bluuebunny/crossref_metadata_2025 huggingface dataset:
A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis
Authors: Basak I. , Wicky H. E. , McDonald K. O. , Xu J. B. , Palmer J. E. , Best H. L. , Lefrancois S. , Lee S. Y. , Schoderboeck L. , Hughes S. M.
Published: April 2021

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.
Recent trends in drugs of abuse metabolism studies for mass spectrometry–based analytical screening procedures
Authors: Wagmann Lea , Gampfer Tanja M. , Meyer Markus R.
Published: April 2021

The still increasing number of drugs of abuse, particularly the so-called new psychoactive substances (NPS), poses an analytical challenge for clinical and forensic toxicologists but also for doping control. NPS usually belong to various classes such as synthetic cannabinoids, phenethylamines, opioids, or benzodiazepines. Like other xenobiotics, NPS undergo absorption, distribution, metabolism, and excretion processes after consumption, but only very limited data concerning their toxicokinetics and safety properties is available once they appear on the market. The inclusion of metabolites in mass spectral libraries is often crucial for the detection of NPS especially in urine screening approaches. Authentic human samples may represent the gold standard for identification of metabolites but are often not available and clinical studies cannot be performed due to ethical concerns. However, numerous alternative in vitro and in vivo models are available. This trends article will give an overview on selected models, discuss current studies, and highlight recent developments.
Prognostic role of the systemic immune–inflammation index in upper tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration
Authors: Mori Keiichiro , Resch Irene , Miura Noriyoshi , Laukhtina Ekaterina , Schuettfort Victor M. , Pradere Benjamin , Katayama Satoshi , D’Andrea David , Kardoust Parizi Mehdi , Abufaraj Mohammad , Fukuokaya Wataru , Collà Ruvolo Claudia , Luzzago Stefano , Knipper Sophie , Palumbo Carlotta , Karakiewicz Pierre I. , Briganti Alberto , Enikeev Dmitry V. , Rouprêt Morgan , Margulis Vitaly , Egawa Shin , Shariat Shahrokh F.
Published: April 2021

Purpose

To investigate the prognostic role of the preoperative systemic immune–inflammation index (SII) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU).

Materials and methods

We retrospectively analyzed our multi-institutional database to identify 2492 patients. SII was calculated as platelet count × neutrophil/lymphocyte count and evaluated at a cutoff of 485. Logistic regression analyses were performed to investigate the association of SII with muscle-invasive and non-organ-confined (NOC) disease. Cox regression analyses were performed to investigate the association of SII with recurrence-free, cancer-specific, and overall survival (RFS/CSS/OS).

Results

Overall, 986 (41.6%) patients had an SII > 485. On univariable logistic regression analyses, SII > 485 was associated with a higher risk of muscle-invasive (P = 0.004) and NOC (P = 0.03) disease at RNU. On multivariable logistic regression, SII remained independently associated with muscle-invasive disease (P = 0.01). On univariable Cox regression analyses, SII > 485 was associated with shorter RFS (P = 0.002), CSS (P = 0.002) and OS (P = 0.004). On multivariable Cox regression analyses SII remained independently associated with survival outcomes (all P < 0.05). Addition of SII to the multivariable models improved their discrimination of the models for predicting muscle-invasive disease (P = 0.02). However, all area under the curve and C-indexes increased by < 0.02 and it did not improve net benefit on decision curve analysis.

Conclusions

Preoperative altered SII is significantly associated with higher pathologic stages and worse survival outcomes in patients treated with RNU for UTUC. However, the SII appears to have relatively limited incremental additive value in clinical use. Further study of SII in prognosticating UTUC is warranted before routine use in clinical algorithms.
Donor lymphocyte infusions after first allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia: a single-center landmark analysis
Authors: Rettig Andrés R. , Ihorst Gabriele , Bertz Hartmut , Lübbert Michael , Marks Reinhard , Waterhouse Miguel , Wäsch Ralph , Zeiser Robert , Duyster Justus , Finke Jürgen
Published: April 2021

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.
Sildenafil and suicide in Sweden
Authors: Catalano Ralph , Goldman-Mellor Sidra , Bruckner Tim A. , Hartig Terry
Published: April 2021

Much theory asserts that sexual intimacy sustains mental health. Experimental tests of such theory remain rare and have not provided compelling evidence because ethical, practical, and cultural constraints bias samples and results. An epidemiologic approach would, therefore, seem indicated given the rigor the discipline brings to quasi-experimental research. For reasons that remain unclear, however, epidemiologist have largely ignored such theory despite the plausibility of the processes implicated, which engender, for example, happiness, feelings of belonging and self-worth, and protection against depression. We use an intent-to-treat design, implemented via interrupted time-series methods, to test the hypothesis that the monthly incidence of suicide, a societally important distal measure of mental health in a population, decreased among Swedish men aged 50–59 after July 2013 when patent rights to sildenafil (i.e., Viagra) ceased, prices fell, and its use increased dramatically. The test uses 102 pre, and 18 post, price-drop months. 65 fewer suicides than expected occurred among men aged 50–59 over test months following the lowering of sildenafil prices. Our findings could not arise from shared trends or seasonality, biased samples, or reverse causation. Our results would appear by chance fewer than once in 10,000 experiments. Our findings align with theory indicating that sexual intimacy reinforces mental health. Using suicide as our distal measure of mental health further implies that public health programming intended to address the drivers of self-destructive behavior should reduce barriers to intimacy in the middle-aged populations.
Bulk nanocomposite made of ZnO lamellae embedded in the ZnWO4 matrix: growth from the melt
Authors: Tomczyk Monika , Osewski Pawel , Berger Marie-Helene , Diduszko Ryszard , Jóźwik Iwona , Adamo Giorgio , Pawlak Dorota A.
Published: April 2021

Zinc oxide (ZnO) nanostructures exhibiting high exciton binding energy and efficient radiative recombination, even at the room temperature, are of increasing interest due to their prospective exploitation in optoelectronic and laser applications. However, attempts to synthesize well-ordered structures through simple and fast process have faced many difficulties. Here, we demonstrate a novel manufacturing method of ZnO lamellae embedded in a crystalline wide band gap dielectric matrix of the zinc tungstate, ZnWO4. The manufacturing method is based on a directional solidification of a eutectic composite, directly from the melt, resulting in a nanostructured bulk material. Electron microscopy studies revealed clear phase separation between the ZnO and ZnWO4 phases, and cathodoluminescence confirmed exciton emission at room temperature and thus high quality and crystallinity of the ZnO lamellae, without defect emission. Hence, utilization of directional solidification of eutectics may enable cost-efficient manufacturing of bulk nanostructured ZnO composites and their use in optical devices.

Graphical abstract
The Role of Family and Friends in Return Migration and Its Labor Market Outcomes
Authors: Gillespie Brian Joseph , Mulder Clara H. , von Reichert Christiane
Published: April 2021

Drawing on survey data on individuals’ motives for migration in Sweden (N = 2172), we examine the importance of family and friends for return versus onward migration, including their importance for different age groups and in different communities on the rural–urban spectrum. The results point to a significant relationship between the importance of family and return versus onward migration, with family importance decreasing with age among returning migrants. At the same time, the importance of friends for returning increases with age. The findings did not suggest a significant relationship between urbanicity and returning versus migration elsewhere. Based on a subset of respondents who were employed prior to migrating (n = 1056), we further examined labor market outcomes for onward versus returning migrants. The results broadly indicate that return migrations are linked to lower likelihoods of labor market deterioration and improvement, suggesting greater labor market stability for return vis-à-vis onward migrations. However, the importance of family for returning (versus moving elsewhere) is associated with higher likelihoods of labor market deterioration and improvement compared with staying the same, indicating greater volatility in labor market outcomes when the importance of family is considered.
Continuous quality improvement in measure development: Lessons from building a novel clinical feedback system
Authors: Nordberg Samuel S. , McAleavey Andrew A. , Moltu Christian
Published: April 2021

Purpose

While the use of clinical feedback systems has become commonplace in psychological treatment, many of the most common instruments used for this purpose have not changed in decades. This paper describes the first four cycles of a measure development method designed to embrace continuous quality improvement.

Methods

Using techniques and philosophies developed in business management and academia—lean continuous quality improvement, action research, and practice research networks—we iterated through multiple cycles of development with the goal of creating an optimal clinical feedback system. These cycles emphasize building capacity to receive and implement feedback from a variety of stakeholders, especially patients and providers of behavioral health services, while also being responsive to quantitative findings from measure development.

Results

Iterating measure development with stakeholder feedback over the course of 5 years has resulted in a novel measurement system with 19 subscales administered via branching logic, and a supporting practice research network to sustain development.

Conclusion

In developing a new clinical feedback system, the less-frequently-discussed practical aspects of measure development require close attention. Specifically, being willing to embrace change, planning for iteration, and systematically seeking stakeholder feedback are identified as central methods for improving clinical feedback systems.
Conservation of Marine Foundation Species: Learning from Native Oyster Restoration from California to British Columbia
Authors: Ridlon April D. , Marks Althea , Zabin Chela J. , Zacherl Danielle , Allen Brian , Crooks Jeffrey , Fleener Gary , Grosholz Edwin , Peabody Betsy , Toft Jodie , Wasson Kerstin
Published: April 2021

Marine foundation species are critical to the structure and resilience of coastal ecosystems and provide key ecosystem services. Since many have suffered severe population declines, restoration of foundation species has been undertaken worldwide. The Olympia oyster (Ostrea lurida) is a foundation species, and the restoration of depleted populations is a priority for maintaining ecosystem function of estuaries along the west coast of North America. Here, we synthesize all native oyster restoration projects conducted from California, USA, to British Columbia, Canada, and analyze project goals, methods, and outcomes. Currently, restoration projects are spread unevenly across the species’ range, driven by locally varying goals and implemented with contrasting approaches. We highlight the value of regional strategic planning and decision support tools to evaluate project design and methods for restoration, including the selection of substrates and the targeted use of aquaculture. We recommend future investment in larger projects, which our analysis found were more cost-effective, but which have been relatively rare for this species. We also recommend that funders support monitoring over broader temporal and spatial scales than in the past to better characterize long-term effects of restoration on oyster populations and the services they provide beyond the project footprint. We found that most projects successfully supported native oysters and engaged local communities, and recommend similar efforts to continue to enhance understanding of Olympia oysters, which remain unfamiliar to many coastal residents. We believe that the results of this synthesis are broadly applicable to marine foundation species generally, and can inform restoration and conservation efforts worldwide.
Der Brexit-Prozess und die Austrittsdoktrin: Die Führungsrolle des Europäischen Rats
Authors: Bujard Birgit , Wessels Wolfgang
Published: April 2021

Zum Verständnis des Brexit-Prozesses ist eine Analyse der Rolle des Europäischen Rats unumgänglich. Er hat bei der Gestaltung der Beziehung zum Vereinigten Königreich die Führung übernommen und zentrale Entscheidungen zum Verfahren und den Unionszielen getroffen. Er hat sie in ein Narrativ gefasst, das die Errungenschaften der EU und die Unterschiede zwischen Mitgliedern und Nichtmitgliedern nachhaltig hervorhebt. Wie die Beitrittskriterien könnten diese Vorgaben und Beschlüsse zur Austrittsdoktrin werden.
Mindfulness Is Linked with Affectivity in Daily Life: An Experience-Sampling Study with Meditators
Authors: Tschacher Wolfgang , Lienhard Noëmi
Published: April 2021

Objectives

An increasing number of findings indicate associations between mindfulness and affect as well as mindfulness and stress. Most studies have conceptualized and measured these variables on a trait level, often in student samples or clinical contexts.

Methods

We adopted an experience-sampling approach to measure mindfulness, affect, and stress repeatedly as states in naturalistic environments. In assessing mindfulness, we factorized items from the trait questionnaire CHIME to conceptualize state mindfulness, finding two mindfulness facets labeled Awareness and Acceptance. Affect was measured using the Positive and Negative Affect Schedule, and perceived stress was rated by a single item. Data was gathered by a smartphone app that prompted participants six times a day for 10 consecutive days. Using hierarchical regression, we examined associations at the same time-point as well as with time lags, in order to also elucidate Granger causal relationships. Fifty-six practicing meditators participated in this study.

Results

Concerning the associations of state mindfulness facets with affectivity at the same time, both Awareness and Acceptance were linked with positive affect and negatively with stress. Negative affect was associated negatively with Acceptance. The lagged analyses suggested the Granger causal interpretation that Acceptance reduced negative affect. We also found reversed lagged effects, in that positive affect attenuated subsequent Awareness and negative affect subsequent Acceptance.

Conclusions

The bidirectional Granger causal effects between mindfulness and affect challenged a one-sided interpretation of mindfulness-affect associations. One implication for psychotherapy may be to clarify why mindfulness and resilience (i.e., therapists’ hardiness with respect to adversity) are properties of efficient therapists.
COVID-19 infection map generation and detection from chest X-ray images
Authors: Degerli Aysen , Ahishali Mete , Yamac Mehmet , Kiranyaz Serkan , Chowdhury Muhammad E. H. , Hameed Khalid , Hamid Tahir , Mazhar Rashid , Gabbouj Moncef
Published: April 2021

Computer-aided diagnosis has become a necessity for accurate and immediate coronavirus disease 2019 (COVID-19) detection to aid treatment and prevent the spread of the virus. Numerous studies have proposed to use Deep Learning techniques for COVID-19 diagnosis. However, they have used very limited chest X-ray (CXR) image repositories for evaluation with a small number, a few hundreds, of COVID-19 samples. Moreover, these methods can neither localize nor grade the severity of COVID-19 infection. For this purpose, recent studies proposed to explore the activation maps of deep networks. However, they remain inaccurate for localizing the actual infestation making them unreliable for clinical use. This study proposes a novel method for the joint localization, severity grading, and detection of COVID-19 from CXR images by generating the so-calledinfection maps. To accomplish this, we have compiled the largest dataset with 119,316 CXR images including 2951 COVID-19 samples, where the annotation of the ground-truth segmentation masks is performed on CXRs by a novel collaborative human–machine approach. Furthermore, we publicly release the first CXR dataset with the ground-truth segmentation masks of the COVID-19 infected regions. A detailed set of experiments show that state-of-the-art segmentation networks can learn to localize COVID-19 infection with an F1-score of 83.20%, which is significantly superior to the activation maps created by the previous methods. Finally, the proposed approach achieved a COVID-19 detection performance with 94.96% sensitivity and 99.88% specificity.
Identification of nonlinear dynamical systems with time delay
Authors: Leylaz Ghazaale , Wang Shuo , Sun Jian-Qiao
Published: April 2021

This paper proposes a technique to identify nonlinear dynamical systems with time delay. The sparse optimization algorithm is extended to nonlinear systems with time delay. The proposed algorithm combines cross-validation techniques from machine learning for automatic model selection and an algebraic operation for preprocessing signals to filter the noise and for removing the dependence on initial conditions. We further integrate the bootstrapping resampling technique with the sparse regression to obtain the statistical properties of estimation. We use Taylor expansion to parameterize time delay. The proposed algorithm in this paper is computationally efficient and robust to noise. A nonlinear Duffing oscillator is simulated to demonstrate the efficiency and accuracy of the proposed technique. An experimental example of a nonlinear rotary flexible joint is presented to further validate the proposed method.
Computation of Energy Absorption and Residual Voltage in a Fourth Rail LRT Station Arresters in EMTP-RV: A Comparative Study
Authors: Abd Rahman Farah Asyikin , Ab Kadir Mohd Zainal Abidin , Ungku Amirulddin Ungku Anisa , Osman Miszaina
Published: April 2021

This paper presents a study on the performance of a fourth rail direct current (DC) urban transit affected by an indirect lightning strike. The indirect lightning strike was replicated and represented by a lightning-induced overvoltage by means of the Rusck model, with the sum of two Heidler functions as its lightning channel base current input, on a perfect conducting ground. This study aims to determine whether an indirect lightning strike has any influence with regard to the performance of the LRT Kelana Jaya line, a fourth rail DC urban transit station arrester. The simulations were carried out using the Electromagnetic Transients Program–Restructured Version (EMTP–RV), which includes the comparison performance results between the 3EB4-010 arrester and PDTA09 arrester when induced by a 90 kA (9/200 µs). The results demonstrated that the PDTA09 arrester showed better coordination with the insulated rail bracket of the fourth rail. It allowed a lower residual voltage and a more dynamic response, eventually resulting in better voltage gradient in the pre-breakdown region and decreased residual voltage ratio in the high current region.
Coping with religious conflicts
Authors: Heyden Katharina , Mona Martino
Published: April 2021

This article presents conceptual results from the Interfaculty Research Cooperation “Religious Conflicts and Coping Strategies” at the University of Bern. Since 2018, researchers from various academic disciplines—theology, psychology, law, religious studies, social anthropology, jewish studies, islamic studies, political sciences, history, communication studies, philosophy, gender studies and german studies—have been comparatively investigating past and present conflicts with religious dimensions.

Conflicts involving religion often intensify, elude resolution or lose their constructive and socializing potential, because strong emotional, factual and interpretive aspects are interwoven. Established strategies of conflict resolution therefore often reach their limits in such conflicts. We show that the concept of coping has the advantage of focusing on the process rather than on the resolution of conflicts. It does not aim at solving a conflict that may not be solved, but it aims at looking for ways to shape and manage conflicts with religious dimensions. Coping as a concept originates from psychologists, who describe individuals as active beings who are able to deal with stressful situations on emotional, factual and interpretative-evaluative levels. The different types of coping correlate with three essential dimensions of religion. Therefore, coping as a travelling concept can be particularly fruitful for the interdisciplinary study of conflicts with religious dimensions. It fosters a context-sensitive and differentiated analysis of the dynamics of religious conflicts and may therefore contribute to develop the approach of conflict transformation. First, this paper presents guiding questions for such a context-sensitive conflict analysis; second, it presents an analytical model that visualizes the relevant conflict factors, dimensions of religion and types of coping and facilitates questions about their interactions.
Secondary metabolites, antibacterial and antioxidant properties of the leaf extracts of Acacia rigidula benth. and Acacia berlandieri benth.
Authors: Cavazos Peter , Gonzalez David , Lanorio Jocelyn , Ynalvez Ruby
Published: April 2021

The use of plants as sources for novel antimicrobial as well as antioxidant agents offers advantages. Plants are readily accessible and inexpensive, extracts or compounds from plant sources often demonstrate high level of biological activities. Previous studies have reported antibacterial and antifungal activities within the Fabaceae family that included Acacia species. This study aims to determine presence of antibacterial activity, antioxidant activity, and the secondary metabolites of sequential solvent extracts (acetone, methanol, and acetic acid) of Acacia berlandieri and Acacia rigidula leaves. The antibacterial activity was investigated using a disc diffusion assay. The ferric thiocyanate method was used to assess the ability of all extracts to prevent oxidation. Qualitative phytochemical tests, NMR, IR, and UV–Vis spectroscopy were done to identify potential secondary metabolites. P. alcalifaciens (p < 0.001), E. faecalis (p < 0.01), S. aureus (p < 0.001), and Y. enterocolitica (p < 0.001) were significantly inhibited by A. rigidula extracts when compared to A. berlandieri extracts. A. rigidula’s acetone extract exhibited the significantly (p < 0.001) highest inhibition of peroxidation, 42%. Qualitative phytochemical tests showed positive results for presence of phenols, flavonoids, saponins, terpenes and tannins. NMR, IR, and UV–Vis spectroscopy revealed chemical structures found in flavonoids, saponins, terpenes and tannins, supporting the results of qualitative phytochemical tests. A. berlandieri and A. rigidula leaf extracts have revealed presence of medicinally valued bioactive components. The results of this study provide a basis for further investigations of the A. rigidula leaf extracts. A. rigidula leaf extracts have the potential to serve as a source of novel antimicrobial and antioxidant agents.

Graphic abstract
Assessment of endogenous fibrinolysis in clinical practice using novel tests: ready for clinical roll-out?
Authors: Gue Ying X. , Ding Wern Yew , Lip Gregory Y. H. , Gorog Diana A.
Published: April 2021

The occurrence of thrombotic complications, which can result in excess mortality and morbidity, represent an imbalance between the pro-thrombotic and fibrinolytic equilibrium. The mainstay treatment of these complications involves the use of antithrombotic agents but despite advances in pharmacotherapy, there remains a significant proportion of patients who continue to remain at risk. Endogenous fibrinolysis is a physiological counter-measure against lasting thrombosis and may be measured using several techniques to identify higher risk patients who may benefit from more aggressive pharmacotherapy. However, the assessment of the fibrinolytic system is not yet accepted into routine clinical practice. In this review, we will revisit the different methods of assessing endogenous fibrinolysis (factorial assays, turbidimetric lysis assays, viscoelastic and the global thrombosis tests), including the strengths, limitations, correlation to clinical outcomes of each method and how we might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.
An evolutionary perspective on the emergence and implementation of mission-oriented innovation policy: the example of the change of the leitmotif from biotechnology to bioeconomy
Authors: Prochaska Leonard , Schiller Daniel
Published: April 2021

The design and implementation of innovation policy funding programmes has been the subject of scientific and political debate for decades. Especially the increasingly popular approach of mission-oriented innovation policies is a much discussed subject. The question of how missions arise, what rhetoric accompanies them and how they are eventually implemented has not yet been sufficiently clarified and specification is lacking. Whether mission-oriented innovation policy actually follows a strict top-down logic, or whether the policymaking process rather resembles a certain evolutionary scheme is questioned in this study. On the basis of the change within many policy strategy papers from biotechnology to a much broader bioeconomy, it is shown that, in reality, the transition does not follow a linear sequence. Neither excessive prioritisation nor neglect of a selected sector can be confirmed in this analysis. Within the bioeconomy, however, a clear change can be identified. Biotechnology funding was visibly reduced as part of the change of leitmotif while R&D increased in the agricultural sector in particular. Furthermore, it becomes clear that the issue of missing markets, which is predicted in theoretical studies, can also be confirmed empirically. So far, in terms of public involvement, little effort has been invested in the practical application of bioeconomical knowledge, which is why the intended transition towards bio-based economic activities is lagging behind expectations.
Green hydrogen: The only oxygen and water balanced fuel
Authors: Newborough Marcus , Cooley Graham
Published: April 2021

The use of any fuel depletes the oxygen content of the atmosphere, with one exception: hydrogen produced from water. Water electrolysis liberates oxygen from water in the precise stoichiometric ratio required to oxidise (and hence release energy from) the co-produced hydrogen. As a commercial fuel production process, electrolysis is unique in providing the oxidant as well as the fuel; electrolytic oxygen can thereby replenish the consumption of atmospheric oxygen due to hydrogen use. Furthermore, the amount of water consumed during electrolysis is reproduced when the hydrogen is oxidised. So the use of electrolysers and electrolytic hydrogen does not affect global oxygen and water resources: ‘green’ hydrogen may thus be described as the only oxygen and water balanced fuel. Conversely, the use of hydrogen derived from fossil fuels (with or without carbon capture and storage, CCS) depletes the oxygen resource and increases water vapour emissions to the atmosphere, which enhances the rate of global warming. Therefore, a worldwide multi-TW deployment of electrolysers could provide very substantial amounts of hydrogen for the energy system, and oxygen for the global ecosystem. This should be done in combination with other measures for combatting oxygen depletion (such as reducing combustion, increasing forestation, and reducing nutrient inputs to the ocean from sewage and agriculture). In this way the long-term objective should be to stabilise, or even increase slightly, the concentrations of atmospheric and aquatic oxygen, and possibly speed up the decay of atmospheric methane. Clearly the production-and-use of hydrogen derived from fossil fuels contravenes this objective, and should cease without delay.
June Fourth
Authors: Brown Jeremy
Published: April 2021

The Tiananmen protests and Beijing massacre of 1989 were a major turning point in recent Chinese history. In this new analysis of 1989, Jeremy Brown tells the vivid stories of participants and victims, exploring the nationwide scope of the democracy movement and the brutal crackdown that crushed it. At each critical juncture in the spring of 1989, demonstrators and decision makers agonized over difficult choices and saw how events could have unfolded differently. The alternative paths that participants imagined confirm that bloodshed was neither inevitable nor necessary. Using a wide range of previously untapped sources and examining how ordinary citizens throughout China experienced the crackdown after the massacre, this ambitious social history sheds fresh light on events that continue to reverberate in China to this day.
Molecular evidence for hybridization in the aquatic plant Limosella on sub-Antarctic Marion Island
Authors: Chau John H. , Greve Michelle , Jansen van Vuuren Bettine
Published: April 2021

DNA sequence data have become a crucial tool in assessing the relationship between morphological variation and genetic and taxonomic groups, including in the Antarctic biota. Morphologically distinct populations of submersed aquatic vascular plants were observed on sub-Antarctic Marion Island, potentially representing the two species of such plants listed in the island's flora, Limosella australis R.Br. (Scrophulariaceae) and Ranunculus moseleyi Hook.f. (Ranunculaceae). To confirm their taxonomic identity, we sequenced a nuclear locus (internal transcribed spacer; ITS) and two plastid loci (trnL-trnF, rps16) from three specimens collected on Marion Island and compared the sequences with those in public sequence databases. For all three loci, sequences from the Marion Island specimens were nearly identical despite morphological dissimilarity, and phylogenetic analyses resolved them to a position in Limosella. In phylogenetic trees and comparisons of species-specific sequence polymorphisms, the Marion Island specimens were closest to a clade comprising Limosella aquatica L., L. curdieana F.Muell. and L. major Diels for ITS and closest to L. australis for the plastid loci. Cytonuclear discordance suggests a history of hybridization or introgression, which may have consequences for morphological variability and ecological adaptation.
Lern-Managementsystem ILIAS
Authors: Westhof Sadija
Published: April 2021

Zusammenfassung. Das Lern-Management-System ILIAS (Integriertes Lern-, Informations- und Arbeitskooperations-System) bietet Instrumente und Werkzeuge, die reine E-Learning Szenarien ermöglichen z. B. virtuelle Seminare. Zudem kann das Lern-Management-System auch in Lernszenarien agieren, die Präsenz- und Computerbasiertes Lernen im sinnvollen Wechsel einsetzen.
Research on neck dissection for oral squamous-cell carcinoma: a bibliometric analysis
Authors: Jiang Zhou , Wu Chenzhou , Hu Shoushan , Liao Nailin , Huang Yingzhao , Ding Haoran , Li Ruohan , Li Yi
Published: April 2021

Neck dissection for oral squamous-cell carcinoma (OSCC) is a clinically controversial issue and has therefore been the subject of abundant research. However, no one has performed a bibliometric study on this topic to date. The aim of this study was to assess the development of research on neck dissection for OSCC in terms of the historical evolution, current hotspots and future directions, particularly including research trends and frontiers from 2010 to 2019. Literature records related to research on neck dissection for OSCC were retrieved from the Web of Science Core Collection (WoSCC). CiteSpace was used as a tool to perform a bibliometric analysis of this topic. The survey included 2 096 papers. “Otorhinolaryngology” was the most popular research area. The most active institutions and countries were Memorial Sloan Kettering Cancer Center and the USA, respectively. Shah J.P. was the most cited author. Among the six identified “core journals”,Head & Neckranked first. The top three trending keywords were ‘invasion’, ‘upper aerodigestive’ and ‘negative neck’. ‘D’Cruz AK (2015)’ was the most cited and the strongest burst reference in the last decade. The study evaluated the effect on survival of elective versus therapeutic neck dissection in patients with lateralized early-stage OSCC. The depth of invasion and the management of N0 OSCC were research frontiers in this field. The present study provides a comprehensive bibliometric analysis of research on neck dissection for OSCC, which will assist investigators in exploring potential research directions.
Depression patient-derived cortical neurons reveal potential biomarkers for antidepressant response
Authors: Avior Yishai , Ron Shiri , Kroitorou Dana , Albeldas Claudia , Lerner Vitaly , Corneo Barbara , Nitzan Erez , Laifenfeld Daphna , Cohen Solal Talia
Published: April 2021

Major depressive disorder is highly prevalent worldwide and has been affecting an increasing number of people each year. Current first line antidepressants show merely 37% remission, and physicians are forced to use a trial-and-error approach when choosing a single antidepressant out of dozens of available medications. We sought to identify a method of testing that would provide patient-specific information on whether a patient will respond to a medication using in vitro modeling. Patient-derived lymphoblastoid cell lines from the Sequenced Treatment Alternatives to Relieve Depression study were used to rapidly generate cortical neurons and screen them for bupropion effects, for which the donor patients showed remission or non-remission. We provide evidence for biomarkers specific for bupropion response, including synaptic connectivity and morphology changes as well as specific gene expression alterations. These biomarkers support the concept of personalized antidepressant treatment based on in vitro platforms and could be utilized as predictors to patient response in the clinic.
HomeoboxC6 promotes metastasis by orchestrating the DKK1/Wnt/β-catenin axis in right-sided colon cancer
Authors: Qi Lina , Chen Jiani , Zhou Biting , Xu Kailun , Wang Kailai , Fang Zhihao , Shao Yingkuan , Yuan Ying , Zheng Shu , Hu Wangxiong
Published: April 2021

Patients with right-sided colon cancer (RCC) generally have a poorer prognosis than those with left-sided colon cancer (LCC). We previously found that homeobox C6 (HOXC6) was the most significantly upregulated gene in RCC compared to LCC. However, it remains unclear whether HOXC6 plays a role in tumor proliferation and metastasis. Our study aimed to explore the potential oncogenic role and the detailed molecular mechanism of HOXC6 in RCC. In this study, HOXC6 was validated to be overexpressed in RCC and associated with poor prognosis. Furthermore, overexpression of HOXC6 promoted the migration and invasion of colon cancer cells through inducing EMT by activating the Wnt/β-catenin signaling pathway and inhibition of DKK1 secretion. Lastly, we preliminary explored the translational effect of HOXC6 and found that silencing of HOXC6 made HCT116 and HT29 cells more sensitive to irinotecan.
A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes
Authors: Hildebrand Joanne M. , Lo Bernice , Tomei Sara , Mattei Valentina , Young Samuel N. , Fitzgibbon Cheree , Murphy James M. , Fadda Abeer
Published: April 2021

Maturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.
CRISPR/Cas9-mediated mutagenesis of ClBG1 decreased seed size and promoted seed germination in watermelon
Authors: Wang Yanping , Wang Jinfang , Guo Shaogui , Tian Shouwei , Zhang Jie , Ren Yi , Li Maoying , Gong Guoyi , Zhang Haiying , Xu Yong
Published: April 2021

Abscisic acid (ABA) is a critical regulator of seed development and germination. β-glucosidases (BGs) have been suggested to be contributors to increased ABA content because they catalyze the hydrolysis of ABA-glucose ester to release free ABA. However, whether BGs are involved in seed development is unclear. In this study, a candidate gene,ClBG1, in watermelon was selected for targeted mutagenesis via the CRISPR/Cas9 system. Seed size and weight were significantly reduced in theClbg1-mutant watermelon lines, which was mainly attributed to decreased cell number resulting from decreased ABA levels. A transcriptome analysis showed that the expression of 1015 and 1429 unique genes was changed 10 and 18 days after pollination (DAP), respectively. Cytoskeleton- and cell cycle-related genes were enriched in the differentially expressed genes of wild type andClbg1-mutant lines during seed development. Moreover, the expression of genes in the major signaling pathways of seed size control was also changed. In addition, seed germination was promoted in theClbg1-mutant lines due to decreased ABA content. These results indicate thatClBG1may be critical for watermelon seed size regulation and germination mainly through the modulation of ABA content and thereby the transcriptional regulation of cytoskeleton-, cell cycle- and signaling-related genes. Our results lay a foundation for dissecting the molecular mechanisms of controlling watermelon seed size, a key agricultural trait of significant economic importance.
Venous thromboembolism is caused by prothrombin p.Arg541Trp mutation in Japanese individuals
Authors: Yamamoto Jumpei , Yamamoto Masaya , Takano Kozue , Okazaki Toru , Arakawa Reiko , Hara Hisao , Okazaki Atsuko , Takeuchi Fumihiko , Hiroi Yukio , Kato Norihiro
Published: April 2021

Venous thromboembolism (VTE) is a multifactorial disease. Because low-frequency variants and rare mutations have been found to predispose carriers toward VTE, there is a need for variant discovery in clinical settings. Therefore, we used a whole-exome approach for a young VTE patient with a positive family history. We identified in the proband and his affected mother a rare, functional missense variant of prothrombin, p.Arg541Trp, which contributes to the clinical picture of VTE.
Structure of the complete, membrane-assembled COPII coat reveals a complex interaction network
Authors: Hutchings Joshua , Stancheva Viktoriya G. , Brown Nick R. , Cheung Alan C. M. , Miller Elizabeth A. , Zanetti Giulia
Published: April 2021

COPII mediates Endoplasmic Reticulum to Golgi trafficking of thousands of cargoes. Five essential proteins assemble into a two-layer architecture, with the inner layer thought to regulate coat assembly and cargo recruitment, and the outer coat forming cages assumed to scaffold membrane curvature. Here we visualise the complete, membrane-assembled COPII coat by cryo-electron tomography and subtomogram averaging, revealing the full network of interactions within and between coat layers. We demonstrate the physiological importance of these interactions using genetic and biochemical approaches. Mutagenesis reveals that the inner coat alone can provide membrane remodelling function, with organisational input from the outer coat. These functional roles for the inner and outer coats significantly move away from the current paradigm, which posits membrane curvature derives primarily from the outer coat. We suggest these interactions collectively contribute to coat organisation and membrane curvature, providing a structural framework to understand regulatory mechanisms of COPII trafficking and secretion.
Differential controls of MAIT cell effector polarization by mTORC1/mTORC2 via integrating cytokine and costimulatory signals
Authors: Tao Huishan , Pan Yun , Chu Shuai , Li Lei , Xie Jinhai , Wang Peng , Zhang Shimeng , Reddy Srija , Sleasman John W. , Zhong Xiao-Ping
Published: April 2021

Mucosal-associated invariant T (MAIT) cells have important functions in immune responses against pathogens and in diseases, but mechanisms controlling MAIT cell development and effector lineage differentiation remain unclear. Here, we report that IL-2/IL-15 receptor β chain and inducible costimulatory (ICOS) not only serve as lineage-specific markers for IFN-γ-producing MAIT1 and IL-17A-producing MAIT17 cells, but are also important for their differentiation, respectively. Both IL-2 and IL-15 induce mTOR activation, T-bet upregulation, and subsequent MAIT cell, especially MAIT1 cell, expansion. By contrast, IL-1β induces more MAIT17 than MAIT1 cells, while IL-23 alone promotes MAIT17 cell proliferation and survival, but synergizes with IL-1β to induce strong MAIT17 cell expansion in an mTOR-dependent manner. Moreover, mTOR is dispensable for early MAIT cell development, yet pivotal for MAIT cell effector differentiation. Our results thus show that mTORC2 integrates signals from ICOS and IL-1βR/IL-23R to exert a crucial role for MAIT17 differentiation, while the IL-2/IL-15R-mTORC1-T-bet axis ensures MAIT1 differentiation.
Skeletal muscle transcriptome in healthy aging
Authors: Tumasian Robert A. , Harish Abhinav , Kundu Gautam , Yang Jen-Hao , Ubaida-Mohien Ceereena , Gonzalez-Freire Marta , Kaileh Mary , Zukley Linda M. , Chia Chee W. , Lyashkov Alexey , Wood William H. , Piao Yulan , Coletta Christopher , Ding Jun , Gorospe Myriam , Sen Ranjan , De Supriyo , Ferrucci Luigi
Published: April 2021

Age-associated changes in gene expression in skeletal muscle of healthy individuals reflect accumulation of damage and compensatory adaptations to preserve tissue integrity. To characterize these changes, RNA was extracted and sequenced from muscle biopsies collected from 53 healthy individuals (22–83 years old) of the GESTALT study of the National Institute on Aging–NIH. Expression levels of 57,205 protein-coding and non-coding RNAs were studied as a function of aging by linear and negative binomial regression models. From both models, 1134 RNAs changed significantly with age. The most differentially abundant mRNAs encoded proteins implicated in several age-related processes, including cellular senescence, insulin signaling, and myogenesis. Specific mRNA isoforms that changed significantly with age in skeletal muscle were enriched for proteins involved in oxidative phosphorylation and adipogenesis. Our study establishes a detailed framework of the global transcriptome and mRNA isoforms that govern muscle damage and homeostasis with age.