bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial oxidative phosphorylation in cutaneous melanoma
Authors: Kumar Prakrit R. , Moore Jamie A. , Bowles Kristian M. , Rushworth Stuart A. , Moncrieff Marc D.
Published: November 2020

The Warburg effect in tumour cells is associated with the upregulation of glycolysis to generate ATP, even under normoxic conditions and the presence of fully functioning mitochondria. However, scientific advances made over the past 15 years have reformed this perspective, demonstrating the importance of oxidative phosphorylation (OXPHOS) as well as glycolysis in malignant cells. The metabolic phenotypes in melanoma display heterogeneic dynamism (metabolic plasticity) between glycolysis and OXPHOS, conferring a survival advantage to adapt to harsh conditions and pathways of chemoresistance. Furthermore, the simultaneous upregulation of both OXPHOS and glycolysis (metabolic symbiosis) has been shown to be vital for melanoma progression. The tumour microenvironment (TME) has an essential supporting role in promoting progression, invasion and metastasis of melanoma. Mesenchymal stromal cells (MSCs) in the TME show a symbiotic relationship with melanoma, protecting tumour cells from apoptosis and conferring chemoresistance. With the significant role of OXPHOS in metabolic plasticity and symbiosis, our review outlines how mitochondrial transfer from MSCs to melanoma tumour cells plays a key role in melanoma progression and is the mechanism by which melanoma cells regain OXPHOS capacity even in the presence of mitochondrial mutations. The studies outlined in this review indicate that targeting mitochondrial trafficking is a potential novel therapeutic approach for this highly refractory disease.
Copper-zirconia interfaces in UiO-66 enable selective catalytic hydrogenation of CO2 to methanol
Authors: Zhu Yifeng , Zheng Jian , Ye Jingyun , Cui Yanran , Koh Katherine , Kovarik Libor , Camaioni Donald M. , Fulton John L. , Truhlar Donald G. , Neurock Matthew , Cramer Christopher J. , Gutiérrez Oliver Y. , Lercher Johannes A.
Published: November 2020

Molecular interactions with both oxides and metals are essential for heterogenous catalysis, leading to remarkable synergistic impacts on activity and selectivity. Here, we show that the direct link between the two phases (and not merely being together) is required to selectively hydrogenate CO2 to methanol on catalysts containing Cu and ZrO2. Materials consisting of isolated Cu particles or atomically dispersed Cu–O–Zr sites only catalyze the reverse water-gas shift reaction. In contrast, a metal organic framework structure (UiO-66) with Cu nanoparticles occupying missing-linker defects maximizes the fraction of metallic Cu interfaced to ZrO2 nodes leading to a material with high adsorption capacity for CO2 and high activity and selectivity for low-temperature methanol synthesis.
A cross-sectional study of cardiovascular disease risk clustering at different socio-geographic levels in India
Authors: Bischops Anne C. , De Neve Jan-Walter , Awasthi Ashish , Vollmer Sebastian , Bärnighausen Till , Geldsetzer Pascal
Published: November 2020

Despite its importance for the targeting of interventions, little is known about the degree to which cardiovascular disease (CVD) risk factors cluster within different socio-geographic levels in South Asia. Using two jointly nationally representative household surveys, which sampled 1,082,100 adults across India, we compute the intra-cluster correlation coefficients (ICCs) of five major CVD risk factors (raised blood glucose, raised blood pressure, smoking, overweight, and obesity) at the household, community, district, and state level. Here we show that except for smoking, the level of clustering is generally highest for households, followed by communities, districts, and then states. On average, more economically developed districts have a higher household ICC in rural areas. These findings provide critical information for sample size calculations of cluster-randomized trials and household surveys, and inform the targeting of policies and prevention programming aimed at reducing CVD in India.
Neonicotinoid Clothianidin reduces honey bee immune response and contributes to Varroa mite proliferation
Authors: Annoscia Desiderato , Di Prisco Gennaro , Becchimanzi Andrea , Caprio Emilio , Frizzera Davide , Linguadoca Alberto , Nazzi Francesco , Pennacchio Francesco
Published: November 2020

The neonicotinoid Clothianidin has a negative impact on NF-κB signaling and on immune responses controlled by this transcription factor, which can boost the proliferation of honey bee parasites and pathogens. This effect has been well documented for the replication of deformed wing virus (DWV) induced by Clothianidin in honey bees bearing an asymptomatic infection. Here, we conduct infestation experiments of treated bees to show that the immune-suppression exerted by Clothianidin is associated with an enhanced fertility of the parasitic mite Varroa destructor, as a possible consequence of a higher feeding efficiency. A conceptual model is proposed to describe the synergistic interactions among different stress agents acting on honey bees.
In-situ visualization of the space-charge-layer effect on interfacial lithium-ion transport in all-solid-state batteries
Authors: Wang Longlong , Xie Ruicong , Chen Bingbing , Yu Xinrun , Ma Jun , Li Chao , Hu Zhiwei , Sun Xingwei , Xu Chengjun , Dong Shanmu , Chan Ting-Shan , Luo Jun , Cui Guanglei , Chen Liquan
Published: November 2020

The space charge layer (SCL) is generally considered one of the origins of the sluggish interfacial lithium-ion transport in all-solid-state lithium-ion batteries (ASSLIBs). However, in-situ visualization of the SCL effect on the interfacial lithium-ion transport in sulfide-based ASSLIBs is still a great challenge. Here, we directly observe the electrode/electrolyte interface lithium-ion accumulation resulting from the SCL by investigating the net-charge-density distribution across the high-voltage LiCoO2/argyrodite Li6PS5Cl interface using the in-situ differential phase contrast scanning transmission electron microscopy (DPC-STEM) technique. Moreover, we further demonstrate a built-in electric field and chemical potential coupling strategy to reduce the SCL formation and boost lithium-ion transport across the electrode/electrolyte interface by the in-situ DPC-STEM technique and finite element method simulations. Our findings will strikingly advance the fundamental scientific understanding of the SCL mechanism in ASSLIBs and shed light on rational electrode/electrolyte interface design for high-rate performance ASSLIBs.
Local electric-field control of multiferroic spin-spiral domains in TbMnO3
Authors: Schoenherr Peggy , Manz Sebastian , Kuerten Lukas , Shapovalov Konstantin , Iyama Ayato , Kimura Tsuyoshi , Fiebig Manfred , Meier Dennis
Published: November 2020

Spin-spiral multiferroics exhibit a magnetoelectric coupling effects, leading to the formation of hybrid domains with inseparably entangled ferroelectric and antiferromagnetic order parameters. Due to this strong magnetoelectric coupling, conceptually advanced ways for controlling antiferromagnetism become possible and it has been reported that electric fields and laser pulses can reversibly switch the antiferromagnetic order. This switching of antiferromagnetic spin textures is of great interest for the emergent field of antiferromagnetic spintronics. Established approaches, however, require either high voltages or intense laser fields and are currently limited to the micrometer length scale, which forfeits the technological merit. Here, we image and control hybrid multiferroic domains in the spin-spiral system TbMnO3 using low-temperature electrostatic force microscopy (EFM). First, we show that image generation in EFM happens via surface screening charges, which allows for probing the previously hidden magnetically induced ferroelectric order in TbMnO3 (PS = 6 × 10−4 C/m2). We then set the antiferromagnetic domain configuration by acting on the surface screening charges with the EFM probe tip. Our study enables detection of entangled ferroelectric and antiferromagnetic domains with high sensitivity. The spatial resolution is limited only by the physical size of the probe tip, introducing a pathway towards controlling antiferromagnetic order at the nanoscale and with low energy.
The landscape of childhood vaccine exemptions in the United States
Authors: Zipfel Casey M. , Garnier Romain , Kuney Madeline C. , Bansal Shweta
Published: November 2020

Once-eliminated vaccine-preventable childhood diseases, such as measles, are resurging across the United States. Understanding the spatio-temporal trends in vaccine exemptions is crucial to targeting public health intervention to increase vaccine uptake and anticipating vulnerable populations as cases surge. However, prior available data on childhood disease vaccination is either at too rough a spatial scale for this spatially-heterogeneous issue, or is only available for small geographic regions, making general conclusions infeasible. Here, we have collated school vaccine exemption data across the United States and provide it at the county-level for all years included. We demonstrate the fine-scale spatial heterogeneity in vaccine exemption levels, and show that many counties may fall below the herd immunity threshold. We also show that vaccine exemptions increase over time in most states, and non-medical exemptions are highly prevalent where allowed. Our dataset also highlights the need for greater data sharing and standardized reporting across the United States.
The architecture of starch blocklets follows phyllotaxic rules
Authors: Spinozzi Francesco , Ferrero Claudio , Perez Serge
Published: November 2020

The starch granule is Nature’s way to store energy in green plants over long periods. Irrespective of their origins, starches display distinct structural features that are the fingerprints of levels of organization over six orders of magnitude. We hypothesized that Nature retains hierarchical material structures at all levels and that some general rules control the morphogenesis of these structures. We considered the occurrence of a «phyllotaxis» like features that would develop at scales ranging from nano to micrometres, and developed a novel geometric model capable of building complex structures from simple components. We applied it, according to the Fibonacci Golden Angle, to form several Golden Spirals, and derived theoretical models to simulate scattering patterns. A GSE, constructed with elements made up of parallel stranded double-helices, displayed shapes, sizes and high compactness reminiscent of the most intriguing structural element: the ‘blocklet’. From the convergence between the experimental findings and the theoretical construction, we suggest that the «phyllotactic» model represents an amylopectin macromolecule, with a high molecular weight. Our results offer a new vision to some previous models of starch. They complete a consistent description of the levels of organization over four orders of magnitude of the starch granule.
Investigating duration and intensity of Covid-19 social-distancing strategies
Authors: Neuwirth C. , Gruber C. , Murphy T.
Published: November 2020

The exponential character of the recent Covid-19 outbreak requires a change in strategy from containment to mitigation. Meanwhile, most countries apply social distancing with the objective to keep the number of critical cases below the capabilities of the health care system. Due to the novelty and rapid spread of the virus, an a priori assessment of this strategy was not possible. In this study, we present a model-based systems analysis to assess the effectiveness of social distancing measures in terms of intensity and duration of application. Results show a super-linear scaling between intensity (percent contact reduction) and required duration of application to have an added value (a lower number of fatalities). This holds true for an effective reproduction of $$R>1$$

R
>
1

and is reverted for $$R<1$$

R
<
1

. If R is not reduced below 1, secondary effects of required long-term isolation are likely to unravel the added value of disease mitigation. If an extinction is not feasible, we recommend moderate social-distancing that is well balanced against capability limits of national health-care systems.
Characteristics of peptic ulcer bleeding in cirrhotic patients with esophageal and gastric varices
Authors: Lu Zheng , Sun Xiaotian , Han Jingjing , Jin Bo , Zhang Wenhui , Han Jun , Ma Xuemei , Liu Bo , Yu Xiaoli , Wu Qin , Wang Yanling , Li Hanwei
Published: November 2020

Upper gastrointestinal bleeding (UGIB) is common in liver cirrhosis. Although esophageal and gastric varices (EGV) is the main bleeding source, there were still a proportion of patients with peptic ulcer bleeding. Thus, this study aimed to analyze the characteristic of variceal bleeding and peptic ulcer bleeding in liver cirrhosis. Cirrhotic patients with confirmed UGIB by urgent endoscopy from July 2012 to June 2018 were enrolled, and classified into peptic ulcer bleeding group (n = 248) and variceal bleeding group (n = 402). Clinical and endoscopic characteristics, therapeutic efficacy and prognosis were evaluated, and independent risk factors for 42-day morality were determined. The mean age and gender ratio of peptic ulcer bleeding group were higher than those in variceal bleeding group (55.58 ± 11.37 vs. 52.87 ± 11.57, P < 0.01; 4.51:1 vs. 2.87:1, P = 0.023). Variceal bleeding group most commonly presented as red blood emesis and coffee grounds (67.16%), while peptic ulcer group primarily manifested as melena (62.10%). Hepatocellular carcinoma was more prevalent in peptic ulcer group (141 vs. 119, P < 0.01). Albumin level in variceal bleeding group was lower higher (P < 0.01), but serum bilirubin, creatinine and prothrombin time were significantly higher (all P < 0.01). Success rate of endoscopic hemostasis for variceal bleeding and peptic ulcer bleeding was 89.05% and 94.35% (P = 0.021). Univariate and multivariate analysis identified prothrombin time (P = 0.041, OR [95% CI] 0.884 [0.786–0.995]), MELD score (P = 0.000, OR [95% CI] 1.153 [1.073–1.240]), emergency intervention (P = 0.002, OR [95% CI] 8.656 [2.219–33.764]), hepatic encephalopathy before bleeding (P = 0.003, OR [95% CI] 8.119 [2.084–31.637]) and hepatic renal syndrome before bleeding (P = 0.029, OR [95% CI] 3.877 [1.152–13.045]) as the independent predictors for 42-day mortality. Peptic ulcer bleeding should be distinguished from variceal bleeding by clinical and endoscopic characteristics.
Automatic detection of valve events by epicardial accelerometer allows estimation of the left ventricular pressure trace and pressure–displacement loop area
Authors: Wajdan Ali , Krogh Magnus Reinsfelt , Villegas-Martinez Manuel , Halvorsen Per Steinar , Elle Ole Jakob , Remme Espen Wattenberg
Published: November 2020

Measurements of the left ventricular (LV) pressure trace are rarely performed despite high clinical interest. We estimated the LV pressure trace for an individual heart by scaling the isovolumic, ejection and filling phases of a normalized, averaged LV pressure trace to the time-points of opening and closing of the aortic and mitral valves detected in the individual heart. We developed a signal processing algorithm that automatically detected the time-points of these valve events from the motion signal of a miniaturized accelerometer attached to the heart surface. Furthermore, the pressure trace was used in combination with measured displacement from the accelerometer to calculate the pressure–displacement loop area. The method was tested on data from 34 animals during different interventions. The accuracy of the accelerometer-detected valve events was very good with a median difference of 2 ms compared to valve events defined from hemodynamic reference recordings acquired simultaneously with the accelerometer. The average correlation coefficient between the estimated and measured LV pressure traces was r = 0.98. Finally, the LV pressure–displacement loop areas calculated using the estimated and measured pressure traces showed very good correlation (r = 0.98). Hence, the pressure–displacement loop area can be assessed solely from accelerometer recordings with very good accuracy.
The adhesion of clots in wounds contributes to hemostasis and can be enhanced by coagulation factor XIII
Authors: Chan Karen Y. T. , Yong Alyssa S. M. , Wang Xu , Ringgold Kristyn M. , St. John Alexander E. , Baylis James R. , White Nathan J. , Kastrup Christian J.
Published: November 2020

The adhesion of blood clots to wounds is necessary to seal injured vasculature and achieve hemostasis. However, it has not been specifically tested if adhesive failure of clots is a major contributor to rebleeding and what mechanisms prevent clot delamination. Here, we quantified the contribution of adhesive and cohesive failure to rebleeding in a rat model of femoral artery injury, and identified mechanisms that contribute to the adhesive strength of bulk clots in a lap-shear test in vitro. In the rat bleeding model, the frequency of clot failures correlated positively with blood loss (R = 0.81, p = 0.014) and negatively with survival time (R =  − 0.89, p = 0.0030), with adhesive failures accounting for 51 ± 14% of rebleeds. In vitro, adhesion depended on fibrinogen and coagulation factor XIII (FXIII), and supraphysiological FXIII improved adhesive strength. Furthermore, when exogenous FXIII was topically applied into the wound pocket of rats, eleven adhesive failures occurred between eight rats, compared to seventeen adhesive failures between eight untreated rats, whereas the number of cohesive failures remained the same at sixteen in both groups. In conclusion, rebleeding from both adhesive and cohesive failure of clots decreases survival from hemorrhage in vivo. Both endogenous and exogenous FXIII improves the adhesive strength of clots.
Western diet, obesity and bariatric surgery sequentially modulated anxiety, eating patterns and brain responses to sucrose in adult Yucatan minipigs
Authors: Gautier Yentl , Bergeat Damien , Serrand Yann , Réthoré Noémie , Mahérault Mathilde , Malbert Charles-Henri , Meurice Paul , Coquery Nicolas , Moirand Romain , Val-Laillet David
Published: November 2020

Palatable sweet/fatty foods overconsumption is a major risk factor for obesity and eating disorders, also having an impact on neuro-behavioural hedonic and cognitive components comparable to what is described for substance abuse. We hypothesized that Yucatan minipigs would show hedonic, cognitive, and affective neuro-behavioral shifts when subjected to western diet (WD) exposure without weight gain, after the onset of obesity, and finally after weight loss induced by caloric restriction with (RYGB) or without (Sham) gastric bypass. Eating behavior, cognitive and affective abilities were assessed with a spatial discrimination task (holeboard test) and two-choice feed tests. Brain responses to oral sucrose were mapped using 18F-FDG positron emission tomography. WD exposure impaired working memory and led to an “addiction-type” neuronal pattern involving hippocampal and cortical brain areas. Obesity induced anxiety-like behavior, loss of motivation, and snacking-type eating behavior. Weight loss interventions normalized the motivational and affective states but not eating behavior patterns. Brain glucose metabolism increased in gustatory (insula) and executive control (aPFC) areas after weight loss, but RYGB showed higher responses in inhibition-related areas (dorsal striatum). These results showed that diet quality, weight loss, and the type of weight loss intervention differently impacted brain responses to sucrose in the Yucatan minipig model.
Experimental sleep disruption attenuates morphine analgesia: findings from a randomized trial and implications for the opioid abuse epidemic
Authors: Smith Michael T. , Mun Chung Jung , Remeniuk Bethany , Finan Patrick H. , Campbell Claudia M. , Buenaver Luis F. , Robinson Mercedes , Fulton Brook , Tompkins David Andrew , Tremblay Jean-Michel , Strain Eric C. , Irwin Michael R.
Published: November 2020

Preclinical studies demonstrate that sleep disruption diminishes morphine analgesia and modulates reward processing. We sought to translate these preclinical findings to humans by examining whether sleep disruption alters morphine’s analgesic and hedonic properties. We randomized 100 healthy adults to receive morphine versus placebo after two nights of undisturbed sleep (US) and two nights of forced awakening (FA) sleep disruption. Sleep conditions were counterbalanced, separated by a two-week washout. The morning after both sleep conditions, we tested cold pressor pain tolerance before and 40-min after double-blind injection of .08 mg/kg morphine or placebo. The primary outcome was the analgesia index, calculated as the change in cold pressor hand withdrawal latency (HWL) before and after drug injection. Secondary outcomes were ratings of feeling “high,” drug “liking,” and negative drug effects. We found a significant sleep condition by drug interaction on the analgesia index (95% CI − 0.57, − 0.001). After US, subjects receiving morphine demonstrated significantly longer HWL compared to placebo (95% CI 0.23, 0.65), but not after FA (95% CI − 0.05, 0.38). Morphine analgesia was diminished threefold under FA, relative to US. After FA, females (95% CI − 0.88, − 0.05), but not males (95% CI − 0.23, 0.72), reported decreased subjective “high” effects compared to US. After FA, females (95% CI 0.05, 0.27), but not males (95% CI − 0.10, 0.11), administered morphine reported increased negative drug effects compared to US. These data demonstrate that sleep disruption attenuates morphine analgesia in humans and suggest that sleep disturbed males may be at greatest risk for problematic opioid use.
Aerosol-induced atmospheric heating rate decreases over South and East Asia as a result of changing content and composition
Authors: Ramachandran S. , Rupakheti Maheswar , Lawrence Mark G.
Published: November 2020

Aerosol emissions from human activities are extensive and changing rapidly over Asia. Model simulations and satellite observations indicate a dipole pattern in aerosol emissions and loading between South Asia and East Asia, two of the most heavily polluted regions of the world. We examine the previously unexplored diverging trends in the existing dipole pattern of aerosols between East and South Asia using the high quality, two-decade long ground-based time series of observations of aerosol properties from the Aerosol Robotic Network (AERONET), from satellites (Moderate Resolution Imaging Spectroradiometer (MODIS) and Ozone Monitoring Instrument (OMI)), and from model simulations (Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2). The data cover the period since 2001 for Kanpur (South Asia) and Beijing (East Asia), two locations taken as being broadly representative of the respective regions. Since 2010 a dipole in aerosol optical depth (AOD) is maintained, but the trend is reversed—the decrease in AOD over Beijing (East Asia) is rapid since 2010, being 17% less in current decade compared to first decade of twenty-first century, while the AOD over South Asia increased by 12% during the same period. Furthermore, we find that the aerosol composition is also changing over time. The single scattering albedo (SSA), a measure of aerosol’s absorption capacity and related to aerosol composition, is slightly higher over Beijing than Kanpur, and has increased from 0.91 in 2002 to 0.93 in 2017 over Beijing and from 0.89 to 0.92 during the same period over Kanpur, confirming that aerosols in this region have on an average become more scattering in nature. These changes have led to a notable decrease in aerosol-induced atmospheric heating rate (HR) over both regions between the two decades, decreasing considerably more over East Asia (− 31%) than over South Asia (− 9%). The annual mean HR is lower now, it is still large (≥ 0.6 K per day), which has significant climate implications. The seasonal trends in AOD, SSA and HR are more pronounced than their respective annual trends over both regions. The seasonal trends are caused mainly by the increase/decrease in anthropogenic aerosol emissions (sulfate, black carbon and organic carbon) while the natural aerosols (dust and sea salt) did not change significantly over South and East Asia during the last two decades. The MERRA-2 model is able to simulate the observed trends in AODs well but not the magnitude, while it also did not simulate the SSA values or trends well. These robust findings based on observations of key aerosol parameters and previously unrecognized diverging trends over South and East Asia need to be accounted for in current state-of-the-art climate models to ensure accurate quantification of the complex and evolving impact of aerosols on the regional climate over Asia.
Complexities of a protonatable substrate in measurements of Hoechst 33342 transport by multidrug transporter LmrP
Authors: Swain Brendan M. , Guo Dawei , Singh Himansha , Rawlins Philip B. , McAlister Mark , van Veen Hendrik W.
Published: November 2020

Multidrug transporters can confer drug resistance on cells by extruding structurally unrelated compounds from the cellular interior. In transport assays, Hoechst 33342 (referred to as Hoechst) is a commonly used substrate, the fluorescence of which changes in the transport process. With three basic nitrogen atoms that can be protonated, Hoechst can exist as cationic and neutral species that have different fluorescence emissions and different abilities to diffuse across cell envelopes and interact with lipids and intracellular nucleic acids. Due to this complexity, the mechanism of Hoechst transport by multidrug transporters is poorly characterised. We investigated Hoechst transport by the bacterial major facilitator superfamily multidrug-proton antiporter LmrP in Lactococcus lactis and developed a novel assay for the direct quantitation of cell-associated Hoechst. We observe that changes in Hoechst fluorescence in cells do not always correlate with changes in the amount of Hoechst. Our data indicate that chemical proton gradient-dependent efflux by LmrP in cells converts populations of highly fluorescent, membrane-intercalated Hoechst in the alkaline interior into populations of less fluorescent, cell surface-bound Hoechst in the acidic exterior. Our methods and findings are directly relevant for the transport of many amphiphilic antibiotics, antineoplastic agents and cytotoxic compounds that are differentially protonated within the physiological pH range.
Dynamic changes of timing precision in timed actions during a behavioural task in guinea pigs
Authors: Nishimura Masataka , Wang Chi , Shu Reika , Song Wen-Jie
Published: November 2020

Temporal precision is a determinant of performance in various motor activities. Although the accuracy and precision of timing in activities have been previously measured and quantified, temporal dynamics with flexible precision have not been considered. Here, we examined the temporal dynamics in timed motor activities (timed actions) using a guinea pig model in a behavioural task requiring an animal to control action timing to obtain a water reward. In well-trained animals, momentary variations in timing precision were extracted from the temporal distribution of the timed actions measured over daily 12-h sessions. The resampling of the observed time of action in each session demonstrated significant changes of timing precision within a session. Periods with higher timing precision appeared indiscriminately during the same session, and such periods lasted ~ 20 min on average. We conclude that the timing precision in trained actions is flexible and changes dynamically in guinea pigs. By elucidating the brain mechanisms involved in flexibility and dynamics with an animal model, future studies should establish more effective methods to actively enhance timing precision in our motor activities, such as sports.
Identification of the HECT E3 ligase UBR5 as a regulator of MYC degradation using a CRISPR/Cas9 screen
Authors: Schukur Lina , Zimmermann Tamara , Niewoehner Ole , Kerr Grainne , Gleim Scott , Bauer-Probst Beatrice , Knapp Britta , Galli Giorgio G. , Liang Xiaoyou , Mendiola Angelica , Reece-Hoyes John , Rapti Melivoia , Barbosa Ines , Reschke Markus , Radimerski Thomas , Thoma Claudio R.
Published: November 2020

MYC oncoprotein is a multifunctional transcription factor that regulates the expression of a large number of genes involved in cellular growth, proliferation and metabolism. Altered MYC protein level lead to cellular transformation and tumorigenesis. MYC is deregulated in > 50% of human cancers, rendering it an attractive drug target. However, direct inhibition of this class of proteins using conventional small molecules is challenging due to their intrinsically disordered state. To discover novel posttranslational regulators of MYC protein stability and turnover, we established a genetic screen in mammalian cells by combining a fluorescent protein-based MYC abundance sensor, CRISPR/Cas9-based gene knockouts and next-generation sequencing. Our screen identifies UBR5, an E3 ligase of the HECT-type family, as a novel regulator of MYC degradation. Even in the presence of the well-described and functional MYC ligase, FBXW7, UBR5 depletion leads to accumulation of MYC in cells. We demonstrate interaction of UBR5 with MYC and reduced K48-linked ubiquitination of MYC upon loss of UBR5 in cells. Interestingly, in cancer cell lines with amplified MYC expression, depletion of UBR5 resulted in reduced cell survival, as a consequence of MYC stabilization. Finally, we show that MYC and UBR5 are co-amplified in more than 40% of cancer cells and that MYC copy number amplification correlates with enhanced transcriptional output of UBR5. This suggests that UBR5 acts as a buffer in MYC amplified settings and protects these cells from apoptosis.
Unravelling colloid filter cake motions in membrane cleaning procedures
Authors: Lüken Arne , Linkhorst John , Fröhlingsdorf Robin , Lippert Laura , Rommel Dirk , De Laporte Laura , Wessling Matthias
Published: November 2020

The filtration performance of soft colloid suspensions suffers from the agglomeration of the colloids on the membrane surface as filter cakes.

Backflushing of fluid through the membrane and cross-flow flushing across the membrane are widely used methods to temporally remove the filter cake and restore the flux through the membrane. However, the phenomena occurring during the recovery of the filtration performance are not yet fully described. In this study, we filtrate poly(N-isopropylacrylamide) microgels and analyze the filter cake in terms of its composition and its dynamic mobility during removal using on-line laser scanning confocal microscopy. First, we observe uniform cake build-up that displays highly ordered and amorphous regions in the cake layer. Second, backflushing removes the cake in coherent pieces and their sizes depend on the previous cake build-up. And third, cross-flow flushing along the cake induces a pattern of longitudinal ridges on the cake surface, which depends on the cross-flow velocity and accelerates cake removal. These observations give insight into soft colloid filter cake arrangement and reveal the cake’s unique behaviour exposed to shear-stress.
Yoda1 and phosphatidylserine exposure in red cells from patients with sickle cell anaemia
Authors: Wadud R. , Hannemann A. , Rees D. C. , Brewin J. N. , Gibson J. S.
Published: November 2020

Phosphatidylserine (PS) exposure is increased in red cells from sickle cell anaemia (SCA) patients. Externalised PS is prothrombotic and attractive to phagocytes and activated endothelial cells and thus contributes to the anaemic and ischaemic complications of SCA. The mechanism of PS exposure remains uncertain but it can follow increased intracellular Ca2+ concentration ([Ca2+]i). Normally, [Ca2+]i is maintained at very low levels but in sickle cells, Ca2+ permeability is increased, especially following deoxygenation and sickling, mediated by a pathway sometimes called Psickle. The molecular identity of Psickle is also unclear but recent work has implicated the mechanosensitive channel, PIEZO1. We used Yoda1, an PIEZO1 agonist, to investigate its role in sickle cells. Yoda1 caused an increase in [Ca2+]i and PS exposure, which was inhibited by its antagonist Dooku1 and the PIEZO1 inhibitor GsMTx4, consistent with functional PIEZO1. However, PS exposure did not necessitate an increase in [Ca2+]i. Two PKC inhibitors were also tested, chelerytherine chloride and calphostin C. Both reduced PS exposure whilst chelerytherine chloride also reduced Yoda1-induced increases in [Ca2+]i. Findings are therefore consistent with the presence of PIEZO1 in sickle cells, able to mediate Ca2+ entry but that PKC was also involved in both Ca2+ entry and PS exposure.
Salivary microbiome composition changes after bariatric surgery
Authors: Džunková Mária , Lipták Róbert , Vlková Barbora , Gardlík Roman , Čierny Michal , Moya Andrés , Celec Peter
Published: November 2020

Recent studies show that the salivary microbiome in subjects with obesity differ from those without obesity, but the mechanism of interaction between the salivary microbiome composition and body weight is unclear. Herein we investigate this relation by analyzing saliva samples from 35 adult patients with obesity undergoing bariatric surgery. Our aim was to describe salivary microbiome changes during body weight loss on an individual-specific level, and to elucidate the effect of bariatric surgery on the salivary microbiome which has not been studied before. Analysis of samples collected before and 1 day after surgery, as well as 3 and 12 months after surgery, showed that the salivary microbiome changed in all study participants, but these changes were heterogeneous. In the majority of participants proportions of Gemella species, Granulicatella elegans, Porphyromonas pasteri, Prevotella nanceiensis and Streptococcus oralis decreased, while Veillonella species, Megasphaera micronuciformis and Prevotella saliva increased. Nevertheless, we found participants deviating from this general trend which suggests that a variety of individual-specific factors influence the salivary microbiome composition more effectively than the body weight dynamics alone. The observed microbiome alternations could be related to dietary changes. Therefore, further studies should focus on association with altered taste preferences and potential oral health consequences.
Mechanisms of ranolazine pretreatment in preventing ventricular tachyarrhythmias in diabetic db/db mice with acute regional ischemia–reperfusion injury
Authors: Chou Chung-Chuan , Lee Hui-Ling , Chang Gwo-Jyh , Wo Hung-Ta , Yen Tzung-Hai , Wen Ming-Shien , Chu Yen , Liu Hao-Tien , Chang Po-Cheng
Published: November 2020

Studies have demonstrated that diabetic (db/db) mice have increased susceptibility to myocardial ischemia–reperfusion (IR) injury and ventricular tachyarrhythmias (VA). We aimed to investigate the antiarrhythmic and molecular mechanisms of ranolazine in db/db mouse hearts with acute IR injury. Ranolazine was administered for 1 week before coronary artery ligation. Diabetic db/db and control db/+ mice were divided into ranolazine-given and -nongiven groups. IR model was created by 15-min left coronary artery ligation and 10-min reperfusion. In vivo electrophysiological studies showed that the severity of VA inducibility was higher in db/db mice than control (db/ +) mice. Ranolazine suppressed the VA inducibility and severity. Optical mapping studies in Langendorff-perfused hearts showed that ranolazine significantly shortened action potential duration, Cai transient duration, Cai decay time, ameliorated conduction inhomogeneity, and suppressed arrhythmogenic alternans induction. Western blotting studies showed that the expression of pThr17-phospholamban, calsequestrin 2 and voltage-gated sodium channel in the IR zone was significantly downregulated in db/db mice, which was ameliorated with ranolazine pretreatment and might play a role in the anti-arrhythmic actions of ranolazine in db/db mouse hearts with IR injury.
Precise nanoscale temperature mapping in operational microelectronic devices by use of a phase change material
Authors: Cheng Qilong , Rajauria Sukumar , Schreck Erhard , Smith Robert , Wang Na , Reiner Jim , Dai Qing , Bogy David
Published: November 2020

The microelectronics industry is pushing the fundamental limit on the physical size of individual elements to produce faster and more powerful integrated chips. These chips have nanoscale features that dissipate power resulting in nanoscale hotspots leading to device failures. To understand the reliability impact of the hotspots, the device needs to be tested under the actual operating conditions. Therefore, the development of high-resolution thermometry techniques is required to understand the heat dissipation processes during the device operation. Recently, several thermometry techniques have been proposed, such as radiation thermometry, thermocouple based contact thermometry, scanning thermal microscopy, scanning transmission electron microscopy and transition based threshold thermometers. However, most of these techniques have limitations including the need for extensive calibration, perturbation of the actual device temperature, low throughput, and the use of ultra-high vacuum. Here, we present a facile technique, which uses a thin film contact thermometer based on the phase change material $$Ge_2 Sb_2 Te_5$$

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, to precisely map thermal contours from the nanoscale to the microscale. $$Ge_2 Sb_2 Te_5$$

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undergoes a crystalline transition at $$\hbox {T}_{{g}}$$

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with large changes in its electric conductivity, optical reflectivity and density. Using this approach, we map the surface temperature of a nanowire and an embedded micro-heater on the same chip where the scales of the temperature contours differ by three orders of magnitude. The spatial resolution can be as high as 20 nanometers thanks to the continuous nature of the thin film.
Interaction of neuropsychiatric symptoms with APOE ε4 and conversion to dementia in MCI patients in a Memory Clinic
Authors: Valero Sergi , Marquié Marta , De Rojas Itziar , Espinosa Ana , Moreno-Grau Sonia , Orellana Adelina , Montrreal Laura , Hernández Isabel , Mauleón Ana , Rosende-Roca Maitée , Alegret Montse , Pérez-Cordón Alba , Ortega Gemma , Roberto Natalia , Sanabria Angela , Abdelnour Carla , Gil Silvia , Tartari Juan Pablo , Vargas Liliana , Esteban-De Antonio Ester , Benaque Alba , Tárraga Lluís , Boada Mercè , Ruíz Agustín
Published: November 2020

To date, very few studies have been focused on the impact of the convergence of neuropsychiatric symptoms (NPS) and APOE ε4 on the conversion to dementia in patients with Mild Cognitive Impairment patients (MCI), and none has been based in a clinical setting. The objective of the study is to determine the predictive value of additive and multiplicative interactions of NPS and APOE ε4 status on the prediction of incident dementia among MCI patients monitored in a Memory Clinic. 1512 patients (aged 60 and older) with prevalent MCI were followed for a mean of 2 years. Neuropsychiatric symptoms were assessed at baseline using the Neuropsychiatric Inventory Questionnaire. Cox proportional hazards models were calculated. Additive interactions for depression, apathy, anxiety, agitation, appetite, or irritability and a positive ε4 carrier status were obtained, significantly increasing the hazard ratios of incident dementia (HR range 1.3–2.03). Synergistic interactions between NPS and APOE ε4 are identified among MCI patients when predicting incident dementia. The combination of the behavioral status and the genetic trait could be considered a useful strategy to identify the most vulnerable MCI patients to dementia conversion in a Memory Clinic.
An increase of CD8+ T cell infiltration following recurrence is a good prognosticator in HNSCC
Authors: So Yoon Kyoung , Byeon Sun-Ju , Ku Bo Mi , Ko Young Hyeh , Ahn Myung-Ju , Son Young-Ik , Chung Man Ki
Published: November 2020

Programmed death-ligand 1 (PD-L1) expression and CD8-positive tumor-infiltrating lymphocyte (CD8+ TIL) infiltration are essential biomarkers for immune checkpoint inhibitor therapy. The objective of this study was to compare the expression of those biomarkers between initial and recurrent HNSCCs using paired analysis. Prognostic significance of those immunological changes was also investigated. Forty-two consecutive patients with locally recurrent HNSCCs were included. Immunohistochemical staining of CD8 and PD-L1 was done for both initial and recurrent tumor specimens. The IHC findings were verified with mRNA expression profiling. Also, the prognostic impact was analyzed based on overall survival (OS). Recurrent-to-initial (R/I) ratios of CD8+ TILs and PD-L1 were widely variable. CD8+ TIL density and PD-L1 expression decreased in 59.5% and 69% of patients, respectively (R/I ratio < 1). The R/I ratio of CD8A mRNA was significantly higher in patients with a CD8 R/I ratio > 1 (1.7 ± 1.5 vs. 0.6 ± 0.6, p = 0.042). CD8 R/I ratio (> 1) was a good prognosticator for OS (HR 0.293, 95% CI 0.091–0.945, p = 0.040). CD8+ TIL infiltration and PD-L1 expression changed variably following local recurrence of HNSCC. The increase of CD8+ TILs at recurrence was an excellent independent prognosticator.
Reliable and mobile all-fiber modular optical tweezers
Authors: Ti Chaoyang , Shen Yao , Ho Thanh Minh-Tri , Wen Qi , Liu Yuxiang
Published: November 2020

Miniaturization and integration of optical tweezers are attractive. Optical fiber-based trapping systems allow optical traps to be realized in miniature systems, but the optical traps in these systems lack reliability or mobility. Here, we present the all-fiber modular optical tweezers (AFMOTs), in which an optical trap can be reliably created and freely moved on a sample substrate. Two inclined optical fibers are permanently fixed to a common board, rendering a modular system where fiber alignments are maintained over months. The freely movable optical trap allows particles to be trapped in their native locations. As a demonstration, we applied AFMOTs to trap and deform freely floating individual cells. By the cell mechanical responses, we differentiated the nontumorigenic breast epithelial cell line (MCF10A) from its cancerous PTEN mutants (MCF10 PTEN-/-). To further expand the functionalities, three modalities of AFMOTs are demonstrated by changing the types of fibers for both the optical trap creation and particle position detection. As a miniature and modular system that creates a reliable and mobile optical trap, AFMOTs can find potential applications ranging from point-of-care diagnostics to education, as well as helping transition the optical trapping technology from the research lab to the field.
Dietary zinc enrichment reduces the cadmium burden of mealworm beetle (Tenebrio molitor) larvae
Authors: Keil Claudia , Maares Maria , Kröncke Nina , Benning Rainer , Haase Hajo
Published: November 2020

The industrial production of Tenebrio molitor L. requires optimized rearing and processing conditions to generate insect biomass with high nutritional value in large quantities. One of the problems arising from processing is a tremendous loss in mineral accessibility, affecting, amongst others, the essential trace element Zn. As a feasible strategy this study investigates Zn-enrichment of mealworms during rearing to meet the nutritional requirements for humans and animals. Following feeding ZnSO4-spiked wheat bran substrates late instar mealworm larvae were evaluated for essential micronutrients and human/animal toxic elements. In addition, growth rate and viability were assessed to select optimal conditions for future mass-rearing. Zn-feeding dose-dependently raised the total Zn content, yet the Znlarvae/Znwheat bran ratio decreased inversely related to its concentration, indicating an active Zn homeostasis within the mealworms. The Cu status remained stable, suggesting that, in contrast to mammals, the intestinal Cu absorption in mealworm larvae is not affected by Zn. Zn biofortification led to a moderate Fe and Mn reduction in mealworms, a problem that certainly can be overcome by Fe/Mn co-supplementation during rearing. Most importantly, Zn feeding massively reduced the levels of the human/animal toxicant Cd within the mealworm larvae, a technological novelty of outstanding importance to be implemented in the future production process to ensure the consumer safety of this edible insect species.
Morphological and cytokine profiles as key parameters to distinguish between Gram-negative and Gram-positive bacterial keratitis
Authors: Konstantopoulos Aris , Cendra Maria del Mar , Tsatsos Michael , Elabiary Mariam , Christodoulides Myron , Hossain Parwez
Published: November 2020

Bacterial keratitis (BK) is an ocular disorder associated with poor visual prognosis. Quantification of the associated inflammatory response may provide insight into the pathogenesis of BK and guide treatment options. In this exploratory study, we evaluated 45 BK patients and 20 healthy controls by optical coherence tomography and pro-inflammatory tear cytokine analysis. The aim was to quantify the differential morphological and cytokine inflammatory response between Gram-negative and Gram-positive BK and to determine the diagnostic value of corneal thickness (CT) and infiltrate thickness (IT) in distinguishing Gram−ve BK in a clinical cohort. Greater CT and IT, at clinical presentation, were indicative of Gram−ve infection with values detected of ≥ 950 μm and ≥ 450 μm, respectively. Combination of these CT and IT values had a 100% sensitivity and 83.3% specificity as a diagnostic indicator of Gram−ve infection. Similarly, there were higher levels of IL-1β, IL-6 and IL-8 cytokines were quantified in keratitis caused by Gram-negative bacteria. Among the different tear cytokines analysed, a significant reduction after three days of treatment was detected for pro-inflammatory cytokines IL-1β, IL-2, IL-6, IL-8 and TNF-α, prior to starting with the administration of steroid drops. Overall, this study shows the potential value of serial OCT and tear cytokine measurements in the management of BK.
Blood-derived extracellular vesicles isolated from healthy donors exposed to air pollution modulate in vitro endothelial cells behavior
Authors: Rota Federica , Ferrari Luca , Hoxha Mirjam , Favero Chiara , Antonioli Rita , Pergoli Laura , Greco Maria Francesca , Mariani Jacopo , Lazzari Lorenza , Bollati Valentina
Published: November 2020

The release of Extracellular Vesicles (EVs) into the bloodstream is positively associated with Particulate Matter (PM) exposure, which is involved in endothelial dysfunction and related to increased risk of cardiovascular disease. Obesity modifies the effects of PM exposure on heart rate variability and markers of inflammation, oxidative stress, and acute phase response. We isolated and characterized plasmatic EVs from six healthy donors and confirmed a positive association with PM exposure. We stratified for Body Mass Index (BMI) and observed an increased release of CD61+ (platelets) and CD105+ (endothelium) derived-EVs after high PM level exposure in Normal Weight subjects (NW) and no significant variations in Overweight subjects (OW). We then investigated the ability to activate endothelial primary cells by plasmatic EVs after both high and low PM exposure. NW-high-PM EVs showed an increased endothelial activation, measured as CD105+/CD62e+ (activated endothelium) EVs ratio. On the contrary, cells treated with OW-high-PM EVs showed reduced endothelial activation. These results suggest the ability of NW plasmatic EVs to communicate to endothelial cells and promote the crosstalk between activated endothelium and peripheral cells. However, this capacity was lost in OW subjects. Our findings contribute to elucidate the role of EVs in endothelial activation after PM exposure.