bluuebunny/crossref_metadata_2025 huggingface dataset:
Economic Activity and the Value of Medical Innovation during a Pandemic
Authors: Mulligan Casey B.
Published: June 2021

The “shutdown” economy of April 2020 is compared to a normally functioning economy both in terms of market and nonmarket activities. Three novel methods and data indicate that a full shutdown of “nonessential” activities puts market production about 25 % below normal in the short run. At an annual rate, a full shutdown costs $9 trillion, or about $18,000 per household per quarter. Employment already fell 24 million by early April 2020. These costs indicate, among other things, the value of innovation in both health and general business sectors that can accelerate the time when, and the degree to which, normal activity resumes.
The Preparedness of Primary Health Care Network in terms of Emergency Risk Communication: A Study in Iran
Authors: Bagheri Zeinab , Dehdari Tahereh , Lotfizadeh Masoud
Published: June 2021

Objective:

Emergency Risk Communication (ERC) is known as 1 of the important components of an effective response to public health emergencies. In this study, we aimed to investigate the preparedness of the Primary Health Care Network (PHCN) of Iran in terms of the ERC.

Methods:

This study was conducted in 136 Primary Health Care Facilities (PHCFs) affilated to Shahrekord University of Medical Sciences, Chaharmahal and Bakhtiari Province, Iran. Data in terms of ERC were collected using a checklist developed by the Center of Disease Control and Prevention (CDC).

Results:

The findings of the study revealed that 65.9% of the PHCFs had low preparedness in terms of the ERC, 33.3% had a moderate level and 0.8% had high preparedness in this regard. There was a significant difference between the level of ERC and the history of crisis in the past year, PHCF type, and the education level of the responsible employees in the crisis unit in the PHCF.

Conclusions:

The results showed that the PHCFs studied need to increase their capacity and capability in the field of ERC. Further efforts to provide ERC components may increase the preparedness of PHCN in Iran in terms of the ERC.
Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges
Authors: Reinius Marika A. V. , Smyth Elizabeth
Published: June 2021

The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.
Stable colonization of native plants and early invaders by arbuscular mycorrhizal fungi after exposure to recent invaders from the Asteraceae family
Authors: Řezáčová Veronika , Řezáč Milan , Líblová Zuzana , Michalová Tereza , Heneberg Petr
Published: June 2021

Arbuscular mycorrhizal fungi (AMF, Glomeromycota) are globally distributed symbionts of plant roots. Relationships with arbuscular mycorrhizae can provide crucial support for the establishment of any plant in an unfavorable environment. We hypothesized that invasions of neophytes are associated with changes in the colonization of native plants and early invaders (archeophytes) by AMF. We examined changes in AMF colonization in yarrow (Achillea millefolium L.) and wild carrot (Daucus carota L.) (native plants) and tansy (Tanacetum vulgare L.) and false oatgrass [Arrhenatherum elatius (L.) P. Beauv. ex J. Presl & C. Presl] (archeophytes) in response to the invasion of four neophytes from the Asteraceae family, namely great globethistle (Echinops sphaerocephalus L.), New York aster [Symphyotrichum novi-belgii (L.) G. L. Nesom agg.], annual fleabane [Erigeron annuus (L.) Pers.], and Canada goldenrod (Solidago canadensis L.). We found that the AMF colonization of the Asteraceae neophytes was high in the studied monodominant invasions, and the AMF colonization of the neophytes was higher than or equal to that of the studied native plants and archeophytes. Changes in plant dominance did not serve as predictors of the extent of AMF colonization of the native plants and archeophytes despite the invaded plots being associated with strong changes in the availability of primary and secondary mineral nutrients. The absence of a response of AMF colonization of native and archeophyte plant species to the invasion of neophytes suggests that AMF are passengers, rather than drivers, in the course of Asteraceae invasions in central European environments.
Effect of low and high concentrate supplementation on health and welfare indicators in different breeds in small-scale mountain dairy farms
Authors: Flach Laura , Kühl Sarah , Lambertz Christian , DeMonte Erica , Gauly Matthias
Published: June 2021

We investigated and compared the effects of low and high concentrate supplementation in terms of animal welfare, health and reproductive performance in two different dairy cow breeds on small-scale mountain farms. 64 South Tyrolean dairy farms were evaluated using an on-farm assessment for animal-based and resource-based welfare indicators, data from test day records, and a questionnaire for the farmer. Farms were divided into four groups: low input Tyrolean Grey (L-TG), low input Brown Swiss (L-BS), high input Tyrolean Grey (H-TG) and high input Brown Swiss (H-BS). Effects of intensity level, breed and their interaction were calculated and analyzed statistically. The predominant husbandry system across all groups was tie-stall. The average energy-corrected milk yield increased with increasing concentrate level, with L-TG showing the lowest and H-BS showing the highest milk yield. Age at first calving was lowest in H-BS when compared to all other systems, while numbers of lactations were higher in L-TG compared to H-BS. Feed efficiency (percentage of milk out of roughage) was significantly higher in L-TG and L-BS when compared to H-TG and H-BS. L-BS showed the poorest results for most of the welfare indicators such as lean cows, lesions and percentage of dirty animals. In conclusion, a higher concentrate level in diets does not lead automatically to lower animal welfare for dairy cows in alpine regions. Indeed, keeping high yielding breeds in extensive systems seems to be challenging. The dual-purpose breed TG showed some clear advantages in that calving interval was lower and the number of lactations greater.
Samuel P. Huntington, Brazilian ‘Decompression’ and Democracy
Authors: Pereira Anthony W.
Published: June 2021

The Harvard political science professor Samuel P. Huntington (1927–2008) made visits to Brazil in 1972 and 1974 to advise the government about ‘decompression’ or regime liberalisation. The literature on Brazil's dictatorship references these visits as having had a major causal impact. This article argues that his influence on Brazilian regime change is greatly exaggerated. It also argues that Huntington, who became a leading theorist of democratisation, had an interest in and commitment to democracy that was more recent and circumstantial than is often thought. This helps to explain the current period of democratic ‘deconsolidation’ associated with the rise of authoritarian national populism in Brazil.
The co-occurrence of overweight/obesity and anaemia among adult women, adolescent girls and children living in fifty-two low- and middle-income countries
Authors: Irache Ana , Gill Paramjit , Caleyachetty Rishi
Published: June 2021

Objective:

To investigate the magnitude and distribution of concurrent overweight/obesity and anaemia among adult women, adolescent girls and children living in low- and middle-income countries (LMIC).

Design:

We selected the most recent Demographic and Health Surveys with anthropometric and Hb level measures. Prevalence estimates and 95 % CI of concurrent overweight/obesity and anaemia were calculated for every country, overall and stratified by household wealth quintile, education level, area of residence and sex (for children only). Regional and overall pooled prevalences were estimated using a random-effects model. We measured gaps, expressed in percentage points, to display inequalities in the distribution of the double burden of malnutrition (DBM).

Setting:

Nationally representative surveys from fifty-two LMIC.

Participants:

Adult women (n825 769) aged 20–49 years, adolescent girls (n192 631) aged 15–19 years and children (n391 963) aged 6–59 months.

Results:

The pooled prevalence of concurrent overweight/obesity and anaemia was 12·4 % (95 % CI 11·1, 13·7) among adult women, 4·5 % (95 % CI 4·0, 5·0) among adolescent girls and 3·0 % (95 % CI 2·7, 3·3) among children. Overall, the DBM followed an inverse social gradient, with a higher prevalence among the richest quintile, most educated groups and in urban areas; however, important variations exist. The largest inequality gaps were observed among adult women in Yemen by household wealth (24·0 percentage-points) and in Niger by education level (19·6 percentage-points) and area of residence (11·9 percentage-points). Differences were predominantly significant among adult women, but less among girls and children.

Conclusions:

Context-specific, multifaceted, responses with an equity lens are needed to reduce all forms of malnutrition.
Reference values for intake of six types of soluble and insoluble fibre in healthy UK inhabitants based on the UK Biobank data
Authors: Shevlyakov Artem , Nikogosov Dimitri , Stewart Leigh-Ann , Toribio-Mateas Miguel
Published: June 2021

Objective:

To obtain a set of reference values for the intake of different types of dietary fibre in a healthy UK population.

Design:

This descriptive cross-sectional study used the UK Biobank data to estimate the dietary patterns of healthy individuals. Data on fibre content in different foods were used to calculate the reference values which were then calibrated using real-world data on total fibre intake.

Setting:

UK Biobank is a prospective cohort study of over 500 000 individuals from across the United Kingdom with the participants aged between 40 and 69 years.

Participants:

UK Biobank contains information on over 500 000 participants. This study was performed using the data on 19 990 individuals (6941 men, 13 049 women) who passed stringent quality control and filtering procedures and had reported above-zero intake of the analysed foods.

Results:

A set of reference values for the intake of six different types of soluble and insoluble fibres (cellulose, hemicelluloses, pectin and lignin), including the corresponding totals, was developed and calibrated using real-world data.

Conclusions:

To our knowledge, this is the first study to establish specific reference values for the intake of different types of dietary fibre. It is well known that effects exerted by different types of fibre both directly and through modulation of microbiota are numerous. Conceivably, a deficit or excess intake of specific types of dietary fibre may detrimentally affect human health. Filling this knowledge gap opens new avenues for research in discussion in studies of nutrition and microbiota and offers valuable tools for practitioners worldwide.
Australia – Anti-Dumping Measures on A4 Copy Paper: Opening a Door to More Anti-Dumping Investigations
Authors: Eliason Antonia , Fiorini Matteo
Published: June 2021

This paper analyzes the Australia – Anti-Dumping Measures on A4 Copy Paper panel report, the second recent WTO dispute to involve a challenge to Indonesia's paper industry. The Indonesian paper industry benefits from reduced-cost inputs because of the Indonesian government's influence and subsidies over the timber and pulp market. The report offers the first interpretation of ‘particular market situation’ under Article 2.2 of the WTO's Anti-Dumping Agreement. At the same time, it raises questions regarding the appropriateness of using anti-dumping measures to address what are fundamentally subsidy issues. While the panel ultimately found that Australia's measure was inconsistent with Article 2.2, the paper shows that the panel's interpretation of ‘particular market situation’ increases the relative attractiveness of using anti-dumping duties instead of countervailing measures. Two key points on the welfare implications of the decision can be made. The first relates to the motivations of the Australian paper industry and the imperfectly competitive market in which Australian Paper operates. The second is the importance of challenging subsidies rather than imposing anti-dumping duties where the subsidies in question have negative environmental effects.
Strategies of Decolonization: Economic Sovereignty and National Security in Libyan–US Relations, 1949–1971
Authors: Dietrich Christopher R. W.
Published: June 2021

This article examines Libyan–US relations through the historical lenses of decolonization, international law, the Cold War, and the international political economy. The Libyan government exercised its newfound sovereignty in the postwar era through the negotiation of ‘base rights’ for the US government and ‘oil rights’ for corporations owned by US nationals. They did so in conjunction with other petrostates and through international organizations such as the United Nations, the Arab League, and the Organization of Petroleum Exporting Countries. Libyan leaders’ strategy of using sovereignty to promote corporate competition relied on connections with similarly situated nations, and it was through global circuits of knowledge that they pressed the outer limits of economic sovereignty. At the same time, the US government consistently accommodated Libyan policies through Cold War arguments that linked the alliance with Libya to US national security. Those deep foundations of sovereignty and security created the conditions for the transformation of the global oil industry after Libya’s 1969 revolution.
Tracking-Systeme bei Menschen mit Demenz in der stationären Langzeitpflege
Authors: Müller Kathrin , Peters Miriam
Published: June 2021

Zusammenfassung. Hintergrund: Dieser Beitrag ist eine Aktualisierung von 11-1Hülsken-Giesler et al. (2019) und beschreibt die neuesten Erkenntnisse zu Tracking-Systemen in der stationären Langzeitpflege. Fragestellung: Die Fragestellung schließt sich ebenfalls an den zugrunde gelegten Artikel an und behandelt erneut die Anwendung von Tracking-Systemen und deren Konsequenzen für Bewohner_innen sowie für das Pflegefachpersonal. Methode: Es wurde eine systematische Literaturrecherche in den Datenbanken MEDLINE via PubMed und CINAHL sowie eine Handsuche für den Zeitraum ab August 2017 durchgeführt. Die eingeschlossene Literatur wurde von zwei unabhängigen Personen inhaltlich und methodisch bewertet. Ergebnisse: Neben deduktiven Kategorien, die dem Artikel von 11-2Hülsken-Giesler et al. (2019) entnommen wurden, konnten weitere induktive Kategorien gebildet werden. Insbesondere ethische und implementierungswissenschaftliche Aspekte werden in den einbezogenen Studien diskutiert. Schlussfolgerungen: Seit der ersten Analyse hat sich der Fokus in pflegewissenschaftlichen Studien zum Einsatz von Tracking-Systemen in der stationären Langzeitpflege von funktionalen Aspekten hin zu ethischen Aspekten verschoben. Auch die erfolgreiche und langfristige Einbindung in die Versorgungspraxis ist nun von Relevanz.
Intercomparison of Thermal Regime Algorithms in 1‐D Lake Models
Authors: Guo Mingyang , Zhuang Qianlai , Yao Huaxia , Golub Malgorzata , Leung L. Ruby , Tan Zeli
Published: June 2021

Lakes are an important component of the global weather and climate system, but the modeling of their thermal regimes has shown large uncertainties due to the highly diverse lake properties and model configurations. Here, we evaluate the algorithms of four key lake thermal processes including turbulent heat fluxes, wind‐driven mixing, light extinction, and snow density, using a highly diverse lake data set provided by the Inter‐Sectoral Impact Model Intercomparison Project (ISIMIP) 2a lake sector. Algorithm codes are configured and run separately within the same parent model to rule out any interference from factors apart from the algorithms examined. Evaluations are based on both simulation accuracy and recalibration complexity for application to global lakes. For turbulent heat fluxes, the non‐Monin–Obukhov similarity (MOS) based, more simplified algorithms perform better in predicting lake epilimnion temperatures and achieve high convergence in the values of the calibrated parameters. For wind‐driven mixing, a two‐algorithm strategy considering lake shape and season is suggested with the regular mixing algorithm used for spring and earlier summer and the mixing‐enhanced algorithm for summer steady stratification and fall overturn periods. There are no evident differences in the simulated thermocline depths using different light extinction algorithms or the observation. Finally, for lake ice phenology, an optimal algorithm is decided for most northern lakes while the Arctic lakes require separate consideration. Our study provides highly practical guides for improving 1‐D lake models and feasible parameterization strategies to better simulate global lake thermal regimes.
Efficient Graphics Processing Unit Modeling of Street‐Scale Weather Effects in Support of Aerial Operations in the Urban Environment
Authors: Muñoz‐Esparza Domingo , Shin Hyeyum Hailey , Sauer Jeremy A. , Steiner Matthias , Hawbecker Patrick , Boehnert Jennifer , Pinto James O. , Kosović Branko , Sharman Robert D.
Published: June 2021

Over the last few years, the concept of incorporating aerial vehicles into the urban environment for diverse purposes has attracted ample interest and investment. These purposes cover a broad spectrum of applications, from larger vehicles designed for passenger transport, to package delivery and inspection/surveillance missions performed by small unmanned drones. While these Advanced Air Mobility (AAM) operations have the potential to alleviate bottlenecks arising from saturated surface transportation networks, there are a number of challenges that need to be addressed to make these operations safe and viable. One challenge is predicting weather effects within the urban environment with the required level of spatiotemporal fidelity, which current operational weather models fail to provide due to the use of coarse grid spacings (a few kilometers) constrained by the predictive performance limitations of traditional computer architectures. Herein, we demonstrate how FastEddy®, a microscale model that exploits the accelerated nature of graphics processing units for high‐performance computing, can be used to understand and predict urban weather impacts from seasonal, day‐to‐day, diurnal, and sub‐hourly scales. To that end, we efficiently perform more than 50 telescoped simulations of microscale urban effects at street‐scale (5 m grid spacing) driven by realistic weather over a 20 km2 region centered at the downtown area of Dallas, Texas. Our analyses demonstrate that urban‐weather interactions at the street‐scale are complex and tightly connected, which is of utmost relevance to AAM operations. These demonstrations reveal the capability of such models to provide real‐time weather hazard avoidance products tailored to capture microscale urban effects.
Paleoclimate Significance of Reconstructed Rainfall Isotope Changes in Asian Monsoon Region
Authors: Zhao Cheng , Cheng Jun , Wang Jingjing , Yan Hong , Leng Chengcheng , Zhang Can , Feng Xiaoping , Liu Weiguo , Yang Xiangdong , Shen Ji
Published: June 2021

Speleothem oxygen isotope (δ18Oc) records have been regarded as a critical reference to study past Asian monsoon variability. However, existing δ18Oc records in the Indian monsoon region are fragmented in time coverage and/or sampling resolution since the last deglaciation. Also, the climatic interpretation of δ18Oc is still obscure. Here, we report a continuous and centennial‐resolved leaf wax hydrogen isotope (δDwax) record over the past ∼28 ka from Lugu Lake in Indian‐monsoon influenced southwestern China. Our new record shows striking consistency with the well‐established δ18Oc record in East Asian monsoon‐influenced southeastern China, revealing a spatially coherent change and thus a similar physical process in rainfall isotopes in the broader Asian monsoon region. Based on the combination with the TraCE21ka simulation, we propose reconstructed long‐term and millennial‐scale isotope changes could be influenced by the intensity of local convection along the monsoon trough, which extends from the Indian subcontinent across to the Philippines in summer.
Communication Between the Northern and Southern Central San Andreas Fault via Dynamically Triggered Creep
Authors: Hirao Brenton , Savage Heather , Brodsky Emily E.
Published: June 2021

The interaction between creep events and earthquakes at the regional scale has implications for earthquake cycles, yet few examples of such interaction have been found on continental faults. We report shallow triggered creep along the northern edge of the central creeping section of the San Andreas Fault following the 2003 San Simeon Mw 6.5 and 2004 Parkfield Mw 6.0 earthquakes. Following both earthquakes, we observe a delayed creep event beginning at depth on a strainmeter and continuing on a nearby creepmeter. In addition, between the regional earthquakes, the average slip rate at one creepmeter increased from 10 mm/yr to 30 mm/yr, and returned to 10 mm/yr after the Parkfield earthquake. Creep events and creep rate changes indicate that triggering connects behavior in the northern San Andreas Fault to the southern section and other regional faults.
Origin of the Co‐Seismic Variations of Elastic Properties in the Crust: Insight From the Laboratory
Authors: Paglialunga F. , Passelègue F. X. , Acosta M. , Violay M.
Published: June 2021

Seismological observations highlighted that earthquakes are often followed by changes in elastic properties around the fault zone. Here, we studied the origin of these variations using stick‐slip experiments on saw‐cut granite samples presenting different degrees of bulk damage (i.e., microcracks). Stick‐slip events were induced under triaxial compression configuration with continuous active ultrasonic measurements at confining pressures representative of upper crustal conditions (15–120 MPa). Both the P‐wave velocity () and amplitude () showed drops, concurrently with stress drops, and had a non‐monotonic dependence toward the fault's stress state. Our experimental results suggest that co‐seismic changes in were mostly controlled by the elastic re‐opening of microcracks in the bulk, rather than by co‐seismic damage or the formation of fault gouge. Co‐seismic changes in were controlled by a combination of elastic re‐opening of microcracks in the bulk and inelastic processes (i.e., co‐seismic damage and gouge formation and dilation).
A Westward Shift in Tropical Cyclone Potential Intensity and Genesis Regions in the North Atlantic During the Last Interglacial
Authors: Yan Qing , Korty Robert , Wei Ting , Jiang Nanxuan
Published: June 2021

Given the longstanding debate on geomorphological features (i.e., megaboulders, chevron‐shaped sand ridges, and runup deposits) observed around the Bahamas, it is unclear whether Earth experienced superstorms over the North Atlantic during the Last Interglacial (LIG). Based on multimodels from the Paleoclimate Modeling Intercomparison Project, we illustrate that the tropical North Atlantic exhibits an overall warming (∼0.9°C) during the storm season of the LIG relative to preindustrial. Potential intensity shows a zonal dipole anomaly over the main development region during the LIG, with positive anomalies in the west, offering an increased probability of extremely strong storms. Favorable conditions for storm formation shift from the eastern to the western main development region during the LIG, with enhanced large‐scale steering flows at higher latitudes (∼15 – 30°N). These results suggest a westward migration of storm activity during the LIG, with potentially more frequent and intense storms over the western North Atlantic and increased coastal erosions.
Silicon/2D-material photodetectors: from near-infrared to mid-infrared
Authors: Liu Chaoyue , Guo Jingshu , Yu Laiwen , Li Jiang , Zhang Ming , Li Huan , Shi Yaocheng , Dai Daoxin
Published: June 2021

Two-dimensional materials (2DMs) have been used widely in constructing photodetectors (PDs) because of their advantages in flexible integration and ultrabroad operation wavelength range. Specifically, 2DM PDs on silicon have attracted much attention because silicon microelectronics and silicon photonics have been developed successfully for many applications. 2DM PDs meet the imperious demand of silicon photonics on low-cost, high-performance, and broadband photodetection. In this work, a review is given for the recent progresses of Si/2DM PDs working in the wavelength band from near-infrared to mid-infrared, which are attractive for many applications. The operation mechanisms and the device configurations are summarized in the first part. The waveguide-integrated PDs and the surface-illuminated PDs are then reviewed in details, respectively. The discussion and outlook for 2DM PDs on silicon are finally given.
Biophotonic probes for bio-detection and imaging
Authors: Pan Ting , Lu Dengyun , Xin Hongbao , Li Baojun
Published: June 2021

The rapid development of biophotonics and biomedical sciences makes a high demand on photonic structures to be interfaced with biological systems that are capable of manipulating light at small scales for sensitive detection of biological signals and precise imaging of cellular structures. However, conventional photonic structures based on artificial materials (either inorganic or toxic organic) inevitably show incompatibility and invasiveness when interfacing with biological systems. The design of biophotonic probes from the abundant natural materials, particularly biological entities such as virus, cells and tissues, with the capability of multifunctional light manipulation at target sites greatly increases the biocompatibility and minimizes the invasiveness to biological microenvironment. In this review, advances in biophotonic probes for bio-detection and imaging are reviewed. We emphatically and systematically describe biological entities-based photonic probes that offer appropriate optical properties, biocompatibility, and biodegradability with different optical functions from light generation, to light transportation and light modulation. Three representative biophotonic probes, i.e., biological lasers, cell-based biophotonic waveguides and bio-microlenses, are reviewed with applications for bio-detection and imaging. Finally, perspectives on future opportunities and potential improvements of biophotonic probes are also provided.
A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease
Authors: Fløisand Yngvar , Schroeder Mark A. , Chevallier Patrice , Selleslag Dominik , Devine Steven , Renteria Anne S. , Mohty Mohamad , Yakoub-Agha Ibrahim , Chen Chunlin , Parfionovas Andrejus , Quadri Syed , Jansson Johan , Akbari Mona , Chen Yi-Bin
Published: June 2021

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn’s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.
SLC7A2 deficiency promotes hepatocellular carcinoma progression by enhancing recruitment of myeloid-derived suppressors cells
Authors: Xia Suhong , Wu Jingwen , Zhou Wangdong , Zhang Mingyu , Zhao Kai , Liu Jingmei , Tian Dean , Liao Jiazhi
Published: June 2021

The main reason for poor prognosis in hepatocellular carcinoma (HCC) patients is high metastasis and recurrence. Cancer progression depends on a tumor-supportive microenvironment. Therefore, illustrating the mechanisms of tumor immunity in underlying HCC metastasis is essential. Here, we report a novel role of solute carrier family 7 member 2 (SLC7A2), a member of the solute carrier family, in HCC metastasis. The reduction of SLC7A2 was an independent and significant risk factor for the survival of HCC patients. Upregulation of SLC7A2 decreased HCC invasion and metastasis, whereas downregulation of SLC7A2 promoted HCC invasion and metastasis. We further found that deficient SLC7A2 medicated the upregulation of CXCL1 through PI3K/Akt/NF-kκB pathway to recruit myeloid-derived suppressor cells (MDSCs), exerting tumor immunosuppressive effect. Moreover, we found that G9a-mediated di-methylation of H3K9 (H3K9me2) silenced the expression of SLC7A2 to suppress HCC metastasis and immune escape. In conclusion, G9a-mediated silencing of SLC7A2 exerts unexpected functions in cancer metastasis by fostering a tumor-supportive microenvironment through CXCL1 secretion and MDSCs recruitment. Thus, SLC7A2 may provide new mechanistic insight into the cancer-promoting property of MDSCs.
Effects of acyl-coenzyme A binding protein (ACBP)/diazepam-binding inhibitor (DBI) on body mass index
Authors: Joseph Adrien , Chen Hui , Anagnostopoulos Gerasimos , Montégut Léa , Lafarge Antoine , Motiño Omar , Castedo Maria , Maiuri Maria Chiara , Clément Karine , Terrisse Safae , Martin Anne Laure , Vaz-Luis Ines , Andre Fabrice , Grundler Franziska , de Toledo Françoise Wilhelmi , Madeo Frank , Zitvogel Laurence , Goldwasser François , Blanchet Benoit , Fumeron Frédéric , Roussel Ronan , Martins Isabelle , Kroemer Guido
Published: June 2021

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor acyl-coenzyme A binding protein (ACBP, also called diazepam-binding inhibitor, DBI) acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. Here, we show that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3–9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels. Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.
Structure and mechanism of the human NHE1-CHP1 complex
Authors: Dong Yanli , Gao Yiwei , Ilie Alina , Kim DuSik , Boucher Annie , Li Bin , Zhang Xuejun C. , Orlowski John , Zhao Yan
Published: June 2021

Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.
Nitrogen and phosphorus fertilization consistently favor pathogenic over mutualistic fungi in grassland soils
Authors: Lekberg Ylva , Arnillas Carlos A. , Borer Elizabeth T. , Bullington Lorinda S. , Fierer Noah , Kennedy Peter G. , Leff Jonathan W. , Luis Angela D. , Seabloom Eric W. , Henning Jeremiah A.
Published: June 2021

Ecosystems across the globe receive elevated inputs of nutrients, but the consequences of this for soil fungal guilds that mediate key ecosystem functions remain unclear. We find that nitrogen and phosphorus addition to 25 grasslands distributed across four continents promotes the relative abundance of fungal pathogens, suppresses mutualists, but does not affect saprotrophs. Structural equation models suggest that responses are often indirect and primarily mediated by nutrient-induced shifts in plant communities. Nutrient addition also reduces co-occurrences within and among fungal guilds, which could have important consequences for belowground interactions. Focusing only on plots that received no nutrient addition, soil properties influence pathogen abundance globally, whereas plant community characteristics influence mutualists, and climate influence saprotrophs. We show consistent, guild-level responses that enhance our ability to predict shifts in soil function related to anthropogenic eutrophication, which can have longer-term consequences for plant communities.
Diffusionless transformation of soft cubic superstructure from amorphous to simple cubic and body-centered cubic phases
Authors: Liu Jie , Liu Wenzhe , Guan Bo , Wang Bo , Shi Lei , Jin Feng , Zheng Zhigang , Wang Jingxia , Ikeda Tomiki , Jiang Lei
Published: June 2021

In a narrow temperature window in going from the isotropic to highly chiral orders, cholesteric liquid crystals exhibit so-called blue phases, consisting of different morphologies of long, space-filling double twisted cylinders. Those of cubic spatial symmetry have attracted considerable attention in recent years as templates for soft photonic materials. The latter often requires the creation of monodomains of predefined orientation and size, but their engineering is complicated by a lack of comprehensive understanding of how blue phases nucleate and transform into each other at a submicrometer length scale. In this work, we accomplish this by intercepting nucleation processes at intermediate stages with fast cross-linking of a stabilizing polymer matrix. We reveal using transmission electron microscopy, synchrotron small-angle X-ray diffraction, and angle-resolved microspectroscopy that the grid of double-twisted cylinders undergoes highly coordinated, diffusionless transformations. In light of our findings, the implementation of several applications is discussed, such as temperature-switchable QR codes, micro-area lasing, and fabrication of blue phase liquid crystals with large domain sizes.
Limited application of reflective surfaces can mitigate urban heat pollution
Authors: Sen Sushobhan , Khazanovich Lev
Published: June 2021

Elevated air temperatures in urban neighborhoods due to the Urban Heat Island effect is a form of heat pollution that causes thermal discomfort, higher energy consumption, and deteriorating public health. Mitigation measures can be expensive, with the need to maximize benefits from limited resources. Here we show that significant mitigation can be achieved through a limited application of reflective surfaces. We use a Computational Fluid Dynamics model to resolve the air temperature within a prototypical neighborhood for different wind directions, building configurations, and partial application of reflective surfaces. While reflective surfaces mitigate heat pollution, their effectiveness relative to cost varies with spatial distribution. Although downstream parts experience the highest heat pollution, applying reflective surfaces to the upstream part has a disproportionately higher benefit relative to cost than applying them downstream.
Ecology of inorganic sulfur auxiliary metabolism in widespread bacteriophages
Authors: Kieft Kristopher , Zhou Zhichao , Anderson Rika E. , Buchan Alison , Campbell Barbara J. , Hallam Steven J. , Hess Matthias , Sullivan Matthew B. , Walsh David A. , Roux Simon , Anantharaman Karthik
Published: June 2021

Microbial sulfur metabolism contributes to biogeochemical cycling on global scales. Sulfur metabolizing microbes are infected by phages that can encode auxiliary metabolic genes (AMGs) to alter sulfur metabolism within host cells but remain poorly characterized. Here we identified 191 phages derived from twelve environments that encoded 227 AMGs for oxidation of sulfur and thiosulfate (dsrA, dsrC/tusE, soxC, soxD and soxYZ). Evidence for retention of AMGs during niche-differentiation of diverse phage populations provided evidence that auxiliary metabolism imparts measurable fitness benefits to phages with ramifications for ecosystem biogeochemistry. Gene abundance and expression profiles of AMGs suggested significant contributions by phages to sulfur and thiosulfate oxidation in freshwater lakes and oceans, and a sensitive response to changing sulfur concentrations in hydrothermal environments. Overall, our study provides fundamental insights on the distribution, diversity, and ecology of phage auxiliary metabolism associated with sulfur and reinforces the necessity of incorporating viral contributions into biogeochemical configurations.
H3K27me3 demethylases alter HSP22 and HSP17.6C expression in response to recurring heat in Arabidopsis
Authors: Yamaguchi Nobutoshi , Matsubara Satoshi , Yoshimizu Kaori , Seki Motohide , Hamada Kouta , Kamitani Mari , Kurita Yuko , Nomura Yasuyuki , Nagashima Kota , Inagaki Soichi , Suzuki Takamasa , Gan Eng-Seng , To Taiko , Kakutani Tetsuji , Nagano Atsushi J. , Satake Akiko , Ito Toshiro
Published: June 2021

Acclimation to high temperature increases plants’ tolerance of subsequent lethal high temperatures. Although epigenetic regulation of plant gene expression is well studied, how plants maintain a memory of environmental changes over time remains unclear. Here, we show that JUMONJI (JMJ) proteins, demethylases involved in histone H3 lysine 27 trimethylation (H3K27me3), are necessary for Arabidopsis thaliana heat acclimation. Acclimation induces sustained H3K27me3 demethylation at HEAT SHOCK PROTEIN22 (HSP22) and HSP17.6C loci by JMJs, poising the HSP genes for subsequent activation. Upon sensing heat after a 3-day interval, JMJs directly reactivate these HSP genes. Finally, jmj mutants fail to maintain heat memory under fluctuating field temperature conditions. Our findings of an epigenetic memory mechanism involving histone demethylases may have implications for environmental adaptation of field plants.
Spin-orbital coupling and slow phonon effects enabled persistent photoluminescence in organic crystal under isomer doping
Authors: Dou Yixuan , Demangeat Catherine , Wang Miaosheng , Xu Hengxing , Dryzhakov Bogdan , Kim Eunkyoung , Le Bahers Tangui , Lee Kwang-Sup , Attias André-Jean , Hu Bin
Published: June 2021

When periodically packing the intramolecular donor-acceptor structures to form ferroelectric-like lattice identified by second harmonic generation, our CD49 molecular crystal shows long-wavelength persistent photoluminescence peaked at 542 nm with the lifetime of 0.43 s, in addition to the short-wavelength prompt photoluminescence peaked at 363 nm with the lifetime of 0.45 ns. Interestingly, the long-wavelength persistent photoluminescence demonstrates magnetic field effects, showing as crystalline intermolecular charge-transfer excitons with singlet spin characteristics formed within ferroelectric-like lattice based on internal minority/majority carrier-balancing mechanism activated by isomer doping effects towards increasing electron-hole pairing probability. Our photoinduced Raman spectroscopy reveals the unusual slow relaxation of photoexcited lattice vibrations, indicating slow phonon effects occurring in ferroelectric-like lattice. Here, we show that crystalline intermolecular charge-transfer excitons are interacted with ferroelectric-like lattice, leading to exciton-lattice coupling within periodically packed intramolecular donor-acceptor structures to evolve ultralong-lived crystalline light-emitting states through slow phonon effects in ferroelectric light-emitting organic crystal.
Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition
Authors: Obaji Ezeogo , Maksimainen Mirko M. , Galera-Prat Albert , Lehtiö Lari
Published: June 2021

Human PARP2/ARTD2 is an ADP-ribosyltransferase which, when activated by 5′-phosphorylated DNA ends, catalyses poly-ADP-ribosylation of itself, other proteins and DNA. In this study, a crystal structure of PARP2 in complex with an activating 5′-phosphorylated DNA shows that the WGR domain bridges the dsDNA gap and joins the DNA ends. This DNA binding results in major conformational changes, including reorganization of helical fragments, in the PARP2 regulatory domain. A comparison of PARP1 and PARP2 crystal structures reveals how binding to a DNA damage site leads to formation of a catalytically competent conformation. In this conformation, PARP2 is capable of binding substrate NAD+ and histone PARylation factor 1 that changes PARP2 residue specificity from glutamate to serine when initiating DNA repair processes. The structure also reveals how the conformational changes in the autoinhibitory regulatory domain would promote the flexibility needed by the enzyme to reach the target macromolecule for ADP-ribosylation.
TcpC inhibits neutrophil extracellular trap formation by enhancing ubiquitination mediated degradation of peptidylarginine deiminase 4
Authors: Ou Qian , Fang Jia-qi , Zhang Zhe-sheng , Chi Zhe , Fang Jie , Xu Di-yan , Lu Kai-zhong , Qian Meng-qing , Zhang Da-yong , Guo Jun-ping , Gao Wei , Zhang Na-ru , Pan Jian-ping
Published: June 2021

TcpC is a multifunctional virulence factor of uropathogenicE. coli(UPEC). Neutrophil extracellular trap formation (NETosis) is a crucial anti-infection mechanism of neutrophils. Here we show the influence of TcpC on NETosis and related mechanisms. We show NETosis in the context of a pyelonephritis mouse model induced by TcpC-secreting wild-typeE. coliCFT073 (CFT073wt) and LPS-induced in vitro NETosis with CFT073wtor recombinant TcpC (rTcpC)-treated neutrophils are inhibited. rTcpC enters neutrophils through caveolin-mediated endocytosis and inhibits LPS-induced production of ROS, proinflammatory cytokines and protein but not mRNA levels of peptidylarginine deiminase 4 (PAD4). rTcpC treatment enhances PAD4 ubiquitination and accumulation in proteasomes. Moreover, in vitro ubiquitination kit analyses show that TcpC is a PAD4-targetd E3 ubiquitin-ligase. These data suggest that TcpC inhibits NETosis primarily by serving as an E3 ligase that promotes degradation of PAD4. Our findings provide a novel mechanism underlying TcpC-mediated innate immune evasion.
Tight finite-key analysis for quantum key distribution without monitoring signal disturbance
Authors: Liu Hang , Yin Zhen-Qiang , Wang Rong , Wang Ze-Hao , Wang Shuang , Chen Wei , Guo Guang-Can , Han Zheng-Fu
Published: June 2021

Unlike traditional communication, quantum key distribution (QKD) can reach unconditional security and thus attracts intensive studies. Among all existing QKD protocols, round-robin-differential-phase-shift (RRDPS) protocol can be running without monitoring signal disturbance, which significantly simplifies its flow and improves its tolerance of error rate. Although several security proofs of RRDPS have been given, a tight finite-key analysis with a practical phase-randomized source is still missing. In this paper, we propose an improved security proof of RRDPS against the most general coherent attack based on the entropic uncertainty relation. What’s more, with the help of Azuma’s inequality, our proof can tackle finite-key effects primely. The proposed finite-key analysis keeps the advantages of phase randomization source and indicates experimentally acceptable numbers of pulses are sufficient to approach the asymptotical bound closely. The results shed light on practical QKD without monitoring signal disturbance.
Immunogenicity of Ad26.COV2.S vaccine against SARS-CoV-2 variants in humans
Authors: Alter Galit , Yu Jingyou , Liu Jinyan , Chandrashekar Abishek , Borducchi Erica N. , Tostanoski Lisa H. , McMahan Katherine , Jacob-Dolan Catherine , Martinez David R. , Chang Aiquan , Anioke Tochi , Lifton Michelle , Nkolola Joseph , Stephenson Kathryn E. , Atyeo Caroline , Shin Sally , Fields Paul , Kaplan Ian , Robins Harlan , Amanat Fatima , Krammer Florian , Baric Ralph S. , Le Gars Mathieu , Sadoff Jerald , de Groot Anne Marit , Heerwegh Dirk , Struyf Frank , Douoguih Macaya , van Hoof Johan , Schuitemaker Hanneke , Barouch Dan H.
Published: June 2021

The Ad26.COV2.S vaccine1–3 has demonstrated clinical efficacy against symptomatic COVID-19, including against the B.1.351 variant that is partially resistant to neutralizing antibodies1. However, the immunogenicity of this vaccine in humans against SARS-CoV-2 variants of concern remains unclear. Here we report humoral and cellular immune responses from 20 Ad26.COV2.S vaccinated individuals from the COV1001 phase I–IIa clinical trial2 against the original SARS-CoV-2 strain WA1/2020 as well as against the B.1.1.7, CAL.20C, P.1 and B.1.351 variants of concern. Ad26.COV2.S induced median pseudovirus neutralizing antibody titres that were 5.0-fold and 3.3-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020 on day 71 after vaccination. Median binding antibody titres were 2.9-fold and 2.7-fold lower against the B.1.351 and P.1 variants, respectively, as compared with WA1/2020. Antibody-dependent cellular phagocytosis, complement deposition and natural killer cell activation responses were largely preserved against the B.1.351 variant. CD8 and CD4 T cell responses, including central and effector memory responses, were comparable among the WA1/2020, B.1.1.7, B.1.351, P.1 and CAL.20C variants. These data show that neutralizing antibody responses induced by Ad26.COV2.S were reduced against the B.1.351 and P.1 variants, but functional non-neutralizing antibody responses and T cell responses were largely preserved against SARS-CoV-2 variants. These findings have implications for vaccine protection against SARS-CoV-2 variants of concern.