bluuebunny/crossref_metadata_2025 huggingface dataset:
New directions for emerging therapies in acute myeloid leukemia: the next chapter
Authors: Daver Naval , Wei Andrew H. , Pollyea Daniel A. , Fathi Amir T. , Vyas Paresh , DiNardo Courtney D.
Published: October 2020

Conventional therapy for acute myeloid leukemia is composed of remission induction with cytarabine- and anthracycline-containing regimens, followed by consolidation therapy, including allogeneic stem cell transplantation, to prolong remission. In recent years, there has been a significant shift toward the use of novel and effective, target-directed therapies, including inhibitors of mutant FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase (IDH), the B-cell lymphoma 2 inhibitor venetoclax, and the hedgehog pathway inhibitor glasdegib. In older patients the combination of a hypomethylating agent or low-dose cytarabine, venetoclax achieved composite response rates that approximate those seen with standard induction regimens in similar populations, but with potentially less toxicity and early mortality. Preclinical data suggest synergy between venetoclax and FLT3- and IDH-targeted therapies, and doublets of venetoclax with inhibitors targeting these mutations have shown promising clinical activity in early stage trials. Triplet regimens involving the hypomethylating agent and venetoclax with FLT3 or IDH1/2 inhibitor, the TP53-modulating agent APR-246 and magrolimab, myeloid cell leukemia-1 inhibitors, or immune therapies such as CD123 antibody-drug conjugates and programmed cell death protein 1 inhibitors are currently being evaluated. It is hoped that such triplets, when applied in appropriate patient subsets, will further enhance remission rates, and more importantly remission durations and survival.
Correction: Overactivated sonic hedgehog signaling aggravates intrauterine adhesion via inhibiting autophagy in endometrial stromal cells
Authors: Wei Cheng , Pan Yibin , Zhang Yinli , Dai Yongdong , Jiang Lingling , Shi Libing , Yang Weijie , Xu Shiqian , Zhang Yingyi , Xu Wenzhi , Zhang Yanling , Lin Xiaona , Zhang Songying
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Age-related cerebral small vessel disease and inflammaging
Authors: Li Tiemei , Huang Yinong , Cai Wei , Chen Xiaodong , Men Xuejiao , Lu Tingting , Wu Aiming , Lu Zhengqi
Published: October 2020

The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of “inflammaging” has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.
Role of export industries on ozone pollution and its precursors in China
Authors: Ou Jiamin , Huang Zhijiong , Klimont Zbigniew , Jia Guanglin , Zhang Shaohui , Li Cheng , Meng Jing , Mi Zhifu , Zheng Heran , Shan Yuli , Louie Peter K. K. , Zheng Junyu , Guan Dabo
Published: October 2020

This study seeks to estimate how global supply chain relocates emissions of tropospheric ozone precursors and its impacts in shaping ozone formation. Here we show that goods produced in China for foreign markets lead to an increase of domestic non-methane volatile organic compounds (NMVOCs) emissions by 3.5 million tons in 2013; about 13% of the national total or, equivalent to half of emissions from European Union. Production for export increases concentration of NMVOCs (including some carcinogenic species) and peak ozone levels by 20–30% and 6–15% respectively, in the coastal areas. It contributes to an estimated 16,889 (3,839–30,663, 95% CI) premature deaths annually combining the effects of NMVOCs and ozone, but could be reduced by nearly 40% by closing the technology gap between China and EU. Export demand also alters the emission ratios between NMVOCs and nitrogen oxides and hence the ozone chemistry in the east and south coast.
Gene duplication drives genome expansion in a major lineage of Thaumarchaeota
Authors: Sheridan Paul O. , Raguideau Sebastien , Quince Christopher , Holden Jennifer , Zhang Lihong ,   Thames Consortium, Gaze William H. , Holden Jennifer , Mead Andrew , Raguideau Sebastien , Quince Christopher , Singer Andrew C. , Wellington Elizabeth M. H. , Zhang Lihong , Williams Tom A. , Gubry-Rangin Cécile
Published: October 2020

Ammonia-oxidising archaea of the phylum Thaumarchaeota are important organisms in the nitrogen cycle, but the mechanisms driving their radiation into diverse ecosystems remain underexplored. Here, existing thaumarchaeotal genomes are complemented with 12 genomes belonging to the previously under-sampled Nitrososphaerales to investigate the impact of lateral gene transfer (LGT), gene duplication and loss across thaumarchaeotal evolution. We reveal a major role for gene duplication in driving genome expansion subsequent to early LGT. In particular, two large LGT events are identified into Nitrososphaerales and the fate of these gene families is highly lineage-specific, being lost in some descendant lineages, but undergoing extensive duplication in others, suggesting niche-specific roles. Notably, some genes involved in carbohydrate transport or coenzyme metabolism were duplicated, likely facilitating niche specialisation in soils and sediments. Overall, our results suggest that LGT followed by gene duplication drives Nitrososphaerales evolution, highlighting a previously under-appreciated mechanism of genome expansion in archaea.
SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks
Authors: Rageul Julie , Park Jennifer J. , Zeng Ping Ping , Lee Eun-A , Yang Jihyeon , Hwang Sunyoung , Lo Natalie , Weinheimer Alexandra S. , Schärer Orlando D. , Yeo Jung-Eun , Kim Hyungjin
Published: October 2020

Protecting replication fork integrity during DNA replication is essential for maintaining genome stability. Here, we report that SDE2, a PCNA-associated protein, plays a key role in maintaining active replication and counteracting replication stress by regulating the replication fork protection complex (FPC). SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression. Like TIM deficiency, knockdown of SDE2 leads to impaired fork progression and stalled fork recovery, along with a failure to activate CHK1 phosphorylation. Moreover, loss of SDE2 or TIM results in an excessive MRE11-dependent degradation of reversed forks. Together, our study uncovers an essential role for SDE2 in maintaining genomic integrity by stabilizing the FPC and describes a new role for TIM in protecting stalled replication forks. We propose that TIM-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization.
Hikarchaeia demonstrate an intermediate stage in the methanogen-to-halophile transition
Authors: Martijn Joran , Schön Max E. , Lind Anders E. , Vosseberg Julian , Williams Tom A. , Spang Anja , Ettema Thijs J. G.
Published: October 2020

Halobacteria (henceforth: Haloarchaea) are predominantly aerobic halophiles that are thought to have evolved from anaerobic methanogens. This remarkable transformation most likely involved an extensive influx of bacterial genes. Whether it entailed a single massive transfer event or a gradual stream of transfers remains a matter of debate. To address this, genomes that descend from methanogen-to-halophile intermediates are necessary. Here, we present five such near-complete genomes of Marine Group IV archaea (Hikarchaeia), the closest known relatives of Haloarchaea. Their inclusion in gene tree-aware ancestral reconstructions reveals an intermediate stage that had already lost a large number of genes, including nearly all of those involved in methanogenesis and the Wood-Ljungdahl pathway. In contrast, the last Haloarchaea common ancestor gained a large number of genes and expanded its aerobic respiration and salt/UV resistance gene repertoire. Our results suggest that complex and gradual patterns of gain and loss shaped the methanogen-to-halophile transition.
Molecular mechanisms underlying the extreme mechanical anisotropy of the flaviviral exoribonuclease-resistant RNAs (xrRNAs)
Authors: Niu Xiaolin , Liu Qiuhan , Xu Zhonghe , Chen Zhifeng , Xu Linghui , Xu Lilei , Li Jinghong , Fang Xianyang
Published: October 2020

Mechanical anisotropy is an essential property for many biomolecules to assume their structures, functions and applications, however, the mechanisms for their direction-dependent mechanical responses remain elusive. Herein, by using a single-molecule nanopore sensing technique, we explore the mechanisms of directional mechanical stability of the xrRNA1 RNA from ZIKA virus (ZIKV), which forms a complex ring-like architecture. We reveal extreme mechanical anisotropy in ZIKV xrRNA1 which highly depends on Mg2+ and the key tertiary interactions. The absence of Mg2+ and disruption of the key tertiary interactions strongly affect the structural integrity and attenuate mechanical anisotropy. The significance of ring structures in RNA mechanical anisotropy is further supported by steered molecular dynamics simulations in combination with force distribution analysis. We anticipate the ring structures can be used as key elements to build RNA-based nanostructures with controllable mechanical anisotropy for biomaterial and biomedical applications.
Crbn modulates calcium influx by regulating Orai1 during efferocytosis
Authors: Moon Hyunji , Min Chanhyuk , Kim Gayoung , Kim Deokhwan , Kim Kwanhyeong , Lee Sang-Ah , Moon Byeongjin , Yang Susumin , Lee Juyeon , Yang Seung-Joo , Cho Steve K. , Lee Gwangrog , Lee Chang Sup , Park Chul-Seung , Park Daeho
Published: October 2020

Calcium flux regulating intracellular calcium levels is essential and modulated for efficient efferocytosis. However, the molecular mechanism by which calcium flux is modulated during efferocytosis remains elusive. Here, we report that Orai1, a Crbn substrate, is upregulated via its attenuated interaction with Crbn during efferocytosis, which increases calcium influx into phagocytes and thereby promotes efferocytosis. We found that Crbn deficiency promoted phagocytosis of apoptotic cells, which resulted from facilitated phagocytic cup closure and was nullified by a CRAC channel inhibitor. In addition, Orai1 associated with Crbn, resulting in ubiquitination and proteasomal degradation of Orai1 and alteration of SOCE-mediated calcium influx. The association of Orai1 with Crbn was attenuated during efferocytosis, leading to reduced ubiquitination of Orai1 and consequently upregulation of Orai1 and calcium influx. Collectively, our study reveals a regulatory mechanism by which calcium influx is modulated by a Crbn-Orai1 axis to facilitate efferocytosis.
Proline rich 11 (PRR11) overexpression amplifies PI3K signaling and promotes antiestrogen resistance in breast cancer
Authors: Lee Kyung-min , Guerrero-Zotano Angel L. , Servetto Alberto , Sudhan Dhivya R. , Lin Chang-Ching , Formisano Luigi , Jansen Valerie M. , González-Ericsson Paula , Sanders Melinda E. , Stricker Thomas P. , Raj Ganesh , Dean Kevin M. , Fiolka Reto , Cantley Lewis C. , Hanker Ariella B. , Arteaga Carlos L.
Published: October 2020

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.
Control of single-ligand chemistry on thiolated Au25 nanoclusters
Authors: Cao Yitao , Fung Victor , Yao Qiaofeng , Chen Tiankai , Zang Shuangquan , Jiang De-en , Xie Jianping
Published: October 2020

Diverse methods have been developed to tailor the number of metal atoms in metal nanoclusters, but control of surface ligand number at a given cluster size is rare. Here we demonstrate that reversible addition and elimination of a single surface thiolate ligand (-SR) on gold nanoclusters can be realized, opening the door to precision ligand engineering on atomically precise nanoclusters. We find that oxidative etching of [Au25SR18]− nanoclusters adds an excess thiolate ligand and generates a new species, [Au25SR19]0. The addition reaction can be reversed by CO reduction of [Au25SR19]0, leading back to [Au25SR18]− and eliminating precisely one surface ligand. Intriguingly, we show that the ligand shell of Au25 nanoclusters becomes more fragile and rigid after ligand addition. This reversible addition/elimination reaction of a single surface ligand on gold nanoclusters shows potential to precisely control the number of surface ligands and to explore new ligand space at each nuclearity.
Electron tunneling at the molecularly thin 2D perovskite and graphene van der Waals interface
Authors: Leng Kai , Wang Lin , Shao Yan , Abdelwahab Ibrahim , Grinblat Gustavo , Verzhbitskiy Ivan , Li Runlai , Cai Yongqing , Chi Xiao , Fu Wei , Song Peng , Rusydi Andrivo , Eda Goki , Maier Stefan A. , Loh Kian Ping
Published: October 2020

Quasi-two-dimensional perovskites have emerged as a new material platform for optoelectronics on account of its intrinsic stability. A major bottleneck to device performance is the high charge injection barrier caused by organic molecular layers on its basal plane, thus the best performing device currently relies on edge contact. Herein, by leveraging on van der Waals coupling and energy level matching between two-dimensional Ruddlesden-Popper perovskite and graphene, we show that the plane-contacted perovskite and graphene interface presents a lower barrier than gold for charge injection. Electron tunneling across the interface occurs via a gate-tunable, direct tunneling-to-field emission mechanism with increasing bias, and photoinduced charge transfer occurs at femtosecond timescale (~50 fs). Field effect transistors fabricated on molecularly thin Ruddlesden-Popper perovskite using graphene contact exhibit electron mobilities ranging from 0.1 to 0.018 cm2V−1s−1 between 1.7 to 200 K. Scanning tunneling spectroscopy studies reveal layer-dependent tunneling barrier and domain size on few-layered Ruddlesden-Popper perovskite.
Sequential generation of linear cluster states from a single photon emitter
Authors: Istrati D. , Pilnyak Y. , Loredo J. C. , Antón C. , Somaschi N. , Hilaire P. , Ollivier H. , Esmann M. , Cohen L. , Vidro L. , Millet C. , Lemaître A. , Sagnes I. , Harouri A. , Lanco L. , Senellart P. , Eisenberg H. S.
Published: October 2020

Light states composed of multiple entangled photons—such as cluster states—are essential for developing and scaling-up quantum computing networks. Photonic cluster states can be obtained from single-photon sources and entangling gates, but so far this has only been done with probabilistic sources constrained to intrinsically low efficiencies, and an increasing hardware overhead. Here, we report the resource-efficient generation of polarization-encoded, individually-addressable photons in linear cluster states occupying a single spatial mode. We employ a single entangling-gate in a fiber loop configuration to sequentially entangle an ever-growing stream of photons originating from the currently most efficient single-photon source technology—a semiconductor quantum dot. With this apparatus, we demonstrate the generation of linear cluster states up to four photons in a single-mode fiber. The reported architecture can be programmed for linear-cluster states of any number of photons, that are required for photonic one-way quantum computing schemes.
Optimized design of single-cell RNA sequencing experiments for cell-type-specific eQTL analysis
Authors: Mandric Igor , Schwarz Tommer , Majumdar Arunabha , Hou Kangcheng , Briscoe Leah , Perez Richard , Subramaniam Meena , Hafemeister Christoph , Satija Rahul , Ye Chun Jimmie , Pasaniuc Bogdan , Halperin Eran
Published: October 2020

Single-cell RNA-sequencing (scRNA-Seq) is a compelling approach to directly and simultaneously measure cellular composition and state, which can otherwise only be estimated by applying deconvolution methods to bulk RNA-Seq estimates. However, it has not yet become a widely used tool in population-scale analyses, due to its prohibitively high cost. Here we show that given the same budget, the statistical power of cell-type-specific expression quantitative trait loci (eQTL) mapping can be increased through low-coverage per-cell sequencing of more samples rather than high-coverage sequencing of fewer samples. We use simulations starting from one of the largest available real single-cell RNA-Seq data from 120 individuals to also show that multiple experimental designs with different numbers of samples, cells per sample and reads per cell could have similar statistical power, and choosing an appropriate design can yield large cost savings especially when multiplexed workflows are considered. Finally, we provide a practical approach on selecting cost-effective designs for maximizing cell-type-specific eQTL power which is available in the form of a web tool.
Regioselective Markovnikov hydrodifluoroalkylation of alkenes using difluoroenoxysilanes
Authors: Hu Xiao-Si , He Jun-Xiong , Dong Su-Zhen , Zhao Qiu-Hua , Yu Jin-Sheng , Zhou Jian
Published: October 2020

Alkene hydrodifluoroalkylation is a fruitful strategy for synthesizing difluoromethylated compounds that are interesting for developing new medicinal agents, agrochemicals, and advanced materials. Whereas the anti-Markovnikov hydrodifluoroalkylation to linear-type products is developed, employing radical-based processes, the Markovnikov synthesis of branched adducts remains unexplored. Herein, we describe acid-catalyzed processes involving carbocation intermediates as a promising strategy to secure the Markovnikov regioselectivity. Accordingly, the Markovnikov hydrodifluoroalkylation of mono-, di-, tri-, and tetrasubstituted alkenes using difluoroenoxysilanes, catalyzed by Mg(ClO4)2·6H2O, is achieved. This allows the diversity-oriented synthesis of α,α-difluoroketones with a quaternary or tertiary carbon at the β-position that are otherwise difficult to access. The method is applied to the modification of natural products and drug derivatives. The resulting α,α-difluorinated ketones could be converted to the corresponding α,α-difluorinated esters or alcohols, or organofluorine compounds featuring a CF2H or CF2CF2Ph moiety. Mechanistic studies support that Mg(ClO4)2·6H2O functions as a hidden Brønsted acid catalyst.
Engineered lactobacilli display anti-biofilm and growth suppressing activities against Pseudomonas aeruginosa
Authors: Chappell Todd C. , Nair Nikhil U.
Published: October 2020

Biofilms are an emerging target for new therapeutics in the effort to address the continued increase in resistance and tolerance to traditional antimicrobials. In particular, the distinct nature of the biofilm growth state often means that traditional antimcirobials, developed to combat planktonic cells, are ineffective. Biofilm treatments are designed to both reduce pathogen load at an infection site and decrease the development of resistance by rendering the embedded organisms more susceptible to treatment at lower antimicrobial concentrations. In this work, we developed a new antimicrobial treatment modality using engineered lactic acid bacteria (LAB). We first characterized the natural capacity of two lactobacilli, L. plantarum and L. rhamnosus, to inhibit P. aeruginosa growth, biofilm formation, and biofilm viability, which we found to be dependent upon the low pH generated during culture of the LAB. We further engineered these LAB to secrete enzymes known to degrade P. aeruginosa biofilms and show that our best performing engineered LAB, secreting a pathogen-derived enzyme (PelAh), degrades up to 85% of P. aeruginosa biofilm.
Bio-priming with a hypovirulent phytopathogenic fungus enhances the connection and strength of microbial interaction network in rapeseed
Authors: Qu Zheng , Zhao Huizhang , Zhang Hongxiang , Wang Qianqian , Yao Yao , Cheng Jiasen , Lin Yang , Xie Jiatao , Fu Yanping , Jiang Daohong
Published: October 2020

Plant disease is one of the most important causes of crop losses worldwide. The effective control of plant disease is related to food security.Sclerotiniastem rot (SSR) caused bySclerotinia sclerotiorumleads to serious yield losses in rapeseed (Brassica napus) production. Hypovirulent strain DT-8 ofS. sclerotiorum, infected with Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 (SsHADV-1), has the potential to control SSR. In this study, we found rapeseed bio-priming with strain DT-8 could significantly decrease the disease severity of SSR and increase yield in the field. After bio-priming, strain DT-8 could be detected on the aerial part of the rapeseed plant. By 16S rRNA gene and internal transcribed spacer (ITS) sequencing technique, the microbiome on different parts of the SSR lesion on bioprimed and non-bioprimed rapeseed stem was determined. The results indicated that SSR and bio-priming treatment could influence the structure and composition of fungal and bacterial communities. Bio-priming treatment could reduce the total abundance of possible plant pathogens and enhance the connectivity and robustness of the interaction network at the genus level. This might be one of the mechanisms that rapeseed bioprimed with strain DT-8 had excellent tolerance on SSR. It might be another possible mechanism of biocontrol and will provide a theoretical guide for agricultural practical production.
Electrochemical drag effect on grain boundary motion in ionic ceramics
Authors: Vikrant K. S. N. , Rheinheimer Wolfgang , García R. Edwin
Published: October 2020

The effects of drag imposed by extrinsic ionic species and point defects on the grain boundary motion of ionic polycrystalline ceramics were quantified for the generality of electrical, chemical, or structural driving forces. In the absence of, or for small driving forces, the extended electrochemical grain boundary remains pinned and symmetrically distributed about the structural interface. As the grain boundary begins to move, charged defects accumulate unsymmetrically about the structural grain boundary core. Above the critical driving force for motion, grain boundaries progressively shed individual ionic species, from heavier to lighter, until they display no interfacial electrostatic charge and zero Schottky potential. Ionic p–n junction moving grain boundaries that induce a finite electrostatic potential difference across entire grains are identified for high velocity grains. The developed theory is demonstrated for Fe-doped SrTiO3. The increase in average Fe concentration and grain boundary crystallographic misorientation enhances grain boundary core segregation and results in thick space charge layers, which leads to a stronger drag force that reduces the velocity of the interface. The developed theory sets the stage to assess the effects of externally applied fields such as temperature, electromagnetic fields, and chemical stimuli to control the grain growth for developing textured, oriented microstructures desirable for a wide range of applications.
Dysfunction in superior frontal gyrus associated with diphasic dyskinesia in Parkinson’s disease
Authors: Shen Yu-Ting , Yuan Yong-Sheng , Wang Min , Zhi Yan , Wang Jian-Wei , Wang Li-Na , Ma Ke-Wei , Si Qian-Qian , Zhang Ke-Zhong
Published: October 2020

Alterations in brain function in Parkinson’s disease (PD) patients with diphasic dyskinesia have not been investigated. We aimed to explore the alterations in regional brain function. Each of 53 levodopa (LD)-treated PD patients had two resting-state functional magnetic resonance imaging (rs-fMRI) scans in the same morning, before and after taking LD. The regional homogeneity (ReHo) approach was used to reveal local synchronization changes. Two-way factorial repeated measures analysis of covariance, with group as a between-subject factor and LD effect as a within-subject factor, was performed to explore the two main effects and interaction. Interactive analysis was used to show outcomes that combined disease status and LD effect. Spearman’s correlations were used to detect associations between interactive brain regions and severity of dyskinetic symptoms, assessed by the Unified Dyskinesia Rating Scale (UDyRS) scores, along with moderation analyses. There was no significant difference in the main group effect analysis. Significantly different clusters obtained from main LD effect analysis were in left caudate nucleus and putamen. ReHo values decreased in the caudate nucleus and increased in the putamen during the ON state after taking LD. Interaction between group and LD effect was found in left medial superior frontal gyrus (mSFG), where there were the lowest ReHo values, and was negatively correlated with UDyRS scores in the diphasic dyskinetic group during the ON state. The relationship was independent of LD dose. Abnormal local synchronization in the mSFG is closely associated with the development of diphasic dyskinesia in PD patients.
Macular vessel density and foveal avascular zone parameters in patients after acute primary angle closure determined by OCT angiography
Authors: Liu Kangcheng , Xu Huizhuo , Jiang Haibo , Wang Hua , Wang Pingbao , Xu Yi , Li Fangling , Xu Bei , Yao Xueyan , Zou Jing
Published: October 2020

This study analyzed the optical coherence tomography angiography (OCTA) macular parameters in primary angle-closure glaucoma (PACG) patients after acute primary angle closure (APAC) episodes. Thirty-three patients with 33 APAC eyes and 33 primary angle closure suspect (PACS) eyes and 33 age-matched normal subjects (controls) were enrolled. Macular vessel density (VD) in central, inner, outer and full regions and foveal avascular zone (FAZ) parameters (area, perimeter and circularity index) were compared between APAC, PACS, and control eyes. For resolved APAC eyes, the VD in each macular region was significantly lower than that in control eyes, with less central and inner macular VD than PACS eyes. The central macular VD was significantly lower in PACS eyes than in controls. There was no difference in FAZ area and perimeter between APAC, PACS, and control eyes. FAZ circularity was highest in control eyes, followed by PACS eyes, and lowest in APAC eyes. The AUC, sensitivity and specificity of FAZ circularity were 0.944, 93.9% and 84.8%, respectively, in APAC eyes and 0.881, 84.8% and 81.8%, respectively, in PACS eyes. Therefore, FAZ circularity had the best discrimination capability for detecting both APAC and PACS eyes. Macular assessment with OCTA could provide an accurate early-stage diagnostic tool for PACG.
Complex societies and the growth of the law
Authors: Katz Daniel Martin , Coupette Corinna , Beckedorf Janis , Hartung Dirk
Published: October 2020

While many informal factors influence how people interact, modern societies rely upon law as a primary mechanism to formally control human behaviour. How legal rules impact societal development depends on the interplay between two types of actors: the people who create the rules and the people to which the rules potentially apply. We hypothesise that an increasingly diverse and interconnected society might create increasingly diverse and interconnected rules, and assert that legal networks provide a useful lens through which to observe the interaction between law and society. To evaluate these propositions, we present a novel and generalizable model of statutory materials as multidimensional, time-evolving document networks. Applying this model to the federal legislation of the United States and Germany, we find impressive expansion in the size and complexity of laws over the past two and a half decades. We investigate the sources of this development using methods from network science and natural language processing. To allow for cross-country comparisons over time, based on the explicit cross-references between legal rules, we algorithmically reorganise the legislative materials of the United States and Germany into cluster families that reflect legal topics. This reorganisation reveals that the main driver behind the growth of the law in both jurisdictions is the expansion of the welfare state, backed by an expansion of the tax state. Hence, our findings highlight the power of document network analysis for understanding the evolution of law and its relationship with society.
Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis
Authors: Tabibzadeh Alireza , Tameshkel Fahimeh Safarnezhad , Moradi Yousef , Soltani Saber , Moradi-Lakeh Maziar , Ashrafi G. Hossein , Motamed Nima , Zamani Farhad , Motevalian Seyed Abbas , Panahi Mahshid , Esghaei Maryam , Ajdarkosh Hossein , Mousavi-Jarrahi Alireza , Niya Mohammad Hadi Karbalaie
Published: October 2020

The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3–8%), 12% (95% CI: 8–18%), 17% (95% CI: 14–20%), and 20% (95% CI: 5–41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14–33%) and 20% (95% CI, 17–24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
Preoperative communication with anesthetists via anesthesia service platform (ASP) helps alleviate patients’ preoperative anxiety
Authors: Peng Fei ,  Peng Tao , Yang Qiange , Liu Meihan , Chen Guangxiang , Wang Maohua
Published: October 2020

Female gender has been identified as one of the risk factors closely linked to perioperative anxiety and a lower level of satisfaction. A successful preoperative anesthesia education may improve such negative outcomes. The aim of this study was to investigate whether preoperative anesthesia education via an Anesthesia Service Platform (ASP) could reduce the anxiety levels in female patients scheduled for laparoscopic cholecystectomy under general anesthesia, and accelerate rehabilitation. A total of 222 patients scheduled for elective laparoscopic cholecystectomy were randomly assigned to the control group and the ASP group. Patients’ baseline and post-intervention psychological status was measured by the State-Trait Anxiety Inventory and General Well-Being Schedule. Pain management and recovery were assessed by VAS every 12 h for 48 h after surgery; length of stay (LOS) and postoperative analgesic consumption were also assessed. Patients in the control group experienced higher anxiety levels before surgery and had longer LOS than those in the ASP group. Patients in the ASP group had a higher general well-being score; however, they suffered more pain and consumed more analgesics after surgery. ASP is effective for preventing anxiety in female patients before laparoscopic cholecystectomy, improving patients’ general well-being levels, and shortening their LOS, but negatively influences patients’ postoperative pain levels.
Nanofluid flow containing carbon nanotubes with quartic autocatalytic chemical reaction and Thompson and Troian slip at the boundary
Authors: Ramzan Muhammad , Chung Jae Dong , Kadry Seifedine , Chu Yu-Ming , Akhtar Muhammad
Published: October 2020

A mathematical model is envisioned to discourse the impact of Thompson and Troian slip boundary in the carbon nanotubes suspended nanofluid flow near a stagnation point along an expanding/contracting surface. The water is considered as a base fluid and both types of carbon nanotubes i.e., single-wall (SWCNTs) and multi-wall (MWCNTs) are considered. The flow is taken in a Dacry-Forchheimer porous media amalgamated with quartic autocatalysis chemical reaction. Additional impacts added to the novelty of the mathematical model are the heat generation/absorption and buoyancy effect. The dimensionless variables led the envisaged mathematical model to a physical problem. The numerical solution is then found by engaging MATLAB built-in bvp4c function for non-dimensional velocity, temperature, and homogeneous-heterogeneous reactions. The validation of the proposed mathematical model is ascertained by comparing it with a published article in limiting case. An excellent consensus is accomplished in this regard. The behavior of numerous dimensionless flow variables including solid volume fraction, inertia coefficient, velocity ratio parameter, porosity parameter, slip velocity parameter, magnetic parameter, Schmidt number, and strength of homogeneous/heterogeneous reaction parameters are portrayed via graphical illustrations. Computational iterations for surface drag force are tabulated to analyze the impacts at the stretched surface. It is witnessed that the slip velocity parameter enhances the fluid stream velocity and diminishes the surface drag force. Furthermore, the concentration of the nanofluid flow is augmented for higher estimates of quartic autocatalysis chemical.
Male sexual orientation, gender nonconformity, and neural activity during mental rotations: an fMRI study
Authors: Folkierska-Żukowska Monika , Rahman Qazi , Marchewka Artur , Wypych Marek , Droździel Dawid , Sokołowski Andrzej , Dragan Wojciech Ł.
Published: October 2020

The cross-sex shift hypothesis predicts that gay men should perform more like heterosexual women on important neurocognitive tasks on which men score higher than women, such as mental rotation. Studies also suggest sex differences exist in the neural correlates of mental rotation. However, no studies have taken sexual orientation into account or considered within-group variation attributable to recalled gender nonconformity (a developmental trait reliably associated with human nonheterosexuality). We quantified the neural correlates of mental rotation by comparing two groups of gay men, gender conforming (n = 23) and gender nonconforming (n = 23), to gender conforming heterosexual men (n = 22) and women (n = 22). We observed a sex difference between heterosexual men and women in the premotor cortex/supplementary motor cortex and left medial superior frontal gyrus. We also observed a sex difference as well as a cross-sex shift in gay men who recalled being gender nonconforming as children in the right superior frontal gyrus, right angular gyrus, right amygdala/parahippocampal gyrus, and bilaterally in the middle temporal gyrus and precuneus. Thus, cross-sex shifts may be associated with underlying developmental factors which are associated with sexual orientation (such as gender nonconformity). The results also suggest that gay men should not be studied as a homogenous group.
Characterising the effect of crop species and fertilisation treatment on root fungal communities
Authors: Soonvald Liina , Loit Kaire , Runno-Paurson Eve , Astover Alar , Tedersoo Leho
Published: October 2020

Information about the root mycobiome may improve the overall quality of the plants and contribute to a valuable strategy to enhance sustainable agriculture. Therefore, we assessed differences in fungal community diversity and composition in the roots of potato, wheat and barley grown under mineral nitrogen fertilisation at five rates, with and without farmyard manure amendment. The same factorial combination of treatments has been used since 1989. Species richness and diversity, as well as community composition, of different fungal guilds were characterised using Illumina MiSeq sequencing of the ITS2 region. Crop species was the main factor determining overall fungal richness and diversity, with wheat showing the highest, and potato the lowest, richness and diversity. Pathogen diversity indices were highest in wheat plots amended with farmyard manure, whereas the lowest values were observed for potato roots. Fertilisation treatments and the interaction between crop species and fertilisation had the strongest impact on arbuscular mycorrhiza and saprotroph diversity. Crop species also determined the composition of the overall fungal community and that of fungal guilds, whereas fertilisation treatment had only a minor effect. This study highlights crop species as the main driver in shaping root fungal diversity and composition under the same environmental conditions.
First molecular examination of Vietnamese mudflat snails in the genus Naranjia Golding, Ponder & Byrne, 2007 (Gastropoda: Amphibolidae)
Authors: Saito Takumi , Prozorova Larisa , Quang Ngo Xuan , Chiba Satoshi
Published: October 2020

Maritime ecosystems in Vietnam such as mangroves and mud flats are characterized by high biodiversity. However, elements of its biodiversity remain unclear and highly threatened. In this context, the assessment of rare species is a starting point to develop effective strategies for the conservation of entire ecosystems. In this paper, we report upon cryptic amphibolid gastropods in Vietnamese mangrove forests from the Mekong Delta. The snail fauna in the mangrove forests was previously known from published literature and three museum specimens as three amphibolid species, ‘Amphibola’ burmana, A. quadrasi, Salinator fragilis and ‘S.’ quadrasi. We investigated the identities of such snails using molecular and morphological methods. The amphibolids found in this survey were identified to belong to the genus Naranjia, new for Vietnam fauna. In addition, our phylogenetic analyses suggested that the Vietnamese amphibolids were the same species as Naranjia sp. reported from Thailand, and the amphibolids have both genetic and morphological polymorphisms within the population. These findings add to the great biodiversity of Vietnamese mangrove forests and mudflats.
Brief localised monocular deprivation in adults alters binocular rivalry predominance retinotopically and reduces spatial inhibition
Authors: Han Shui’er , Alais David , MacDougall Hamish , Verstraten Frans A. J.
Published: October 2020

Short-term deprivation (2.5 h) of an eye has been shown to boost its relative ocular dominance in young adults. Here, we show that a much shorter deprivation period (3–6 min) produces a similar paradoxical boost that is retinotopic and reduces spatial inhibition on neighbouring, non-deprived areas. Partial deprivation was conducted in the left hemifield, central vision or in an annular region, later assessed with a binocular rivalry tracking procedure. Post-deprivation, dominance of the deprived eye increased when rivalling images were within the deprived retinotopic region, but not within neighbouring, non-deprived areas where dominance was dependent on the correspondence between the orientation content of the stimuli presented in the deprived and that of the stimuli presented in non-deprived areas. Together, these results accord with other deprivation studies showing V1 activity changes and reduced GABAergic inhibition.
CHA2DS2-VASc score, cerebral small vessel disease, and frailty in older patients with atrial fibrillation
Authors: Choi Jung-Yeon , Sunwoo Leonard , Kim Sun-wook , Kim Kwang-il , Kim Cheol-Ho
Published: October 2020

The CHA2DS2-VASc score is a validated predictor of ischemic stroke in atrial fibrillation (AF) patients. However, data are limited on whether the CHA2DS2-VASc score is associated with subclinical brain structural changes or physical frailty among older AF patients. We assessed the relationship between CHA2DS2-VASc scores and brain structural changes or physical frailty in AF patients without history of stroke. Overall, 117 patients completed a comprehensive geriatric assessment for physical frailty. In brain magnetic resonance imaging sub-study (n = 49), brain volume and white matter hyperintensity lesion burden were automatically quantified using the LESIONQUANT software program. Patients with high risk of CHA2DS2-VASc scores (≥ 2 in men or ≥ 3 in women) tended to be older and had more comorbidities, higher frailty index, and slower gait speed. Total white matter hyperintensity lesion burden was higher in those with high risk of CHA2DS2-VASc score than in those with intermediate risk (score of 1 in men or 2 in women) of CHA2DS2-VASc score (1.67 [interquartile range: 0.70–3.45] vs. 0.64 [0.19–1.44],p = 0.036). Cognitive function was associated with brain volume, but gait speed was related with white matter hyperintensity lesion burden. In conclusion, we showed a positive relationship between CHA2DS2-VASc scores, white matter hyperintensity lesion burden, and physical frailty in older AF patients. Subclinical brain changes associated with high CHA2DS2-VASc scores may predict physical frailty risk.
p39-associated Cdk5 activity regulates dendritic morphogenesis
Authors: Ouyang Li , Chen Yu , Wang Ye , Chen Yuewen , Fu Amy K. Y. , Fu Wing-Yu , Ip Nancy Y.
Published: October 2020

Dendrites, branched structures extending from neuronal cell soma, are specialized for processing information from other neurons. The morphogenesis of dendritic structures is spatiotemporally regulated by well-orchestrated signaling cascades. Dysregulation of these processes impacts the wiring of neuronal circuit and efficacy of neurotransmission, which contribute to the pathogeneses of neurological disorders. While Cdk5 (cyclin-dependent kinase 5) plays a critical role in neuronal dendritic development, its underlying molecular control is not fully understood. In this study, we show that p39, one of the two neuronal Cdk5 activators, is a key regulator of dendritic morphogenesis. Pyramidal neurons deficient in p39 exhibit aberrant dendritic morphology characterized by shorter length and reduced arborization, which is comparable to dendrites in Cdk5-deficient neurons. RNA sequencing analysis shows that the adaptor protein, WDFY1 (WD repeat and FYVE domain-containing 1), acts downstream of Cdk5/p39 to regulate dendritic morphogenesis. While WDFY1 is elevated in p39-deficient neurons, suppressing its expression rescues the impaired dendritic arborization. Further phosphoproteomic analysis suggests that Cdk5/p39 mediates dendritic morphogenesis by modulating various downstream signaling pathways, including PI3K/Akt-, cAMP-, or small GTPase-mediated signaling transduction pathways, thereby regulating cytoskeletal organization, protein synthesis, and protein trafficking.
Changes in peripheral immune populations during pregnancy and modulation by probiotics and ω-3 fatty acids
Authors: Forsberg A. , Abrahamsson T. R. , Nilsson L. , Ernerudh J. , Duchén K. , Jenmalm M. C.
Published: October 2020

Allergic diseases have become a major health problem, partly due to reduced microbial stimulation and a decreased dietary ω-3/ω-6 long-chain polyunsaturated fatty acid ratio. Prenatal exposures have been reported to influence allergy development, possibly induced via changes in maternal immune regulation. In a randomized double-blind placebo-controlled multicenter allergy prevention trial (PROOM-3), pregnant women were recruited at gestational week 20, and randomized to four study groups, one receiving bothL. reuterioil drops and ω-3 PUFA capsules (n = 22), the second receiving ω-3 PUFA supplementation and placebo regardingL. reuteri(n = 21), the third receivingL. reuteriand placebo regarding ω-3 PUFA (n = 22) and the fourth group receiving placebo capsules and placebo oil drops (n = 23). In this substudy, supplemental and pregnancy-related effects on maternal peripheral immune cell populations during pregnancy were assessed by flow cytometry immune phenotyping at gestational week 20, 32 and 4 days after delivery. The numbers of activated and regulatory T (Treg) cells (CD45RA−Foxp3++/CD45RA+Foxp3+) were reduced after delivery, with the lowest count in theL. reuterisupplemented group compared with the placebo group 4 days after delivery, while the ω-3 PUFA group did not differ from the placebo group. Several treatment-independent changes were observed during and after pregnancy in lymphocytes (CD4+/8+/19+/56+/45RA+/−), CD14+16+/−monocytes, and in subpopulations of T helper cells (Th) CD4+CD45RA−Tbet+(Th1) and CD4+CD45RA−RORC+(Th17) cells. In conclusion, probiotic supplementation to the mother during the second half of pregnancy resulted in immunomodulatory effects among activated and resting Treg cells. Furthermore, several systemic immune modifying effects of pregnancy were observed.
Application of peptides with an affinity for phospholipid membranes during the automated purification of extracellular vesicles
Authors: Ishida Takenori , Hashimoto Takuma , Masaki Kanako , Funabashi Hisakage , Hirota Ryuichi , Ikeda Takeshi , Tajima Hideji , Kuroda Akio
Published: October 2020

Extracellular vesicles (EVs), such as exosomes, have garnered increasing interest because of their potential clinical applications that range from diagnostics to therapeutics. The development of an automated and reproducible EV purification platform would therefore aid the introduction of EV biomarkers and therapies into the clinic. Here, we demonstrate that K8- as well as K-16 peptides (containing 8 and 16 lysine residues with dissociation constants of 102 nM and 11.6 nM for phosphatidylserine, respectively) immobilized on magnetic beads can capture small EVs (< 0.2 µm) from culture supernatants of MCF7 human breast cancer cells. Importantly, the bound EVs could be dissociated from the beads under mild conditions (e.g. 0.5 M NaCl), and the isolated EVs had the typical shapes of EVs under SEM and TEM with a mean particle size of 99 nm. Using the peptide-immobilized beads, we adapted a pre-existing bench top instrument for magnetic separation to perform automated EV purification with higher purity and yield than that obtained using the standard ultracentrifugation method.