bluuebunny/crossref_metadata_2025 huggingface dataset:
Tocqueville, Democratic Poetry, and the Religion of Humanity
Authors: Daglier Üner
Published: July 2021

The Religion of Humanity has typically been associated with Auguste Comte's positivism. Within liberal philosophical debate, John Stuart Mill's measured advocacy for it has received some attention, especially given his otherwise well-known emphasis on the tension between religion and liberty. Yet Alexis de Tocqueville's perceptive awareness of the Religion of Humanity as an evolving phenomenon, expressed through his discussion of democratic poetry, remained largely unnoticed. Of course, Tocqueville's essential religio-political task was to promote a modified version of Christianity and buttress the standing of religious morality as an outside barrier against human action motivated by democratic materialism, notwithstanding the secular doctrine of self-interest well understood. Indeed, despite the neutral tone of Tocqueville's discussion of democratic poetry, elsewhere his critique of democratic pantheism, writers and orators, theatre, and historians warned against excessive veneration of humanity, which amounted to a sublimation of the dogma of the sovereignty of the people.
The threatened Rufous Limestone BabblerGypsophila calcicola—not a quarry species, but a “quarried species”
Authors: ROUND PHILIP D. , TANTIPISANUH NARUEMON , EIAMAMPAI KRAIRAT , ASENSIO NORBERTO
Published: July 2021

Limestone karst habitats are threatened globally by quarrying for production of concrete and cement. A significant area of limestone karst shared among the provinces of Saraburi, Lopburi and Nakhon Ratchasima in Thailand encompasses the entire global range of a threatened bird taxon, the Rufous Limestone BabblerGypsophila calcicola.We estimate that 10% of the suitable habitat for this species had already been lost to quarrying by 2020, and the extension of already proposed concessions could increase this to one-quarter, with the total area impacted by proposed future quarrying as great as 273 km2, or one and a half times greater than the entire area thought to support the species, within a few years. Only 2.66 km2(1.4% of the species’ range) has received formal habitat protection as national park. We propose further surveys of the babbler be incorporated as part of a wider biotic survey of the Saraburi Group Limestones, leading to the development of an integrated management and zoning plan that takes account of the distributional knowledge of other threatened endemic taxa of this region.
On directed analogues of expander and hyperfinite graph sequences
Authors: Csóka Endre , Grabowski Łukasz
Published: July 2021

We introduce and study analogues of expander and hyperfinite graph sequences in the context of directed acyclic graphs, which we call ‘extender’ and ‘hypershallow’ graph sequences, respectively. Our main result is a probabilistic construction of non-hypershallow graph sequences.
A Fast Algorithm for Scanning Transmission Electron Microscopy Imaging and 4D-STEM Diffraction Simulations
Authors: Pelz Philipp M. , Rakowski Alexander , Rangel DaCosta Luis , Savitzky Benjamin H. , Scott Mary C. , Ophus Colin
Published: July 2021

Scanning transmission electron microscopy (STEM) is an extremely versatile method for studying materials on the atomic scale. Many STEM experiments are supported or validated with electron scattering simulations. However, using the conventional multislice algorithm to perform these simulations can require extremely large calculation times, particularly for experiments with millions of probe positions as each probe position must be simulated independently. Recently, the plane-wave reciprocal-space interpolated scattering matrix (PRISM) algorithm was developed to reduce calculation times for large STEM simulations. Here, we introduce a new method for STEM simulation: partitioning of the STEM probe into “beamlets,” given by a natural neighbor interpolation of the parent beams. This idea is compatible with PRISM simulations and can lead to even larger improvements in simulation time, as well requiring significantly less computer random access memory (RAM). We have performed various simulations to demonstrate the advantages and disadvantages of partitioned PRISM STEM simulations. We find that this new algorithm is particularly useful for 4D-STEM simulations of large fields of view. We also provide a reference implementation of the multislice, PRISM, and partitioned PRISM algorithms.
Impulsivität und assoziierte Konstrukte bei drogenabhängigen Patienten
Authors: Reichl Daniela , Bonn Elisabeth , Enewoldsen Niklas , Schwenzner Stefanie , Steins-Loeber Sabine
Published: July 2021

Zusammenfassung. Zielsetzung: Die vorliegende Pilotstudie untersuchte, ob selbstberichtete Achtsamkeit bei drogenabhängigen Patienten negativ mit impulsivem Verhalten assoziiert ist und ob dieser Zusammenhang über eine effektivere Emotionsregulation vermittelt wird. Ferner wurde die Relevanz der Differenzierung verschiedener Impulsivitäts-Facetten im Zusammenhang mit Craving und Abstinenzzuversicht untersucht. Methodik: Einunddreißig männliche drogenabhängige Patienten in stationärer Entwöhnung beantworteten Fragen zu Achtsamkeit (MAAS), Emotionsregulationskompetenzen (SEK-27), Depressivität (PHQ-9), Craving (MaCS) und Abstinenzzuversicht (HEISA-16). Impulsivität wurde zum einen als selbstberichtetes Trait-Merkmal (BIS-15) erfasst. Weiterhin wurden die verhaltensbezogenen Komponenten impulsives Entscheidungsverhalten (Delay Discouting Task) und substanzbezogene Inhibitionskontrolle (Go-/No-Go-Aufgabe) erhoben. Ergebnisse: Achtsamkeit war negativ mit Trait-Impulsivität assoziiert und hing, mediiert über höhere Emotionsregulationskompetenzen, positiv mit Inhibitionskontrolle zusammen. Trait-Impulsivität und Delay Discounting erwiesen sich als Korrelate von Craving. Keine der Impulsivitäts-Facetten war mit Abstinenzzuversicht assoziiert. Schlussfolgerungen: Die Differenzierung der Impulsivitäts-Facetten stellte sich als bedeutsam heraus. Experimentelle Designs sind nun notwendig, um die in der vorliegenden Pilotstudie gefundenen Zusammenhänge hinsichtlich ihrer Kausalität zu prüfen.
Adult Mental Health and Loneliness During the COVID-19 Pandemic in Late 2020
Authors: Emir Öksüz Elif , Kalkan Bilal , Can Nesime , Haktanir Abdulkadir
Published: July 2021

Abstract. The COVID-19 pandemic had an adverse impact on the mental health of numerous people. To examine the psychological status of the general public across Turkey during the COVID-19 pandemic, we collected data from 1,109 adults, ages ranging from 18 to 72 years. We used a demographic questionnaire, the Symptom Checklist-90-R (SCL-90-R), and the abbreviated version of the UCLA Loneliness Scale. The mean score of the participants on the SCL-90-R was 1.14 ( SD = .78), and 16% of the participants scored 1 standard deviation above the mean. Some groups, including women and students, showed more severe psychological symptoms. The obsessive-compulsiveness, interpersonal sensitivity, and depression subscales had the highest three mean scores. We compared the SCL-90-R scores to previous study results and found a significant increase during the pandemic. Finally, individual stressors, COVID-19-related stressors, and perceived loneliness were found to be significant predictors, explaining 31% of the variance in psychological symptoms. Although collecting data online through self-report inventories limits the generalizability of the results, this study has important implications. Its results suggest that future clinical interventions should focus on obsessive-compulsiveness, interpersonal sensitivity, and depression among specific risk groups.
Temporal Variability in Bottom Water Structures of the Continental Slope in the Northern South China Sea
Authors: Qu Ling , Lu Yuan‐Zheng , Cen Xian‐Rong , Guo Shuang‐Xi , Huang Peng‐Qi , Yu Lu‐Sha , Zhou Sheng‐Qi , Shang Xiao‐Dong , Mao Hua‐Bin , Chen Ju , Sun Zong‐Xun
Published: July 2021

Temporal variability in bottom water structures has been observed in 37‐h high‐resolution temperature data at the ocean bottom up to 67.4 m on the continental shelf of the northern South China Sea. The water temperature is generally hot (cold) in the downslope (upslope) flow, but rapid temperature change is associated with the cross‐slope flow intensity changes. Downslope, wandering, and upslope phases are classified depending on the flow directions. Ellison scale method is used to evaluate the turbulent mixing. Intensive dissipation is observed in the wandering phase, the vertically integrated dissipation Eɛ ∼ 322 mW/m2 and the eddy diffusivity 〈Kz〉 in 0.01–0.15 m2/s, which is attributed to the critical interaction between the semidiurnal tides and the slope boundary. Eɛ is gradually reduced to 38.1 mW/m2 in the upslope phase, in which the topography is subcritical to the internal tides, while 〈Kz〉 is occasionally promoted to 0.077 m2/s owing to the weaker stratification. The bottom mixed layer is persistently exhibited, but highly intermittent around 13.9 m and varies from 0.2 m to greater than 67.4 m. Its thickness depends strongly on the water stratification and seems not to be directly linked with the turbulent mixing. The bottom unstable layer occurs mainly in the period slightly before and in the first half of the upslope flow phase. The induced convection makes a substantial contribution to the turbulent mixing when the overall mixing is relatively mild. In the intense mixing, even though the convectively driven mixing becomes much stronger, its contribution is less significant.
Can a data driven obesity classification system identify those at risk of severe COVID-19 in the UK Biobank cohort study?
Authors: Clark Stephen , Morris Michelle , Lomax Nik , Birkin Mark
Published: July 2021

COVID-19 is a disease that has been shown to have outcomes that vary by certain socio-demographic and socio-economic groups. It is increasingly important that an understanding of these outcomes should be derived not from the consideration of one aspect, but by a more multi-faceted understanding of the individual. In this study use is made of a recent obesity driven classification of participants in the United Kingdom Biobank (UKB) to identify trends in COVID-19 outcomes. This classification is informed by a recently created obesity systems map, and the COVID-19 outcomes are: undertaking a test, a positive test, hospitalisation and mortality. It is demonstrated that the classification is able to identify meaningful differentials in these outcomes. This more holistic approach is recommended for identification and prioritisation of COVID-19 risk and possible long-COVID determination.
Learning of food preferences: mechanisms and implications for obesity & metabolic diseases
Authors: Berthoud Hans-Rudolf , Morrison Christopher D. , Ackroff Karen , Sclafani Anthony
Published: July 2021

Omnivores, including rodents and humans, compose their diets from a wide variety of potential foods. Beyond the guidance of a few basic orosensory biases such as attraction to sweet and avoidance of bitter, they have limited innate dietary knowledge and must learn to prefer foods based on their flavors and postoral effects. This review focuses on postoral nutrient sensing and signaling as an essential part of the reward system that shapes preferences for the associated flavors of foods. We discuss the extensive array of sensors in the gastrointestinal system and the vagal pathways conveying information about ingested nutrients to the brain. Earlier studies of vagal contributions were limited by nonselective methods that could not easily distinguish the contributions of subsets of vagal afferents. Recent advances in technique have generated substantial new details on sugar- and fat-responsive signaling pathways. We explain methods for conditioning flavor preferences and their use in evaluating gut–brain communication. The SGLT1 intestinal sugar sensor is important in sugar conditioning; the critical sensors for fat are less certain, though GPR40 and 120 fatty acid sensors have been implicated. Ongoing work points to particular vagal pathways to brain reward areas. An implication for obesity treatment is that bariatric surgery may alter vagal function.
Sex steroids receptors, hypertension, and vascular ageing
Authors: Connelly Paul J. , Casey Helen , Montezano Augusto C. , Touyz Rhian M. , Delles Christian
Published: July 2021

Sex hormone receptors are expressed throughout the vasculature and play an important role in the modulation of blood pressure in health and disease. The functions of these receptors may be important in the understanding of sexual dimorphism observed in the pathophysiology of both hypertension and vascular ageing. The interconnectivity of these factors can be exemplified in postmenopausal females, who with age and estrogen deprivation, surpass males with regard to hypertension prevalence, despite experiencing significantly less disease burden in their estrogen replete youth. Estrogen and androgen receptors mediate their actions via direct genomic effects or rapid non-genomic signaling, involving a host of mediators. The expression and subtype composition of these receptors changes through the lifespan in response to age, disease and hormonal exposure. These factors may promote sex steroid receptor-mediated alterations to the Renin–Angiotensin–Aldosterone System (RAAS), and increases in oxidative stress and inflammation, thereby contributing to the development of hypertension and vascular injury with age.
Effects of single family room architecture on parent–infant closeness and family centered care in neonatal environments—a single-center pre–post study
Authors: Kainiemi Emma , Hongisto Pilvi , Lehtonen Liisa , Pape Bernd , Axelin Anna
Published: July 2021

Objective

The aim of this study was to evaluate the effects of a single family room architecture in a neonatal intensive care unit (SFR-NICU) on parents’ presence, parent–infant skin-to-skin contact (SSC) and the quality of family centered care.

Study design

Two cohorts of parents of preterm infants were compared: those in the unit before and after the move to SFR-NICU. The parents used daily diaries to report their presence and SSC, and they responded to daily text message questions about the quality of family centered care.

Results

Parents spent more time in the SFR-NICU, but no significant change was found in SSC. Parents rated the quality of family centered care highly in both unit architectures, without a change in rating after the move.

Conclusion

The SFR-NICU increased parents’ presence but not SSC. The change in architecture did not affect parents’ evaluations of the quality of family centered care, which was already highly rated before the move.
Integration of genome-level data to allow identification of subtype-specific vulnerability genes as novel therapeutic targets
Authors: Schwalbe Edward C. , H Lalchungnunga , Lafta Fadhel , Barrow Timothy M. , Strathdee Gordon
Published: July 2021

The identification of cancer-specific vulnerability genes is one of the most promising approaches for developing more effective and less toxic cancer treatments. Cancer genomes exhibit thousands of changes in DNA methylation and gene expression, with the vast majority likely to be passenger changes. We hypothesised that, through integration of genome-wide DNA methylation/expression data, we could exploit this inherent variability to identify cancer subtype-specific vulnerability genes that would represent novel therapeutic targets that could allow cancer-specific cell killing. We developed a bioinformatics pipeline integrating genome-wide DNA methylation/gene expression data to identify candidate subtype-specific vulnerability partner genes for the genetic drivers of individual genetic/molecular subtypes. Using acute lymphoblastic leukaemia as an initial model, 21 candidate subtype-specific vulnerability genes were identified across the five common genetic subtypes, with at least one per subtype. To confirm the approach was applicable across cancer types, we also assessed medulloblastoma, identifying 15 candidate subtype-specific vulnerability genes across three of four established subtypes. Almost all identified genes had not previously been implicated in these diseases. Functional analysis of seven candidate subtype-specific vulnerability genes across the two tumour types confirmed that siRNA-mediated knockdown induced significant inhibition of proliferation/induction of apoptosis, which was specific to the cancer subtype in which the gene was predicted to be specifically lethal. Thus, we present a novel approach that integrates genome-wide DNA methylation/expression data to identify cancer subtype-specific vulnerability genes as novel therapeutic targets. We demonstrate this approach is applicable to multiple cancer types and identifies true functional subtype-specific vulnerability genes with high efficiency.
Applicability of liquid biopsies to represent the mutational profile of tumor tissue from different cancer entities
Authors: Liebs Sandra , Eder Theresa , Klauschen Frederick , Schütte Moritz , Yaspo Marie-Laure , Keilholz Ulrich , Tinhofer Ingeborg , Kidess-Sigal Evelyn , Braunholz Diana
Published: July 2021

Genetic investigation of tumor heterogeneity and clonal evolution in solid cancers could be assisted by the analysis of liquid biopsies. However, tumors of various entities might release different quantities of circulating tumor cells (CTCs) and cell-free DNA (cfDNA) into the bloodstream, potentially limiting the diagnostic potential of liquid biopsy in distinct tumor histologies. Patients with advanced colorectal cancer (CRC), head and neck squamous cell carcinoma (HNSCC), and melanoma (MEL) were enrolled in the study, representing tumors with different metastatic patterns. Mutation profiles of cfDNA, CTCs, and tumor tissue were assessed by panel sequencing, targeting 327 cancer-related genes. In total, 30 tissue, 18 cfDNA, and 7 CTC samples from 18 patients were sequenced. Best concordance between the mutation profile of tissue and cfDNA was achieved in CRC and MEL, possibly due to the remarkable heterogeneity of HNSCC (63%, 55% and 11%, respectively). Concordance especially depended on the amount of cfDNA used for library preparation. While 21 of 27 (78%) tissue mutations were retrieved in high-input cfDNA samples (30–100 ng, N = 8), only 4 of 65 (6%) could be detected in low-input samples (<30 ng, N = 10). CTCs were detected in 13 of 18 patients (72%). However, downstream analysis was limited by poor DNA quality, allowing targeted sequencing of only seven CTC samples isolated from four patients. Only one CTC sample reflected the mutation profile of the respective tumor. Private mutations, which were detected in CTCs but not in tissue, suggested the presence of rare subclones. Our pilot study demonstrated superiority of cfDNA- compared to CTC-based mutation profiling. It was further shown that CTCs may serve as additional means to detect rare subclones possibly involved in treatment resistance. Both findings require validation in a larger patient cohort.
Cancer detection rates of the PI-RADSv2.1 assessment categories: systematic review and meta-analysis on lesion level and patient level
Authors: Oerther Benedict , Engel Hannes , Bamberg Fabian , Sigle August , Gratzke Christian , Benndorf Matthias
Published: July 2021

Background

The Prostate Imaging Reporting and Data System, version 2.1 (PI-RADSv2.1) standardizes reporting of multiparametric MRI of the prostate. Assigned assessment categories are a risk stratification algorithm, higher categories indicate a higher probability of clinically significant cancer compared to lower categories. PI-RADSv2.1 does not define these probabilities numerically. We conduct a systematic review and meta-analysis to determine the cancer detection rates (CDR) of the PI-RADSv2.1 assessment categories on lesion level and patient level.

Methods

Two independent reviewers screen a systematic PubMed and Cochrane CENTRAL search for relevant articles (primary outcome: clinically significant cancer, index test: prostate MRI reading according to PI-RADSv2.1, reference standard: histopathology). We perform meta-analyses of proportions with random-effects models for the CDR of the PI-RADSv2.1 assessment categories for clinically significant cancer. We perform subgroup analysis according to lesion localization to test for differences of CDR between peripheral zone lesions and transition zone lesions.

Results

A total of 17 articles meet the inclusion criteria and data is independently extracted by two reviewers. Lesion level analysis includes 1946 lesions, patient level analysis includes 1268 patients. On lesion level analysis, CDR are 2% (95% confidence interval: 0–8%) for PI-RADS 1, 4% (1–9%) for PI-RADS 2, 20% (13–27%) for PI-RADS 3, 52% (43–61%) for PI-RADS 4, 89% (76–97%) for PI-RADS 5. On patient level analysis, CDR are 6% (0–20%) for PI-RADS 1, 9% (5–13%) for PI-RADS 2, 16% (7–27%) for PI-RADS 3, 59% (39–78%) for PI-RADS 4, 85% (73–94%) for PI-RADS 5. Higher categories are significantly associated with higher CDR (P < 0.001, univariate meta-regression), no systematic difference of CDR between peripheral zone lesions and transition zone lesions is identified in subgroup analysis.

Conclusions

Our estimates of CDR demonstrate that PI-RADSv2.1 stratifies lesions and patients as intended. Our results might serve as an initial evidence base to discuss management strategies linked to assessment categories.
Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers
Authors: Baxter Mark A. , Middleton Fearghas , Cagney Hannah P. , Petty Russell D.
Published: July 2021

Immune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.
Prolonged SARS-CoV-2 RNA virus shedding and lymphopenia are hallmarks of COVID-19 in cancer patients with poor prognosis
Authors: Goubet Anne-Gaëlle , Dubuisson Agathe , Geraud Arthur , Danlos François-Xavier , Terrisse Safae , Silva Carolina Alves Costa , Drubay Damien , Touri Lea , Picard Marion , Mazzenga Marine , Silvin Aymeric , Dunsmore Garett , Haddad Yacine , Pizzato Eugenie , Ly Pierre , Flament Caroline , Melenotte Cléa , Solary Eric , Fontenay Michaela , Garcia Gabriel , Balleyguier Corinne , Lassau Nathalie , Maeurer Markus , Grajeda-Iglesias Claudia , Nirmalathasan Nitharsshini , Aprahamian Fanny , Durand Sylvère , Kepp Oliver , Ferrere Gladys , Thelemaque Cassandra , Lahmar Imran , Fahrner Jean-Eudes , Meziani Lydia , Ahmed-Belkacem Abdelhakim , Saïdani Nadia , La Scola Bernard , Raoult Didier , Gentile Stéphanie , Cortaredona Sébastien , Ippolito Giuseppe , Lelouvier Benjamin , Roulet Alain , Andre Fabrice , Barlesi Fabrice , Soria Jean-Charles , Pradon Caroline , Gallois Emmanuelle , Pommeret Fanny , Colomba Emeline , Ginhoux Florent , Kazandjian Suzanne , Elkrief Arielle , Routy Bertrand , Miyara Makoto , Gorochov Guy , Deutsch Eric , Albiges Laurence , Stoclin Annabelle , Gachot Bertrand , Florin Anne , Merad Mansouria , Scotte Florian , Assaad Souad , Kroemer Guido , Blay Jean-Yves , Marabelle Aurélien , Griscelli Frank , Zitvogel Laurence , Derosa Lisa
Published: July 2021

Patients with cancer are at higher risk of severe coronavirus infectious disease 2019 (COVID-19), but the mechanisms underlying virus–host interactions during cancer therapies remain elusive. When comparing nasopharyngeal swabs from cancer and noncancer patients for RT-qPCR cycle thresholds measuring acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in 1063 patients (58% with cancer), we found that malignant disease favors the magnitude and duration of viral RNA shedding concomitant with prolonged serum elevations of type 1 IFN that anticorrelated with anti-RBD IgG antibodies. Cancer patients with a prolonged SARS-CoV-2 RNA detection exhibited the typical immunopathology of severe COVID-19 at the early phase of infection including circulation of immature neutrophils, depletion of nonconventional monocytes, and a general lymphopenia that, however, was accompanied by a rise in plasmablasts, activated follicular T-helper cells, and non-naive Granzyme B+FasL+, EomeshighTCF-1high, PD-1+CD8+ Tc1 cells. Virus-induced lymphopenia worsened cancer-associated lymphocyte loss, and low lymphocyte counts correlated with chronic SARS-CoV-2 RNA shedding, COVID-19 severity, and a higher risk of cancer-related death in the first and second surge of the pandemic. Lymphocyte loss correlated with significant changes in metabolites from the polyamine and biliary salt pathways as well as increased blood DNA from Enterobacteriaceae and Micrococcaceae gut family members in long-term viral carriers. We surmise that cancer therapies may exacerbate the paradoxical association between lymphopenia and COVID-19-related immunopathology, and that the prevention of COVID-19-induced lymphocyte loss may reduce cancer-associated death.
Ten-year panel data confirm generation gap but climate beliefs increase at similar rates across ages
Authors: Milfont Taciano L. , Zubielevitch Elena , Milojev Petar , Sibley Chris G.
Published: July 2021

Accumulating evidence indicates that climate change awareness and concern has increased globally, but commentators suggest a climate change generation gap whereby younger people care more about climate change than older people. Here we use a decade of panel data from 56,513 New Zealanders to test whether belief that “Climate change is real” and “Climate change is caused by humans” increased over the 2009-2018 period; and whether changes are uniform across 12 five-year birth cohorts spanning those born from 1936 to 1995. Results confirm a generation gap in mean (intercept) climate change beliefs but not in over-time increase (slope). The generation gap occurs because older cohorts started from a lower initial belief level (circa 2009), but all age cohorts increased their belief level at a similar rate over the last decade; and these results were not qualified by respondents’ gender. The findings offer hope for collective action that bridges efforts across generations.
Global distribution patterns of marine nitrogen-fixers by imaging and molecular methods
Authors: Pierella Karlusich Juan José , Pelletier Eric , Lombard Fabien , Carsique Madeline , Dvorak Etienne , Colin Sébastien , Picheral Marc , Cornejo-Castillo Francisco M. , Acinas Silvia G. , Pepperkok Rainer , Karsenti Eric , de Vargas Colomban , Wincker Patrick , Bowler Chris , Foster Rachel A.
Published: July 2021

Nitrogen fixation has a critical role in marine primary production, yet our understanding of marine nitrogen-fixers (diazotrophs) is hindered by limited observations. Here, we report a quantitative image analysis pipeline combined with mapping of molecular markers for mining >2,000,000 images and >1300 metagenomes from surface, deep chlorophyll maximum and mesopelagic seawater samples across 6 size fractions (<0.2–2000 μm). We use this approach to characterise the diversity, abundance, biovolume and distribution of symbiotic, colony-forming and particle-associated diazotrophs at a global scale. We show that imaging and PCR-free molecular data are congruent. Sequence reads indicate diazotrophs are detected from the ultrasmall bacterioplankton (<0.2 μm) to mesoplankton (180–2000 μm) communities, while images predict numerous symbiotic and colony-forming diazotrophs (>20 µm). Using imaging and molecular data, we estimate that polyploidy can substantially affect gene abundances of symbiotic versus colony-forming diazotrophs. Our results support the canonical view that larger diazotrophs (>10 μm) dominate the tropical belts, while unicellular cyanobacterial and non-cyanobacterial diazotrophs are globally distributed in surface and mesopelagic layers. We describe co-occurring diazotrophic lineages of different lifestyles and identify high-density regions of diazotrophs in the global ocean. Overall, we provide an update of marine diazotroph biogeographical diversity and present a new bioimaging-bioinformatic workflow.
Majorana zero modes in impurity-assisted vortex of LiFeAs superconductor
Authors: Kong Lingyuan , Cao Lu , Zhu Shiyu , Papaj Michał , Dai Guangyang , Li Geng , Fan Peng , Liu Wenyao , Yang Fazhi , Wang Xiancheng , Du Shixuan , Jin Changqing , Fu Liang , Gao Hong-Jun , Ding Hong
Published: July 2021

The iron-based superconductor is emerging as a promising platform for Majorana zero mode, which can be used to implement topological quantum computation. One of the most significant advances of this platform is the appearance of large vortex level spacing that strongly protects Majorana zero mode from other low-lying quasiparticles. Despite the advantages in the context of physics research, the inhomogeneity of various aspects hampers the practical construction of topological qubits in the compounds studied so far. Here we show that the stoichiometric superconductor LiFeAs is a good candidate to overcome this obstacle. By using scanning tunneling microscopy, we discover that the Majorana zero modes, which are absent on the natural clean surface, can appear in vortices influenced by native impurities. Our detailed analysis reveals a new mechanism for the emergence of those Majorana zero modes, i.e. native tuning of bulk Dirac fermions. The discovery of Majorana zero modes in this homogeneous material, with a promise of tunability, offers an ideal material platform for manipulating and braiding Majorana zero modes, pushing one step forward towards topological quantum computation.
EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer
Authors: Zoma Marita , Curti Laura , Shinde Dheeraj , Albino Domenico , Mitra Abhishek , Sgrignani Jacopo , Mapelli Sarah N. , Sandrini Giada , Civenni Gianluca , Merulla Jessica , Chiorino Giovanna , Kunderfranco Paolo , Cacciatore Alessia , Kokanovic Aleksandra , Rinaldi Andrea , Cavalli Andrea , Catapano Carlo V. , Carbone Giuseppina M.
Published: July 2021

The TMPRSS2-ERG gene fusion is the most frequent alteration observed in human prostate cancer. However, its role in disease progression is still unclear. In this study, we uncover an important mechanism promoting ERG oncogenic activity. We show that ERG is methylated by Enhancer of zest homolog 2 (EZH2) at a specific lysine residue (K362) located within the internal auto-inhibitory domain. Mechanistically, K362 methylation modifies intra-domain interactions, favors DNA binding and enhances ERG transcriptional activity. In a genetically engineered mouse model of ERG fusion-positive prostate cancer (Pb-Cre4 Ptenflox/floxRosa26-ERG, ERG/PTEN), ERG K362 methylation is associated with PTEN loss and progression to invasive adenocarcinomas. In both ERG positive VCaP cells and ERG/PTEN mice, PTEN loss results in AKT activation and EZH2 phosphorylation at serine 21 that favors ERG methylation. We find that ERG and EZH2 interact and co-occupy several sites in the genome forming trans-activating complexes. Consistently, ERG/EZH2 co-regulated target genes are deregulated preferentially in tumors with concomitant ERG gain and PTEN loss and in castration-resistant prostate cancers. Collectively, these findings identify ERG methylation as a post-translational modification sustaining disease progression in ERG-positive prostate cancers.
High spatiotemporal resolution optoacoustic sensing with photothermally induced acoustic vibrations in optical fibres
Authors: Liang Yizhi , Sun Huojiao , Cheng Linghao , Jin Long , Guan Bai-Ou
Published: July 2021

Optoacoustic vibrations in optical fibres have enabled spatially resolved sensing, but the weak electrostrictive force hinders their application. Here, we introduce photothermally induced acoustic vibrations (PTAVs) to realize high-performance fibre-based optoacoustic sensing. Strong acoustic vibrations with a wide range of axial wavenumbers kz are photothermally actuated by using a focused pulsed laser. The local transverse resonant frequency and loss coefficient can be optically measured by an intra-core acoustic sensor via spectral analysis. Spatially resolved sensing is further achieved by mechanically scanning the laser spot. The experimental results show that the PTAVs can be used to resolve the acoustic impedance of the surrounding fluid at a spatial resolution of approximately 10 μm and a frame rate of 50 Hz. As a result, PTAV-based optoacoustic sensing can provide label-free visualization of the diffusion dynamics in microfluidics at a higher spatiotemporal resolution.
Coordination of endothelial cell positioning and fate specification by the epicardium
Authors: Quijada Pearl , Trembley Michael A. , Misra Adwiteeya , Myers Jacquelyn A. , Baker Cameron D. , Pérez-Hernández Marta , Myers Jason R. , Dirkx Ronald A. , Cohen Ethan David , Delmar Mario , Ashton John M. , Small Eric M.
Published: July 2021

The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
Linking deeply-sourced volatile emissions to plateau growth dynamics in southeastern Tibetan Plateau
Authors: Zhang Maoliang , Guo Zhengfu , Xu Sheng , Barry Peter H. , Sano Yuji , Zhang Lihong , Halldórsson Sæmundur A. , Chen Ai-Ti , Cheng Zhihui , Liu Cong-Qiang , Li Si-Liang , Lang Yun-Chao , Zheng Guodong , Li Zhongping , Li Liwu , Li Ying
Published: July 2021

The episodic growth of high-elevation orogenic plateaux is controlled by a series of geodynamic processes. However, determining the underlying mechanisms that drive plateau growth dynamics over geological history and constraining the depths at which growth originates, remains challenging. Here we present He-CO2-N2systematics of hydrothermal fluids that reveal the existence of a lithospheric-scale fault system in the southeastern Tibetan Plateau, whereby multi-stage plateau growth occurred in the geological past and continues to the present. He isotopes provide unambiguous evidence for the involvement of mantle-scale dynamics in lateral expansion and localized surface uplift of the Tibetan Plateau. The excellent correlation between3He/4He values and strain rates, along the strike of Indian indentation into Asia, suggests non-uniform distribution of stresses between the plateau boundary and interior, which modulate southeastward growth of the Tibetan Plateau within the context of India-Asia convergence. Our results demonstrate that deeply-sourced volatile geochemistry can be used to constrain deep dynamic processes involved in orogenic plateau growth.
High-throughput 5′ UTR engineering for enhanced protein production in non-viral gene therapies
Authors: Cao Jicong , Novoa Eva Maria , Zhang Zhizhuo , Chen William C. W. , Liu Dianbo , Choi Gigi C. G. , Wong Alan S. L. , Wehrspaun Claudia , Kellis Manolis , Lu Timothy K.
Published: July 2021

Despite significant clinical progress in cell and gene therapies, maximizing protein expression in order to enhance potency remains a major technical challenge. Here, we develop a high-throughput strategy to design, screen, and optimize 5′ UTRs that enhance protein expression from a strong human cytomegalovirus (CMV) promoter. We first identify naturally occurring 5′ UTRs with high translation efficiencies and use this information with in silico genetic algorithms to generate synthetic 5′ UTRs. A total of ~12,000 5′ UTRs are then screened using a recombinase-mediated integration strategy that greatly enhances the sensitivity of high-throughput screens by eliminating copy number and position effects that limit lentiviral approaches. Using this approach, we identify three synthetic 5′ UTRs that outperform commonly used non-viral gene therapy plasmids in expressing protein payloads. In summary, we demonstrate that high-throughput screening of 5′ UTR libraries with recombinase-mediated integration can identify genetic elements that enhance protein expression, which should have numerous applications for engineered cell and gene therapies.
Solar energy and regional coordination as a feasible alternative to large hydropower in Southeast Asia
Authors: Siala Kais , Chowdhury Afm Kamal , Dang Thanh Duc , Galelli Stefano
Published: July 2021

Strategic dam planning and the deployment of decentralized renewable technologies are two elements of the same problem, yet normally addressed in isolation. Here, we show that an integrated view of the power system capacity expansion problem could have transformative effects for Southeast Asia’s hydropower plans. We demonstrate that Thailand, Laos, and Cambodia have tangible opportunities for meeting projected electricity demand and CO2 emission targets with less hydropower than currently planned—options range from halting the construction of all dams in the Lower Mekong to building 82% of the planned ones. The key enabling strategies for these options to succeed are solar PV and regional coordination, expressed in the form of centralized planning and cross-border power trading. The alternative expansion plans would slightly increase the cumulative costs (up to 2.4%), but substantially limit the fragmentation of additional river reaches, thereby offering more sustainable pathways for the Mekong’s ecosystems and riparian people.
Oncogenic cooperation between TCF7-SPI1 and NRAS(G12D) requires β-catenin activity to drive T-cell acute lymphoblastic leukemia
Authors: Van Thillo Quentin , De Bie Jolien , Seneviratne Janith A. , Demeyer Sofie , Omari Sofia , Balachandran Anushree , Zhai Vicki , Tam Wai L. , Sweron Bram , Geerdens Ellen , Gielen Olga , Provost Sarah , Segers Heidi , Boeckx Nancy , Marshall Glenn M. , Cheung Belamy B. , Isobe Kiyotaka , Kato Itaru , Takita Junko , Amos Timothy G. , Deveson Ira W. , McCalmont Hannah , Lock Richard B. , Oxley Ethan P. , Garwood Maximilian M. , Dickins Ross A. , Uyttebroeck Anne , Carter Daniel R. , Cools Jan , de Bock Charles E.
Published: July 2021

Spi-1 Proto-Oncogene (SPI1) fusion genes are recurrently found in T-cell acute lymphoblastic leukemia (T-ALL) cases but are insufficient to drive leukemogenesis. Here we show that SPI1 fusions in combination with activating NRAS mutations drive an immature T-ALL in vivo using a conditional bone marrow transplant mouse model. Addition of the oncogenic fusion to the NRAS mutation also results in a higher leukemic stem cell frequency. Mechanistically, genetic deletion of the β-catenin binding domain within Transcription factor 7 (TCF7)-SPI1 or use of a TCF/β-catenin interaction antagonist abolishes the oncogenic activity of the fusion. Targeting the TCF7-SPI1 fusion in vivo with a doxycycline-inducible knockdown results in increased differentiation. Moreover, both pharmacological and genetic inhibition lead to down-regulation of SPI1 targets. Together, our results reveal an example where TCF7-SPI1 leukemia is vulnerable to pharmacological targeting of the TCF/β-catenin interaction.
Colonization of Warsaw by the red fox Vulpes vulpes in the years 1976–2019
Authors: Jackowiak Mateusz , Gryz Jakub , Jasińska Karolina , Brach Michał , Bolibok Leszek , Kowal Piotr , Krauze-Gryz Dagny
Published: July 2021

The red fox is one of the most adaptable carnivores inhabiting cities. The aim of our study was to describe the process of Warsaw colonization by the red fox. We focused on: (1) the fox distribution in Warsaw on the basis of presence-absence data (2005–2012) over a grid of 1 × 1 km2, (2) the process of settlement in 29 green areas (study periods 1976–1978, 2004–2012, and 2016–2019) in relation to habitat type, and (3) temporal and spatial patterns of the red fox incidents (1998–2015) reported by Warsaw citizens. We found out that: (1) the red fox penetrated the whole city (i.e. its presence was confirmed in all squares of the grid), (2) 21% of the green areas were colonized in 1976–1978 but 93% in 2016–2019. Forests and riparian habitats were occupied more frequently than parks and cemeteries in 1976–1978 with no difference in the further years; (3) the probability of the fox incidents increased over years, was higher in June-October, on working days, and around noon, and with the share of discontinuous urban fabric in the buffers around incident locations. Nevertheless, the incidents only partially reflect population abundance trends and activity patterns of the species, so should be treated cautiously.
Both T cell priming in lymph node and CXCR3-dependent migration are the key events for predicting the response of atezolizumab
Authors: Iwai Toshiki , Sugimoto Masamichi , Patil Namrata S. , Bower Daniel , Suzuki Miho , Kato Chie , Yorozu Keigo , Kurasawa Mitsue , Shames David S. , Kondoh Osamu
Published: July 2021

Anti-PD-L1 antibodies benefit many cancer patients, even those with “non-inflamed tumor”. Determining which patients will benefit remains an important clinical goal. In a non-inflamed tumor mouse model, we found that PD-L1 was highly expressed on antigen-presenting cells (APCs) especially on CD103+ CD11c+ dendritic cells in tumor-draining lymph nodes (dLNs), suppressing T-cell priming by APCs. In this model, anti-PD-L1 antibodies enhanced T-cell priming and increased CXCR3+ activated T-cells in dLNs, which was followed by the trafficking of T-cells to tumors in response to CXCR3 ligands. As predictive biomarker, each APCs-related gene expression (AP score) alone or T-cells trafficking-related chemokine gene expression (T score) alone were still less than perfect among the 17 mouse models examined. However a combining score of AP score and T score (AP/T score) precisely identified anti-PD-L1-sensitive tumors. In the phase 3 trial of atezolizumab vs docetaxel in advanced NSCLC patients (OAK), the AP/T score could identify atezolizumab-treated NSCLC patients who achieved significant improvement in overall survival. This biomarker concept would be a clinically valuable for prediction of anti-PD-L1 antibody efficacy.
Discovery of a novel brown algal genus and species Setoutiphycus delamareoides (Phaeophyceae, Ectocarpales) from the Seto Inland Sea, Japan
Authors: Kawai Hiroshi , Hanyuda Takeaki
Published: July 2021

We describe a new genus and species of brown algae from the Seto Inland Sea, Japan. This species is similar to Delamarea in gross morphology and anatomy, but distinctive in having longer thalli with rare branching and shorter cortical cells. In culture, pluri-zoids derived from plurilocular zoidangia on the erect thalli developed into filamentous gametophytes bearing ectocarpoid plurilocular zoidangia, but also formed parenchymatous erect thalli of sub-sympodial growth similar to Trachynema often having branches, and formed lateral and terminal plurilocular zoidangia. Molecular phylogenies using concatenated chloroplast and mitochondrial gene sequences showed the new alga nested in the clade composed of ectocarpalean genera with diffuse growth, parenchymatous thalli, and multiple chloroplasts, but this species is distinctive. Therefore, we propose Setoutiphycus delamareoides gen. & sp. nov. for this new alga, and provisionally place it in Chordariaceae, Ectocarpales. The Seto Inland Sea repeatedly dried during sea level regressions during glacial periods, and the present sea level recovered after the last glacial maximums (LGM), ca. 10,000 years ago. Therefore, it is unlikely that the species evolved within this area. Its distribution in the area may be explained as a remnant population that survived in refugia in southern Japan during the LGM.
Accurate prediction of mega-electron-volt electron beam properties from UED using machine learning
Authors: Zhang Zhe , Yang Xi , Huang Xiaobiao , Li Junjie , Shaftan Timur , Smaluk Victor , Song Minghao , Wan Weishi , Wu Lijun , Zhu Yimei
Published: July 2021

To harness the full potential of the ultrafast electron diffraction (UED) and microscopy (UEM), we must know accurately the electron beam properties, such as emittance, energy spread, spatial-pointing jitter, and shot-to-shot energy fluctuation. Owing to the inherent fluctuations in UED/UEM instruments, obtaining such detailed knowledge requires real-time characterization of the beam properties for each electron bunch. While diagnostics of these properties exist, they are often invasive, and many of them cannot operate at a high repetition rate. Here, we present a technique to overcome such limitations. Employing a machine learning (ML) strategy, we can accurately predict electron beam properties for every shot using only parameters that are easily recorded at high repetition rate by the detector while the experiments are ongoing, by training a model on a small set of fully diagnosed bunches. Applying ML as real-time noninvasive diagnostics could enable some new capabilities, e.g., online optimization of the long-term stability and fine single-shot quality of the electron beam, filtering the events and making online corrections of the data for time-resolved UED, otherwise impossible. This opens the possibility of fully realizing the potential of high repetition rate UED and UEM for life science and condensed matter physics applications.