bluuebunny/crossref_metadata_2025 huggingface dataset:
Early response to trazodone once-a-day in major depressive disorder: review of the clinical data and putative mechanism for faster onset of action
Authors: Albert Umberto , Lamba Pallavi , Stahl Stephen M.
Published: March 2021

Background

Most antidepressants have a delayed onset of action and must be administered for several weeks to generate therapeutic effects. Trazodone is a serotonin antagonist and reuptake inhibitor approved for the treatment of major depressive disorder. The once-a-day (OAD) formulation of trazodone has an improved tolerability profile compared to its conventional formulations. In this study, we systematically reviewed the evidence available for the antidepressant efficacy and early improvement in depressive symptoms with trazodone OAD treatment.

Method

We conducted a PubMed database search for randomized controlled trials published from 2005 to 2020.

Results

Two studies, a placebo-controlled and an active-comparator (venlafaxine extended-release or XR) study were found. Both the studies demonstrated that trazodone exhibits antidepressant activity at a starting dose of 150 mg/day and results in statistically significant greater reduction in Hamilton Depression Rating Scale (HAM-D17) scores within 1 week of starting treatment compared to placebo or venlafaxine XR (P < .05). Trazodone also resulted in significant early improvement in the HAM-D17 sleep disturbance factor compared to placebo or venlafaxine XR at day 7 (P < .05). This clinical effect is supported by in vitro proprietary data for the affinity of trazodone for different target receptors. Activity at these receptors may underlie trazodone’s fast antidepressant action.

Conclusions

Trazodone, if properly dosed, can be an effective antidepressant with early onset of action and good tolerability. Future studies designed to specifically evaluate onset and timing of improvement of depressive symptoms remain necessary to confirm and extend these results.
The updated ICRC Commentary on the Third Geneva Convention: A new tool to protect prisoners of war in the twenty-first century
Authors: Arman Jemma , Henckaerts Jean-Marie , Hiemstra Heleen , Krotiuk Kvitoslava
Published: March 2021

Since their publication in the 1950s and 1980s respectively, the Commentaries on the Geneva Conventions of 1949 and their Additional Protocols of 1977 have become a major reference for the application and interpretation of those treaties. The International Committee of the Red Cross, together with a team of renowned experts, is currently updating these Commentaries in order to document developments and provide up-to-date interpretations of the treaty texts. This article highlights key points of interest covered in the updated Commentary on the Third Geneva Convention. It explains the fundamentals of the Convention: the historical background, the personal scope of application of the Convention and the fundamental protections that apply to all prisoners of war (PoWs). It then looks at the timing under which certain obligations are triggered, those prior to holding PoWs, those triggered by the taking of PoWs and during their captivity, and those at the end of a PoW's captivity. Finally, the article summarizes key substantive protections provided in the Third Convention.
Humanitarian aid in the age of COVID-19: A review of big data crisis analytics and the General Data Protection Regulation
Authors: Gazi Theodora , Gazis Alexandros
Published: March 2021

The COVID-19 pandemic has served as a wake-up call for humanitarian aid actors to reconsider data collection methods, as old ways of doing business become increasingly obsolete. Although access to information on the affected population is critical now more than ever to support the pandemic response, the limitation of aid workers’ presence in the field imposes hard constraints on relief projects. In this article, we consider how aid actors can use “big data” as a crisis response tool to support humanitarian projects, in cases when the General Data Protection Regulation is applicable. We also provide a framework for examining open-source platforms, and discuss the advantages and privacy challenges of big data.
EEG Cortical Activities and Networks Altered by Watching 2D/3D Virtual Reality Videos
Authors: Xu Xiaoying , Sui Li
Published: March 2021

Abstract. Virtual reality (VR), which can represent real-life events and situations, is being increasingly applied to many fields, such as education, entertainment, and medical rehabilitation. Correspondingly, the neural information processing of VR has attracted attention. However, the underlying neural mechanisms of VR environments have not yet been fully revealed. The purpose of this study was to examine the possible differences in brain activities and networks between the less immersive 2D and the fully immersive 3D VR environments. 3D VR videos and the same 2D scenes were presented to the participants and the scalp electroencephalogram (EEG) was recorded, respectively. Power spectral density (PSD) and the functional connectivity of these EEG signals were analyzed. The results showed that 3D VR videos significantly enhanced the PSD of θ rhythm (4–7 Hz) in the frontal lobe; decreased the PSD of α rhythm (8–13 Hz) in the parietal and the occipital lobes; increased the PSD of β rhythm (14–30 Hz) in the frontal, the parietal, the temporal, and the occipital lobes, relative to 2D VR watching. Furthermore, 3D versus 2D VR-induced alterations in the patterns of brain networks were similar to the patterns of PSD. Specifically, for the θ rhythm, 3D VR significantly enhanced the frontal and the temporal brain functional connectivity; for the α rhythm, 3D VR increased the parietal and the occipital networks; for the β rhythm, 3D VR remarkably increased the frontal, the occipital, the frontal-temporal and the frontal-occipital brain functional connectivity, relative to 2D VR. These significant differences between 3D and 2D VR video-watching suggest that the neural information processing of cortical activities and networks is correlated to the degree of immersion. The present results, collected with previous researches, implicate that some visual-related information processes, such as visual attention, visual perception, and visual immersion are more robust in 3D VR environments.
Imaging VGOS Observations and Investigating Source Structure Effects
Authors: Xu Ming H. , Savolainen Tuomas , Zubko Nataliya , Poutanen Markku , Lunz Susanne , Schuh Harald , Wang Guang L.
Published: March 2021

The next‐generation, broadband geodetic very long baseline interferometry system, named VGOS, is being developed globally with an aim to achieve 1 mm accuracy for station positions. Currently, the systematic errors in VGOS broadband delays are still about 20 ps. In this study, we demonstrate that it is feasible to make images directly from VGOS observations without the need of complicated calibrations and determine the source structure effects in VGOS broadband delays through the process of model fitting to the structure phases from our imaging results. Source structure effects are investigated in detail, and it is shown that the systematic errors in VGOS observations are well explained by these effects. For instance, the root‐mean‐square (RMS) closure delays of the observations of sources 0016 + 731 and 1030 + 415 are 24.9 and 50.2 ps in session VO0034, respectively; after correcting source structure effects based on the images, the RMS values of the residual closure delays are 5.5 and 10.1 ps. The jumps in delay observables with magnitudes of several hundreds of picoseconds are found to be caused by 2π phase shifts among the four bands due to strong source structure effects. The impact of the alignment of the images at the four frequency bands in VGOS is discussed. Our study provides a methodology for deriving images of radio sources at the four bands of VGOS observations and discusses the alignment of the images at the four bands, which is fundamental to mitigating these systematic effects.
Mechanical Compaction of Crustal Analogs Made of Sintered Glass Beads: The Influence of Porosity and Grain Size
Authors: Carbillet Lucille , Heap Michael J. , Baud Patrick , Wadsworth Fabian B. , Reuschlé Thierry
Published: March 2021

The fundamentals of our understanding of the mechanical compaction of porous rocks stem from experimental studies. Yet, many of these studies use natural materials for which microstructural parameters are intrinsically coupled, hampering the diagnosis of relationships between microstructure and bulk sample behavior. To probe the influence of porosity and grain size on the mechanical compaction of granular rocks, we performed experiments on synthetic samples prepared by sintering monodisperse populations of glass beads, which allowed us to independently control porosity and grain diameter. We conducted hydrostatic and triaxial compression tests on synthetic samples with grain diameters and porosities in the ranges 0.2–1.15 mm and 0.18–0.38 mm, respectively. During hydrostatic compaction, sample porosity decreased suddenly and substantially at the onset of inelastic compaction due to contemporaneous and extensive grain crushing, a consequence of the monodisperse grain size. During triaxial tests at high confining pressure, our synthetic samples failed by shear‐enhanced compaction and showed evidence for the development of compaction bands. Critical stresses at the onset of inelastic compaction map out linear‐shaped yield caps for the porosity‐grain diameter combinations for which the critical stress for inelastic hydrostatic compaction is known. Our yield caps reinforce the first‐order importance of porosity on the compactive yield strength and show, all else being equal, that grain size also exerts a first‐order control and should therefore be routinely measured. Our study further reveals the suitability of sintered glass beads as analogs for crustal rocks, which facilitate the study of the deconvolved influence of microstructural parameters on their mechanical behavior.
Groundwater Regulates Interannual Variations in Evapotranspiration in a Riparian Semiarid Ecosystem
Authors: Missik Justine E. C. , Liu Heping , Gao Zhongming , Huang Maoyi , Chen Xingyuan , Arntzen Evan , Mcfarland Douglas P. , Verbeke Brittany
Published: March 2021

Drylands are an important component of Earth's carbon, water, and energy budgets. Changes in hydroclimatic conditions can significantly alter land surface fluxes in these ecosystems. In regions with groundwater‐river water exchange, land surface fluxes are strongly modulated by groundwater table fluctuations in response to river stage variations; however, interactions between fluxes and groundwater remain poorly understood in drylands. Here, we use eddy covariance data collected in paired upland and riparian semiarid ecosystems (AmeriFlux sites US‐Hn1 and US‐Hn2) during 4 years with contrasting river flow conditions to examine interactions among river stage, water table dynamics, meteorological drivers, and ecosystem fluxes. Elevated groundwater availability resulting from groundwater‐surface water exchange at the riparian site enhanced the latent heat flux (LE, the energy form of evapotranspiration), which was sustained longer in the growing season. Interannual variation of dry season LE was small at the upland site, while at the riparian site contrasting river flow conditions resulted in large interannual variability in LE, with June LE of high‐flow years being 2.3 times that of low‐flow years. The 4‐year mean summer LE at the riparian site was 2.1 times larger than that at the upland site. Carbon uptake (NEP) and LE were well correlated at the upland site at the monthly and annual timescales, but at the riparian site enhanced LE due to shallow water table depth did not correspond to enhanced NEP. Our results demonstrate that enhanced groundwater availability modulated by river stage is a critical driver of land surface fluxes in semiarid riparian ecosystems.
Nitrous Oxide Formation by Corona Discharge: Isotopic Composition Measurements and Atmospheric Applications
Authors: Smith Mica C. , Carlstad Julia M. , Hunter P. Quinby , Randazzo John , Boering Kristie A.
Published: March 2021

The expanding use of nitrogen‐containing fertilizers in agriculture has led to an increase in N2O, an important greenhouse gas and ozone‐depleting substance, since preindustrial times. Isotopic measurements are a valuable tool to distinguish the contribution of different sources of N2O, but the isotopic composition of N2O formed in the low temperature plasma regimes in lightning has not previously been measured. Here, a corona discharge was generated in flowing or static zero air, and the N2O formed at discharge cell pressures from ∼0.1 to 10 Torr (∼13–1,300 Pa) at a discharge voltage of 5 kV and discharge current of 1,500 μA was collected and measured by isotope ratio mass spectrometry. Experiments were also conducted by varying the discharge current from 75 to 1,500 μA at ∼0.5 Torr (∼67 Pa) and 5 kV. The results show enrichments in 15N in product N2O of up to 32‰ relative to the reactant N2 and even larger enrichments in 15N of up to 77‰ at the central nitrogen atom. Depletions in 18O as large as −71‰ relative to reactant O2 were also measured. The isotope‐isotope relationships of the N2O produced in the corona discharge are distinct from those of other sources of N2O, suggesting that isotope measurements can be used to determine whether local or regional variations in the atmospheric concentration of N2O – such as the enhanced N2O levels measured in the upper tropical and subtropical troposphere during the HIPPO mission – can be attributed to lightning activity, soil emissions, or biomass burning.
Calving of a Large Greenlandic Tidewater Glacier has Complex Links to Meltwater Plumes and Mélange
Authors: Cook Samuel J. , Christoffersen Poul , Truffer Martin , Chudley Thomas R. , Abellán Antonio
Published: March 2021

Calving and solid ice discharge into fjords account for approximately half of the annual net ice loss from the Greenland ice sheet, but these processes are rarely observed. To gain insights into the spatiotemporal nature of calving, we use a terrestrial radar interferometer to derive a 3‐week record of 8,026 calving events from Sermeq Kujalleq (Store Glacier, West Greenland), including the transition between a mélange‐filled and ice‐free fjord. We show that calving rates double across this transition and that the interferometer record is in good agreement with volumetric estimates of calving losses from contemporaneous unmanned aerial vehicle surveys. We report significant variations in calving activity over time, which obfuscate any simple power‐law relationship. While there is a statistically significant relationship between surface melt and the number of calving events, no such relationship exists between surface melt and the volume of these events. Similarly, we find a 70% increase in the number of calving events in the presence of visible meltwater plumes but only a 3% increase in calving volumes. While calving losses appear to have no clear single control, we find a bimodal distribution of iceberg sizes due to small blocks breaking off the subaerial part of the glacier front and large capsizing icebergs forming by full‐thickness failure. Whereas previous work has hypothesized that tidewater glaciers can be grouped according to whether they calve predominantly by the former or latter mechanism, our observations indicate that calving here inherently comprises both and that the dominant process can change over relatively short periods.
Influence of Thermal Stratification on Seasonal Net Ecosystem Production and Dissolved Inorganic Carbon in a Shallow Subtropical Lake
Authors: Lin Hao‐Chi , Chiu Chih‐Yu , Tsai Jeng‐Wei , Liu Wen‐Cheng , Tada Kazufumi , Nakayama Keisuke
Published: March 2021

Thermal stratification is a critical physical process controlling carbon (C) flux from lakes into the atmosphere. In general, vertical water temperature profiles in shallow subtropical lakes can vary significantly because typhoons frequently induce vertical mixing across the entire lake due to strong winds and rapid flushing from river inputs. Since C fluxes are driven by dissolved inorganic C (DIC), it is necessary to understand stratification's influence on DIC dynamics in shallow subtropical lakes. Therefore, we aimed to clarify the impact of stratification on DIC in Yuan‐Yang Lake, a typical shallow subtropical mountain lake, by developing a net ecosystem production (NEP) model. We measured the vertical profile of water temperature and DIC once or twice a month from July 2004 to December 2017. We applied a three‐dimensional hydrological model to estimate residence time and NEP, which revealed that large amounts of DIC are stored in the lower layer from spring to summer due to the suppression of vertical mixing by stratification. In autumn and winter, the lake was well mixed, and DIC was evenly distributed in the water column due to vertical mixing. This was confirmed by vertical DIC profiles.
Mantle Upwelling Beneath the Cathaysia Block, South China
Authors: He Chuansong , Santosh M.
Published: March 2021

A large low‐velocity anomaly (LLVA) beneath the Cathaysia Block in South China that may be associated with mantle upwelling was revealed by seismic tomography. However, seismological and geological studies indicate that ascending mantle must have a higher temperature than the surrounding mantle, and a low‐velocity anomaly alone is not indicative of mantle upwelling. The receiver function technique has been used as a robust tool to characterize the topographic relief of the upper mantle discontinuities, which are closely related to temperature variations and mantle upwelling. In this study, we extracted 25,187 receiver functions and performed common‐conversion‐point stacking of those receiver functions in South China and across the location of the LLVA beneath the Cathaysia Block. The results show that the 410 km discontinuity is depressed and that the 660 km discontinuity is elevated at the location of the LLVA. The structure of the mantle transition zone seems to be the passage of an upwelling mantle plume, which implies that the LLVA is a signature of mantle upwelling.
Turbulence Structure and Momentum Exchange in Compound Channel Flows With Shore Ice Covered on the Floodplains
Authors: Wang Feifei , Huai Wenxin , Guo Yakun , Liu Mengyang
Published: March 2021

Ice cover formed on a river surface is a common natural phenomenon during the winter season in cold high latitude northern regions. For the ice‐covered river with compound cross‐section, the interaction of the turbulence caused by the ice cover and the channel bed bottom affects the transverse mass and momentum exchange between the main channel and floodplains. In this study, laboratory experiments are performed to investigate the turbulent flow of a compound channel with shore ice covered on the floodplains. Results show that the shore ice resistance restricts the development of the water flow and creates a relatively strong shear layer near the edge of the ice‐covered floodplain. The mean streamwise velocity in the main channel and on the ice‐covered floodplains shows an opposite variation pattern along with the longitudinal distance and finally reaches the longitudinal uniformity. The mixing layer bounded by the velocity inflection point consists of two layers that evolve downstream to their respective fully developed states. The velocity inflection point and strong transverse shear near the interface in the fully developed profile generate the Kelvin‐Helmholtz instability and horizontal coherent vortices. These coherent vortices induce quasi‐periodic velocity oscillations, while the dominant frequency of the vortical energy is determined through the power spectral analysis. Subsequently, quadrant analysis is used in ascertaining the mechanism for the lateral momentum exchange, which exhibits the governing contributions of sweeps and ejections within the vortex center. Finally, an eddy viscosity model is presented to investigate the transverse momentum exchange. The presented model is well validated through comparison with measurements, whereas the constants α and β appeared in the model need to be further investigated.
How Did Diatoms Evolve to Swap Zinc for the Toxic Metal Cadmium?
Authors: Stanley Sarah
Published: March 2021

New network analysis suggests that zinc and cadmium sulfides weathered simultaneously in geological history, making cadmium a suitable substitute in photosynthetic pathways when zinc was scarce.
Ultrastable low-cost colloidal quantum dot microlasers of operative temperature up to 450 K
Authors: Chang Hao , Zhong Yichi , Dong Hongxing , Wang Zhenyu , Xie Wei , Pan Anlian , Zhang Long
Published: March 2021

Quantum dot microlasers, as multifunctional optical source components, are of great importance for full-color high-pixel display, miniaturized coherent lighting, and on-chip integrated photonic and electronic circuits. Since the first synthesis of colloidal quantum dots (CQD) in the 1990s, motivation to realize high-performance low-cost CQD micro-/nanolasers has been a driving force for more than three decades. However, the low packing density, inefficient coupling of CQDs with optical cavities, and the poor thermal stability of miniaturized complex systems make it challenging to achieve practical CQD micro-/nanolasers, especially to combine the continuous working ability at high temperatures and the low-cost potential with mass-produced synthesis technologies. Herein, we developed close-packed CQD-assembled microspheres and embedded them in a silica matrix through the rapid self-aggregation and solidification of CdSe/ZnS CQD. This technology addresses the core issues of photoluminescence (PL) quenching effect and low optical gain in traditional CQD laser research. High-efficiency low-threshold CQD microlasers are demonstrated together with long-playing (40 min) working stability even at 450 K under pulsed laser excitation, which is the highest operational temperature for CQD lasers. Moreover, single-mode CQD microlasers are obtained with tunable wavelengths across the entire visible spectral range. The chemosynthesis process supports the mass-produced potential of high-density integrated CQD microlasers, promoting CQD-based low-cost high-temperature microdevices.
HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias
Authors: Mshaik Rony , Simonet John , Georgievski Aleksandra , Jamal Layla , Bechoua Shaliha , Ballerini Paola , Bellaye Pierre-Simon , Mlamla Zandile , Pais de Barros Jean-Paul , Geissler Audrey , Francin Pierre-Jean , Girodon François , Garrido Carmen , Quéré Ronan
Published: March 2021

T-cell and B-cell acute lymphoblastic leukemias (T-ALL, B-ALL) are aggressive hematological malignancies characterized by an accumulation of immature T- or B-cells. Although patient outcomes have improved, novel targeted therapies are needed to reduce the intensity of chemotherapy and improve the prognosis of high-risk patients. Using cell lines, primary cells and patient-derived xenograft (PDX) models, we demonstrate that ALL cells viability is sensitive to NVP-BEP800, an ATP-competitive inhibitor of Heat shock protein 90 (HSP90). Furthermore, we reveal that lymphocyte-specific SRC family kinases (SFK) are important clients of the HSP90 chaperone in ALL. When PDX mice are treated with NVP-BEP800, we found that there is a decrease in ALL progression. Together, these results demonstrate that the chaperoning of SFK by HSP90 is involved in the growth of ALL. These novel findings provide an alternative approach to target SRC kinases and could be used for the development of new treatment strategies for ALL.
Prioritizing antiviral drugs against SARS-CoV-2 by integrating viral complete genome sequences and drug chemical structures
Authors: Peng Lihong , Shen Ling , Xu Junlin , Tian Xiongfei , Liu Fuxing , Wang Juanjuan , Tian Geng , Yang Jialiang , Zhou Liqian
Published: March 2021

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of − 7.0 kcal/mol and − 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.
Sparsely methylated mitochondrial cell free DNA released from cardiomyocytes contributes to systemic inflammatory response accompanied by atrial fibrillation
Authors: Yamazoe Masahiro , Sasano Tetsuo , Ihara Kensuke , Takahashi Kentaro , Nakamura Wakana , Takahashi Naomi , Komuro Hiroaki , Hamada Satomi , Furukawa Tetsushi
Published: March 2021

Systemic inflammation is assumed to be the consequence and the cause of atrial fibrillation (AF); however, the underlying mechanism remains unclear. We aimed to evaluate the level of cell-free DNA (cfDNA) in patients with AF and AF mimicking models, and to illuminate its impact on inflammation. Peripheral blood was obtained from 54 patients with AF and 104 non-AF controls, and cfDNA was extracted. We extracted total cfDNA from conditioned medium after rapid pacing to HL-1 cells. Nuclear and mitochondrial DNA were separately extracted and fragmented to simulate nuclear-cfDNA (n-cfDNA) and mitochondrial-cfDNA (mt-cfDNA). The AF group showed higher cfDNA concentration than the non-AF group (12.6 [9.0–17.1] vs. 8.1 [5.3–10.8] [ng/mL], p < 0.001). The copy numbers of n-cfDNA and mt-cfDNA were higher in AF groups than in non-AF groups; the difference of mt-cfDNA was particularly apparent (p = 0.011 and p < 0.001, respectively). Administration of total cfDNA and mt-cfDNA to macrophages significantly promoted IL-1β and IL-6 expression through TLR9, whereas n-cfDNA did not. Induction of cytokine expression by methylated mt-cfDNA was lower than that by unmethylated mt-cfDNA. Collectively, AF was associated with an increased cfDNA level, especially mt-cfDNA. Sparsely methylated mt-cfDNA released from cardiomyocytes may be involved in sterile systemic inflammation accompanied by AF.
Computational evidence for nitro derivatives of quinoline and quinoline N-oxide as low-cost alternative for the treatment of SARS-CoV-2 infection
Authors: Assis Letícia C. , de Castro Alexandre A. , de Jesus João P. A. , Nepovimova Eugenie , Kuca Kamil , Ramalho Teodorico C. , La Porta Felipe A.
Published: March 2021

A new and more aggressive strain of coronavirus, known as SARS-CoV-2, which is highly contagious, has rapidly spread across the planet within a short period of time. Due to its high transmission rate and the significant time–space between infection and manifestation of symptoms, the WHO recently declared this a pandemic. Because of the exponentially growing number of new cases of both infections and deaths, development of new therapeutic options to help fight this pandemic is urgently needed. The target molecules of this study were the nitro derivatives of quinoline and quinoline N-oxide. Computational design at the DFT level, docking studies, and molecular dynamics methods as a well-reasoned strategy will aid in elucidating the fundamental physicochemical properties and molecular functions of a diversity of compounds, directly accelerating the process of discovering new drugs. In this study, we discovered isomers based on the nitro derivatives of quinoline and quinoline N-oxide, which are biologically active compounds and may be low-cost alternatives for the treatment of infections induced by SARS-CoV-2.
Integrated multi-omics analysis of ovarian cancer using variational autoencoders
Authors: Hira Muta Tah , Razzaque M. A. , Angione Claudio , Scrivens James , Sawan Saladin , Sarker Mosharraf
Published: March 2021

Cancer is a complex disease that deregulates cellular functions at various molecular levels (e.g., DNA, RNA, and proteins). Integrated multi-omics analysis of data from these levels is necessary to understand the aberrant cellular functions accountable for cancer and its development. In recent years, Deep Learning (DL) approaches have become a useful tool in integrated multi-omics analysis of cancer data. However, high dimensional multi-omics data are generally imbalanced with too many molecular features and relatively few patient samples. This imbalance makes a DL based integrated multi-omics analysis difficult. DL-based dimensionality reduction technique, including variational autoencoder (VAE), is a potential solution to balance high dimensional multi-omics data. However, there are few VAE-based integrated multi-omics analyses, and they are limited to pancancer. In this work, we did an integrated multi-omics analysis of ovarian cancer using the compressed features learned through VAE and an improved version of VAE, namely Maximum Mean Discrepancy VAE (MMD-VAE). First, we designed and developed a DL architecture for VAE and MMD-VAE. Then we used the architecture for mono-omics, integrated di-omics and tri-omics data analysis of ovarian cancer through cancer samples identification, molecular subtypes clustering and classification, and survival analysis. The results show that MMD-VAE and VAE-based compressed features can respectively classify the transcriptional subtypes of the TCGA datasets with an accuracy in the range of 93.2-95.5% and 87.1-95.7%. Also, survival analysis results show that VAE and MMD-VAE based compressed representation of omics data can be used in cancer prognosis. Based on the results, we can conclude that (i) VAE and MMD-VAE outperform existing dimensionality reduction techniques, (ii) integrated multi-omics analyses perform better or similar compared to their mono-omics counterparts, and (iii) MMD-VAE performs better than VAE in most omics dataset.
Acetic-acid-induced jasmonate signaling in root enhances drought avoidance in rice
Authors: Ogawa Daisuke , Suzuki Yuya , Yokoo Takayuki , Katoh Etsuko , Teruya Miyu , Muramatsu Masayuki , Ma Jian Feng , Yoshida Yuri , Isaji Shunsaku , Ogo Yuko , Miyao Mitsue , Kim Jong-Myong , Kojima Mikiko , Takebayashi Yumiko , Sakakibara Hitoshi , Takeda Shin , Okada Kazunori , Mori Naoki , Seki Motoaki , Habu Yoshiki
Published: March 2021

Conferring drought resistant traits to crops is one of the major aims of current breeding programs in response to global climate changes. We previously showed that exogenous application of acetic acid to roots of various plants could induce increased survivability under subsequent drought stress conditions, but details of the metabolism of exogenously applied acetic acid, and the nature of signals induced by its application, have not been unveiled. In this study, we show that rice rapidly induces jasmonate signaling upon application of acetic acid, resulting in physiological changes similar to those seen under drought. The major metabolite of the exogenously applied acetic acid in xylem sap was determined as glutamine—a common and abundant component of xylem sap—indicating that acetic acid is not the direct agent inducing the observed physiological responses in shoots. Expression of drought-responsive genes in shoot under subsequent drought conditions was attenuated by acetic acid treatment. These data suggest that acetic acid activates root-to-shoot jasmonate signals that partially overlap with those induced by drought, thereby conferring an acclimated state on shoots prior to subsequent drought.
Controlling metal–insulator transitions in reactively sputtered vanadium sesquioxide thin films through structure and stoichiometry
Authors: Thorsteinsson Einar B. , Shayestehaminzadeh Seyedmohammad , Ingason Arni S. , Magnus Fridrik , Arnalds Unnar B.
Published: March 2021

We present a study of $$\hbox {V}_{2}\hbox {O}_{3}$$

V
2

O
3

thin films grown on c-plane $$\hbox {Al}_{2}\hbox {O}_{3}$$

Al
2

O
3

substrates by reactive dc-magnetron sputtering. Our results reveal three distinct types of films displaying different metal–insulator transitions dependent on the growth conditions. We observe a clear temperature window, spanning 200 $$^{\circ }$$

∘

C, where highly epitaxial films of $$\hbox {V}_{2}\hbox {O}_{3}$$

V
2

O
3

can be obtained wherein the transition can be tuned by controlling the amount of interstitial oxygen in the films through the deposition conditions. Although small structural variations are observed within this window, large differences are observed in the electrical properties of the films with strong differences in the magnitude and temperature of the metal–insulator transition which we attribute to small changes in the stoichiometry and local strain in the films. Altering the sputtering power we are able to tune the characteristics of the metal–insulator transition suppressing and shifting the transition to lower temperatures as the power is reduced. Combined results for all the films fabricated for the study show a preferential increase in the a lattice parameter and reduction in the c lattice parameter with reduced deposition temperature with the film deviating from a constant volume unit cell to a higher volume.
Suppressing the impact of the COVID-19 pandemic using controlled testing and isolation
Authors: Cohen Kobi , Leshem Amir
Published: March 2021

The Corona virus disease has significantly affected lives of people around the world. Existing quarantine policies led to large-scale lock-downs because of the slow tracking of the infection paths, and indeed we see new waves of the disease. This can be solved by contact tracing combined with efficient testing policies. Since the number of daily tests is limited, it is crucial to exploit them efficiently to improve the outcome of contact tracing (technological or human-based epidemiological investigations). We develop a controlled testing framework to achieve this goal. The key is to test individuals with high probability of being infected to identify them before symptoms appear. These probabilities are updated based on contact tracing and test results. We demonstrate that the proposed method could reduce the quarantine and morbidity rates compared to existing methods by up to a 50%. The results clearly demonstrate the necessity of accelerating the epidemiological investigations by using technological contact tracing. Furthermore, proper use of the testing capacity using the proposed controlled testing methodology leads to significantly improved results under both small and large testing capacities. We also show that for small new outbreaks controlled testing can prevent the large spread of new waves. Author contributions statement: The authors contributed equally to this work, including conceptualization, analysis, methodology, software, and drafting the work.
Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
Authors: Minnis Christopher J. , Townsend StJohn , Petschnigg Julia , Tinelli Elisa , Bähler Jürg , Russell Claire , Mole Sara E.
Published: March 2021

Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102–208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype–phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.
4-methylumbelliferone-mediated polarization of M1 macrophages correlate with decreased hepatocellular carcinoma aggressiveness in mice
Authors: Rodríguez Marcelo M. , Onorato Agostina , Cantero María José , Domínguez Luciana , Bayo Juan , Fiore Esteban , García Mariana , Atorrasagasti Catalina , Canbay Ali , Malvicini Mariana , Mazzolini Guillermo D.
Published: March 2021

Hepatocellular carcinoma (HCC) arises in the setting of advanced liver fibrosis, a dynamic and complex inflammatory disease. The tumor microenvironment (TME) is a mixture of cellular components including cancer cells, cancer stem cells (CSCs), tumor-associated macrophages (TAM), and dendritic cells (DCs), which might drive to tumor progression and resistance to therapies. In this work, we study the effects of 4-methylumbelliferone (4Mu) on TME and how this change could be exploited to promote a potent immune response against HCC. First, we observed that 4Mu therapy induced a switch of hepatic macrophages (Mϕ) towards an M1 type profile, and HCC cells (Hepa129 cells) exposed to conditioned medium (CM) derived from Mϕ treated with 4Mu showed reduced expression of several CSCs markers and aggressiveness. HCC cells incubated with CM derived from Mϕ treated with 4Mu grew in immunosuppressed mice while presented delayed tumor progression in immunocompetent mice. HCC cells treated with 4Mu were more susceptible to phagocytosis by DCs, and when DCs were pulsed with HCC cells previously treated with 4Mu displayed a potent antitumoral effect in therapeutic vaccination protocols. In conclusion, 4Mu has the ability to modulate TME into a less hostile milieu and to potentiate immunotherapeutic strategies against HCC.
Quantification of Phytophthora infestans population densities and their changes in potato field soil using real-time PCR
Authors: Osawa Hisashi , Suzuki Nobuyuki , Akino Seishi , Araki Hiromichi , Asano Kenji , Akai Kotaro , Kondo Norio
Published: March 2021

Tuber infection of Phytophthora infestans often occurs at harvest. However, it is difficult to accurately estimate the population densities of P. infestans in soil, especially Japanese soil. In the present study, P. infestans DNA was extracted from soil samples using a modified CTAB-bead method and quantified using real-time PCR to accurately, rapidly and easily estimate the P. infestans population densities in upland soils in Japan. P. infestans was well quantified in eleven types of soil samples, including nine types of upland soils in Japan, that were artificially inoculated with a zoosporangia suspension. The amounts of P. infestans DNA estimated by the real-time PCR were proportional to the inoculum densities. In the non-controlled experimental potato field, P. infestans population densities in soil corresponded to the development of symptoms and were correlated with the number of lesions on the potato foliage. These results imply that the proposed real-time PCR assay is suitable for the estimation or monitoring of P. infestans population densities in upland soils in Japan. The population densities at the ridge bottoms were larger than those at any other location in commercial potato fields. These results were similar to those of a previous report using a bioassay. Moreover, a correlation between DNA quantity and inoculum potential was observed. In conclusion, the real-time PCR assay developed in this study is suitable for indirect estimation of the inoculum potential of P. infestans.
Exploring dementia and neuronal ceroid lipofuscinosis genes in 100 FTD-like patients from 6 towns and rural villages on the Adriatic Sea cost of Apulia
Authors: Sassi Celeste , Capozzo Rosa , Hammer Monia , Zecca Chiara , Federoff Monica , Blauwendraat Cornelis , Bernstein Nick , Ding Jinhui , Gibbs J. Raphael , Price Timothy , Singleton Andrew , Logroscino Giancarlo
Published: March 2021

Frontotemporal dementia (FTD) refers to a complex spectrum of clinically and genetically heterogeneous disorders. Although fully penetrant mutations in several genes have been identified and can explain the pathogenic mechanisms underlying a great portion of the Mendelian forms of the disease, still a significant number of families and sporadic cases remains genetically unsolved. We performed whole exome sequencing in 100 patients with a late-onset and heterogeneous FTD-like clinical phenotype from Apulia and screened mendelian dementia and neuronal ceroid lipofuscinosis genes. We identified a nonsense mutation inSORL1VPS domain (p.R744X), in 2 siblings displaying AD with severe language problems and primary progressive aphasia and a near splice-site mutation inCLCN6(p.S116P) segregating with an heterogeneous phenotype, ranging from behavioural FTD to FTD with memory onset and to the logopenic variant of primary progressive aphasia in one family. Moreover 2 sporadic cases with behavioural FTD carried heterozygous mutations in theCSF1RTyrosin kinase flanking regions (p.E573K and p.R549H). By contrast, only a minority of patients carried pathogenicC9orf72repeat expansions (1%) and likely moderately pathogenic variants inGRN(p.C105Y, p.C389fs and p.C139R) (3%). In concert with recent studies, our findings support a common pathogenic mechanisms between FTD and neuronal ceroid lipofuscinosis and suggests that neuronal ceroid lipofuscinosis genes should be investigated also in dementia patients with predominant frontal symptoms and language impairments.
Adipose most abundant 2 protein is a predictive marker for cisplatin sensitivity in cancers
Authors: Kamimura Kenya , Suda Takeshi , Fukuhara Yasuo , Okuda Shujiro , Watanabe Yu , Yokoo Takeshi , Osaki Akihiko , Waguri Nobuo , Ishikawa Toru , Sato Toshihiro , Aoyagi Yutaka , Takamura Masaaki , Wakai Toshifumi , Terai Shuji
Published: March 2021

Cisplatin (CDDP) is one of the chemotherapeutic drugs being used to treat various cancers. Although effective in many cases, as high doses of CDDP cause cytotoxic effects that may worsen patients’ condition, therefore, a marker of sensitivity to CDDP is necessary to enhance the safety and efficiency of CDDP administration. This study focused on adipose most abundant 2 (APM2) to examine its potential as a marker of CDDP sensitivity. The relationship of APM2 expression with the mechanisms of CDDP resistance was examined in vitro and in vivo using hepatocellular carcinoma (HCC) cells, tissues and serum of HCC patients (n = 71) treated initially with intrahepatic arterial infusion of CDDP followed by surgical resection. The predictability of serum APM2 for CDDP sensitivity was assessed in additional 54 HCC patients and 14 gastric cancer (GC) patients. APM2 expression in CDDP-resistant HCC was significantly higher both in serum and the tissue. Bioinformatic analyses and histological analyses demonstrated upregulation of ERCC6L (DNA excision repair protein ERCC6-like) by APM2, which accounts for the degree of APM2 expression. The serum APM2 level and chemosensitivity for CDDP were assessed and cut-off value of serum APM2 for predicting the sensitivity to CDDP was determined to be 18.7 µg/mL. The value was assessed in HCC (n = 54) and GC (n = 14) patients for its predictability of CDDP sensitivity, resulted in predictive value of 77.3% and 100%, respectively. Our study demonstrated that APM2 expression is related to CDDP sensitivity and serum APM2 can be an effective biomarker of HCC and GC for determining the sensitivity to CDDP.

Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000028487).
The undetected loss of aged carbon from boreal mineral soils
Authors: Hensgens Geert , Laudon Hjalmar , Johnson Mark S. , Berggren Martin
Published: March 2021

The boreal forest is among the largest terrestrial biomes on earth, storing more carbon (C) than the atmosphere. Due to rapid climatic warming and enhanced human development, the boreal region may have begun transitioning from a net C sink to a net source. This raises serious concern that old biogenic soil C can be re-introduced into the modern C cycle in near future. Combining bio-decay experiments, mixing models and the Keeling plot method, we discovered a distinct old pre-bomb organic carbon fraction with high biodegradation rate. In total, 34 ± 12% of water-extractable organic carbon (WEOC) in podzols, one of the dominating boreal soil types, consisted of aged (~ 1000 year) labile C. The omission of this aged (i.e., Δ14C depleted) WEOC fraction in earlier studies is due to the co-occurrence with Δ14C enriched modern C formed following 1950s nuclear bomb testing masking its existence. High lability of aged soil WEOC and masking effects of modern Δ14C enriched C suggests that the risk for mobilization and re-introduction of this ancient C pool into the modern C cycle has gone undetected. Our findings have important implications for earth systems models in terms of climate-carbon feedbacks and the future C balance of the boreal forest.
The TOMM40 ‘523’ polymorphism in disease risk and age of symptom onset in two independent cohorts of Parkinson’s disease
Authors: Bakeberg Megan C. , Hoes Madison E. , Gorecki Anastazja M. , Theunissen Frances , Pfaff Abigail L. , Kenna Jade E. , Plunkett Kai , Kõks Sulev , Akkari P. Anthony , Mastaglia Frank L. , Anderton Ryan S.
Published: March 2021

Abnormal mitochondrial function is a key process in the pathogenesis of Parkinson’s disease (PD). The central pore-forming protein TOM40 of the mitochondria is encoded by the translocase of outer mitochondrial membrane 40 homologue gene (TOMM40). The highly variant ‘523’ poly-T repeat is associated with age-related cognitive decline and age of onset in Alzheimer’s disease, but whether it plays a role in modifying the risk or clinical course of PD it yet to be elucidated. The TOMM40 ‘523’ allele length was determined in 634 people with PD and 422 healthy controls from an Australian cohort and the Parkinson’s Progression Markers Initiative (PPMI) cohort, using polymerase chain reaction or whole genome sequencing analysis. Genotype and allele frequencies of TOMM40 ‘523’ and APOE ε did not differ significantly between the cohorts. Analyses revealed TOMM40 ‘523’ allele groups were not associated with disease risk, while considering APOE ε genotype. Regression analyses revealed the TOMM40 S/S genotype was associated with a significantly later age of symptom onset in the PPMI PD cohort, but not after correction for covariates, or in the Australian cohort. Whilst variation in the TOMM40 ‘523’ polymorphism was not associated with PD risk, the possibility that it may be a modifying factor for age of symptom onset warrants further investigation in other PD populations.