bluuebunny/crossref_metadata_2025 huggingface dataset:
A general toxicity and biodistribution study of human natural killer cells by single or repeated intravenous dose in severe combined immune deficient mice
Authors: Park Sang-Jin , Yoon Hae-Jin , Gu Eun-Young , Lee Byoung-Seok , Kim Yongman , Jung Jaeseob , Kim Jinmoon , Moon Kyoung-Sik
Published: June 2022

Natural killer (NK) cells are a part of the innate immune system and represent the first line of defense against infections and tumors. NK cells can eliminate tumor cells without major histocompatibility restriction and are independent of the expression of tumor-associated antigens. Therefore, they are considered an emerging tool for cancer immunotherapy. However, the general toxicity and biodistribution of NK cells after transplantation remain to be understood. This study was conducted to evaluate the general toxicity and biodistribution of human NK cells after single or repeated intravenous dosing in severely combined immunodeficient (SCID) mice. There were no test item-related toxicological changes in single and repeated administration groups. The no observed adverse effect level of human NK cells was 2 × 107 cells/head for both male and female SCID mice. Results from the biodistribution study showed that human NK cells were mainly distributed in the lungs, and a small number of the cells were detected in the liver, heart, spleen, and kidney of SCID mice, in both the single and repeated dose groups. Additionally, human NK cells were completely eliminated from all organs of the mice in the single dose group on day 7, while the cells persisted in mice in the repeated dose group until day 64. In conclusion, transplantation of human NK cells in SCID mice had no toxic effects. The cells were mainly distributed in the lungs and completely disappeared from the body over time after single or repeated intravenous administration.
Metaphysical Realism and Anti-Realism
Authors: Miller J. T. M.
Published: June 2022

Minimally, metaphysical realists hold that there exist some mind-independent entities. Metaphysical realists also (tend to) hold that we can speak meaningfully or truthfully about mind-independent entities. Those who reject metaphysical realism deny one or more of these commitments. This Element aims to introduce the reader to the core commitments of metaphysical realism and to illustrate how these commitments have changed over time by surveying some of the main families of views that realism has been contrasted with: such as (radical) scepticism, idealism, and anti-realism.
Second chances in antecedent retrieval: The processing of reflexives in two types of reconstruction environments
Authors: Chapman Cassandra , Moulton Keir
Published: June 2022

A body of psycholinguistic research shows that structural constraints play a large role in guiding anaphora resolution in the early moments of processing (Nicol and Swinney 1989; Harris et al. 2000; Sturt 2003; Kazanina et al. 2007; Xiang et al. 2009; Chow et al. 2014). Omaki (2010) and Omaki et al. (2019) report on an interesting case where reflexives in wh-predicate fronting constructions launch a search that is not structurally guided. We further investigate this phenomenon, by asking whether non-structurally guided retrievals of this sort result in comprehenders ever committing to ungrammatical antecedents, perhaps as a ‘lingering’ interpretation of the sort found with garden path sentences (Christianson et al. 2001; Ferreira et al. 2001; Slattery et al. 2013). In two forced-choice studies, we find evidence that ungrammatical dependencies resulting from a non-structural search are sometimes maintained in offline comprehension, particularly with a more demanding task. We then probe the incremental processing that follows non-structurally guided retrieval, asking if and when the processor initiates a renewed search. In a self-paced reading experiment, we show that the processor continues its search for an antecedent very soon after retrieving a non-structurally guided antecedent. Surprisingly, however, we found a similar processing profile in cases where a structurally licensed antecedent was already encountered. While it has been recently shown that cataphoric pronouns persist in an antecedent search after a failed retrieval (Giskes and Kush 2021), our results suggest that when reflexives locate a preceding antecedent – by either a structural or non-structural search – this does not terminate further consideration of a different dependency. We consider these data in light of the comparison between cataphoric elements and wh-fillers in launching an active search to complete a dependency.
Towards a Science of Scaling for Urban Climate Action and Governance
Authors: van der Heijden Jeroen
Published: June 2022

The scaling of urban climate action and its governance is rapidly becoming a central focus in the urban climate governance literature and policy debates. Building on the broader scaling literature and inspired by related initiatives in other fields, this article calls for the development of a systematic “science of scaling” for urban climate governance. Such a science of scaling may help to give a better understanding of how well-performing urban climate action and its governance can be multiplied, accelerated and broadened (ie horizontal and vertical scaling and scaling out, up and down), and it may help to uncover scaling trajectories towards systemic change in cities (ie deep scaling).
Surface area matters: An evaluation of swabs and surface area for environmental surface sampling of healthcare pathogens
Authors: West Rolieria M. , Shams Alicia M. , Chan Monica Y. , Rose Laura J. , Noble-Wang Judith A.
Published: June 2022

Flocked and foam swabs were used to sample five healthcare pathogens from three sizes of steel and plastic coupons; 26 cm2, 323 cm2, and 645 cm2. As surface area increased, 1–2 log10 decrease in recovered organisms (P < .05) was observed. Sampling 26-cm2 yielded the optimal median percent of pathogens recovered.
Healthy lifestyle changes favourably affect common carotid intima-media thickness: the Healthy Lifestyle Community Programme (cohort 2)
Authors: Koeder Christian , Husain Sarah , Kranz Ragna-Marie , Anand Corinna , Alzughayyar Dima , Schoch Nora , Hahn Andreas , Englert Heike
Published: June 2022

Common carotid intima-media thickness (ccIMT) progression is a risk marker for cardiovascular disease (CVD), whereas healthy lifestyle habits are associated with lower ccIMT. The objective of the present study was to test whether a healthy lifestyle intervention can beneficially affect ccIMT progression. A community-based non-randomised, controlled lifestyle intervention was conducted, focusing on a predominantly plant-based diet (strongest emphasis), physical activity, stress management and social health. Assessments of ccIMT were made at baseline, 6 months and 1 year. Participants had an average age of 57 years and were recruited from the general population in rural northwest Germany (intervention: n 114; control: n 87). From baseline to 1 year, mean ccIMT significantly increased in both the intervention (0⋅026 [95 % CI 0⋅012, 0⋅039] mm) and control group (0⋅045 [95 % CI 0⋅033, 0⋅056] mm). The 1-year trajectory of mean ccIMT was lower in the intervention group (P = 0⋅022; adjusted for baseline). In a subgroup analysis with participants with high baseline mean ccIMT (≥0⋅800 mm), mean ccIMT non-significantly decreased in the intervention group (−0⋅016 [95 % CI −0⋅050, 0⋅017] mm; n 18) and significantly increased in the control group (0⋅065 [95 % CI 0⋅033, 0⋅096] mm; n 12). In the subgroup, the 1-year trajectory of mean ccIMT was significantly lower in the intervention group (between-group difference: −0⋅051 [95 % CI −0⋅075, −0⋅027] mm; P < 0⋅001; adjusted for baseline). The results indicate that healthy lifestyle changes may beneficially affect ccIMT within 1 year, particularly if baseline ccIMT is high.
Comparing 2 crystal structures and 12 AlphaFold2-predicted human membrane glucose transporters and their water-soluble glutamine, threonine and tyrosine variants
Authors: Smorodina Eva , Tao Fei , Qing Rui , Jin David , Yang Steve , Zhang Shuguang
Published: June 2022

Membrane transporters including glucose transporters (GLUTs) are involved in cellular energy supplies, cell metabolism and other vital biological activities. They have also been implicated in cancer proliferation and metastasis, thus they represent an important target in combatting cancer. However, membrane transporters are very difficult to study due to their multispan transmembrane properties. The new computational tool, AlphaFold2, offers highly accurate predictions of three-dimensional protein structures. The glutamine, threonine and tyrosine (QTY) code provides a systematic method of rendering hydrophobic sequences into hydrophilic ones. Here, we present computational studies of native integral membrane GLUTs with 12 transmembrane helical segments determined by X-ray crystallography and CryoEM, comparing the AlphaFold2-predicted native structure to their water-soluble QTY variants predicted by AlphaFold2. In the native structures of the transmembrane helices, there are hydrophobic amino acids leucine (L), isoleucine (I), valine (V) and phenylalanine (F). Applying the QTY code, these hydrophobic amino acids are systematically replaced by hydrophilic amino acids, glutamine (Q), threonine (T) and tyrosine (Y) rendering them water-soluble. We present the superposed structures of native GLUTs and their water-soluble QTY variants. The superposed structures show remarkable similar residue mean square distance values between 0.47 and 3.6 Å (most about 1–2 Å) despite >44% transmembrane amino acid differences. We also show the differences of hydrophobicity patches between the native membrane transporters and their QTY variants. We explain the rationale why the membrane protein QTY variants become water-soluble. Our study provides insight into the differences between the hydrophobic helices and hydrophilic helices, and offers confirmation of the QTY method for studying multispan transmembrane proteins and other aggregated proteins through their water-soluble variants.
Taxonomy and palaeoenvironmental distribution of palaeopascichnids
Authors: Kolesnikov Anton , Desiatkin Vladislav
Published: June 2022

Palaeopascichnida is a problematic group of extinct organisms that is globally distributed in Ediacaran sequences of Avalonia, Baltica, Siberia, South China and Australia. The fossils related to Palaeopascichnida consist of serially or cluster-like arranged, millimetre- to centimetre-scale globular or allantoid chambers, which are characterized by substantial differences in preservation, leading to no consistent diagnosis for these organisms. Here we integrate morphometric variation, stratigraphic distribution and habitat settings of more than 1200 specimens from all known fossil localities. The results of the morphological analysis demonstrate variation in chamber shape and size, and allow us to recognize six valid species within the group. Statistical analysis of the specimen distribution with respect to sedimentary environments indicates a significant difference in palaeoecological settings between species, making a significant contribution to the evolution and systematic palaeontology of these problematic organisms and perspective on their use in Neoproterozoic biostratigraphy. Our revision and systematic study sheds new light on one of the least studied groups of the late Ediacaran biota.
Financialisation and private equity in early childhood care and education in England
Authors: SIMON ANTONIA , SHAH ATUL , QUY KATIE , OWEN CHARLIE
Published: June 2022

The Government in England contributes an estimated £3.9 billion funding to support childcare and education for three- and four-year olds and for some two-year olds. A significant proportion of this money is spent on private sector childcare. However, little is known about how the money paid to companies providing private sector childcare is used. Through a cross-case analysis, the financial accounts of a sample of medium-to large private ‘for-profit’ childcare groups were compared with some ‘not-for-profit’ childcare providers. We found that for the for-profit companies, a considerable amount of money is being extracted for debt repayment and relatively little goes into staff wages. We found that large private for-profit nursery groups predominately use ‘private equity’ models which are characterised by borrowings and debt, with a focus on short-term financial returns. This ‘for-profit’ financial operating model arguably risks the sustainability of provision in the sector. Reformed regulation and transparency in the accounting of such providers and a consideration of alternative ‘not-for-profit’ financial models could provide greater stability and resilience.
Access for Augustus: The ‘House of Livia’ and the Palatine Passages
Authors: Wiseman T. P.
Published: June 2022

This article draws attention to a neglected archaeological datum (pointed out by Amanda Claridge in 2014) that has important consequences for our understanding of the Augustan Palatine. The ‘house of Livia’, excavated in 1869, has always been thought of as belonging to the Augustan complex, but the evidence suggests that it did not exist above ground level after the 30sb.c.; its basement, on the other hand, was connected with an underground passage that was evidently an integral part of the building project begun by Imperator Caesar (‘Octavian’) in 36b.c. Claridge's argument, with its corollary, that the Apollo temple faced north-east to the summit plateau of the hill, explains the surviving textual sources much more satisfactorily than the current orthodoxy. In particular, it casts significant new light on Suetonius’ statement that the name ‘Augustus’ referred to Romulus’augustum auguriumat the foundation of the city.
An online scalarization multi-objective reinforcement learning algorithm: TOPSIS Q-learning
Authors: Mirzanejad Mohammad , Ebrahimi Morteza , Vamplew Peter , Veisi Hadi
Published: June 2022

Conventional reinforcement learning focuses on problems with single objective. However, many problems have multiple objectives or criteria that may be independent, related, or contradictory. In such cases, multi-objective reinforcement learning is used to propose a compromise among the solutions to balance the objectives. TOPSIS is a multi-criteria decision method that selects the alternative with minimum distance from the positive ideal solution and the maximum distance from the negative ideal solution, so it can be used effectively in the decision-making process to select the next action. In this research a single-policy algorithm called TOPSIS Q-Learning is provided with focus on its performance in online mode. Unlike all single-policy methods, in the first version of the algorithm, there is no need for the user to specify the weights of the objectives. The user’s preferences may not be completely definite, so all weight preferences are combined together as decision criteria and a solution is generated by considering all these preferences at once and user can model the uncertainty and weight changes of objectives around their specified preferences of objectives. If the user only wants to apply the algorithm for a specific set of weights the second version of the algorithm efficiently accomplishes that.
Rapid star identification algorithm for fish-eye camera based on PPP/INS assistance
Authors: Li Chonghui , Yang Yuanxi , Xiao Guorui , Chen Zhanglei , Tong Shuai , Liu Zihao
Published: June 2022

The fish-eye star sensor with a field of view (FOV) of 180° is an important piece of equipment for attitude determination, which improves the visibility of stars significantly. However, it also brings the star identification (star-ID) difficulties because of imprecise calibrations. Thus, a fish-eye star-ID algorithm supported by the integration of the precise point positioning/inertial navigation system (PPP/INS) is proposed. At first, a reference star map is generated in combination with the distortion model of the fish-eye camera based on the position and attitude information from the PPP/INS. Then the star points are extracted in a specific neighbourhood of the reference star points. Subsequently, the extracted star points are individually tested and identified according to angular distance error. Finally, the real-time precise attitude is determined based on the star-ID results. Experimental results show that, 270–310 stars can be identified in a fish-eye star map with an average time of 0.03 s if the initial attitude error is smaller than 1.5° and an attitude determination accuracy better than 10″ can be achieved by support from PPP/INS.
The popularity of the light comedy during the late era of Kim Jong-il
Authors: Hong Jae-Beom , Paik Seung-Moo , Cho Seong-Kwan
Published: June 2022

This paper examines the political and cultural context of the popular 2010 revival of the light comedy theatre productionSanullimin North Korea. The play, originally written and performed in 1961, portrays the spirit of revolutionary optimism as the characters resolve an unhostile conflict and unite to expand socialist production to contribute to overcoming the (real-life) political and economic crisis of the Chollima era. The 2010 revival of this propaganda responded to similar political and economic crisis, and was designed to instil confidence that the present crisis would be overcome as successfully as in the first Chollima era, provided that people could conjure the same revolutionary optimism. This paper examines why this particular play was revived over others from the Kim Il-sung era, and its particular potential to serve as effective propaganda during the transition from military-first to party-first policy in the Kim Jong-un era, in reference to parallels between 1961 and 2010. The play immerses the audience in the dramatic situations through verisimilitude to the lives of the audience, though the emotional excess of the characters is often exaggerated. Such laughter ignited by dramatic irony contributed to creating a heightened ideological thought of the audience who would spontaneously (re-)internalise the communist human character. The revival of the play was the most appropriate choice according to the object of justification of the succession of power from Kim Jung-il to Kim Jung-un.
The bond that binds or drives us apart? An empirical test of the national identity argument in three countries
Authors: Rapp Carolin Hjort
Published: June 2022

Solidarity is a key ingredient to making society work. Yet, recent developments such as the refugee crisis and the declining support for social democratic parties question the degree of solidarity in Western societies. So what could increase solidarity? The national identity argument (NIA) claims that a stronger national identity can foster solidarity. While this claim was proven in some cases, several others challenged it. This paper sets out to put the NIA to a severe empirical test by distinguishing five different forms of national identity: national belonging, national pride, patriotism, national chauvinism, and the normative perception of national boundaries. The data stems from national surveys in Germany, the UK, and the USA linked to the ISSP. The results reveal no clear support for the NIA. Whether national identity fosters solidarity depends on what type of national identity and what country one is looking at.
Country or party? Variations in party membership around the globe
Authors: van Haute Emilie , Ribeiro Pedro Floriano
Published: June 2022

This paper explores external (country-level) and internal (party-level) drivers of membership variations across parties. Relying on the Political Party Database combined with other datasets, we provide original, cross-sectional analyses of membership variation across 223 parties in 38 countries, innovatively covering third-wave democracies, post-communist countries, and advanced democracies. It allows for a unique analysis of recruitment patterns of parties under quite different contexts. Departing from the dominant view that parties are the powerless victims of external trends, we show that, while context matters, parties’ choices regarding affiliation rules and organization structure also matter. They are more powerful determinants of membership ratios than country-level variables. Especially, the representation of sub-groups in the party structure is a key driver of membership recruitment. We also show how party origins, and the foundational environment in which they emerged, are important to understand how membership varies across parties today. Overall, this study strongly advocates for a broad comparative, multilevel approach to party membership.
Eine Gesellschaft zwischen Narzissmus, Hysterie und Abhängigkeit
Authors: Schneider Wolfgang
Published: June 2022

Verunsicherung und Dramatisierung angemessen begegnen Das Buch beschäftigt sich mit den immer komplexer werdenden Lebensbedingungen und -verhältnissen in der globalisierten Welt. Klimakrise, Armut, Pandemien, Kriege, Migration, nationale Egoismen, technischer Fortschritt und soziale Medien, wirtschaftliche Umorientierung oder Wertewandel sind einige Schlagworte dazu. Doch wie wirken sie auf gesamtgesellschaftlicher Ebene, wie auf das Individuum? In der Bevölkerung sind kognitive Überforderung, zunehmende psychische Verunsicherung und soziale Deprivation, Identitätsverlust sowie die Häufung psychischer und psychosomatischer Gesundheitsstörungen auffallend. Im Kontext dieser Probleme beschreibt der Autor die Wechselwirkungen zwischen gesellschaftlichen und individuellen Entwicklungen unter Rückgriff auf aktuelle, authentische Fallbeispiele. So analysiert und diskutiert er etwa die Gründe für das Anwachsen autoritärer Tendenzen wie auch die zunehmende Irritation in Bezug auf demokratisch-freiheitliche Haltungen. Für die Darlegung seiner Beobachtungen greift der Autor auf seine umfangreichen Erfahrungen aus Wissenschaft und ärztlicher Praxis im Bereich der Psychosomatik und Psychotherapie sowie aus seiner sozialmedizinischen Gutachtertätigkeit zurück. Insbesondere auch denjenigen, die in ihrem beruflichen Umfeld beratend oder therapeutisch tätig sind, ermöglicht dieses Buch wertvolle Einblicke in die Herausforderungen unserer Zeit. Zusammenfassend werden Ideen und Lösungsansätze auf der Ebene der Politik sowie des medizinischen Versorgungssystems mit speziellem Fokus auf die Psychotherapie skizziert.
Vermittlung psychotherapeutischer Fertigkeiten durch die Arbeit mit Simulationspatientinnen
Authors: Deisenhofer Anne-Katharina , Meyer Lukas , Schaffrath Jana , Weinmann-Lutz Birgit , Poster Kaitlyn , Bennemann Björn , Prinz Jessica , Lutz Wolfgang
Published: June 2022

Zusammenfassung. Theoretischer Hintergrund: In der Ausbildung von Psychotherapeutinnen konnte bereits ein subjektiver Kompetenzgewinn durch die Arbeit mit Simulationspatientinnen (SP) belegt werden. Fragestellung: Neben der Replikation dieser Befunde, welche auf Selbstberichten basieren, untersuchte vorliegende Studie die objektive Behandlungsintegrität von Studierenden anhand von Beobachterratings. Methode: Die Stichprobe setzte sich aus 39 Studierenden aus 4 Fallseminaren zusammen. Zur Validierung der objektiven Behandlungsintegrität wurde eine Vergleichsstichprobe von Psychologischen Psychotherapeutinnen in Ausbildung (PPiA) herangezogen (Videos N = 763). Zusätzlich wurden Charakteristika der Studierenden hinsichtlich ihrer prädiktiven Fähigkeiten untersucht. Ergebnisse: Die Ergebnisse belegten neben einem selbstberichteten Kompetenzzuwachs auch eine zufriedenstellende objektive Behandlungsintegrität, die signifikant niedriger ausfiel als die der PPiA. Zusätzlich konnten Prädiktoren für die Behandlungsintegrität identifiziert werden. Schlussfolgerungen: Die Ergebnisse zeigen, dass Studierende Therapiesituationen, die ihrem Novizen-Status entsprechen, in zufriedenstellendem Maße ausgestalten können.
Individual Differences in the Evolution of Counting
Authors: Dewi Jasinta D. M. , Thevenot Catherine
Published: June 2022

Abstract. The alphabet–arithmetic paradigm, in which adults are asked to add a numeral addend to a letter augend (e.g., D + 3 = G), was conceived to mimic the way children learn addition. Studies using this paradigm often conclude that procedural learning leads to the memorization of associations between operands and answers. However, as recently suggested, memorization might only be used by a minority of participants and only for problems with the largest addend. In the present paper, we aim at investigating these individual differences through transfer effects from trained problems to new ones. Participants were trained over 12 learning sessions, followed by 3 transfer sessions. A group of participants, that we called the nonbreakers, showed a linear function associating solution times and addends throughout the experiment. In this group, transfer was observed during the first transfer session, suggesting that a procedural strategy, transferable to new items, was still used at the end of training. In another group of participants, that we called the breakers, we observed a decrease in solution times for problems with the largest addend. In this group, transfer was only observed after two transfer sessions, suggesting that procedural strategies were not used as often in this group than in the other group. This was especially true for problems with the largest addend because transfer effects were stronger when they were excluded. Therefore, during learning and for breakers, the answers to problems with larger addends are retrieved first and, as for non-breakers, the answers to problems with very small operands remain computed.
Mechanical and Thermal Impacts of the Tibetan–Iranian Plateau on the North Pacific Storm Track: Numerical Experiments by FGOALS‐f3‐L
Authors: Yang Minghao , Li Chongyin , Luo Dehai , Yao Yao , Li Xin , Chen Xiong , Lu Yang
Published: June 2022

By employing a state‐of‐the‐art global atmospheric general circulation model from the Global Monsoons Model Inter‐comparison Project, this study investigates the mechanical and thermal impacts of the Tibetan‐Iranian Plateau (TIP) on the North Pacific storm track (NPST). When the TIP‐associated mechanical forcing is removed, the winter NPST strengthens remarkably on the northern flank of its climatological maximum and becomes inconspicuously separated from storm track activities over the Asian continent. The midwinter suppression of the NPST is almost inapparent but still exists. In contrast, when TIP‐associated thermal forcing is absent, the winter NPST amplitudes weaken prominently on the north and west sides, and the midwinter suppression remains obvious. The mechanical and thermal impact of the TIP on the NPST are robust not only in winter but also in other seasons. Without the TIP‐associated mechanical forcing, the intensified winter NPST may be dependent on the weakened and widened upper‐level jet, strengthened atmospheric baroclinicity on the north side of climatological winter upper‐level jet, enhanced baroclinic energy conversion, and attenuated East Asian trough. In contrast, without the TIP‐associated thermal forcing, the weakened winter NPST may be determined by the strengthened and narrowed upper‐level jet, reduced atmospheric baroclinicity on the northern flank of upper‐level jet, decreased baroclinic energy conversion, and intensified East Asian trough.
Electron Scattering by Very‐Low‐Frequency and Low‐Frequency Waves From Ground Transmitters in the Earth's Inner Radiation Belt and Slot Region
Authors: Ma Q. , Gu W. , Claudepierre S. G. , Li W. , Bortnik J. , Hua M. , Shen X.‐C.
Published: June 2022

The very‐low frequency (VLF) and low frequency (LF) waves from ground transmitters propagate in the ionospheric waveguide, and a portion of their power leaks to the Earth's inner radiation belt and slot region where it can cause electron precipitation loss. Using Van Allen Probes observations, we perform a survey of the VLF and LF transmitter waves at frequencies from 14 to 200 kHz. The statistical electric and magnetic wave amplitudes and frequency spectra are obtained at 1 < L < 3. Based on a recent study on the propagation of VLF transmitter waves, we divide the total wave power into ducted and unducted portions, and model the wave normal angle of unducted waves with dependences on L shell, magnetic latitude, and wave frequency. At lower frequencies, the unducted waves are launched along the vertical direction and the wave normal angle increases during the propagation until reaching the Gendrin angle; at higher frequencies, the normal angle of unducted waves follows the variation of Gendrin angle. We calculate the bounce‐averaged pitch angle and momentum diffusion coefficients of electrons due to ducted and unducted VLF and LF waves. Unducted and ducted waves cause efficient pitch angle scattering at L = 1.5 and 2.5, respectively. Although the wave power from ground transmitters at frequencies higher than 30 kHz is low, these waves can cause the pitch angle scattering of lower energy (2–200 keV at L = 1.5) electrons, which cannot resonate with the VLF transmitter waves at frequencies below 30 kHz, lightning generated whistlers, or plasmaspheric hiss.
Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy
Authors: Suzuki Naoki , Nishiyama Ayumi , Warita Hitoshi , Aoki Masashi
Published: June 2022

Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS is motor neurons. The success of antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a motor neuron disease, has triggered a paradigm shift in developing ALS therapies. The causative genes of ALS and disease-modifying genes, including those of sporadic ALS, have been identified one after another. Thus, the freedom of target choice for gene therapy has expanded by ASO strategy, leading to new avenues for therapeutic development. Tofersen for superoxide dismutase 1 (SOD1) was a pioneer in developing ASO for ALS. Improving protocols and devising early interventions for the disease are vital. In this review, we updated the knowledge of causative genes in ALS. We summarized the genetic mutations identified in familial ALS and their clinical features, focusing onSOD1, fused in sarcoma(FUS), and transacting response DNA-binding protein. The frequency of theC9ORF72mutation is low in Japan, unlike in Europe and the United States, whileSOD1andFUSare more common, indicating that the target mutations for gene therapy vary by ethnicity. A genome-wide association study has revealed disease-modifying genes, which could be the novel target of gene therapy. The current status and prospects of gene therapy development were discussed, including ethical issues. Furthermore, we discussed the potential of axonal pathology as new therapeutic targets of ALS from the perspective of early intervention, including intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired axonal transport, aberrant cytoskeleton, and axon branching. We simultaneously discuss important pathological states of cell bodies: persistent stress granules, disrupted nucleocytoplasmic transport, and cryptic splicing. The development of gene therapy based on the elucidation of disease-modifying genes and early intervention in molecular pathology is expected to become an important therapeutic strategy in ALS.
Fully lignocellulose-based PET analogues for the circular economy
Authors: Wu Xianyuan , Galkin Maxim V. , Stern Tobias , Sun Zhuohua , Barta Katalin
Published: June 2022

Polyethylene terephthalate is one of the most abundantly used polymers, but also a significant pollutant in oceans. Due to growing environmental concerns, polyethylene terephthalate alternatives are highly sought after. Here we present readily recyclable polyethylene terephthalate analogues, made entirely from woody biomass. Central to the concept is a two-step noble metal free catalytic sequence (Cu20-PMO catalyzed reductive catalytic fractionation and Raney Ni mediated catalytic funneling) that allows for obtaining a single aliphatic diol 4-(3-hydroxypropyl) cyclohexan-1-ol in high isolated yield (11.7 wt% on lignin basis), as well as other product streams that are converted to fuels, achieving a total carbon yield of 29.5%. The diol 4-(3-hydroxypropyl) cyclohexan-1-ol is co-polymerized with methyl esters of terephthalic acid and furan dicarboxylic acid, both of which can be derived from the cellulose residues, to obtain polyesters with competitive Mw and thermal properties (Tg of 70–90 °C). The polymers show excellent chemical recyclability in methanol and are thus promising candidates for the circular economy.
Ion complexation waves emerge at the curved interfaces of layered minerals
Authors: Whittaker Michael L. , Ren David , Ophus Colin , Zhang Yugang , Waller Laura , Gilbert Benjamin , Banfield Jillian F.
Published: June 2022

Visualizing hydrated interfaces is of widespread interest across the physical sciences and is a particularly acute need for layered minerals, whose properties are governed by the structure of the electric double layer (EDL) where mineral and solution meet. Here, we show that cryo electron microscopy and tomography enable direct imaging of the EDL at montmorillonite interfaces in monovalent electrolytes with ångstrom resolution over micron length scales. A learning-based multiple-scattering reconstruction method for cryo electron tomography reveals ions bound asymmetrically on opposite sides of curved, exfoliated layers. We observe conserved ion-density asymmetry across stacks of interacting layers in cryo electron microscopy that is associated with configurations of inner- and outer-sphere ion-water-mineral complexes that we term complexation waves. Coherent X-ray scattering confirms that complexation waves propagate at room-temperature via a competition between ion dehydration and charge interactions that are coupled across opposing sides of a layer, driving dynamic transitions between stacked and aggregated states via layer exfoliation.
Hydrogenated Cs2AgBiBr6 for significantly improved efficiency of lead-free inorganic double perovskite solar cell
Authors: Zhang Zeyu , Sun Qingde , Lu Yue , Lu Feng , Mu Xulin , Wei Su-Huai , Sui Manling
Published: June 2022

Development of lead-free inorganic perovskite material, such as Cs2AgBiBr6, is of great importance to solve the toxicity and stability issues of traditional lead halide perovskite solar cells. However, due to a wide bandgap of Cs2AgBiBr6 film, its light absorption ability is largely limited and the photoelectronic conversion efficiency is normally lower than 4.23%. In this text, by using a hydrogenation method, the bandgap of Cs2AgBiBr6 films could be tunable from 2.18 eV to 1.64 eV. At the same time, the highest photoelectric conversion efficiency of hydrogenated Cs2AgBiBr6 perovskite solar cell has been improved up to 6.37% with good environmental stability. Further investigations confirmed that the interstitial doping of atomic hydrogen in Cs2AgBiBr6 lattice could not only adjust its valence and conduction band energy levels, but also optimize the carrier mobility and carrier lifetime. All these works provide an insightful strategy to fabricate high performance lead-free inorganic perovskite solar cells.
NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility
Authors: Gleixner Amanda M. , Verdone Brandie Morris , Otte Charlton G. , Anderson Eric N. , Ramesh Nandini , Shapiro Olivia R. , Gale Jenna R. , Mauna Jocelyn C. , Mann Jacob R. , Copley Katie E. , Daley Elizabeth L. , Ortega Juan A. , Cicardi Maria Elena , Kiskinis Evangelos , Kofler Julia , Pandey Udai B. , Trotti Davide , Donnelly Christopher J.
Published: June 2022

A G4C2 hexanucleotide repeat expansion in theC9orf72gene is the most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed in regions of neurodegeneration. The accumulation of repetitive RNAs and dipeptide repeat protein (DPR) are two proposed mechanisms of toxicity in C9-ALS/FTLD and linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport is regulated by the phenylalanine-glycine nucleoporins (FG nups) that comprise the nuclear pore complex (NPC) permeability barrier. However, the relationship between FG nups and TDP-43 pathology remains elusive. Our studies show that nuclear depletion and cytoplasmic mislocalization of one FG nup, NUP62, is linked to TDP-43 mislocalization in C9-ALS/FTLD iPSC neurons. Poly-glycine arginine (GR) DPR accumulation initiates the formation of cytoplasmic RNA granules that recruit NUP62 and TDP-43. Cytoplasmic NUP62 and TDP-43 interactions promotes their insolubility and NUP62:TDP-43 inclusions are frequently found in C9orf72 ALS/FTLD as well as sporadic ALS/FTLD postmortem CNS tissue. Our findings indicate NUP62 cytoplasmic mislocalization contributes to TDP-43 proteinopathy in ALS/FTLD.
Triiodothyronine (T3) promotes brown fat hyperplasia via thyroid hormone receptor α mediated adipocyte progenitor cell proliferation
Authors: Liu Shengnan , Shen Siyi , Yan Ying , Sun Chao , Lu Zhiqiang , Feng Hua , Ma Yiruo , Tang Zhili , Yu Jing , Wu Yuting , Gereben Balázs , Mohácsik Petra , Fekete Csaba , Feng Xiaoyun , Yuan Feixiang , Guo Feifan , Hu Cheng , Shao Mengle , Gao Xin , Zhao Lin , Li Yuying , Jiang Jingjing , Ying Hao
Published: June 2022

The thyroid hormone (TH)-controlled recruitment process of brown adipose tissue (BAT) is not fully understood. Here, we show that long-term treatment of T3, the active form of TH, increases the recruitment of thermogenic capacity in interscapular BAT of male mice through hyperplasia by promoting the TH receptor α-mediated adipocyte progenitor cell proliferation. Our single-cell analysis reveals the heterogeneous nature and hierarchical trajectory within adipocyte progenitor cells of interscapular BAT. Further analyses suggest that T3 facilitates cell state transition from a more stem-like state towards a more committed adipogenic state and promotes cell cycle progression towards a mitotic state in adipocyte progenitor cells, through mechanisms involving the action of Myc on glycolysis. Our findings elucidate the mechanisms underlying the TH action in adipocyte progenitors residing in BAT and provide a framework for better understanding of the TH effects on hyperplastic growth and adaptive thermogenesis in BAT depot at a single-cell level.
Wild bees respond differently to sampling traps with vanes of different colors and light reflectivity in a livestock pasture ecosystem
Authors: Acharya Roshani S. , Burke Joan M. , Leslie Timothy , Loftin Kelly , Joshi Neelendra K.
Published: June 2022

Wild bees are important pollinators and monitoring their abundance and diversity is necessary to develop conservation protocols. It is imperative to understand differences in sampling efficiency among different trap types to help guide monitoring efforts. This study used a new vane trap design to collect bees in a livestock pasture ecosystem and examined the impact of six different vane colors on wild bee sampling. We recorded 2230 bees comprising 49 species and five families. The most abundant species were Augochlorella aurata (25.8%), Lasioglossum disparile (18.3%), Lasioglossum imitatum (10.85%), Agapostemon texanus (10.8%), Melissodes vernoniae (9.9%) and Halictus ligatus (4.7%). Traps with bright blue vanes captured the greatest number and diversity of bees as compared to traps with bright yellow, dark blue, dark yellow, and purple vanes. Red vanes had the lowest captures rates of individuals and species. Different colors were associated with different bee species arrays and only nine species were found in all vane color types. Vanes with higher light reflectance properties (within 400–600 nm range) attracted the greatest number of bees. These results show that different light wavelengths and reflectivity of vane traps influence bee capture rates, and such findings can help optimize bee sampling methods in different ecosystems.
Moraines in the Austrian Alps record repeated phases of glacier stabilization through the Late Glacial and the Early Holocene
Authors: Braumann Sandra M. , Schaefer Joerg M. , Neuhuber Stephanie , Fiebig Markus
Published: June 2022

Climate is currently warming due to anthropogenic impact on the Earth’s atmosphere. To better understand the processes and feedbacks within the climate system that underlie this accelerating warming trend, it is useful to examine past periods of abrupt climate change that were driven by natural forcings. Glaciers provide an excellent natural laboratory for reconstructing the climate of the past as they respond sensitively to climate oscillations. Therefore, we study glacier systems and their behavior during the transition from colder to warmer climate phases, focusing on the period between 15 and 10 ka. Using a combination of geomorphological mapping and beryllium-10 surface exposure dating, we reconstruct ice extents in two glaciated valleys of the Silvretta Massif in the Austrian Alps. The mountain glacier record shows that general deglaciation after the Last Glacial Maximum (LGM) was repeatedly interrupted by glacier stabilization or readvance, perhaps during the Oldest Dryas to Bølling transition (landform age: 14.4 ± 1.0 ka) and certainly during the Younger Dryas (YD; 12.9–11.7 ka) and the Early Holocene (EH; 12–10 ka). The oldest landform age indicates a lateral ice margin that postdates the ‘Gschnitz’ stadial (ca. 17–16 ka) and predates the YD. It shows that local inner-alpine glaciers were more extensive until the onset of the Bølling warm phase (ca. 14.6 ka), or possibly even into the Bølling than during the subsequent YD. The second age group, ca. 80 m below the (pre-)Bølling ice margin, indicates glacier extents during the YD cold phase and captures the spatial and temporal fine structure of glacier retreat during this period. The ice surface lowered approximately 50–60 m through the YD, which is indicative of milder climate conditions at the end of the YD compared to its beginning. Finally, the third age group falls into a period of more substantial warming, the YD–EH transition, and shows discontinuous glacier retreat during the glacial to interglacial transition. The new geochronologies synthesized with pre-existing moraine records from the Silvretta Massif evidence multiple cold phases that punctuated the general post-LGM warming trend and illustrate the sensitive response of Silvretta glaciers to abrupt climate oscillations in the past.
Integrative analysis to explore the biological association between environmental skin diseases and ambient particulate matter
Authors: Kim Hyun Soo , Na Hye-Won , Jang Yujin , Kim Su Ji , Kee Nam Gook , Shin Dong Yeop , Choi Hyunjung , Kim Hyoung-June , Seo Young Rok
Published: June 2022

Although numerous experimental studies have suggested a significant association between ambient particulate matter (PM) and respiratory damage, the etiological relationship between ambient PM and environmental skin diseases is not clearly understood. Here, we aimed to explore the association between PM and skin diseases through biological big data analysis. Differential gene expression profiles associated with PM and environmental skin diseases were retrieved from public genome databases. The co-expression among them was analyzed using a text-mining-based network analysis software. Activation/inhibition patterns from RNA-sequencing data performed with PM2.5-treated normal human epidermal keratinocytes (NHEK) were overlapped to select key regulators of the analyzed pathways. We explored the adverse effects of PM on the skin and attempted to elucidate their relationships using public genome data. We found that changes in upstream regulators and inflammatory signaling networks mediated by MMP-1, MMP-9, PLAU, S100A9, IL-6, and S100A8 were predicted as the key pathways underlying PM-induced skin diseases. Our integrative approach using a literature-based co-expression analysis and experimental validation not only improves the reliability of prediction but also provides assistance to clarify underlying mechanisms of ambient PM-induced dermal toxicity that can be applied to screen the relationship between other chemicals and adverse effects.
PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients
Authors: Hsu Kuo-Hsuan , Tseng Jeng-Sen , Yang Tsung-Ying , Chen Kun-Chieh , Su Kang-Yi , Yu Sung-Liang , Chen Jeremy J. W. , Huang Yen-Hsiang , Chang Gee-Chen
Published: June 2022

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.
Using directional OCT to analyze photoreceptor visibility over AMD-related drusen
Authors: Marsh-Armstrong Brennan , Murrell Kelly S. , Valente Denise , Jonnal Ravi S.
Published: June 2022

Investigators have reported reduced visibility of the cone photoreceptors overlying drusen using adaptive optics (AO) imaging techniques. Two hypotheses have been proposed to explain this phenomenon. First, the disease-related deformation of the photoreceptor outer segment (OS) may reduce its ability to act as a wave guide, thus decreasing the cell’s familiar reflectance pattern. Second, drusen could disorient the photoreceptors away from the eye’s pupil, reducing the amount of light reflected back out the pupil. In this work, we use directional OCT (dOCT) images of drusen in AMD patients to measure the respective contributions of these deforming and disorienting factors.