bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosing and treating major depressive episodes that lie along the mood disorders spectrum: focus on depression with mixed features
Authors: McElroy Susan L. , Guerdjikova Anna I. , Romo-Nava Francisco
Published: March 2021

Growing evidence indicates that historical descriptions of mixed depression—broadly defined as major depressive episodes with subthreshold manic or hypomanic (hypo/manic) symptoms—are incredibly clinically relevant in this day-and-age. However, the first operational definition of mixed depression did not occur in the modern nomenclature until 2013 with publication of Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), and there has not been enough time to evaluate these criteria empirically. Thus, the most valid operational definition of a mixed depressive episode is still unknown, widely accepted treatment guidelines are not available, and no treatment has regulatory approval for mixed depression—whether associated with bipolar I disorder, bipolar II disorder, or major depressive disorder. This is despite seven drugs having regulatory indications for mixed episodes, defined as the co-occurrence of syndromal depression and syndromal mania, and now recognized as mania with mixed features by DSM-5. Indeed, we found only two randomized, placebo-controlled trials in patients with protocol defined mixed depression, one with ziprasidone and one with lurasidone. Both studies were positive, suggesting treatment with second-generation antipsychotics may be helpful for mixed depressive episodes associated with bipolar II or unipolar disorder. We found no randomized control trial of antidepressant monotherapy in mixed depression and many clinical reports that such treatment may worsen mixed depression Randomized, placebo-controlled trials of antidepressants, antipsychotics, and mood stabilizers—alone and in combination—in individuals with carefully defined mixed depression are needed before firm treatment guidelines can be produced.
Colonialism and Compromise: The Shanghai Municipal Police and the Arrest of Communists, 1927–37
Authors: LAW PETER KWOK-FAI
Published: March 2021

The Shanghai Municipal Council (SMC), which was mainly controlled by British residents in the treaty port of Shanghai, and protected by the British Foreign Office, came under serious challenge from the Guomindang (GMD) (the rising Nationalist Party of China) from 1927 onwards. The Shanghai Municipal Police (SMP)—an imperial police force with powers to arrest, prosecute and detain—was forced to collaborate with the GMD, and practice unlawful arrest, extradition and re-indoctrination of Communist suspects and convicts. This resulted in the erosion of state powers and the management of prisons. This article argues that the dismantling of British colonialism began to take place in Shanghai during the inter-war period at the expense of some English legal conventions, as demonstrated by SMP violations of existing legal practices and humanitarian commitments. Second, it also suggests that English judicial conventions had an unintended impact on some Chinese civilians, who were keen to safeguard their rights during their detention and trial in and beyond the Shanghai Legation. This article, therefore, offers a new periodisation of British decolonisation and a re-examination of colonial legacy in East Asia.
Regulative Principles and Kinds of the Unconditioned
Authors: Breitenbach Angela
Published: March 2021

In his Kant on Laws, Eric Watkins presents an account of reason on which the principles of specification and continuity are regulative instructions to search for different kinds of the unconditioned. I suggest that we correct Watkins’ account in two ways. First, we need to complete Watkins’ claim to the plurality of the unconditioned: reason aims for three kinds of the unconditioned, associated with the lowest, next and highest concepts. Second, we need to look beyond reason’s search for the unconditioned in order to properly understand the nature of the aim of reason. I argue that we construe reason’s aim as the systematic unity of cognition considered as a whole or, in Kant’s teleological terms, as the realization of an ‘idea’, or a ‘purposive unity’.
Biodiversity conservation as infectious disease prevention: why a social-ecological perspective is essential
Authors: Schneider Florian D. , Matias Denise Margaret , Burkhart Stefanie , Drees Lukas , Fickel Thomas , Hummel Diana , Liehr Stefan , Schramm Engelbert , Mehring Marion
Published: March 2021

Non-technical summary

Investing in stricter biodiversity conservation and wildlife protection to reduce the number of emerging diseases and, consequently, the risk of pandemics such as coronavirus disease-19 (COVID-19), must integrate a social-ecological perspective. Biodiversity conservation, in order to be effective as disease prevention, requires consideration of people's needs, knowledge and institutions within their locally specific contexts. To meet this goal, future biodiversity research and conservation policy should apply six social-ecological principles for shaping future practices of co-existence of societies and nature.

Technical summary

The COVID-19 pandemic, presumably originating in a spillover event from natural wildlife reservoirs into the human population, sets a new benchmark for the indirect cost of biodiversity exploitation. To reverse the trend of increasing pandemic risk, biodiversity conservation and wildlife protection must be strengthened globally. In this paper, we argue that such preventive measures explicitly need to employ a social-ecological approach. In particular, attention must be paid to the societal relations to nature to avoid falling for simplistic solutions that neglect regional and local particularities of both, biodiversity and local communities. We emphasize the importance of avoiding a Western-biased view and acknowledging the factors and causations of infectious disease emergence in industrialized countries. To reduce the emergence of zoonotic and vector-borne diseases in their specific contexts, we propose applying a social-ecological systems approach by integrating plural local knowledge and values, established practices, formal and informal institutions, as well as technology. We further introduce six social-ecological principles for shaping transformations in the Anthropocene to maintain and build more resilient and sustainable communities. By operationalizing these inter- and transdisciplinary principles, biodiversity conservation can be effectively implemented as infectious disease prevention.

Social media summary

A social-ecological approach to biodiversity conservation can pave the way for an effective and socially just reduction of future pandemic risks.
Psychometric Properties of the Positive Mental Health Scale	(PMH-Scale) Among Turkish University Students
Authors: Çeçen Ayşe R. , Vatandaşlar Senem E.
Published: March 2021

Abstract. Background: The PMH-scale is a person-centered, brief and psychometrically sound scale measuring positive mental health. Considering the practicality of the scale and the good psychometric properties reported previously, the adaptation of the PMH-scale to Turkish may provide professionals and researchers a beneficial tool to assess well-being. Aims: This study was designed to investigate the psychometric properties of the Positive Mental Health Scale among Turkish university students by utilizing a cross-sectional correlational survey model. Method: For the adaptation of the scale, different validity and reliability tests were performed. Confirmatory factor analysis was run for construct validity. Convergent validity was assessed by examining relations of the scale with Life Orientation Test, Short Depression-Happiness Scale, Depression Anxiety Stress Scale, and General Self-Efficacy Scale. Reliability was assessed with internal consistency and composite reliability. Measurement invariance across genders was tested through Structural Equation Modelling. Results: Validity and reliability analyses provided satisfactory results. Results of confirmatory factor analysis revealed that current data fit the original unidimensional model. Besides, measurement invariance analysis provided validity evidence in terms of gender invariance. Limitations: Findings of the present study were limited to university students, most of whom were female. Conclusion: In conclusion, the Turkish Positive Mental Health Scale was found to be valid and reliable in the sample of university students.
Prediction of Gas Hydrate Formation at Blake Ridge Using Machine Learning and Probabilistic Reservoir Simulation
Authors: Eymold William K. , Frederick Jennifer M. , Nole Michael , Phrampus Benjamin J. , Wood Warren T.
Published: March 2021

Methane hydrates are solid structures containing methane inside of a water lattice that form under low temperature and relatively high pressure. Appropriate hydrate‐forming conditions exist along continental shelves or are associated with permafrost. Hydrates have garnered scientific interest via their potential as a source of natural gas and their role in the global carbon cycle. While methane hydrates have been collected in multiple diverse geographic settings, their quantities and distribution in sediments remain poorly constrained due to sparse relevant data. Using statistical and machine learning approaches, we have developed a workflow to probabilistically predict methane hydrate occurrence from local microbial methane sourcing. This approach utilizes machine‐learned global maps produced by the Global Predictive Seabed Model (GPSM) as inputs for the statistical sampling software, Dakota, and multiphase reservoir simulation software, PFLOTRAN. Dakota performs Latin hypercube sampling of the GPSM‐predicted values and uncertainties to generate unique sets of input parameters for 1‐D PFLOTRAN simulations of gas hydrate and free gas formation resulting from methanogenesis to steady state. We ran 100 1‐D simulations spanning a kilometer in depth at 5,297 locations near Blake Ridge. Masses of hydrate and free gas formed at each location were determined by integrating the predicted saturation profiles. Elevated hydrate formation is predicted to occur at depths >500 meters below sea level at this location, and is strongly associated with high seafloor total organic carbon values. We produce representative maps of expected hydrate occurrence for the study area based on multiple realizations that can be validated against geophysical observations.
Over‐Darkening of Pulsating Aurora
Authors: Hosokawa K. , Miyoshi Y. , Oyama S.‐I. , Ogawa Y. , Kurita S. , Kasahara Y. , Kasaba Y. , Yagitani S. , Matsuda S. , Ozaki M. , Tsuchiya F. , Kumamoto A. , Takashima T. , Shinohara I. , Fujii R.
Published: March 2021

Recent analyses of high‐time resolution ground‐based optical observations of pulsating aurora (PsA) have reported that the brightness of PsA sometimes decreases below the diffuse background level immediately after the ON phase of the main pulsation finishes. To date, however, the generation mechanism of such an “over‐darkening PsA” is still unclarified. In this study, we investigated the characteristics of the over‐darkening PsA by using simultaneous observations of PsA with an electron multiplying charge coupled device all‐sky camera in Sodankylä, Finland and the Arase satellite. During one of the conjunction events in Scandinavia on March 29, 2017, almost all the PsA pulses showed clear over‐darkening characteristics. By analyzing the 2D all‐sky images at the times of over‐darkening we discovered that over‐darkening areas appeared in the trailing edge of PsA patches and moved in tandem with the poleward propagating patches. It was also found that similar over‐decreasing characteristics were not seen in the chorus data from the wave instruments onboard Arase located at the magnetospheric counterpart of PsA. These results indicate that the over‐darkening PsA is not caused by a temporal variation of chorus at a fixed point, but is produced by a propagation of over‐darkening area with PsA patches. That is, the over‐darkening PsA is a result of compounding effects of spatial structure and recurrent propagation of PsA. The mechanism creating the dark area is still unknown, but the existence of over‐darkening PsA suggests that the temporal variation of PsA is not always a perfect copy of the modulation of lower‐band chorus waves in the magnetosphere.
The Origin of Felsic Intrusions Within the Mantle Section of the Samail Ophiolite: Geochemical Evidence for Three Distinct Mixing and Fractionation Trends
Authors: Rioux Matthew , Benoit Mathieu , Amri Isma , Ceuleneer Georges , Garber Joshua M. , Searle Michael , Leal Kayla
Published: March 2021

An isotopically diverse suite of felsic dikes, sills, and plugs (εNd(t) = −7.8 to +7.8) intrude the uppermost mantle and lower crust in the Samail ophiolite in Oman and the United Arab Emirates (UAE). These features have been interpreted to represent amphibolite and metasediment melts from an underthrust sheet of oceanic lithosphere. As such, the intrusions provide a record of melting of oceanic crust and sediment at depth, with implications for mass transfer from the down‐going plate in young, hot subduction settings. Several studies have used geochemical data to constrain the magmatic sources of the dikes; here we build on this previous work using integrated whole rock major element, trace element and Nd isotopic data from a more geographically extensive suite of dikes. New and existing data suggest the felsic intrusions preserved within mantle peridotites in the Oman portion of the ophiolite were generated by three distinct mixing and fractionation trends: (1) three‐component mixing between sediment melt, amphibolite melt and a mantle component; (2) two component mixing between amphibolite and sediment melts, with little mantle contribution; and (3) fractional crystallization of depleted, mantle derived magmas, likely related to the ophiolite V2 volcanic series. Combined geochemical and pseudosection modeling suggest that amphibolite melting occurred at P ≤ 1.4 GPa (∼40–45 km) and T ≥ 700–750°C. Felsic intrusions in the mantle section in the UAE, including garnet‐andalusite‐cordierite leucogranites, follow similar mixing trends, but crystallized ∼0.9–4.0 Ma after the Oman intrusions.
Evidence for Fluids at the Hypocenter of the 2017 Ms 7.0 Jiuzhaigou Earthquake Revealed by Local Earthquake Tomography
Authors: Chen Shuze , Zhao Junmeng , Xu Qiang , Liu Hongbing , Ju Changhui
Published: March 2021

The seismogenic structure of the 2017 Ms 7.0 Jiuzhaigou earthquake is still under debate. To address this issue, we use arrival times of P‐ and S‐ waves from 1766 local earthquakes recorded by our deployed 18 temporary seismic stations to perform the local earthquake tomography and present the 3‐D distributions of the P‐ wave and S‐ wave velocities (Vp and Vs), Vp/Vs ratio and the locations of the relocated aftershocks in the source region of the 2017 Jiuzhaigou earthquake. The aftershocks occurred at depths of 2–10 km, and can be divided into a NNW‐SSE trending northern segment and a NW‐SE trending southern segment relative to hypocenter of the main shock. Combined with previous observations, it is proposed that the Jiuzhaigou earthquake occurred on an unmapped fault which is a branch of the easternmost segment of the eastern Kunlun fault zone. The source region of the Jiuzhaigou earthquake is characterized by high Vp and low Vs anomalies as well as high Vp/Vs ratios, suggesting the presence of fluids in the fractured rocks. These fluids may have contributed to the occurrence of the Jiuzhaigou earthquake by reducing the effective normal stress and thus causing the brittle failure of rocks.
ENSO Variability During the Medieval Climate Anomaly as Recorded by Porites Corals From the Northern South China Sea
Authors: Jiang Leilei , Yu Kefu , Tao Shichen , Wang Shaopeng , Han Tao , Jiang Wei
Published: March 2021

The El Niño–Southern Oscillation (ENSO) dominates interannual climate variability worldwide and has important environmental and socio‐economic consequences. However, determining the evolution of ENSO variability and its long‐term response to climate forcing remains an ongoing challenge owing to the limited instrumental records. In this study, we quantified ENSO variability via an empirically calibrated threshold and sliding variance windows using monthly sea‐surface temperature (SST) anomalies based on Porites coral Sr/Ca records from the Xisha Islands in the northern South China Sea. Instrumental SST anomalies from the Xisha Islands correctly captured increasing ENSO variability in the twentieth century, with ENSO detection skills similar to those for Niño3.4 regions. Coral Sr/Ca‐SST anomalies can also serve as sensitive and robust proxies for ENSO variability. Sub‐fossil coral Sr/Ca‐SST anomalies indicated intensified ENSO variability at the end of the Medieval Climate Anomaly (MCA) from 1149 to 1205 ± 4.9 (2σ) Common Era (CE). Combining our records with other ENSO‐sensitive proxy reconstructions from the tropical Pacific, we observed fluctuating ENSO variability during the MCA and intensified ENSO variability for the late MCA. Considering the fewer and low intensity fluctuations associated with external climate forcing and the absence of a coherent temporal correspondence of ENSO activity with solar irradiance and volcanic eruption during the MCA, we hypothesized that the internal dynamics of the climate system play a prominent role in modulating ENSO variability and its evolution, which is supported by unforced climate model simulations and coral reconstructions across the tropical Pacific.
Plasmonic semiconductor nanogroove array enhanced broad spectral band millimetre and terahertz wave detection
Authors: Tong Jinchao , Suo Fei , Zhang Tianning , Huang Zhiming , Chu Junhao , Zhang Dao Hua
Published: March 2021

High-performance uncooled millimetre and terahertz wave detectors are required as a building block for a wide range of applications. The state-of-the-art technologies, however, are plagued by low sensitivity, narrow spectral bandwidth, and complicated architecture. Here, we report semiconductor surface plasmon enhanced high-performance broadband millimetre and terahertz wave detectors which are based on nanogroove InSb array epitaxially grown on GaAs substrate for room temperature operation. By making a nanogroove array in the grown InSb layer, strong millimetre and terahertz wave surface plasmon polaritons can be generated at the InSb–air interfaces, which results in significant improvement in detecting performance. A noise equivalent power (NEP) of 2.2 × 10−14 W Hz−1/2 or a detectivity (D*) of 2.7 × 1012 cm Hz1/2 W−1 at 1.75 mm (0.171 THz) is achieved at room temperature. By lowering the temperature to the thermoelectric cooling available 200 K, the corresponding NEP and D* of the nanogroove device can be improved to 3.8 × 10−15 W Hz−1/2 and 1.6 × 1013 cm Hz1/2 W−1, respectively. In addition, such a single device can perform broad spectral band detection from 0.9 mm (0.330 THz) to 9.4 mm (0.032 THz). Fast responses of 3.5 µs and 780 ns are achieved at room temperature and 200 K, respectively. Such high-performance millimetre and terahertz wave photodetectors are useful for wide applications such as high capacity communications, walk-through security, biological diagnosis, spectroscopy, and remote sensing. In addition, the integration of plasmonic semiconductor nanostructures paves a way for realizing high performance and multifunctional long-wavelength optoelectrical devices.
Microbial hitchhiking: how Streptomyces spores are transported by motile soil bacteria
Authors: Muok Alise R , Claessen Dennis , Briegel Ariane
Published: March 2021

Streptomycetes are sessile bacteria that produce metabolites that impact the behavior of microbial communities. Emerging studies have demonstrated that Streptomyces spores are distributed through various mechanisms, but it remains unclear how spores are transported to their preferred microenvironments, such as plant roots. Here, we show that Streptomyces spores are capable of utilizing the motility machinery of other soil bacteria. Motility assays and microscopy studies reveal that Streptomyces spores are transported to plant tissues by interacting directly with the flagella of both gram-positive and gram-negative bacteria. Genetics experiments demonstrate that this form of motility is facilitated by structural proteins on the spore coat. These results demonstrate that nonmotile bacteria are capable of utilizing the motility machinery of other microbes to complete necessary stages of their lifecycle.
COVID-19 patient transcriptomic and genomic profiling reveals comorbidity interactions with psychiatric disorders
Authors: Moni Mohammad Ali , Lin Ping-I , Quinn Julian M. W. , Eapen Valsamma
Published: March 2021

Psychiatric symptoms are seen in some COVID-19 patients, as direct or indirect sequelae, but it is unclear whether SARS-CoV-2 infection interacts with underlying neuronal or psychiatric susceptibilities. Such interactions might arise from COVID-19 immune responses, from infection of neurons themselves or may reflect social-psychological causes. To clarify this we sought the key gene expression pathways altered in COVID-19 also affected in bipolar disorder, post-traumatic stress disorder (PTSD) and schizophrenia, since this may identify pathways of interaction that could be treatment targets. We performed large scale comparisons of whole transcriptome data and immune factor transcript data in peripheral blood mononuclear cells (PBMC) from COVID-19 patients and patients with psychiatric disorders. We also analysed genome-wide association study (GWAS) data for symptomatic COVID-19 patients, comparing GWAS and whole-genome sequence data from patients with bipolar disorder, PTSD and schizophrenia patients. These studies revealed altered signalling and ontology pathways shared by COVID-19 patients and the three psychiatric disorders. Finally, co-expression and network analyses identified gene clusters common to the conditions. COVID-19 patients had peripheral blood immune system profiles that overlapped with those of patients with psychiatric conditions. From the pathways identified, PTSD profiles were the most highly correlated with COVID-19, perhaps consistent with stress-immune system interactions seen in PTSD. We also revealed common inflammatory pathways that may exacerbate psychiatric disorders, which may support the usage of anti-inflammatory medications in these patients. It also highlights the potential clinical application of multi-level dataset studies in difficult-to-treat psychiatric disorders in this COVID-19 pandemic.
Retraction Note to: Natural product pectolinarigenin inhibits osteosarcoma growth and metastasis via SHP-1-mediated STAT3 signaling inhibition
Authors: Zhang Tao , Li Suoyuan , Li Jingjie , Yin Fei , Hua Yingqi , Wang Zhouying , Lin Binhui , Wang Hongsheng , Zou Dongqing , Zhou Zifei , Xu Jing , Yi Chengqing , Cai Zhengdong
Published: March 2021

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1038/s41419-021-03529-7
Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models
Authors: Riess Christin , Koczan Dirk , Schneider Björn , Linke Charlotte , del Moral Katharina , Classen Carl Friedrich , Maletzki Claudia
Published: March 2021

Current therapeutic approaches have met limited clinical success for glioblastoma multiforme (GBM). Since GBM harbors genomic alterations in cyclin-dependent kinases (CDKs), targeting these structures with specific inhibitors (CDKis) is promising. Here, we describe the antitumoral potential of selective CDKi on low-passage GBM 2D- and 3D models, cultured as neurospheres (NSCs) or glioma stem-like cells (GSCs). By applying selective CDK4/6i abemaciclib and palbociclib, and the more global CDK1/2/5/9-i dinaciclib, different effects were seen. Abemaciclib and dinaciclib significantly affected viability in 2D- and 3D models with clearly visible changes in morphology. Palbociclib had weaker and cell line-specific effects. Motility and invasion were highly affected. Abemaciclib and dinaciclib additionally induced senescence. Also, mitochondrial dysfunction and generation of mitochondrial reactive oxygen species (ROS) were seen. While autophagy was predominantly visible after abemaciclib treatment, dinaciclib evoked γ-H2AX-positive double-strand breaks that were boosted by radiation. Notably, dual administration of dinaciclib and abemaciclib yielded synergistic effects in most cases, but the simultaneous combination with standard chemotherapeutic agent temozolomide (TMZ) was antagonistic. RNA-based microarray analysis showed that gene expression was significantly altered by dinaciclib: genes involved in cell-cycle regulation (different CDKs and their cyclins, SMC3), mitosis (PLK1, TTK), transcription regulation (IRX3, MEN1), cell migration/division (BCAR1), and E3 ubiquitination ligases (RBBP6, FBXO32) were downregulated, whereas upregulation was seen in genes mediating chemotaxis (CXCL8, IL6, CCL2), and DNA-damage or stress (EGR1, ARC, GADD45A/B). In a long-term experiment, resistance development was seen in 1/5 cases treated with dinaciclib, but this could be prevented by abemaciclib. Vice versa, adding TMZ abrogated therapeutic effects of dinaciclib and growth was comparable to controls. With this comprehensive analysis, we confirm the therapeutic activity of selective CDKi in GBM. In addition to the careful selection of individual drugs, the timing of each combination partner needs to be considered to prevent resistance.
Voltage controlled Néel vector rotation in zero magnetic field
Authors: Mahmood Ather , Echtenkamp Will , Street Mike , Wang Jun-Lei , Cao Shi , Komesu Takashi , Dowben Peter A. , Buragohain Pratyush , Lu Haidong , Gruverman Alexei , Parthasarathy Arun , Rakheja Shaloo , Binek Christian
Published: March 2021

Multi-functional thin films of boron (B) doped Cr2O3 exhibit voltage-controlled and nonvolatile Néel vector reorientation in the absence of an applied magnetic field, H. Toggling of antiferromagnetic states is demonstrated in prototype device structures at CMOS compatible temperatures between 300 and 400 K. The boundary magnetization associated with the Néel vector orientation serves as state variable which is read via magnetoresistive detection in a Pt Hall bar adjacent to the B:Cr2O3 film. Switching of the Hall voltage between zero and non-zero values implies Néel vector rotation by 90 degrees. Combined magnetometry, spin resolved inverse photoemission, electric transport and scanning probe microscopy measurements reveal B-dependent TN and resistivity enhancement, spin-canting, anisotropy reduction, dynamic polarization hysteresis and gate voltage dependent orientation of boundary magnetization. The combined effect enables H = 0, voltage controlled, nonvolatile Néel vector rotation at high-temperature. Theoretical modeling estimates switching speeds of about 100 ps making B:Cr2O3 a promising multifunctional single-phase material for energy efficient nonvolatile CMOS compatible memory applications.
Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Authors: De Biasi Sara , Gibellini Lara , Lo Tartaro Domenico , Puccio Simone , Rabacchi Claudio , Mazza Emilia M. C. , Brummelman Jolanda , Williams Brandon , Kaihara Kelly , Forcato Mattia , Bicciato Silvio , Pinti Marcello , Depenni Roberta , Sabbatini Roberto , Longo Caterina , Dominici Massimo , Pellacani Giovanni , Lugli Enrico , Cossarizza Andrea
Published: March 2021

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.
Tensile strength analysis of automatic periodic stimulation for continuous intraoperative neural monitoring in a piglet model
Authors: Wang Tie , Dionigi Gianlorenzo , Zhao Yishen , Zhang Daqi , Pino Antonella , Dralle Henning , Wu Che-Wei , Zhou Le , Sun Hui
Published: March 2021

Continuous intraoperative neural monitoring (C-IONM) during thyroid surgery is a useful tool for preventing recurrent laryngeal nerve (RLN) injury. The present study aims to analyze the tensile strength tolerance of C-IONM electrodes on the vagal nerve (VN). A C-IONM wire was enclosed in a hand-held tensile testing system. The probe displacement on the VN was continuously monitored by positioning a second probe far-up/proximally in a piglet model, and an automatic periodic stimulation (APS) accessory was used. The 3-mm and 2-mm APS accessory has a mean tensile strength of 20.6 ± 10 N (range, 14.6–24.4 N) and 11.25 ± 8 N (range, 8.4–15.6 N), respectively (P = 0.002). There was no difference between bilateral VNs. The mean amplitude before and during electrode displacement was 1.835 ± 102 μV and 1.795 ± 169 μV, respectively (P = 0.45). The mean percentage of amplitude decrease on the electromyography (EMG) was 6.9 ± 2.5%, and the mean percentage of latency increase was 1.9 ± 1.5%. No significant amplitude reduction or loss of signal (LOS) was observed after > 50 probe dislocations. C-IONM probe dislocation does not cause any LOS or significant EMG alterations on the VN.
A systematic review and meta-analysis of treatment-related toxicities of curative and palliative radiation therapy in non-small cell lung cancer
Authors: Or M. , Liu B. , Lam J. , Vinod S. , Xuan W. , Yeghiaian-Alvandi R. , Hau E.
Published: March 2021

Treatment-related toxicity is an important component in non-small cell lung cancer (NSCLC) management decision-making. Our aim was to evaluate and compare the toxicity rates of curative and palliative radiotherapy with and without chemotherapy. This meta-analysis provides better quantitative estimates of the toxicities compared to individual trials. A systematic review of randomised trials with > 50 unresectable NSCLC patients, treated with curative or palliative conventional radiotherapy (RT) with or without chemotherapy. Data was extracted for oesophagitis, pneumonitis, cardiac events, pulmonary fibrosis, myelopathy and neutropenia by any grade, grade ≥ 3 and treatment-related deaths. Mantel–Haenszel fixed-effect method was used to obtain pooled risk ratio. Forty-nine trials with 8609 evaluable patients were included. There was significantly less grade ≥ 3 acute oesophagitis (6.4 vs 22.2%, p < 0.0001) and any grade oesophagitis (70.4 vs 79.0%, p = 0.04) for sequential CRT compared to concurrent CRT, with no difference in pneumonitis (grade ≥ 3 or any grade), neutropenia (grade ≥ 3), cardiac events (grade ≥ 3) or treatment-related deaths. Although the rate of toxicity increased with intensification of treatment with RT, the only significant difference between treatment regimens was the rate of oesophagitis between the use of concurrent and sequential CRT. This can aid clinicians in radiotherapy decision making for NSCLC.
Patterns of dendritic cell and monocyte subsets are associated with disease severity and mortality in liver cirrhosis patients
Authors: Cardoso Chandra Chiappin , Matiollo Camila , Pereira Carolina Hilgert Jacobsen , Fonseca Janaina Santana , Alves Helder Emmanuel Leite , da Silva Otavio Marcos , de Souza Menegassi Vivian , dos Santos Claudia Regina , de Moraes Ana Carolina Rabello , de Lucca Schiavon Leonardo , Santos-Silva Maria Claudia
Published: March 2021

Liver cirrhosis is often complicated by an immunological imbalance known as cirrhosis-associated immune dysfunction. This study aimed to investigate disturbances in circulating monocytes and dendritic cells in patients with acute decompensation (AD) of cirrhosis. The sample included 39 adult cirrhotic patients hospitalized for AD, 29 patients with stable cirrhosis (SC), and 30 healthy controls (CTR). Flow cytometry was used to analyze monocyte and dendritic cell subsets in whole blood and quantify cytokines in plasma samples. Cirrhotic groups showed higher frequencies of intermediate monocytes (iMo) than CTR. AD patients had lower percentages of nonclassical monocytes than CTR and SC. Cirrhotic patients had a profound reduction in absolute and relative dendritic cell numbers compared with CTR and showed higher plasmacytoid/classical dendritic cell ratios. Increased plasma levels of IL-6, IL-10, and IL-17A, elevated percentages of CD62L+ monocytes, and reduced HLA-DR expression on classical monocytes (cMo) were also observed in cirrhotic patients. Patients with more advanced liver disease showed increased cMo and reduced tissue macrophages (TiMas) frequencies. It was found that cMo percentages greater than 90.0% within the monocyte compartment and iMo and TiMas percentages lower than 5.7% and 8.6%, respectively, were associated with increased 90-day mortality. Monocytes and dendritic cells are deeply altered in cirrhotic patients, and subset profiles differ between stable and advanced liver disease. High cMo and low TiMas frequencies may be useful biomarkers of disease severity and mortality in liver cirrhosis.
Usefulness of virtual reality-based training to diagnose strabismus
Authors: Moon Hyun Sik , Yoon Hyeon Jeong , Park Sang Woo , Kim Chae Yeon , Jeong Mu Seok , Lim Sung Min , Ryu Jee Heon , Heo Hwan
Published: March 2021

To study the usefulness of virtual reality (VR)-based training for diagnosing strabismus. Fourteen residents in ophthalmology performed at least 30 VR training sessions to diagnose esotropia and exotropia. Examinations of real patients with esotropia or exotropia before and after the VR training were video-recorded and presented to a strabismus expert to assess accuracy and performance scores for measuring the deviation angle and diagnosing strabismus with anonymization. A feedback survey regarding the usefulness and ease of use of the VR application was conducted for participants. The mean age of the 14 ophthalmology residents (10 men and 4 women), was 29.7 years. Before VR training, participants showed a mean accuracy score of 14.50 ± 5.45 and a performance score of 9.64 ± 4.67 for measuring the deviation angle and diagnosing strabismus in real patients with strabismus. After VR training, they showed a significantly improved accuracy score of 22.14 ± 4.37 (p = 0.012) and a performance score of 15.50 ± 1.99 (p = 0.011). According to the survey, most participants agreed on the usefulness of VR applications. This study suggests that VR-based training improved ophthalmology residents’ clinical diagnostic skills for strabismus in a short period.
The importance of cellular and exosomal miRNAs in mesenchymal stem cell osteoblastic differentiation
Authors: Shirazi Sajjad , Huang Chun-Chieh , Kang Miya , Lu Yu , Ravindran Sriram , Cooper Lyndon F.
Published: March 2021

The differentiation of osteoblasts is under complex regulation that includes autocrine and paracrine signaling from MSCs. Exosomes are important components of the MSC secretome and their cargo contains numerous miRNAs. In this study, the importance of MSC miRNAs in modulation of osteoblastic differentiation was examined by global reduction of miRNA biosynthesis in Dicer knock down hMSCs. We additionally impaired hMSC responses to miRNAs by knockdown of Argonaute 2 expression. Knockdown of Dicer and Argonaute 2 both reduced osteoblastic differentiation of hMSCs. This was observed at the levels of hMSC culture mineralization and osteoblastic gene expression. The treatment of Dicer deficient hMSCs with wild type hMSC exosomes effectively recovered the impaired osteoblastic differentiation. Dicer knockdown reduced the quantity and diversity of miRNAs present in hMSC exosomes. miRSeq data and KEGG analysis implicated the miRNA-dependent effects on multiple osteoinductive pathways in Dicer deficient cells, including the Hippo signaling and TGF-beta signaling pathways. Treatment of hMSCs with mimics of miRNAs significantly downregulated in Dicer knockdown cells recovered functions of exosome-mediated signaling in hMSCs. These results indicate that hMSC exosomes exert miRNA-dependent control that contributes to osteoblastic differentiation.
Cystatin C predicts long term mortality better than creatinine in a nationwide study of intensive care patients
Authors: Helmersson-Karlqvist Johanna , Lipcsey Miklos , Ärnlöv Johan , Bell Max , Ravn Bo , Dardashti Alain , Larsson Anders
Published: March 2021

Decreased glomerular filtration rate (GFR) is linked to poor survival. The predictive value of creatinine estimated GFR (eGFR) and cystatin C eGFR in critically ill patients may differ substantially, but has been less studied. This study compares long-term mortality risk prediction by eGFR using a creatinine equation (CKD-EPI), a cystatin C equation (CAPA) and a combined creatinine/cystatin C equation (CKD-EPI), in 22,488 patients treated in intensive care at three University Hospitals in Sweden, between 2004 and 2015. Patients were analysed for both creatinine and cystatin C on the same blood sample tube at admission, using accredited laboratory methods. During follow-up (median 5.1 years) 8401 (37%) patients died. Reduced eGFR was significantly associated with death by all eGFR-equations in Cox regression models. However, patients reclassified to a lower GFR-category by using the cystatin C-based equation, as compared to the creatinine-based equation, had significantly higher mortality risk compared to the referent patients not reclassified. The cystatin C equation increased C-statistics for death prediction (p < 0.001 vs. creatinine, p = 0.013 vs. combined equation). In conclusion, this data favours the sole cystatin C equation rather than the creatinine or combined equations when estimating GFR for risk prediction purposes in critically ill patients.
Elevation of plasma tRNA fragments as a promising biomarker for liver fibrosis in nonalcoholic fatty liver disease
Authors: Huang Peng , Tu Biao , Liao Hui-jun , Huang Fei-zhou , Li Zhen-zhou , Zhu Kuang-ye , Dai Feng , Liu Huai-zheng , Zhang Tian-yi , Sun Chuan-zheng
Published: March 2021

Fibrotic tissue remodelling in nonalcoholic fatty liver disease (NAFLD) will probably emerge as the leading cause of end-stage liver disease in the coming decades, but the ability to diagnose liver fibrosis in NAFLD patients noninvasively is limited. The abnormal expression of tRNA-derived small RNA (tsRNA) in plasma provides a novel idea for noninvasive diagnosis of various diseases, however, the relationship between tsRNAs and NAFLD is still unknown. Here, we took advantage of small RNA-Seq technology to profile tsRNAs in NAFLD patients and found the ubiquitous presence of hepatic tsRNAs secreted into circulating blood. Verification in a cohort of 114 patients with NAFLD and 42 patients without NAFLD revealed that three tsRNAs (tRF-Val-CAC-005, tiRNA-His-GTG-001, and tRF-Ala-CGC-006) were significantly elevated in the plasma of NAFLD patients, and the expression level are associated with NAFLD activity score (calculated from 0 to 8) and fibrosis stage (scored from 0 to 4). In mouse models, we further found that increased plasma levels of these three tsRNAs were positively correlated with the degree of liver fibrosis. Our study potentially identifies a new class of NAFLD biomarkers and reveal the possible existence of tsRNAs in the blood that can be used to predict fibrogenesis risk in patients diagnosed with NAFLD.
Individual separation of surface, bulk and Begrenzungs effect components in the surface electron energy spectra
Authors: Yang Lihao , Da Bo , Tőkési Károly , Ding Z. J.
Published: March 2021

We present the first theoretical recipe for the clear and individual separation of surface, bulk and Begrenzungs effect components in surface electron energy spectra. The procedure ends up with the spectral contributions originated from surface and bulk-Begrenzungs excitations by using a simple method for dealing with the mixed scatterings. As an example, the model is applied to the reflection electron energy loss spectroscopy spectrum of Si. The electron spectroscopy techniques can directly use the present calculation schema to identify the origin of the electron signals from a sample. Our model provides the possibility for the detailed and accurate quantitative analysis of REELS spectra.
In situ synchrotron diffraction and modeling of non-equilibrium solidification of a MnFeCoNiCu alloy
Authors: Schneiderman Benjamin , Chuang Andrew Chihpin , Kenesei Peter , Yu Zhenzhen
Published: March 2021

The solidification mechanism and segregation behavior of laser-melted Mn35Fe5Co20Ni20Cu20was firstly investigated via in situ synchrotron x-ray diffraction at millisecond temporal resolution. The transient composition evolution of the random solid solution during sequential solidification of dendritic and interdendritic regions complicates the analysis of synchrotron diffraction data via any single conventional tool, such as Rietveld refinement. Therefore, a novel approach combining a hard-sphere approximation model, thermodynamic simulation, thermal expansion measurement and microstructural characterization was developed to assist in a fundamental understanding of the evolution of local composition, lattice parameter, and dendrite volume fraction corresponding to the diffraction data. This methodology yields self-consistent results across different methods. Via this approach, four distinct stages were identified, including: (I) FCC dendrite solidification, (II) solidification of FCC interdendritic region, (III) solid-state interdiffusion and (IV) final cooling with marginal diffusion. It was found out that in Stage I, Cu and Mn were rejected into liquid as Mn35Fe5Co20Ni20Cu20solidified dendritically. During Stage II, the lattice parameter disparity between dendrite and interdendritic region escalated as Cu and Mn continued segregating into the interdendritic region. After complete solidification, during Stage III, the lattice parameter disparity gradually decreases, demonstrating a degree of composition homogenization. The volume fraction of dendrites slightly grew from 58.3 to 65.5%, based on the evolving composition profile across a dendrite/interdendritic interface in diffusion calculations. Postmortem metallography further confirmed that dendrites have a volume fraction of 64.7% ± 5.3% in the final microstructure.
High intraluminal pressure promotes vascular inflammation via caveolin-1
Authors: Michell Danielle L. , Shihata Waled A. , Andrews Karen L. , Abidin Nurul Aisha Zainal , Jefferis Ann-Maree , Sampson Amanda K. , Lumsden Natalie G. , Huet Olivier , Parat Marie-Odile , Jennings Garry L. , Parton Robert G. , Woollard Kevin J. , Kaye David M. , Chin-Dusting Jaye P. F. , Murphy Andrew J.
Published: March 2021

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.
The influence of sex and body mass index on the association between soluble neprilysin and risk of heart failure hospitalizations
Authors: Núñez Julio , Núñez Eduardo , Revuelta-López Elena , Miñana Gema , Barallat Jaume , Bodi Vicent , Sanchis Juan , Aimo Alberto , Emdin Michele , Lupón Josep , Husser Oliver , Bayes-Genis Antoni
Published: March 2021

A higher neprilysin activity has been suggested in women. In this retrospective analysis, we evaluated the association of sex and body mass index (BMI) with soluble neprilysin (sNEP) and recurrent admissions among 1021 consecutive HF outpatients. The primary and secondary endpoints were the number of HF hospitalizations and all-cause mortality, respectively. The association between sNEP with either endpoint was evaluated across sex and BMI categories (≥ 25 kg/m2 vs. < 25 kg/m2). Bivariate count regression (Poisson) was used, and risk estimates were expressed as incidence rates ratio (IRR). During a median follow-up of 6.65 years (percentile 25%-percentile 75%:2.83–10.25), 702 (68.76%) patients died, and 406 (40%) had at least 1 HF hospitalization. Median values of sNEP and BMI were 0.64 ng/mL (0.39–1.22), and 26.9 kg/m2 (24.3–30.4), respectively. Left ventricle ejection fraction was < 40% in 78.9% of patients, and 28% were women. In multivariable analysis, sNEP (main effect) was positively associated with HF hospitalizations (p = 0.001) but not with mortality (p = 0.241). The predictive value of sNEP for HF hospitalizations varied non-linearly across sex and BMI categories (p-value for interaction = 0.003), with significant and positive effect only on women with BMI ≥ 25 kg/m2 (p = 0.039). For instance, compared to men, women with sNEP of 1.22 ng/mL (percentile 75%) showed a significantly increased risk (IRRs: 1.26; 95% CI: 1.05–1.53). The interaction analysis for mortality did not support a differential prognostic effect for sNEP (p = 0.072). In conclusion, higher sNEP levels in overweight women better predicted an increased risk of HF hospitalization.
A method for EMCCD multiplication gain measurement with comprehensive correction
Authors: Qiao Li , Wang Mingfu , Jin Zheng
Published: March 2021

In order to improve the image quality, it is imperative to conduct the non-uniformity correction of EMCCD, for which the measurement accuracy of the internal electron multiplication gain of each channel is a prerequisite within multi-channel output EMCCD. It is known that the smaller the image standard deviation of each channel, the better the image uniformity, and the closer the calculated multiplier gain is to the real value. In order to minimize the influence of non-uniformity of background between pixels and light response existing in traditional measurement, a comprehensively modified EMCCD multiplication gain measurement is proposed after the working principle of EMCCD is described. The output images of the camera working in the normal CCD mode and EMCCD mode are corrected comprehensively through this method. The experimental results show that after the comprehensive correction, the standard deviation of the output image of each channel within the camera decreases to about one third of the original when the camera works in the normal CCD mode, while it decreases to about one fifth of the original when the camera works in the EMCCD mode, the signal stability is significantly improved, and the measured multiplier gain of each channel is closer to the true value of the detector, which proves the effectiveness of the proposed method.