bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the Role of Dignity in the Experience of Meaningfulness: a Process-Relational View on Meaningful Work
Authors: Haarjärvi Tuure , Laari-Salmela Sari
Published: August 2022

The objective of the present study is to examine the ethical grounding and process-relational nature of meaningful work through the relationship of dignity and meaningfulness. Adopting a practice lens, we show how a shift from methodological individualism to a process-relational worldview allows meaningful work to be understood through organizational activities rather than individual characteristics. Building on practice-based theorization, we present a process-relational model of meaningful work that 1) examines meaningfulness as a flow of experience in the stream of work activity events; 2) highlights how experiencing meaningfulness is embedded in social practices, distinguishing it as a social phenomenon that is defined by this embeddedness; 3) delineates situationality, historicity, and contextuality of meaningfulness; and 4) shows how meaningful work is grounded in the prioritization of dignity in the logic of practice. Accordingly, our model enables a more holistic understanding of how dignity functions as the ethical basis for the experience of meaningfulness in the context of work and organization.
Structural design and mechanical performance of composite vascular grafts
Authors: Zia Abdul Wasy , Liu Rong , Wu Xinbo
Published: August 2022

This study reviews the state of the art in structural design and the corresponding mechanical behaviours of composite vascular grafts. We critically analyse surface and matrix designs composed of layered, embedded, and hybrid structures along the radial and longitudinal directions; materials and manufacturing techniques, such as tissue engineering and the use of textiles or their combinations; and the corresponding mechanical behaviours of composite vascular grafts in terms of their physical–mechanical properties, especially their stress–strain relationships and elastic recovery. The role of computational studies is discussed with respect to optimizing the geometrics designs and the corresponding mechanical behaviours to satisfy specialized applications, such as those for the aorta and its subparts. Natural and synthetic endothelial materials yield improvements in the mechanical and biological compliance of composite graft surfaces with host arteries. Moreover, the diameter, wall thickness, stiffness, compliance, tensile strength, elasticity, and burst strength of the graft matrix are determined depending on the application and the patient. For composite vascular grafts, hybrid architectures are recommended featuring multiple layers, dimensions, and materials to achieve the desired optimal flexibility and function for complying with user-specific requirements. Rapidly emerging artificial intelligence and big data techniques for diagnostics and the three-dimensional (3D) manufacturing of vascular grafts will likely yield highly compliant, subject-specific, long-lasting, and economical vascular grafts in the near-future.

Graphic abstract
Exploiting the legacy of N.N. Ambraseys: known and unknown earthquakes in the Anatolian area
Authors: Stucchi M. , Sesetyan K. , Augusto Antonio Gomez Capera , Sbeinati M. R.
Published: August 2022

N.N. Ambraseys left us a wealth of papers and volumes on a number of topics; many of them concern the historical earthquake investigation. One of the last works is the 2009 volume (Ambraseys in Earthquakes in the Eastern Mediterranean and the Middle East: a multidisciplinary study of 2000 years of seismicity, Cambridge, Cambridge, UK, 2009), where he summarizes the results of more than thirty years of investigation through archives and libraries, covering earthquakes of a large area, from Albania to Caucasus. For each earthquake, a short summary of the main effects is supplied, together with the list of the sources used. Such information is intended as material for assessing location and size of the earthquakes, task that the author accomplished only in a very preliminary way for a few earthquakes, only. In addition to exhaustive descriptions of the most known earthquakes and the relevant historical sources, the volume contains information on a large number of earthquakes, so far unknown to the current earthquake catalogues. This paper intends to represent a homage to his immense work, partially showing the potential of his volume. We briefly present here some case histories, including the preliminary location and size of the earthquakes – known and unknown—around Anatolia. We add some examples of how he was able to prove that some alleged earthquakes are actually to be considered as fake or very doubtful. We also present the damage information supplied for some known and unknown earthquakes, and how they can be used for assessing location and size of them.
Epidermal growth factor receptor (EGFR) expression in high grade glioma and relationship with histopathologic findings, a cross sectional study
Authors: Miratashi Yazdi Seyed Amir , Bakhshi Niousha , Nazar Elham , Tabriz Hedieh Moradi , Gorji Reza
Published: August 2022

ABSTRACT

Introduction:

There are some evidences for the relationship between the expression of epidermal growth factor receptor (EGFR) gene and the clinical and histopathological behavior of the high grade glioma. However, such a relationship can take quite different forms in different societies. We aimed to evaluate the EGFR expression status in high grade of glioma and its relationship with histopathological patterns in the tumor.

Methods:

We studied the immunohistochemichal expression of EGFR in 30 brain surgical resection specimens with different high grades. All samples were from pathology department of Sina Hospital in Tehran-Iran from 2020 to 2021.

Results:

EGFR positivity was reported in 56.6% of all tissue samples assessed. The assessment of relationship between EGFR expression and baseline and tumor characteristics showed no significant association of EGFR expression and patients’ gender, age, tumor location, tumor size, its type, grade, and also existence of necrosis (P value > 0.05).

Conclusion:

EGFR expression can be found in about half of our patients suffering high grade glioma. The over-expression of EGFR seems to be independent to demographic characteristics. Also, over-expression of EGFR may not predict the presence of necrosis in tumor tissue.

Highlights
Morphodynamics of wave-dominated beaches
Authors: Castelle Bruno , Masselink Gerd
Published: August 2022

Wave-dominated sandy beaches are highly valued by societies and are amongst the world’s most energetic and dynamic environments. On wave-dominated beaches with unlimited sand supply and limited influence of tide and geology, beach change has long been conceptualised in the morphodynamic framework of Wright and Short (1984). Such framework describes the occurrence of beach types based on wave conditions and sediment characteristics across the complete reflective–dissipative spectrum. Building on theoretical work, field/laboratory measurements and monitoring programmes, the physical mechanisms underpinning this morphodynamic framework have been progressively unravelled. Cross-shore morphological changes are primarily controlled by equilibrium and beach memory principles with below (above) average wave conditions driving down-state (up-state) transitions associated with onshore (offshore) sediment transport. Such cross-shore behaviour mostly reflects the imbalance between the onshore-directed sediment transport driven by wave nonlinearities and the offshore-directed sediment transport driven by the undertow. Self-organised morphological instabilities resulting from different positive feedback mechanisms are primarily responsible for alongshore morphological variability and the generation of rhythmic morphological features, such as crescentic bars, rip channels and beach cusps. Critically, wave climate and changes in wave regimes are key in driving the coupled cross-shore and longshore behaviour that ultimately explains modal beach state and frequency-response characteristics of beach morphological time series.
Programmable thermocapillary shaping of thin liquid films
Authors: Eshel Ran , Frumkin Valeri , Nice Matan , Luria Omer , Ferdman Boris , Opatovski Nadav , Gommed Khaled , Shusteff Maxim , Shechtman Yoav , Bercovici Moran
Published: August 2022

We present a method that leverages projected light patterns as a mechanism for freeform deformation of a thin liquid film via the thermocapillary effect. We developed a closed-form solution for the inverse problem of the thin-film evolution equation, allowing us to obtain the projection pattern required in order to achieve a desired topography. We experimentally implement the method using a computer controlled light projector, which illuminates any desired pattern onto the bottom of a fluidic chamber patterned with heat–absorbing metal pads. The resulting heat map induces surface tension gradients in the liquid–air interface, giving rise to thermocapillary flow that deforms the liquid surface. If a polymer is used for the liquid film, it can then be photocured to yield a solid device. Based on the inverse-problem solutions and using this system, we demonstrate the fabrication of several diffractive optical elements, including phase masks for extended depth of field imaging, and for three-dimensional localization microscopy. The entire process, from projection to solidification, is completed in less than five minutes, and yields a sub-nanometric surface quality without any post-processing.
Long-time-scale transients in an industrial-scale slurry pipeline near the laminar–turbulent transition
Authors: Dash Amitosh , Poelma Christian
Published: August 2022

We revisit the laminar–turbulent transition of a fine-grained slurry in a large pipe. The combination of long measurement times in an industrial-scale facility and ultrasound imaging allows us to observe and address anomalous trends. Under turbulent conditions, the flow is homogeneous and steady. However, under laminar conditions, two types of long-time-scale transient behaviours are captured. In the first scenario, the system has been homogenized, following which the flow rate is reduced to laminar conditions. The flow rate continues to gradually drop, while particles settle and form a stationary bed. In the second scenario, the system has been shut down for a prolonged period and the flow rate is slowly increased. The flow rate continues to rise while particles are slowly resuspended from the gradually eroding bed. Near the laminar–turbulent transition point, two types of intermittent structures are responsible for resuspension. The equilibrium phase, with steady flow rate, coincides with complete resuspension. These two long-time-scale transients correspond to the phenomena of ‘slow settling’ and ‘self-equilibration’, respectively. While the former can lead to shutdowns, the latter generates a stable system. Being aware of these phenomena is of relevance while operating slurry pipelines near the favourable operating point of the laminar–turbulent transition.
Costs of common perinatal mental health problems in South Africa
Authors: Bauer Annette , Garman Emily , Besada Donela , Field Sally , Knapp Martin , Honikman Simone
Published: August 2022

Background

Perinatal mental health problems, defined as mental health problems occurring from the start of pregnancy to one year after birth, substantially affect women's and children's quality of life in low- and middle-income countries. In South Africa, despite high prevalence and documented negative impacts, most women do not receive any care.

Methods

A modelling study examined the costs of perinatal mental health problems, namely depression and anxiety, for a hypothetical cohort of women and their children in South Africa over part of their life course (10 years for women, 40 years for children). In sensitivity analysis, additional impacts of post-traumatic stress disorder (PTSD) and completed suicide were included. Data sources were published findings from cohort studies, as well as epidemiological and economic data from South Africa. Data from international studies were considered where no data from South Africa were available.

Results

Lifetime costs of perinatal depression and anxiety in South Africa amount to USD 2.8 billion per annual cohort of births. If the impacts of PTSD and suicide are included, costs increase to USD 2.9 billion. This includes costs linked to losses in quality of life (USD 1.8 billion), losses in income (USD 1.1 billion) and public sector costs (USD 3.5 million).

Conclusions

Whilst important progress has been made in South Africa with regards to mental health policies and interventions that include assessment and management of perinatal mental health problems, substantial underinvestment prevents progress. Findings from this study strengthen the economic case for investing in perinatal mental health care.
A randomized trial to determine whether wearing slippers reduces transfer of bacteriophage MS2 from floors to patients and surfaces in hospital rooms
Authors: Haq Muhammed F. , Alhmidi Heba , Redmond Sarah N. , Cadnum Jennifer L. , Silva Sandra Y. , Wilson Brigid M. , Donskey Curtis J.
Published: August 2022

In a randomized trial, patients wearing slippers whenever out of bed transferred bacteriophage MS2 from hospital room floors to patients and surfaces significantly less often than controls not provided with slippers. Wearing slippers could provide a simple means to reduce the risk for acquisition of healthcare-associated pathogens from contaminated floors.

Registration: ClinicalTrials.gov; NCT04935892
Is the number of prescriptions an appropriate metric for outpatient antimicrobial consumption? A comparison between the prescription counts and days supplied
Authors: Kakiuchi Satoshi , Perencevich Eli N. , Livorsi Daniel J. , Goto Michihiko
Published: August 2022

The optimal metric for outpatient antimicrobial stewardship has not been well defined. The number of antibiotic prescriptions per clinic visit does not account for the therapeutic duration. We found only moderate association between prescription-based metrics and days-supplied–based metrics. Outpatient antibiotic consumption metrics should incorporate the duration of therapy.
NON-PERVERSE PARITY SHEAVES ON THE FLAG VARIETY
Authors: MCNAMARA PETER J.
Published: August 2022

We give examples of non-perverse parity sheaves on Schubert varieties for all primes.
“The People Do Not Understand”: R. Ḥayim Hirschensohn and Political Elitism in Modern Judaism (The Vilna Gaon, Rabbi N.Ts.Y. Berlin, I. B. Levinsohn, and Herzl)
Authors: Brown Benjamin
Published: August 2022

Rabbi Ḥayim (Chaim) Hirschensohn (1857–1935) was one of only a handful of Jewish thinkers to work out a Jewish political theology, and on account of his progressive stances he became a favorite of liberal circles within contemporary Judaism. Therefore, a passage in his book Malki Bakodesh, in which he expresses clear opposition to universal suffrage, “invited” mitigating interpretations. Yet, a survey of Hirschensohn’s various writings reveals that they contain a trend of political elitism. Is this surprising? Hirschensohn’s progressiveness notwithstanding, the article argues that his elitist sentiments are rooted in three major intellectual trends within modern Judaism: Mitnagdism, Haskalah, and Zionism. In the writings of seminal thinkers in each of these movements, we find political elitism and reservations about government “by the people.” Hirschensohn’s personal history positioned him at the confluence of these trends, and so his elitist opinions should be viewed as the outgrowth of these intellectual traditions.
Fatigue in older persons: the role of nutrition
Authors: Azzolino Domenico , Coelho-Junior Hélio José , Proietti Marco , Manzini Valentina Maria , Cesari Matteo
Published: August 2022

Fatigue is defined as a symptom leading to the inability to continue functioning at the expected activity level. It is a highly prevalent symptom, challenging to frame into monodimensional pathophysiological mechanisms. As a result, fatigue is often underestimated in the clinical setting and is wrongly considered an unavoidable consequence of ageing. Several potential mechanisms responsible for fatigue have been proposed, including sleep patterns, autonomic nervous system abnormalities and biological complexity. Inflammation and mitochondrial dysfunction are among the most promising mechanisms through which malnutrition may cause fatigue. Not surprisingly, fatigue is highly prevalent in inflammatory conditions (e.g. COVID-19 infection). The nutritional status may also represent a critical factor in the development and presentation of fatigue, which may mimic the exhaustion of the individual's metabolic reserves. For example, the insufficient dietary intake of energy and proteins may determine the catabolism of body fat and muscles, disrupt the homeostatic balance and cause the onset of fatigue. It is necessary to conduct research on fatigue. By characterising its pathophysiological mechanisms, it will be possible to (1) support the design and development of targeted interventions, (2) improve the quality of life of many persons by acting on the symptom and (3) reduce the direct and indirect costs of a burdening condition typical of advancing age. In the present review, we provide an overview of the role that nutrition may play as a determinant of fatigue in older people, also in the context of the COVID-19 pandemic.
The complete mitogenome of the Asian lung fluke Paragonimus skrjabini miyazakii and its implications for the family Paragonimidae (Trematoda: Platyhelminthes)
Authors: Le Thanh Hoa , Nguyen Khue Thi , Pham Linh Thi Khanh , Doan Huong Thi Thanh , Agatsuma Takeshi , Blair David
Published: August 2022

The complete circular mitogenome of Paragonimus skrjabini miyazakii (Platyhelminthes: Paragonimidae) from Japan, obtained by PacBio long-read sequencing, was 17 591 bp and contained 12 protein-coding genes (PCGs), 2 mitoribosomal RNA and 22 transfer RNA genes. The atp8 gene was absent, and there was a 40 bp overlap between nad4L and nad4. The long non-coding region (4.3 kb) included distinct types of long and short repeat units. The pattern of base usage for PCGs and the mtDNA coding region overall in Asian and American Paragonimus species (P. s. miyazakii, P. heterotremus, P. ohirai and P. kellicotti) and the Indian form of P. westermani was T > G > A > C. On the other hand, East-Asian P. westermani used T > G > C > A. Five Asian and American Paragonimus species and P. westermani had TTT/Phe, TTG/Leu and GTT/Val as the most frequently used codons, whereas the least-used codons were different in each species and between regional forms of P. westermani. The phylogenetic tree reconstructed from a concatenated alignment of amino acids of 12 PCGs from 36 strains/26 species/5 families of trematodes confirmed that the Paragonimidae is monophyletic, with 100% nodal support. Paragonimus skrjabini miyazakii was resolved as a sister to P. heterotremus. The P. westermani clade was clearly separate from remaining congeners. The latter clade was comprised of 2 subclades, one of the East-Asian and the other of the Indian Type 1 samples. Additional mitogenomes in the Paragonimidae are needed for genomic characterization and are useful for diagnostics, identification and genetic/ phylogenetic/ epidemiological/ evolutionary studies of the Paragonimidae.
Bain's Theory of Moral Judgment and the Development of Mill's Utilitarianism
Authors: Zimmerman Aaron
Published: August 2022

InUtilitarianism, Mill defers to Alexander Bain's expertise on the subject of moral judgment to answer common criticisms of the creed. First, we do not blame people or label them immoral when they are less than ideal. Judgments of immorality are commonly reserved for substandard behavior, not suboptimal comportment. Second, we do not commonly insist on full neutrality in benevolence. Indeed, some philosophers argue that we are obliged to exhibit partiality, insofar as it is demanded by our roles as friends, parents, or children. My primary aim in this essay is to explicate Bain's theory of moral judgment and explain how Mill used Bain's psychological doctrines to inform his development of an indirect utilitarian moral philosophy, immune to the criticisms described above.
Syllable weight and natural duration in textsetting popular music in English
Authors: RYAN KEVIN M.
Published: August 2022

Hayes & Kaun (1996) argue that the mapping of syllables onto a metrical grid in textsetting is sensitive to natural duration, not just categorical weight (heavy or light). Most of their evidence, however, derives the final lengthening effects, which admit of another possible analysis (Halle 2004). Drawing on a corpus of 2,371 popular songs in English, I confirm that even when one controls for final lengthening and other factors, the setting of syllables to a discrete grid is sensitive to natural duration. Moreover, onset effects reveal that the domain of weight for textsetting is not the syllable, rime, or vowel-to-vowel interval, but rather the interval between p-centers (perceptual centers). Finally, I argue that the textsetting grammar invokes both natural duration and categorical weight; weight mapping cannot be reduced to one or the other.
1751 and Thereabout: A Quantitative and Comparative Approach to Notarial Records
Authors: Lemercier Claire , Trivellato Francesca
Published: August 2022

This article asks a simple question that nevertheless has broad implications for historians of premodern continental Europe: What did notaries do? It answers it by applying descriptive statistics, principal component analysis, and clustering techniques to the typological distribution of all deeds preserved in the notarial collections of six French and Italian cities—Paris, Toulouse, Mende, Turin, Florence, and Livorno—for the year 1751, as well as smaller datasets for other dates and locations. The results of this analysis are surprising. In spite of a high degree of consistency in the notarial profession and terminology (a trait that facilitates our comparisons), the notarial style of each city varied greatly. Variations within a single state were sometimes greater than those across state borders. Both supply and demand of notarial services differed from city to city. Overall, our conclusions are as important as the methodology that we adopt to reach them. Our aim is to offer a replicable analysis that puts quantitative methods in the service not only of the study of a source (notarial records) that is widespread across late medieval and early modern continental Europe and its overseas empires but also of a renewed comparative social history that does not shy away from the heterogeneity of primary sources.
Effects of different application methods of spent coffee grounds on weed growth
Authors: Hirooka Yoshihiro , Kurashige Shintaro , Yamane Koji , Kakiuchi Misako , Miyagawa Taku , Iwai Kazuya , Iijima Morio
Published: August 2022

The extensive and intensive use of herbicides has resulted in the spread of herbicide-resistant weeds in many crop production systems; therefore, it is imperative to devise new organic weed control methods. Recently, the application of spent coffee grounds (SCG) in agricultural fields has been found to inhibit plant growth and germination and is thus considered a potentially effective weed control measure. This study aimed to evaluate the effects of different amounts and methods of SCG application on weed growth through field experiments. The field experiments were conducted in an upland field converted from a paddy in western Japan. The results show that the plow-in application of over 10 kg m−2 of SCG and mulching application of 20 kg m−2 decreased the weed dry weight compared with the control. In addition, the growth of weed species of families other than Gramineae, such as wingleaf primrose-willow and horseweed, was not significantly affected by SCG application. Weed species of families other than Gramineae are dominant in some upland fields. Hence, the inhibitory effect of SCG on weeds may be lower in original upland fields than in the upland field converted from paddy field that was investigated in the present study. Overall, this study demonstrated that the plow-in application of 10 kg m−2 of SCG every 4 mo was effective for weed control in an upland field converted from a paddy field. Because SCG worked against grass weeds under the specific conditions in this study, it would be valuable to explore other potential applications of this novel means of weed control.
Soziale Teilhabe in Pflegeheimen mit Covid-19-Schutzmaßnahmen in der zweiten Pandemiewelle?
Authors: Gangnus Annabell , Hering Christian , Kohl Raphael , Henson Clara-Sophia , Schwinger Antje , Steinhagen-Thiessen Elisabeth , Kuhlmey Adelheid , Gellert Paul
Published: August 2022

Zusammenfassung: Hintergrund: Die Umsetzung von Schutzmaßnahmen in Pflegeheimen während der Covid-19-Pandemie war mit dem Wegfall sozialer Teilhabeangebote in der ersten Covid-19-Welle verbunden, für die zweite Covid-Welle ist dies unzureichend untersucht. Ziel: Die Evaluation des Zusammenhangs von Schutzmaßnahmen und Einschränkungen der sozialen Teilhabe für die zweite Covid-19-Welle zur Ausarbeitung von Handlungsempfehlungen. Methode: Mixed-Methods-Online-Survey von Pflegeheimleitungen ( n = 873) in der zweiten Welle. Mithilfe binärlogistischer verallgemeinerter Schätzgleichungen wurde die Wahrscheinlichkeit für das Wegfallen sozialer Teilhabeangebote in den Pflegeheimen in Abhängigkeit gesetzlicher Schutzmaßnahmen evaluiert. Offene Antworten zur Aufrechterhaltung sozialer Teilhabe wurden inhaltsanalytisch untersucht ( n = 1042). Ergebnisse: Mehr als jede zweite Pflegeheimleitung berichtet über untersagte Gruppenveranstaltungen (66,6%), mehr als jede dritte untersagte kreative Angebote (42,3%). Besuchseinschränkungen (85,2%) waren in der zweiten Welle weit verbreitet. Der Wegfall von Teilhabeangeboten und die angeordneten Schutzmaßnahmen waren eng assoziiert. Qualitative Daten zeigten, dass zum Beispiel das Anschaffen mobiler Einkaufsläden Maßnahmen waren, der sozialen Exklusion der Bewohnenden entgegenzuwirken. Diskussion: Der Zusammenhang zwischen dem Wegfall sozialer Teilhabeangebote und der Umsetzung von Schutzmaßnahmen war deutlich ausgeprägt. Die Pflegepraxis sollte die Umsetzung von sozialer Teilhabe ermöglichen und gleichzeitig einen bestmöglichen Infektionsschutz garantieren.
The Initiation and Growth of Transpressional Shear Zones Through Continental Arc Lithosphere, Southwest New Zealand
Authors: Klepeis Keith A. , Schwartz Joshua J. , Miranda Elena , Lindquist Peter , Jongens Richard , Turnbull Rose , Stowell Harold
Published: August 2022

Structural analyses combined with new U‐Pb zircon and titanite geochronology show how two Early Cretaceous transpressional shear zones initiated and grew through a nearly complete section of continental arc crust during oblique convergence. Both shear zones reactivated Carboniferous faults that penetrated the upper mantle below Zealandia's Median Batholith but show opposite growth patterns and dissimilar relationships with respect to arc magmatism. The Grebe‐Indecision Creek shear zone was magma‐starved and first reactivated at ∼136 Ma as an oblique‐reverse fault, along which an outboard batholith partially subducted beneath Gondwana. This system nucleated at or above ∼20 km depth and propagated downward at 2–3 mm yr−1, accumulating at least 35–45 km of horizontal (arc‐normal) shortening by ∼124 Ma. In contrast, the magma‐rich George Sound shear zone first reactivated in the lower crust (∼55 km depth) at ∼124 Ma and grew upward at ∼3 mm yr−1, reaching the upper crust by ∼110 Ma. In this latter system, magmatism influenced shear zone architecture and drove its growth while subduction and oblique convergence ended. As magma entered the roots of the system and began to solidify, deformation was driven out of the lower crust and into the middle crust where the system widened by a factor of three when fold‐thrust belts formed on either side of a steep, central transpressional shear zone. This study illustrates how the reactivation of structural weaknesses localizes deformation at all depths in the lithosphere and shows how magma‐deformation feedbacks influence shear zone connectivity and built a batholith from the bottom up.
Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-small cell lung cancer cells
Authors: Park Soonbum , Cho Eun A , Chun Jung Nyeo , Lee Da Young , Lee Sanghoon , Kim Mi Yeon , Bae Sang Mun , Jo Su In , Lee So Hee , Park Hyun Ho , Kim Tae Min , So Insuk , Kim Sang-Yeob , Jeon Ju-Hong
Published: August 2022

Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells. In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance our understanding of the anticancer action of crizotinib and provide insight into future clinical investigations.
DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor–resistant lung cancer therapy
Authors: Heo Haejeong , Kim Jong-Hwan , Lim Hyun Jung , Kim Jeong-Hwan , Kim Miso , Koh Jaemoon , Im Joo-Young , Kim Bo-Kyung , Won Misun , Park Ji-Hwan , Shin Yang-Ji , Yun Mi Ran , Cho Byoung Chul , Kim Yong Sung , Kim Seon-Young , Kim Mirang
Published: August 2022

Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenotype switching that occurs during the epithelial-to-mesenchymal transition (EMT). Although drug-induced epigenetic reprogramming is believed to alter the sensitivity of cancer cells to anticancer treatments, there is still much to learn about overcoming drug resistance. In this study, we used an in vitro model of ceritinib-resistant NSCLC and employed genome-wide DNA methylation analysis in combination with single-cell (sc) RNA-seq to identify cytidine deaminase (CDA), a pyrimidine salvage pathway enzyme, as a candidate drug target. CDA was hypomethylated and upregulated in ceritinib-resistant cells. CDA-overexpressing cells were rarely but definitively detected in the naïve cell population by scRNA-seq, and their abundance was increased in the acquired-resistance population. Knockdown of CDA had antiproliferative effects on resistant cells and reversed the EMT phenotype. Treatment with epigenome-related nucleosides such as 5-formyl-2′-deoxycytidine selectively ablated CDA-overexpressing resistant cells via accumulation of DNA damage. Collectively, our data suggest that targeting CDA metabolism using epigenome-related nucleosides represents a potential new therapeutic strategy for overcoming ALK inhibitor resistance in NSCLC.
Integrative tumour mutation burden with CD39 and PD-L1 for the prediction of response to PD-L1 blockade and adjuvant chemotherapy in muscle-invasive bladder cancer patients
Authors: Liu Chunnan , Liu Zhaopei , Jin Kaifeng , Zeng Han , Shao Fei , Chang Yuan , Wang Yiwei , Xu Le , Wang Zewei , Zhu Yu , Zhang Weijuan
Published: August 2022

Background

CD39, a rate-limiting enzyme to convert extracellular ATP (eATP) to adenosine, has been reported to be a key modulator of immune response, but its correlation with therapeutic sensitivity remains obscure. We conducted this study to determine whether the integration of CD39 and traditional biomarkers could improve the prediction of responsiveness to PD-L1 blockade and platinum-based chemotherapy.

Methods

We retrospectively enrolled a total of 760 patients from IMvigor210 trial, TCGA database and Zhongshan Hospital in this study. We constructed the CPT scoring system based on CD39, PD-L1 and tumour mutation burden (TMB) and validated its efficacy in predicting therapeutic responsiveness in MIBC patients. Kaplan–Meier survival and Cox regression analyses were applied to assess clinical outcomes of patients.

Results

The CPT scoring system could predict the response to PD-L1 blockade and platinum-based chemotherapy. The CPT score was positively correlated with APOBEC mutational signature and SNV neoantigens enrichment, antigen presentation, and TCR signalling. High CPT score also indicated the inflamed immune phenotype and basal/squamous molecular subtype.

Conclusions

CD39 expression is closely correlated with the immunogenic contexture of MIBC. Integrating CD39 with PD-L1 and TMB could stratify the sensitivity of patients with MIBC to PD-L1 blockade and platinum-based chemotherapy.
Cancer associated fibroblasts secreted exosomal miR-1290 contributes to prostate cancer cell growth and metastasis via targeting GSK3β
Authors: Wang Shuo , Du Peng , Cao Yudong , Ma Jinchao , Yang Xiao , Yu Ziyi , Yang Yong
Published: August 2022

Cancer-associated fibroblasts (CAFs) play crucial roles in mediating tumor growth and metastasis via transferring exosomes to neighboring cells, whereas the mechanisms by which CAFs regulate the tumorgenesis of prostate cancer (PC) remain largely unknown. In this study, CAFs and normal fibroblasts (NFs) were isolated from PC tissues and adjacent normal tissues, respectively. Exosomes (NFs-Exo and CAFs-Exo) were then isolated from the supernatant of NFs and CAFs. Next, the differentially expressed miRNAs (DEMs) between NFs-Exo and CAFs-Exo were identified using RNA-sequencing. Cell viability, migration and invasion were detected with CCK-8 and Transwell assays. Protein expression was measured with western blot. We found that CAFs-Exo remarkably enhanced PC cell migration, invasion, stemness, epithelial-mesenchymal transition (EMT) and metastasis. Significantly, miR-1290 level was upregulated in CAFs-Exo compared to NFs-Exo. In addition, CAFs could transfer exosomes to PC cells, resulting in a marked increase of miR-1290 level in cells. Moreover, exosomal miR-1290 could inhibit GSK3β/β-catenin signaling by binding with the downstream target GSK3β mRNA. Meanwhile, miR-1290 antagomir notably reversed the effects of CAFs-Exo on PC cells through activating GSK3β/β-catenin signaling. Collectively, exosomal miR-1290 from CAFs could promote PC cell growth and metastasis via inhibiting GSK3β/β-catenin signaling, suggesting that miR-1290 may serve as potential therapeutic target for the treatment of PC.
Parents’ understanding of genome and exome sequencing for pediatric health conditions: a systematic review
Authors: Gereis Jessica , Hetherington Kate , Ha Lauren , Robertson Eden G. , Ziegler David S. , Barlow-Stewart Kristine , Tucker Katherine M. , Marron Jonathan M. , Wakefield Claire E.
Published: August 2022

Genome and exome sequencing (GS/ES) are increasingly being used in pediatric contexts. We summarize evidence regarding the actual and perceived understanding of GS/ES of parents of a child offered testing for diagnosis and/or management of a symptomatic health condition. We searched four databases (2008–2021) and identified 1264 unique articles, of which 16 met inclusion criteria. We synthesized data from qualitative and quantitative studies and organized results using Ayuso et al. (2013)’s framework of key elements of information for informed consent to GS/ES. Many of the parents represented had prior experience with genetic testing and accessed a form of genetic counseling. Parents’ understanding was varied across the domains evaluated. Parents demonstrated understanding of the various potential direct clinical benefits to their child undergoing GS/ES, including in relation to other genetic tests. We found parents had mixed understanding of the nature of potential secondary findings, and of issues related to data privacy, confidentiality, and usage of sequencing results beyond their child’s clinical care. Genetic counseling consultations improved understanding. Our synthesis indicates that ES/GS can be challenging for families to understand and underscores the importance of equipping healthcare professionals to explore parents’ understanding of ES/GS and the implications of testing for their child.
Integrated 3D printing of flexible electroluminescent devices and soft robots
Authors: Zhang Pei , Lei Iek Man , Chen Guangda , Lin Jingsen , Chen Xingmei , Zhang Jiajun , Cai Chengcheng , Liang Xiangyu , Liu Ji
Published: August 2022

Flexible and stretchable light emitting devices are driving innovation in myriad applications, such as wearable and functional electronics, displays and soft robotics. However, the development of flexible electroluminescent devices via conventional techniques remains laborious and cost-prohibitive. Here, we report a facile and easily-accessible route for fabricating a class of flexible electroluminescent devices and soft robotics via direct ink writing-based 3D printing. 3D printable ion conducting, electroluminescent and insulating dielectric inks were developed, enabling facile and on-demand creation of flexible and stretchable electroluminescent devices with good fidelity. Robust interfacial adhesion with the multilayer electroluminescent devices endowed the 3D printed devices with attractive electroluminescent performance. Integrated our 3D printed electroluminescent devices with a soft quadrupedal robot and sensing units, an artificial camouflage that can instantly self-adapt to the environment by displaying matching color was fabricated, laying an efficient framework for the next generation soft camouflages.
Rhythmic transcription of Bmal1 stabilizes the circadian timekeeping system in mammals
Authors: Abe Yasuko O. , Yoshitane Hikari , Kim Dae Wook , Kawakami Satoshi , Koebis Michinori , Nakao Kazuki , Aiba Atsu , Kim Jae Kyoung , Fukada Yoshitaka
Published: August 2022

In mammals, the circadian clock consists of transcriptional and translational feedback loops through DNA cis-elements such as E-box and RRE. The E-box-mediated core feedback loop is interlocked with the RRE-mediated feedback loop, but biological significance of the RRE-mediated loop has been elusive. In this study, we established mutant cells and mice deficient for rhythmic transcription of Bmal1 gene by deleting its upstream RRE elements and hence disrupted the RRE-mediated feedback loop. We observed apparently normal circadian rhythms in the mutant cells and mice, but a combination of mathematical modeling and experiments revealed that the circadian period and amplitude of the mutants were more susceptible to disturbance of CRY1 protein rhythm. Our findings demonstrate that the RRE-mediated feedback regulation of Bmal1 underpins the E-box-mediated rhythm in cooperation with CRY1-dependent posttranslational regulation of BMAL1 protein, thereby conferring the perturbation-resistant oscillation and chronologically-organized output of the circadian clock.
Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes
Authors: Akbari Parsa , Sosina Olukayode A. , Bovijn Jonas , Landheer Karl , Nielsen Jonas B. , Kim Minhee , Aykul Senem , De Tanima , Haas Mary E. , Hindy George , Lin Nan , Dinsmore Ian R. , Luo Jonathan Z. , Hectors Stefanie , Geraghty Benjamin , Germino Mary , Panagis Lampros , Parasoglou Prodromos , Walls Johnathon R. , Halasz Gabor , Atwal Gurinder S. ,   Regeneron Genetics Center, Della Gatta Giusy ,   DiscovEHR Collaboration, Jones Marcus , LeBlanc Michelle G. , Still Christopher D. , Carey David J. , Giontella Alice , Orho-Melander Marju , Berumen Jaime , Kuri-Morales Pablo , Alegre-Díaz Jesus , Torres Jason M. , Emberson Jonathan R. , Collins Rory , Rader Daniel J. , Zambrowicz Brian , Murphy Andrew J. , Balasubramanian Suganthi , Overton John D. , Reid Jeffrey G. , Shuldiner Alan R. , Cantor Michael , Abecasis Goncalo R. , Ferreira Manuel A. R. , Sleeman Mark W. , Gusarova Viktoria , Altarejos Judith , Harris Charles , Economides Aris N. , Idone Vincent , Karalis Katia , Della Gatta Giusy , Mirshahi Tooraj , Yancopoulos George D. , Melander Olle , Marchini Jonathan , Tapia-Conyer Roberto , Locke Adam E. , Baras Aris , Verweij Niek , Lotta Luca A.
Published: August 2022

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.
Sub-10-fs observation of bound exciton formation in organic optoelectronic devices
Authors: Maimaris Marios , Pettipher Allan J. , Azzouzi Mohammed , Walke Daniel J. , Zheng Xijia , Gorodetsky Andrei , Dong Yifan , Tuladhar Pabitra Shakya , Crespo Helder , Nelson Jenny , Tisch John W. G. , Bakulin Artem A.
Published: August 2022

Fundamental mechanisms underlying exciton formation in organic semiconductors are complex and elusive as it occurs on ultrashort sub-100-fs timescales. Some fundamental aspects of this process, such as the evolution of exciton binding energy, have not been resolved in time experimentally. Here, we apply a combination of sub-10-fs Pump-Push-Photocurrent, Pump-Push-Photoluminescence, and Pump-Probe spectroscopies to polyfluorene devices to track the ultrafast formation of excitons. While Pump-Probe is sensitive to the total concentration of excited states, Pump-Push-Photocurrent and Pump-Push-Photoluminescence are sensitive to bound states only, providing access to exciton binding dynamics. We find that excitons created by near-absorption-edge photons are intrinsically bound states, or become such within 10 fs after excitation. Meanwhile, excitons with a modest >0.3 eV excess energy can dissociate spontaneously within 50 fs before acquiring bound character. These conclusions are supported by excited-state molecular dynamics simulations and a global kinetic model which quantitatively reproduce experimental data.
Rainfall and sea level drove the expansion of seasonally flooded habitats and associated bird populations across Amazonia
Authors: Sawakuchi A. O. , Schultz E. D. , Pupim F. N. , Bertassoli D. J. , Souza D. F. , Cunha D. F. , Mazoca C. E. , Ferreira M. P. , Grohmann C. H. , Wahnfried I. D. , Chiessi C. M. , Cruz F. W. , Almeida R. P. , Ribas C. C.
Published: August 2022

Spatial arrangement of distinct Amazonian environments through time and its effect on specialized biota remain poorly known, fueling long-lasting debates about drivers of biotic diversification. We address the late Quaternary sediment deposition that assembled the world's largest seasonally flooded ecosystems. Genome sequencing was used to reconstruct the demographic history of bird species specialized in either early successional vegetation or mature floodplain forests. Sediment deposition that built seasonally flooded habitats accelerated throughout the Holocene (last 11,700 years) under sea level highstand and intensification of the South American Monsoon, at the same time as global increases in atmospheric methane concentration. Bird populations adapted to seasonally flooded habitats expanded due to enlargement of Amazonian river floodplains and archipelagos. Our findings suggest that the diversification of the biota specialized in seasonally flooded habitats is coupled to sedimentary budget changes of large rivers, which rely on combined effects of sea level and rainfall variations.
De novo protein design of photochemical reaction centers
Authors: Ennist Nathan M. , Zhao Zhenyu , Stayrook Steven E. , Discher Bohdana M. , Dutton P. Leslie , Moser Christopher C.
Published: August 2022

Natural photosynthetic protein complexes capture sunlight to power the energetic catalysis that supports life on Earth. Yet these natural protein structures carry an evolutionary legacy of complexity and fragility that encumbers protein reengineering efforts and obfuscates the underlying design rules for light-driven charge separation. De novo development of a simplified photosynthetic reaction center protein can clarify practical engineering principles needed to build new enzymes for efficient solar-to-fuel energy conversion. Here, we report the rational design, X-ray crystal structure, and electron transfer activity of a multi-cofactor protein that incorporates essential elements of photosynthetic reaction centers. This highly stable, modular artificial protein framework can be reconstituted in vitro with interchangeable redox centers for nanometer-scale photochemical charge separation. Transient absorption spectroscopy demonstrates Photosystem II-like tyrosine and metal cluster oxidation, and we measure charge separation lifetimes exceeding 100 ms, ideal for light-activated catalysis. This de novo-designed reaction center builds upon engineering guidelines established for charge separation in earlier synthetic photochemical triads and modified natural proteins, and it shows how synthetic biology may lead to a new generation of genetically encoded, light-powered catalysts for solar fuel production.
Duplicated ribosomal protein paralogs promote alternative translation and drug resistance
Authors: Malik Ghulam Mustafa , Catala Mathieu , Reulet Gaspard , Scott Michelle S. , Abou Elela Sherif
Published: August 2022

Ribosomes are often seen as monolithic machines produced from uniformly regulated genes. However, in yeast most ribosomal proteins come from duplicated genes. Here, we demonstrate that gene duplication may serve as a stress-adaptation mechanism modulating the global proteome through the differential expression of ribosomal protein paralogs. Our data indicate that the yeast paralog pair of the ribosomal protein L7/uL30 produces two differentially acetylated proteins. Under normal conditions most ribosomes incorporate the hypo-acetylated major form favoring the translation of genes with short open reading frames. Exposure to drugs, on the other hand, increases the production of ribosomes carrying the hyper-acetylated minor paralog that increases translation of long open reading frames. Many of these paralog-dependent genes encode cell wall proteins that could promote tolerance to drugs as their translation increases after exposure to drugs. Together our data suggest a mechanism of translation control that functions through a differential use of near-identical ribosomal protein isoforms.