bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast cancer colonization by Fusobacterium nucleatum accelerates tumor growth and metastatic progression
Authors: Parhi Lishay , Alon-Maimon Tamar , Sol Asaf , Nejman Deborah , Shhadeh Amjad , Fainsod-Levi Tanya , Yajuk Olga , Isaacson Batya , Abed Jawad , Maalouf Naseem , Nissan Aviram , Sandbank Judith , Yehuda-Shnaidman Einav , Ponath Falk , Vogel Jörg , Mandelboim Ofer , Granot Zvi , Straussman Ravid , Bachrach Gilad
Published: June 2020

Fusobacterium nucleatum is an oral anaerobe recently found to be prevalent in human colorectal cancer (CRC) where it is associated with poor treatment outcome. In mice, hematogenous F. nucleatum can colonize CRC tissue using its lectin Fap2, which attaches to tumor-displayed Gal-GalNAc. Here, we show that Gal-GalNAc levels increase as human breast cancer progresses, and that occurrence of F. nucleatum gDNA in breast cancer samples correlates with high Gal-GalNAc levels. We demonstrate Fap2-dependent binding of the bacterium to breast cancer samples, which is inhibited by GalNAc. Intravascularly inoculated Fap2-expressing F. nucleatum ATCC 23726 specifically colonize mice mammary tumors, whereas Fap2-deficient bacteria are impaired in tumor colonization. Inoculation with F. nucleatum suppresses accumulation of tumor infiltrating T cells and promotes tumor growth and metastatic progression, the latter two of which can be counteracted by antibiotic treatment. Thus, targeting F. nucleatum or Fap2 might be beneficial during treatment of breast cancer.
Genetic drug target validation using Mendelian randomisation
Authors: Schmidt Amand F. , Finan Chris , Gordillo-Marañón Maria , Asselbergs Folkert W. , Freitag Daniel F. , Patel Riyaz S. , Tyl Benoît , Chopade Sandesh , Faraway Rupert , Zwierzyna Magdalena , Hingorani Aroon D.
Published: June 2020

Mendelian randomisation (MR) analysis is an important tool to elucidate the causal relevance of environmental and biological risk factors for disease. However, causal inference is undermined if genetic variants used to instrument a risk factor also influence alternative disease-pathways (horizontal pleiotropy). Here we report how the ‘no horizontal pleiotropy assumption’ is strengthened when proteins are the risk factors of interest. Proteins are typically the proximal effectors of biological processes encoded in the genome. Moreover, proteins are the targets of most medicines, so MR studies of drug targets are becoming a fundamental tool in drug development. To enable such studies, we introduce a mathematical framework that contrasts MR analysis of proteins with that of risk factors located more distally in the causal chain from gene to disease. We illustrate key model decisions and introduce an analytical framework for maximising power and evaluating the robustness of analyses.
Selective ion sensing with high resolution large area graphene field effect transistor arrays
Authors: Fakih Ibrahim , Durnan Oliver , Mahvash Farzaneh , Napal Ilargi , Centeno Alba , Zurutuza Amaia , Yargeau Viviane , Szkopek Thomas
Published: June 2020

Real-time, high resolution, simultaneous measurement of multiple ionic species is challenging with existing chromatographic, spectrophotometric and potentiometric techniques. Potentiometric ion sensors exhibit limitations in both resolution and selectivity. Herein, we develop wafer scale graphene transistor technology for overcoming these limitations. Large area graphene is an ideal material for high resolution ion sensitive field effect transistors (ISFETs), while simultaneously enabling facile fabrication as compared to conventional semiconductors. We develop the ISFETs into an array and apply Nikolskii–Eisenman analysis to account for cross-sensitivity and thereby achieve high selectivity. We experimentally demonstrate real-time, simultaneous concentration measurement of K+, Na+, $${{\rm{NH}}}_{4}^{+}$$NH4+, $${{\rm{NO}}}_{3}^{-}$$NO3−, $${{\rm{SO}}}_{4}^{2-}$$SO42−, $${{\rm{HPO}}}_{4}^{2-}$$HPO42− and Cl− with a resolution of $$\sim\! 2\times 1{0}^{-3}\,{\mathrm{log}}\,$$~2×10−3log concentration units. The array achieves an accuracy of  ±0.05 log concentration. Finally, we demonstrate real-time ion concentration measurement in an aquarium with lemnoideae lemna over three weeks, where mineral uptake by aquatic organisms can be observed during their growth.
Fishing for newly synthesized proteins with phosphonate-handles
Authors: Kleinpenning Fleur , Steigenberger Barbara , Wu Wei , Heck Albert J. R.
Published: June 2020

Bioorthogonal chemistry introduces affinity-labels into biomolecules with minimal disruption to the original system and is widely applicable in a range of contexts. In proteomics, immobilized metal affinity chromatography (IMAC) enables enrichment of phosphopeptides with extreme sensitivity and selectivity. Here, we adapt and combine these superb assets in a new enrichment strategy using phosphonate-handles, which we term PhosID. In this approach, click-able phosphonate-handles are introduced into proteins via 1,3-dipolar Huisgen-cycloaddition to azido-homo-alanine (AHA) and IMAC is then used to enrich exclusively for phosphonate-labeled peptides. In interferon-gamma (IFNγ) stimulated cells, PhosID enabled the identification of a large number of IFN responsive newly synthesized proteins (NSPs) whereby we monitored the differential synthesis of these proteins over time. Collectively, these data validate the excellent performance of PhosID with efficient analysis and quantification of hundreds of NSPs by single LC-MS/MS runs. We envision PhosID as an attractive and alternative tool for studying stimuli-sensitive proteome subsets.
Employing a MEMS plasma switch for conditioning high-voltage kinetic energy harvesters
Authors: Zhang Hemin , Marty Frédéric , Xia Xin , Zi Yunlong , Bourouina Tarik , Galayko Dimitri , Basset Philippe
Published: June 2020

Triboelectric nanogenerators have attracted wide attention due to their promising capabilities of scavenging the ambient environmental mechanical energy. However, efficient energy management of the generated high-voltage for practical low-voltage applications is still under investigation. Autonomous switches are key elements for improving the harvested energy per mechanical cycle, but they are complicated to implement at such voltages higher than several hundreds of volts. This paper proposes a self-sustained and automatic hysteresis plasma switch made from silicon micromachining, and implemented in a two-stage efficient conditioning circuit for powering low-voltage devices using triboelectric nanogenerators. The hysteresis of this microelectromechanical switch is controllable by topological design and the actuation of the switch combines the principles of micro-discharge and electrostatic pulling, without the need of any power-consuming control electronic circuits. The experimental results indicate that the energy harvesting efficiency is improved by two orders of magnitude compared to the conventional full-wave rectifying circuit.
A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Authors: Bery Nicolas , Miller Ami , Rabbitts Terry
Published: June 2020

Tumour-associated KRAS mutations are the most prevalent in the three RAS-family isoforms and involve many different amino-acids. Therefore, molecules able to interfere with mutant KRAS protein are potentially important for wide-ranging tumour therapy. We describe the engineering of two RAS degraders based on protein macromolecules (macrodrugs) fused to specific E3 ligases. A KRAS-specific DARPin fused to the VHL E3 ligase is compared to a pan-RAS intracellular single domain antibody (iDAb) fused to the UBOX domain of the CHIP E3 ligase. We demonstrate that while the KRAS-specific DARPin degrader induces specific proteolysis of both mutant and wild type KRAS, it only inhibits proliferation of cancer cells expressing mutant KRAS in vitro and in vivo. Pan-RAS protein degradation, however, affects proliferation irrespective of the RAS mutation. These data show that specific KRAS degradation is an important therapeutic strategy to affect tumours expressing any of the range of KRAS mutations.
Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing
Authors: Wei Tuo , Cheng Qiang , Min Yi-Li , Olson Eric N. , Siegwart Daniel J.
Published: June 2020

CRISPR-Cas9 has emerged as a powerful technology that relies on Cas9/sgRNA ribonucleoprotein complexes (RNPs) to target and edit DNA. However, many therapeutic targets cannot currently be accessed due to the lack of carriers that can deliver RNPs systemically. Here, we report a generalizable methodology that allows engineering of modified lipid nanoparticles to efficiently deliver RNPs into cells and edit tissues including muscle, brain, liver, and lungs. Intravenous injection facilitated tissue-specific, multiplexed editing of six genes in mouse lungs. High carrier potency was leveraged to create organ-specific cancer models in livers and lungs of mice though facile knockout of multiple genes. The developed carriers were also able to deliver RNPs to restore dystrophin expression in DMD mice and significantly decrease serum PCSK9 level in C57BL/6 mice. Application of this generalizable strategy will facilitate broad nanoparticle development for a variety of disease targets amenable to protein delivery and precise gene correction approaches.
miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling
Authors: Knarr Matthew , Avelar Rita A. , Sekhar Sreeja C. , Kwiatkowski Lily J. , Dziubinski Michele L. , McAnulty Jessica , Skala Stephanie , Avril Stefanie , Drapkin Ronny , DiFeo Analisa
Published: June 2020

Genomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.
Focus on the spectra that matter by clustering of quantification data in shotgun proteomics
Authors: The Matthew , Käll Lukas
Published: June 2020

In shotgun proteomics, the analysis of label-free quantification experiments is typically limited by the identification rate and the noise level in the quantitative data. This generally causes a low sensitivity in differential expression analysis. Here, we propose a quantification-first approach for peptides that reverses the classical identification-first workflow, thereby preventing valuable information from being discarded in the identification stage. Specifically, we introduce a method, Quandenser, that applies unsupervised clustering on both MS1 and MS2 level to summarize all analytes of interest without assigning identities. This reduces search time due to the data reduction. We can now employ open modification and de novo searches to identify analytes of interest that would have gone unnoticed in traditional pipelines. Quandenser+Triqler outperforms the state-of-the-art method MaxQuant+Perseus, consistently reporting more differentially abundant proteins for all tested datasets. Software is available for all major operating systems at https://github.com/statisticalbiotechnology/quandenser, under Apache 2.0 license.
Groundwater level observations in 250,000 coastal US wells reveal scope of potential seawater intrusion
Authors: Jasechko Scott , Perrone Debra , Seybold Hansjörg , Fan Ying , Kirchner James W.
Published: June 2020

Seawater intrusion into coastal aquifers can increase groundwater salinity beyond potable levels, endangering access to freshwater for millions of people. Seawater intrusion is particularly likely where water tables lie below sea level, but can also arise from groundwater pumping in some coastal aquifers with water tables above sea level. Nevertheless, no nation-wide, observation-based assessment of the scope of potential seawater intrusion exists. Here we compile and analyze ~250,000 coastal groundwater-level observations made since the year 2000 in the contiguous United States. We show that the majority of observed groundwater levels lie below sea level along more than 15% of the contiguous coastline. We conclude that landward hydraulic gradients characterize a substantial fraction of the East Coast (>18%) and Gulf Coast (>17%), and also parts of the West Coast where groundwater pumping is high. Sea level rise, coastal land subsidence, and increasing water demands will exacerbate the threat of seawater intrusion.
Acoustic spin-Chern insulator induced by synthetic spin–orbit coupling with spin conservation breaking
Authors: Deng Weiyin , Huang Xueqin , Lu Jiuyang , Peri Valerio , Li Feng , Huber Sebastian D. , Liu Zhengyou
Published: June 2020

Topologically protected surface modes of classical waves hold the promise to enable a variety of applications ranging from robust transport of energy to reliable information processing networks. However, both the route of implementing an analogue of the quantum Hall effect as well as the quantum spin Hall effect are obstructed for acoustics by the requirement of a magnetic field, or the presence of fermionic quantum statistics, respectively. Here, we construct a two-dimensional topological acoustic crystal induced by the synthetic spin-orbit coupling, a crucial ingredient of topological insulators, with spin non-conservation. Our setup allows us to free ourselves of symmetry constraints as we rely on the concept of a non-vanishing “spin” Chern number. We experimentally characterize the emerging boundary states which we show to be gapless and helical. More importantly, we observe the spin flipping transport in an H-shaped device, demonstrating evidently the spin non-conservation of the boundary states.
An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
Authors: Ai Youwei , He Haibing , Chen Peihao , Yan Bo , Zhang Wenbin , Ding Zhangcheng , Li Dianrong , Chen Jie , Ma Yan , Cao Yang , Zhu Jie , Li Jiaojiao , Ou Jinjie , Du Shan , Wang Xiaodong , Ma Jianzhang , Gao Shuanhu , Qi Xiangbing
Published: June 2020

The promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A’s phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A’s canonical function. We demonstrate that PDE3A’s H840, Q975, Q1001, and F1004 residues—as well as I105 in SLFN12—are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.
In planta study of photosynthesis and photorespiration using NADPH and NADH/NAD+ fluorescent protein sensors
Authors: Lim Shey-Li , Voon Chia Pao , Guan Xiaoqian , Yang Yi , Gardeström Per , Lim Boon Leong
Published: June 2020

The challenge of monitoring in planta dynamic changes of NADP(H) and NAD(H) redox states at the subcellular level is considered a major obstacle in plant bioenergetics studies. Here, we introduced two circularly permuted yellow fluorescent protein sensors, iNAP and SoNar, into Arabidopsis thaliana to monitor the dynamic changes in NADPH and the NADH/NAD+ ratio. In the light, photosynthesis and photorespiration are linked to the redox states of NAD(P)H and NAD(P) pools in several subcellular compartments connected by the malate-OAA shuttles. We show that the photosynthetic increases in stromal NADPH and NADH/NAD+ ratio, but not ATP, disappear when glycine decarboxylation is inhibited. These observations highlight the complex interplay between chloroplasts and mitochondria during photosynthesis and support the suggestions that, under normal conditions, photorespiration supplies a large amount of NADH to mitochondria, exceeding its NADH-dissipating capacity, and the surplus NADH is exported from the mitochondria to the cytosol through the malate-OAA shuttle.
Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids
Authors: Du Xiaoyong , Xiao Ye , Huang Jia-Ming , Zhang Yao , Duan Ya-Nan , Wang Heng , Shi Chuan , Chen Gen-Qiang , Zhang Xumu
Published: June 2020

Asymmetric hydrogenation of α,β-unsaturated acids catalyzed by noble metals has been well established, whereas, the asymmetric hydrogenation with earth-abundant-metal was rarely reported. Here, we describe a cobalt-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids. By using chiral cobalt catalyst bearing electron-donating diphosphine ligand, high activity (up to 1860 TON) and excellent enantioselectivity (up to >99% ee) are observed. Furthermore, the cobalt-catalyzed asymmetric hydrogenation is successfully applied to a broad spectrum of α,β-unsaturated carboxylic acids, such as various α-aryl and α-alkyl cinnamic acid derivatives, α-oxy-functionalized α,β-unsaturated acids, α-substituted acrylic acids and heterocyclic α,β-unsaturated acids (30 examples). The synthetic utility of the protocol is highlighted by the synthesis of key intermediates for chiral drugs (6 cases). Preliminary mechanistic studies reveal that the carboxy group may be involved in the control of the reactivity and enantioselectivity through an interaction with the metal centre.
Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression
Authors: Guo Yubin , Ye Qing , Deng Pan , Cao Yanan , He Daheng , Zhou Zhaohe , Wang Chi , Zaytseva Yekaterina Y. , Schwartz Charles E. , Lee Eun Y. , Evers B. Mark , Morris Andrew J. , Liu Side , She Qing-Bai
Published: June 2020

Dysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC.
The receptor PTPRU is a redox sensitive pseudophosphatase
Authors: Hay Iain M. , Fearnley Gareth W. , Rios Pablo , Köhn Maja , Sharpe Hayley J. , Deane Janet E.
Published: June 2020

The receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.
The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure
Authors: Turnbull Robert E. , Fairall Louise , Saleh Almutasem , Kelsall Emma , Morris Kyle L. , Ragan T. J. , Savva Christos G. , Chandru Aditya , Millard Christopher J. , Makarova Olga V. , Smith Corinne J. , Roseman Alan M. , Fry Andrew M. , Cowley Shaun M. , Schwabe John W. R.
Published: June 2020

MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
Ultrafast diffusion exchange nuclear magnetic resonance
Authors: Mankinen Otto , Zhivonitko Vladimir V. , Selent Anne , Mailhiot Sarah , Komulainen Sanna , Prisle Nønne L. , Ahola Susanna , Telkki Ville-Veikko
Published: June 2020

The exchange of molecules between different physical or chemical environments due to diffusion or chemical transformations has a crucial role in a plethora of fundamental processes such as breathing, protein folding, chemical reactions and catalysis. Here, we introduce a method for a single-scan, ultrafast NMR analysis of molecular exchange based on the diffusion coefficient contrast. The method shortens the experiment time by one to four orders of magnitude. Consequently, it opens the way for high sensitivity quantification of important transient physical and chemical exchange processes such as in cellular metabolism. As a proof of principle, we demonstrate that the method reveals the structure of aggregates formed by surfactants relevant to aerosol research.
Histopathologic, immunophenotypic, and proteomics characteristics of low-grade phyllodes tumor and fibroadenoma: more similarities than differences
Authors: Zhang Lingxin , Yang Chen , Pfeifer John D. , Caprioli Richard M. , Judd Audra M. , Patterson Nathan H. , Reyzer Michelle L. , Norris Jeremy L. , Maluf Horacio M.
Published: June 2020

Distinguishing low-grade phyllodes tumor from fibroadenoma is practically challenging due to their overlapping histologic features. However, the final interpretation is essential to surgeons, who base their management on the final pathology report. Patients who receive a diagnosis of fibroadenoma might not undergo any additional intervention while lumpectomy with wide margins is the standard of care for phyllodes tumor, which can have significant cosmetic consequences. We studied the clinical, immunophenotypic, and proteomics profiles of 31 histologically confirmed low-grade phyllodes tumor and 30 fibroadenomas. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) and immunohistochemistry for Ki-67, p53, β-catenin, and E-cadherin were performed on all cases. After the mass spectra for all 31 cases of low-grade phyllodes tumor and 30 cases of fibroadenoma were collected, an average peak value for all cases was generated. There was no significant difference in the overall mass spectra pattern in any of the peaks identified. There was also overlap in the percentage of cells staining positive for Ki-67, p53, β-catenin, and E-cadherin. The two groups of patients showed no statistically significant difference in age, tumor size, or disease-free survival. Neither group developed malignant transformation, distant metastases, or disease-related mortality. We have demonstrated low-grade phyllodes tumor and fibroadenoma to show significant overlapping clinical and proteomics features.
In vivo evaluation of porous nanohydroxyapatite/polyamide 66 struts in a goat cervical fusion model
Authors: Liang Xi , Li Feilong , Gong Xuan , Li Junchao , Yin Shijie , Li Qi , Liu Ziming , Zhao Zenghui , Tu Xiaolin , Huang Wei , Hu Ning
Published: June 2020

The hollow cylindrical nanohydroxyapatite/polyamide 66 strut (n-HA/PA66) has been used clinically for anterior cervical reconstruction. However, rates of occurrence of a “radiolucent gap” between the dense strut and adjacent endplates were reported. The aim of this in vivo study was to evaluate the viability and advantages of the novel porous n-HA/PA66 strut. The goat C3/4 partial discectomy and fusion model was built, and two groups of n-HA/PA66 struts were implanted into C3/4: group 1, porous n-HA/PA66 strut; and group 2, hollow cylindrical n-HA/PA66 strut filled with autogenous cancellous bone. CT evaluation was performed to assess the fusion status after 12 and 24 weeks. The cervical spines were harvested. Histomorphological analysis was performed to determine new bone formation. Biomechanical testing was performed to determine range of motion (ROM). CT confirmed the disappearance of the boundary of the porous strut and host bone, while the radiolucent gap remained clearly discernible in the dense strut group. The mean CT fusion scores of the porous group were significantly higher. Histologic evaluation showed that the porous struts promoted better osteointegration. Calcein fluorochrome labelling indicated faster bone ingrowth in the porous struts. Biomechanical tests revealed that the porous struts had significantly reduced micromotion. The porous n-HA/PA66 strut could offer interesting potential for cervical reconstruction after corpectomy.
Relationship between the characteristic traits of polycystic ovary syndrome and susceptibility genes
Authors: Hong So-hyeon , Hong Young Sun , Jeong Kyungah , Chung Hyewon , Lee Hyejin , Sung Yeon-Ah
Published: June 2020

Polycystic ovary syndrome (PCOS) is a highly complex disorder influenced by genetic and environmental factors. Previous genome-wide association studies (GWAS) on Han Chinese, Korean, and European populations identified multiple PCOS-susceptible loci; however, only a few studies reported the association of susceptibility genes with disease phenotypic traits. This cross-sectional study aimed to investigate the association between PCOS susceptibility genes from GWAS and disease-related clinical features. A total of 1,810 reproductive-aged women were recruited, including 927 control women and 883 women with PCOS, diagnosed based on the European Society for Human Reproduction and Embryology criteria. Genomic DNA was extracted and genotyped, and a Bonferroni test was performed to determine the association between 12 independent SNPs and the clinical features of PCOS. In women with PCOS, rs11031006, nearest to FSHB, was significantly associated with free testosterone (P = 1.94 × 10−3) and luteinizing hormone (P = 1.96 × 10−3) levels. The menstruation number per year, ovarian follicular number, ovarian volume, and insulin sensitivity index were not associated with any SNP. In the control group, no SNPs were associated with any PCOS traits. Collectively, our results suggest that FSHB may play an important role in the development and progression of PCOS.
Exploratory dynamics of vocal foraging during infant-caregiver communication
Authors: Ritwika V. P. S. , Pretzer Gina M. , Mendoza Sara , Shedd Christopher , Kello Christopher T. , Gopinathan Ajay , Warlaumont Anne S.
Published: June 2020

We investigated the hypothesis that infants search in an acoustic space for vocalisations that elicit adult utterances and vice versa, inspired by research on animal and human foraging. Infant-worn recorders were used to collect day-long audio recordings, and infant speech-related and adult vocalisation onsets and offsets were automatically identified. We examined vocalisation-to-vocalisation steps, focusing on inter-vocalisation time intervals and distances in an acoustic space defined by mean pitch and mean amplitude, measured from the child’s perspective. Infant inter-vocalisation intervals were shorter immediately following a vocal response from an adult. Adult intervals were shorter following an infant response and adult inter-vocalisation pitch differences were smaller following the receipt of a vocal response from the infant. These findings are consistent with the hypothesis that infants and caregivers are foraging vocally for social input. Increasing infant age was associated with changes in inter-vocalisation step sizes for both infants and adults, and we found associations between response likelihood and acoustic characteristics. Future work is needed to determine the impact of different labelling methods and of automatic labelling errors on the results. The study represents a novel application of foraging theory, demonstrating how infant behaviour and infant-caregiver interaction can be characterised as foraging processes.
LoTToR: An Algorithm for Missing-Wedge Correction of the Low-Tilt Tomographic 3D Reconstruction of a Single-Molecule Structure
Authors: Zhai Xiaobo , Lei Dongsheng , Zhang Meng , Liu Jianfang , Wu Hao , Yu Yadong , Zhang Lei , Ren Gang
Published: June 2020

A single-molecule three-dimensional (3D) structure is essential for understanding the thermal vibrations and dynamics as well as the conformational changes during the chemical reaction of macromolecules. Individual-particle electron tomography (IPET) is an approach for obtaining a snap-shot 3D structure of an individual macromolecule particle by aligning the tilt series of electron tomographic (ET) images of a targeted particle through a focused iterative 3D reconstruction method. The method can reduce the influence on the 3D reconstruction from large-scale image distortion and deformation. Due to the mechanical tilt limitation, 3D reconstruction often contains missing-wedge artifacts, presented as elongation and an anisotropic resolution. Here, we report a post-processing method to correct the missing-wedge artifact. This low-tilt tomographic reconstruction (LoTToR) method contains a model-free iteration process under a set of constraints in real and reciprocal spaces. A proof of concept is conducted by using the LoTToR on a phantom, i.e., a simulated 3D reconstruction from a low-tilt series of images, including that within a tilt range of ±15°. The method is validated by using both negative-staining (NS) and cryo-electron tomography (cryo-ET) experimental data. A significantly reduced missing-wedge artifact verifies the capability of LoTToR, suggesting a new tool to support the future study of macromolecular dynamics, fluctuation and chemical activity from the viewpoint of single-molecule 3D structure determination.
Quantitative analysis of proteins which are members of the same protein complex but cause locus heterogeneity in disease
Authors: Gamba Alessio , Salmona Mario , Bazzoni Gianfranco
Published: June 2020

It is still largely unknown how mutations in different genes cause similar diseases – a condition known as locus heterogeneity. A likely explanation is that the different proteins encoded by the locus heterogeneity genes participate in the same biological function and, specifically, that they belong to the same protein complex. Here we report that, in up to 30% of the instances of locus heterogeneity, the disease-causing proteins are indeed members of the same protein complex. Moreover, we observed that, in many instances, the diseases and protein complexes only partially intersect. Among the possible explanations, we surmised that some genes that encode proteins in the complex have not yet been reported as causing disease and are therefore candidate disease genes. Mutations of known human disease genes and murine orthologs of candidate disease genes that encode proteins in the same protein complex do in fact often cause similar phenotypes in humans and mice. Furthermore, we found that the disease-complex intersection is not only incomplete but also non-univocal, with many examples of one disease intersecting more than one protein complex or one protein complex intersecting more than one disease. These limits notwithstanding, this study shows that action on proteins in the same complex is a widespread pathogenic mechanism underlying numerous instances of locus heterogeneity.
Distal lung epithelial progenitor cell function declines with age
Authors: Watson Julie K. , Sanders Philip , Dunmore Rebecca , Rosignoli Guglielmo , Julé Yvon , Rawlins Emma L. , Mustelin Tomas , May Richard , Clarke Deborah , Finch Donna K.
Published: June 2020

Tissue stem cell exhaustion is a key hallmark of aging, and in this study, we characterised its manifestation in the distal lung. We compared the lungs of 3- and 22-month old mice. We examined the gross morphological changes in these lungs, the density and function of epithelial progenitor populations and the epithelial gene expression profile. Bronchioles became smaller in their cross-sectional area and diameter. Using long-term EdU incorporation analysis and immunohistochemistry, we found that bronchiolar cell density remained stable with aging, but inferred rates of bronchiolar club progenitor cell self-renewal and differentiation were reduced, indicative of an overall slowdown in cellular turnover. Alveolar Type II progenitor cell density and self-renewal were maintained per unit tissue area with aging, but rates of inferred differentiation into Type I cells, and indeed overall density of Type I cells was reduced. Microarray analysis revealed age-related changes in multiple genes, including some with roles in proliferation and differentiation, and in IGF and TGFβ signalling pathways. By characterising how lung stem cell dynamics change with aging, this study will elucidate how they contribute to age-related loss of pulmonary function, and pathogenesis of common age-related pulmonary diseases.
Using critical slowing down indicators to understand economic growth rate variability and secular stagnation
Authors: Rye Craig D. , Jackson Tim
Published: June 2020

This paper utilizes Critical Slowing Down (CSD; instability) indicators developed by statistical physics to analyse economic growth rate variability and secular stagnation in historical GDP data. Understanding these phenomena is vital, particularly in advanced economies faced with declining growth rates. Two novel indicators - the autocorrelation (AR1) and the variance – are found particularly useful in providing insight into inter-decadal GDP variability over this period. These indicators are first applied to the Maddison-Project historical dataset, which includes almost a century of data for some 80 countries and almost two centuries of data for 9 countries. They are additionally applied to ~50 years of recent annual data for around 130 countries from the World Bank dataset as well as ~60 years of recent quarterly data for around 20 countries from the OECD dataset. Analysis reveals inter-decadal variability in growth cycles (the recession cycle), highlighting periods of large slow growth cycles and periods of small fast growth cycles. The most commonly occurring pattern is characterised by an increase in CSD from the 1900s to 1940s, a decline in CSD between the 1930s and the 1970s, then a further increase in CSD from the 1960s to 2010. This pattern is significant in ~70% of the advanced economies. CSD indicators may then provide invaluable insights into specific aspects of inter-decadal GDP variability, such as on the nature of the business cycle, secular stagnation and the implicit “restoring forces” of the economy.
A population-based survey for dietary patterns and prediabetes among 7555 Chinese adults in urban and rural areas in Jiangsu Province
Authors: Cao Ye , Chen Chong , Cui Lan , Han Aohan , Tu Qingyun , Lou Peian , Ding Ganling , Qin Yu , Xiang Quanyong
Published: June 2020

Background: Prediabetes is an important public health problem concern globally, to which dietary patterns have shown varied effects. This study aims to analyze the relationship between dietary patterns and prediabetes in Chinese adults. Methods: A total of 7555 adults from Jiangsu province, China, were recruited using a stratified multistage cluster sampling method. Information on diet intake, demographic, blood glucose and other indices were collected by structured questionnaires. Four dietary patterns of Meat diet, Healthy diet, Traditional diet and Fried food with staple diet were identified using Principle Component Analysis and followingly divided into T1 - T4 groups according to their quartiles of factor scores. Multivariate logistic regression analysis was used to investigate the association between dietary patterns and prediabetes. Results: Healthy diet was found to be associated with the lowest prevalence of prediabetes (P < 0.05). Multivariate logistic regression analysis after adjusting the confounding factors demonstrated that the lowest odds ratio with prediabetes was associated with the third quartile (T3 group) of Healthy diet (Odds Ratio = 0.745, 95% Confidence Interval: 0.645–0.860, P < 0.01), compared with the lower quartile (T1 group). The Meat diet was a potential risk factor for the isolated IFG (Odds Ratio = 1.227, 95%Confidence Interval: 1.070–1.406, P-value<0.01) while Fried food with staple diet was positively linked to the presence of IFG combined with IGT (Odds Ratio = 1.735, 95% Confidence Interval: 1.184–2.543, P-value < 0.01). Conclusions: Dietary patterns rich in meat but low in fresh fruit, fresh vegetable, milk, and fish are positively associated with higher risk of prediabetes, particularly the IFG. Higher Healthy diet consumption was associated with significantly lower risk of prediabetes.
The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production
Authors: An Hongying , Wang Yu , Qin Caolitao , Li Mingsong , Maheshwari Akhil , He Ling
Published: June 2020

Metformin has been used to treat patients with type 2 diabetes for over 60 years, however, its mechanism of action is still not completely understood. Our previous reports showed that high-fat-diet (HFD)-fed mice with liver-specific knockout of both AMPK catalytic α1 and α2 subunits exhibited significantly higher fasting blood glucose levels and produced more glucose than floxed AMPK catalytic α1 and α2 mice after long-term metformin treatment, and that metformin promotes the formation of the functional AMPK αβγ heterotrimeric complex. We tested the importance of each regulatory γ subunit isoform to metformin action in this current study. We found that depletion of γ1, but not γ2 or γ3, drastically reduced metformin activation of AMPK. HFD-fed mice with depletion of the γ1 subunit are resistant to metformin suppression of liver glucose production. Furthermore, we determined the role of each regulatory cystathionine-β-synthase (CBS) domain in the γ1 subunit in metformin action and found that deletion of either CBS1 or CBS4 negated metformin’s effect on AMPKα phosphorylation at T172 and suppression of glucose production in hepatocytes. Our data indicate that the γ1 subunit is required for metformin’s control of glucose metabolism in hepatocytes. Furthermore, in humans and animal models, metformin treatment leads to the loss of body weight, we found that the decrease in body weight gain in mice treated with metformin is not directly attributable to increased energy expenditure.
REM versus Non-REM sleep disturbance specifically affects inter-specific emotion processing in family dogs (Canis familiaris)
Authors: Bolló Henrietta , Kovács Krisztina , Lefter Radu , Gombos Ferenc , Kubinyi Enikő , Topál József , Kis Anna
Published: June 2020

Dogs have outstanding capabilities to read human emotional expressions, both vocal and facial. It has also been shown that positively versus negatively valenced dog-human social interactions substantially affect dogs’ subsequent sleep. In the present study, we manipulated dogs’ (N = 15, in a within subject design) sleep structure by specifically disrupting REM versus Non-REM sleep, while maintaining equal sleep efficiency (monitored via non-invasive polysomnography). We found that both the number of awakenings as well as relative Non-REM (but not relative REM) duration influenced dogs’ viewing patterns in a task where sad and happy human faces were simultaneously projected with sad or happy human voice playbacks. In accordance with the emotion laterality hypothesis, the interaction between sound valence and Non-REM sleep duration was specific to images projected to the left (regardless of image-sound congruency). These results reveal the first evidence of a causal link between sleep structure and inter-specific emotion-processing in the family dog.
Impact of controlled-release urea on rice yield, nitrogen use efficiency and soil fertility in a single rice cropping system
Authors: Chen Zhaoming , Wang Qiang , Ma Junwei , Zou Ping , Jiang Lina
Published: June 2020

Overuse of nitrogen (N) fertilizer has led to low N use efficiency (NUE) and high N loss in single rice cropping systems in southeast China. Application of controlled-release urea (CRU) is considered as an effective N fertilizer practice for improving crop yields and NUE. Here, field experiments were conducted during 2015–2017 to assess the effects of two CRUs (resin-coated urea (RCU) and polyurethane-coated urea (PCU)) on rice yields, NUE and soil fertility at two sites (Lincheng town (LC) and Xintang town (XT)). Four treatments were established at each site: (1) control with no N application (CK), (2) split application of conventional urea (U, 270 kg N ha−1), (3) single basal application of RCU (RCU, 216 kg N ha−1), and (4) single basal application of PCU (PCU, 216 kg N ha−1). The N application rate in the CRU treatment compared to the U treatment was reduced by 20%. However, the results showed that, compared to split application of urea, single basal application of CRU led to similar rice grain yields and aboveground biomass at both sites. No significant difference in the N uptake by rice plant was observed between the U and CRU treatments at either site. There were no significant differences in the N apparent recovery efficiency (NARE) among the U, RCU and PCU treatments, with the exception of that in XT in 2015. Compared to application of U, application of CRU increased the N agronomic efficiency (NAE) and N partial factor productivity (NPFP) by 17.4–52.6% and 23.4–29.8% at the LC site, and 15.0–84.1% and 23.2–33.4% at the XT site, respectively, during 2015–2017. Yield component analysis revealed that greater rice grain yield in response to N fertilizer was attributed mainly to the number of panicles per m2, which increased in the fertilized treatments compared to the CK treatment. The application of CRU did not affect the soil fertility after rice harvest in 2016. Overall, these results suggest that single basal application of CRU constitutes a promising alternative N management practice for reducing N application rates, time- and labor-consuming in rice production in southeast China.
Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice
Authors: Goodlett Charles R. , Stringer Megan , LaCombe Jonathan , Patel Roshni , Wallace Joseph M. , Roper Randall J.
Published: June 2020

Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS.
Individual differences in local functional brain connectivity affect TMS effects on behavior
Authors: Gießing Carsten , Alavash Mohsen , Herrmann Christoph S. , Hilgetag Claus C. , Thiel Christiane M.
Published: June 2020

Behavioral effects of transcranial magnetic stimulation (TMS) often show substantial differences between subjects. One factor that might contribute to these inter-individual differences is the interaction of current brain states with the effects of local brain network perturbation. The aim of the current study was to identify brain regions whose connectivity before and following right parietal perturbation affects individual behavioral effects during a visuospatial target detection task. 20 subjects participated in an fMRI experiment where their brain hemodynamic response was measured during resting state, and then during a visuospatial target detection task following 1 Hz rTMS and sham stimulation. To select a parsimonious set of associated brain regions, an elastic net analysis was used in combination with a whole-brain voxel-wise functional connectivity analysis. TMS-induced changes in accuracy were significantly correlated with the pattern of functional connectivity during the task state following TMS. The functional connectivity of the left superior temporal, angular, and precentral gyri was identified as key explanatory variable for the individual behavioral TMS effects. Our results suggest that the brain must reach an appropriate state in which right parietal TMS can induce improvements in visual target detection. The ability to reach this state appears to vary between individuals.