bluuebunny/crossref_metadata_2025 huggingface dataset:
Local linear stability of plumes generated along vertical heated cylinders in stratified environments
Authors: Yu Ziheng , Hunt Gary R.
Published: September 2023

The linear temporal and absolute/convective stability characteristics of a thermal plume generated along a heated vertical cylinder are investigated theoretically under the Boussinesq approximation. Special focus is given to the uniform-wall-buoyancy-flux case whereby the cylinder surface sustains the same linear temperature gradient as the environment. A competition between the axisymmetric and helical modes is a remarkable feature of the instability, distinguishing these ‘annular plumes’ from free plumes/jets for which the helical mode is generally dominant. It is found that higher surface curvature stabilises the temporal axisymmetric mode significantly, but only has moderate effects on the helical mode. The most temporally unstable perturbation mode switches from a helical into an axisymmetric mode when the Prandtl number increases beyond a critical value. Both the roles of shear and buoyancy during the destabilisation are identified through an energy analysis which indicates that, while the shear work is usually a major source of perturbation energy, the buoyancy work manifests for long-wave axisymmetric perturbation modes, and for thin cylinders and high Prandtl numbers. For the specific temperature configuration considered herein, an annular plume is always convectively unstable whereas decreasing the cylinder radius from the planar limiting case first decreases and then increases the tendency of the flow towards being absolutely unstable. The helical mode is especially susceptible to being absolutely unstable on very thin cylinders. Several conditions for the onset of cellular thermal convection and plume detrainment are proposed based on our results and a hypothesis which connects the absolute instability to the detrainment phenomenon.
The heterobranch subgenusTrochactaeon(Trochactaeon) in the Campanian (Late Cretaceous) of the northern Arabian Platform and its paleoenvironmental and paleobiogeographic implications
Authors: Hoşgör Izzet , Yılmaz Ismail Ö. , Özer Sacit
Published: September 2023

Acteonellids were one of the most significant groups of marine macro-invertebrates in the Late Cretaceous biota of the Tethyan Realm. They were common faunal elements associated with Cretaceous carbonate platform communities most notable for their abundance of rudist frameworks and thrived in coeval lagoons. The Upper Cretaceous fossil-bearing Karababa Formation, cropping out in southeastern Turkey, yields a remarkable assemblage of acteonellid gastropods and rudists. Cretaceous gastropods from sedimentary successions in Turkey barely have been studied over the past 80 years. The subgenusTrochactaeon, a very successful and widespread taxon of heterobranch gastropods within the family Acteonellidae, dominated acteonellid assemblages throughout the Late Cretaceous. In the present work, we present the first record ofTrochactaeon(Trochactaeon)giganteus subglobosusfrom Turkey. It is from a single lower Campanian bed in the upper part of the Karababa Formation of the Gölbaşı region (south of Adıyaman), corresponding to the northwestern part of the Arabian Platform. This record complements information on the temporal and spatial distribution ofTrochactaeonat the southern margin of the Tethyan Ocean during the last part of the Cretaceous Period. This discovery increases the documented diversity of the paleofauna from the Upper Cretaceous succession in southeastern Turkey and provides new insights into the paleoenvironment of the carbonate ramp of the northern Arabian plate, and the paleobiogeography of Campanian gastropods in general.
ON THE DISTRIBUTION OF IWASAWA INVARIANTS ASSOCIATED TO MULTIGRAPHS
Authors: DION CÉDRIC , LEI ANTONIO , RAY ANWESH , VALLIÈRES DANIEL
Published: September 2023

Let$\ell $be a prime number. The Iwasawa theory of multigraphs is the systematic study of growth patterns in the number of spanning trees in abelian$\ell $-towers of multigraphs. In this context, growth patterns are realized by certain analogs of Iwasawa invariants, which depend on the prime$\ell $and the abelian$\ell $-tower of multigraphs. We formulate and study statistical questions about the behavior of the Iwasawa$\mu $and$\lambda $invariants.
Cross and Crown™: Trademarks and the Legal Naming of American Religions
Authors: Ventimiglia Andrew
Published: September 2023

Can religious organizations use American trademark law to assert control over the name of a religion? Further, what is the relationship between a religious organization as guarantor of fundamental spiritual truths and the signs by which it is known? To answer these questions, this article traces the history and role of trademarks in American religion with a focus on Christian Science's faith-branding strategy. This narrative explores the religious use of trademarks as an emergent strategy in the early twentieth century to manage religious practice through brand management and trademark law. Using a combination of archival research and legal analysis, this article explores legal debates about the place of trademarks in American religion followed by a close analysis of the Church of Christ, Scientist—an American religious organization “discovered and founded” by Mary Baker Eddy in the late nineteenth century—which is exemplary in the way it strategically utilized branding and marking strategies as a means of distinguishing Christian Science within a diverse marketplace of competing turn-of-the-century spiritual practices. This article argues that religious trademarks, while controversial, can be used to secure legal authority over licensed Churches, teachings, and materials in lieu of established Church hierarchy. This article interrogates the nature and origins of religious trademark strategies to demonstrate that religious organizations like the Church of Christ, Scientist could operate as particularly savvy users of the law to establish spiritual authority via control of the religious name.
Anarchy, Scarcity, Nature: Rousseau’s Stag Hunt and the Arctic Walrus Hunt Compared
Authors: SALTER MARK B.
Published: September 2023

Under conditions of anarchy, the predominant assumption is that scarcity leads to conflict. I contrast traditional Inuit walrus hunt practices to Rousseau’s stag hunt to demonstrate how mainstream international relations has it wrong on three counts: (1) radical scarcity need not lead to conflict-prone outcomes, (2) the historical eighteenth-century context of the stag hunt does not prove a predisposition against cooperation, and (3) the conditions of anarchy are irreducible to cultural institutions or to material constraints alone. I leverage Latour’s “symmetrical anthropology” to demonstrate that ideas and things have an equal potential to structure the culture of anarchical relations and to build on the literature which has established that comparative cultural data can be used to theorize anarchy. Rethinking the logic of anarchy is especially important in the age of the Anthropocene, given the prospects for radical ecological change in the near future.
Sŭ-pung-er’s pillar: The recent significant discovery of a relic related to the Franklin Expedition
Authors: Taichman Russell S.
Published: September 2023

In 1866, Charles F. Hall recorded testimony from a Pelly Bay native named Sŭ-pung-er who reported that together with his uncle, they had visited the Northwest coast of King William Island 4 years prior in search of materials abandoned by the Franklin Expedition. Sŭ-pung-er told Hall that he had identified a site which Hall believed was a “vault” which might contain documents and speculated that it could have been a burial site for a high-ranking officer. Sŭ-pung-er’s testimony also included the description of a wooden “pillar, stick or post” which marked the spot of the vault. The location of this site and the pillar have never been found. Yet they remain sought-after for both their significance and the potential bonanza of information about the expedition. Any clue or artefact, which could provide clarity for this site, is therefore of great value. This paper describes a model of the pillar seen on King Williams Island, replicated by Sŭ-pung-er, which Hall brought back from the Arctic and included in his list of Franklin relics. The model, now housed in the Smithsonian Museum of American History, was first featured in a drawing of relics appearing in 1869 in Harper’s Weekly magazine. The fact that this artefact has been in plain sight for so long, but unrecognised for what it is, is significant. The pillar model both provides clarity and continues the mystery surrounding the Franklin Expedition.
Global enhancement network underwater archaeology scene parsing method
Authors: Pan Junyan , Jia Jishen , Cai Lei
Published: September 2023

Underwater archaeology is of great significance for historical and cultural transmission and preservation of underwater heritage, but it is also a challenging task. Underwater heritage is located in an environment with high sediment content, objects are mostly buried, and the water is turbid, resulting in some of the features of objects missing or blurred, making it difficult to accurately identify and understand the semantics of various objects in the scene. To tackle these issues, this paper proposes a global enhancement network (GENet) underwater scene parsing method. We introduce adaptive dilated convolution by adding an extra regression layer, which can automatically deduce adaptive dilated coefficients according to the different scene objects. In addition, considering the easy confusion in the process of fuzzy feature classification, an enhancement classification network is proposed to increase the difference between various types of probabilities by reducing the loss function. We verified the validity of the proposed model by conducting numerous experiments on the Underwater Shipwreck Scenes (USS) dataset. We achieve state-of-the-art performance compared to the current state-of-the-art algorithm under three different conditions: conventional, relic semi-buried, and turbidified water quality. The experimental results show that the proposed algorithm performs best in different situations. To verify the generalizability of the proposed algorithm, we conducted comparative experiments on the current publicly available Cityscapes, ADE20K, and the underwater dataset SUIM. The experimental results show that this paper achieves good performance on the public dataset, indicating that the proposed algorithm is generalizable.
Natural resource extraction and ethnic inequality in Dak Lak, Vietnam
Authors: Bierkamp Sina , Nguyen Trung Thanh , Grote Ulrike
Published: September 2023

Natural resource extraction is an important livelihood strategy for poor rural households in developing and emerging countries. Despite the sharp decline in poverty in Vietnam, inequality still exists between the ethnic majority and minority. This paper aims to analyze the impact of natural resource extraction on ethnic inequality. We use panel data from Dak Lak in the Central Highlands of Vietnam. The Oaxaca-Blinder decomposition shows that ethnic differences in extraction are due to different group characteristics and different returns to these characteristics. Endogenous switching regressions find that extraction has heterogeneous effects on consumption across extracting and non-extracting households, and between majority and minority households. Treatment effects suggest that extraction sustains the consumption of extracting minority households because their consumption would decline if they stopped extracting. Our results indicate that it is important to improve the natural resource base and the ability of minorities to cope with shocks.
Impact of a mental training program for pediatric cancer patients after allogeneic hematopoietic stem cell transplantation or high-dose chemotherapy – Results of a randomized controlled trial
Authors: Döring Michaela , Xemaire Johanna , Werle Dustin , Thiel Stefanie , Schneider Veronika , Michaelis Sebastian , Schlösser Manuel , Lang Peter , Svaldi Jennifer , Cabanillas Stanchi Karin Melanie
Published: September 2023

Objectives

Hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy for the treatment of malignant diseases is a highly distressing experience. The affected person’s resilience is crucial to coping with this challenging experience. Experience with resilience-enhancing interventions in children and young adults during cancer therapy is scarce. The major objective of this work was developing and evaluating an effective psycho-oncological mental training that complements the standard psychosocial care.

Methods

In this prospective, randomized single-center study, a total of 30 patients (12 to 22 years of age) who underwent HSCT or high-dose chemotherapy received either the standard psychosocial care (control group [CG]) or additionally underwent a novel and specifically developed resilience-enhancing 14-session mental training (therapy group [TG]). The patients were observed over an 8-month period and were screened for distress, thyroid, and immune function parameters, as well as generalized anxiety, affect, and sports orientation.

Results

Patients of the TG showed significantly greater improvements in all assessed mental aspects, including anxiety, affect, competitiveness, win orientation, goal orientation, self-optimization, self-blocking, and loss of focus, as well as cortisol levels within 8 months, as opposed to patients of the CG (effect size range ξ: 0.74–1.00).

Significance of results

Patients who underwent the mental training displayed less anxiety, better affect, and improved mental performance with less self-blocking. This resulted in improved goal orientation, competitiveness, self-optimization, and focus when compared to the CG patients. However, larger prospective trials are necessary to substantiate these findings.
The temporal dependencies between social, emotional and physical health factors in young people receiving mental healthcare: a dynamic Bayesian network analysis
Authors: Iorfino Frank , Varidel Mathew , Marchant Roman , Cripps Sally , Crouse Jacob , Prodan Ante , Oliveria Rafael , Carpenter Joanne S. , Hermens Daniel F. , Guastella Adam , Scott Elizabeth , Shah Jai , Merikangas Kathleen , Scott Jan , Hickie Ian B.
Published: September 2023

Aims

The needs of young people attending mental healthcare can be complex and often span multiple domains (e.g., social, emotional and physical health factors). These factors often complicate treatment approaches and contribute to poorer outcomes in youth mental health. We aimed to identify how these factors interact over time by modelling the temporal dependencies between these transdiagnostic social, emotional and physical health factors among young people presenting for youth mental healthcare.

Methods

Dynamic Bayesian networks were used to examine the relationship between mental health factors across multiple domains (social and occupational function, self-harm and suicidality, alcohol and substance use, physical health and psychiatric syndromes) in a longitudinal cohort of 2663 young people accessing youth mental health services. Two networks were developed: (1) ‘initial network’, that shows the conditional dependencies between factors at first presentation, and a (2) ‘transition network’, how factors are dependent longitudinally.

Results

The ‘initial network’ identified that childhood disorders tend to precede adolescent depression which itself was associated with three distinct pathways or illness trajectories; (1) anxiety disorder; (2) bipolar disorder, manic-like experiences, circadian disturbances and psychosis-like experiences; (3) self-harm and suicidality to alcohol and substance use or functioning. The ‘transition network’ identified that over time social and occupational function had the largest effect on self-harm and suicidality, with direct effects on ideation (relative risk [RR], 1.79; CI, 1.59–1.99) and self-harm (RR, 1.32; CI, 1.22–1.41), and an indirect effect on attempts (RR, 2.10; CI, 1.69–2.50). Suicide ideation had a direct effect on future suicide attempts (RR, 4.37; CI, 3.28–5.43) and self-harm (RR, 2.78; CI, 2.55–3.01). Alcohol and substance use, physical health and psychiatric syndromes (e.g., depression and anxiety, at-risk mental states) were independent domains whereby all direct effects remained within each domain over time.

Conclusions

This study identified probable temporal dependencies between domains, which has causal interpretations, and therefore can provide insight into their differential role over the course of illness. This work identified social, emotional and physical health factors that may be important early intervention and prevention targets. Improving social and occupational function may be a critical target due to its impacts longitudinally on self-harm and suicidality. The conditional independence of alcohol and substance use supports the need for specific interventions to target these comorbidities.
Media Use and Black Emerging Adults’ Acceptance of Jezebel and	Sapphire Stereotypes
Authors: Ward L. Monique , Bridgewater Enrica E. , Overstreet Nicole M.
Published: September 2023

Abstract: Although African Americans are increasingly featured on TV, persistent stereotypes of Black women remain that frame them as hypersexual Jezebels or verbally aggressive Sapphires. Priming participants with these stereotypes negatively affects White emerging adults’ perceptions of Black women; however, parallel findings among Black participants have yet to emerge. We investigated this dynamic via two studies, testing mechanisms proposed by cultivation, social cognitive, and social identity theories. In Study 1, 204 Black emerging adults reported their exposure to 6 reality programs and 17 dramas that prominently feature Black women, their perceptions of the realism of TV, and their endorsement of Jezebel and Sapphire stereotypes. As expected, viewing of TV dramas that prominently feature Black women predicted notably greater support of the Jezebel stereotype among women and statistically greater support among men. Attributing greater realism to TV portrayals was associated with stronger support of the Sapphire stereotype among women. In Study 2, we exposed 438 Black and White emerging adults to depictions of the Sapphire stereotype and examined whether evaluations of women, Black women, and a Black woman job applicant varied by race or condition. Participants who had viewed Sapphire depictions perceived women, in general, to be less “feminine,” and White participants viewed Black women to be less warm. Our results offer support for multiple mechanisms and highlight implications for workplace and romantic relationships.
Reconstructing and Nowcasting the Rainfall Field by a CML Network
Authors: Zhang Peng , Liu Xichuan , Zou Mingzhong
Published: September 2023

Currently, the opportunistic method to estimate rainfall using commercial microwave links (CMLs) has been shown as an efficient way to complement traditional instruments in terms of spatial‐temporal resolution and coverage. In this paper, we collected data from 26 CMLs in Jiangyin City, Jiangsu Province, and conducted experiments on rainfall field reconstruction and nowcasting. First, the raw CML data were processed to invert the path‐averaged rainfall intensity. Second, the algorithms of inverse distance weighting (IDW) and ordinary kriging (OK) interpolation were employed to reconstruct the rainfall field. Then a 10‐min prediction of the rainfall field was achieved using a nowcasting model based on the long short‐term memory neural network and a setup window was introduced to improve the prediction performance of the first few minutes. The reconstruction results show that the average correlation coefficient (ACC) and the average root mean square error (ARMSE) between the IDW‐based results and daily cumulative rainfall from rain gauges (RGs) are 0.89 and 8.69 mm, respectively, while the ACC and ARMSE between the OK‐based results and RG data are 0.89 and 9.13 mm, respectively. The nowcasting results show that the ACC between the prediction results with a 5‐min setup window and the IDW‐retrieved rainfall fields can reach 0.91 at the first minute and gradually decrease to 0.20 within 10 min. Furthermore, the model has better nowcasting performance for stratiform precipitation and mixed precipitation compared to convective precipitation.
Laboratory Investigation of Hydrodynamic and Sand Dune Morphology Changes Under Wave Overwash
Authors: Liang Bingchen , Qu Zhipeng , Lee Dong Young , Zhang Xuecheng
Published: September 2023

Since the field measurement of wave overwash is difficult to obtain during severe storms, a laboratory experiment is conducted to measure the time and space evolution of the overwash and beach profile over the sand dune continuously using high‐speed video image analysis for different wave conditions of irregular waves and solitary waves. Characteristics of the cross‐shore sediment transport and morphology change are discussed from the laboratory experiment data. The inflection point, which marks the shifting turn in dune crest movement during overwash, is determined by analyzing feature points in the variation of dune geometry. It is confirmed that the overwash water volume rate reaches a maximum value when the inflection point occurs. Additionally, the overwash water volume is found to be linearly related to the deposited sediment volume, and the dune erosion volume is proportional to wave energy flux during the overwash process. The presence of secondary dunes is found to significantly alleviate coast erosion during overwash and reduce shoreline retreat by more than 40%, regardless of the height of the secondary dune crest. Furthermore, the advances and limitations in overwash hydrodynamics are discussed. It is recommended that this continuous morphological change monitoring data be combined with a wave resolution model for detailed hydrodynamic simulations to further understand the overwash process.
The Safe Drinking Water Act at 50: A Policy Model for Grand Challenges
Authors: Sowby Robert B.
Published: September 2023

Since its passage in 1974, the U.S. Safe Drinking Water Act (SDWA) has become a pillar of water resources engineering, utility management, and public health policy. Complementing other environmental legislation from the same period, SDWA set standards for drinking water suppliers, service, and quality and has made an unmistakable positive impact on U.S. communities for the past 50 years. While drinking water faces different specific challenges today, the general principles established by SDWA are the same. Its success may be attributed to its broad political commitment at the federal level, firm enforcement at the state level, and dutiful execution at the local (public water supplier) level—all while customers know exactly what to expect—thus creating clear accountability for safe water. Just as SDWA helped resolve last century's drinking water problems, it can serve as a policy model for addressing this century's grand challenges.
Leucine-rich repeat kinase 2 limits dopamine D1 receptor signaling in striatum and biases against heavy persistent alcohol drinking
Authors: da Silva Daniel , Matsui Aya , Murray Erin M. , Mamais Adamantios , Authement Michael E. , Shin Jung Hoon , Shaw Marlisa , Ron Dorit , Cookson Mark R. , Alvarez Veronica A.
Published: September 2023

The transition from hedonic alcohol drinking to problematic drinking is a hallmark of alcohol use disorder that occurs only in a subset of drinkers. This transition requires long-lasting changes in the synaptic drive and the activity of striatal neurons expressing dopamine D1 receptor (D1R). The molecular mechanisms that generate vulnerability in some individuals to undergo the transition are less understood. Here, we report that the Parkinson’s-related protein leucine-rich repeat kinase 2 (LRRK2) modulates striatal D1R function to affect the behavioral response to alcohol and the likelihood that mice transition to heavy, persistent alcohol drinking. Constitutive deletion of the Lrrk2 gene specifically from D1R-expressing neurons potentiated D1R signaling at the cellular and synaptic level and enhanced alcohol-related behaviors and drinking. Mice with cell-specific deletion of Lrrk2 were more prone to heavy alcohol drinking, and consumption was insensitive to punishment. These findings identify a potential novel role for LRRK2 function in the striatum in promoting resilience against heavy and persistent alcohol drinking.
A new wave of innovations within the DNA damage response
Authors: Li Qi , Qian Wenyuan , Zhang Yang , Hu Lihong , Chen Shuhui , Xia Yuanfeng
Published: September 2023

Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance of genome integrity in cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting DDR processes could induce excessive DNA damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit to patients with breast cancer gene (BRCA) mutation or homologous recombination deficiency (HRD), which proves the concept of synthetic lethality in cancer treatment. Moreover, the other two scenarios of DDR inhibitor application, replication stress and combination with chemo- or radio- therapy, are under active clinical exploration. In this review, we revisited the progress of DDR targeting therapy beyond the launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, which could maintain the efficacy while mitigating side effects, may diversify the application scenarios of PARP inhibitor in clinic. Albeit with unavoidable on-mechanism toxicities, several small molecules targeting DNA damage checkpoints (gatekeepers) have shown great promise in preliminary clinical results, which may warrant further evaluations. In addition, inhibitors for other DNA repair pathways (caretakers) are also under active preclinical or clinical development. With these progresses and efforts, we envision that a new wave of innovations within DDR has come of age.
Rumination symptoms in treatment-resistant major depressive disorder, and outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) treatment
Authors: Chu Stephanie A. , Tadayonnejad Reza , Corlier Juliana , Wilson Andrew C. , Citrenbaum Cole , Leuchter Andrew F.
Published: September 2023

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.
Dental amalgam teaching phase-out - a step too soon? Foundation trainees' experience of amalgam use in dental school compared to practice: a mixed-methods survey
Authors: Jebur Noor , Vinall-Collier Karen , Umair Abdul-Ahad , Aggarwal Vishal R.
Published: September 2023

Aim This study aimed to explore disparities in experience of UK dental foundation trainees in amalgam use at dental school compared to their first year in dental practice.

Methods A modified version of the 'survey of Yorkshire dentists' targeted the dental foundation trainees. A mixed-method of quantitative and thematic content analysis was undertaken for the close-ended and free-text responses, respectively.

Results Only 35% of participants described their confidence level as 'satisfactory' in placing dental amalgam before starting their dental foundation training and 51% scored the level of teaching between 'very poor' and 'satisfactory'. In total, 63% of respondents were in favour of receiving additional support in placing amalgam restorations during their undergraduate training. Participants indicated that the consequences of amalgam phase-out are increased appointment times and decreased quality of care due to patient and health service unaffordability of amalgam alternatives.

Conclusion These findings raise concerns regarding newly qualified undergraduates' confidence, experience and skill in placing amalgams. This suggests the need to increase undergraduate education and training to improve undergraduates' skills and confidence in amalgam procedures to reduce the gap between the dental schools and real-world practice.
Axitinib in patients with advanced/metastatic soft tissue sarcoma (Axi-STS): an open-label, multicentre, phase II trial in four histological strata
Authors: Woll Penella J. , Gaunt Piers , Gaskell Charlotte , Young Robin , Benson Charlotte , Judson Ian R. , Seddon Beatrice M. , Marples Maria , Ali Nasim , Strauss Sandra J. , Lee Alexander , Hughes Ana , Kaur Baljit , Hughes David , Billingham Lucinda
Published: September 2023

Background

Axitinib is an oral vascular endothelial growth factor receptor inhibitor with anti-tumour activity in renal, thyroid, and pancreatic cancer.

Methods

Axi-STS was a pathologically-stratified, non-randomised, open-label, multi-centre, phase II trial of continuous axitinib treatment in patients ≥16 years, performance status ≤2, with pathologically-confirmed advanced/metastatic soft tissue sarcoma (STS). Patients were recruited within four tumour strata, each analysed separately: angiosarcoma, leiomyosarcoma, synovial sarcoma, or other eligible STSs. The primary outcome was progression-free survival at 12 weeks (PFS12). A Simon’s two-stage design with activity defined as PFS12 rate of 40% determined a sample size of 33 patients per strata.

Results

Between 31-August-2010 and 29-January-2016, 145 patients were recruited: 38 angiosarcoma, 37 leiomyosarcoma, 36 synovial sarcoma, and 34 other subtypes. PFS12 rate for each stratum analysed was 42% (95% lower confidence interval (LCI); 29), 45% (95% LCI; 32), 57% (95% LCI; 42), and 33% (95% LCI; 21), respectively. There were 74 serious adverse events including two treatment-related deaths of pulmonary haemorrhage and gastrointestinal bleeding. Fatigue and hypertension were the most common grade 3 adverse events.

Conclusions

Axitinib showed clinical activity in all STS strata investigated. The adverse event profile was acceptable, supporting further investigation in phase III trials.

Clinical Trial Registration

ISRCTN 60791336
Activation of the integrated stress response by inhibitors of its kinases
Authors: Szaruga Maria , Janssen Dino A. , de Miguel Claudia , Hodgson George , Fatalska Agnieszka , Pitera Aleksandra P. , Andreeva Antonina , Bertolotti Anne
Published: September 2023

Phosphorylation of the translation initiation factor eIF2α to initiate the integrated stress response (ISR) is a vital signalling event. Protein kinases activating the ISR, including PERK and GCN2, have attracted considerable attention for drug development. Here we find that the widely used ATP-competitive inhibitors of PERK, GSK2656157, GSK2606414 and AMG44, inhibit PERK in the nanomolar range, but surprisingly activate the ISR via GCN2 at micromolar concentrations. Similarly, a PKR inhibitor, C16, also activates GCN2. Conversely, GCN2 inhibitor A92 silences its target but induces the ISR via PERK. These findings are pivotal for understanding ISR biology and its therapeutic manipulations because most preclinical studies used these inhibitors at micromolar concentrations. Reconstitution of ISR activation with recombinant proteins demonstrates that PERK and PKR inhibitors directly activate dimeric GCN2, following a Gaussian activation-inhibition curve, with activation driven by allosterically increasing GCN2 affinity for ATP. The tyrosine kinase inhibitors Neratinib and Dovitinib also activate GCN2 by increasing affinity of GCN2 for ATP. Thus, the mechanism uncovered here might be broadly relevant to ATP-competitive inhibitors and perhaps to other kinases.
Sequential order dependent dark-exciton modulation in bi-layered TMD heterostructure
Authors: Sebait Riya , Rosati Roberto , Yun Seok Joon , Dhakal Krishna P. , Brem Samuel , Biswas Chandan , Puretzky Alexander , Malic Ermin , Lee Young Hee
Published: September 2023

We report the emergence of dark-excitons in transition-metal-dichalcogenide (TMD) heterostructures that strongly rely on the stacking sequence, i.e., momentum-dark K-Q exciton located exclusively at the top layer of the heterostructure. The feature stems from band renormalization and is distinct from those of typical neutral excitons or trions, regardless of materials, substrates, and even homogeneous bilayers, which is further confirmed by scanning tunneling spectroscopy. To understand the unusual stacking sequence, we introduce the excitonic Elliot formula by imposing strain exclusively on the top layer that could be a consequence of the stacking process. We further find that the intensity ratio of Q- to K-excitons in the same layer is inversely proportional to laser power, unlike for conventional K-K excitons. This can be a metric for engineering the intensity of dark K-Q excitons in TMD heterostructures, which could be useful for optical power switches in solar panels.
Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
Authors: Cortellino S. , Quagliariello V. , Delfanti G. , Blaževitš O. , Chiodoni C. , Maurea N. , Di Mauro A. , Tatangelo F. , Pisati F. , Shmahala A. , Lazzeri S. , Spagnolo V. , Visco E. , Tripodo C. , Casorati G. , Dellabona P. , Longo V. D.
Published: September 2023

Immune checkpoint inhibitors cause side effects ranging from autoimmune endocrine disorders to severe cardiotoxicity. Periodic Fasting mimicking diet (FMD) cycles are emerging as promising enhancers of a wide range of cancer therapies including immunotherapy. Here, either FMD cycles alone or in combination with anti-OX40/anti-PD-L1 are much more effective than immune checkpoint inhibitors alone in delaying melanoma growth in mice. FMD cycles in combination with anti-OX40/anti-PD-L1 also show a trend for increased effects against a lung cancer model. As importantly, the cardiac fibrosis, necrosis and hypertrophy caused by immune checkpoint inhibitors are prevented/reversed by FMD treatment in both cancer models whereas immune infiltration of CD3+ and CD8+ cells in myocardial tissues and systemic and myocardial markers of oxidative stress and inflammation are reduced. These results indicate that FMD cycles in combination with immunotherapy can delay cancer growth while reducing side effects including cardiotoxicity.
Cyclic AMP induces reversible EPAC1 condensates that regulate histone transcription
Authors: Iannucci Liliana Felicia , D’Erchia Anna Maria , Picardi Ernesto , Bettio Daniela , Conca Filippo , Surdo Nicoletta Concetta , Di Benedetto Giulietta , Musso Deborah , Arrigoni Cristina , Lolicato Marco , Vismara Mauro , Grisan Francesca , Salviati Leonardo , Milanesi Luciano , Pesole Graziano , Lefkimmiatis Konstantinos
Published: September 2023

The second messenger cyclic AMP regulates many nuclear processes including transcription, pre-mRNA splicing and mitosis. While most functions are attributed to protein kinase A, accumulating evidence suggests that not all nuclear cyclic AMP-dependent effects are mediated by this kinase, implying that other effectors may be involved. Here we explore the nuclear roles of Exchange Protein Activated by cyclic AMP 1. We find that it enters the nucleus where forms reversible biomolecular condensates in response to cyclic AMP. This phenomenon depends on intrinsically disordered regions present at its amino-terminus and is independent of protein kinase A. Finally, we demonstrate that nuclear Exchange Protein Activated by cyclic AMP 1 condensates assemble at genomic loci on chromosome 6 in the proximity of Histone Locus Bodies and promote the transcription of a histone gene cluster. Collectively, our data reveal an unexpected mechanism through which cyclic AMP contributes to nuclear spatial compartmentalization and promotes the transcription of specific genes.
Global land and water limits to electrolytic hydrogen production using wind and solar resources
Authors: Tonelli Davide , Rosa Lorenzo , Gabrielli Paolo , Caldeira Ken , Parente Alessandro , Contino Francesco
Published: September 2023

Proposals for achieving net-zero emissions by 2050 include scaling-up electrolytic hydrogen production, however, this poses technical, economic, and environmental challenges. One such challenge is for policymakers to ensure a sustainable future for the environment including freshwater and land resources while facilitating low-carbon hydrogen production using renewable wind and solar energy. We establish a country-by-country reference scenario for hydrogen demand in 2050 and compare it with land and water availability. Our analysis highlights countries that will be constrained by domestic natural resources to achieve electrolytic hydrogen self-sufficiency in a net-zero target. Depending on land allocation for the installation of solar panels or wind turbines, less than 50% of hydrogen demand in 2050 could be met through a local production without land or water scarcity. Our findings identify potential importers and exporters of hydrogen or, conversely, exporters or importers of industries that would rely on electrolytic hydrogen. The abundance of land and water resources in Southern and Central-East Africa, West Africa, South America, Canada, and Australia make these countries potential leaders in hydrogen export.
Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids
Authors: Wu Hao , Huang Xing-Yao , Sun Meng-Xu , Wang Yue , Zhou Hang-Yu , Tian Ying , He Beijia , Li Kai , Li De-Yu , Wu Ai-Ping , Wang Hongmei , Qin Cheng-Feng
Published: September 2023

Zika virus (ZIKV) infection during pregnancy threatens pregnancy and fetal health. However, the infectivity and pathological effects of ZIKV on placental trophoblast progenitor cells in early human embryos remain largely unknown. Here, using human trophoblast stem cells (hTSCs), we demonstrated that hTSCs were permissive to ZIKV infection, and resistance to ZIKV increased with hTSC differentiation. Combining gene knockout and transcriptome analysis, we demonstrated that the intrinsic expression of AXL and TIM-1, and the absence of potent interferon (IFN)-stimulated genes (ISGs) and IFNs contributed to the high sensitivity of hTSCs to ZIKV. Furthermore, using our newly developed hTSC-derived trophoblast organoid (hTSC-organoid), we demonstrated that ZIKV infection disrupted the structure of mature hTSC-organoids and inhibited syncytialization. Single-cell RNA sequencing (scRNA-seq) further demonstrated that ZIKV infection of hTSC-organoids disrupted the stemness of hTSCs and the proliferation of cytotrophoblast cells (CTBs) and probably led to a preeclampsia (PE) phenotype. Overall, our results clearly demonstrate that hTSCs represent the major target cells of ZIKV, and a reduced syncytialization may result from ZIKV infection of early developing placenta. These findings deepen our understanding of the characteristics and consequences of ZIKV infection of hTSCs in early human embryos.
Serotonin signaling regulates actomyosin contractility during morphogenesis in evolutionarily divergent lineages
Authors: Karki Sanjay , Saadaoui Mehdi , Dunsing Valentin , Kerridge Stephen , Da Silva Elise , Philippe Jean-Marc , Maurange Cédric , Lecuit Thomas
Published: September 2023

Serotonin is a neurotransmitter that signals through 5-HT receptors to control key functions in the nervous system. Serotonin receptors are also ubiquitously expressed in various organs and have been detected in embryos of different organisms. Potential morphogenetic functions of serotonin signaling have been proposed based on pharmacological studies but a mechanistic understanding is still lacking. Here, we uncover a role of serotonin signaling in axis extension ofDrosophilaembryos by regulating Myosin II (MyoII) activation, cell contractility and cell intercalation. We find that serotonin and serotonin receptors 5HT2A and 5HT2B form a signaling module that quantitatively regulates the amplitude of planar polarized MyoII contractility specified by Toll receptors and the GPCR Cirl. Remarkably, serotonin signaling also regulates actomyosin contractility at cell junctions, cellular flows and epiblast morphogenesis during chicken gastrulation. This phylogenetically conserved mechanical function of serotonin signaling in regulating actomyosin contractility and tissue flow reveals an ancestral role in morphogenesis of multicellular organisms.
Structural convergence endows nuclear transport receptor Kap114p with a transcriptional repressor function toward TATA-binding protein
Authors: Liao Chung-Chi , Wang Yi-Sen , Pi Wen-Chieh , Wang Chun-Hsiung , Wu Yi-Min , Chen Wei-Yi , Hsia Kuo-Chiang
Published: September 2023

The transcription factor TATA-box binding protein (TBP) modulates gene expression in nuclei. This process requires the involvement of nuclear transport receptors, collectively termed karyopherin-β (Kap-β) in yeast, and various regulatory factors. In previous studies we showed that Kap114p, a Kap-β that mediates nuclear import of yeast TBP (yTBP), modulates yTBP-dependent transcription. However, how Kap114p associates with yTBP to exert its multifaceted functions has remained elusive. Here, we employ single-particle cryo-electron microscopy to determine the structure of Kap114p in complex with the core domain of yTBP (yTBPC). Remarkably, Kap114p wraps around the yTBPC N-terminal lobe, revealing a structure resembling transcriptional regulators in complex with TBP, suggesting convergent evolution of the two protein groups for a common function. We further demonstrate that Kap114p sequesters yTBP away from promoters, preventing a collapse of yTBP dynamics required for yeast responses to environmental stress. Hence, we demonstrate that nuclear transport receptors represent critical elements of the transcriptional regulatory network.
Panoramic analysis of coronaviruses carried by representative bat species in Southern China to better understand the coronavirus sphere
Authors: Han Yelin , Xu Panpan , Wang Yuyang , Zhao Wenliang , Zhang Junpeng , Zhang Shuyi , Wang Jianwei , Jin Qi , Wu Zhiqiang
Published: September 2023

Bats, recognized as considerable reservoirs for coronaviruses (CoVs), serve as natural hosts for several highly pathogenic CoVs, including SARS-CoV and SARS-CoV-2. Investigating the bat CoV community provides insights into the origin for highly pathogenic CoVs and highlights bat CoVs with potential spillover risks. This study probes the evolution, recombination, host range, geographical distribution, and cross-species transmission characteristics of bat CoVs across China and its associated CoVs in other regions. Through detailed research on 13,064 bat samples from 14 provinces of China, 1141 CoV strains are found across 10 subgenera and one unclassified Alpha-CoV, generating 399 complete genome sequences. Within bat CoVs, 11 new CoV species are identified and 425 recombination events are detected. Bats in southern China, particularly in Yunnan province, exhibit a pronounced diversity of CoVs. Limited sampling and low detection rates exist for CoVs in Myotacovirus, Nyctacovirus, Hibecovirus, Nobecovirus in China. The genus Myotis is highlighted as a potential ancestral host for Alpha-CoV, with the genus Hipposideros suggested as a likely progenitor host for bat-associated Beta-CoV, indicating the complexity of cross-species transmission dynamics. Through the comprehensive analysis, this study enriches the understanding of bat CoVs and offers a valuable resource for future research.
Structures of liganded glycosylphosphatidylinositol transamidase illuminate GPI-AP biogenesis
Authors: Xu Yidan , Li Tingting , Zhou Zixuan , Hong Jingjing , Chao Yulin , Zhu Zhini , Zhang Ying , Qu Qianhui , Li Dianfan
Published: September 2023

Many eukaryotic receptors and enzymes rely on glycosylphosphatidylinositol (GPI) anchors for membrane localization and function. The transmembrane complex GPI-T recognizes diverse proproteins at a signal peptide region that lacks consensus sequence and replaces it with GPI via a transamidation reaction. How GPI-T maintains broad specificity while preventing unintentional cleavage is unclear. Here, substrates- and products-bound human GPI-T structures identify subsite features that enable broad proprotein specificity, inform catalytic mechanism, and reveal a multilevel safeguard mechanism against its promiscuity. In the absence of proproteins, the catalytic site is invaded by a locally stabilized loop. Activation requires energetically unfavorable rearrangements that transform the autoinhibitory loop into crucial catalytic cleft elements. Enzyme-proprotein binding in the transmembrane and luminal domains respectively powers the conformational rearrangement and induces a competent cleft. GPI-T thus integrates various weak specificity regions to form strong selectivity and prevent accidental activation. These findings provide important mechanistic insights into GPI-anchored protein biogenesis.
Shared and distinct genetic etiologies for different types of clonal hematopoiesis
Authors: Brown Derek W. , Cato Liam D. , Zhao Yajie , Nandakumar Satish K. , Bao Erik L. , Gardner Eugene J. , Hubbard Aubrey K. , DePaulis Alexander , Rehling Thomas , Song Lei , Yu Kai , Chanock Stephen J. , Perry John R. B. , Sankaran Vijay G. , Machiela Mitchell J.
Published: September 2023

Clonal hematopoiesis (CH)—age-related expansion of mutated hematopoietic clones—can differ in frequency and cellular fitness by CH type (e.g., mutations in driver genes (CHIP), gains/losses and copy-neutral loss of chromosomal segments (mCAs), and loss of sex chromosomes). Co-occurring CH raises questions as to their origin, selection, and impact. We integrate sequence and genotype array data in up to 482,378 UK Biobank participants to demonstrate shared genetic architecture across CH types. Our analysis suggests a cellular evolutionary trade-off between different types of CH, with LOY occurring at lower rates in individuals carrying mutations in established CHIP genes. We observed co-occurrence of CHIP and mCAs with overlap at TET2, DNMT3A, and JAK2, in which CHIP precedes mCA acquisition. Furthermore, individuals carrying overlapping CH had high risk of future lymphoid and myeloid malignancies. Finally, we leverage shared genetic architecture of CH traits to identify 15 novel loci associated with leukemia risk.