael addition is used for the construction of the aza-[4.4.3]-propellane structure of (-)-cepharamine, whereas an oxidation/double deprotection/intramolecular hemiaminal forming sequence is developed to forge the bridged 6/6/6/6 tetracycle of (-)-cepharatines A and C and a domino bromination/double deprotection/cyclization sequence allows the build-up of the 6/6/5/5 fused tetracyclic structure of (−)-sinoracutine.
Chain-like gold nanoparticle clusters for multimodal photoacoustic microscopy and optical coherence tomography enhanced molecular imaging
Authors: Nguyen Van Phuc , Qian Wei , Li Yanxiu , Liu Bing , Aaberg Michael , Henry Jessica , Zhang Wei , Wang Xueding , Paulus Yannis M.
Published: January 2021

Colloidal gold nanoparticles (GNPs) serve as promising contrast agents in photoacoustic (PA) imaging, yet their utility is limited due to their absorption peak in the visible window overlapping with that of hemoglobin. To overcome such limitation, this report describes an ultrapure chain-like gold nanoparticle (CGNP) clusters with a redshift peak wavelength at 650 nm. The synthesized CGNP show an excellent biocompatibility and photostability. These nanoparticles are conjugated with arginine-glycine-aspartic acid (RGD) peptides (CGNP clusters-RGD) and validated in 12 living rabbits to perform multimodal photoacoustic microscopy (PAM) and optical coherence tomography (OCT) for visualization of newly developed blood vessels in the sub-retinal pigment epithelium (RPE) space of the retina, named choroidal neovascularization (CNV). The PAM system can achieve a 3D PAM image via a raster scan of 256 × 256 pixels within a time duration of 65 s. Intravenous injection of CGNP clusters-RGD bound to CNV and resulted in up to a 17-fold increase in PAM signal and 176% increase in OCT signal. Histology indicates that CGNP clusters could disassemble, which may facilitate its clearance from the body.
Site-specific incorporation of citrulline into proteins in mammalian cells
Authors: Mondal Santanu , Wang Shu , Zheng Yunan , Sen Sudeshna , Chatterjee Abhishek , Thompson Paul R.
Published: January 2021

Citrullination is a post-translational modification (PTM) of arginine that is crucial for several physiological processes, including gene regulation and neutrophil extracellular trap formation. Despite recent advances, studies of protein citrullination remain challenging due to the difficulty of accessing proteins homogeneously citrullinated at a specific site. Herein, we report a technology that enables the site-specific incorporation of citrulline (Cit) into proteins in mammalian cells. This approach exploits an engineered E. coli-derived leucyl tRNA synthetase-tRNA pair that incorporates a photocaged-citrulline (SM60) into proteins in response to a nonsense codon. Subsequently, SM60 is readily converted to Cit with light in vitro and in living cells. To demonstrate the utility of the method, we biochemically characterize the effect of incorporating Cit at two known autocitrullination sites in Protein Arginine Deiminase 4 (PAD4, R372 and R374) and show that the R372Cit and R374Cit mutants are 181- and 9-fold less active than the wild-type enzyme. This technology possesses the potential to decipher the biology of citrullination.
Functional THz emitters based on Pancharatnam-Berry phase nonlinear metasurfaces
Authors: McDonnell Cormac , Deng Junhong , Sideris Symeon , Ellenbogen Tal , Li Guixin
Published: January 2021

Recent advances in the science and technology of THz waves show promise for a wide variety of important applications in material inspection, imaging, and biomedical science amongst others. However, this promise is impeded by the lack of sufficiently functional THz emitters. Here, we introduce broadband THz emitters based on Pancharatnam-Berry phase nonlinear metasurfaces, which exhibit unique optical functionalities. Using these new emitters, we experimentally demonstrate tunable linear polarization of broadband single cycle THz pulses, the splitting of spin states and THz frequencies in the spatial domain, and the generation of few-cycle pulses with temporal polarization dispersion. Finally, we apply the ability of spin control of THz waves to demonstrate circular dichroism spectroscopy of amino acids. Altogether, we achieve nanoscale and all-optical control over the phase and polarization states of the emitted THz waves.