bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes after stereotactic radiosurgery of brain metastases in patients with malignant melanoma and validation of the melanoma molGPA
Authors: Kessel K. A. , Deichl A. , Gempt J. , Meyer B. , Posch C. , Diehl C. , Zimmer C. , Combs S. E.
Published: May 2021

Introduction

Malignant melanoma is the third most common primary in the diagnosis of brain metastases. Stereotactic radiosurgery (SRS) is a well-established treatment option in limited brain disease. We analyzed outcomes of SRS with a particular focus on the graded prognostic assessment (GPA, melanoma molGPA), prognostic factors, and toxicity.

Methods

We evaluated 173 brain metastases in 83 patients with malignant melanoma. All were treated with SRS median dose of 20 Gy prescribed to the 80 or 100% isodose line between 2002 and 2019. All patients were followed-up regularly, including contrast‐enhanced brain imaging as well as clinical examination, initially 6 weeks after treatment, then in quarterly follow-up.

Results

The median age was 61 years (range 27–80); 36 female and 47 male patients were treated. After a median follow-up of 5.7 months, median OS (overall survival) was 9.7 months 95%-KI 4.7–14.7). LC (local control) at 6 months, 12, 24 months was 89%, 86%, and 72%, respectively (median was not reached). Median DBC (distant brain control) was 8.2 months (95%-KI 4.7–11.7). For OS, a KPS ≥ 80%, a positive BRAF mutation status, a small PTV (planning target volume), the absence of extracranial metastases, as well as a GPA and melanoma molGPA > 2 were prognostic factors. In the MVA, a small PTV and a melanoma molGPA > 2 remained significant.

Conclusion

The present survival outcomes support the use of the disease-specific melanoma molGPA as reliable prognostic score. Favorable outcomes for SRS compared to other studies were observed. In the treatment of brain metastases of malignant melanoma patients, a multidisciplinary approach consisting of surgery, SRS, chemotherapy, and immunotherapy should be considered.
Designing AI for Explainability and Verifiability: A Value Sensitive Design Approach to Avoid Artificial Stupidity in Autonomous Vehicles
Authors: Umbrello Steven , Yampolskiy Roman V.
Published: May 2021

One of the primary, if not most critical, difficulties in the design and implementation of autonomous systems is the black-boxed nature of the decision-making structures and logical pathways. How human values are embodied and actualised in situ may ultimately prove to be harmful if not outright recalcitrant. For this reason, the values of stakeholders become of particular significance given the risks posed by opaque structures of intelligent agents. This paper explores how decision matrix algorithms, via thebelief-desire-intentionmodel for autonomous vehicles, can be designed to minimize the risks of opaque architectures. Primarily through an explicit orientation towards designingforthe values of explainability and verifiability. In doing so, this research adopts the Value Sensitive Design (VSD) approach as a principled framework for the incorporation of such values within design. VSD is recognized as a potential starting point that offers a systematic way for engineering teams to formally incorporate existing technical solutions within ethical design, while simultaneously remaining pliable to emerging issues and needs. It is concluded that the VSD methodology offers at least a strong enough foundation from which designers can begin to anticipate design needs and formulate salient design flows that can be adapted to the changing ethical landscapes required for utilisation in autonomous vehicles.
Physiological response and transcriptome analysis of Prunus mume to early salt stress
Authors: Wang Xiujun , Song Zhenqi , Ti Yujing , Liu Yuxia , Li Qingwei
Published: May 2021

Soil salinisation is an important factor limiting the cultivation and distribution of Prunus mume. Therefore, identifying the regulation mechanism of salt tolerance of P. mume will promote its cultivation and molecular breeding. In this study, the garden tree species P. mume ‘Meiren’ was investigated, with a soil NaCl content (w/w) of 0.3%. Photosynthetic gas exchange parameters, relative electrical conductivity, malondialdehyde, osmoregulation substances, and antioxidant enzyme activity were measured in the early (3d), middle (10d), and late (30d) stages of stress. Salt treatment was applied for 0 h, 6 h, 24 h, and 72 h; following this, the gene library was constructed from the leaves. The results showed that the CBL-CIPK, mitogen-activated protein kinase, calcium-dependent protein kinase, and abscisic acid signalling pathways were involved in salt stress signal transduction of P. mume. Furthermore, bHLH, WRPK, ERF, and MYB were identified as potential key transcription factor families of salt tolerance in P. mume. Combined with determined physiological responses, the results showed that early salt stress inhibited the activities of RuBisCO, chlorophyll synthase, glutamyl tRNA reductase, divinyl reductase, and magnesium chelatase; resultantly, this led to a reduction in the photosynthetic rate. Also, it was found that P5CS, SS, LEA, and dehydrin regulated the synthesis of proline, soluble sugar, and macromolecular protein to alleviate osmotic stress. POD gene plays an important role in scavenging reactive oxygen species due to its regulation of POD activity. The findings of this research reveal the internal mechanism of the physiological response and provide a foundation for the construction of a genetic regulatory network in response to salt stress in P. mume.
The Use of Effective Language and Communication in the Management of Obesity: the Challenge for Healthcare Professionals
Authors: Auckburally Sameera , Davies Elena , Logue Jennifer
Published: May 2021

Purpose of Review

Initial conversations about weight with patients are important to set the tone for future dialogue and management of obesity. There is often reluctance in raising the topic of overweight or obesity in consultations. We aimed to evaluate literature to discover the perceived barriers to optimal discussion about weight status and preferred weight-based terminology for adults, adolescents and parents of younger children.

Recent Findings

Fear of offending patients, insufficient training and lack of knowledge of referral pathways were identified as factors hindering healthcare professionals’ ability to discuss weight with patients. Neutral terms, such as ‘weight’, were preferred by patients, with ‘fat’ and ‘obese’ viewed as undesirable and stigmatising words.

There is a need for greater support and provision of specific training, including education on communicating weight status, for those involved in the management of obesity. More research is necessary to assess the impact of interventions to improve initial discussions with patients about weight.
Health Status of Adults with Autism Spectrum Disorder
Authors: Forde Jennifer , Bonilla Paola Molina , Mannion Arlene , Coyne Rory , Haverty Ross , Leader Geraldine
Published: May 2021

Individuals diagnosed with autism spectrum disorder (ASD) have a higher probability of developing co-occurring mental or physical health conditions. However, little is known about how these health conditions develop and impact the lives of the adult ASD population. This paper reviewed existing studies concerning factors affecting the health status of adults with ASD and described their outcomes and prevalence. A systematic search of electronic databases yielded 21 studies eligible to be included. The most common physical problems affecting health were epilepsy and immune, gastrointestinal, and sleep disorders. Mental health disorders, most prominently mood and anxiety disorders and OCD, were also strong factors for determining health in adults. Future research should focus on measuring the overall health status of the adult ASD population.
Colexification Networks Encode Affective Meaning
Authors: Di Natale Anna , Pellert Max , Garcia David
Published: May 2021

Colexification is a linguistic phenomenon that occurs when multiple concepts are expressed in a language with the same word. Colexification patterns are frequently used to estimate the meaning similarity between words, but the hypothesis that these are related is still missing direct empirical validation at scale. Here, we show for the first time that words linked by colexification patterns capture similar affective meanings. Using pre-existing translation data, we extend colexification databases to cover much longer word lists. We achieve this with an unsupervised method of affective lexicon extension that uses colexification network data to interpolate the affective ratings of words that are not included in the original lexicon. We find positive correlations between network-based estimates and empirical affective ratings, which suggest that colexification networks contain information related to affective meanings. Finally, we compare our network method with state-of-the-art machine learning, trained on a large corpus, and show that our simple linguistics-informed unsupervised algorithm yields comparable performance with high explainability. These results show that it is possible to automatically expand affective norms lexica to cover exhaustive word lists when additional data are available, such as in colexification networks.
Providing online STEM workshops in times of isolation
Authors: Weinhandl Robert , Thrainer Susanne , Lavicza Zsolt , Houghton Tony , Hohenwarter Markus
Published: May 2021

The global spread of COVID-19 has resulted in learning and teaching being confronted with immense challenges and changes since spring 2020. Measures to contain the COVID-19 pandemic had and continue to have a particularly strong impact on non-formal and informal learning, which are important features of out-of-class on-line STEM workshops combining science, technology, engineering and mathematics. We developed and carried out online STEM workshops for approximately 250 students during times of isolation in the spring and summer of 2020. To identify potential success factors and stumbling blocks for designing and implementing online STEM workshops, we conducted a qualitative interview-based study with a selection of eight experts in the summer and autumn 2020, i.e. after the STEM workshops. The experts were Austrian and German teachers who planned and implemented STEM workshops for students age 10 to 18. Our collected data was examined using techniques of grounded theory approaches. Using techniques of qualitative interview studies and grounded theory approaches, we found that removing learning barriers and creating new types of learning spaces, online socio-constructivist learning, and teachers' TPACK for STEM Workshops are important factors when considering and designing STEM workshops for online learning environments. These same factors will also be central when planning and implementing online STEM workshops in post-COVID-19 times. To facilitate student participation and to increase social interaction are critical elements for practitioners working on online STEM workshops—both during and after COVID-19. Highly trained teachers with in-depth technical, pedagogical, and content skills are essential to facilitate participation and interactions among students, teachers, and learning contents.
Against robot taxes: scrutinizing the moral reasons for the preservation of work
Authors: Moser Elias
Published: May 2021

A recent political proposal to address the challenge of technological unemployment suggests that the state should impose a tax on labor-replacing technologies. The idea is to preserve jobs by disincentivizing automation. In this article, I critically assess the proposal from an ethical perspective. I show that, with respect to conceptions of distributive justice, it is unclear that precluding consumers’ potential real-income gains from automation can be justified. But foremost, I examine the moral ideal behind the normative claim to preserve labor. I show that the arguments in favor of a robot tax rely on doubtful moral convictions on the value of work and I conclude that a moral basis for imposing a robot tax is subject to justified scrutiny.
Heritage Tourism
Authors: Zhu Yujie
Published: May 2021

As one of the world's fastest growing industries, heritage tourism is surrounded by political and ethical issues. This research explores the social and political effects and implications of heritage tourism through several pertinent topics. It examines the hegemonic power of heritage tourism and its consequences, the spectre of nationalism and colonialism in heritage-making, particularly for minorities and indigenous peoples, and the paradox of heritage tourism's role in combating these issues. Drawing from global cases, the study addresses a range of approaches and challenges of empowerment within the context of heritage tourism, including cultural landscapes, intangible heritage and eco-museums. The research argues that heritage tourism has the potential to develop as a form of co-production. It can be used to create a mechanism for community-centred governance that integrates recognition and interpretation and promotes dialogue, equity and diversity.
Clinical Characteristics and Abnormal Parameters Evolution in Patients With Novel Coronavirus Infection: A Case Series of 272 Cases in Guangzhou
Authors: Wang Yubing , Hu Zhongwei , Luo Jie , Zhang Fuchun , Huang Lianjiao , Li Hao , Wen Xueliang , Pan Yuejun , Chen Meihong , Ying Ruosu , Jiang Huirong , Chen Sirui , Pan Zhilin , Chen Hongkun , Xu Huimin , Lei Chunliang , Han Yajuan
Published: May 2021

Objective:

The aim of this study was to present the clinical characteristics and dynamic changes in laboratory parameters of the coronavirus disease 2019 (COVID-19) in Guangzhou, and explore the probable early warning indicators of disease progression.

Method:

We enrolled all the patients diagnosed with COVID-19 in the Guangzhou No. 8 People’s Hospital. The patients’ demographic and epidemiologic data were collected, including chief complaints, lab results, and imaging examination findings.

Results:

The characteristics of the patients in Guangzhou are different from those in Wuhan. The patients were younger in age, predominately female, and their condition was not commonly combined with other diseases. A total of 75% of patients suffered fever on admission, followed by cough occurring in 62% patients. Comparing the mild/normal and severe/critical patients, being male, of older age, combined with hypertension, abnormal blood routine test results, raised creatine kinase, glutamic oxaloacetic transaminase, lactate dehydrogenase, C-reactive protein, procalcitonin, D-dimer, fibrinogen, activated partial thromboplastin time, and positive proteinuria were early warning indicators of severe disease.

Conclusion:

The patients outside epidemic areas showed different characteristics from those in Wuhan. The abnormal laboratory parameters were markedly changed 4 weeks after admission, and also were different between the mild and severe patients. More evidence is needed to confirm highly specific and sensitive potential early warning indicators of severe disease.
Ein Plädoyer zur Qualitätssicherung schriftlicher Prüfungen im Psychologiestudium
Authors: Lindner Marlit Annalena , Sparfeldt Jörn R. , Köller Olaf , Lukas Josef , Leutner Detlev
Published: May 2021

Zusammenfassung. Prüfungen sind zentrale, qualitätssichernde Elemente im Hochschulstudium, die hohen Ansprüchen genügen müssen. In der Praxis werden diese Ansprüche jedoch oft nicht idealtypisch erfüllt. Dieser Beitrag skizziert, wie ein evidenzbasiertes Vorgehen bei der Erstellung und Auswertung von schriftlichen Prüfungen aussehen kann, um den Umgang mit typischen Problemen zu erleichtern und kalkulierbare Risiken nach aktuellem Forschungsstand bestmöglich zu reduzieren. Wir diskutieren unter anderem, welche Gütekriterien an Hochschulprüfungen angelegt werden sollten, welche Aufgabenformate mit ihren spezifischen Vor- und Nachteilen wann sinnvoll einsetzbar sind, wie man der Rateproblematik bei geschlossenen Aufgabenformaten begegnen sollte und welche Potenziale computerbasierte Prüfungen bieten. Weiterhin gehen wir auf die Bedeutung von Prüfungen als Lernsteuerungsinstrument ein und diskutieren die Rolle studentischer Testwiseness sowie die Notwendigkeit, durch ineinandergreifende Maßnahmen ein systematisches Qualitätsmanagement für Prüfungen zu implementieren. Darüber hinaus wird im Rahmen des Diskussionsforums ein konstruktiver Dialog über Herausforderungen und Optimierungsbedarfe sowie Voraussetzungen und Gelingensbedingungen auf dem Weg zu besseren Prüfungen im Psychologiestudium fortgeführt.
Anomalous Subduction Initiation: Young Under Old Oceanic Lithosphere
Authors: Zhang Lulu , Zlotnik Sergio , Li Chun‐Feng
Published: May 2021

When subduction initiates along a transform fault, it is often interpreted that the older and therefore denser oceanic lithosphere should evolve into the downgoing plate. However, in the western Pacific, several geological cases are probably characterized by young oceanic plates underthrusting older and denser plates. Using numerical simulations of a transform fault under compression, we propose that subduction polarity depends mainly on the age offset between the two adjacent plates, the strength of the transform fault, and the plasticity of the plates. A small age offset across the plate interface favors the subduction initiation of the younger plate. Furthermore, weak transform faults promote strain localization along the plate boundary and trigger the underthrusting of the older and denser plate. Plastic deformation is prone to localize within the thinner and weaker plates in a location far from the transition zone of the two plates if the rate of strain weakening of plates is fast enough. When plates have a large age offset the younger plate may still underthrust if plasticity plays a role. Our numerical models explore factors controlling the induced subduction polarities and the potential mechanism of young plate subduction and explain certain related subduction geological settings.
Geodetic Extension Across the Southern Basin and Range and Colorado Plateau
Authors: Broermann James , Bennett Richard A. , Kreemer Corné , Blewitt Geoffrey , Pearthree Philip A.
Published: May 2021

Rates of crustal deformation in the southern Basin and Range (SBR) and Colorado Plateau (CP) provinces are relatively low in the context of the Pacific‐North America plate boundary (PA–NA); however, the accumulation of small amounts of strain over long periods of time can lead to large earthquakes such as the Mw 7.5 1887 Sonoran earthquake in northern Mexico. SBR and CP rates of deformation are difficult to quantify due to a dearth of young faulting and seismicity. Moreover, strain accumulation and release related to the adjacent, more active San Andreas and Gulf of California fault systems to the west and southwest can mask the background strain rates associated with SBR and CP tectonics. With data from an enhanced continuous GPS network, we estimate crustal surface velocities of the SBR and CP, after removing coseismic and postseismic displacements, and elastic loading effects arising from major fault zones to the (south)west. We use cluster analysis and geologic data to separate the GPS velocity field into regions and calculate distinct block rotation and uniform strain rates for each region. We find the highest strain rate region includes southwestern Arizona; an area with sparse Quaternary faults, relatively low seismicity, and a relatively large discrepancy between geodetic and geologic rates of deformation. This anomalous strain rate may reflect residual, unmodeled PA‐NA strain seeping into the Arizona study area from the west. Alternatively, it may represent the potential for one or more rare, future, large‐magnitude earthquakes or indicate strain is being released through other process(es).
Global Contrasts Between Oceanic Cycling of Cadmium and Phosphate
Authors: Roshan Saeed , DeVries Tim
Published: May 2021

Cadmium (Cd) is a trace metal whose distribution in the ocean bears a remarkable resemblance to the nutrient phosphate (PO43−). This resemblance has led to the use of Cd as a proxy for ocean nutrient cycling in paleoceanographic applications, but the processes governing the cycling of Cd in the modern ocean remain unclear. In this study, we use previously published Cd observations and an Artificial Neural Network to produce a dissolved Cd climatology that reproduces the observed subtle deviations between the Cd and distributions. We use the Cd and climatologies, along with an ocean circulation inverse model, to diagnose the biogeochemical sources and sinks of dissolved Cd and . Our calculations reveal that dissolved Cd, like , is removed in the surface ocean and has a source in the subsurface, consistent with the simultaneous incorporation of Cd and into sinking organic particles. However, there are also contrasts between the cycling of dissolved Cd and In particular, the surface export ratio varies 8‐fold across latitudes, reaching highest values in the iron‐limited sub‐Antarctic Southern Ocean. This depletes Cd relative to in the low‐latitude thermocline while adding excess Cd to deep waters by the regeneration of Cd‐enriched particles. Also, Cd tends to regenerate slightly deeper than in the subsurface ocean, and the regeneration ratio reaches a maximum at 700–1,500 m. These contrasts are responsible for a slight concavity in the relationship and should be considered when interpreting paleoceanographic Cd records.
Direct Antenna Impedance Measurement for Quantitative AC Electric Field Measurement by Arase
Authors: Matsuda S. , Kojima H. , Kasahara Y. , Kasaba Y. , Kumamoto A. , Tsuchiya F. , Matsuoka A. , Miyoshi Y. , Shinohara I.
Published: May 2021

We developed an in‐situ direct measurement technique for the electric field antenna impedance using onboard signal processing. Antenna impedance is an important parameter for observed electric field calibration. Because it changes depending on local plasma parameters, in‐situ measurements along the orbit are essential for obtaining precise electric field calibration. We installed the onboard signal calibration function (SWCAL) as a part of the onboard software of the plasma wave experiment (PWE) aboard Arase and performed more than 5,500 measurements in the inner magnetosphere from March 2017 to March 2020. The measured the antenna capacitance along the orbit of Arase, which is important for AC electric field calibration. We found that the measured antenna capacitance varies between 70 and 160 pF depending on the ambient electron density. Further, the effects of the antenna impedance on the AC electric field calibration were evaluated. Results indicated that the observed electric field data include ambiguity of up to 7.8 dB and 17° in the main target frequency range of the waveform capture/onboard frequency analyzer of PWE. This ambiguity can be calibrated by considering the real antenna impedance effects measured using SWCAL.
Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours
Authors: Fernando Madushan , Duijf Pascal H. G. , Proctor Martina , Stevenson Alexander J. , Ehmann Anna , Vora Shivam , Skalamera Dubravka , Adams Mark , Gabrielli Brian
Published: May 2021

Defective DNA repair is being demonstrated to be a useful target in cancer treatment. Currently, defective repair is identified by specific gene mutations, however defective repair is a common feature of cancers without these mutations. DNA damage triggers cell cycle checkpoints that are responsible for co-ordinating cell cycle arrest and DNA repair. Defects in checkpoint signalling components such as ataxia telangiectasia mutated (ATM) occur in a low proportion of cancers and are responsible for reduced DNA repair and increased genomic instability. Here we have investigated the AURKA-PLK1 cell cycle checkpoint recovery pathway that is responsible for exit from the G2 phase cell cycle checkpoint arrest. We demonstrate that dysregulation of PP6 and AURKA maintained elevated PLK1 activation to promote premature exit from only ATM, and not ATR-dependent checkpoint arrest. Surprisingly, depletion of the B55α subunit of PP2A that negatively regulates PLK1 was capable of overcoming ATM and ATR checkpoint arrests. Dysregulation of the checkpoint recovery pathway reduced S/G2 phase DNA repair efficiency and increased genomic instability. We found a strong correlation between dysregulation of the PP6-AURKA-PLK1-B55α checkpoint recovery pathway with signatures of defective homologous recombination and increased chromosomal instability in several cancer types. This work has identified an unrealised source of G2 phase DNA repair defects and chromosomal instability that are likely to be sensitive to treatments targeting defective repair.
COVID-19 vaccines: progress and understanding on quality control and evaluation
Authors: Mao Qunying , Xu Miao , He Qian , Li Changgui , Meng Shufang , Wang Yiping , Cui Bopei , Liang Zhenglun , Wang Junzhi
Published: May 2021

The outbreak of COVID-19 has posed a huge threat to global health and economy. Countermeasures have revolutionized norms for working, socializing, learning, and travel. Importantly, vaccines have been considered as most effective tools to combat with COVID-19. As of the beginning of 2021, >200 COVID-19 vaccine candidates, covering nearly all existing technologies and platforms, are being research and development (R&D) by multiple manufacturers worldwide. This has posed a huge obstacle to the quality control and evaluation of those candidate vaccines, especially in China, where five vaccine platforms are deployed in parallel. To accelerate the R&D progress of COVID-19 vaccines, the guidances on R&D of COVID-19 vaccine have been issued by National Regulatory Authorities or organizations worldwide. The Center for Drug Evaluation and national quality control laboratory in China have played a leading role in launching the research on quality control and evaluation in collaboration with relevant laboratories involved in the vaccine R&D, which greatly supported the progression of vaccines R&D, and accelerated the approval for emergency use and conditional marketing of currently vaccine candidates. In this paper, the progress and experience gained in quality control and evaluation of COVID-19 vaccines developed in China are summarized, which might provide references for the R&D of current and next generation of COVID-19 vaccines worldwide.
Population-based body–brain mapping links brain morphology with anthropometrics and body composition
Authors: Gurholt Tiril P. , Kaufmann Tobias , Frei Oleksandr , Alnæs Dag , Haukvik Unn K. , van der Meer Dennis , Moberget Torgeir , O’Connell Kevin S. , Leinhard Olof D. , Linge Jennifer , Simon Rozalyn , Smeland Olav B. , Sønderby Ida E. , Winterton Adriano , Steen Nils Eiel , Westlye Lars T. , Andreassen Ole A.
Published: May 2021

Understanding complex body–brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n = 24,728) and body MRI (n = 4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body–brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body–brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.
Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction
Authors: Li HuiYa , Hu DanQing , Chen Guilin , Zheng DeDong , Li ShuMei , Lin YunLing , Hong HuaShan , Luo Yukun , Ke YiLang , Huang Yu , Wu LingZhen , Lan TingXiang , Wang WenYing , Fang Jun
Published: May 2021

Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.
Reduced O-GlcNAcylation of SNAP-23 promotes cisplatin resistance by inducing exosome secretion in ovarian cancer
Authors: Qian Luomeng , Yang Xiaoshan , Li Shaohui , Zhao Hang , Gao Yunge , Zhao Shuhui , Lv Xiaohui , Zhang Xiyuan , Li Lingxia , Zhai Lianghao , Zhou Fuxing , Chen Biliang
Published: May 2021

Exosomes have been associated with chemoresistance in various cancers, but such a role in ovarian cancer is not yet clear. Here, using in vitro cell-based and in vivo mouse model experiments, we show that downregulation of O-GlcNAcylation, a key post-translational protein modification, promotes exosome secretion. This increases exosome-mediated efflux of cisplatin from cancer cells resulting in chemoresistance. Mechanistically, our data indicate that downregulation of O-GlcNAclation transferase (OGT) reduces O-GlcNAclation of SNAP-23. Notably, O-GlcNAcylation of SNAP-23 is vital for regulating exosome release in ovarian cancer cells. Reduced O-GlcNAclation of SNAP-23 subsequently promotes the formation of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex consisting of SNAP-23, VAMP8, and Stx4 proteins. This enhances exosome release causing chemoresistance by increasing the efflux of intracellular cisplatin.
16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro
Authors: Sundberg Maria , Pinson Hannah , Smith Richard S. , Winden Kellen D. , Venugopal Pooja , Tai Derek J. C. , Gusella James F. , Talkowski Michael E. , Walsh Christopher A. , Tegmark Max , Sahin Mustafa
Published: May 2021

Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.
Reconciling metal–silicate partitioning and late accretion in the Earth
Authors: Suer Terry-Ann , Siebert Julien , Remusat Laurent , Day James M. D. , Borensztajn Stephan , Doisneau Beatrice , Fiquet Guillaume
Published: May 2021

Highly siderophile elements (HSE), including platinum, provide powerful geochemical tools for studying planet formation. Late accretion of chondritic components to Earth after core formation has been invoked as the main source of mantle HSE. However, core formation could also have contributed to the mantle’s HSE content. Here we present measurements of platinum metal-silicate partitioning coefficients, obtained from laser-heated diamond anvil cell experiments, which demonstrate that platinum partitioning into metal is lower at high pressures and temperatures. Consequently, the mantle was likely enriched in platinum immediately following core-mantle differentiation. Core formation models that incorporate these results and simultaneously account for collateral geochemical constraints, lead to excess platinum in the mantle. A subsequent process such as iron exsolution or sulfide segregation is therefore required to remove excess platinum and to explain the mantle’s modern HSE signature. A vestige of this platinum-enriched mantle can potentially account for 186Os-enriched ocean island basalt lavas.
Neuronal genes deregulated in Cornelia de Lange Syndrome respond to removal and re-expression of cohesin
Authors: Weiss Felix D. , Calderon Lesly , Wang Yi-Fang , Georgieva Radina , Guo Ya , Cvetesic Nevena , Kaur Maninder , Dharmalingam Gopuraja , Krantz Ian D. , Lenhard Boris , Fisher Amanda G. , Merkenschlager Matthias
Published: May 2021

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.
Rheology of rounded mammalian cells over continuous high-frequencies
Authors: Fläschner Gotthold , Roman Cosmin I. , Strohmeyer Nico , Martinez-Martin David , Müller Daniel J.
Published: May 2021

Understanding the viscoelastic properties of living cells and their relation to cell state and morphology remains challenging. Low-frequency mechanical perturbations have contributed considerably to the understanding, yet higher frequencies promise to elucidate the link between cellular and molecular properties, such as polymer relaxation and monomer reaction kinetics. Here, we introduce an assay, that uses an actuated microcantilever to confine a single, rounded cell on a second microcantilever, which measures the cell mechanical response across a continuous frequency range ≈ 1–40 kHz. Cell mass measurements and optical microscopy are co-implemented. The fast, high-frequency measurements are applied to rheologically monitor cellular stiffening. We find that the rheology of rounded HeLa cells obeys a cytoskeleton-dependent power-law, similar to spread cells. Cell size and viscoelasticity are uncorrelated, which contrasts an assumption based on the Laplace law. Together with the presented theory of mechanical de-embedding, our assay is generally applicable to other rheological experiments.
Relaxed selection underlies genome erosion in socially parasitic ant species
Authors: Schrader Lukas , Pan Hailin , Bollazzi Martin , Schiøtt Morten , Larabee Fredrick J. , Bi Xupeng , Deng Yuan , Zhang Guojie , Boomsma Jacobus J. , Rabeling Christian
Published: May 2021

Inquiline ants are highly specialized and obligate social parasites that infiltrate and exploit colonies of closely related species. They have evolved many times convergently, are often evolutionarily young lineages, and are almost invariably rare. Focusing on the leaf-cutting ant genus Acromyrmex, we compared genomes of three inquiline social parasites with their free-living, closely-related hosts. The social parasite genomes show distinct signatures of erosion compared to the host lineages, as a consequence of relaxed selective constraints on traits associated with cooperative ant colony life and of inquilines having very small effective population sizes. We find parallel gene losses, particularly in olfactory receptors, consistent with inquiline species having highly reduced social behavioral repertoires. Many of the genomic changes that we uncover resemble those observed in the genomes of obligate non-social parasites and intracellular endosymbionts that branched off into highly specialized, host-dependent niches.
Molecular exclusion limits for diffusion across a porous capsid
Authors: Selivanovitch Ekaterina , LaFrance Benjamin , Douglas Trevor
Published: May 2021

Molecular communication across physical barriers requires pores to connect the environments on either side and discriminate between the diffusants. Here we use porous virus-like particles (VLPs) derived from bacteriophage P22 to investigate the range of molecule sizes able to gain access to its interior. Although there are cryo-EM models of the VLP, they may not accurately depict the parameters of the molecules able to pass across the pores due to the dynamic nature of the P22 particles in the solution. After encapsulating the enzyme AdhD within the P22 VLPs, we use a redox reaction involving PAMAM dendrimer modified NADH/NAD+ to examine the size and charge limitations of molecules entering P22. Utilizing the three different accessible morphologies of the P22 particles, we determine the effective pore sizes of each and demonstrate that negatively charged substrates diffuse across more readily when compared to those that are neutral, despite the negatively charge exterior of the particles.
Perfluoroalkyl substance pollutants activate the innate immune system through the AIM2 inflammasome
Authors: Wang Li-Qiu , Liu Tao , Yang Shuai , Sun Lin , Zhao Zhi-Yao , Li Li-Yue , She Yuan-Chu , Zheng Yan-Yan , Ye Xiao-Yan , Bao Qing , Dong Guang-Hui , Li Chun-Wei , Cui Jun
Published: May 2021

Perfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1β secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca2+-PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2−/− mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants.
Joint inference of CFC lifetimes and banks suggests previously unidentified emissions
Authors: Lickley Megan , Fletcher Sarah , Rigby Matt , Solomon Susan
Published: May 2021

Chlorofluorocarbons (CFCs) are harmful ozone depleting substances and greenhouse gases. CFC production was phased-out under the Montreal Protocol, however recent studies suggest new and unexpected emissions of CFC-11. Quantifying CFC emissions requires accurate estimates of both atmospheric lifetimes and ongoing emissions from old equipment (i.e. ‘banks’). In a Bayesian framework we simultaneously infer lifetimes, banks and emissions of CFC-11, 12 and 113 using available constraints. We find lifetimes of all three gases are likely shorter than currently recommended values, suggesting that best estimates of inferred emissions are larger than recent evaluations. Our analysis indicates that bank emissions are decreasing faster than total emissions, and we estimate new, unexpected emissions during 2014-2016 were 23.2, 18.3, and 7.8 Gg/yr for CFC-11, 12 and 113, respectively. While recent studies have focused on unexpected CFC-11 emissions, our results call for further investigation of potential sources of emissions of CFC-12 and CFC-113, along with CFC-11.
In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy
Authors: Becker Kolja , Klein Holger , Simon Eric , Viollet Coralie , Haslinger Christian , Leparc German , Schultheis Christian , Chong Victor , Kuehn Markus H. , Fernandez-Albert Francesc , Bakker Remko A.
Published: May 2021

Diabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.
Transformation of microbiology data into a standardised data representation using OpenEHR
Authors: Wulff Antje , Baier Claas , Ballout Sarah , Tute Erik , Sommer Kim Katrin , Kaase Martin , Sargeant Anneka , Drenkhahn Cora ,   Infection Control Study Group, Fehling Patrick , Rey Sabine , Suhr Markus , Eichel Vanessa M. , Mutters Nico T. , Heeg Klaus , Gastmeier Petra , Behnke Michael , Diaz Luis Alberto Peña , Thun Sylvia , Eils Roland , Mellmann Alexander , Tönnies Hauke , Zacher Benedikt , Eckmanns Tim , Sztyler Timo , Malone Brandon , Merzweiler Angela , Dugas Martin , Storck Michael , Wunderlich Marcel , von Landesberger Tatiana , Gebel Benjamin , Klingen Thorsten , Glöckner Stephan , Schlüter Dirk , Marschollek Michael , Scheithauer Simone
Published: May 2021

The spread of multidrug resistant organisms (MDRO) is a global healthcare challenge. Nosocomial outbreaks caused by MDRO are an important contributor to this threat. Computer-based applications facilitating outbreak detection can be essential to address this issue. To allow application reusability across institutions, the various heterogeneous microbiology data representations needs to be transformed into standardised, unambiguous data models. In this work, we present a multi-centric standardisation approach by using openEHR as modelling standard. Data models have been consented in a multicentre and international approach. Participating sites integrated microbiology reports from primary source systems into an openEHR-based data platform. For evaluation, we implemented a prototypical application, compared the transformed data with original reports and conducted automated data quality checks. We were able to develop standardised and interoperable microbiology data models. The publicly available data models can be used across institutions to transform real-life microbiology reports into standardised representations. The implementation of a proof-of-principle and quality control application demonstrated that the new formats as well as the integration processes are feasible. Holistic transformation of microbiological data into standardised openEHR based formats is feasible in a real-life multicentre setting and lays the foundation for developing cross-institutional, automated outbreak detection systems.
Super-resolution imaging of platelet-activation process and its quantitative analysis
Authors: Chung Jinkyoung , Jeong Dokyung , Kim Geun-ho , Go Seokran , Song Jaewoo , Moon Eunyoung , Huh Yang Hoon , Kim Doory
Published: May 2021

Understanding the platelet activation molecular pathways by characterizing specific protein clusters within platelets is essential to identify the platelet activation state and improve the existing therapies for hemostatic disorders. Here, we employed various state-of-the-art super-resolution imaging and quantification methods to characterize the platelet spatiotemporal ultrastructural change during the activation process due to phorbol 12-myristate 13-acetate (PMA) stimuli by observing the cytoskeletal elements and various organelles at nanoscale, which cannot be done using conventional microscopy. Platelets could be spread out with the guidance of actin and microtubules, and most organelles were centralized probably due to the limited space of the peripheral thin regions or the close association with the open canalicular system (OCS). Among the centralized organelles, we provided evidence that granules are fused with the OCS to release their cargo through enlarged OCS. These findings highlight the concerted ultrastructural reorganization and relative arrangements of various organelles upon activation and call for a reassessment of previously unresolved complex and multi-factorial activation processes.