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This work is part of a study of different types of plant-based biomass to elucidate their capacity for valorisation via a managed carbonation step involving gaseous carbon dioxide (CO2). The perspectives for broader biomass waste valorisation was reviewed, followed by a proposed closed-loop process for the valorisation of wood in earlier works. The present work newly focusses on combining agricultural biomass with mineralised CO2. Here, the reactivity of selected agricultural biomass ashes with CO2 and their ability to be bound by mineralised carbonate in a hardened product is examined. Three categories of agricultural biomass residues, including shell, fibre and soft peel, were incinerated at 900 ± 25 °C. The biomass ashes were moistened (10% w/w) and moulded into cylindrical samples and exposed to 100% CO2 gas at 50% RH for 24 h, during which they cemented into hardened monolithic products. The calcia in ashes formed a negative relationship with ash yield and the microstructure of the carbonate-cementing phase was distinct and related to the particular biomass feedstock. This work shows that in common with woody biomass residues, carbonated agricultural biomass ash-based monoliths have potential as novel low-carbon construction products.

With the advent of the genetic era in Parkinson’s disease (PD) research in 1997, α-synuclein was identified as an important player in a complex neurodegenerative disease that affects >10 million people worldwide. PD has been estimated to have an economic impact of $51.9 billion in the US alone. Since the initial association with PD, hundreds of researchers have contributed to elucidating the functions of α-synuclein in normal and pathological states, and these remain critical areas for continued research. With this position paper the authors strive to achieve two goals: first, to succinctly summarize the critical features that define α-synuclein’s varied roles, as they are known today; and second, to identify the most pressing knowledge gaps and delineate a multipronged strategy for future research with the goal of enabling therapies to stop or slow disease progression in PD.

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained. We hypothesize that some cases of ND-CA are caused by aberrant DNA methylation leading to dysregulated genome function. Comparing DNA methylation profiles from 489 individuals with ND-CAs against 1534 controls, we identify epivariations as a frequent occurrence in the human genome. De novo epivariations are significantly enriched in cases, while RNAseq analysis shows that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detect and replicate an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations, providing a rationale for interpreting non-coding variation. We propose that epivariations contribute to the pathogenesis of some patients with unexplained ND-CAs, and as such likely have diagnostic relevance., The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai., The authors are grateful to the patients and families who participated in this study and to the collaborators who supported patient recruitment. This work was supported by NIH grant HG006696 and research grant 6-FY13-92 from the March of Dimes to A.J.S., grant HL098123 to B.D.G. and A.J.S., Gulbenkian Programme for Advanced Medical Education and the Portuguese Foundation for Science and Technology (SFRH/BDINT/51549/ 2011, PIC/IC/83026/2007, PIC/IC/83013/2007, SFRH/BD/90167/2012, Portugal) to P.M., F.L., and M.B., by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013) to P.M., a Beatriu de Pinos Postdoctoral Fellowship to R.S.J. (2011BP-A00515), and a Seaver Foundation fellowship to S.D.R. The views expressed are those of the authors and do not necessarily reflect those of the National Heart, Lung, and Blood Institute or the National Institutes of Health. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

In this paper we present an investigation of parental-diet-driven metabolic programming in offspring using a novel computational network analysis tool. The impact of high paternal carbohydrate intake on offsprings’ phospholipid and triglyceride metabolism in F1 and F2 generations is described. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate offspring in serum, liver, brain, heart and abdominal adipose tissues by MS and NMR. Using a purpose-built computational tool for analysing both phospholipid and fat metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of reprogrammings associated with paternal diet. These results are important because they describe the long-term metabolic result of dietary intake by fathers. This analytical approach is important because it offers unparalleled insight into possible mechanisms for alterations in lipid metabolism throughout organisms., Furse et al. use a purpose-built computational tool called Lipid Traffic Analysis to determine the spatial distribution of lipids throughout an organism. They use it to show that high paternal carbohydrate intake influences lipid metabolism in offspring two generations hence.

Scientific software from all areas of scientific research is pivotal to obtaining novel insights. Yet the coding standards adherence of scientific software is rarely assessed, even though it might lead to incorrect scientific results in the worst case. Therefore, we have developed an open source tool and benchmark called , that provides a relative software coding standards adherence ranking of 48 computational tools from diverse research areas. can be used in the review process of software papers and to inform the scientific software selection process.

Local implantable drug delivery system (IDDS) can be used as an effective adjunctive therapy for solid tumor following thermal ablation for destroying the residual cancer cells and preventing the tumor recurrence. In this paper, we develop comprehensive mathematical pharmacokinetic/pharmacodynamic (PK/PD) models for combination therapy using implantable drug delivery system following thermal ablation inside solid tumors with the help of molecular communication paradigm. In this model, doxorubicin (DOX)-loaded implant (act as a transmitter) is assumed to be inserted inside solid tumor (acts as a channel) after thermal ablation. Using this model, we can predict the extracellular and intracellular concentration of both free and bound drugs. Also, Impact of the anticancer drug on both cancer and normal cells is evaluated using a pharmacodynamic (PD) model that depends on both the spatiotemporal intracellular concentration as well as characteristics of anticancer drug and cells. Accuracy and validity of the proposed drug transport model is verified with published experimental data in the literature. The results show that this combination therapy results in high therapeutic efficacy with negligible toxicity effect on the normal tissue. The proposed model can help in optimize development of this combination treatment for solid tumors, particularly, the design parameters of the implant.

On 2 January 2020, the neuroscience community lost not only a pioneering figure, but also a generous and influential thought leader. Bruce Sherman McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at the Rockefeller University, passed away at age 81, following a short illness. A member of the National Academy of Sciences, National Academy of Medicine and American Academy of Arts & Sciences, and former president of the Society for Neuroscience, Bruce will be remembered for his profound scientific impact, measured not only by output of papers, but also by the large family of neuroscientists he trained over a career spanning nearly six decades. Above all, Bruce will be remembered for his generosity, kindness, gentleness of soul, and for being an extraordinary mentor.

High-voltage electrical defibrillation remains the only reliable method of quickly controlling life-threatening cardiac arrhythmias. This paper is devoted to studying an alternative approach, low-voltage cardioversion (LVC), which is based on ideas from non-linear dynamics and aims to remove sources of cardiac arrhythmias by applying high-frequency stimulation to cardiac tissue. We perform a detailed in-silico study of the elimination of arrhythmias caused by rotating spiral waves in a TP06 model of human cardiac tissue. We consider three parameter sets with slopes of the APD restitution curve of 0.7, 1.1 and 1.4, and we study LVC at the baseline and under the blocking of INa and ICaL and under the application of the drugs verapamil and amiodarone. We show that pacing can remove spiral waves; however, its efficiency can be substantially reduced by dynamic instabilities. We classify these instabilities and show that the blocking of INa and the application of amiodarone increase the efficiency of the method, while the blocking of ICaL and the application of verapamil decrease the efficiency. We discuss the mechanisms and the possible clinical applications resulting from our study. © 2020, The Author(s). Supported by Russian Science Foundation Project No. 17-71-20024.

In this paper we develop statistical algorithms to infer possible cardiac pathologies, based on data collected from 24 h Holter recording over a sample of 2829 labelled patients; labels highlight whether a patient is suffering from cardiac pathologies. In the first part of the work we analyze statistically the heart-beat series associated to each patient and we work them out to get a coarse-grained description of heart variability in terms of 49 markers well established in the reference community. These markers are then used as inputs for a multi-layer feed-forward neural network that we train in order to make it able to classify patients. However, before training the network, preliminary operations are in order to check the effective number of markers (via principal component analysis) and to achieve data augmentation (because of the broadness of the input data). With such groundwork, we finally train the network and show that it can classify with high accuracy (at most ~85% successful identifications) patients that are healthy from those displaying atrial fibrillation or congestive heart failure. In the second part of the work, we still start from raw data and we get a classification of pathologies in terms of their related networks: patients are associated to nodes and links are drawn according to a similarity measure between the related heart-beat series. We study the emergent properties of these networks looking for features (e.g., degree, clustering, clique proliferation) able to robustly discriminate between networks built over healthy patients or over patients suffering from cardiac pathologies. We find overall very good agreement among the two paved routes.

The characterization of topology is crucial in understanding network evolution and behavior. This paper presents an innovative approach, the GHuST framework to describe complex-network topology from graphlet decomposition. This new framework exploits the local information provided by graphlets to give a global explanation of network topology. The GHuST framework is comprised of 12 metrics that analyze how 2- and 3-node graphlets shape the structure of networks. The main strengths of the GHuST framework are enhanced topological description, size independence, and computational simplicity. It allows for straight comparison among different networks disregarding their size. It also reduces the complexity of graphlet counting, since it does not use 4- and 5-node graphlets. The application of the novel framework to a large set of networks shows that it can classify networks of distinct nature based on their topological properties. To ease network classification and enhance the graphical representation of them, we reduce the 12 dimensions to their main principal components. Furthermore, the 12 dimensions are easily interpretable. This enables the connection between complex-network analyses and diverse real applications.

This paper reports on a tunable transmission frequency characteristics-based metamaterial absorber of an X band sensing application with a fractional bandwidth. Tunable resonator metamaterial absorbers fabricated with dielectric surface have been the subject of growing attention of late. Absorbers possess electromagnetic properties and range modification capacity, and they have yet to be studied in detail. The proposed microstructure resonator inspired absorber with triple fractional band absorption consists of two balanced symmetrical vertical patches at the outer periphery and a tiny drop hole at two edges. Experimental verification depicted two absorption bands with single negative (SNG) characteristics for two resonances, but double negative (DNG) for single resonance frequency. The mechanism of sensing and absorption was analyzed using the transmission line principle with useful parameter analysis. Cotton, a hygroscopic fiber with moisture content, was chosen to characterize the proposed absorber for the X band application. The electrical properties of the cotton changed depending on the moisture absorption level. The simulation and the measured absorption approximately justified the result; the simulated absorption was above 90% (at 10.62, 11.64, and 12.8 GHz), although the steady level was 80%. The moisture content of the cotton (at different levels from 0 to 32.13%) was simulated, and the transmission resonance frequency changed its point in two significant ranges. However, comparing the two adopted measurement method and algorithm applied to the S parameter showed a closer variation between the two resonances (11.64 and 12.8 GHz) which signified that a much more accurate measurement of the cotton dielectric constant was possible up to a moisture content of 16.1%. However, certain unwanted changes were noted at 8.4–8.9 GHz and 10.6–12.4 GHz. The proposed triple-band absorber has potential applications in the X band sensing of moisture in capsules or tablet bottles.

In this paper an automatic adaptive antenna impedance tuning algorithm is presented that is based on quantum inspired genetic optimization technique. The proposed automatic quantum genetic algorithm (AQGA) is used to find the optimum solution for a low-pass passive T-impedance matching LC-network inserted between an RF transceiver and its antenna. Results of the AQGA tuning method are presented for applications across 1.4 to 5 GHz (satellite services, LTE networks, radar systems, and WiFi bands). Compared to existing genetic algorithm-based tuning techniques the proposed algorithm converges much faster to provide a solution. At 1.4, 2.3, 3.4, 4.0, and 5.0 GHz bands the proposed AQGA is on average 75%, 49.2%, 64.9%, 54.7%, and 52.5% faster than conventional genetic algorithms, respectively. The results reveal the proposed AQGA is feasible for real-time application in RF-front-end systems. This work is partially supported by RTI2018-095499-B-C31, Funded by Ministerio de Ciencia, Innovación y Universidades, Gobierno de España (MCIU/AEI/FEDER,UE), and innovation programme under grant agreement H2020-MSCA-ITN-2016 SECRET-722424 and the financial support from the UK Engineering and Physical Sciences Research Council (EPSRC) under grant EP/E022936/1.

Meiotic recombination is essential for producing healthy gametes, and also generates genetic diversity. DNA double-strand break (DSB) formation is the initiating step of meiotic recombination, producing, among other outcomes, crossovers between homologous chromosomes (homologs), which provide physical links to guide accurate chromosome segregation. The parameters influencing DSB position and repair are thus crucial determinants of reproductive success and genetic diversity. UsingSchizosaccharomyces pombe, we show that the distance between sequence polymorphisms across homologs has a strong impact on meiotic recombination rate. The closer the sequence polymorphisms are to each other across the homologs the fewer recombination events were observed. In the immediate vicinity of DSBs, sequence polymorphisms affect the frequency of intragenic recombination events (gene conversions). Additionally, and unexpectedly, the crossover rate of flanking markers tens of kilobases away from the sequence polymorphisms was affected by their relative position to each other amongst the progeny having undergone intragenic recombination. A major regulator of this distance-dependent effect is the MutSα-MutLα complex consisting of Msh2, Msh6, Mlh1, and Pms1. Additionally, the DNA helicases Rqh1 and Fml1 shape recombination frequency, although the effects seen here are largely independent of the relative position of the sequence polymorphisms.PreambleDue to a mistake during analysis of a batch of Sanger sequencing reactions for Supplementary Figure S1, we erroneously stated that we found evidence for intragenic crossovers. We now show that intragenic crossovers are less likely than we initially thought. We sincerely apologize for our mishap and any inconvenience it might have caused. However, this does not affect the main conclusions of our paper, just how some of our results are interpreted. This new manuscript version has been amended accordingly.

Increased tolerance to light stress in cyanobacteria is a desirable feature for their applications. Here, we obtained a high light tolerant (Tol) strain of Synechocystis sp. PCC6803 through an adaptive laboratory evolution, in which the cells were repeatedly sub-cultured for 52 days under high light stress conditions (7000 to 9000 μmol m−2 s−1). Although the growth of the parental strain almost stopped when exposed to 9000 μmol m−2 s−1, no growth inhibition was observed in the Tol strain. Excitation-energy flow was affected because of photosystem II damage in the parental strain under high light conditions, whereas the damage was alleviated and normal energy flow was maintained in the Tol strain. The transcriptome data indicated an increase in isiA expression in the Tol strain under high light conditions. Whole genome sequence analysis and reverse engineering revealed two mutations in hik26 and slr1916 involved in high light stress tolerance in the Tol strain., In this paper, the authors investigated the high light stress response in Synechocystis sp. PCC6803 and revealed two key mutations in hik26 and slr1916 using whole genome sequencing and reverse engineering. Here, the high light tolerant strain exhibited no growth inhibition in conditions up to 9000 μmol m−2 s−1, which had no effect on excitation-energy flow and instead showed an increase in isiA expression.

The size of the membrane-bound nucleus scales with cell size in a wide range of cell types but the mechanisms determining overall nuclear size remain largely unknown. Here we investigate the role of fission yeast inner nuclear membrane proteins in determining nuclear size, and propose that the Lap2-Emerin-Man1 domain protein Lem2 acts as a barrier to membrane flow between the nucleus and other parts of the cellular membrane system. Lem2 deletion increases membrane flow into and out of the nuclear envelope in response to changes in membrane synthesis and nucleocytoplasmic transport, altering nuclear size. The endoplasmic reticulum protein Lnp1 acts as a secondary barrier to membrane flow, functionally compensating for lack of Lem2. We propose that this is part of the mechanism that maintains nuclear size proportional to cellular membrane content and thus to cell size. Similar regulatory principles may apply to other organelles in the eukaryotic subcellular membrane network., This work was supported by the Francis Crick Institute [www.crick.ac.uk] (to P.N.), which receives its core funding from Cancer Research UK (FC01121), the UK Medical Research Council (FC01121), and the Wellcome Trust (FC01121). This work was also supported by the Wellcome Trust [grant number 093917] [www.wellcome.ac.uk] (to P.N.), JSPS Postdoctoral Fellowships for Research Abroad (to K.K.), JSPS KAKENHI [grants JP26660089 and 17K07756] [http://www.jsps.go.jp/j-grantsinaid/index.html] (to K.K.), JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers (S2902) (to K.K.), the Hiroshima University Education and Research Support Foundation (to K.K.), the Breast Cancer Research Foundation (to P.N.) and The Lord Leonard and Lady Estelle Wolfson Foundation [www.lordandladywolfson.org.uk] (to P.N.)., Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-019-09623-x.

This paper proposes an algorithm for estimating the arterial viscosity using cuff pressures and pulse waves measured by an automatic oscillometric sphygmomanometer. A change in the arterial viscosity during the enclosed-zone flow-mediated dilation test is calculated as an index for evaluating the vascular endothelial function %η. In all, 43 individuals participated in this study. After the index %η was calculated, the accuracy of the index %η in distinguishing healthy subjects and subjects at a high risk of arteriosclerosis was tested via a receiving operating characteristic (ROC) analysis. The calculated %η for the healthy participants and those at a high risk of arteriosclerosis was 13.4 ± 55.1% and −32.7 ± 34.0% (mean ± S.D.), respectively. The area under the ROC curve was 0.77. Thus, it was concluded that the proposed method can be used to evaluate the vascular endothelial function., This research was partly supported by the Transportation Technology Development Promotion Competitive Funding Program from Ministry of Land, Infrastructure, Transport and Tourism, and the Center of Innovation Program from Japan Science and Technology Agency.

Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-39097-2., Bacteriophage endolysins present enormous biotechnological potentials and have been successfully used to control and detect bacterial pathogens. Endolysins targeting Gram-positive bacteria are modular, displaying a cell binding (CBD) and an enzymatically active domain. The CBD of phage endolysins are recognized by their high specificity and?host affinity, characteristics that make them promising diagnostic tools. No CBD able to bind Paenibacillus larvae has been identified so far. P. larvae is a Gram-positive spore forming bacteria that causes the American Foulbrood. This highly contagious infection leads to honeybee larvae sepsis and death, resulting in an adverse impact on pollination and on the beekeeping industry. In this work, the first CBD targeting P. larvae was identified and its core binding sequence was investigated. Moreover, it was shown that the domain is highly specific, targeting exclusively P. larvae cells from all ERIC genotypes. The identification of such a domain represents a step forward for the development of effective methods to detect and control this pathogen., This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the project APILYSE, PTDC/CVT-EPI/4008/2014 (POCI-01-0145-FEDER-016598) and by the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 (POCI-01-0145-FEDER-006684) and BioTecNorte operation (NORTE-01-0145-FEDER-000004) funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. S.B.S. was supported by the grant SFRH/BPD/75311/2010 from FCT. We would also like to acknowledge Doctor Vanessa Corby-Harris for gently providing the strain of Parasaccharibacter apium alpha 2.2., info:eu-repo/semantics/publishedVersion

Since its inception more than 25 years ago, Piezoresponse Force Microscopy (PFM) has become one of the mainstream techniques in the field of nanoferroic materials. This review describes the evolution of PFM from an imaging technique to a set of advanced methods, which have played a critical role in launching new areas of ferroic research, such as multiferroic devices and domain wall nanoelectronics. The paper reviews the impact of advanced PFM modes concerning the discovery and scientific understanding of novel nanoferroic phenomena and discusses challenges associated with the correct interpretation of PFM data. In conclusion, it offers an outlook for future trends and developments in PFM. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

11 páginas.- 4 figuras.- 2 tablas.-- 44 referencias.- Supplementary Information accompanies this paper at https://doi.org/10.1038/s41467-019-10453-0 .- Data availability Estimation of species demographic parameters and pairwise competitive coefficients for both climatic treatments are available at Dryad Digital Repository https://doi.org/10.5061/dryad.5d1s952. Average species means for the 19 functional traits included in this experiment are included in Supplementary Table 1., Functional traits are expected to modulate plant competitive dynamics. However, how traits and their plasticity in response to contrasting environments connect with the mechanisms determining species coexistence remains poorly understood. Here, we couple field experiments under two contrasting climatic conditions to a plant population model describing competitive dynamics between 10 annual plant species in order to evaluate how 19 functional traits, covering physiological, morphological and reproductive characteristics, are associated with species’ niche and fitness differences. We find a rich diversity of univariate and multidimensional associations, which highlight the primary role of traits related to water- and light-use-efficiency for modulating the determinants of competitive outcomes. Importantly, such traits and their plasticity promote species coexistence across climatic conditions by enhancing stabilizing niche differences and by generating competitive trade-offs between species. Our study represents a significant advance showing how leading dimensions of plant function connect to the mechanisms determining the maintenance of biodiversity., Funding support to conduct the experiment was provided by the Spanish Ecological Terrestrial Society (AEET, Jóvenes Investigadores grant 2014/2). I.M. P.-R. and L.M. were funded by a “Ramón & Cajal” contract (RYC-2013-13937) and an “Acción 6 UJA” fellowship (EI_RNM4_2017), respectively. O.G. acknowledges postdoctoral financial support provided by the European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement (No. 661118-BioFUNC). I.M.P.-R. and L.G.-A. also thank support from the MICINN projects DECAFUN (CGL2015-70123-R) and INTERCAPA (CGL-2014-56739-R).

Ce:YAG nanostructures (Ce:YAG = Cerium in Yttrium Aluminium Garnet), easy to control and shape, have been prepared via templating approach using natural and synthetic materials (i.e. paper, cotton wool and glass wool) previously soaked with a gel-like metals precursor and then thermally treated to achieve the wished morphology. The final material, otherwise difficult to process, can be easily moulded, it is lightweight, portable and forms, at the nanoscale, homogeneous layers of interconnected but not agglomerated nanoparticles (15 ± 5 nm). Using the same synthetic route, called Urea-Glass-Route, but in absence of a template, extremely pure Ce:YAG nanoparticle (45 ± 5 nm) can be also prepared, highly crystalline and well-defined in size and shape. Both structural and optical properties of the final materials were investigated, showing high optical quality. The support allows the production of a multifunctional material with mouldable shape and potential lighting application for large structures combining the strength, chemical durability, fire resistance, and translucency of glass fibres. Last, but not least, the synthetic path also allows an easy scaling up of the process: the first, key step for practical application of nanosized rare-earth doped YAG on large scale.

Most cancer-related deaths are a result of metastasis, and thus the importance of this process as a target of therapy cannot be understated. By asking ‘how can we effectively treat cancer?’, we do not capture the complexity of a disease encompassing >200 different cancer types — many consisting of multiple subtypes — with considerable intratumoural heterogeneity, which can result in variable responses to a specific therapy. Moreover, we have much less information on the pathophysiological characteristics of metastases than is available for the primary tumour. Most disseminated tumour cells that arrive in distant tissues, surrounded by unfamiliar cells and a foreign microenvironment, are likely to die; however, those that survive can generate metastatic tumours with a markedly different biology from that of the primary tumour. To treat metastasis effectively, we must inhibit fundamental metastatic processes and develop specific preclinical and clinical strategies that do not rely on primary tumour responses. To address this crucial issue, Cancer Research UK and Cancer Therapeutics CRC Australia formed a Metastasis Working Group with representatives from not-for-profit, academic, government, industry and regulatory bodies in order to develop recommendations on how to tackle the challenges associated with treating (micro)metastatic disease. Herein, we describe the challenges identified as well as the proposed approaches for discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer., Most cancer-related deaths are attributable to metastasis, but few treatments are specifically designed to disrupt this process. In this Position Paper, representatives of the joint Cancer Research UK and Cancer Therapeutics CRC Australia Metastasis Working Group describe the challenges associated with discovering and developing anticancer agents designed specifically to prevent or delay the metastatic outgrowth of cancer and provide guidance on how these challenges might be overcome., Key points Metastasis is associated with a poor patient prognosis and is the foremost cause of cancer-related death, with approximately 90% of patients who succumb to cancer dying of metastatic disease.Metastasis is inherently complex, with different distant sites having a distinct and specific extracellular matrix and cellular composition compared with that of the originating site, and therefore metastases must be considered biologically different from the primary tumour.The standard cancer drug discovery and development pathway, including that for molecularly targeted and immunotherapies, generally ignores the ability of experimental medicines to inhibit metastasis.A wealth of potential preclinical targets for anti-metastatic drug discovery and development have already been identified but remain to be validated using appropriate preclinical models that reflect the pathogenesis of metastatic disease in patients.Despite some successes in the treatment of bone metastases, following extensive analyses in preclinical models, multiple late-stage failures in clinical development have resulted in anti-metastatic drug development efforts being deprioritized by the pharmaceutical industry.Successful development of effective anti-metastatic therapies will require the regulatory agencies to work together with researchers, drug developers and statisticians to redefine the clinical development paradigm in order to encourage development of this complex but high-potential category of oncology drugs.

Communication between osteoblasts and osteoclasts plays a key role in bone metabolism. We describe here an unexpected role for matrix vesicles (MVs), which bud from boneforming osteoblasts and have a well-established role in initiation of bone mineralization, in osteoclastogenesis. We show that the MV cargo miR-125b accumulates in the bone matrix, with increased accumulation in transgenic (Tg) mice overexpressing miR-125b in osteoblasts. Bone formation and osteoblasts in Tg mice are normal, but the number of bone-resorbing osteoclasts is reduced, leading to higher trabecular bone mass. miR-125b in the bone matrix targets and degrades Prdm1, a transcriptional repressor of anti-osteoclastogenic factors, in osteoclast precursors. Overexpressing miR-125b in osteoblasts abrogates bone loss in different mouse models. Our results show that the MV cargo miR-125b is a regulatory element of osteoblast-osteoclast communication, and that bone matrix provides extracellular storage of miR-125b that is functionally active in bone resorption., T.M. and Y.T. were supported in part by MEXT KAKENHI (JP16K11443, T.M.; JP26861548, Y.T.). Y.Y. was supported by MEXT KAKENHI (JP18K19647), the Raffinee International Foundation and the Ono Pharmaceutical Foundation., Supplementary information is available for this paper at https://doi.org/10.1038/s42003-020-0754-2.

Recently, slow earthquakes (slow EQ) have received much attention relative to understanding the mechanisms underlying large earthquakes and to detecting their precursors. Low-frequency earthquakes (LFE) are a specific type of slow EQ. In the present paper, we reveal the relevance of LFEs to the 11 March 2011 Great Tohoku Earthquake (Tohoku-oki EQ) by means of cluster analysis. We classified LFEs in northern Japan in a data-driven manner, based on inter-time, the time interval between neighboring LFEs occurring within 10 km. We found that there are four classes of LFE that are characterized by median inter-times of 24 seconds, 27 minutes, 2.0 days, and 35 days, respectively. Remarkably, in examining the relevance of these classes to the Tohoku-oki EQ, we found that activity in the shortest inter-time class (median 24 seconds) diminished significantly at least three months before the Tohoku-oki EQ, and became completely quiescent 30 days before the event (p-value = 0.00014). Further statistical analysis implies that this class, together with a similar class of volcanic tremor, may have served as a precursor of the Tohoku-oki EQ. We discuss a generative model for these classes of LFE, in which the shortest inter-time class is characterized by a generalized gamma distribution with the product of shape parameters vκ = 1:54 in the domain of inter-time close to zero. We give a possible geodetic interpretation for the relevance of LFE to the Tohoku-oki EQ.

Chronic or sustained hyperglycemia associated to diabetes mellitus leads to many medical complications, thus, it is necessary to track the evolution of patients for providing the adequate management of the disease that is required for the restoration of the carbohydrate metabolism to a normal state. In this paper, a novel monitoring approach based on mm-wave spectroscopy is comprehensively described and experimentally validated using living animal models as target. The measurement method has proved the possibility of non-invasive, in-vivo, detection of hyperglycemia-associated conditions in different mouse models, making possible to clearly differentiate between several hyperglycemic states.

In clinical practice, subjective pain evaluations, e.g., the visual analogue scale and the numeric rating scale, are generally employed, but these are limited in terms of their ability to detect inaccurate reports, and are unsuitable for use in anesthetized patients or those with dementia. We focused on the peripheral sympathetic nerve activity that responds to pain, and propose a method for evaluating pain sensation, including intensity, sharpness, and dullness, using the arterial stiffness index. In the experiment, electrocardiogram, blood pressure, and photoplethysmograms were obtained, and an arterial viscoelastic model was applied to estimate arterial stiffness. The relationships among the stiffness index, self-reported pain sensation, and electrocutaneous stimuli were examined and modelled. The relationship between the stiffness index and pain sensation could be modelled using a sigmoid function with high determination coefficients, where R2 ≥ 0.88, p, This work was supported by the Center of Innovation Program from Japan Science and Technology Agency., Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-018-21223-1.