bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide association study identifies five risk loci for pernicious anemia
Authors: Laisk Triin , Lepamets Maarja , Koel Mariann , Abner Erik ,   Estonian Biobank Research Team, Metspalu Andres , Nelis Mari , Milani Lili , Esko Tõnu , Mägi Reedik
Published: June 2021

Pernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10−24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10−8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10−16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10−8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10−9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
Authors: Cong Zhaotong , Chen Li-Nan , Ma Honglei , Zhou Qingtong , Zou Xinyu , Ye Chenyu , Dai Antao , Liu Qing , Huang Wei , Sun Xianqiang , Wang Xi , Xu Peiyu , Zhao Lihua , Xia Tian , Zhong Wenge , Yang Dehua , Eric Xu H. , Zhang Yan , Wang Ming-Wei
Published: June 2021

The glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
Multifunctional wide-angle optics and lasing based on supercell metasurfaces
Authors: Spägele Christina , Tamagnone Michele , Kazakov Dmitry , Ossiander Marcus , Piccardo Marco , Capasso Federico
Published: June 2021

Metasurfaces are arrays of subwavelength spaced nanostructures that can manipulate the amplitude, phase, and polarization of light to achieve a variety of optical functions beyond the capabilities of 3D bulk optics. However, they suffer from limited performance and efficiency when multiple functions with large deflection angles are required because the non-local interactions due to optical coupling between nanostructures are not fully considered. Here we introduce a method based on supercell metasurfaces to demonstrate multiple independent optical functions at arbitrary large deflection angles with high efficiency. In one implementation the incident laser is simultaneously diffracted into Gaussian, helical and Bessel beams over a large angular range. We then demonstrate a compact wavelength-tunable external cavity laser with arbitrary beam control capabilities – including beam shaping operations and the generation of freeform holograms. Our approach paves the way to novel methods to engineer the emission of optical sources.
Quantum billiards with correlated electrons confined in triangular transition metal dichalcogenide monolayer nanostructures
Authors: Ravnik Jan , Vaskivskyi Yevhenii , Vodeb Jaka , Aupič Polona , Vaskivskyi Igor , Golež Denis , Gerasimenko Yaroslav , Kabanov Viktor , Mihailovic Dragan
Published: June 2021

Forcing systems through fast non-equilibrium phase transitions offers the opportunity to study new states of quantum matter that self-assemble in their wake. Here we study the quantum interference effects of correlated electrons confined in monolayer quantum nanostructures, created by femtosecond laser-induced quench through a first-order polytype structural transition in a layered transition-metal dichalcogenide material. Scanning tunnelling microscopy of the electrons confined within equilateral triangles, whose dimensions are a few crystal unit cells on the side, reveals that the trajectories are strongly modified from free-electron states both by electronic correlations and confinement. Comparison of experiments with theoretical predictions of strongly correlated electron behaviour reveals that the confining geometry destabilizes the Wigner/Mott crystal ground state, resulting in mixed itinerant and correlation-localized states intertwined on a length scale of 1 nm. The work opens the path toward understanding the quantum transport of electrons confined in atomic-scale monolayer structures based on correlated-electron-materials.
Platinum single-atom catalyst coupled with transition metal/metal oxide heterostructure for accelerating alkaline hydrogen evolution reaction
Authors: Zhou Kai Ling , Wang Zelin , Han Chang Bao , Ke Xiaoxing , Wang Changhao , Jin Yuhong , Zhang Qianqian , Liu Jingbing , Wang Hao , Yan Hui
Published: June 2021

Single-atom catalysts provide an effective approach to reduce the amount of precious metals meanwhile maintain their catalytic activity. However, the sluggish activity of the catalysts for alkaline water dissociation has hampered advances in highly efficient hydrogen production. Herein, we develop a single-atom platinum immobilized NiO/Ni heterostructure (PtSA-NiO/Ni) as an alkaline hydrogen evolution catalyst. It is found that Pt single atom coupled with NiO/Ni heterostructure enables the tunable binding abilities of hydroxyl ions (OH*) and hydrogen (H*), which efficiently tailors the water dissociation energy and promotes the H* conversion for accelerating alkaline hydrogen evolution reaction. A further enhancement is achieved by constructing PtSA-NiO/Ni nanosheets on Ag nanowires to form a hierarchical three-dimensional morphology. Consequently, the fabricated PtSA-NiO/Ni catalyst displays high alkaline hydrogen evolution performances with a quite high mass activity of 20.6 A mg−1 for Pt at the overpotential of 100 mV, significantly outperforming the reported catalysts.
Structural basis for the ARF GAP activity and specificity of the C9orf72 complex
Authors: Su Ming-Yuan , Fromm Simon A. , Remis Jonathan , Toso Daniel B. , Hurley James H.
Published: June 2021

Mutation of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontal temporal degeneration (FTD), which is attributed to both a gain and loss of function. C9orf72 forms a complex with SMCR8 and WDR41, which was reported to have GTPase activating protein activity toward ARF proteins, RAB8A, and RAB11A. We determined the cryo-EM structure of ARF1-GDP-BeF3- bound to C9orf72:SMCR8:WDR41. The SMCR8longin and C9orf72longin domains form the binding pocket for ARF1. One face of the C9orf72longin domain holds ARF1 in place, while the SMCR8longin positions the catalytic finger Arg147 in the ARF1 active site. Mutations in interfacial residues of ARF1 and C9orf72 reduced or eliminated GAP activity. RAB8A GAP required ~10-fold higher concentrations of the C9orf72 complex than for ARF1. These data support a specific function for the C9orf72 complex as an ARF GAP. The structure also provides a model for the active forms of the longin domain GAPs of FLCN and NPRL2 that regulate the Rag GTPases of the mTORC1 pathway.
Structural insights into an atypical secretory pathway kinase crucial for Toxoplasma gondii invasion
Authors: Lentini Gaëlle , Ben Chaabene Rouaa , Vadas Oscar , Ramakrishnan Chandra , Mukherjee Budhaditya , Mehta Ved , Lunghi Matteo , Grossmann Jonas , Maco Bohumil , Visentin Rémy , Hehl Adrian B. , Korkhov Volodymyr M. , Soldati-Favre Dominique
Published: June 2021

Active host cell invasion by the obligate intracellular apicomplexan parasites relies on the formation of a moving junction, which connects parasite and host cell plasma membranes during entry. Invading Toxoplasma gondii tachyzoites secrete their rhoptry content and insert a complex of RON proteins on the cytoplasmic side of the host cell membrane providing an anchor to which the parasite tethers. Here we show that a rhoptry-resident kinase RON13 is a key virulence factor that plays a crucial role in host cell entry. Cryo-EM, kinase assays, phosphoproteomics and cellular analyses reveal that RON13 is a secretory pathway kinase of atypical structure that phosphorylates rhoptry proteins including the components of the RON complex. Ultimately, RON13 kinase activity controls host cell invasion by anchoring the moving junction at the parasite-host cell interface.
Live-cell imaging of circadian clock protein dynamics in CRISPR-generated knock-in cells
Authors: Gabriel Christian H. , del Olmo Marta , Zehtabian Amin , Jäger Marten , Reischl Silke , van Dijk Hannah , Ulbricht Carolin , Rakhymzhan Asylkhan , Korte Thomas , Koller Barbara , Grudziecki Astrid , Maier Bert , Herrmann Andreas , Niesner Raluca , Zemojtel Tomasz , Ewers Helge , Granada Adrián E. , Herzel Hanspeter , Kramer Achim
Published: June 2021

The cell biology of circadian clocks is still in its infancy. Here, we describe an efficient strategy for generating knock-in reporter cell lines using CRISPR technology that is particularly useful for genes expressed transiently or at low levels, such as those coding for circadian clock proteins. We generated single and double knock-in cells with endogenously expressed PER2 and CRY1 fused to fluorescent proteins allowing us to simultaneously monitor the dynamics of CRY1 and PER2 proteins in live single cells. Both proteins are highly rhythmic in the nucleus of human cells with PER2 showing a much higher amplitude than CRY1. Surprisingly, CRY1 protein is nuclear at all circadian times indicating the absence of circadian gating of nuclear import. Furthermore, in the nucleus of individual cells CRY1 abundance rhythms are phase-delayed (~5 hours), and CRY1 levels are much higher (>5 times) compared to PER2 questioning the current model of the circadian oscillator.
Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes
Authors: Jiang Xiaoli , Han Bo , Xue Yuhang , Duan Mei , Gui Zhuofan , Wang You , Zhu Shaolin
Published: June 2021

α-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons.
TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells
Authors: Silva Bruno , Arora Rajika , Bione Silvia , Azzalin Claus M.
Published: June 2021

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required to initiate ALT, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby triggering BIR and promoting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.
Large model structural uncertainty in global projections of urban heat waves
Authors: Zheng Zhonghua , Zhao Lei , Oleson Keith W.
Published: June 2021

Urban heat waves (UHWs) are strongly associated with socioeconomic impacts. Here, we use an urban climate emulator combined with large ensemble global climate simulations to show that, at the urban scale a large proportion of the variability results from the model structural uncertainty in projecting UHWs in the coming decades under climate change. Omission of this uncertainty would considerably underestimate the risk of UHW. Results show that, for cities in four high-stake regions – the Great Lakes of North America, Southern Europe, Central India, and North China – a virtually unlikely (0.01% probability) UHW projected by single-model ensembles is estimated by our model with probabilities of 23.73%, 4.24%, 1.56%, and 14.76% respectively in 2061–2070 under a high-emission scenario. Our findings suggest that for urban-scale extremes, policymakers and stakeholders will have to plan for larger uncertainties than what a single model predicts if decisions are informed based on urban climate simulations.
Association of social distancing and face mask use with risk of COVID-19
Authors: Kwon Sohee , Joshi Amit D. , Lo Chun-Han , Drew David A. , Nguyen Long H. , Guo Chuan-Guo , Ma Wenjie , Mehta Raaj S. , Shebl Fatma Mohamed , Warner Erica T. , Astley Christina M. , Merino Jordi , Murray Benjamin , Wolf Jonathan , Ourselin Sebastien , Steves Claire J. , Spector Tim D. , Hart Jaime E. , Song Mingyang , VoPham Trang , Chan Andrew T.
Published: June 2021

Given the continued burden of COVID-19 worldwide, there is a high unmet need for data on the effect of social distancing and face mask use to mitigate the risk of COVID-19. We examined the association of community-level social distancing measures and individual face mask use with risk of predicted COVID-19 in a large prospective U.S. cohort study of 198,077 participants. Individuals living in communities with the greatest social distancing had a 31% lower risk of predicted COVID-19 compared with those living in communities with poor social distancing. Self-reported ‘always’ use of face mask was associated with a 62% reduced risk of predicted COVID-19 even among individuals living in a community with poor social distancing. These findings provide support for the efficacy of mask-wearing even in settings of poor social distancing in reducing COVID-19 transmission. Despite mass vaccination campaigns in many parts of the world, continued efforts at social distancing and face mask use remain critically important in reducing the spread of COVID-19.
Acinetobacter baylyi regulates type IV pilus synthesis by employing two extension motors and a motor protein inhibitor
Authors: Ellison Courtney K. , Dalia Triana N. , Klancher Catherine A. , Shaevitz Joshua W. , Gitai Zemer , Dalia Ankur B.
Published: June 2021

Bacteria use extracellular appendages called type IV pili (T4P) for diverse behaviors including DNA uptake, surface sensing, virulence, protein secretion, and twitching motility. Dynamic extension and retraction of T4P is essential for their function, and T4P extension is thought to occur through the action of a single, highly conserved motor, PilB. Here, we develop Acinetobacter baylyi as a model to study T4P by employing a recently developed pilus labeling method. By contrast to previous studies of other bacterial species, we find that T4P synthesis in A. baylyi is dependent not only on PilB but also on an additional, phylogenetically distinct motor, TfpB. Furthermore, we identify a protein (CpiA) that inhibits T4P extension by specifically binding and inhibiting PilB but not TfpB. These results expand our understanding of T4P regulation and highlight how inhibitors might be exploited to disrupt T4P synthesis.
Tailored cobalt-salen complexes enable electrocatalytic intramolecular allylic C–H functionalizations
Authors: Cai Chen-Yan , Wu Zheng-Jian , Liu Ji-Ying , Chen Ming , Song Jinshuai , Xu Hai-Chao
Published: June 2021

Oxidative allylic C–H functionalization is a powerful tool to streamline organic synthesis as it minimizes the need for functional group activation and generates alkenyl-substituted products amenable to further chemical modifications. The intramolecular variants can be used to construct functionalized ring structures but remain limited in scope and by their frequent requirement for noble metal catalysts and stoichiometric chemical oxidants. Here we report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C–H amination and alkylation by employing tailored cobalt-salen complexes as catalysts. These reactions proceed through a radical mechanism and display broad tolerance of functional groups and alkene substitution patterns, allowing efficient coupling of di-, tri- and even tetrasubstituted alkenes with N- and C-nucleophiles to furnish high-value heterocyclic and carbocyclic structures.
Establishment and characterization of immortalized human breast cancer cell lines from breast cancer patient-derived xenografts (PDX)
Authors: Zhuang Yongxian , Grainger Jordan M. , Vedell Peter T. , Yu Jia , Moyer Ann M. , Gao Huanyao , Fan Xiao-Yang , Qin Sisi , Liu Duan , Kalari Krishna R. , Goetz Matthew P. , Boughey Judy C. , Weinshilboum Richard M. , Wang Liewei
Published: June 2021

The application of patient-derived xenografts (PDX) in drug screening and testing is a costly and time-consuming endeavor. While cell lines permit extensive mechanistic studies, many human breast cancer cell lines lack patient characteristics and clinical treatment information. Establishing cell lines that retain patient’s genetic and drug response information would enable greater drug screening and mechanistic studies. Therefore, we utilized breast cancer PDX from the Mayo Breast Cancer Genome Guided Therapy Study (BEAUTY) to establish two immortalized, genomically unique breast cancer cell lines. Through extensive genetic and therapeutic testing, the cell lines were found to retain the same clinical subtype, major somatic alterations, and drug response phenotypes as their corresponding PDX and patient tumor. Our findings demonstrate PDX can be utilized to develop immortalized breast cancer cell lines and provide a valuable tool for understanding the molecular mechanism of drug resistance and exploring novel treatment strategies.
High-energy magnetic excitations from heavy quasiparticles in CeCu2Si2
Authors: Song Yu , Wang Weiyi , Cao Chongde , Yamani Zahra , Xu Yuanji , Sheng Yutao , Löser Wolfgang , Qiu Yiming , Yang Yi-feng , Birgeneau Robert J. , Dai Pengcheng
Published: June 2021

Magnetic fluctuations is the leading candidate for pairing in cuprate, iron-based, and heavy fermion superconductors. This view is challenged by the recent discovery of nodeless superconductivity in CeCu2Si2, and calls for a detailed understanding of the corresponding magnetic fluctuations. Here, we mapped out the magnetic excitations in superconducting (S-type) CeCu2Si2 using inelastic neutron scattering, finding a strongly asymmetric dispersion for E ≲ 1.5 meV, which at higher energies evolves into broad columnar magnetic excitations that extend to E ≳ 5 meV. While low-energy magnetic excitations exhibit marked three-dimensional characteristics, the high-energy magnetic excitations in CeCu2Si2 are almost two-dimensional, reminiscent of paramagnons found in cuprate and iron-based superconductors. By comparing our experimental findings with calculations in the random-phase approximation,we find that the magnetic excitations in CeCu2Si2 arise from quasiparticles associated with its heavy electron band, which are also responsible for superconductivity. Our results provide a basis for understanding magnetism and superconductivity in CeCu2Si2, and demonstrate the utility of neutron scattering in probing band renormalization in heavy fermion metals.
3D conformal bandpass millimeter-wave frequency selective surface with improved fields of view
Authors: Álvarez H. Fernández , Cadman Darren A. , Goulas Athanasios , de Cos Gómez M. E. , Engstrøm Daniel S. , Vardaxoglou J. C. , Zhang Shiyu
Published: June 2021

Conventional planar frequency selective surfaces (FSSs) are characterized in the far-field region and they are sensitive to the incidence angle of impinging waves. In this paper, a spherical dome FSS is presented, aiming to provide improved angular stable bandpass filtering performance as compared to its planar counterpart when the FSS is placed in the near-field region of an antenna source. A comparison between the conformal FSS and a finite planar FSS is presented through simulations at the frequency range between 26 to 40 GHz in order to demonstrate the advantages of utilizing the conformal FSS in the near-field. The conformal FSS is 3D printed and copper electroplated, which leads to a low-cost and lightweight bandpass filter array. Placing it in the near-field region of a primary antenna can be used as radomes to realize compact high-performance mm-wave systems. The comparison between simulated and measured conformal FSS results is in good agreement. The challenges that arise when designing, manufacturing, and measuring this type of structure are reported and guidelines to overcome these are presented.
Gender specific airway gene expression in COPD sub-phenotypes supports a role of mitochondria and of different types of leukocytes
Authors: Esteve-Codina Anna , Hofer Thomas P. , Burggraf Dorothe , Heiss-Neumann Marion S. , Gesierich Wolfgang , Boland Anne , Olaso Robert , Bihoreau Marie-Therese , Deleuze Jean-Francois , Moeller Winfried , Schmid Otmar , Soler Artigas María , Renner Kathrin , Hohlfeld Jens M. , Welte Tobias , Fuehner Thomas , Jerrentrup Lukas , Koczulla Andreas Rembert , Greulich Timm , Prasse Antje , Müller-Quernheim Joachim , Gupta Sumit , Brightling Christopher , Subramanian Deepak R. , Parr David G. , Kolsum Umme , Gupta Vandana , Barta Imre , Döme Balázs , Strausz János , Stendardo Mariarita , Piattella Marco , Boschetto Piera , Korzybski Damian , Gorecka Dorota , Nowinski Adam , Dabad Marc , Fernández-Callejo Marcos , Endesfelder David , zu Castell Wolfgang , Hiemstra Pieter S. , Venge Per , Noessner Elfriede , Griebel Thasso , Heath Simon , Singh Dave , Gut Ivo , Ziegler-Heitbrock Loems
Published: June 2021

Chronic obstructive pulmonary disease (COPD) is a destructive inflammatory disease and the genes expressed within the lung are crucial to its pathophysiology. We have determined the RNAseq transcriptome of bronchial brush cells from 312 stringently defined ex-smoker patients. Compared to healthy controls there were for males 40 differentially expressed genes (DEGs) and 73 DEGs for females with only 26 genes shared. The gene ontology (GO) term “response to bacterium” was shared, with several different DEGs contributing in males and females. Strongly upregulated genes TCN1 and CYP1B1 were unique to males and females, respectively. For male emphysema (E)-dominant and airway disease (A)-dominant COPD (defined by computed tomography) the term “response to stress” was found for both sub-phenotypes, but this included distinct up-regulated genes for the E-sub-phenotype (neutrophil-related CSF3R, CXCL1, MNDA) and for the A-sub-phenotype (macrophage-related KLF4, F3, CD36). In E-dominant disease, a cluster of mitochondria-encoded (MT) genes forms a signature, able to identify patients with emphysema features in a confirmation cohort. The MT-CO2 gene is upregulated transcriptionally in bronchial epithelial cells with the copy number essentially unchanged. Both MT-CO2 and the neutrophil chemoattractant CXCL1 are induced by reactive oxygen in bronchial epithelial cells. Of the female DEGs unique for E- and A-dominant COPD, 88% were detected in females only. In E-dominant disease we found a pronounced expression of mast cell-associated DEGs TPSB2, TPSAB1 and CPA3. The differential genes discovered in this study point towards involvement of different types of leukocytes in the E- and A-dominant COPD sub-phenotypes in males and females.
Two new long-rostrum cranefly species from the Cretaceous Iberian amber (Diptera, Limoniidae, Helius)
Authors: Kania-Kłosok Iwona , Krzemiński Wiesław , Arillo Antonio
Published: June 2021

First record of the genus Helius—long-rostrum cranefly from Maestrazgo Basin (eastern Spain, Iberian Penisula) is documented. Two new fossil species of the genus Helius are described from Cretaceous Spanish amber and compared with other species of the genus known from fossil record with particular references to these known from Cretaceous period. Helius turolensis sp. nov. is described from San Just amber (Lower Cretaceous, upper Albian) Maestrazgo Basin, eastern Spain, and Helius hispanicus sp. nov. is described from Álava amber (Lower Cretaceous, upper Albian), Basque-Cantabrian Basin, northern Spain. The specific body morphology of representatives of the genus Helius preserved in Spanish amber was discussed in relation to the environmental conditions of the Maestrazgo Basin and Basque-Cantabrian Basin in Cretaceous.
Inverse-designed ultra-compact high efficiency and low crosstalk optical interconnect based on waveguide crossing and wavelength demultiplexer
Authors: Xu Yanhong , Huang Jie , Yang Lina , Ma Hansi , Yuan Huan , Xie Tong , Yang Junbo , Zhang Zhenrong
Published: June 2021

In this paper, we use the inverse design method to design an optical interconnection system composed of wavelength demultiplexer and the same direction waveguide crossing on silicon-on-insulator (SOI) platform. A 2.4 μm × 3.6 μm wavelength demultiplexer with an input wavelength of 1.3–1.6 μm is designed. When the target wavelength of the device is 1.4 μm, the insertion loss of the output port is − 0.93 dB, and there is − 18.4 dB crosstalk, in TE0 mode. The insertion loss of the target wavelength of 1.6 μm in TE0 mode is − 0.88 dB, and the crosstalk is − 19.1 dB. Then, we designed a same direction waveguide crossing, the footprint is only 2.4 μm × 3.6 μm, the insertion loss of the wavelength 1.4 μm and 1.6 μm in TE0 mode is − 0.99 dB and − 1 dB, and the crosstalk is − 12.14 dB and − 14.34 dB, respectively. Finally, an optical interconnect structure composed of two devices is used, which can become the most basic component of the optical interconnect network. In TE0 mode, the insertion loss of the output wavelength of 1.4 μm at the output port is − 1.3 dB, and the crosstalk is − 29.36 dB. The insertion loss of the output wavelength of 1.6 μm is − 1.39 dB, and the crosstalk is − 38.99 dB.
Virtual reality and annotated radiological data as effective and motivating tools to help Social Sciences students learn neuroanatomy
Authors: van Deursen Margot , Reuvers Laura , Duits Jacobus Dylan , de Jong Guido , van den Hurk Marianne , Henssen Dylan
Published: June 2021

Neuroanatomy as a subject is important to learn, because a good understanding of neuroanatomy supports the establishment of a correct diagnosis in neurological patients. However, rapid changes in curricula reduced time assigned to study (neuro)anatomy. Therefore, it is important to find alternative teaching methods to study the complex three-dimensional structure of the brain. The aim of this manuscript was to explore the effectiveness of Virtual Reality (VR) in comparison with Radiological Data (RaD) as suitable learning methods to build knowledge and increase motivation for learning neuroanatomy. Forty-seven students (mean age of 19.47 ± 0.54 years; 43 females; 4 males) were included; 23 students comprised the VR group. Both methods showed to improve knowledge significantly, the improvement between groups was not different. The RaD group showed to have a significantly higher score on expectancy than students in the VR group. Task value scores regarding finding a task interesting, useful and fun were found to be significantly different in favor of the VR group. Consequently, significant higher Motivation scores were found in the VR group. Motivation and expectancy, however, did not moderate learning results, whereas task value impacted the results in favour of the VR group. This study concludes that VR and RaD are effective and diverting methods to learn neuroanatomy, with VR being more motivating than RaD. Future research should investigate motivation and task value when using VR over a longer period of time.
Particle movements provoke avalanche-like compaction in soft colloid filter cakes
Authors: Lüken Arne , Stüwe Lucas , Lohaus Johannes , Linkhorst John , Wessling Matthias
Published: June 2021

During soft matter filtration, colloids accumulate in a compressible porous cake layer on top of the membrane surface. The void size between the colloids predominantly defines the cake-specific permeation resistance and the corresponding filtration efficiency. While higher fluxes are beneficial for the process efficiency, they compress the cake and increase permeation resistance. However, it is not fully understood how soft particles behave during cake formation and how their compression influences the overall cake properties. This study visualizes the formation and compression process of soft filter cakes in microfluidic model systems. During cake formation, we analyze single-particle movements inside the filter cake voids and how they interact with the whole filter cake morphology. During cake compression, we visualize reversible and irreversible compression and distinguish the two phenomena. Finally, we confirm the compression phenomena by modeling the soft particle filter cake using a CFD-DEM approach. The results underline the importance of considering the compression history when describing the filter cake morphology and its related properties. Thus, this study links single colloid movements and filter cake compression to the overall cake behavior and narrows the gap between single colloid events and the filtration process.
Author Correction: Stimulation of hepatocarcinogenesis by activated cholangiocytes via Il17a/f1 pathway in kras transgenic zebrafish model
Authors: Helal Mohamed , Yan Chuan , Gong Zhiyuan
Published: June 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113
Authors: Ueno Makoto , Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Kataoka Tomoko , Ikeda Masafumi , Ozaka Masato , Okano Naohiro , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Yamamoto Tomohisa , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Miyamoto Atsushi , Yamaguchi Hironori , Nishina Tomohiro , Shirakawa Hirofumi , Kojima Yasushi , Oono Takamasa , Kawamoto Yasuyuki , Furukawa Masayuki , Iwai Tomohisa , Sudo Kentaro , Miyakawa Hiroyuki , Yamashita Tatsuya , Yasuda Ichirou , Takahashi Hidenori , Kato Naoya , Shioji Kazuhiko , Shimizu Kyoko , Nakagohri Toshio , Kamata Ken , Ishii Hiroshi , Furuse Junji ,   the members of the Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG-HBPOG).
Published: June 2021

JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
Nano-metals forming bacteria in Egypt. I. Synthesis, characterization and effect on some phytopathogenic bacteria in vitro
Authors: Zaki Sahar Abd El-Fatah , Kamal Ayman , Ashmawy Nader A. , Shoeib Alia A.
Published: June 2021

Bacterial metal reducers were isolated from water samples collected from harsh condition locations in Egypt. Four selected isolates were identified as Enterococcus thailandicus, Pseudomonas putida, Marinobacter hydrocarbonoclasticus, and P. geniculata for Copper (Cu), Iron (Fe), Cobalt (Co) and Zinc (Zn) Nanoparticles (NPs) production sequentially. Nitrate reductase enzyme was assayed for bacterial isolates which demonstrated that P. putida, and M. hydrocarbonoclasticus have the maximum enzyme production. The produced NPs were characterized by using XRD, TEM, UV–VIS spectroscopy. Magnetic properties for all selected metals NPs were measured using Vibrating Sample Magnetometer (VSM) and demonstrated that FeNPs recorded the highest magnetization value. The antibacterial activity of selected metals NPs was tested against some phytopathogenic bacteria causing the following diseases: soft rot (Pectobacterium carotovorum, Enterobacter cloacae), blackleg (Pectobacterium atrosepticum and Dickeya solani), brown rot (Ralstonia solanacearum), fire blight (Erwinia amylovora) and crown gall (Agrobacterium tumefaciens). All metals NPs showed an antagonistic effect against the tested isolates, particularly, FeNPs showed the highest antibacterial activity followed by CuNPs, and ZnNPs. Due to the small size, high reactivity, and large surface area of biologically synthesized NPs, they are used as a good disinfector, and can be considered as a new and alternative approach to traditional disease management methods.
Human intelectin-1 (ITLN1) genetic variation and intestinal expression
Authors: Nonnecke Eric B. , Castillo Patricia A. , Dugan Amanda E. , Almalki Faisal , Underwood Mark A. , De La Motte Carol A. , Yuan Weirong , Lu Wuyuan , Shen Bo , Johansson Malin E. V. , Kiessling Laura L. , Hollox Edward J. , Lönnerdal Bo , Bevins Charles L.
Published: June 2021

Intelectins are ancient carbohydrate binding proteins, spanning chordate evolution and implicated in multiple human diseases. Previous GWAS have linked SNPs in ITLN1 (also known as omentin) with susceptibility to Crohn's disease (CD); however, analysis of possible functional significance of SNPs at this locus is lacking. Using the Ensembl database, pairwise linkage disequilibrium (LD) analyses indicated that several disease-associated SNPs at the ITLN1 locus, including SNPs in CD244 and Ly9, were in LD. The alleles comprising the risk haplotype are the major alleles in European (67%), but minor alleles in African superpopulations. Neither ITLN1 mRNA nor protein abundance in intestinal tissue, which we confirm as goblet-cell derived, was altered in the CD samples overall nor when samples were analyzed according to genotype. Moreover, the missense variant V109D does not influence ITLN1 glycan binding to the glycan β-D-galactofuranose or protein–protein oligomerization. Taken together, our data are an important step in defining the role(s) of the CD-risk haplotype by determining that risk is unlikely to be due to changes in ITLN1 carbohydrate recognition, protein oligomerization, or expression levels in intestinal mucosa. Our findings suggest that the relationship between the genomic data and disease arises from changes in CD244 or Ly9 biology, differences in ITLN1 expression in other tissues, or an alteration in ITLN1 interaction with other proteins.
The impact of inequalities and health expenditure on mortality due to oral and oropharyngeal cancer in Brazil
Authors: da Cunha Amanda Ramos , Bigoni Alessandro , Antunes José Leopoldo Ferreira , Hugo Fernando Neves
Published: June 2021

This study aims to assess the magnitude and trend of mortality rates due to oral (OC) and oropharyngeal cancer (OPC) in the 133 Intermediate Geographic Regions (IGR) of Brazil between 1996 and 2018 and to analyze its association with sociodemographic variables and provision of health services. It also aims to compare the trend of mortality from neoplasms that have been reported as associated with HPV (OPC) with the trend of neoplasms that have been reported as not associated with HPV (OC). We obtained mortality data from the Mortality Information System in Brazil and analyzed the trends using the Prais-Winsten method. Then, we assessed the relationship between mortality trends and socioeconomic, health spending, and health services provision variables. The median of the annual percent change of the country’s mortality rates was 0.63% for OC and 0.83% for OPC. Trends in mortality in the IGRs correlated significantly with the Human Development Index and government expenditure on ambulatory health care and hospitalizations. Mortality from both types of cancer decreased in those IGR in which the government spent more on health and in the more socioeconomically developed ones. This study found no epidemiological indication that HPV plays the leading etiological factor in OPC in Brazil.
An overview of Agaricus section Hondenses and Agaricus section Xanthodermatei with description of eight new species from Pakistan
Authors: Bashir Hira , Chen Jie , Jabeen Sana , Ullah Sadiq , Khan Junaid , Niazi Abdul Rehman , Zhang Mingzhe , Khalid Abdul Nasir , Parra Luis Alberto , Callac Philippe
Published: June 2021

In a recent revision of the genus Agaricus, A. section Xanthodermatei was split into two sections A. sect. Hondenses and A. sect. Xanthodermatei. Our objectives were to investigate the species diversity of both sections in Pakistan and to give an overview of the major clades. Phylogenetic analyses based on the combined nucLSU, ITS and TEF1 dataset from 35 specimens of both sections revealed three major clades. Analyses based on ITS dataset and 106 specimens, including 33 from Pakistan, reveal eight new species and one new record species. These nine species are described in detail. It is noteworthy that intraspecific variability as well as interspecific variability between closely related species were very low in ITS sequences in many cases. In the case of the two new species A.xanthochromaticus and A.griseovariegatus, TEF1 sequence data were much more efficient than ITS to distinguish these species from each other. The other new species are A.atroumbonatus, A.fumidicolor, A.macropeplus, A.parviniveus, A.swaticus and A.bambusetorum. The latter is the only new species of A. sect. Hondenses in which it is morphologically atypical and also the unique (sub)tropical species. Agaricusgregariomyces is recorded for the first time in Pakistan. In addition, brief descriptions are provided not only for A.bisporiticus, A.endoxanthus and A.punjabensis, which are reported again in Pakistan, but also for A.californicus, which is reported for the first time in Spain and outside North America. In total 12 species of both sections were reported in Pakistan and half of them were from subtropical climatic areas, underlining the contribution of the climatic diversity to the high species richness in this country.
Differences in equine spinal kinematics between straight line and circle in trot
Authors: Byström A. , Hardeman A. M. , Serra Bragança F. M. , Roepstorff L. , Swagemakers J. H. , van Weeren P. R. , Egenvall A.
Published: June 2021

Work on curved tracks, e.g. on circles, is commonplace within all forms of horse training. Horse movements in circles are naturally asymmetric, including the load distribution between inner and outer limbs. Within equestrian dressage the horse is expected to bend the back laterally to follow the circle, but this has never been studied scientifically. In the current study 12 horses were measured (optical motion capture, 100 Hz) trotting on left and right circles and on the straight without rider (soft surface). Data from markers placed along the spine indicated increased lateral bending to the inside (e.g. left bending on the left circle) of the thoracolumbar back (difference left circle vs. straight − 3.75°; right circle + 3.61°) and the neck (left − 5.23°; right + 4.80° vs. straight). Lateral bending ROM increased on the circle (+ 0.87° and + 0.62°). Individual variation in straight-circle differences was evident, but each horse was generally consistent over multiple trials. Differences in back movements between circle and straight were generally small and may or may not be visible, but accompanying changes in muscle activity and limb movements may add to the visual impression.
High level of fatty liver index predicts new onset of diabetes mellitus during a 10-year period in healthy subjects
Authors: Higashiura Yukimura , Furuhashi Masato , Tanaka Marenao , Takahashi Satoko , Koyama Masayuki , Ohnishi Hirofumi , Numata Keita , Hisasue Takashi , Hanawa Nagisa , Moniwa Norihito , Tsuchihashi Kazufumi , Miura Tetsuji
Published: June 2021

Fatty liver index (FLI), a predictor of nonalcoholic fatty liver disease, has been reported to be associated with several metabolic disorders. This study aimed to evaluate the relationship between FLI and new onset of diabetes mellitus (DM). We investigated the association of FLI with new onset of DM during a 10-year period in subjects who received annual health examinations (n = 28,990). After exclusion of subjects with DM at baseline and those with missing data, a total of 12,290 subjects (male/female: 7925/4365) who received health examinations were recruited. FLI was significantly higher in males than in females. During the 10-year period, DM was developed in 533 males (6.7%) and 128 females (2.9%). Multivariable Cox proportional hazard models with a restricted cubic spline showed that the risk of new onset of DM increased with a higher FLI at baseline in both sexes after adjustment of age, fasting plasma glucose, habits of alcohol drinking and current smoking, family history of DM and diagnosis of hypertension and dyslipidemia at baseline. When the subjects were divided into subgroups according to tertiles of FLI level at baseline (T1–T3) in the absence and presence of impaired fasting glucose (IFG), hazard ratios after adjustment of the confounders gradually increased from T1 to T3 and from the absence to presence of IFG in both male and female subjects. In conclusion, a high level of FLI predicts new onset of DM in a general population of both male and female individuals.
Identifying HLA DRB1-DQB1 alleles associated with Chlamydia trachomatis infection and in silico prediction of potentially-related peptides
Authors: Pedraza Leidy , Camargo Milena , Moreno-Pérez Darwin A. , Sánchez Ricardo , Del Río-Ospina Luisa , Báez-Murcia Indira M. , Patarroyo Manuel E. , Patarroyo Manuel A.
Published: June 2021

HLA class II (HLA-II) genes’ polymorphism influences the immune response to Chlamydia trachomatis (Ct), it is considered a sexually transmitted infection. However, associations between HLA-II alleles and Ct-infection have been little explored in humans; this study was thus aimed at determining HLA-DRB1-DQB1 alleles/haplotypes’ effect on Ct-infection outcome in a cohort of Colombian women. Cervical sample DNA was used as template for detecting Ct by PCR and typing HLA-DRB1-DQB1 alleles/haplotypes by Illumina MiSeq sequencing. Survival models were adjusted for identifying the alleles/haplotypes’ effect on Ct-outcome; bioinformatics tools were used for predicting secreted bacterial protein T- and B-cell epitopes. Sixteen HLA-DRB1 alleles having a significant effect on Ct-outcome were identified in the 262 women analysed. DRB1*08:02:01G and DRB1*12:01:01G were related to infection-promoting events. Only the DQB1*05:03:01G allele related to clearance/persistence events was found for HLA-DQB1. HLA-DRB1 allele homozygous women were associated with events having a lower probability of clearance and/or early occurrence of persistence. Twenty-seven peptides predicted in silico were associated with protective immunity against Ct; outer membrane and polymorphic membrane protein-derived peptides had regions having dual potential for being T- or B-cell epitopes. This article describes HLA-DRB1-DQB1 alleles/haplotypes related to Ct-infection resolution and the peptides predicted in silico which might probably be involved in host immune response. The data provides base information for developing future studies leading to the development of effective prevention measures against Ct-infection.
Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
Authors: Steffensen L. B. , Stubbe J. , Lindholt J. S. , Beck H. C. , Overgaard M. , Bloksgaard M. , Genovese F. , Holm Nielsen S. , Tha M. L. T. , Bang-Moeller S. K. , Hong Lin M. K. T. , Larsen J. H. , Hansen D. R. , Jones G. T. , Bown M. J. , Karsdal M. A. , Rasmussen L. M.
Published: June 2021

Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/−, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.