bluuebunny/crossref_metadata_2025 huggingface dataset:
The telomere length landscape of prostate cancer
Authors: Livingstone Julie , Shiah Yu-Jia , Yamaguchi Takafumi N. , Heisler Lawrence E. , Huang Vincent , Lesurf Robert , Gebo Tsumugi , Carlin Benjamin , Eng Stefan , Drysdale Erik , Green Jeffrey , van der Kwast Theodorus , Bristow Robert G. , Fraser Michael , Boutros Paul C.
Published: November 2021

Replicative immortality is a hallmark of cancer, and can be achieved through telomere lengthening and maintenance. Although the role of telomere length in cancer has been well studied, its association to genomic features is less well known. Here, we report the telomere lengths of 392 localized prostate cancer tumours and characterize their relationship to genomic, transcriptomic and proteomic features. Shorter tumour telomere lengths are associated with elevated genomic instability, including single-nucleotide variants, indels and structural variants. Genes involved in cell proliferation and signaling are correlated with tumour telomere length at all levels of the central dogma. Telomere length is also associated with multiple clinical features of a tumour. Longer telomere lengths in non-tumour samples are associated with a lower rate of biochemical relapse. In summary, we describe the multi-level integration of telomere length, genomics, transcriptomics and proteomics in localized prostate cancer.
Planar photonic chips with tailored angular transmission for high-contrast-imaging devices
Authors: Kuai Yan , Chen Junxue , Fan Zetao , Zou Gang , Lakowicz Joseph. R. , Zhang Douguo
Published: November 2021

A limitation of standard brightfield microscopy is its low contrast images, especially for thin specimens of weak absorption, and biological species with refractive indices very close in value to that of their surroundings. We demonstrate, using a planar photonic chip with tailored angular transmission as the sample substrate, a standard brightfield microscopy can provide both darkfield and total internal reflection (TIR) microscopy images with one experimental configuration. The image contrast is enhanced without altering the specimens and the microscope configurations. This planar chip consists of several multilayer sections with designed photonic band gaps and a central region with dielectric nanoparticles, which does not require top-down nanofabrication and can be fabricated in a larger scale. The photonic chip eliminates the need for a bulky condenser or special objective to realize darkfield or TIR illumination. Thus, it can work as a miniaturized high-contrast-imaging device for the developments of versatile and compact microscopes.
Single-cell analysis identifies dynamic gene expression networks that govern B cell development and transformation
Authors: Lee Robin D. , Munro Sarah A. , Knutson Todd P. , LaRue Rebecca S. , Heltemes-Harris Lynn M. , Farrar Michael A.
Published: November 2021

Integration of external signals and B-lymphoid transcription factor activities organise B cell lineage commitment through alternating cycles of proliferation and differentiation, producing a diverse repertoire of mature B cells. We use single-cell transcriptomics/proteomics to identify differentially expressed gene networks across B cell development and correlate these networks with subtypes of B cell leukemia. Here we show unique transcriptional signatures that refine the pre-B cell expansion stages into pre-BCR-dependent and pre-BCR-independent proliferative phases. These changes correlate with reciprocal changes in expression of the transcription factor EBF1 and the RNA binding protein YBX3, that are defining features of the pre-BCR-dependent stage. Using pseudotime analysis, we further characterize the expression kinetics of different biological modalities across B cell development, including transcription factors, cytokines, chemokines, and their associated receptors. Our findings demonstrate the underlying heterogeneity of developing B cells and characterise developmental nodes linked to B cell transformation.
A H2O2-activatable nanoprobe for diagnosing interstitial cystitis and liver ischemia-reperfusion injury via multispectral optoacoustic tomography and NIR-II fluorescent imaging
Authors: Chen Junjie , Chen Longqi , Wu Yinglong , Fang Yichang , Zeng Fang , Wu Shuizhu , Zhao Yanli
Published: November 2021

Developing high-quality NIR-II fluorophores (emission in 1000–1700 nm) for in vivo imaging is of great significance. Benzothiadiazole-core fluorophores are an important class of NIR-II dyes, yet ongoing limitations such as aggregation-caused quenching in aqueous milieu and non-activatable response are still major obstacles for their biological applications. Here, we devise an activatable nanoprobe to address these limitations. A molecular probe named BTPE-NO2 is synthesized by linking a benzothiadiazole core with two tetraphenylene groups serving as hydrophobic molecular rotors, followed by incorporating two nitrophenyloxoacetamide units at both ends of the core as recognition moieties and fluorescence quenchers. An FDA-approved amphiphilic polymer Pluronic F127 is then employed to encapsulate the molecular BTPE-NO2 to render the nanoprobe BTPE-NO2@F127. The pathological levels of H2O2 in the disease sites cleave the nitrophenyloxoacetamide groups and activate the probe, thereby generating strong fluorescent emission (950~1200 nm) and ultrasound signal for multi-mode imaging of inflammatory diseases. The nanoprobe can therefore function as a robust tool for detecting and imaging the disease sites with NIR-II fluorescent and multispectral optoacoustic tomography (MSOT) imaging. Moreover, the three-dimensional MSOT images can be obtained for visualizing and locating the disease foci.
Dormant spores sense amino acids through the B subunits of their germination receptors
Authors: Artzi Lior , Alon Assaf , Brock Kelly P. , Green Anna G. , Tam Amy , Ramírez-Guadiana Fernando H. , Marks Debora , Kruse Andrew , Rudner David Z.
Published: November 2021

Bacteria from the orders Bacillales and Clostridiales differentiate into stress-resistant spores that can remain dormant for years, yet rapidly germinate upon nutrient sensing. How spores monitor nutrients is poorly understood but in most cases requires putative membrane receptors. The prototypical receptor from Bacillus subtilis consists of three proteins (GerAA, GerAB, GerAC) required for germination in response to L-alanine. GerAB belongs to the Amino Acid-Polyamine-Organocation superfamily of transporters. Using evolutionary co-variation analysis, we provide evidence that GerAB adopts a structure similar to an L-alanine transporter from this superfamily. We show that mutations in gerAB predicted to disrupt the ligand-binding pocket impair germination, while mutations predicted to function in L-alanine recognition enable spores to respond to L-leucine or L-serine. Finally, substitutions of bulkier residues at these positions cause constitutive germination. These data suggest that GerAB is the L-alanine sensor and that B subunits in this broadly conserved family function in nutrient detection.
Tuning organic crystal chirality by the molar masses of tailored polymeric additives
Authors: Ye Xichong , Li Bowen , Wang Zhaoxu , Li Jing , Zhang Jie , Wan Xinhua
Published: November 2021

Hierarchically ordered chiral crystals have attracted intense research efforts for their huge potential in optical devices, asymmetric catalysis and pharmaceutical crystal engineering. Major barriers to the application have been the use of costly enantiomerically pure building blocks and the difficulty in precise control of chirality transfer from molecular to macroscopic level. Herein, we describe a strategy that offers not only the preferred formation of one enantiomorph from racemic solution but also the subsequent enantiomer-specific oriented attachment of this enantiomorph by balancing stereoselective and non-stereoselective interactions. It is demonstrated by on-demand switching the sign of fan-shaped crystal aggregates and the configuration of their components only by changing the molar mass of tailored polymeric additives. Owing to the simplicity and wide scope of application, this methodology opens an immediate opportunity for facile and efficient fabrication of one-handed macroscopic aggregates of homochiral organic crystals from racemic starting materials.
Breaking the symmetry to suppress the Plateau–Rayleigh instability and optimize hydropower utilization
Authors: Zhao Zhipeng , Li Huizeng , Li An , Fang Wei , Cai Zheren , Li Mingzhu , Feng Xiqiao , Song Yanlin
Published: November 2021

Droplet impact on solid surfaces is essential for natural and industrial processes. Particularly, controlling the instability after droplet impact, and avoiding the satellite drops generation, have aroused great interest for its significance in inkjet printing, pesticide spraying, and hydroelectric power collection. Herein, we found that breaking the symmetry of the droplet impact dynamics using patterned-wettability surfaces can suppress the Plateau–Rayleigh instability during the droplet rebounding and improve the energy collection efficiency. Systematic experimental investigation, together with mechanical modeling and numerical simulation, revealed that the asymmetric wettability patterns can regulate the internal liquid flow and reduce the vertical velocity gradient inside the droplet, thus suppressing the instability during droplet rebounding and eliminating the satellite drops. Accordingly, the droplet energy utilization was promoted, as demonstrated by the improved hydroelectric power generation efficiency by 36.5%. These findings deepen the understanding of the wettability-induced asymmetrical droplet dynamics during the liquid–solid interactions, and facilitate related applications such as hydroelectric power generation and materials transportation.
Molecular-level insights into the electronic effects in platinum-catalyzed carbon monoxide oxidation
Authors: Chen Wenyao , Cao Junbo , Yang Jia , Cao Yueqiang , Zhang Hao , Jiang Zheng , Zhang Jing , Qian Gang , Zhou Xinggui , Chen De , Yuan Weikang , Duan Xuezhi
Published: November 2021

A molecular-level understanding of how the electronic structure of metal center tunes the catalytic behaviors remains a grand challenge in heterogeneous catalysis. Herein, we report an unconventional kinetics strategy for bridging the microscopic metal electronic structure and the macroscopic steady-state rate for CO oxidation over Pt catalysts. X-ray absorption and photoelectron spectroscopy as well as electron paramagnetic resonance investigations unambiguously reveal the tunable Pt electronic structures with well-designed carbon support surface chemistry. Diminishing the electron density of Pt consolidates the CO-assisted O2 dissociation pathway via the O*-O-C*-O intermediate directly observed by isotopic labeling studies and rationalized by density-functional theory calculations. A combined steady-state isotopic transient kinetic and in situ electronic analyses identifies Pt charge as the kinetics indicators by being closely related to the frequency factor, site coverage, and activation energy. Further incorporation of catalyst structural parameters yields a novel model for quantifying the electronic effects and predicting the catalytic performance. These could serve as a benchmark of catalyst design by a comprehensive kinetics study at the molecular level.
NUDT2 initiates viral RNA degradation by removal of 5′-phosphates
Authors: Laudenbach Beatrice T. , Krey Karsten , Emslander Quirin , Andersen Line Lykke , Reim Alexander , Scaturro Pietro , Mundigl Sarah , Dächert Christopher , Manske Katrin , Moser Markus , Ludwig Janos , Wohlleber Dirk , Kröger Andrea , Binder Marco , Pichlmair Andreas
Published: November 2021

While viral replication processes are largely understood, comparably little is known on cellular mechanisms degrading viral RNA. Some viral RNAs bear a 5′-triphosphate (PPP-) group that impairs degradation by the canonical 5′-3′ degradation pathway. Here we show that the Nudix hydrolase 2 (NUDT2) trims viral PPP-RNA into monophosphorylated (P)-RNA, which serves as a substrate for the 5′-3′ exonuclease XRN1. NUDT2 removes 5′-phosphates from PPP-RNA in an RNA sequence- and overhang-independent manner and its ablation in cells increases growth of PPP-RNA viruses, suggesting an involvement in antiviral immunity. NUDT2 is highly homologous to bacterial RNA pyrophosphatase H (RppH), a protein involved in the metabolism of bacterial mRNA, which is 5′-tri- or diphosphorylated. Our results show a conserved function between bacterial RppH and mammalian NUDT2, indicating that the function may have adapted from a protein responsible for RNA turnover in bacteria into a protein involved in the immune defense in mammals.
Dihydroxyacetone valorization with high atom efficiency via controlling radical oxidation pathways over natural mineral-inspired catalyst
Authors: Wang Jinling , Dai Xingchao , Wang Hualin , Liu Honglai , Rabeah Jabor , Brückner Angelika , Shi Feng , Gong Ming , Yang Xuejing
Published: November 2021

Diminishing fossil fuel resources and calls for sustainability are driving the urgent need for efficient valorization of renewable resources with high atom efficiency. Inspired from the natural goethite mineral with Mn paragenesis, we develop cost-effective MnO2/goethite catalysts for the efficient valorization of dihydroxyacetone, an important biomass-based platform molecule, into value-added glycolic acid and formic acid with 83.2% and 93.4% yields. The DHA substrates first undergo C−C cleavage to selectively form glycolic acid and hydroxymethyl (·CH2OH) radicals, which are further oxidized into formic acid. The kinetic and isotopic labeling experiments reveal that the catalase-like activity of MnO2 turns the oxidative radicals into oxygen, which then switches towards a hydroxymethyl peroxide (HMOO) pathway for formic acid generation and prevents formic acid over-oxidation. This nature-inspired catalyst design not only significantly improves the carbon efficiency to 86.6%, but also enhances the oxygen atom utilization efficiency from 11.2% to 46.6%, indicating a promising biomass valorization process.
Learning neural network potentials from experimental data via Differentiable Trajectory Reweighting
Authors: Thaler Stephan , Zavadlav Julija
Published: November 2021

In molecular dynamics (MD), neural network (NN) potentials trained bottom-up on quantum mechanical data have seen tremendous success recently. Top-down approaches that learn NN potentials directly from experimental data have received less attention, typically facing numerical and computational challenges when backpropagating through MD simulations. We present the Differentiable Trajectory Reweighting (DiffTRe) method, which bypasses differentiation through the MD simulation for time-independent observables. Leveraging thermodynamic perturbation theory, we avoid exploding gradients and achieve around 2 orders of magnitude speed-up in gradient computation for top-down learning. We show effectiveness of DiffTRe in learning NN potentials for an atomistic model of diamond and a coarse-grained model of water based on diverse experimental observables including thermodynamic, structural and mechanical properties. Importantly, DiffTRe also generalizes bottom-up structural coarse-graining methods such as iterative Boltzmann inversion to arbitrary potentials. The presented method constitutes an important milestone towards enriching NN potentials with experimental data, particularly when accurate bottom-up data is unavailable.
Experimental observation of localized interfacial phonon modes
Authors: Cheng Zhe , Li Ruiyang , Yan Xingxu , Jernigan Glenn , Shi Jingjing , Liao Michael E. , Hines Nicholas J. , Gadre Chaitanya A. , Idrobo Juan Carlos , Lee Eungkyu , Hobart Karl D. , Goorsky Mark S. , Pan Xiaoqing , Luo Tengfei , Graham Samuel
Published: November 2021

Interfaces impede heat flow in micro/nanostructured systems. Conventional theories for interfacial thermal transport were derived based on bulk phonon properties of the materials making up the interface without explicitly considering the atomistic interfacial details, which are found critical to correctly describing thermal boundary conductance. Recent theoretical studies predicted the existence of localized phonon modes at the interface which can play an important role in understanding interfacial thermal transport. However, experimental validation is still lacking. Through a combination of Raman spectroscopy and high-energy-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope, we report the experimental observation of localized interfacial phonon modes at ~12 THz at a high-quality epitaxial Si-Ge interface. These modes are further confirmed using molecular dynamics simulations with a high-fidelity neural network interatomic potential, which also yield thermal boundary conductance agreeing well with that measured in time-domain thermoreflectance experiments. Simulations find that the interfacial phonon modes have an obvious contribution to the total thermal boundary conductance. Our findings significantly contribute to the understanding of interfacial thermal transport physics and have impact on engineering thermal boundary conductance at interfaces in applications such as electronics thermal management and thermoelectric energy conversion.
Versatile selective evolutionary pressure using synthetic defect in universal metabolism
Authors: Sellés Vidal Lara , Murray James W. , Heap John T.
Published: November 2021

The non-natural needs of industrial applications often require new or improved enzymes. The structures and properties of enzymes are difficult to predict or design de novo. Instead, semi-rational approaches mimicking evolution entail diversification of parent enzymes followed by evaluation of isolated variants. Artificial selection pressures coupling desired enzyme properties to cell growth could overcome this key bottleneck, but are usually narrow in scope. Here we show diverse enzymes using the ubiquitous cofactors nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) can substitute for defective NAD regeneration, representing a very broadly-applicable artificial selection. Inactivation of Escherichia coli genes required for anaerobic NAD regeneration causes a conditional growth defect. Cells are rescued by foreign enzymes connected to the metabolic network only via NAD or NADP, but only when their substrates are supplied. Using this principle, alcohol dehydrogenase, imine reductase and nitroreductase variants with desired selectivity modifications, and a high-performing isopropanol metabolic pathway, are isolated from libraries of millions of variants in single-round experiments with typical limited information to guide design.
A human fetal liver-derived infant MLL-AF4 acute lymphoblastic leukemia model reveals a distinct fetal gene expression program
Authors: Rice Siobhan , Jackson Thomas , Crump Nicholas T. , Fordham Nicholas , Elliott Natalina , O’Byrne Sorcha , Fanego Maria del Mar Lara , Addy Dilys , Crabb Trisevgeni , Dryden Carryl , Inglott Sarah , Ladon Dariusz , Wright Gary , Bartram Jack , Ancliff Philip , Mead Adam J. , Halsey Christina , Roberts Irene , Milne Thomas A. , Roy Anindita
Published: November 2021

Although 90% of children with acute lymphoblastic leukemia (ALL) are now cured, the prognosis for infant-ALL remains dismal. Infant-ALL is usually caused by a single genetic hit that arises in utero: an MLL/KMT2A gene rearrangement (MLL-r). This is sufficient to induce a uniquely aggressive and treatment-refractory leukemia compared to older children. The reasons for disparate outcomes in patients of different ages with identical driver mutations are unknown. Using the most common MLL-r in infant-ALL, MLL-AF4, as a disease model, we show that fetal-specific gene expression programs are maintained in MLL-AF4 infant-ALL but not in MLL-AF4 childhood-ALL. We use CRISPR-Cas9 gene editing of primary human fetal liver hematopoietic cells to produce a t(4;11)/MLL-AF4 translocation, which replicates the clinical features of infant-ALL and drives infant-ALL-specific and fetal-specific gene expression programs. These data support the hypothesis that fetal-specific gene expression programs cooperate with MLL-AF4 to initiate and maintain the distinct biology of infant-ALL.
STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis
Authors: Zhou Siru , Dai Qinggang , Huang Xiangru , Jin Anting , Yang Yiling , Gong Xinyi , Xu Hongyuan , Gao Xin , Jiang Lingyong
Published: November 2021

Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.
Structures of tweety homolog proteins TTYH2 and TTYH3 reveal a Ca2+-dependent switch from intra- to intermembrane dimerization
Authors: Li Baobin , Hoel Christopher M. , Brohawn Stephen G.
Published: November 2021

Tweety homologs (TTYHs) comprise a conserved family of transmembrane proteins found in eukaryotes with three members (TTYH1-3) in vertebrates. They are widely expressed in mammals including at high levels in the nervous system and have been implicated in cancers and other diseases including epilepsy, chronic pain, and viral infections. TTYHs have been reported to form Ca2+- and cell volume-regulated anion channels structurally distinct from any characterized protein family with potential roles in cell adhesion, migration, and developmental signaling. To provide insight into TTYH family structure and function, we determined cryo-EM structures of Mus musculus TTYH2 and TTYH3 in lipid nanodiscs. TTYH2 and TTYH3 adopt a previously unobserved fold which includes an extended extracellular domain with a partially solvent exposed pocket that may be an interaction site for hydrophobic molecules. In the presence of Ca2+, TTYH2 and TTYH3 form homomeric cis-dimers bridged by extracellularly coordinated Ca2+. Strikingly, in the absence of Ca2+, TTYH2 forms trans-dimers that span opposing membranes across a ~130 Å intermembrane space as well as a monomeric state. All TTYH structures lack ion conducting pathways and we do not observe TTYH2-dependent channel activity in cells. We conclude TTYHs are not pore forming subunits of anion channels and their function may involve Ca2+-dependent changes in quaternary structure, interactions with hydrophobic molecules near the extracellular membrane surface, and/or association with additional protein partners.
Current progress of rehabilitative strategies in stem cell therapy for spinal cord injury: a review
Authors: Tashiro Syoichi , Tsuji Osahiko , Shinozaki Munehisa , Shibata Takahiro , Yoshida Takashi , Tomioka Yohei , Unai Kei , Kondo Takahiro , Itakura Go , Kobayashi Yoshiomi , Yasuda Akimasa , Nori Satoshi , Fujiyoshi Kanehiro , Nagoshi Narihito , Kawakami Michiyuki , Uemura Osamu , Yamada Shin , Tsuji Tetsuya , Okano Hideyuki , Nakamura Masaya
Published: November 2021

Stem cell-based regenerative therapy has opened an avenue for functional recovery of patients with spinal cord injury (SCI). Regenerative rehabilitation is attracting wide attention owing to its synergistic effects, feasibility, non-invasiveness, and diverse and systemic properties. In this review article, we summarize the features of rehabilitation, describe the mechanism of combinatorial treatment, and discuss regenerative rehabilitation in the context of SCI. Although conventional rehabilitative methods have commonly been implemented alone, especially in studies of acute-to-subacute SCI, the combinatorial effects of intensive and advanced methods, including various neurorehabilitative approaches, have also been reported. Separating the concept of combined rehabilitation from regenerative rehabilitation, we suggest that the main roles of regenerative rehabilitation can be categorized as conditioning/reconditioning, functional training, and physical exercise, all of which are indispensable for enhancing functional recovery achieved using stem cell therapies.
MCMICRO: a scalable, modular image-processing pipeline for multiplexed tissue imaging
Authors: Schapiro Denis , Sokolov Artem , Yapp Clarence , Chen Yu-An , Muhlich Jeremy L. , Hess Joshua , Creason Allison L. , Nirmal Ajit J. , Baker Gregory J. , Nariya Maulik K. , Lin Jia-Ren , Maliga Zoltan , Jacobson Connor A. , Hodgman Matthew W. , Ruokonen Juha , Farhi Samouil L. , Abbondanza Domenic , McKinley Eliot T. , Persson Daniel , Betts Courtney , Sivagnanam Shamilene , Regev Aviv , Goecks Jeremy , Coffey Robert J. , Coussens Lisa M. , Santagata Sandro , Sorger Peter K.
Published: November 2021

Highly multiplexed tissue imaging makes detailed molecular analysis of single cells possible in a preserved spatial context. However, reproducible analysis of large multichannel images poses a substantial computational challenge. Here, we describe a modular and open-source computational pipeline, MCMICRO, for performing the sequential steps needed to transform whole-slide images into single-cell data. We demonstrate the use of MCMICRO on tissue and tumor images acquired using multiple imaging platforms, thereby providing a solid foundation for the continued development of tissue imaging software.
SDG partnerships may perpetuate the global North–South divide
Authors: Blicharska Malgorzata , Teutschbein Claudia , Smithers Richard J.
Published: November 2021

The 2030 Agenda for Sustainable Development gives equal emphasis to developed (“Northern”) countries and developing (“Southern”) countries. Thus, implementation of the Sustainable Development Goals (SDGs) demands coherent collaboration to transform society across all countries. Yet, there has been little research published on SDG partnerships and this is the first study to explore the extent to which partners from Northern and Southern countries are involved in them and their focus. It identifies that involvement is unequally distributed and may perpetuate the North–South divide in countries’ resources, including access to data and scientific capacities. Most notably, partners from low-income countries are involved in far fewer partnerships than partners from countries in all other World Bank income categories, although the former are least able to develop sustainably. As such, all those promoting sustainable development from governmental, private and third-sector organisations need to address global inequalities in establishing and implementing SDG partnerships if, collectively, they are to facilitate delivery of Agenda 2030.
Pax5 mediates the transcriptional activation of the CD81 gene
Authors: Hosokawa Kohei , Ishimaru Hanako , Watanabe Tadashi , Fujimuro Masahiro
Published: November 2021

CD81 is an integral membrane protein of the tetraspanin family and forms complexes with a variety of other cell surface membrane proteins. CD81 is involved in cell migration and B cell activation. However, the mechanism of the transcriptional regulation of the CD81 gene remains unclear. Here, we revealed that CD81 transcriptional activation was required for binding of the transcription factor Pax5 at the Pax5-binding sequence (-54)GCGGGAC(-48) located upstream of the transcriptional start site (TSS) of the CD81 gene. The reporter assay showed that the DNA sequence between − 130 and − 39 bp upstream of the TSS of the CD81 gene had promoter activity for CD81 transcription. The DNA sequence between − 130 and − 39 bp upstream of TSS of CD81 harbors two potential Pax5-binding sequences (-87)GCGTGAG(-81) and (-54)GCGGGAC(-48). Reporter, electrophoresis mobility shift, and chromatin immunoprecipitation (ChIP) assays disclosed that Pax5 bound to the (-54)GCGGGAC(-48) in the promoter region of the CD81 gene in order to activate CD81 transcription. Pax5 overexpression increased the expression level of CD81 protein, while the Pax5-knockdown by shRNA decreased CD81 expression. Moreover, we found that the expression level of CD81 was positively correlated with Pax5 expression in human tumor cell lines. Because CD81 was reported to be involved in cell migration, we evaluated the effects of Pax5 overexpression by wound healing and transwell assays. The data showed that overexpression of either Pax5 or CD81 promoted the epithelial cell migration. Thus, our findings provide insights into the transcriptional mechanism of the CD81 gene through transcription factor Pax5.
A new p65 isoform that bind the glucocorticoid hormone and is expressed in inflammation liver diseases and COVID-19
Authors: Spinelli Gaetano , Biddeci Giuseppa , Artale Anna , Valentino Francesca , Tarantino Giuseppe , Gallo Giuseppe , Gianguzza Fabrizio , Conaldi Pier Giulio , Corrao Salvatore , Gervasi Francesco , Aronica Tommaso Silvano , Di Leonardo Aldo , Duro Giovanni , Di Blasi Francesco
Published: November 2021

Inflammation is a physiological process whose deregulation causes some diseases including cancer. Nuclear Factor kB (NF-kB) is a family of ubiquitous and inducible transcription factors, in which the p65/p50 heterodimer is the most abundant complex, that play critical roles mainly in inflammation. Glucocorticoid Receptor (GR) is a ligand-activated transcription factor and acts as an anti-inflammatory agent and immunosuppressant. Thus, NF-kB and GR are physiological antagonists in the inflammation process. Here we show that in mice and humans there is a spliced variant of p65, named p65 iso5, which binds the corticosteroid hormone dexamethasone amplifying the effect of the glucocorticoid receptor and is expressed in the liver of patients with hepatic cirrhosis and hepatocellular carcinoma (HCC). Furthermore, we have quantified the gene expression level of p65 and p65 iso5 in the PBMC of patients affected by SARS-CoV-2 disease. The results showed that in these patients the p65 and p65 iso5 mRNA levels are higher than in healthy subjects. The ability of p65 iso5 to bind dexamethasone and the regulation of the glucocorticoid (GC) response in the opposite way of the wild type improves our knowledge and understanding of the anti-inflammatory response and identifies it as a new therapeutic target to control inflammation and related diseases.
Gut microbiota depletion from early adolescence alters anxiety and depression-related behaviours in male mice with Alzheimer-like disease
Authors: Mosaferi Belal , Jand Yahya , Salari Ali-Akbar
Published: November 2021

The gut-microbiota–brain axis plays an important role in stress-related disorders, and dysfunction of this complex bidirectional system is associated with Alzheimer’s disease. This study aimed to assess the idea that whether gut microbiota depletion from early adolescence can alter anxiety- and depression-related behaviours in adult mice with or without Alzheimer-like disease. Male C57BL/6 mice were treated with an antibiotic cocktail from weaning to adulthood. Adult mice received an intracerebroventricular injection of amyloid-beta (Aβ)1–42, and were subjected to anxiety and depression tests. We measured, brain malondialdehyde and glutathione following anxiety tests, and assessed brain oxytocin and the hypothalamic–pituitary–adrenal (HPA) axis function by measuring adrenocorticotrophic hormone (ACTH) and corticosterone following depression tests. Healthy antibiotic-treated mice displayed significant decreases in anxiety-like behaviours, whereas they did not show any alterations in depression-like behaviours and HPA axis function. Antibiotic treatment from early adolescence prevented the development of anxiety- and depression-related behaviours, oxidative stress and HPA axis dysregulation in Alzheimer-induced mice. Antibiotic treatment increased oxytocin in the brain of healthy but not Alzheimer-induced mice. Taken together, these findings suggest that gut microbiota depletion following antibiotic treatment from early adolescence might profoundly affect anxiety- and depression-related behaviours, and HPA axis function in adult mice with Alzheimer-like disease.
A new ankylosaurid from the Upper Cretaceous Nemegt Formation of Mongolia and implications for paleoecology of armoured dinosaurs
Authors: Park Jin-Young , Lee Yuong-Nam , Kobayashi Yoshitsugu , Jacobs Louis L. , Barsbold Rinchen , Lee Hang-Jae , Kim Namsoo , Song Kyo-Young , Polcyn Michael J.
Published: November 2021

A new ankylosaurid dinosaur,Tarchia tumanovaesp. nov., has been recovered from the Upper Cretaceous Nemegt Formation of Mongolia. It includes a well-preserved skull, dorsal, sacral, caudal vertebrae, sixteen dorsal ribs, ilia, a partial ischium, free osteoderms, and a tail club. The squamosal horns ofT. tumanovaeare divided into two layers, the external dermal layer and the underlying squamosal horn proper. The irregular ventral margin of the base of the upper dermal layer may represent a resorption surface, suggesting that the squamosal horns of some ankylosaurids underwent extreme ontogenetic remodeling. Localized pathologies on the dorsosacral ribs and the tail provide evidence of agonistic behaviour. The tail club knob asymmetry ofT. tumanovaeresulted from restricted bone growth due to tail club strikes. Furthermore,T. tumanovaehad an anteriorly protruded shovel-shaped beak, which is a morphological character of selective feeders. Ankylosaurid diets shifted from low-level bulk feeding to selective feeding during the Baruungoyot and the Nemegt “age” (middle Campanian-lower Maastrichtian). This ankylosaurid niche shifting might have been a response to habitat change and competition with other bulk-feeding herbivores.
Assessing countries’ social-ecological resilience to shifting marine commercial species
Authors: Ojea Elena , Fontán Elena , Fuentes-Santos Isabel , Bueno-Pardo Juan
Published: November 2021

Climate change is already impacting fisheries with species moving across fishing areas, crossing institutional borders, and thus creating conflicts over fisheries management. In this scenario, scholars agree that adaptation to climate change requires that fisheries increase their social, institutional, and ecological resilience. The resilience or capacity of a fishery to be maintained without shifting to a different state (e.g., collapse) is at stake under climate change impacts and overexploitation. Despite this urgent need, applying the resilience concept in a spatially explicit and quantitative manner to inform policy remains unexplored. We take a resilience approach and operationalize the concept in industrial fisheries for two species that have been observed to significantly shift distribution in European waters: hake (Merluccius merluccius) and cod (Gadus morhua), in the context of the European Union institutional settings. With a set of resilience factors from the literature and by means of contemporary and historic data, we select indicators that are combined into an index that measures resilience on the ecologic, socioeconomic, and institutional dimensions of the fishery. We find that the resilience index varies among species and countries, with lower resilience levels in the socioeconomic dimension of the fisheries. We also see that resilience largely depends on the overexploitation status of the fishery. The results highlight the need to address social and institutional settings to enhance fisheries adaptation to climate change and allow to inform on climate resilient adaptation pathways for the fisheries.
Genes and regulatory mechanisms associated with experimentally-induced bovine respiratory disease identified using supervised machine learning methodology
Authors: Scott Matthew A. , Woolums Amelia R. , Swiderski Cyprianna E. , Perkins Andy D. , Nanduri Bindu
Published: November 2021

Bovine respiratory disease (BRD) is a multifactorial disease involving complex host immune interactions shaped by pathogenic agents and environmental factors. Advancements in RNA sequencing and associated analytical methods are improving our understanding of host response related to BRD pathophysiology. Supervised machine learning (ML) approaches present one such method for analyzing new and previously published transcriptome data to identify novel disease-associated genes and mechanisms. Our objective was to apply ML models to lung and immunological tissue datasets acquired from previous clinical BRD experiments to identify genes that classify disease with high accuracy. Raw mRNA sequencing reads from 151 bovine datasets (n = 123 BRD, n = 28 control) were downloaded from NCBI-GEO. Quality filtered reads were assembled in a HISAT2/Stringtie2 pipeline. Raw gene counts for ML analysis were normalized, transformed, and analyzed with MLSeq, utilizing six ML models. Cross-validation parameters (fivefold, repeated 10 times) were applied to 70% of the compiled datasets for ML model training and parameter tuning; optimized ML models were tested with the remaining 30%. Downstream analysis of significant genes identified by the top ML models, based on classification accuracy for each etiological association, was performed within WebGestalt and Reactome (FDR ≤ 0.05). Nearest shrunken centroid and Poisson linear discriminant analysis with power transformation models identified 154 and 195 significant genes for IBR and BRSV, respectively; from these genes, the two ML models discriminated IBR and BRSV with 100% accuracy compared to sham controls. Significant genes classified by the top ML models in IBR (154) and BRSV (195), but not BVDV (74), were related to type I interferon production and IL-8 secretion, specifically in lymphoid tissue and not homogenized lung tissue. Genes identified inMannheimia haemolyticainfections (97) were involved in activating classical and alternative pathways of complement. Novel findings, including expression of genes related to reduced mitochondrial oxygenation and ATP synthesis in consolidated lung tissue, were discovered. Genes identified in each analysis represent distinct genomic events relevant to understanding and predicting clinical BRD. Our analysis demonstrates the utility of ML with published datasets for discovering functional information to support the prediction and understanding of clinical BRD.
The evolution of basal mantle structure in response to supercontinent aggregation and dispersal
Authors: Cao Xianzhi , Flament Nicolas , Bodur Ömer F. , Müller R. Dietmar
Published: November 2021

Seismic studies have revealed two Large Low-Shear Velocity Provinces (LLSVPs) in the lowermost mantle. Whether these structures remain stable over time or evolve through supercontinent cycles is debated. Here we analyze a recently published mantle flow model constrained by a synthetic plate motion model extending back to one billion years ago, to investigate how the mantle evolves in response to changing plate configurations. Our model predicts that sinking slabs segment the basal thermochemical structure below an assembling supercontinent, and that this structure eventually becomes unified due to slab push from circum-supercontinental subduction. In contrast, the basal thermochemical structure below the superocean is generally coherent due to the persistence of a superocean in our imposed plate reconstruction. The two antipodal basal thermochemical structures exchange material several times when part of one of the structures is carved out and merged with the other one, similarly to “exotic” tectonic terranes. Plumes mostly rise from thick basal thermochemical structures and in some instances migrate from the edges towards the interior of basal thermochemical structures due to slab push. Our results suggest that the topography of basal structures and distribution of plumes change over time due to the changing subduction network over supercontinent cycles.
Estimating the effective fields of spin configurations using a deep learning technique
Authors: Lee D. B. , Yoon H. G. , Park S. M. , Choi J. W. , Kwon H. Y. , Won C.
Published: November 2021

The properties of complicated magnetic domain structures induced by various spin–spin interactions in magnetic systems have been extensively investigated in recent years. To understand the statistical and dynamic properties of complex magnetic structures, it is crucial to obtain information on the effective field distribution over the structure, which is not directly provided by magnetization. In this study, we use a deep learning technique to estimate the effective fields of spin configurations. We construct a deep neural network and train it with spin configuration datasets generated by Monte Carlo simulation. We show that the trained network can successfully estimate the magnetic effective field even though we do not offer explicit Hamiltonian parameter values. The estimated effective field information is highly applicable; it is utilized to reduce noise, correct defects in the magnetization data, generate spin configurations, estimate external field responses, and interpret experimental images.
Skin irritation and potential antioxidant, anti-collagenase, and anti-elastase activities of edible insect extracts
Authors: Yeerong Kankanit , Sriyab Suwannee , Somwongin Suvimol , Punyoyai Chanun , Chantawannakul Panuwan , Anuchapreeda Songyot , Prommaban Adchara , Chaiyana Wantida
Published: November 2021

This study aimed to investigate antioxidant, anti-aging, and irritation properties of Thai edible insect extracts, including Bombyx mori, Omphisa fuscidentalis, Euconocephalus sp., Patanga succincta, Acheta domesticus, and Lethocerus indicus. Insects were extracted by 2 different methods, including maceration using ethanol or hexane and digestion using DI water. Then the extracts were determined for protein content using bicinchoninic acid assay and antioxidant activities using 2,2′-azinobis (3-ethylbenzothiazoline-6-sulfonic acid), 2,2-diphenyl-1-picrylhydrazyl, ferric reducing antioxidant power, and ferric thiocyanate assays. Anti-aging activities were investigated by determination of collagenase and elastase inhibitory activities using spectrophotometric assay. Maceration by hexane yielded the highest extract content, whereas aqueous extract from digestion possessed the significantly highest protein content and biological activities (p < 0.05). Interestingly, aqueous extracts of A. domesticus possessed the significantly highest biological activities (p < 0.05) with Trolox equivalent antioxidant capacity value of 8.8 ± 0.1 mmol Trolox/mg, DPPH· inhibition of 19.5 ± 3.8%, equivalent concentration of 12.1 ± 0.7 µM FeSO4/mg, lipid peroxidation inhibition of 31.3 ± 2.4%, collagenase inhibition of 60.8 ± 2.1%, elastase inhibition of 17.0 ± 0.1%, and no irritation effect on chorioallantoic membrane and volunteers. Therefore, aqueous extract of A. domesticus would be suggested for further topical product development.
Data-driven identification of diagnostically useful extrastriatal signal in dopamine transporter SPECT using explainable AI
Authors: Nazari Mahmood , Kluge Andreas , Apostolova Ivayla , Klutmann Susanne , Kimiaei Sharok , Schroeder Michael , Buchert Ralph
Published: November 2021

This study used explainable artificial intelligence for data-driven identification of extrastriatal brain regions that can contribute to the interpretation of dopamine transporter SPECT with 123I-FP-CIT in parkinsonian syndromes. A total of 1306 123I-FP-CIT-SPECT were included retrospectively. Binary classification as ‘reduced’ or ‘normal’ striatal 123I-FP-CIT uptake by an experienced reader served as standard-of-truth. A custom-made 3-dimensional convolutional neural network (CNN) was trained for classification of the SPECT images with 1006 randomly selected images in three different settings: “full image”, “striatum only” (3-dimensional region covering the striata cropped from the full image), “without striatum” (full image with striatal region removed). The remaining 300 SPECT images were used to test the CNN classification performance. Layer-wise relevance propagation (LRP) was used for voxelwise quantification of the relevance for the CNN-based classification in this test set. Overall accuracy of CNN-based classification was 97.0%, 95.7%, and 69.3% in the “full image”, “striatum only”, and “without striatum” setting. Prominent contributions in the LRP-based relevance maps beyond the striatal signal were detected in insula, amygdala, ventromedial prefrontal cortex, thalamus, anterior temporal cortex, superior frontal lobe, and pons, suggesting that 123I-FP-CIT uptake in these brain regions provides clinically useful information for the differentiation of neurodegenerative and non-neurodegenerative parkinsonian syndromes.
Solid-state fermented brewer's spent grain enzymatic extract increases in vitro and in vivo feed digestibility in European seabass
Authors: Fernandes Helena , Moyano Francisco , Castro Carolina , Salgado José , Martínez Francisca , Aznar María , Fernandes Nelson , Ferreira Patrícia , Gonçalves Margarida , Belo Isabel , Oliva-Teles Aires , Peres Helena
Published: November 2021

Brewer’s spent grain (BSG) is the largest by-product originated from the brewery industry with a high potential for producing carbohydrases by solid-state fermentation. This work aimed to test the efficacy of a carbohydrases-rich extract produced from solid-state fermentation of BSG, to enhance the digestibility of a plant-based diet for European seabass (Dicentrarchus labrax). First, BSG was fermented withA. ibericusto obtain an aqueous lyophilized extract (SSF-BSG extract) and incorporated in a plant-based diet at increasing levels (0—control; 0.1%, 0.2%, and 0.4%). Another diet incorporating a commercial carbohydrases-complex (0.04%; Natugrain; BASF) was formulated. Then, all diets were tested in in vitro and in vivo digestibility assays. In vitro assays, simulating stomach and intestine digestion in European seabass, assessed dietary phosphorus, phytate phosphorus, carbohydrates, and protein hydrolysis, as well as interactive effects between fish enzymes and dietary SSF-BSG extract. After, an in vivo assay was carried out with European seabass juveniles fed selected diets (0—control; 0.1%, and 0.4%). In vitro digestibility assays showed that pentoses release increased 45% with 0.4% SSF-BSG extract and 25% with Natugrain supplemented diets, while amino acids release was not affected. A negative interaction between endogenous fish enzymes and SSF-BSG extract was observed in both diets. The in vivo digestibility assay corroborated in vitro data. Accordingly, the dietary supplementation with 0.4% SSF-BSG increased the digestibility of dry matter, starch, cellulose, glucans, and energy and did not affect protein digestibility. The present work showed the high potential of BSG to produce an added-value functional supplement with high carbohydrases activity and its potential contribution to the circular economy by improving the nutritional value of low-cost and sustainable ingredients that can be included in aquafeeds.