bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line surgery in prolactinomas: lessons from a long-term follow-up study in a tertiary referral center
Authors: Andereggen L. , Frey J. , Andres R. H. , Luedi M. M. , El-Koussy M. , Widmer H. R. , Beck J. , Mariani L. , Seiler R. W. , Christ E.
Published: April 2021

Context

Although consensus guidelines recommend dopamine agonists (DAs) as the first-line approach in prolactinomas, some patients may opt instead for upfront surgery, with the goal of minimizing the need for continuation of DAs over the long term. While this approach can be recommended in selected patients with a microprolactinoma, the indication for upfront surgery in macroprolactinomas remains controversial, with limited long-term data in large cohorts. We aimed at elucidating whether first-line surgery is equally safe and effective for patients with micro- or macroprolactinomas not extending beyond the median carotid line (i.e., Knosp grade ≤ 1).

Methodology

Retrospective study of patients with prolactinomas Knosp grade ≤ 1 treated with upfront surgery. The primary endpoint was patients’ dependence on DAs at last follow-up. The secondary endpoint was postoperative complications. Independent risk factors for long-term dependence on DAs were analyzed.

Results

A microadenoma was noted in 45 patients (52%) and a macroadenoma in 41 (48%), with 17 (20%) harboring a Knosp grade 1 prolactinoma. Median follow-up was 80 months. First-line surgery resulted in long-term remission in 31 patients (72%) with a microprolactinoma and in 18 patients (45%) with a macroprolactinoma (p = 0.02). DA therapy was ultimately required in 11 patients (24%) with microadenomas vs. 20 (49%) with macroadenomas (p = 0.03). As for the latter, DA was required in 13 patients (76%) with Knosp grade 1 macroadenomas vs. 7 patients (29%) with Knosp grade 0 macroadenomas (p = 0.004). There was no mortality, and morbidity was minimal. Knosp grade 1 prolactinomas (OR 7.3, 95% CI 1.4–37.7,p = 0.02) but not adenoma size (i.e., macroprolactinomas) were an independent predictor of long-term dependence on DAs.

Conclusions

First-line surgery in patients with microprolactinomas or macroprolactinomas Knosp grade 0 resulted in a good chance of non-dependency on DA therapy. However, in patients with prolactinomas Knosp grade 1, first-line surgery cannot be recommended, as adjuvant DA therapy after surgery is required in the majority of them over the long term.
An Investigation on performance of the cut off wall and numerical analysis of seepage and pore water pressure of Eyvashan earth dam
Authors: Beiranvand Behrang , Komasi Mehdi
Published: April 2021

One of the most important issues in earth dams is the control rate of seepage from the foundation and dam bodies. Due to the site of the dams, to increase the creep length and reduce the seepage, there are several methods for sealing the reservoir of dams that construction of the cut-off wall under the clay core of the dams is one of the most effective methods. In this study, the seepage rate and pore water pressure of the Eyvashan earth dam, comparison of instrument results with the results of numerical analysis and, finally, the performance of the cut-off wall are investigated. According to the results of instrumental and numerical analysis, the maximum seepage rate in full reservoir conditions is equal to 831,604 m3/year. To fit the data of instrumentation and numerical analysis, multivariate regression was used and the coefficient of determination was used which R2 = 0.9892 and R2 = 0.9834, respectively, were obtained for seepage and pore water pressure. Very good agreement between the results of the observed data and the predicted data indicates the proper behavior of the dam in terms of pore water pressure. Also, due to the results of numerical simulation and instrumentation, the pore water pressure in the downstream part of the cut-off wall is suddenly dropped, which indicates the correct operation of the cut-off wall.
Length scale for the estimation of buzz frequency in the limit of high mechanical blockage in mixed-compression intakes
Authors: Devaraj Manoj Kumar K. , Jutur Prahallada , Rao Srisha M.V. , Jagadeesh Gopalan , Anavardham Ganesh T.K.
Published: April 2021

Oscillatory flow features are common in the unstart of hypersonic mixed-compression intakes and can be classified as low-amplitude or high-amplitude oscillatory unstarted flows. The low-amplitude oscillatory unstarted flow is driven by the shear layer from shock interactions ahead of the cowl, while the high-amplitude oscillatory unstarted flow is driven by the separation caused by shock–boundary-layer interaction on the ramp. While previous studies have observed these flow features and reported their associated frequency, there is no simple criterion available for predicting which mode will occur, and there is a lack of consensus on the appropriate frequency scaling parameter. We study a mixed-compression hypersonic intake in a hypersonic wind tunnel by varying the internal contraction ratio and the throttling ratio to observe various kinds of unstart regimes. Two significant conclusions emerge from considering the results for high-throttling-ratio conditions

$(TR > 0.55)$

from the current as well as previous studies. Firstly, the actual shock-on-lip condition at the cowl corresponding to the unthrottled condition, as observed from schlieren images, demarcates the boundary between the two modes of oscillatory unstart flows upon throttling. Secondly, a suitable length scale

$(l^*)$

, defined as the extent of the subsonic region in the unstarted flow (as observed from the experimental schlieren images), gives the appropriate frequency scaling parameter (

$f^* = a_0/4l^*$

where

$a_0$

is the stagnation acoustic speed).
Semi-automated counting of complex varves through image autocorrelation
Authors: Van Wyk de Vries Maximillian , Ito Emi , Shapley Mark , Brignone Guido
Published: April 2021

Annual resolution sediment layers, known as varves, can provide continuous and high-resolution chronologies of sedimentary sequences. In addition, varve counting is not burdened with the high laboratory costs of geochronological analyses. Despite a more than 100-year history of use, many existing varve counting techniques are time consuming and difficult to reproduce. We present countMYvarves, a varve counting toolbox which uses sliding-window autocorrelation to count the number of repeated patterns in core scans or outcrop photos. The toolbox is used to build an annually-resolved record of sedimentation rates, which are depth-integrated to provide ages. We validate the model with repeated manual counts of a high sedimentation rate lake with biogenic varves (Herd Lake, USA) and a low sedimentation rate glacial lake (Lago Argentino, Argentina). In both cases, countMYvarves is consistent with manual counts and provides additional sedimentation rate data. The toolbox performs multiple simultaneous varve counts, enabling uncertainty to be quantified and propagated into the resulting age-depth model. The toolbox also includes modules to automatically exclude non-varved portions of sediment and interpolate over missing or disrupted sediment. CountMYvarves is open source, runs through a graphical user interface, and is available online for download for use on Windows, macOS or Linux at https://doi.org/10.5281/zenodo.4031811.
BEING CAYLEY AUTOMATIC IS CLOSED UNDER TAKING WREATH PRODUCT WITH VIRTUALLY CYCLIC GROUPS
Authors: BERDINSKY DMITRY , ELDER MURRAY , TABACK JENNIFER
Published: April 2021

We extend work of Berdinsky and Khoussainov [‘Cayley automatic representations of wreath products’, International Journal of Foundations of Computer Science27(2) (2016), 147–159] to show that being Cayley automatic is closed under taking the restricted wreath product with a virtually infinite cyclic group. This adds to the list of known examples of Cayley automatic groups.
Late-life cynical hostility is associated with white matter alterations and the risk of Alzheimer's disease
Authors: Cyprien Fabienne , Berr Claudine , Maller Jerome J. , Meslin Chantal , Gentreau Mélissa , Mura Thibault , Gabelle Audrey , Courtet Philippe , Ritchie Karen , Ancelin Marie-Laure , Artero Sylvaine
Published: April 2021

Background

Cynical hostility (CH), a specific dimension of hostility that consists of a mistrust of others, has been suggested as a high-risk trait for dementia. However, the influence of CH on the incidence of Alzheimer's disease (AD) remains poorly understood. This study investigated whether late-life CH is associated with AD risk and structural neuroimaging markers of AD.

Methods

In community-dwelling older adults from the French ESPRIT cohort (n = 1388), incident dementia rate according to CH level was monitored during an 8-year follow-up and analyzed using Cox proportional hazards regression models. Brain magnetic resonance imaging volumes were measured at baseline (n = 508). Using automated segmentation procedures (Freesurfer 6.0), the authors assessed brain grey and white volumes on all magnetic resonance imaging scans. They also measured white matter hyperintensities volumes using semi-automated procedures. Mean volumes according to the level of CH were compared using ANOVA.

Results

Eighty-four participants developed dementia (32 with AD). After controlling for potential confounders, high CH was predictive of AD (HR 2.74; 95% CI 1.10–6.85; p = 0.030) and all dementia types are taken together (HR 2.30; 95% CI 1.10–4.80; p = 0.027). High CH was associated with white matter alterations, particularly smaller anterior corpus callosum volume (p < 0.01) after False Discovery Rate correction, but not with grey matter volumes.

Conclusions

High CH in late life is associated with cerebral white matter alterations, designated as early markers of dementia, and higher AD risk. Identifying lifestyle and biological determinants related to CH could provide clues on AD physiopathology and avenues for prevention strategies.
Towards affinoid Duflo’s theorem I: twisted differential operators
Authors: STANCIU IOAN
Published: April 2021

For a commutative ring R, we define the notions of deformed Picard algebroids and deformed twisted differential operators on a smooth, separated, locally of finite type R-scheme and prove these are in a natural bijection. We then define the pullback of a sheaf of twisted differential operators that reduces to the classical definition when R = ℂ. Finally, for modules over twisted differential operators, we prove a theorem for the descent under a locally trivial torsor.
Public health response to an outbreak of SARS-CoV2 infection in a Barcelona prison
Authors: Marco A. , Gallego C. , Pérez-Cáceres V. , Guerrero R. A. , Sánchez-Roig M. , Sala-Farré R. M. , Fernández-Náger J. , Turu E.
Published: April 2021

An outbreak of SARS-CoV2 infection in a Barcelona prison was studied. One hundred and forty-eight inmates and 36 prison staff were evaluated by rt-PCR, and 24.1% (40 prisoners, two health workers and four non-health workers) tested positive. In all, 94.8% of cases were asymptomatic. The inmates were isolated in prison module 4, which was converted into an emergency COVID unit. There were no deaths. Generalised screening and the isolation and evaluation of the people infected were key measures. Symptom-based surveillance must be supplemented by rapid contact-based monitoring in order to avoid asymptomatic spread among prisoners and the community at large.
Mass-conserving diffusion-based dynamics on graphs
Authors: BUDD J.M , VAN GENNIP Y.
Published: April 2021

An emerging technique in image segmentation, semi-supervised learning and general classification problems concerns the use of phase-separating flows defined on finite graphs. This technique was pioneered in Bertozzi and Flenner (2012, Multiscale Modeling and Simulation10(3), 1090–1118), which used the Allen–Cahn flow on a graph, and was then extended in Merkurjev et al. (2013, SIAM J. Imaging Sci.6(4), 1903–1930) using instead the Merriman–Bence–Osher (MBO) scheme on a graph. In previous work by the authors, Budd and Van Gennip (2020, SIAM J. Math. Anal.52(5), 4101–4139), we gave a theoretical justification for this use of the MBO scheme in place of Allen–Cahn flow, showing that the MBO scheme is a special case of a ‘semi-discrete’ numerical scheme for Allen–Cahn flow. In this paper, we extend this earlier work, showing that this link via the semi-discrete scheme is robust to passing to the mass-conserving case. Inspired by Rubinstein and Sternberg (1992, IMA J. Appl. Math.48, 249–264), we define a mass-conserving Allen–Cahn equation on a graph. Then, with the help of the tools of convex optimisation, we show that our earlier machinery can be applied to derive the mass-conserving MBO scheme on a graph as a special case of a semi-discrete scheme for mass-conserving Allen–Cahn. We give a theoretical analysis of this flow and scheme, proving various desired properties like existence and uniqueness of the flow and convergence of the scheme, and also show that the semi-discrete scheme yields a choice function for solutions to the mass-conserving MBO scheme.
Ordering the city: revolution, modernity and road renaming in Shanghai, 1949–1966
Authors: Howlett Jonathan J.
Published: April 2021

Between 1949 and 1966, the Chinese Communist Party (CCP)-led municipal government of Shanghai renamed more than one in seven of the city's roads. Renaming was an important marker of revolutionary change in China's largest and most foreign-influenced city. Road renaming in socialist China has been commonly understood to have been extensive. This article argues, however, that the nature and extent of renaming in socialist Shanghai was less dramatic than has been assumed. It demonstrates that renaming was not simply an iconoclastic process, but rather involved the pragmatic weighing of symbolic change against potential disruption. Further, it contends that renaming was driven by a desire to order the city, in line with the CCP's modernist worldview.
Support for Governmental Income Redistribution in Nordic Countries
Authors: Greve Bent , Hussain M. Azhar
Published: April 2021

In many countries, we have seen an increase in economic inequality over the past 20 to 25 years. The populations might therefore have changed their attitude about how and how much different countries should intervene to reduce the extent of economic inequality. A question is whether there is any connection between changes in redistribution preferences and trends in economic inequality in the prosperous Nordic welfare states. This article contributes by examining whether there are differences in redistribution attitude and changes herein based upon socio-economic criteria, which might include self-interest arguments. Nordic countries are interesting because there have been differences in development, and even strong growth in economic inequality, especially in Sweden and Denmark, although these countries in the literature have been seen as highly equal societies. The analysis shows that support for redistribution is relatively stable over time in each country, but also that there are major differences between countries, with support being much higher in Finland compared with Denmark. Females, discriminated groups and the unemployed generally support redistribution to a higher degree. Ageing generally increases redistributional support, while more education reduces support for government redistribution in Finland. In all four countries, the highest income groups are less supportive of redistribution of income.
Association of Adult Socioeconomic Status with Body Mass Index: A Within- and Between-Twin Study
Authors: Crofts Samuel J. C. , Lam Janine , Scurrah Katrina J. , Dite Gillian S.
Published: April 2021

Adult socioeconomic status (SES) has been consistently associated with body mass index (BMI), but it is unclear whether it is linked to BMI independently of childhood SES or other potentially confounding factors. Twin studies can address this issue by implicitly controlling for childhood SES and unmeasured confounders. This co-twin control study used cross-sectional data from Twins Research Australia’s Health and Lifestyle Questionnaire (N= 1918 twin pairs). We investigated whether adult SES, as measured by both the Index of Relative Socioeconomic Disadvantage (IRSD) and the Australian Socioeconomic Index 2006 (AUSEI06), was associated with BMI after controlling for factors shared by twins within a pair. The primary analysis was a linear mixed-effects model that estimated effects both within and between pairs. Between pairs, a 10-unit increase in AUSEI06 was associated with a 0.29 kg/m2decrease in BMI (95% CI [−.42, −.17],p< .001), and a 1-decile increase in IRSD was associated with a 0.26 kg/m2decrease in BMI (95% CI [−.35, −.17],p< .001). No association was observed within pairs. In conclusion, higher adult SES was associated with lower BMI between pairs, but no association was observed within pairs. Thus, the link between adult SES and BMI may be due to confounding factors common to twins within a pair.
A Technique for the Analysis of Radio Occultation Data to Retrieve Atmospheric Properties and Associated Uncertainties
Authors: Petricca Flavio , Cascioli Gael , Genova Antonio
Published: April 2021

Among the techniques for atmospheric sounding, radio occultation enables an in depth investigation of vertical profiles from the ionosphere to the troposphere by measuring the radio frequency signal associated to the propagation medium. A precise characterization of the atmospheric layers requires a thorough processing of the raw radio tracking data to estimate the thermodynamic properties of the atmosphere and their related uncertainties. In this work, we present a method to retrieve refractivity, density, pressure, and temperature profiles with the associated uncertainties by analyzing a set of raw radio tracking data occulted by the atmosphere. This technique is also well suited to process two‐way Doppler measurements that are not acquired during dedicated occultation campaigns. The NASA mission Mars Reconnaissance Orbiter (MRO) provided a significant amount of radio occultation data that were not planned for atmospheric sounding, but were caused by the spacecraft orbit geometry. Our analysis of one of these occultation profiles with the proposed method allows indicating that MRO occultation datasets provide crucial information regarding Mars’ troposphere that can be used as input of general circulation models.
Deep Learning for Daily Precipitation and Temperature Downscaling
Authors: Wang Fang , Tian Di , Lowe Lisa , Kalin Latif , Lehrter John
Published: April 2021

Downscaling is a critical step to bridge the gap between large‐scale climate information and local‐scale impact assessment. This study presents a novel deep learning approach: Super Resolution Deep Residual Network (SRDRN) for downscaling daily precipitation and temperature. This approach was constructed based on an advanced deep convolutional neural network with residual blocks and batch normalizations. The data augmentation technique was utilized to address overfitting that is due to highly imbalanced precipitation and nonprecipitation days and sparse precipitation extremes. Synthetic experiments were designed to downscale daily maximum/minimum temperature and precipitation data from coarse resolutions (25, 50, and 100 km) to a high resolution (4 km). The results showed that, during the validation period, the SRDRN approach not only captured the spatial and temporal patterns remarkably well, but also reproduced both precipitation and temperature extremes in different locations and time at the local scale. Through transfer learning, the trained SRDRN model in one region was directly applied to downscale precipitation in another region with a different environment, and the results showed notable improvement compared to classic statistical downscaling methods. The outstanding performance of the SRDRN approach stemmed from its ability to fully extract spatial features without suffering from degradation and overfitting issues due to the incorporations of residual blocks, batch normalizations, and data augmentations. The SRDRN approach is thus a powerful tool for downscaling daily precipitation and temperature and can potentially be leveraged to downscale any hydrologic, climate, and earth system data.
Using Volatile Element Concentration Profiles in Crystal‐Hosted Melt Embayments to Estimate Magma Decompression Rate: Assumptions and Inherited Errors
Authors: deGraffenried R. L. , Shea T.
Published: April 2021

Magma decompression rate has profound impacts on volcanic eruption style as it determines the time available for most kinetic processes (e.g., volatile exsolution, crystal nucleation and growth) that influence the explosive‐effusive eruption transition. Thus, accurately quantifying decompression rate is a critical goal for understanding volcanic eruption dynamics. A recently developed technique uses crystal‐hosted pockets of melt that remain open to the host magma (melt embayments) to calculate an average decompression rate. Diffusion of volatile elements (e.g., H2O, CO2) out of the embayment during decompression creates “frozen” concentration gradients upon quenching that can be modeled to calculate the time needed to create the gradients. This geospeedometer is increasingly used, but inherent assumptions associated with the modeling and their impact on calculated decompression rates are poorly quantified. Therefore, we have conducted a numerical investigation to assess the impact of three common model simplifications pertaining to rhyolitic magmas: 1D diffusion models, equilibrium degassing, and isothermal decompression. We find that the greatest deviation between imposed and calculated decompression rates occur when 1D models are applied to “necked” embayments that have a constriction where the embayment joins with the far field melt. Simplifying to equilibrium degassing can also introduce modeling errors when disequilibrium conditions exist, though the prevalence of one or the other condition in nature is currently under debate. Assuming isothermal conditions introduces little error into modeled timescales. All of our modeling results are summarized into a list of best practices to minimize error in modeled timescales due to modeling assumptions.
Engineering single-molecule fluorescence with asymmetric nano-antennas
Authors: Zhao Wenqi , Tian Xiaochaoran , Fang Zhening , Xiao Shiyi , Qiu Meng , He Qiong , Feng Wei , Li Fuyou , Zhang Yuanbo , Zhou Lei , Tan Yan-Wen
Published: April 2021

As a powerful tool for studying molecular dynamics in bioscience, single-molecule fluorescence detection provides dynamical information buried in ensemble experiments. Fluorescence in the near-infrared (NIR) is particularly useful because it offers higher signal-to-noise ratio and increased penetration depth in tissue compared with visible fluorescence. The low quantum yield of most NIR fluorophores, however, makes the detection of single-molecule fluorescence difficult. Here, we use asymmetric plasmonic nano-antenna to enhance the fluorescence intensity of AIEE1000, a typical NIR dye, by a factor up to 405. The asymmetric nano-antenna achieve such an enhancement mainly by increasing the quantum yield (to ~80%) rather than the local field, which degrades the molecules’ photostability. Our coupled-mode-theory analysis reveals that the enhancements stem from resonance-matching between antenna and molecule and, more importantly, from optimizing the coupling between the near- and far-field modes with designer asymmetric structures. Our work provides a universal scheme for engineering single-molecule fluorescence in the near-infrared regime.
Optical actuation of a micromechanical photodiode via the photovoltaic-piezoelectric effect
Authors: Rampal A. , Kleiman R. N.
Published: April 2021

Radiation pressure and photothermal forces have been previously used to optically actuate micro/nanomechanical structures fabricated from semiconductor piezoelectric materials such as gallium arsenide (GaAs). In these materials, coupling of the photovoltaic and piezoelectric properties has not been fully explored and leads to a new type of optical actuation that we call the photovoltaic-piezoelectric effect (PVPZ). We demonstrate this effect by electrically measuring, via the direct piezoelectric effect, the optically induced strain in a novel torsional resonator. The micron-scale torsional resonator is fabricated from a lattice-matched single-crystal molecular beam epitaxy (MBE)-grown GaAs photodiode heterostructure. We find that the strain depends on the product of the electro-optic responsivity and piezoelectric constant of GaAs. The photovoltaic-piezoelectric effect has important potential applications, such as in the development of configurable optical circuits, which can be used in neuromorphic photonic chips, processing of big data with deep learning and the development of quantum circuits.
GOLM1 restricts colitis and colon tumorigenesis by ensuring Notch signaling equilibrium in intestinal homeostasis
Authors: Pu Yang , Song Ya , Zhang Mengdi , Long Caifeng , Li Jie , Wang Yanan , Xu Yinzhe , Pan Fei , Zhao Na , Zhang Xinyu , Xu Yanan , Cui Jianxin , Wang Hongying , Li Yan , Zhao Yong , Jin Di , Zhang Hongbing
Published: April 2021

Intestinal epithelium serves as the first barrier against the infections and injuries that mediate colonic inflammation. Colorectal cancer is often accompanied with chronic inflammation. Differed from its well-known oncogenic role in many malignancies, we present here that Golgi membrane protein 1 (GOLM1, also referred to as GP73) suppresses colorectal tumorigenesis via maintenance of intestinal epithelial barrier. GOLM1 deficiency in mice conferred susceptibility to mucosal inflammation and colitis-induced epithelial damage, which consequently promoted colon cancer. Mechanistically, depletion of GOLM1 in intestinal epithelial cells (IECs) led to aberrant Notch activation that interfered with IEC differentiation, maturation, and lineage commitment in mice. Pharmacological inhibition of Notch pathway alleviated epithelial lesions and restrained pro-tumorigenic inflammation in GOLM1-deficient mice. Therefore, GOLM1 maintains IEC homeostasis and protects against colitis and colon tumorigenesis by modulating the equilibrium of Notch signaling pathway.
Nucleoside reverse transcriptase inhibitors and Kamuvudines inhibit amyloid-β induced retinal pigmented epithelium degeneration
Authors: Narendran Siddharth , Pereira Felipe , Yerramothu Praveen , Apicella Ivana , Wang Shao-bin , Ambati Kameshwari , Hirahara Shuichiro , Kim Younghee , Ambati Meenakshi , Ambati Vidya L. , Huang Peirong , Varshney Akhil , Nagasaka Yosuke , Fukuda Shinichi , Baker Kirstie L. , Marion Kenneth M. , Deussing Jan M. , Sadda Srinivas R. , Gelfand Bradley D. , Ambati Jayakrishna
Published: April 2021

Nonfibrillar amyloid-β oligomers (AβOs) are a major component of drusen, the sub-retinal pigmented epithelium (RPE) extracellular deposits characteristic of age-related macular degeneration (AMD), a common cause of global blindness. We report that AβOs induce RPE degeneration, a clinical hallmark of geographic atrophy (GA), a vision-threatening late stage of AMD that is currently untreatable. We demonstrate that AβOs induce activation of the NLRP3 inflammasome in the mouse RPE in vivo and that RPE expression of the purinergic ATP receptor P2RX7, an upstream mediator of NLRP3 inflammasome activation, is required for AβO-induced RPE degeneration. Two classes of small molecule inflammasome inhibitors—nucleoside reverse transcriptase inhibitors (NRTIs) and their antiretrovirally inert modified analog Kamuvudines—both inhibit AβOs-induced RPE degeneration. These findings crystallize the importance of P2RX7 and NLRP3 in a disease-relevant model of AMD and identify inflammasome inhibitors as potential treatments for GA.
Intensification of functional neural control on heartbeat dynamics in subclinical depression
Authors: Catrambone Vincenzo , Messerotti Benvenuti Simone , Gentili Claudio , Valenza Gaetano
Published: April 2021

Subclinical depression (dysphoria) is a common condition that may increase the risk of major depression and leads to impaired quality of life and severe comorbid somatic diseases. Despite its prevalence, specific biological markers are unknown; consequently, the identification of dysphoria currently relies exclusively on subjective clinical scores and structured interviews. Based on recent neurocardiology studies that link brain and cardiovascular disorders, it was hypothesized that multi-system biomarkers of brain–body interplay may effectively characterize dysphoria. Thus, an ad hoc computational technique was developed to quantify the functional bidirectional brain–heart interplay. Accordingly, 32-channel electroencephalographic and heart rate variability series were obtained from 24 young dysphoric adults and 36 healthy controls. All participants were females of a similar age, and results were obtained during a 5-min resting state. The experimental results suggest that a specific feature of dysphoria is linked to an augmented functional central-autonomic control to the heart, which originates from central, frontopolar, and occipital oscillations and acts through cardiovascular sympathovagal activity. These results enable further development of a large set of novel biomarkers for mood disorders based on comprehensive brain–body measurements.
Endocannabinoid signaling in the lateral habenula regulates pain and alcohol consumption
Authors: Fu Rao , Tang Ying , Li Wenfu , Ren Zhiheng , Li Ding , Zheng Jiayi , Zuo Wanhong , Chen Xuejun , Zuo Qi Kang , Tam Kelsey L. , Zou Yucong , Bachmann Thomas , Bekker Alex , Ye Jiang-Hong
Published: April 2021

Hyperalgesia, which often occurs in people suffering from alcohol use disorder, may drive excessive drinking and relapse. Emerging evidence suggests that the lateral habenula (LHb) may play a significant role in this condition. Previous research suggests that endocannabinoid signaling (eCBs) is involved in drug addiction and pain, and that the LHb contains core components of the eCBs machinery. We report here our findings in rats subjected to chronic ethanol vapor exposure. We detected a substantial increase in endocannabinoid-related genes, includingMgllandDaglbmRNA levels, as well as monoacylglycerol lipase (MAGL) protein levels, as well as a decrease inCnr1mRNA and type-1 cannabinoid receptor (CB1R) protein levels, in the LHb of ethanol-exposed rats. Also, rats withdrawing from ethanol exposure displayed hypersensitivity to mechanical and thermal nociceptive stimuli. Conversely, intra-LHb injection of the MAGL inhibitor JZL184, the fatty acid amide hydrolase inhibitor URB597, or the CB1R agonist WIN55,212-2 produced an analgesic effect, regardless of ethanol or air exposure history, implying that alcohol exposure does not change eCB pain responses. Intra-LHb infusion of the CB1R inverse agonist rimonabant eliminated the analgesic effect of these chemicals. Rimonabant alone elicited hyperalgesia in the air-, but not ethanol-exposed animals. Moreover, intra-LHb JZL184, URB597, or WIN55,212-2 reduced ethanol consumption in both homecages and operant chambers in rats exposed to ethanol vapor but not air. These findings suggest that LHb eCBs play a pivotal role in nociception and facilitating LHb eCBs may attenuate pain in drinkers.
HIF-1α promoted vasculogenic mimicry formation in lung adenocarcinoma through NRP1 upregulation in the hypoxic tumor microenvironment
Authors: Fu Ran , Du Wenwen , Ding Zongli , Wang Yi , Li Yue , Zhu Jianjie , Zeng Yuanyuan , Zheng Yulong , Liu Zeyi , Huang Jian-an
Published: April 2021

Neovascularization is a key factor that contributes to tumor metastasis, and vasculogenic mimicry (VM) is an important form of neovascularization found in highly invasive tumors, including lung cancer. Despite the increasing number of studies focusing on VM, the mechanisms underlying VM formation remain unclear. Herein, our study explored the role of the HIF-1α/NRP1 axis in mediating lung adenocarcinoma metastasis and VM formation. HIF-1α, NRP1 expression, and VM in lung adenocarcinoma (LUAD) patient samples were examined by immunohistochemical staining. Quantitative real-time (qRT-PCR), western blot, transwell assay, wound healing assay, and tube formation assay were performed to verify the role of HIF-1α/NRP1 axis in LUAD metastasis and VM formation. ChIP and luciferase reporter assay were used to confirm whether NRP1 is a direct target of HIF-1α. In LUAD tissues, we confirmed a positive relationship between HIF-1α and NRP1 expression. Importantly, high HIF-1α and NRP1 expression and the presence of VM were correlated with poor prognosis. We also found that HIF-1α could induce LUAD cell migration, invasion, and VM formation by regulating NRP1. Moreover, we demonstrated that HIF-1α can directly bind to the NRP1 promoter located between −2009 and −2017 of the promoter. Mechanistically, MMP2, VE-cadherin, and Vimentin expression were affected. HIF-1α plays an important role in inducing lung adenocarcinoma cell metastasis and VM formation via upregulation of NRP1. This study highlights the potential therapeutic value of targeting NRP1 for suppressing lung adenocarcinoma metastasis and progression.
Targeting K-Ras and apoptosis-driven cellular transformation in cancer
Authors: Godwin Isha , Anto Nikhil Ponnoor , Bava Smitha V. , Babu Mani Shankar , Jinesh Goodwin G.
Published: April 2021

Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.
Incidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics
Authors: van Werkhoven Cornelis H. , Ducher Annie , Berkell Matilda , Mysara Mohamed , Lammens Christine , Torre-Cisneros Julian , Rodríguez-Baño Jesús , Herghea Delia , Cornely Oliver A. , Biehl Lena M. , Bernard Louis , Dominguez-Luzon M. Angeles , Maraki Sofia , Barraud Olivier , Nica Maria , Jazmati Nathalie , Sablier-Gallis Frederique , de Gunzburg Jean , Mentré France , Malhotra-Kumar Surbhi , Bonten Marc J. M. , Vehreschild Maria J. G. T. ,   the ANTICIPATE Study Group, Engbers Annemarie M. S. , de Regt Marieke J. A. , Goossens Herman , Xavier Basil Britto , Bouverne Marie-Noelle , Monsieurs Pieter , Merle Uta , Stallmach Andreas , Rupp Jan , Bogner Johannes , Lübbert Christoph , Silling Gerda , Witzke Oliver , Gikas Achilleas , Daikos George , Tsiodras Sotirios , Skoutelis Athanasios , Sambatakou Helen , Pujol Miquel , Aguado Jose M. , Bouza Emilio , Cobo Javier , Almirante Benito , Florescu Simin A. , Vata Andrei , Hristea Adriana , Lupse Mihaela , Postil Deborah , Molina Jean-Michel , De Lastours Victoire , Guimard Thomas , Talarmin Jean-Philippe , Duval Xavier , Launay Odile
Published: April 2021

Trial enrichment using gut microbiota derived biomarkers by high-risk individuals can improve the feasibility of randomized controlled trials for prevention of Clostridioides difficile infection (CDI). Here, we report in a prospective observational cohort study the incidence of CDI and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients ≥ 50 years receiving newly initiated antibiotic treatment with penicillins plus a beta-lactamase inhibitor, 3rd/4th generation cephalosporins, carbapenems, fluoroquinolones or clindamycin from 34 European hospitals. The estimated 90-day cumulative incidences of a first CDI episode is 1.9% (95% CI 1.1-3.0). Carbapenem treatment (Hazard Ratio (95% CI): 5.3 (1.7-16.6)), toxigenic C. difficile rectal carriage (10.3 (3.2-33.1)), high intestinal abundance of Enterococcus spp. relative to Ruminococcus spp. (5.4 (2.1-18.7)), and low Shannon alpha diversity index as determined by 16 S rRNA gene profiling (9.7 (3.2-29.7)), but not normalized urinary 3-indoxyl sulfate levels, predicts an increased CDI risk.
Microbiota-based markers predictive of development of Clostridioides difficile infection
Authors: Berkell Matilda , Mysara Mohamed , Xavier Basil Britto , van Werkhoven Cornelis H. , Monsieurs Pieter , Lammens Christine , Ducher Annie , Vehreschild Maria J. G. T. , Goossens Herman , de Gunzburg Jean , Bonten Marc J. M. , Malhotra-Kumar Surbhi ,   the ANTICIPATE study group, Engbers Annemarie , de Regt Marieke , Biehl Lena M. , Cornely Oliver A. , Jazmati Nathalie , Bouverne Marie-Noelle , Sablier-Gallis Frederique , Mentré France , Merle Uta , Stallmach Andreas , Rupp Jan , Bogner Johannes , Lübbert Christoph , Silling Gerda , Witzke Oliver , Gikas Achilleas , Maraki Sofia , Daikos George , Tsiodras Sotirios , Skoutelis Athanasios , Sambatakou Helen , Pujol Miquel , Dominguez-Luzon M. Angeles , Aguado Jose M. , Bouza Emilio , Cobo Javier , Rodríguez-Baño Jesús , Almirante Benito , de la Torre Cisneros Julian , Florescu Simin A. , Nica Maria , Vata Andrei , Hristea Adriana , Lupse Mihaela , Herghea Delia , Postil Deborah , Barraud Olivier , Molina Jean-Michel , De Lastours Victoire , Guimard Thomas , Talarmin Jean-Philippe , Duval Xavier , Bernard Louis , Launay Odile
Published: April 2021

Antibiotic-induced modulation of the intestinal microbiota can lead to Clostridioides difficile infection (CDI), which is associated with considerable morbidity, mortality, and healthcare-costs globally. Therefore, identification of markers predictive of CDI could substantially contribute to guiding therapy and decreasing the infection burden. Here, we analyze the intestinal microbiota of hospitalized patients at increased CDI risk in a prospective, 90-day cohort-study before and after antibiotic treatment and at diarrhea onset. We show that patients developing CDI already exhibit significantly lower diversity before antibiotic treatment and a distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients. We find that antibiotic treatment-induced dysbiosis is class-specific with beta-lactams further increasing enterococcal abundance. Our findings, validated in an independent prospective patient cohort developing CDI, can be exploited to enrich for high-risk patients in prospective clinical trials, and to develop predictive microbiota-based diagnostics for management of patients at risk for CDI.
Improving organic photovoltaic cells by forcing electrode work function well beyond onset of Ohmic transition
Authors: Zhao Chao , Tang Cindy G. , Seah Zong-Long , Koh Qi-Mian , Chua Lay-Lay , Png Rui-Qi , Ho Peter K. H.
Published: April 2021

As electrode work function rises or falls sufficiently, the organic semiconductor/electrode contact reaches Fermi-level pinning, and then, few tenths of an electron-volt later, Ohmic transition. For organic solar cells, the resultant flattening of open-circuit voltage (Voc) and fill factor (FF) leads to a ‘plateau’ that maximizes power conversion efficiency (PCE). Here, we demonstrate this plateau in fact tilts slightly upwards. Thus, further driving of the electrode work function can continue to improve Voc and FF, albeit slowly. The first effect arises from the coercion of Fermi level up the semiconductor density-of-states in the case of ‘soft’ Fermi pinning, raising cell built-in potential. The second effect arises from the contact-induced enhancement of majority-carrier mobility. We exemplify these using PBDTTPD:PCBM solar cells, where PBDTTPD is a prototypal face-stacked semiconductor, and where work function of the hole collection layer is systematically ‘tuned’ from onset of Fermi-level pinning, through Ohmic transition, and well into the Ohmic regime.
Generating biomembrane-like local curvature in polymersomes via dynamic polymer insertion
Authors: Sun Jiawei , Rijpkema Sjoerd J. , Luan Jiabin , Zhang Shaohua , Wilson Daniela A.
Published: April 2021

Biomembrane curvature formation has long been observed to be essential in the change of membrane morphology and intracellular processes. The significant importance of curvature formation has attracted scientists from different backgrounds to study it. Although magnificent progress has been achieved using liposome models, the instability of these models restrict further exploration. Here, we report a new approach to mimic biomembrane curvature formation using polymersomes as a model, and poly(N-isopropylacrylamide) to induce the local curvature based on its co-nonsolvency phenomenon. Curvatures form when poly(N-isopropylacrylamide) becomes hydrophobic and inserts into the membrane through solvent addition. The insertion area can be fine-tuned by adjusting the poly(N-isopropylacrylamide) concentration, accompanied by the formation of new polymersome-based non-axisymmetric shapes. Moreover, a systematic view of curvature formation is provided through investigation of the segregation, local distribution and dissociation of inserted poly(N-isopropylacrylamide). This strategy successfully mimicks biomembrane curvature formation in polymersomes and a detailed observation of the insertion can be beneficial for a further understanding of the curvature formation process. Furthermore, polymer insertion induced shape changing could open up new routes for the design of non-axisymmetric nanocarriers and nanomachines to enrich the boundless possibilities of nanotechnology.
Fine-scale multiannual survey of benthic invertebrates in a glacier-fed stream used for hydropower generation
Authors: Scotti Alberto , Bottarin Roberta
Published: April 2021

The present dataset contains information about aquatic macroinvertebrates and environmental variables collected before and after the implementation of a small “run-of-river” hydropower plant on the Saldur stream, a glacier-fed stream located in the Italian Central-Eastern Alps. Between 2015 and 2019, with two sampling events per year, we collected and identified 34,836 organisms in 6 sampling sites located within a 6 km stretch of the stream. Given the current boom of the hydropower sector worldwide, and the growing contribution of small hydropower plants to energy production, data here included may represent an important – and long advocated – baseline to assess the effects that these kinds of powerplants have on the riverine ecosystem. Moreover, since the Saldur stream is part of the International Long Term Ecological Research network, this dataset also constitutes part of the data gathered within this research programme. All samples are preserved at Eurac Research facilities.
Author Correction: Influence of NOS3 rs2070744 genotypes on hepatocellular carcinoma patients treated with lenvatinib
Authors: Azuma Shintaro , Uojima Haruki , Chuma Makoto , Shao Xue , Hidaka Hisashi , Nakazawa Takahide , Kondo Masaaki , Numata Kazushi , Iwabuchi Shogo , Kako Makoto , Maeda Shin , Koizumi Wasaburo , Atsuda Koichiro
Published: April 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Validation of three predictive models for suboptimal cytoreductive surgery in advanced ovarian cancer
Authors: Llueca Antoni , Climent María Teresa , Escrig Javier , Carrasco Paula , Serra Anna ,   MUAPOS working group (Multidisciplinary Unit of Abdominal Pelvic Oncology Surgery), Gomez-Quiles L. , Játiva R. , Cebrian G. , Bosso V. , Villarin A. , Maiocchi K. , Delgado-Barriga K. , Rodrigo-Aliaga M. , Ruiz N. , Herrero C. , Frances A. , Beato I. , Ferrer C. , Aracil J. P. , Boldo E. , Boldo A. , Adell R.
Published: April 2021

The standard treatment for advanced ovarian cancer (AOC) is cytoreduction surgery and adjuvant chemotherapy. Tumor volume after surgery is a major prognostic factor for these patients. The ability to perform complete cytoreduction depends on the extent of disease and the skills of the surgical team. Several predictive models have been proposed to evaluate the possibility of performing complete cytoreductive surgery (CCS). External validation of the prognostic value of three predictive models (Fagotti index and the R3 and R4 models) for predicting suboptimal cytoreductive surgery (SCS) in AOC was performed in this study. The scores of the 3 models were evaluated in one hundred and three consecutive patients diagnosed with AOC treated in a tertiary hospital were evaluated. Clinicopathological features were collected prospectively and analyzed retrospectively. The performance of the three models was evaluated, and calibration and discrimination were analyzed. The calibration of the Fagotti, R3 and R4 models showed odds ratios of obtaining SCSs of 1.5, 2.4 and 2.4, respectively, indicating good calibration. The discrimination of the Fagotti, R3 and R4 models showed an area under the ROC curve of 83%, 70% and 81%, respectively. The negative predictive values of the three models were higher than the positive predictive values for SCS. The three models were able to predict suboptimal cytoreductive surgery for advanced ovarian cancer, but they were more reliable for predicting CCS. The R4 model discriminated better because it includes the laparotomic evaluation of the peritoneal carcinomatosis index.
A toolbox for the comprehensive analysis of small volume human intestinal samples that can be used with gastrointestinal sampling capsules
Authors: Rios-Morales Melany , van Trijp Mara P. H. , Rösch Christiane , An Ran , Boer Theo , Gerding Albert , de Ruiter Naomi , Koehorst Martijn , Heiner-Fokkema M. Rebecca , Schols Henk A. , Reijngoud Dirk-Jan , Hooiveld Guido J. E. J. , Bakker Barbara M.
Published: April 2021

Detailed knowledge on the fate of dietary components inside the human intestinal tract is lacking. Access to this inner world of digestion is now possible through novel human gastrointestinal sampling capsules. Due to the novelty of such devices, no methodology has been published to stabilise and analyse the resulting samples. A complicating factor is that excretion of such capsules in faeces may take days, while degradation of the dietary components continues. Therefore a stabilising reagent should be pre-loaded in the capsule to ensure the measurement of a representative sample. Considering the small volume of recovered samples, analytical methods must be optimized to collect as many data as possible from little material. We present a complete workflow for stabilising and analysing the fermentation status of dietary fibres in such samples, including microbiota, fibre degradation, and short chain fatty acids. The final quenching reagent was designed based on safety and effectiveness to inhibit fructo- and galacto-oligosaccharides degradation and short chain fatty acids production by human ileostomy microbiota, and subsequently validated in faecal samples. The final composition of the stock quenching reagent is 175 mM Tris, 525 mM NaCl, 35 mM EDTA, 12% SDS, and 8 M urea at pH 8.5.