bluuebunny/crossref_metadata_2025 huggingface dataset:
European consensus on essential steps of Minimally Invasive Ivor Lewis and McKeown Esophagectomy through Delphi methodology
Authors: Eddahchouri Yassin , van Workum Frans , van den Wildenberg Frits J. H. , van Berge Henegouwen Mark I. , Polat Fatih , van Goor Harry ,   MIE Delphi Collaboration, Chaudry M. Asif , Cheong E. , Daams F. , van Det M. J. , Gutschow C. , Heisterkamp J. , Van Hillegersberg R. , Hölscher A. , Kouwenhoven E. A. , Luyer M. D. P. , Martijnse I. S. , Nafteux P. , Nieuwenhuijzen G. A. P. , Nilsson M. , Pattyn P. , van der Peet D. L. , Räsänen J. V. , Ruurda J. P. , Schneider P. , Schröder W. , van Veer H. , Wijnhoven B. P. L. , Pierie Jean-Pierre E. N. , Klarenbeek Bastiaan R. , Gisbertz Suzanne S. , Rosman Camiel
Published: February 2021

Background

Minimally invasive esophagectomy (MIE) is a complex and technically demanding procedure with a long learning curve, which is associated with increased morbidity and mortality. To master MIE, training in essential steps is crucial. Yet, no consensus on essential steps of MIE is available. The aim of this study was to achieve expert consensus on essential steps in Ivor Lewis and McKeown MIE through Delphi methodology.

Methods

Based on expert opinion and peer-reviewed literature, essential steps were defined for Ivor Lewis (IL) and McKeown (McK) MIE. In a round table discussion, experts finalized the lists of steps and an online Delphi questionnaire was sent to an international expert panel (7 European countries) of minimally invasive upper GI surgeons. Based on replies and comments, steps were adjusted and rephrased and sent in iterative fashion until consensus was achieved.

Results

Two Delphi rounds were conducted and response rates were 74% (23 out of 31 experts) for the first and 81% (27 out of 33 experts) for the second round. Consensus was achieved on 106 essential steps for both the IL and McK approach. Cronbach’s alpha in the first round was 0.78 (IL) and 0.78 (McK) and in the second round 0.92 (IL) and 0.88 (McK).

Conclusions

Consensus among European experts was achieved on essential surgical steps for both Ivor Lewis and McKeown minimally invasive esophagectomy.
The relationship of global sagittal malalignment to fatty infiltration in the aging spine
Authors: Elysee Jonathan Charles , Lovecchio Francis , Lafage Renaud , Ang Bryan , Huang Alex , Bannwarth Mathieu , Kim Han Jo , Schwab Frank , Lafage Virginie
Published: February 2021

Purpose

To investigate associations between muscle size, fat infiltration (FI), and global sagittal alignment in patients with adult spinal deformity (ASD).

Methods

Retrospective cohort study was conducted on a single-institution database of ASD patients with preoperative radiographs and CTs. Following multiplanar reconstructions of CTs, images in the plane of each vertebra were generated. The posterior vertebral musculature (PVM) was contoured on axial images at three vertebral levels (T2, T10, L3). FI was calculated by comparing Hounsfield units within muscles to the normative values of fat. Correlation analyses were conducted between demographics, alignment, and muscle characteristics.

Results

107 patients underwent preoperative spine CT (58yo, 79%F, BMI 27 kg/m2). Muscle data were available for 49 pts at T2, 39 pts at T10, and 81 pts at L3. Mean FI was T2 = 33% ± 18, T10 = 28% ± 19, L3_Erector = 39% ± 19, and L3_Psoas = 19% ± 9. FI correlated across levels (T2 vs. T10 r = 0.698; T10 vs L3_Erector r = 0.506; L3_Erector vs Psoas r = 0.419) and with demographics; older pts had greater fat percentages (r = 0.31–0.45) and BMIs (r = 0.24–0.51). Increased FI at T2, T10, and L3 was associated with increased pelvic retroversion (PT: r = 0.25–0.43), global deformity (TPA: r = 0.27–0.45), and anterior malalignment (SVA: r = 0.23–0.41). The degree of FI in the PVM increased with the severity of SRS-Schwab PT and SVA modifiers.

Conclusion

In ASD patients, global sagittal malalignment is related to FI of the PVM throughout the lumbar and thoracic spine, as identified through CT. Future research should investigate how FI relates to ASD pathogenesis.
Combined inhibition of PD-1/PD-L1, Lag-3, and Tim-3 axes augments antitumor immunity in gastric cancer–T cell coculture models
Authors: Mimura Kosaku , Kua Ley-Fang , Xiao Jin-Fen , Asuncion Bernadette Reyna , Nakayama Yuko , Syn Nicholas , Fazreen Zul , Soong Richie , Kono Koji , Yong Wei-Peng
Published: February 2021

Background

Immunotherapy targeting PD-1 provides a limited survival benefit in patients with unresectable advanced or recurrent gastric cancer (GC). Beside PD-L1, the expression of inhibitory ligands such as CEACAM-1 and LSECtin on GC cells account for this limitation. Here we assessed their expression and immune suppressive effect in GC patients.

Methods

Using multiplexed immunohistochemistry staining, we evaluated the distribution of different inhibitory ligands, including PD-L1, CEACAM-1, LSECtin, and MHC class II, in 365 GC patients. We analyzed their correlations and overall survival (OS) based on the expression of each inhibitory ligand and the independent prognostic factors that affect OS. Subsequently, we evaluated the additive effect of anti-PD-1 mAb or anti-PD-L1 mAb with/without anti-Lag-3 mAb with/without anti-Tim-3 mAb in cytotoxic assay using tumor-antigen specific CTL clones against GC cell lines.

Results

Co-expression of the inhibitory ligands for PD-1, Tim-3, and Lag-3 was observed in the largest proportion (34.7%). CEACAM-1, LSECtin, and MHC class II expression showed significant correlation with PD-L1 expression and OS. Multivariable analysis demonstrated that CEACAM-1 low is an independent prognostic factor. Furthermore, combining dual and triple ICIs yielded additive effect on cytotoxicity of CTL clones against each immune inhibitory ligand positive GC cell lines.

Conclusions

Our findings suggested that the expression of inhibitory ligands for Tim-3 and Lag-3 on GC cells serve as potential biomarkers to predict the response to anti-PD-1 therapy and the combinatorial immunotherapy with ICIs targeting for PD-1, Tim-3, and Lag-3 has a therapeutic potential for GC patients.
Stagnierender Mehrjähriger Finanzrahmen trotz zunehmender Herausforderungen
Authors: Schratzenstaller Margit
Published: February 2021

Schlussbemerkung

Der europäische Aufbauplan, der gleichzeitig einen Impuls zur Bekämpfung der pandemiebedingten wirtschaftlichen Krise setzen und zur Bewältigung bedeutender Zukunftsaufgaben, vor allem des digitalen Wandels sowie des Klimawandels, beitragen soll, ist aus mehreren Gründen bemerkenswert (Schratzenstaller, 2020). Mit nicht rückzahlbaren Finanzhilfen von 390 Mrd. Euro weist NGEU eine beachtliche Transferkomponente auf. NGEU wird durch die gemeinsame Aufnahme von Schulden durch die Mitgliedsländer finanziert. Die für die Transfers aufgenommenen Schulden sollen mit Hilfe innovativer Eigenmittelquellen zwischen 2028 und 2058 zurückgezahlt werden. Es darf jedoch nicht übersehen werden, dass den strukturellen Defiziten der Ausgaben im Rahmen des MFR sowie im Eigenmittelsystem der EU nur mit sehr zaghaften Reformschritten begegnet worden ist. Umso wichtiger ist es, die laufende MFR-Periode für die Ausarbeitung substanzieller Reformvorschläge für den MFR nach 2027 sowie die Herstellung eines entsprechenden Konsenses für deren Implementierung unter den Mitgliedsländern zu nutzen.
Debatte über die Doppik: Replik und Erwiderung
Authors: Stüber Stephan , Christofzik Désirée I. , Dorn Florian , Gäbler Stefanie , Raffer Christian , Rösel Felix
Published: February 2021

In der Septemberausgabe 2020 veröffentlichte der Wirtschaftsdienst einen Aufsatz mit dem Titel „Bremst die Doppik öffentliche Investitionen? Ergebnisse aus drei aktuellen Evaluationsstudien“ von Désirée Christofzik, Florian Dorn, Stefanie Gäbler, Christian Raffer und Felix Rösel. Stephan Stüber vertritt in einer Replik eine andere Auffassung, im Anschluss erläutern Christofzik et al. ihren Standpunkt in einer Erwiderung.
Dyadic Emotion Regulation in Women with Borderline Personality Disorder
Authors: Miano Annemarie , Barnow Sven , Wagner Stina , Roepke Stefan , Dziobek Isabel
Published: February 2021

Background

Emotion regulation (ER) and interpersonal dysfunction constitute key features of borderline personality disorder (BPD). Here, we tested if females with BPD show impairments in dyadic ER, that is in their support seeking and creation of closeness. We investigated if women with BPD might over-rely on their male partner by excessive support seeking and establishing of closeness, during conversations with personally and relationship-threatening topics.

Methods

Thirty couples in which the women were diagnosed with BPD and 34 healthy control (HC) couples were videotaped while discussing neutral, personally threatening, and relationship-threatening topics. Support seeking was rated by three independent raters, using a naïve observer method. The creation of closeness was rated using a continuous video-rating. Perceived emotions were assessed using self-report after each conversation.

Results

Women with BPD engaged in more support seeking than HC women, especially in more negative behaviors to elicit support, they created less closeness to their partner than HCs and reported a greater decline of positive emotions in both threatening conditions. Women with BPD displayed more fluctuations than controls between creating closeness and distance in the personally-threatening situation. They reported a larger increase in negative emotions after the relationship threatening conversation compared to female HC.

Conclusions

The present study indicates an increased demand of dyadic ER in BPD. Increased negative support seeking and less creation of closeness to the partner might reflect ineffective strategies to actually receive support from the partner.
Towards Autonomous Robotic Assembly: Using Combined Visual and Tactile Sensing for Adaptive Task Execution
Authors: Nottensteiner Korbinian , Sachtler Arne , Albu-Schäffer Alin
Published: February 2021

Robotic assembly tasks are typically implemented in static settings in which parts are kept at fixed locations by making use of part holders. Very few works deal with the problem of moving parts in industrial assembly applications. However, having autonomous robots that are able to execute assembly tasks in dynamic environments could lead to more flexible facilities with reduced implementation efforts for individual products. In this paper, we present a general approach towards autonomous robotic assembly that combines visual and intrinsic tactile sensing to continuously track parts within a single Bayesian framework. Based on this, it is possible to implement object-centric assembly skills that are guided by the estimated poses of the parts, including cases where occlusions block the vision system. In particular, we investigate the application of this approach for peg-in-hole assembly. A tilt-and-align strategy is implemented using a Cartesian impedance controller, and combined with an adaptive path executor. Experimental results with multiple part combinations are provided and analyzed in detail.
Association Mapping of Thousand Grain Weight using SSR and SNP Markers in Rice (Oryza sativa L.) Across Six Environments
Authors: Chen Xiangong , Dang Xiaojing , Wang Ya , Yang Yufeng , Yang Guohong , Sun Jianjun , Yin Haiqing , Liu Erbao , Hong Delin
Published: February 2021

Thousand grain weight (TGW) is an important determinant of rice yield, and correlates with grain size, plumpness and grain number per panicle. In rice, there are fewer association mapping studies relating grain weight traits using both SSR and SNP markers. In this study, in order to find robust SSR markers associated with TGW trait and mine elite accessions in rice, we investigated the TGW trait across six environments using a natural population consisted of 462 accessions, and then performed association mapping using both SSR and SNP markers. Using the six datasets from the six environments and their best linear unbiased estimator, we identified eight TGW associated SSR markers, with three environmentally stable and one newly found, on five chromosomes. The associated markers have genetic effect from 3.44% to 20.84%, and two of them carry stable elite allele with positive effect across different environments. Candidate interval association mapping using re-sequencing derived SNP/InDel markers further confirms the TGW-SSR association, and also suggests that 3 TGW-SSR associations were high confident in intervals of size from 176 to 603 kb. These results not only shed more lights on the genetics of TGW trait, but also suggest that the multi-allelic SSR markers should be used as an alternative power tool in gene or QTL mapping.
Potential application of gold nanoparticles in food packaging: a mini review
Authors: Paidari Saeed , Ibrahim Salam Adnan
Published: February 2021

In the past few decades, there have been remarkable advances in our knowledge of gold nanoparticles (AuNPs) and synthesizing methods. AuNPs have become increasingly important in biomedical and industrial applications. As a newly implemented method, AuNPs are being used in nanopackaging industries for their therapeutic and antibacterial characteristics as well as their inert and nontoxic nature. As with other NPs, AuNPs have privileges and disadvantages when utilized in the food sector, yet a significant body of research has shown that, due to the specific nontoxic characteristics, AuNPs could be used to address other NP flaws. In this mini review, we present synthesizing methods, food industry applications, and mechanisms of action of gold nanoparticles. Regarding the investigations, gold nanoparticles can play a major role to reduce microbial load in foodstuff and therefore can be implemented in food packaging as an effective approach.
The Efficacy of Interdisciplinary Near-Peer Teaching Within Neuroanatomical Education—Preliminary Observations
Authors: Taylor Charles F. C. , Kurn Octavia R. , Glautier Steven P. , Anbu Deepika , Dean Oliver , Nagy Eva , Geoghan Kate R. , Harrison Charlie H. , Payne December R. , Hall Sam , Border Scott
Published: February 2021

Near-Peer Teaching (NPT) is increasingly becoming an integral part of the medical curriculum. When considered alongside the increasing popularity of interdisciplinary education, it seems appropriate to explore NPT within an interdisciplinary context. In these observations, 3rd-year medical students taught 2nd-year psychology students neuroanatomy. The session was evaluated using three objective and subjective assays. A knowledge assessment test showed significant improvement after teaching, and there were significant improvements on self-perceived knowledge/attitudes towards neuroanatomy, as well as positive feedback on the use of NPT. These observations evidence the successful use of Interdisciplinary Near-Peer Teaching (INPT) within a neuroanatomical curriculum.
Back to the past: the historical roots of labor-saving automation
Authors: Staccioli Jacopo , Virgillito Maria Enrica
Published: February 2021

This paper, relying on a still relatively unexplored long-term dataset on U.S. patenting activity, provides empirical evidence on the history of labor-saving innovations back to early nineteenth century. The identification of mechanization/automation heuristics, retrieved via textual content analysis on current robotic technologies by Montobbio et al. (Robots and the origin of their labour-saving impact, LEM Working Paper Series 2020/03), allows to focus on a limited set of CPC codes where mechanization and automation technologies are more prevalent. We track their time evolution, clustering, eventual emergence of wavy behavior, and their comovements with long-term GDP growth. Our results challenge both the general-purpose technology approach and the strict 50-year Kondratiev cycle, while they provide evidence of the emergence of erratic constellations of heterogeneous technological artefacts, in line with the development-block approach enabled by autocatalytic systems.
Development of an Imaging Evaluation System for Low Back Pain
Authors: Sun Ping-En , Yang Bing-Shiang
Published: February 2021

Purpose

To design a low back pain (LBP) imaging evaluation system for non-professional operators, quantifying risk of LBP in patients and asymptomatic individuals.

Methods

Twenty-one previously asymptomatic subjects and five LBP patients diagnosed by a physician performed a series of test movements under a fixed camera, including hip abduction test, forward bending test, side bending test, double legs lowering test (DLLT), and modified Thomas test. The video clips were analyzed by a system program interface and were classified into a score from 1 to 4. The average total scores of the two groups were compared. Five intact subjects were retested to verify reliability. Twelve intact subjects and three patients’ clips were viewed by an experienced therapist to verify system validity.

Results

The average total scores of two groups were significantly different (p = 0.0004). The results of hip abduction test, forward bending test, side bending test and DLLT showed significant differences between the two groups. The total score of two trials in the retest experiment exhibited a similar result (p = 0.058), with good linear correlation (r = 0.98). The total scores of the evaluations by the experienced therapist and the system program interface agreed with each other (p = 0.141; linear correlation r = 0.90).

Conclusion

The evaluation system showed potential utility in screening LBP risk, with acceptable test–retest reliability and expert validity.
A Simultaneous Observation of Lightning by ASIM, Colombia‐Lightning Mapping Array, GLM, and ISS‐LIS
Authors: Montanyà Joan , López Jesús A. , Morales Rodriguez Carlos A. , van der Velde Oscar A. , Fabró Ferran , Pineda Nicolau , Navarro‐González Javier , Reglero Víctor , Neubert Torsten , Chanrion Olivier , Goodman Steven J. , Østgaard Nikolai , Ladino‐Rincon Alfonso , Romero David , Solà Glòria , Horta Ricard , Freijó Modesto
Published: February 2021

The Atmosphere‐Space Interactions Monitor (ASIM) on the International Space Station (ISS) provides optical radiances and images of lightning flashes in several spectral bands. This work presents a lightning flash simultaneously observed from space by ASIM, the Geostationary Lightning Mapper (GLM) and the Lightning Imaging Sensor on the International Space Station (ISS‐LIS); and from ground by the Colombia‐Lightning Mapping Array (Colombia‐LMA). Volumetric weather radar provides reflectivity data to help to interpret the effects of the cloud particles on the observed optical features. We found that surges in radiance in the band at 777.4 nm appear to be related mostly with lightning processes involving currents as well with branching of lightning leaders with new leader development. In cloud areas with reflectivity <18 dBZ above the lightning leader channels at altitudes >7 km, these have been imaged by ASIM and GLM. But in the region with reflectivity <23 dBZ above the lightning leader channels, despite its lower cloud tops and similar altitudes of lightning channels, these have been almost undetectable. The calculated relative optical depths are consistent with the observed optical intensity at the cloud top. Despite the effects of the cloud particles and the altitude of the lightning channels on the attenuation of the luminosity, the luminosity of the lightning channels due to different processes is fundamental for the imaging of lightning from space.
Concurrent Measurements of Soil and Ecosystem Respiration in a Mature Eucalypt Woodland: Advantages, Lessons, and Questions
Authors: Renchon A. A. , Drake J. E. , Macdonald C. A. , Sihi D. , Hinko‐Najera N. , Tjoelker M. G. , Arndt S. K. , Noh N. J. , Davidson E. , Pendall E.
Published: February 2021

Understanding seasonal and diurnal dynamics of ecosystem respiration (Reco) in forests is challenging, because Reco can only be measured directly during night‐time by eddy‐covariance flux towers. Reco is the sum of soil respiration (Rsoil) and above‐ground respiration (in theory, RAG = Reco − Rsoil). Rsoil can be measured day and night and can provide a check of consistency on Reco, as the difference in magnitude and time dynamic between Reco and Rsoil should be explained by RAG. We assessed the temporal patterns and climatic drivers of Rsoil and Reco in a mature eucalypt woodland, using continuous measurements (only at night for Reco) at half‐hourly resolution over 4 years (2014–2017). Our data showed large seasonal and diurnal (overnight) variation of Reco, while Rsoil had a low diurnal amplitude and their difference (Reco − Rsoil, or RAG) had a low seasonal amplitude. This result implies at first glance that seasonal variation of Reco was mainly influenced by Rsoil while its diurnal variation was mainly influenced by RAG. However, our analysis suggests that the night‐time Reco decline cannot realistically be explained by a decline of RAG. Chamber measurements of autotrophic components at half‐hourly time resolution are needed to quantify how much of the Reco decline overnight is due to declines in leaf or stem respiration, and how much is due to missing storage or advection, which may create a systematic bias in Reco measurements. Our findings emphasize the need for reconciling bottom‐up (via components measured with chambers) and direct estimates of Reco (via eddy‐covariance method).
Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing
Authors: Yan Huifang , Ji Haoran , Kubisiak Thomas , Wu Ye , Xiao Jiangxi , Gu Qiang , Yang Yanling , Xie Han , Ji Taoyun , Gao Kai , Li Dongxiao , Xiong Hui , Shi Zhen , Li Ming , Zhang Yuehua , Duan Ruoyu , Bao Xinhua , Jiang Yuwu , Burmeister Margit , Wang Jingmin
Published: February 2021

Hypomyelinating leukodystrophies (HLDs) are a rare group of disorders characterized by myelin deficit of the brain-based on MRI. Here, we studied 20 patients with unexplained HLD to uncover their genetic etiology through whole-exome sequencing (WES). Trio-based WES was performed for 20 unresolved HLDs families after genetic tests for the PLP1 duplication and a panel of 115 known leukodystrophy-related genes. Variants in both known genes that related to HLDs and promising candidate genes were analyzed. Minigene splicing assay was conducted to confirm the effect of splice region variant. All 20 patients were diagnosed with HLDs clinically based on myelin deficit on MRI and impaired motor ability. Through WES, in 11 of 20 trios, 15 causative variants were detected in seven genes TUBB4A, POLR1C, POLR3A, SOX10, TMEM106B, DEGS1, and TMEM63A. The last three genes have just been discovered. Of 15 variants, six were novel. Using minigene splicing assay, splice variant POLR3A c.1770 + 5 G > C was proved to disrupt the normal splicing of intron 13 and led to a premature stop codon at position 618 (p.(P591Vfs*28)). Our analysis determined the molecular diagnosis of 11 HLDs patients. It emphasizes the heterogenicity of HLDs, the diagnostic power of trio-based WES for HLDs. Comprehensive analysis including a focus on candidate genes helps to discover novel disease-causing genes, determine the diagnosis for the first time, and improve the yield of WES. Moreover, novel mutations identified in TUBB4A, POLR3A, and POLR1C expand the mutation spectrum of these genes.
Analysis of transient membrane protein interactions by single-molecule diffusional mobility shift assay
Authors: Jeong Min Gyu , Zhou Kai , Park Soyeon , An HyeongJeon , Kwon Yonghoon , Chang Yeonho , Kim Do-Hyeon , Ryu Sung Ho
Published: February 2021

Various repertoires of membrane protein interactions determine cellular responses to diverse environments around cells dynamically in space and time. Current assays, however, have limitations in unraveling these interactions in the physiological states in a living cell due to the lack of capability to probe the transient nature of these interactions on the crowded membrane. Here, we present a simple and robust assay that enables the investigation of transient protein interactions in living cells by using the single-molecule diffusional mobility shift assay (smDIMSA). Utilizing smDIMSA, we uncovered the interaction profile of EGFR with various membrane proteins and demonstrated the promiscuity of these interactions depending on the cancer cell line. The transient interaction profile obtained by smDIMSA will provide critical information to comprehend the crosstalk among various receptors on the plasma membrane.
Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial
Authors: Röllig Christoph , Serve Hubert , Noppeney Richard , Hanoun Maher , Krug Utz , Baldus Claudia D. , Brandts Christian H. , Kunzmann Volker , Einsele Hermann , Krämer Alwin , Müller-Tidow Carsten , Schäfer-Eckart Kerstin , Neubauer Andreas , Burchert Andreas , Giagounidis Aristoteles , Krause Stefan W. , Mackensen Andreas , Aulitzky Walter , Herbst Regina , Hänel Mathias , Frickhofen Norbert , Kullmer Johannes , Kaiser Ulrich , Kiani Alexander , Link Hartmut , Geer Thomas , Reichle Albrecht , Junghanß Christian , Repp Roland , Meinhardt Achim , Dürk Heinz , Klut Ina-Maria , Bornhäuser Martin , Schaich Markus , Parmentier Stefani , Görner Martin , Thiede Christian , von Bonin Malte , Platzbecker Uwe , Schetelig Johannes , Kramer Michael , Berdel Wolfgang E. , Ehninger Gerhard ,   for the Study Alliance Leukaemia (SAL)
Published: February 2021

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.
Small molecule induces mitochondrial fusion for neuroprotection via targeting CK2 without affecting its conventional kinase activity
Authors: Zeng Ke-Wu , Wang Jing-Kang , Wang Li-Chao , Guo Qiang , Liu Ting-Ting , Wang Fu-Jiang , Feng Na , Zhang Xiao-Wen , Liao Li-Xi , Zhao Mei-Mei , Liu Dan , Jiang Yong , Tu Pengfei
Published: February 2021

Mitochondrial fusion/fission dynamics plays a fundamental role in neuroprotection; however, there is still a severe lack of therapeutic targets for this biological process. Here, we found that the naturally derived small molecule echinacoside (ECH) significantly promotes mitochondrial fusion progression. ECH selectively binds to the previously uncharacterized casein kinase 2 (CK2) α′ subunit (CK2α′) as a direct cellular target, and genetic knockdown of CK2α′ abolishes ECH-mediated mitochondrial fusion. Mechanistically, ECH allosterically regulates CK2α′ conformation to recruit basic transcription factor 3 (BTF3) to form a binary protein complex. Then, the CK2α′/BTF3 complex facilitates β-catenin nuclear translocation to activate TCF/LEF transcription factors and stimulate transcription of the mitochondrial fusion gene Mfn2. Strikingly, in a mouse middle cerebral artery occlusion (MCAO) model, ECH administration was found to significantly improve cerebral injuries and behavioral deficits by enhancing Mfn2 expression in wild-type but not CK2α′+/− mice. Taken together, our findings reveal, for the first time, that CK2 is essential for promoting mitochondrial fusion in a Wnt/β-catenin-dependent manner and suggest that pharmacologically targeting CK2 is a promising therapeutic strategy for ischemic stroke.
Host genotype and genetic diversity shape the evolution of a novel bacterial infection
Authors: Ekroth Alice K E , Gerth Michael , Stevens Emily J , Ford Suzanne A , King Kayla C
Published: February 2021

Pathogens continue to emerge from increased contact with novel host species. Whilst these hosts can represent distinct environments for pathogens, the impacts of host genetic background on how a pathogen evolves post-emergence are unclear. In a novel interaction, we experimentally evolved a pathogen (Staphylococcus aureus) in populations of wild nematodes (Caenorhabditis elegans) to test whether host genotype and genetic diversity affect pathogen evolution. After ten rounds of selection, we found that pathogen virulence evolved to vary across host genotypes, with differences in host metal ion acquisition detected as a possible driver of increased host exploitation. Diverse host populations selected for the highest levels of pathogen virulence, but infectivity was constrained, unlike in host monocultures. We hypothesise that population heterogeneity might pool together individuals that contribute disproportionately to the spread of infection or to enhanced virulence. The genomes of evolved populations were sequenced, and it was revealed that pathogens selected in distantly-related host genotypes diverged more than those in closely-related host genotypes. S. aureus nevertheless maintained a broad host range. Our study provides unique empirical insight into the evolutionary dynamics that could occur in other novel infections of wildlife and humans.
The neural basis underlying impaired attentional control in problematic smartphone users
Authors: Choi Jihye , Cho Hyun , Choi Jung-Seok , Choi In Young , Chun Ji-Won , Kim Dai-Jin
Published: February 2021

As a portable media device that enables ubiquitous access to friends and entertainment, smartphones are inextricably linked with our lives. Although there is growing concern about the detrimental effect of problematic smartphone use on attentional control, the underlying neural mechanisms of impaired attentional control in problematic smartphone users (PSU) has yet to be investigated. Using a modified cognitive conflict task, we examined behavioral performance in the presence of distracting words during functional magnetic resonance imaging in 33 PSU and 33 control participants (CON). Compared with the CON group, the PSU group demonstrated impaired performance that was accompanied by constantly enhanced but not differentiated activation in the frontoparietal regions across all conditions, regardless of distractor saliency. The inferior parietal lobule (IPL) activation in the PSU group, in particular, showed an association with performance deficits in the distractor conditions. Furthermore, the PSU group exhibited decreased functional connectivity of the right IPL with the right superior temporal gyrus of the ventral attention system in the attention-demanding condition relative to the easiest condition, which was associated with the severe dependence on smartphone use. Our findings suggest that greater distractibility in the PSU group during the attentional control task may be associated with inefficient recruitment of the ventral attention network involved in bottom-up attentional processing, as indicated by hyperactivation but less coherence within the network. The present study provides evidence for understanding the neural mechanisms underlying the impaired ability to keep attention from being oriented to task-irrelevant stimuli observed in PSU.
From warrior genes to translational solutions: novel insights into monoamine oxidases (MAOs) and aggression
Authors: Mentis Alexios-Fotios A. , Dardiotis Efthimios , Katsouni Eleni , Chrousos George P.
Published: February 2021

The pervasive and frequently devastating nature of aggressive behavior calls for a collective effort to understand its psychosocial and neurobiological underpinnings. Regarding the latter, diverse brain areas, neural networks, neurotransmitters, hormones, and candidate genes have been associated with antisocial and aggressive behavior in humans and animals. This review focuses on the role of monoamine oxidases (MAOs) and the genes coding for them, in the modulation of aggression. During the past 20 years, a substantial number of studies using both pharmacological and genetic approaches have linked the MAO system with aggressive and impulsive behaviors in healthy and clinical populations, including the recent discovery ofMAALIN, a long noncoding RNA (lncRNA) regulating theMAO-Agene in the human brain. Here, we first provide an overview of the MAOs and their physiological functions, we then summarize recent key findings linking MAO-related enzymatic and gene activity and aggressive behavior, and, finally, we offer novel insights into the mechanisms underlying this association. Using the existing experimental evidence as a foundation, we discuss the translational implications of these findings in clinical practice and highlight what we believe are outstanding conceptual and methodological questions in the field. Ultimately, we propose that unraveling the specific role of MAO in aggression requires an integrated approach, where this question is pursued by combining psychological, radiological, and genetic/genomic assessments. The translational benefits of such an approach include the discovery of novel biomarkers of aggression and targeting the MAO system to modulate pathological aggression in clinical populations.
Ibrutinib and venetoclax target distinct subpopulations of CLL cells: implication for residual disease eradication
Authors: Lu Pin , Wang Shengchun , Franzen Carrie A. , Venkataraman Girish , McClure Rebecca , Li Lei , Wu Wenjun , Niu Nifang , Sukhanova Madina , Pei Jianming , Baldwin Donald A. , Nejati Reza , Wasik Mariusz A. , Khan Nadia , Tu Yifan , Gao Juehua , Chen Yihua , Ma Shuo , Larson Richard A. , Wang Y. Lynn
Published: February 2021

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients’ actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.
The Y chromosome ancestry marker R1b1b2: a surrogate of the SARS-CoV-2 population affinity
Authors: Ibrahim Muntaser , Salih Abdalhameed
Published: February 2021

Individual and population susceptibilities to disease remain a murky area of investigation, clouded by past bias based on ideological differences and wars. The current SARS-CoV-2 pandemic, the largest in living memory, brought this matter to forefront as the disparity in disease burden became apparent. A timeline analysis of the pandemic revealed the presence of country clusters that display a marked preponderance of disease among populations carrying the ancestry marker R1b1b2, notably associated with both infection and mortality. This marker is a relic of past human expansions from western Asia and subsequently Europe and the rest of the world, which may have been accompanied by peculiar biological events rendering these populations vulnerable to SARS-CoV-2.
Scaling advantage over path-integral Monte Carlo in quantum simulation of geometrically frustrated magnets
Authors: King Andrew D. , Raymond Jack , Lanting Trevor , Isakov Sergei V. , Mohseni Masoud , Poulin-Lamarre Gabriel , Ejtemaee Sara , Bernoudy William , Ozfidan Isil , Smirnov Anatoly Yu. , Reis Mauricio , Altomare Fabio , Babcock Michael , Baron Catia , Berkley Andrew J. , Boothby Kelly , Bunyk Paul I. , Christiani Holly , Enderud Colin , Evert Bram , Harris Richard , Hoskinson Emile , Huang Shuiyuan , Jooya Kais , Khodabandelou Ali , Ladizinsky Nicolas , Li Ryan , Lott P. Aaron , MacDonald Allison J. R. , Marsden Danica , Marsden Gaelen , Medina Teresa , Molavi Reza , Neufeld Richard , Norouzpour Mana , Oh Travis , Pavlov Igor , Perminov Ilya , Prescott Thomas , Rich Chris , Sato Yuki , Sheldan Benjamin , Sterling George , Swenson Loren J. , Tsai Nicholas , Volkmann Mark H. , Whittaker Jed D. , Wilkinson Warren , Yao Jason , Neven Hartmut , Hilton Jeremy P. , Ladizinsky Eric , Johnson Mark W. , Amin Mohammad H.
Published: February 2021

The promise of quantum computing lies in harnessing programmable quantum devices for practical applications such as efficient simulation of quantum materials and condensed matter systems. One important task is the simulation of geometrically frustrated magnets in which topological phenomena can emerge from competition between quantum and thermal fluctuations. Here we report on experimental observations of equilibration in such simulations, measured on up to 1440 qubits with microsecond resolution. By initializing the system in a state with topological obstruction, we observe quantum annealing (QA) equilibration timescales in excess of one microsecond. Measurements indicate a dynamical advantage in the quantum simulation compared with spatially local update dynamics of path-integral Monte Carlo (PIMC). The advantage increases with both system size and inverse temperature, exceeding a million-fold speedup over an efficient CPU implementation. PIMC is a leading classical method for such simulations, and a scaling advantage of this type was recently shown to be impossible in certain restricted settings. This is therefore an important piece of experimental evidence that PIMC does not simulate QA dynamics even for sign-problem-free Hamiltonians, and that near-term quantum devices can be used to accelerate computational tasks of practical relevance.
Predicting mammalian hosts in which novel coronaviruses can be generated
Authors: Wardeh Maya , Baylis Matthew , Blagrove Marcus S. C.
Published: February 2021

Novel pathogenic coronaviruses – such as SARS-CoV and probably SARS-CoV-2 – arise by homologous recombination between co-infecting viruses in a single cell. Identifying possible sources of novel coronaviruses therefore requires identifying hosts of multiple coronaviruses; however, most coronavirus-host interactions remain unknown. Here, by deploying a meta-ensemble of similarity learners from three complementary perspectives (viral, mammalian and network), we predict which mammals are hosts of multiple coronaviruses. We predict that there are 11.5-fold more coronavirus-host associations, over 30-fold more potential SARS-CoV-2 recombination hosts, and over 40-fold more host species with four or more different subgenera of coronaviruses than have been observed to date at >0.5 mean probability cut-off (2.4-, 4.25- and 9-fold, respectively, at >0.9821). Our results demonstrate the large underappreciation of the potential scale of novel coronavirus generation in wild and domesticated animals. We identify high-risk species for coronavirus surveillance.
A game theoretic approach reveals that discretizing clinical information can reduce antibiotic misuse
Authors: Diamant Maya , Baruch Shoham , Kassem Eias , Muhsen Khitam , Samet Dov , Leshno Moshe , Obolski Uri
Published: February 2021

The overuse of antibiotics is exacerbating the antibiotic resistance crisis. Since this problem is a classic common-goods dilemma, it naturally lends itself to a game-theoretic analysis. Hence, we designed a model wherein physicians weigh whether antibiotics should be prescribed, given that antibiotic usage depletes its future effectiveness. The physicians’ decisions rely on the probability of a bacterial infection before definitive laboratory results are available. We show that the physicians’ equilibrium decision rule of antibiotic prescription is not socially optimal. However, we prove that discretizing the information provided to physicians can mitigate the gap between their equilibrium decisions and the social optimum of antibiotic prescription. Despite this problem’s complexity, the effectiveness of the discretization solely depends on the type of information available to the physician to determine the nature of infection. This is demonstrated on theoretic distributions and a clinical dataset. Our results provide a game-theory based guide for optimal output of current and future decision support systems of antibiotic prescription.
Tumour gene expression signature in primary melanoma predicts long-term outcomes
Authors: Garg Manik , Couturier Dominique-Laurent , Nsengimana Jérémie , Fonseca Nuno A. , Wongchenko Matthew , Yan Yibing , Lauss Martin , Jönsson Göran B. , Newton-Bishop Julia , Parkinson Christine , Middleton Mark R. , Bishop D. Timothy , McDonald Sarah , Stefanos Nikki , Tadross John , Vergara Ismael A. , Lo Serigne , Newell Felicity , Wilmott James S. , Thompson John F. , Long Georgina V. , Scolyer Richard A. , Corrie Pippa , Adams David J. , Brazma Alvis , Rabbie Roy
Published: February 2021

Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.
Annual aboveground carbon uptake enhancements from assisted gene flow in boreal black spruce forests are not long-lasting
Authors: Girardin Martin P. , Isabel Nathalie , Guo Xiao Jing , Lamothe Manuel , Duchesne Isabelle , Lenz Patrick
Published: February 2021

Assisted gene flow between populations has been proposed as an adaptive forest management strategy that could contribute to the sequestration of carbon. Here we provide an assessment of the mitigation potential of assisted gene flow in 46 populations of the widespread boreal conifer Picea mariana, grown in two 42-year-old common garden experiments and established in contrasting Canadian boreal regions. We use a dendroecological approach taking into account phylogeographic structure to retrospectively analyse population phenotypic variability in annual aboveground net primary productivity (NPP). We compare population NPP phenotypes to detect signals of adaptive variation and/or the presence of phenotypic clines across tree lifespans, and assess genotype‐by‐environment interactions by evaluating climate and NPP relationships. Our results show a positive effect of assisted gene flow for a period of approximately 15 years following planting, after which there was little to no effect. Although not long lasting, well-informed assisted gene flow could accelerate the transition from carbon source to carbon sink after disturbance.
Eltrombopag directly inhibits BAX and prevents cell death
Authors: Spitz Adam Z. , Zacharioudakis Emmanouil , Reyna Denis E. , Garner Thomas P. , Gavathiotis Evripidis
Published: February 2021

The BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is transformed from an inactive cytosolic conformation to a toxic mitochondrial oligomer. Although the BAX transformation process is not well understood, drugs that interfere with this process are useful research tools and potential therapeutics. Here, we show that Eltrombopag,  an FDA-approved drug,  is a direct inhibitor of BAX. Eltrombopag binds the BAX trigger site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Accordingly, Eltrombopag is capable of inhibiting BAX-mediated apoptosis induced by cytotoxic stimuli. Our data demonstrate structure-function insights into a mechanism of BAX inhibition and reveal a mechanism for Eltrombopag that may expand its use in diseases of uncontrolled cell death.
High-efficiency magnetic refrigeration using holmium
Authors: Terada Noriki , Mamiya Hiroaki
Published: February 2021

Magnetic refrigeration (MR) is a method of cooling matter using a magnetic field. Traditionally, it has been studied for use in refrigeration near room temperature; however, recently MR research has also focused on a target temperature as low as 20 K for hydrogen liquefaction. Most research to date has employed high magnetic fields (at least 5 T) to obtain a large entropy change, which requires a superconducting magnet and, therefore, incurs a large energy cost. Here we propose an alternative highly efficient cooling technique in which small magnetic field changes, Δμ0H≤ 0.4 T, can obtain a cooling efficiency of −ΔSM/Δμ0H = 32 J kg−1K−1T−1, which is one order of magnitude higher than what has been achieved using typical magnetocaloric materials. Our method uses holmium, which exhibits a steep magnetization change with varying temperature and magnetic field. The proposed technique can be implemented using permanent magnets, making it a suitable alternative to conventional gas compression–based cooling for hydrogen liquefaction.