bluuebunny/crossref_metadata_2025 huggingface dataset:
NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation
Authors: Hu Yuanbo , Chen Chenbin , Tong Xinya , Chen Sian , Hu Xianjing , Pan Bujian , Sun Xiangwei , Chen Zhiyuan , Shi Xinyu , Hu Yingying , Shen Xian , Xue Xiangyang , Lu Mingdong
Published: September 2021

The 5-methylcytosine (m5C) RNA methyltransferase NSUN2 is involved in the regulation of cell proliferation and metastasis formation and is upregulated in multiple cancers. However, the biological significance of NSUN2 in gastric cancer (GC) and the modification of NSUN2 itself have not been fully investigated. Here, we analyzed the expression level of NSUN2 in tissue microarrays containing 403 GC tissues by immunohistochemistry. NSUN2 was upregulated in GC, and that it was a predictor of poor prognosis. NSUN2 promotes the proliferation, migration, and invasion of GC cells in vitro. We also demonstrated that small ubiquitin-like modifier (SUMO)-2/3 interacts directly with NSUN2 by stabilizing it and mediating its nuclear transport. This facilitates the carcinogenic activity of NSUN2. Furthermore, m5C bisulfite sequencing (Bis-seq) in NSUN2-deficient GC cells showed that m5C-methylated genes are involved in multiple cancer-related signaling pathways. PIK3R1 and PCYT1A may be the target genes that participate in GC progression. Our findings revealed a novel mechanism by which NSUN2 functions in GC progression. This may provide new treatment options for GC patients.
Spatial localisation meets biomolecular networks
Authors: Menon Govind , Krishnan J.
Published: September 2021

Spatial organisation through localisation/compartmentalisation of species is a ubiquitous but poorly understood feature of cellular biomolecular networks. Current technologies in systems and synthetic biology (spatial proteomics, imaging, synthetic compartmentalisation) necessitate a systematic approach to elucidating the interplay of networks and spatial organisation. We develop a systems framework towards this end and focus on the effect of spatial localisation of network components revealing its multiple facets: (i) As a key distinct regulator of network behaviour, and an enabler of new network capabilities (ii) As a potent new regulator of pattern formation and self-organisation (iii) As an often hidden factor impacting inference of temporal networks from data (iv) As an engineering tool for rewiring networks and network/circuit design. These insights, transparently arising from the most basic considerations of networks and spatial organisation, have broad relevance in natural and engineered biology and in related areas such as cell-free systems, systems chemistry and bionanotechnology.
Variant PCGF1-PRC1 links PRC2 recruitment with differentiation-associated transcriptional inactivation at target genes
Authors: Sugishita Hiroki , Kondo Takashi , Ito Shinsuke , Nakayama Manabu , Yakushiji-Kaminatsui Nayuta , Kawakami Eiryo , Koseki Yoko , Ohinata Yasuhide , Sharif Jafar , Harachi Mio , Blackledge Neil P. , Klose Robert J. , Koseki Haruhiko
Published: September 2021

Polycomb repressive complexes-1 and -2 (PRC1 and 2) silence developmental genes in a spatiotemporal manner during embryogenesis. How Polycomb group (PcG) proteins orchestrate down-regulation of target genes upon differentiation, however, remains elusive. Here, by differentiating embryonic stem cells into embryoid bodies, we reveal a crucial role for the PCGF1-containing variant PRC1 complex (PCGF1-PRC1) to mediate differentiation-associated down-regulation of a group of genes. Upon differentiation cues, transcription is down-regulated at these genes, in association with PCGF1-PRC1-mediated deposition of histone H2AK119 mono-ubiquitination (H2AK119ub1) and PRC2 recruitment. In the absence of PCGF1-PRC1, both H2AK119ub1 deposition and PRC2 recruitment are disrupted, leading to aberrant expression of target genes. PCGF1-PRC1 is, therefore, required for initiation and consolidation of PcG-mediated gene repression during differentiation.
Climate warming promotes pesticide resistance through expanding overwintering range of a global pest
Authors: Ma Chun-Sen , Zhang Wei , Peng Yu , Zhao Fei , Chang Xiang-Qian , Xing Kun , Zhu Liang , Ma Gang , Yang He-Ping , Rudolf Volker H. W.
Published: September 2021

Climate change has the potential to change the distribution of pests globally and their resistance to pesticides, thereby threatening global food security in the 21st century. However, predicting where these changes occur and how they will influence current pest control efforts is a challenge. Using experimentally parameterised and field-tested models, we show that climate change over the past 50 years increased the overwintering range of a global agricultural insect pest, the diamondback moth (Plutella xylostella), by ~2.4 million km2 worldwide. Our analysis of global data sets revealed that pesticide resistance levels are linked to the species’ overwintering range: mean pesticide resistance was 158 times higher in overwintering sites compared to sites with only seasonal occurrence. By facilitating local persistence all year round, climate change can promote and expand pesticide resistance of this destructive species globally. These ecological and evolutionary changes would severely impede effectiveness of current pest control efforts and potentially cause large economic losses.
Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations
Authors: Rees Elliott , Creeth Hugo D. J. , Hwu Hai-Gwo , Chen Wei J. , Tsuang Ming , Glatt Stephen J. , Rey Romain , Kirov George , Walters James T. R. , Holmans Peter , Owen Michael J. , O’Donovan Michael C.
Published: September 2021

People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10−6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.
Conformational rearrangements enable iterative backbone N-methylation in RiPP biosynthesis
Authors: Miller Fredarla S. , Crone Kathryn K. , Jensen Matthew R. , Shaw Sudipta , Harcombe William R. , Elias Mikael H. , Freeman Michael F.
Published: September 2021

Peptide backbone α-N-methylations change the physicochemical properties of amide bonds to provide structural constraints and other favorable characteristics including biological membrane permeability to peptides. Borosin natural product pathways are the only known ribosomally encoded and posttranslationally modified peptides (RiPPs) pathways to incorporate backbone α-N-methylations on translated peptides. Here we report the discovery of type IV borosin natural product pathways (termed ‘split borosins’), featuring an iteratively acting α-N-methyltransferase and separate precursor peptide substrate from the metal-respiring bacterium Shewanella oneidensis. A series of enzyme-precursor complexes reveal multiple conformational states for both α-N-methyltransferase and substrate. Along with mutational and kinetic analyses, our results give rare context into potential strategies for iterative maturation of RiPPs.
Reconfigurable multi-component micromachines driven by optoelectronic tweezers
Authors: Zhang Shuailong , Elsayed Mohamed , Peng Ran , Chen Yujie , Zhang Yanfeng , Peng Jiaxi , Li Weizhen , Chamberlain M. Dean , Nikitina Adele , Yu Siyuan , Liu Xinyu , Neale Steven L. , Wheeler Aaron R.
Published: September 2021

There is great interest in the development of micromotors which can convert energy to motion in sub-millimeter dimensions. Micromachines take the micromotor concept a step further, comprising complex systems in which multiple components work in concert to effectively realize complex mechanical tasks. Here we introduce light-driven micromotors and micromachines that rely on optoelectronic tweezers (OET). Using a circular micro-gear as a unit component, we demonstrate a range of new functionalities, including a touchless micro-feed-roller that allows the programming of precise three-dimensional particle trajectories, multi-component micro-gear trains that serve as torque- or velocity-amplifiers, and micro-rack-and-pinion systems that serve as microfluidic valves. These sophisticated systems suggest great potential for complex micromachines in the future, for application in microrobotics, micromanipulation, microfluidics, and beyond.
Decay and renormalization of a longitudinal mode in a quasi-two-dimensional antiferromagnet
Authors: Do Seung-Hwan , Zhang Hao , Williams Travis J. , Hong Tao , Garlea V. Ovidiu , Rodriguez-Rivera J. A. , Jang Tae-Hwan , Cheong Sang-Wook , Park Jae-Hoon , Batista Cristian D. , Christianson Andrew D.
Published: September 2021

An ongoing challenge in the study of quantum materials, is to reveal and explain collective quantum effects in spin systems where interactions between different modes types are important. Here we approach this problem through a combined experimental and theoretical study of interacting transverse and longitudinal modes in an easy-plane quantum magnet near a continuous quantum phase transition. Our inelastic neutron scattering measurements of Ba2FeSi2O7 reveal the emergence, decay, and renormalization of a longitudinal mode throughout the Brillouin zone. The decay of the longitudinal mode is particularly pronounced at the zone center. To account for the many-body effects of the interacting low-energy modes in anisotropic magnets, we generalize the standard spin-wave theory. The measured mode decay and renormalization is reproduced by including all one-loop corrections. The theoretical framework developed here is broadly applicable to quantum magnets with more than one type of low energy mode.
Aridity-driven shift in biodiversity–soil multifunctionality relationships
Authors: Hu Weigang , Ran Jinzhi , Dong Longwei , Du Qiajun , Ji Mingfei , Yao Shuran , Sun Yuan , Gong Chunmei , Hou Qingqing , Gong Haiyang , Chen Renfei , Lu Jingli , Xie Shubin , Wang Zhiqiang , Huang Heng , Li Xiaowei , Xiong Junlan , Xia Rui , Wei Maohong , Zhao Dongmin , Zhang Yahui , Li Jinhui , Yang Huixia , Wang Xiaoting , Deng Yan , Sun Ying , Li Hailing , Zhang Liang , Chu Qipeng , Li Xinwei , Aqeel Muhammad , Manan Abdul , Akram Muhammad Adnan , Liu Xianghan , Li Rui , Li Fan , Hou Chen , Liu Jianquan , He Jin-Sheng , An Lizhe , Bardgett Richard D. , Schmid Bernhard , Deng Jianming
Published: September 2021

Relationships between biodiversity and multiple ecosystem functions (that is, ecosystem multifunctionality) are context-dependent. Both plant and soil microbial diversity have been reported to regulate ecosystem multifunctionality, but how their relative importance varies along environmental gradients remains poorly understood. Here, we relate plant and microbial diversity to soil multifunctionality across 130 dryland sites along a 4,000 km aridity gradient in northern China. Our results show a strong positive association between plant species richness and soil multifunctionality in less arid regions, whereas microbial diversity, in particular of fungi, is positively associated with multifunctionality in more arid regions. This shift in the relationships between plant or microbial diversity and soil multifunctionality occur at an aridity level of ∼0.8, the boundary between semiarid and arid climates, which is predicted to advance geographically ∼28% by the end of the current century. Our study highlights that biodiversity loss of plants and soil microorganisms may have especially strong consequences under low and high aridity conditions, respectively, which calls for climate-specific biodiversity conservation strategies to mitigate the effects of aridification.
Field-tunable toroidal moment in a chiral-lattice magnet
Authors: Ding Lei , Xu Xianghan , Jeschke Harald O. , Bai Xiaojian , Feng Erxi , Alemayehu Admasu Solomon , Kim Jaewook , Huang Fei-Ting , Zhang Qiang , Ding Xiaxin , Harrison Neil , Zapf Vivien , Khomskii Daniel , Mazin Igor I. , Cheong Sang-Wook , Cao Huibo
Published: September 2021

Ferrotoroidal order, which represents a spontaneous arrangement of toroidal moments, has recently been found in a few linear magnetoelectric materials. However, tuning toroidal moments in these materials is challenging. Here, we report switching between ferritoroidal and ferrotoroidal phases by a small magnetic field, in a chiral triangular-lattice magnet BaCoSiO4 with tri-spin vortices. Upon applying a magnetic field, we observe multi-stair metamagnetic transitions, characterized by equidistant steps in the net magnetic and toroidal moments. This highly unusual ferri-ferroic order appears to come as a result of an unusual hierarchy of frustrated isotropic exchange couplings revealed by first principle calculations, and the antisymmetric exchange interactions driven by the structural chirality. In contrast to the previously known toroidal materials identified via a linear magnetoelectric effect, BaCoSiO4 is a qualitatively new multiferroic with an unusual coupling between several different orders, and opens up new avenues for realizing easily tunable toroidal orders.
Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling
Authors: van der Stel Anne-Xander , Gordon Emily R. , Sengupta Arnab , Martínez Allyson K. , Klepacki Dorota , Perry Thomas N. , Herrero del Valle Alba , Vázquez-Laslop Nora , Sachs Matthew S. , Cruz-Vera Luis R. , Innis C. Axel
Published: September 2021

Free L-tryptophan (L-Trp) stalls ribosomes engaged in the synthesis of TnaC, a leader peptide controlling the expression of the Escherichia coli tryptophanase operon. Despite extensive characterization, the molecular mechanism underlying the recognition and response to L-Trp by the TnaC-ribosome complex remains unknown. Here, we use a combined biochemical and structural approach to characterize a TnaC variant (R23F) with greatly enhanced sensitivity for L-Trp. We show that the TnaC–ribosome complex captures a single L-Trp molecule to undergo termination arrest and that nascent TnaC prevents the catalytic GGQ loop of release factor 2 from adopting an active conformation at the peptidyl transferase center. Importantly, the L-Trp binding site is not altered by the R23F mutation, suggesting that the relative rates of L-Trp binding and peptidyl-tRNA cleavage determine the tryptophan sensitivity of each variant. Thus, our study reveals a strategy whereby a nascent peptide assists the ribosome in detecting a small metabolite.
Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy
Authors: Bertolin Joan , Sánchez Víctor , Ribera Albert , Jaén Maria Luisa , Garcia Miquel , Pujol Anna , Sánchez Xavier , Muñoz Sergio , Marcó Sara , Pérez Jennifer , Elias Gemma , León Xavier , Roca Carles , Jimenez Veronica , Otaegui Pedro , Mulero Francisca , Navarro Marc , Ruberte Jesús , Bosch Fatima
Published: September 2021

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused byN-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encodingGalns(AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galnsgene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.
Fractionalized conductivity and emergent self-duality near topological phase transitions
Authors: Wang Yan-Cheng , Cheng Meng , Witczak-Krempa William , Meng Zi Yang
Published: September 2021

The experimental discovery of the fractional Hall conductivity in two-dimensional electron gases revealed new types of quantum particles, called anyons, which are beyond bosons and fermions as they possess fractionalized exchange statistics. These anyons are usually studied deep inside an insulating topological phase. It is natural to ask whether such fractionalization can be detected more broadly, say near a phase transition from a conventional to a topological phase. To answer this question, we study a strongly correlated quantum phase transition between a topological state, called a $${{\mathbb{Z}}}_{2}$$

Z

2

quantum spin liquid, and a conventional superfluid using large-scale quantum Monte Carlo simulations. Our results show that the universal conductivity at the quantum critical point becomes a simple fraction of its value at the conventional insulator-to-superfluid transition. Moreover, a dynamically self-dual optical conductivity emerges at low temperatures above the transition point, indicating the presence of the elusive vison particles. Our study opens the door for the experimental detection of anyons in a broader regime, and has ramifications in the study of quantum materials, programmable quantum simulators, and ultra-cold atomic gases. In the latter case, we discuss the feasibility of measurements in optical lattices using current techniques.
Saliva-derived microcosm biofilms grown on different oral surfaces in vitro
Authors: Li Xiaolan , Shang Lin , Brandt Bernd W. , Buijs Mark J. , Roffel Sanne , van Loveren Cor , Crielaard Wim , Gibbs Susan , Deng Dong Mei
Published: September 2021

The microbial composition of a specific oral niche could be influenced by initial bacterial adherence, nutrient and physiological property of the local surface. To investigate the influence of nutrient and surface properties on microbial composition, saliva-derived biofilms were grown in agar on three substrata: Reconstructed Human Gingiva (RHG), a hydroxyapatite (HAP) surface, and a titanium (TI) surface. Agar was mixed with either Brain Heart Infusion (BHI) or Thompson (TP) medium. After 1, 3, or 5 days, biofilm viability (by colony forming units) and microbiome profiles (by 16 S rDNA amplicon sequencing) were determined. On RHG, biofilm viability and composition were similar between BHI and TP. However, on the abiotic substrata, biofilm properties greatly depended on the type of medium and substratum. In BHI, the viability of HAP-biofilm first decreased and then increased, whereas that of TI-biofilm decreased in time until a 6-log reduction. In TP, either no or a 2-log reduction in viability was observed for HAP- or TI-biofilms respectively. Furthermore, different bacterial genera (or higher level) were differentially abundant in the biofilms on 3 substrata: Haemophilus and Porphyromonas for RHG; Bacilli for HAP and Prevotella for TI. In conclusion, RHG, the biotic substratum, is able to support a highly viable and diverse microbiome. In contrast, the viability and diversity of the biofilms on the abiotic substrata were influenced by the substrata type, pH of the environment and the richness of the growth media. These results suggest that the host (oral mucosa) plays a vital role in the oral ecology.
Interim clinical trial analysis of intraoperative mass spectrometry for breast cancer surgery
Authors: Basu Sankha S. , Stopka Sylwia A. , Abdelmoula Walid M. , Randall Elizabeth C. , Gimenez-Cassina Lopez Begoña , Regan Michael S. , Calligaris David , Lu Fake F. , Norton Isaiah , Mallory Melissa A. , Santagata Sandro , Dillon Deborah A. , Golshan Mehra , Agar Nathalie Y. R.
Published: September 2021

Optimal resection of breast tumors requires removing cancer with a rim of normal tissue while preserving uninvolved regions of the breast. Surgical and pathological techniques that permit rapid molecular characterization of tissue could facilitate such resections. Mass spectrometry (MS) is increasingly used in the research setting to detect and classify tumors and has the potential to detect cancer at surgical margins. Here, we describe the ex vivo intraoperative clinical application of MS using a liquid micro-junction surface sample probe (LMJ-SSP) to assess breast cancer margins. In a midpoint analysis of a registered clinical trial, surgical specimens from 21 women with treatment naïve invasive breast cancer were prospectively collected and analyzed at the time of surgery with subsequent histopathological determination. Normal and tumor breast specimens from the lumpectomy resected by the surgeon were smeared onto glass slides for rapid analysis. Lipidomic profiles were acquired from these specimens using LMJ-SSP MS in negative ionization mode within the operating suite and post-surgery analysis of the data revealed five candidate ions separating tumor from healthy tissue in this limited dataset. More data is required before considering the ions as candidate markers. Here, we present an application of ambient MS within the operating room to analyze breast cancer tissue and surgical margins. Lessons learned from these initial promising studies are being used to further evaluate the five candidate biomarkers and to further refine and optimize intraoperative MS as a tool for surgical guidance in breast cancer.
Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer
Authors: Bortolini Silveira Amanda , Bidard François-Clément , Tanguy Marie-Laure , Girard Elodie , Trédan Olivier , Dubot Coraline , Jacot William , Goncalves Anthony , Debled Marc , Levy Christelle , Ferrero Jean-Marc , Jouannaud Christelle , Rios Maria , Mouret-Reynier Marie-Ange , Dalenc Florence , Hego Caroline , Rampanou Aurore , Albaud Benoit , Baulande Sylvain , Berger Frédérique , Lemonnier Jérôme , Renault Shufang , Desmoulins Isabelle , Proudhon Charlotte , Pierga Jean-Yves
Published: September 2021

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are two cancer-derived blood biomarkers that inform on patient prognosis and treatment efficacy in breast cancer. We prospectively evaluated the clinical validity of quantifying both CTCs (CellSearch) and ctDNA (targeted next-generation sequencing). Their combined value as prognostic and early monitoring markers was assessed in 198 HER2-negative metastatic breast cancer patients. All patients were included in the prospective multicenter UCBG study COMET (NCT01745757) and treated by first-line chemotherapy with weekly paclitaxel and bevacizumab. Blood samples were obtained at baseline and before the second cycle of chemotherapy. At baseline, CTCs and ctDNA were respectively detected in 72 and 74% of patients and were moderately correlated (Kendall’s τ = 0.3). Only 26 (13%) patients had neither detectable ctDNA nor CTCs. Variants were most frequently observed in TP53 and PIK3CA genes. KMT2C/MLL3 variants detected in ctDNA were significantly associated with a lower CTC count, while the opposite trend was seen with GATA3 alterations. Both CTC and ctDNA levels at baseline and after four weeks of treatment were correlated with survival. For progression-free and overall survival, the best multivariate prognostic model included tumor subtype (triple negative vs other), grade (grade 3 vs other), ctDNA variant allele frequency (VAF) at baseline (per 10% increase), and CTC count at four weeks (≥5CTC/7.5 mL). Overall, this study demonstrates that CTCs and ctDNA have nonoverlapping detection profiles and complementary prognostic values in metastatic breast cancer patients. A comprehensive liquid-biopsy approach may involve simultaneous detection of ctDNA and CTCs.
Proteomics-derived basal biomarker DNA-PKcs is associated with intrinsic subtype and long-term clinical outcomes in breast cancer
Authors: Asleh Karama , Riaz Nazia , Cheng Angela S. , Gao Dongxia , Leung Samuel C. Y. , Anurag Meenakshi , Nielsen Torsten O.
Published: September 2021

Precise biomarkers are needed to guide better diagnostics and therapeutics for basal-like breast cancer, for which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has been recently reported by the Clinical Proteomic Tumor Analysis Consortium as the most specific biomarker. We evaluated DNA-PKcs expression in clinically-annotated breast cancer tissue microarrays and correlated results with immune biomarkers (training set:n = 300; validation set:n = 2401). Following a pre-specified study design per REMARK criteria, we found that high expression of DNA-PKcs was significantly associated with stromal and CD8 + tumor infiltrating lymphocytes. Within the basal-like subtype, tumors with low DNA-PKcs and high tumor-infiltrating lymphocytes displayed the most favourable survival. DNA-PKcs expression by immunohistochemistry identified estrogen receptor-positive cases with a basal-like gene expression subtype. Non-silent mutations inPRKDCwere significantly associated with poor outcomes. Integrating DNA-PKcs expression with validated immune biomarkers could guide patient selection for DNA-PKcs targeting strategies, DNA-damaging agents, and their combination with an immune-checkpoint blockade.
Plasma-assisted multiscale topographic scaffolds for soft and hard tissue regeneration
Authors: Kim Woochan , Gwon Yonghyun , Kim Yang-Kyung , Park Sunho , Kang Sung-Ju , Park Hyeng-Kyu , Kim Myung-Sun , Kim Jangho
Published: September 2021

The design of transplantable scaffolds for tissue regeneration requires gaining precise control of topographical properties. Here, we propose a methodology to fabricate hierarchical multiscale scaffolds with controlled hydrophilic and hydrophobic properties by employing capillary force lithography in combination with plasma modification. Using our method, we fabricated biodegradable biomaterial (i.e., polycaprolactone (PCL))-based nitrogen gas (N-FN) and oxygen gas plasma-assisted flexible multiscale nanotopographic (O-FMN) patches with natural extracellular matrix-like hierarchical structures along with flexible and controlled hydrophilic properties. In response to multiscale nanotopographic and chemically modified surface cues, the proliferation and osteogenic mineralization of cells were significantly promoted. Furthermore, the O-FMN patch enhanced regeneration of the mineralized fibrocartilage tissue of the tendon–bone interface and the calvarial bone tissue in vivo in rat models. Overall, the PCL-based O-FMN patches could accelerate soft- and hard-tissue regeneration. Thus, our proposed methodology was confirmed as an efficient approach for the design and manipulation of scaffolds having a multiscale topography with controlled hydrophilic property.
Immobilization of active ammonia-oxidizing archaea in hydrogel beads
Authors: Landreau Matthieu , You HeeJun , Stahl David A. , Winkler Mari K. H.
Published: September 2021

Ammonia-oxidizing archaea (AOA) are major players in the nitrogen cycle but their cultivation represents a major challenge due to their slow growth rate and limited tendency to form biofilms. In this study, AOA was embedded in small (~2.5 mm) and large (~4.7 mm) poly(vinyl alcohol) (PVA)—sodium alginate (SA) hydrogel beads cross-linked with four agents (calcium, barium, light, or sulfate) to compare the differences in activity, the diffusivity of nitrogen species (NH4+, NO2−, and NO3−), and polymer leakage in batch systems over time. Sulfate-bound PVA-SA beads were the most stable, releasing the lowest amount of polymer without shrinking. Diffusion coefficients were found to be 2 to 3 times higher in hydrogels than in granules, with ammonium diffusivity being ca. 35% greater than nitrite and nitrate. Despite a longer lag phase in small beads, embedded AOA sustained a high per volume rate of ammonia oxidation compatible with applications in research and wastewater treatment.
Prognostic role of Ki-67 in glioblastomas excluding contribution from non-neoplastic cells
Authors: Dahlrot Rikke H. , Bangsø Julie A. , Petersen Jeanette K. , Rosager Ann Mari , Sørensen Mia D. , Reifenberger Guido , Hansen Steinbjørn , Kristensen Bjarne W.
Published: September 2021

Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas (p = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate (p = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas (p = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.
Impact of overlapping risks of type 2 diabetes and obesity on coronavirus disease severity in the United States
Authors: Ando Wataru , Horii Takeshi , Uematsu Takayuki , Hanaki Hideaki , Atsuda Koichiro , Otori Katsuya
Published: September 2021

The impact of overlapping risk factors on coronavirus disease (COVID-19) severity is unclear. To evaluate the impact of type 2 diabetes (T2D) and obesity on COVID-19 severity, we conducted a cohort study with 28,095 anonymized COVID-19 patients using data from the COVID-19 Research Database from January 1, 2020 to November 30, 2020. The mean age was 50.8 ± 17.5 years, and 11,802 (42%) patients were male. Data on age, race, sex, T2D complications, antidiabetic medication prescription, and body mass index ≥ 30 kg/m2 (obesity) were analysed using Cox proportional hazard models, with hospitalization risk and critical care within 30 days of COVID-19 diagnosis as the main outcomes. The risk scores were 0–4 for age ≥ 65 years, male sex, T2D, and obesity. Among the participants, 11,294 (61.9%) had obesity, and 4445 (15.8%) had T2D. T2D, obesity, and male sex were significantly associated with COVID-19 hospitalization risk. Regarding hospitalization risk scores, compared with those for hospitalization risk score 0 and critical care risk score 0, hazard ratios [95% confidence intervals] were 19.034 [10.470–34.600] and 55.803 [12.761–244.015] (P < 0.001) (P < 0.001), respectively, for risk score 4. Complications from diabetes and obesity increased hospitalization and critical care risks for COVID-19 patients.
Correlations between autoantibodies and the ATR-FTIR spectra of sera from rheumatoid arthritis patients
Authors: Durlik-Popińska Katarzyna , Żarnowiec Paulina , Konieczna-Kwinkowska Iwona , Lechowicz Łukasz , Gawęda Józef , Kaca Wiesław
Published: September 2021

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases worldwide. Due to high heterogeneity in disease manifestation, accurate and fast diagnosis of RA is difficult. This study analyzed the potential relationship between the infrared (IR) spectra obtained by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and the presence of autoantibodies and antibodies against urease in sera. Additionally, the wave number of the IR spectrum that enabled the best differentiation between patients and healthy blood donors was investigated. Using a mathematical model involving principal component analysis and discriminant analysis, it was shown that the presence of anti-citrullinated protein antibody, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, and anti-nuclear antibodies correlated significantly with the wave numbers in the IR spectra of the tested sera. The most interesting findings derived from determination of the best predictors for distinguishing RA. Characteristic features included an increased reaction with urease mimicking peptides and a correspondence with particular nucleic acid bands. Taken together, the results demonstrated the potential application of ATR-FTIR in the study of RA and identified potential novel markers of the disease.
Floquet prethermalization and Rabi oscillations in optically excited Hubbard clusters
Authors: Okamoto Junichi , Peronaci Francesco
Published: September 2021

We study the properties of Floquet prethermal states in two-dimensional Mott-insulating Hubbard clusters under continuous optical excitation. With exact-diagonalization simulations, we show that Floquet prethermal states emerge not only off resonance, but also for resonant excitation, provided a small field amplitude. In the resonant case, the long-lived quasi-stationary Floquet states are characterized by Rabi oscillations of observables such as double occupation and kinetic energy. At stronger fields, thermalization to infinite temperature is observed. We provide explanations to these results by means of time-dependent perturbation theory. The main findings are substantiated by a finite-size analysis.
Research on improved convolutional wavelet neural network
Authors: Liu Jingwei , Li Peixuan , Tang Xuehan , Li Jiaxin , Chen Jiaming
Published: September 2021

Artificial neural networks (ANN) which include deep learning neural networks (DNN) have problems such as the local minimal problem of Back propagation neural network (BPNN), the unstable problem of Radial basis function neural network (RBFNN) and the limited maximum precision problem of Convolutional neural network (CNN). Performance (training speed, precision, etc.) of BPNN, RBFNN and CNN are expected to be improved. Main works are as follows: Firstly, based on existing BPNN and RBFNN, Wavelet neural network (WNN) is implemented in order to get better performance for further improving CNN. WNN adopts the network structure of BPNN in order to get faster training speed. WNN adopts the wavelet function as an activation function, whose form is similar to the radial basis function of RBFNN, in order to solve the local minimum problem. Secondly, WNN-based Convolutional wavelet neural network (CWNN) method is proposed, in which the fully connected layers (FCL) of CNN is replaced by WNN. Thirdly, comparative simulations based on MNIST and CIFAR-10 datasets among the discussed methods of BPNN, RBFNN, CNN and CWNN are implemented and analyzed. Fourthly, the wavelet-based Convolutional Neural Network (WCNN) is proposed, where the wavelet transformation is adopted as the activation function in Convolutional Pool Neural Network (CPNN) of CNN. Fifthly, simulations based on CWNN are implemented and analyzed on the MNIST dataset. Effects are as follows: Firstly, WNN can solve the problems of BPNN and RBFNN and have better performance. Secondly, the proposed CWNN can reduce the mean square error and the error rate of CNN, which means CWNN has better maximum precision than CNN. Thirdly, the proposed WCNN can reduce the mean square error and the error rate of CWNN, which means WCNN has better maximum precision than CWNN.
Detecting anchored fish aggregating devices (AFADs) and estimating use patterns from vessel tracking data in small-scale fisheries
Authors: Widyatmoko Ahmad Catur , Hardesty Britta Denise , Wilcox Chris
Published: September 2021

Monitoring the use of anchored fish aggregating devices (AFADs) is essential for effective fisheries management. However, detecting the use of these devices is a significant challenge for fisheries management in Indonesia. These devices are continually deployed at large scales, due to large numbers of users and high failure rates, increasing the difficulty of monitoring AFADs. To address this challenge, tracking devices were attached to 34 handline fishing vessels in Indonesia over a month period each. Given there are an estimated 10,000–50,000 unlicensed AFADs in operation, Indonesian fishing grounds provided an ideal case study location to evaluate whether we could apply spatial modeling approaches to detect AFAD usage and fish catch success. We performed a spatial cluster analysis on tracking data to identify fishing grounds and determine whether AFADs were in use. Interviews with fishers were undertaken to validate these findings. We detected 139 possible AFADs, of which 72 were positively classified as AFADs. Our approach enabled us to estimate AFAD use and sharing by vessels, predict catches, and infer AFAD lifetimes. Key implications from our study include the potential to estimate AFAD densities and deployment rates, and thus compliance with Indonesia regulations, based on vessel tracking data.
Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma
Authors: Zenlander Robin , Havervall Sebastian , Magnusson Maria , Engstrand Jennie , Ågren Anna , Thålin Charlotte , Stål Per
Published: September 2021

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin–antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child–Pugh and MELD score. TAT was increased in all Child–Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.
Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort
Authors: Lithgow K. , Venkataraman H. , Hughes S. , Shah H. , Kemp-Blake J. , Vickrage S. , Smith S. , Humphries S. , Elshafie M. , Taniere P. , Diaz-Cano S. , Dasari B. V. M. , Almond M. , Ford S. , Ayuk J. , Shetty S. , Shah T. , Geh I.
Published: September 2021

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.
Explaining COVID-19 outbreaks with reactive SEIRD models
Authors: Menda Kunal , Laird Lucas , Kochenderfer Mykel J. , Caceres Rajmonda S.
Published: September 2021

COVID-19 epidemics have varied dramatically in nature across the United States, where some counties have clear peaks in infections, and others have had a multitude of unpredictable and non-distinct peaks. Our lack of understanding of how the pandemic has evolved leads to increasing errors in our ability to predict the spread of the disease. This work seeks to explain this diversity in epidemic progressions by considering an extension to the compartmental SEIRD model. The model we propose uses a neural network to predict the infection rate as a function of both time and the disease’s prevalence. We provide a methodology for fitting this model to available county-level data describing aggregate cases and deaths. Our method uses Expectation-Maximization to overcome the challenge of partial observability, due to the fact that the system’s state is only partially reflected in available data. We fit a single model to data from multiple counties in the United States exhibiting different behavior. By simulating the model, we show that it can exhibit both single peak and multi-peak behavior, reproducing behavior observed in counties both in and out of the training set. We then compare the error of simulations from our model with a standard SEIRD model, and show that ours substantially reduces errors. We also use simulated data to compare our methodology for handling partial observability with a standard approach, showing that ours is significantly better at estimating the values of unobserved quantities.
Heavy metals content in ashes of wood pellets and the health risk assessment related to their presence in the environment
Authors: Pazalja Mirha , Salihović Mirsada , Sulejmanović Jasmina , Smajović Alisa , Begić Sabina , Špirtović-Halilović Selma , Sher Farooq
Published: September 2021

Efforts to reduce air pollution in developing countries may require increased use of biomass fuels. Even biomass fuels are a sustainable alternative to fossil fuels there is limited quantitative information concerning heavy metal content in their ashes. Therefore, this study focuses on the determination of the heavy metal concentrations in wood pellet ash obtained from the combustion of 10 pellet brans from Bosnia and Herzegovina and Italy, the effects of adding the ashes to soils, and the assessment of health risk assessment. Ash content was determined by gravimetric method. The amount and composition of ash remaining after combustion of wood pellets varies considerably according to the type of biomass and wood from which the pellet is made. Samples were prepared by wet digestion using HNO3, and heavy metals are determined by atomic absorption spectroscopy-flame and graphite furnace. The results showed that the lowest concentration in ashes was obtained for Co 0.01 mg kg−1and the highest for Fe 571.63 mg kg−1. The Hazard Index (HI), calculated for non-cancerous substances for children was 2.23E−01, and the total Risk index was 4.54E−05. As for adults, HI was 1.51E−02, while the Risk index value was 3.21E−06. Human health risk calculated through HI and Risk index for children and adults associated with analyzed pellets is not of significant concern. The calculated enrichment factor and metal pollution index for wood pellet ashes indicate the risk of soil contamination with heavy metals. From this point of view, analyzed samples of ashes could be a serious contaminant of soil, so further monitoring is required.
Distinct calcium regulation of TRPM7 mechanosensitive channels at plasma membrane microdomains visualized by FRET-based single cell imaging
Authors: Starostina Irina , Jang Yoon-Kwan , Kim Heon-Su , Suh Jung-Soo , Ahn Sang-Hyun , Choi Gyu-Ho , Suk Myungeun , Kim Tae-Jin
Published: September 2021

Transient receptor potential subfamily M member 7 (TRPM7), a mechanosensitive Ca2+ channel, plays a crucial role in intracellular Ca2+ homeostasis. However, it is currently unclear how cell mechanical cues control TRPM7 activity and its associated Ca2+ influx at plasma membrane microdomains. Using two different types of Ca2+ biosensors (Lyn-D3cpv and Kras-D3cpv) based on fluorescence resonance energy transfer, we investigate how Ca2+ influx generated by the TRPM7-specific agonist naltriben is mediated at the detergent-resistant membrane (DRM) and non-DRM regions. This study reveals that TRPM7-induced Ca2+ influx mainly occurs at the DRM, and chemically induced mechanical perturbations in the cell mechanosensitive apparatus substantially reduce Ca2+ influx through TRPM7, preferably located at the DRM. Such perturbations include the disintegration of lipid rafts, microtubules, or actomyosin filaments; the alteration of actomyosin contractility; and the inhibition of focal adhesion and Src kinases. These results suggest that the mechanical membrane environment contributes to the TRPM7 function and activity. Thus, this study provides a fundamental understanding of how the mechanical aspects of the cell membrane regulate the function of mechanosensitive channels.