bluuebunny/crossref_metadata_2025 huggingface dataset:
The Circular Decision-Making Tree: an Operational Framework
Authors: Greer Rachel , von Wirth Timo , Loorbach Derk
Published: September 2022

Because of the need to limit extraction of raw materials and reduce amounts and impacts of waste, countries and businesses are challenged to transition to a circular economy: an economic system in which the materials are reduced, reused, or recycled, but not wasted. Yet, transitioning from a linear to a circular economy implies societal-level, structural changes that have deep implications for existing business models and practices–and the current economic system is still largely organized around virgin material extraction and linear modes of production and consumption. Despite stated ambitions at various geographical scales to become more or fully circular, the outcomes still fall short of such visions. One important reason why the transition towards a circular economy is not proceeding as quickly as hoped can be found in the decision processes used by companies, investors, and policy makers. Suitable frameworks that support decision-making could thus be a key enabler of this transition, if based upon a circular and transformative, rather than a linear optimization logic. In this paper, we therefore explore a different decision-making logic that is developed based on circularity. This provides the basis for an operational framework designed to help decision-makers such as policymakers, investors, and entrepreneurs navigate tradeoffs and take decisions considering the quality of innovation circularity and its respective diffusion potential. To develop, test, and refine our framework—the “Circular Decision-Making Tree”—we synthesized insights from existing frameworks and conceptually integrated these with our understanding of transition theory and the circular economy. We then verified the internal logics and applicability of the framework in a series of usability workshops across four application contexts (Netherlands, Brazil, UK, and South Africa) with feedback from a total of n = 50 stakeholders from policy, practice, and academia. We critically discuss the application potential as well as the limitations and describe implications for future research to further validate the framework’s logics and operationalization.
Acaricide resistance and novel photosensitizing approach as alternative acaricides against the camel tick, Hyalomma dromedarii
Authors: Mohammed Shaimaa H. , Baz Mohamed M. , Ibrahim Moustafa , Radwan Ibrahim T. , Selim Abdelfattah , Dawood Abdel-Fattah D. , Taie Hanan A. A. , Abdalla Salwa , Khater Hanem F.
Published: September 2022

The control of the camel tick, Hyalomma dromedarii is very crucial. This study evaluated the novel toxicity of photosensitizers and Phoxim insecticide against H. dromedarii males using the adult immersion tests. Ticks were subjected to sunlight for 10 min post-treatment (PT). The optical characters of the applied materials were determined by UV–Vis spectroscopy (250–900 nm wavelengths). The intensity of spectra decreased as dye concentration decreased. The optical bandgap energies of the dyes at different concentrations were not changed as the concentration changed and decreased as the absorption peak of individual dyes red-shifted. The mortalities 72 h PT reached 42.2%, 44.4%, 51.1%, 71.1%, 46.7%, 48.9%, 44.4%, and 55.6% for chlorophyllin, echinochrome, field stain, methylene blue, phthalocyanine, rhodamine 6G, riboflavin, and safranin, respectively. Methylene blue recorded the highest median lethal concentration (LC50 = 127 ppm) followed by safranin, field stain, rhodamine 6G, phthalocyanine, echinochrome riboflavin, and chlorophyllin (LC50 = 209, 251, 271, 303, 324, 332, and 362 ppm, respectively, 72 h PT). Their median lethal time, LT50, values PT with 240 ppm were 45, 87, 96, 72, 129, 115, 131, and 137 h, respectively. The relative toxicities of the LC50 values 72 h PT showed that chlorophyllin, echinochrome, field stain, methylene blue, phthalocyanine, rhodamine 6G, riboflavin, and safranin were 3.2, 3.6, 4.6, 9.1, 3.8, 4.3, 3.5, and 5.6 times, respectively, more effective than Phoxim. Methylene blue, safranin, and field stain showed a broad absorbance area indicating a large photoactivity and better phototoxicity and could be used as alternative agents to synthetic acaricides.

Graphical Abstract
Analysis of local governments’ marine governance efficiency using a spatiotemporal coupling coordination model: a case study of coastal cities in Liaoning Province, China
Authors: Liu Wanbo , Shen Fangfang , Zhao Dongxia
Published: September 2022

Coastal areas have the most obvious ocean–land interaction and experience the most frequent human activities. As the development of coastal areas has a high degree of spatiotemporal variability, local governments bear direct responsibility for marine governance, yet accurately evaluating and analyzing local governments’ marine governance efficiency in coastal areas is challenging. This study constructs a spatiotemporal coupling coordination model to comprehensively evaluate local governments’ marine governance efficiency in six coastal cities in Liaoning Province from 2004 to 2019. A complex system was necessary to obtain the development level, discrete degree, and development speed of each subsystem. The construction of the evaluation index system was the foundation, and the construction of the spatiotemporal weight matrix was the key. The results show that overall, the local governments’ marine governance efficiency level is generally increasing, and the agglomeration effect is obvious. The efficiency of each cities’ economic, ecological, and social governance subsystem is in a process of continuous and dynamic change. The coupling and coordination degrees of the six governance systems have continuously improved and the spatial and temporal differences have decreased; each city shows different coupling and coordination degrees in each subsystem. Regarding the factors affecting comprehensive marine management, Liaoning’s coastal areas fail to attract foreign tourists; the discharge and treatment of industrial wastewater restricts ecological governance; and the reduction of fisheries hinders the social governance system’s efficiency. The results contribute to the understanding of costal cities’ marine governance and promote the sustainable development of coastal areas.
Environmental Health Intelligence New Zealand (EHINZ): intelligence for public health action
Authors: Borman Barry , Haenfling Carolin , Kowalik-Tait Agnieszka , Hipgrave Patrick
Published: September 2022

The New Zealand health system is data-rich, information-poor, and intelligence meagre. However, there is widespread confusion about the definitions of these terms, so they are often used synonymously. Like many jurisdictions, we continue to collect and collate vast quantities of data at an increasing rate. Many tools are available to “analyse” the data deluge with the false expectation that “intelligence” will be produced. Naively, such a data-driven, machine-analysed paradigm is often thought to produce the “evidence” for decision-making and policy development. Continuing such a blinded approach poses potential health risks to New Zealanders and remains a major impediment to improving our health status

Creating intelligence from information involves humans (perhaps in concert with AI) utilising their interpretative abilities, asking the “so what, “what does it mean” questions, and employing their communication skills to disseminate the answers. To move from information to intelligence requires agencies to employ, develop and maintain a sufficiently skilled workforce over a long period, rather than the quick and easy investment in more and faster machines and software.

Only through a human-driven evaluation of intelligence-based decisions and policies will our knowledge about the environmental health system increase and ultimately yield better health outcomes.

Environmental Health Intelligence NZ (EHINZ) provides intelligence as evidence for decision-making and policy development in environmental health. It is based on the interpretation, communication, and dissemination of information from the surveillance more than seventy environmental health indicators (EHIs) across twelve domains (e.g., air and water quality, climate change), exposure to hazardous substances, and social vulnerability indicators to environmental hazards (e.g., flooding, climate change, sea-level rise, wildfires, heat waves).

The paper details our approach, with two case studies, in providing the NZ health system with “intelligence for environmental health decisions.”
The Politics of Data in EU Law: Will It Succeed?
Authors: Pagallo Ugo
Published: September 2022

The paper examines recent initiatives of the European Commission that aim to complement today’s legislation on the internet, data governance, and technological innovation, and how scholars have attempted to sum up current trends of EU law according to some catchy formulas: digital sovereignty, digital constitutionalism, or a renewed Brussels effect. Although such narratives have their merits, they can also be misleading and should be taken with a pinch of salt. The paper intends to complement such narratives in connection with the open issues on the balance of powers between EU institutions and member states (MS), with a new generation of digital rights at both EU and MS constitutional levels, down to the interplay between new models of legal governance and the potential fragmentation of the system. Whether and to what extent EU law will be successful in the regulation of data-driven societies and complex digital ecosystems do not only regard acts, policies, and proposals against misuses and overuses of technology but also how well mechanisms of coordination and models of cooperation set up by EU law will fare against technological underuses with their opportunity costs.
Unsteady convective–diffusive transport in semicircular microchannels with irreversible wall reaction
Authors: Azari Milad , Sadeghi Arman
Published: September 2022

The unsteady dispersion of a solute band by a steady pressure-driven flow in a semicircular microchannel is theoretically studied via the generalized dispersion model. Considering an irreversible first-order reaction at the curved wall while assuming a no-flux boundary condition at the flat wall, analytical solutions are obtained for the exchange, convection and dispersion coefficients as well as the dimensionless forms of solute concentration and mean solute concentration. The solutions are obtained assuming an initial solute band of arbitrary cross-sectional shape and axial distribution and the results are presented for both circular and semicircular shapes with the uniform distribution being a special case of the latter. Besides the general solutions, special solutions are also derived for uniform velocity and no-reaction cases. In the following, the influences of the initial concentration distribution and the Damköhler number, a measure of the reaction rate, on the transport coefficients and the concentration distribution are investigated in depth. It is demonstrated that the combination of the initial concentration distribution and the Damköhler number specifies the variations of the transport coefficients in the short term but the Damköhler number is the only parameter dominating the long-term values: the exchange and convection coefficients are increasing functions of the Damköhler number whereas the opposite is true for the dispersion coefficient. Moreover, we show that, provided the solute injection is appropriately positioned and shaped, liquid-phase transportation with little dispersion is possible in typical microchannels utilizing semicircular geometry.
The dynamics of a rigid inverted flag
Authors: Leontini Justin S. , Sader John E.
Published: September 2022

An ‘inverted flag’ – a flexible plate clamped at its trailing edge – undergoes large-amplitude flow-induced flapping when immersed in a uniform and steady flow. Here, we report direct numerical simulations of a related single degree-of-freedom mechanical system: a rigid plate attached at its trailing edge to a torsional spring. This system is termed a ‘rigid inverted flag’ and exhibits the dynamical states reported for the (flexible) inverted flag, with additional behaviour. This finding shows that the flapping dynamics of inverted flags is not reliant on their continuous flexibility, i.e. many degrees of freedom. The rigid inverted flag exhibits additional, novel states including a heteroclinic-type orbit that results in small-amplitude flapping, and a number of chaotic large-amplitude flapping regimes. We show that the various routes to chaos are driven by a series of periodic states, including at least two which are subharmonic. The instability and competition between these periodic states lead to chaos via type-I intermittency, mode competition and mode locking. The rigid inverted flag allows these periodic states and their subsequent interaction to be explained simply: they arise from an interaction between a preferred vortex shedding frequency and a single natural frequency of the structure. The dynamics of rigid inverted flags is yet to be studied experimentally, and this numerical study provides impetus for such future work.
Experimental study of bubble competition and spike competition in Richtmyer–Meshkov flows
Authors: Liang Yu , Liu Lili , Luo Xisheng
Published: September 2022

Shock-tube experiments on various two-bubble and two-spike interfaces are performed to examine the dependence of bubble competition and spike competition on the initial spectra and density ratio of the interface. The differences in the influences of bubble competition and spike competition on the Richtmyer–Meshkov instability are highlighted for the first time. The bubble-competition effect is mainly dependent on the initial spectra of the two-bubble configuration. In contrast, the spike-competition effect is determined by both the initial spectra and density ratio. The extended buoyancy–drag model is adopted to explain the variation of the drag force imposed on the long-wavelength and short-wavelength structures as the initial conditions change. Based on the spectrum analysis, it is found that the constituent modes of two-bubble and two-spike interfaces have different contributions to the long-wavelength and short-wavelength perturbation growths. A generalised, nonlinear, analytical model is then established to quantify the bubble-competition effect and spike-competition effect considering arbitrary initial spectra and density ratio. The bubble-competition effect is believed to be stronger than the spike-competition effect at a high density ratio because it suppresses the high-frequency perturbation growth more evidently.
State-Enabled Killing of Same-Sex-Attracted People: A Legal Pluralist Account
Authors: Alexander Christopher , Sato Mai , Zanghellini Aleardo
Published: September 2022

In eleven countries, same-sex sexual intimacy is punishable by death. Applying a legal pluralistic framework, we argue that “state-enabled killing” of same-sex-attracted people occurs in at least twenty-three countries. State-enabled killings range from extrajudicial and quasi-judicial killings, where state actors carry out the killing, through instances where the state retrospectively authorizes, through bias or lawful excuses to homicide, the killing of same-sex-attracted people by private actors, to cases where the state permits or endorses forms of so-called “conversion therapy” that can lead to death. We contend that a narrow focus on the death penalty as the only genuine form of state-enabled killing of same-sex-attracted people is analytically unwarranted and strategically dubious in terms of law reform advocacy. Critical legal pluralism allows us to pursue the practical and normative implications of hypothesizing a functional equivalence between the death penalty and these other forms of state-enabled killing.
A test of Bergmann's rule in the Early Triassic: latitude, body size, and sampling in Lystrosaurus
Authors: Kulik Zoe T. , Sidor Christian A.
Published: September 2022

The ecogeographic rule known as Bergmann's rule suggests that there is a positive relationship between body size and latitude when comparing closely related taxa. The underlying mechanism or mechanisms to explain this pattern vary as widely as the taxa that seem to follow it, which has led to skepticism over whether Bergmann's rule should be considered a rule at all. Despite this, Bergmann's rule is widespread among modern birds, mammals, beetles, and some amphibians, but far fewer extinct taxa have been subjected to tests of Bergmann's rule. To examine whether Bergmann's rule is detected in extinct taxa, we compared body-size proxies in Lystrosaurus recovered from Early Triassic–aged strata in Antarctica, South Africa, India, and China. Our results reveal that average body size is largest at mid-northern paleolatitudes (~45°N) instead of the highest southern paleolatitudes (~70°S). Additionally, maximum body size is consistent across the Northern and Southern Hemispheres, indicating that Bergmann's rule did not apply for Lystrosaurus during the Early Triassic. To test potential sample size biases in our results, we used rarefaction and subsampling to show that only the Karoo Basin is well sampled and that large individuals are exceedingly rare, except in the Turpan-Junggar Basin of Xinjiang, China. Taken together, our results suggest that Lystrosaurus had the potential to reach large body sizes in each of the latitudinally widespread geologic basins studied here, but that local conditions may have allowed individuals at mid-northern paleolatitudes a greater chance of reaching a large size compared with southern congeners that suffered increased mortality when young or at a small size.
Towards Augmented Microscopy with Reinforcement Learning-Enhanced Workflows
Authors: Xu Michael , Kumar Abinash , LeBeau James M
Published: September 2022

Here, we report a case study implementation of reinforcement learning (RL) to automate operations in the scanning transmission electron microscopy workflow. To do so, we design a virtual, prototypical RL environment to test and develop a network to autonomously align the electron beam position without prior knowledge. Using this simulator, we evaluate the impact of environment design and algorithm hyperparameters on alignment accuracy and learning convergence, showing robust convergence across a wide hyperparameter space. Additionally, we deploy a successful model on the microscope to validate the approach and demonstrate the value of designing appropriate virtual environments. Consistent with simulated results, the on-microscope RL model achieves convergence to the goal alignment after minimal training. Overall, the results highlight that by taking advantage of RL, microscope operations can be automated without the need for extensive algorithm design, taking another step toward augmenting electron microscopy with machine learning methods.
Häufigkeit, Heimlichkeit und Einstellung bei der Pornographienutzung und deren Zusammenhänge mit der sexuellen Paarzufriedenheit
Authors: Re Ursina Brun del , Hilpert Peter , Bodenmann Guy
Published: September 2022

Zusammenfassung. Theoretischer Hintergrund: Bisherige Befunde zeigen, dass Pornographienutzung einen Zusammenhang mit der Zufriedenheit in der Paarsexualität hat. Fragestellung: Um diesen Zusammenhang besser zu verstehen, soll diese Studie aufzeigen, welche Faktoren dabei von Bedeutung sind. Methode: Dafür wurden 18- bis 60-Jährige in einer Beziehung ( N = 1’091) anhand eines Online-Fragebogens befragt. Ergebnisse: Sowohl die Häufigkeit der Pornographienutzung, als auch eine negative Einstellung und die Heimlichkeit weisen bei den jungen und Männern mittleren Alters einen negativen Zusammenhang mit der sexuellen Paarzufriedenheit auf. Bei den Frauen jeden Alters hat lediglich eine heimliche Nutzung einen negativen Zusammenhang mit der Paarsexualität. Schlussfolgerungen: Das bedeutet für die Beratung, dass auf die Häufigkeit der Nutzung und die Einstellung zu der Nutzung geachtet werden soll.
Praxisorientierte Forschung in der Psychotherapie
Authors: Herzog Philipp , Kaiser Tim , Brakemeier Eva-Lotta
Published: September 2022

Zusammenfassung. In den letzten Jahrzehnten hat sich durch randomisiert-kontrollierte Studien (RCTs) eine breite Evidenzbasis von Psychotherapie mit mittleren bis großen Effekten für verschiedene psychische Störungen gebildet. Neben der Bestimmung dieser Wirksamkeit („Efficacy“) ebneten Studien zur Wirksamkeit unter alltäglichen Routinebedingungen („Effectiveness“) historisch den Weg zur Entwicklung eines praxisorientierten Forschungsparadigmas. Im Beitrag wird argumentiert, dass im Rahmen dieses Paradigmas praxisbasierte Studien eine wertvolle Ergänzung zu RCTs darstellen, da sie existierende Probleme in der Psychotherapieforschung adressieren können. In der gegenwärtigen praxisorientierten Forschung liefern dabei neue Ansätze aus der personalisierten Medizin und Methoden aus der ‚Computational Psychiatry‘ wichtige Anhaltspunkte zur Optimierung von Effekten in der Psychotherapie. Im Kontext der Personalisierung werden bspw. klinische multivariable Prädiktionsmodelle entwickelt, welche durch Rückmeldeschleifen an Praktiker_innen kurzfristig ein evidenzbasiertes Outcome-Monitoring ermöglicht und langfristig das Praxis-Forschungsnetzwerk in Deutschland stärkt. Am Ende des Beitrags werden zukünftige Richtungen für die praxisorientierte Forschung im Sinne des ‘Precision Mental Health Care’ -Paradigmas abgeleitet und diskutiert.
Social Representations Theory in Creativity Research
Authors: Bonetto Eric , Pichot Nicolas , Lo Monaco Grégory , Girandola Fabien , Bonnardel Nathalie
Published: September 2022

Abstract. Due to the difficulties of understanding all the aspects of creativity, the study of this complex phenomenon has been placed at the crossroads of various disciplines. Among these, social psychology has been interested in this exploration. Incidentally, various approaches in creativity research highlighted the importance of social factors in the production, judgment, and acceptance of creative ideas. Contributions adopting such a social perspective naturally convoked different social psychological theories, among which is the Social Representations Theory. This theory focuses on the collective construction of shared knowledge and beliefs (social representations) within social groups. Interesting perspectives about the contribution of social representations to the study of creativity have been described in previous works. Nevertheless, these works remain rare despite the many possibilities offered by the theoretical and methodological framework of social representations. Consequently, the present contribution recalls briefly the main objectives that these previous works have pursued in order to highlight several unexplored lines of research that could promote theoretical, methodological, and applied advancement. These lines could enrich research related to the evaluation of creativity, the study of creativity as deviance, the stimulation of group creativity, and promote interdisciplinary work. This contribution aims to draw the attention of researchers to these under-exploited perspectives and stimulate the creation of many others to understand better the complex phenomenon of creativity.
Dynamic Assessment of Creativity for Diagnostic Purposes
Authors: Zbainos Dimitrios , Sagia Charis
Published: September 2022

Abstract. The present paper aims to propose the dynamic assessment of creativity for diagnostic purposes, which combines the sociocultural approach to creativity with the findings of creative cognition research. A traditional theorization viewed creativity mainly as an ability of individuals and its expression depending on the extent to which their environment allows and supports it. According to the individualistic approach of creativity, static testing has been its predominant psychological assessment. However, the traditional approach to creativity has been criticized from a sociocultural theoretical perspective that regards creativity as distributed cognition between the mind and culture in recent years. Based on sociocultural theory, dynamic assessment of creativity is an alternative process to static testing for assessing creative potential. Besides testing, in dynamic assessment, the cognitive strategies of creativity that creative cognition research has revealed are mediated in children as symbolic tools or signs. Therefore, in dynamic assessment, sociocultural theory is combined with creative cognition. In the present paper, initially, we present the relevant theory and research on dynamic assessment and creative cognition. Next, studies applying dynamic assessment to children of different ages and devising the mediation protocol will be discussed. Finally, we will consider the psychological and educational implications of dynamic assessment of children’s creativity.
Leveraging Spatial Patterns in Precipitation Forecasts Using Deep Learning to Support Regional Water Management
Authors: Zhang Chen , Brodeur Zachary P. , Steinschneider Scott , Herman Jonathan D.
Published: September 2022

Short‐term precipitation forecasts are critical to regional water management, particularly in the Western U.S. where atmospheric rivers can be predicted reliably days in advance. However, spatial error in these forecasts may reduce their utility when the costs of false positives and negatives differ greatly. Here we investigate whether deep learning methods can leverage spatial patterns in precipitation forecasts to (a) improve the skill of predicting the occurrence of precipitation events at lead times from 1 to 14 days, and (b) balance the tradeoff between the rate of false negatives and false positives by modifying the discrimination threshold of the classifiers. This approach is demonstrated for the Sacramento River Basin, California, using the Global Ensemble Forecast System (GEFS) v2 precipitation fields as input to convolutional neural network (CNN) and multi‐layer perceptron models. Results show that the deep learning models do not significantly improve the overall skill (F1 score) relative to the ensemble mean GEFS forecast with bias‐corrected threshold. However, additional analysis of the CNN models suggests they often correct missed predictions from GEFS by compensating for spatial error at longer lead times. Additionally, the deep learning models provide the ability to adjust the rate of false positives and negatives based on the ratio of costs. Finally, analysis of the network activations (saliency) indicates spatial patterns consistent with physical understanding of atmospheric river events in this region, lending additional confidence in the ability of the method to support water management applications.
Written in Stone: Inca Buildings Remember Ancient Earthquakes
Authors: Martin-Jones Erin
Published: September 2022

Damage to the Inca buildings of Cusco reveals a forgotten earthquake history that could help scientists understand modern seismic hazards.
Model Predictions of Wave Overwash Extent Into the Marginal Ice Zone
Authors: Pitt Jordan P. A. , Bennetts Luke G. , Meylan Michael H. , Massom Robert A. , Toffoli Alessandro
Published: September 2022

In the marginal ice zone (MIZ), where ocean waves and sea ice interact, waves can produce flows of water across ice floe surfaces in a process known as wave overwash. Overwash potentially influences wave propagation characteristics, floe thermodynamics, and floe surface biological and chemical processes. However, the extent of the MIZ affected by overwash and its dependence on prevailing wave and ice conditions is unknown. In this paper, we propose a model of overwash extent caused by irregular incoming waves into a MIZ consisting of a random floe field. We validate the overwash extent model against laboratory experiments. We use the model to study mild to extreme incoming waves to floe field characteristics of the spring–summer ice retreat and autumn–winter ice advance and with compact ice edges. Overwash is typically predicted to extend a few kilometers and is generally greater for the autumn–winter advance than the spring–summer retreat. The model predictions provide a basis for improved understanding of the impacts of ocean waves on the ice cover. We also apply the model to incoming waves and a floe field with a diffuse ice edge representative of conditions during a field experiment, predicting overwash extents up to 16 km. During the field experiment, the wave and ice floe properties were intermittently monitored by a camera system, demonstrating how the sparse field data available on overwash can be advanced.
Internal Tides Responsible for Lithogenic Inputs Along the Iberian Continental Slope
Authors: Barbot Simon , Lagarde Marion , Lyard Florent , Marsaleix Patrick , Lherminier Pascale , Jeandel Catherine
Published: September 2022

This study proposes new insights for the interpretation of GEOVIDE particle measurements. Potential resuspension sites due to internal tides (ITs) have been identified along the western Iberian shelf slope using a tidal regional model. Iberian shelf is mainly a source of lithogenic material whereas Galicia Bank is a source of biogenic matter. The potential pathways for particles from the resuspension sites toward the GEOVIDE stations are identified using IBIRYS reanalysis to infer their transport by the ocean circulation. It appears that each station is influenced by a specific pathway and mixed particles from several resuspension sites. This methodology reveals that the criticality of the bathymetry slope, commonly used to track resuspension sites from internal waves, is not sufficient to investigate ITs. An explicit resolution of ITs using a numerical tidal model is required for an exhaustive identification of the resuspension sites.
Inhibition of phospholipase D1 induces immunogenic cell death and potentiates cancer immunotherapy in colorectal cancer
Authors: Hwang Won Chan , Song Doona , Lee Hyesung , Oh Changmok , Lim Seong Hun , Bae Hyeon Jeong , Kim Nam Doo , Han Gyoonhee , Min Do Sik
Published: September 2022

Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of “do not eat-me” signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of “eat-me” signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.
The serum metabolomic profile of a distinct, inflammatory subtype of acute psychosis
Authors: Lennox Belinda , Xiong Wenzheng , Waters Patrick , Coles Alasdair , Jones Peter B. , Yeo Tianrong , May Jeanne Tan May , Yeeles Ksenija , Anthony Daniel , Probert Fay
Published: September 2022

A range of studies suggest that a proportion of psychosis may have an autoimmune basis, but this has not translated through into clinical practice—there is no biochemical test able to accurately identify psychosis resulting from an underlying inflammatory cause. Such a test would be an important step towards identifying who might require different treatments and have the potential to improve outcomes for patients. To identify novel subgroups within patients with acute psychosis we measured the serum nuclear magnetic resonance (NMR) metabolite profiles of 75 patients who had identified antibodies (anti-glycine receptor [GlyR], voltage-gated potassium channel [VGKC], Contactin-associated protein-like 2 [CASPR2], leucine-rich glioma inactivated 1 [LGI1], N-methyl-D-aspartate receptor [NMDAR] antibody) and 70 antibody negative patients matched for age, gender, and ethnicity. Clinical symptoms were assessed using the positive and negative syndrome scale (PANSS). Unsupervised principal component analysis identified two distinct biochemical signatures within the cohort. Orthogonal partial least squared discriminatory analysis revealed that the serum metabolomes of NMDAR, LGI1, and CASPR2 antibody psychosis patients were indistinct from the antibody negative control group while VGKC and GlyR antibody patients had significantly decreased lipoprotein fatty acids and increased amino acid concentrations. Furthermore, these patients had more severe presentation with higher PANSS scores than either the antibody negative controls or the NMDAR, LGI1, and CASPR2 antibody groups. These results suggest that a proportion of patients with acute psychosis have a distinct clinical and biochemical phenotype that may indicate an inflammatory subtype.
High-throughput design of functional-engineered MXene transistors with low-resistive contacts
Authors: Guha Sirsha , Kabiraj Arnab , Mahapatra Santanu
Published: September 2022

Two-dimensional material-based transistors are being extensively investigated for CMOS (complementary metal oxide semiconductor) technology extension; nevertheless, downscaling appears to be challenging owing to high metal-semiconductor contact resistance. Here, we propose a functional group-engineered monolayer transistor architecture that takes advantage of MXenes’ natural material chemistry to offer low-resistive contacts. We design an automated, high-throughput computational pipeline that first performs hybrid density functional theory-based calculations to find 16 sets of complementary transistor configurations by screening more than 23,000 materials from an MXene database and then conducts self-consistent quantum transport calculations to simulate their current-voltage characteristics for channel lengths ranging from 10 nm to 3 nm. Performance of these devices has been found to meet the requirements of the international roadmap for devices and systems (IRDS) for several benchmark metrics (on current, power dissipation, delay, and subthreshold swing). The proposed balanced-mode, functional-engineered MXene transistors may lead to a realistic solution for the sub-decananometer technology scaling by enabling doping-free intrinsically low contact resistance.
Antibody targeting of E3 ubiquitin ligases for receptor degradation
Authors: Marei Hadir , Tsai Wen-Ting K. , Kee Yee-Seir , Ruiz Karen , He Jieyan , Cox Chris , Sun Tao , Penikalapati Sai , Dwivedi Pankaj , Choi Meena , Kan David , Saenz-Lopez Pablo , Dorighi Kristel , Zhang Pamela , Kschonsak Yvonne T. , Kljavin Noelyn , Amin Dhara , Kim Ingrid , Mancini Andrew G. , Nguyen Thao , Wang Chunling , Janezic Eric , Doan Alexander , Mai Elaine , Xi Hongkang , Gu Chen , Heinlein Melanie , Biehs Brian , Wu Jia , Lehoux Isabelle , Harris Seth , Comps-Agrar Laetitia , Seshasayee Dhaya , de Sauvage Frederic J. , Grimmer Matthew , Li Jing , Agard Nicholas J. , de Sousa e Melo Felipe
Published: September 2022

Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein. Indeed, targeted protein degradation technologies, including proteolysis-targeting chimeras1 (PROTACs), have highlighted clinically important advantages of target degradation over inhibition2. However, the generation of heterobifunctional compounds binding to two targets with high affinity is complex, particularly when oral bioavailability is required3. Here we describe the development of proteolysis-targeting antibodies (PROTABs) that tether cell-surface E3 ubiquitin ligases to transmembrane proteins, resulting in target degradation both in vitro and in vivo. Focusing on zinc- and ring finger 3 (ZNRF3), a Wnt-responsive ligase, we show that this approach can enable colorectal cancer-specific degradation. Notably, by examining a matrix of additional cell-surface E3 ubiquitin ligases and transmembrane receptors, we demonstrate that this technology is amendable for ‘on-demand’ degradation. Furthermore, we offer insights on the ground rules governing target degradation by engineering optimized antibody formats. In summary, this work describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins.
Structural basis for directional chitin biosynthesis
Authors: Chen Wei , Cao Peng , Liu Yuansheng , Yu Ailing , Wang Dong , Chen Lei , Sundarraj Rajamanikandan , Yuchi Zhiguang , Gong Yong , Merzendorfer Hans , Yang Qing
Published: September 2022

Chitin, the most abundant aminopolysaccharide in nature, is an extracellular polymer consisting ofN-acetylglucosamine (GlcNAc) units1. The key reactions of chitin biosynthesis are catalysed by chitin synthase2–4, a membrane-integrated glycosyltransferase that transfers GlcNAc from UDP-GlcNAc to a growing chitin chain. However, the precise mechanism of this process has yet to be elucidated. Here we report five cryo-electron microscopy structures of a chitin synthase from the devastating soybean root rot pathogenic oomycetePhytophthora sojae(PsChs1). They represent the apo, GlcNAc-bound, nascent chitin oligomer-bound, UDP-bound (post-synthesis) and chitin synthase inhibitor nikkomycin Z-bound states of the enzyme, providing detailed views into the multiple steps of chitin biosynthesis and its competitive inhibition. The structures reveal the chitin synthesis reaction chamber that has the substrate-binding site, the catalytic centre and the entrance to the polymer-translocating channel that allows the product polymer to be discharged. This arrangement reflects consecutive key events in chitin biosynthesis from UDP-GlcNAc binding and polymer elongation to the release of the product. We identified a swinging loop within the chitin-translocating channel, which acts as a ‘gate lock’ that prevents the substrate from leaving while directing the product polymer into the translocating channel for discharge to the extracellular side of the cell membrane. This work reveals the directional multistep mechanism of chitin biosynthesis and provides a structural basis for inhibition of chitin synthesis.
The Anglo-Saxon migration and the formation of the early English gene pool
Authors: Gretzinger Joscha , Sayer Duncan , Justeau Pierre , Altena Eveline , Pala Maria , Dulias Katharina , Edwards Ceiridwen J. , Jodoin Susanne , Lacher Laura , Sabin Susanna , Vågene Åshild J. , Haak Wolfgang , Ebenesersdóttir S. Sunna , Moore Kristjan H. S. , Radzeviciute Rita , Schmidt Kara , Brace Selina , Bager Martina Abenhus , Patterson Nick , Papac Luka , Broomandkhoshbacht Nasreen , Callan Kimberly , Harney Éadaoin , Iliev Lora , Lawson Ann Marie , Michel Megan , Stewardson Kristin , Zalzala Fatma , Rohland Nadin , Kappelhoff-Beckmann Stefanie , Both Frank , Winger Daniel , Neumann Daniel , Saalow Lars , Krabath Stefan , Beckett Sophie , Van Twest Melanie , Faulkner Neil , Read Chris , Barton Tabatha , Caruth Joanna , Hines John , Krause-Kyora Ben , Warnke Ursula , Schuenemann Verena J. , Barnes Ian , Dahlström Hanna , Clausen Jane Jark , Richardson Andrew , Popescu Elizabeth , Dodwell Natasha , Ladd Stuart , Phillips Tom , Mortimer Richard , Sayer Faye , Swales Diana , Stewart Allison , Powlesland Dominic , Kenyon Robert , Ladle Lilian , Peek Christina , Grefen-Peters Silke , Ponce Paola , Daniels Robin , Spall Cecily , Woolcock Jennifer , Jones Andy M. , Roberts Amy V. , Symmons Robert , Rawden Anooshka C. , Cooper Alan , Bos Kirsten I. , Booth Tom , Schroeder Hannes , Thomas Mark G. , Helgason Agnar , Richards Martin B. , Reich David , Krause Johannes , Schiffels Stephan
Published: September 2022

The history of the British Isles and Ireland is characterized by multiple periods of major cultural change, including the influential transformation after the end of Roman rule, which precipitated shifts in language, settlement patterns and material culture1. The extent to which migration from continental Europe mediated these transitions is a matter of long-standing debate2–4. Here we study genome-wide ancient DNA from 460 medieval northwestern Europeans—including 278 individuals from England—alongside archaeological data, to infer contemporary population dynamics. We identify a substantial increase of continental northern European ancestry in early medieval England, which is closely related to the early medieval and present-day inhabitants of Germany and Denmark, implying large-scale substantial migration across the North Sea into Britain during the Early Middle Ages. As a result, the individuals who we analysed from eastern England derived up to 76% of their ancestry from the continental North Sea zone, albeit with substantial regional variation and heterogeneity within sites. We show that women with immigrant ancestry were more often furnished with grave goods than women with local ancestry, whereas men with weapons were as likely not to be of immigrant ancestry. A comparison with present-day Britain indicates that subsequent demographic events reduced the fraction of continental northern European ancestry while introducing further ancestry components into the English gene pool, including substantial southwestern European ancestry most closely related to that seen in Iron Age France5,6.
Crosswalks among stewardship maturity assessment approaches promoting trustworthy FAIR data and repositories
Authors: Peng Ge , Gross Wendy S. , Edmunds Rorie
Published: September 2022

Various maturity assessment approaches have been developed to help research data repositories effectively manage their holdings at both the organizational and dataset levels. Repositories can use these approaches as self-assessment tools—potentially leading to formal certification—to benchmark the maturity of their data holdings, highlight gaps in their practices, and improve their sustainability. Understanding the differences among these assessment approaches can provide beneficial information on stewardship best practices for supporting FAIR data managed by Trustworthy Data Repositories. However, it is a daunting task due to diversity in the perspectives of the approaches and the potential for subjective interpretation of individual criteria. In this article, we outline the commonalities and distinctions of three established assessment approaches: i) CoreTrustSeal Trustworthy Data Repositories Requirements, ii) Data Stewardship Maturity Matrix, and iii) FAIR Guiding Principles. Strong correlations are found in data discovery, accessibility, interoperability, and usability due to overlapping requirements in digital object management. The study also reveals that the complexity of the approaches can lead to a large variety of inferred crosswalks among them.
Diagnostic features and management options for duodenal neuroendocrine neoplasms: a retrospective, multi-centre study
Authors: Mandair Dalvinder , Kamieniarz Lukasz , Pizanias Michail , Weickert Martin O. , Narayan Akshay , O’Mahony Luke Furtado , Caplin Martyn , Ramage John , Prachalias Andreas , Srirajaskanthan Rajaventhan , Toumpanakis Christos
Published: September 2022

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32–87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9–130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54–13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56–29.5) (p < 0.05) in the multivariate analysis. Lesions 11–20 mm in size had OR 11.1 (1.16–106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81–0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed.
Association of TSHR gene single nucleotide intronic polymorphism with the risk of hypothyroid and hyperthyroid disorders in Yazd province
Authors: Naghibi Fahime Sadat , Miresmaeili Seyed Mohsen , Javid Amaneh
Published: September 2022

The present study was carried out, for the first time, to evaluate the association of rs2268458 polymorphism, biochemical and environmental factors on hypothyroid and hyperthyroid disorders in thyroid patients and healthy individuals in Yazd province, Iran. In this study, blood samples were collected from a total of 100 cases, including 60 hypothyroid, 20 hyperthyroid and 20 normal individuals. DNA was extracted from blood samples and the rs2268458 single nucleotide intronic polymorphism was evaluated using Restriction Fragment Length Polymorphism PCR (RFLP-PCR). The results have shown that 59 individuals were homozygote (TT), 40 cases were heterozygote (TC) and one homozygote (CC) case. Of 59 TT homozygote cases, 25 cases were hypothyroid females and 7 hypothyroid male patients. While, heterozygote TC group consisted of 20 hypothyroid females and 7 hypothyroid male cases. Furthermore, only 1 (CC) homozygote male hypothyroid patient was observed in this study. The hyperthyroid population consisted of 7 (TT) homozygote hyperthyroid female cases, 8 (TC) heterozygote hyperthyroid female cases, 3 (TT) homozygote hyperthyroid male cases and 2 (TC) heterozygote hyperthyroid male cases. According to our study, heterozygote cases (TC) showed less severe symptoms, while homozygote cases (TT) showed no serious symptoms and the (CC) homozygote case showed severe thyroid abnormalities. So, it can be concluded that the TSHR-related rs2268458 polymorphism is associated with hypothyroidism and hyperthyroidism in the male and female populations of Yazd Province, Iran and C allele can be a risk factor for some physio-biochemical and hormonal imbalance in the thyroid disorder patients.