bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypermethylated GPR135 gene expression is a favorable independent prognostic factor in nasopharyngeal carcinoma
Authors: Gan Chunqiao , Qin Guanjie , Liao Shufang , Liao Xiaofei , Xu Jinping , Jiang Wei
Published: July 2023

Purpose

To investigate the methylation status and expression level of G protein-coupled receptor 135 (GPR135) in nasopharyngeal carcinoma (NPC) and determine its prognostic value.

Methods

The GPR135 methylation data of NPC and normal nasopharyngeal tissues were obtained from the Gene Expression Omnibus (GEO) GSE52068 dataset. The GPR135 promoter region methylation level in four normal nasopharyngeal epithelial tissues and eight NPC tissues was detected by bisulfite sequencing. GPR135 expression in NPC and normal nasopharyngeal tissue was obtained from the GEO GSE13597 dataset.The GPR135 mRNA expression levels in 13 NPC and 26 healthy control tissues were assessed with quantitative real-time PCR (qRT-PCR). The GPR135 expression level in 124 NPC tissue sections was analyzed by immunohistochemistry. The correlation between GPR135 expression and clinicopathological features was analyzed by a chi-square test. GPR135 expression in patients with NPC was evaluated by immunohistochemistry, and its influence on prognosis was assessed by Kaplan-Meier and Cox regression analyses.

Results

The bisulfite sequencing demonstrated that the GPR135 promoter region was highly methylated in NPC tissues. The immunohistochemistry results revealed that patients with high GPR135 expression had better overall survival (hazard ratio [HR] = 0.177, 95% confidence interval [95%CI]: 0.072–0.437, P = 0.008), disease-free survival (HR = 0.4401, 95%CI: 0.222–0.871, P = 0.034), and local recurrence-free survival (HR = 0.307, 95%CI: 0.119–0.790, P = 0.046) than those with low GPR135 expression.

Conclusion

GPR135 is hypermethylated in NPC, where high GPR135 expression indicates a positive prognosis. Therefore, GPR135 might be a prognostic indicator.
Novel Endovascular Techniques for Dialysis Access-Associated Steal Syndrome (DASS)
Authors: AlShammeri Owayed , AlEidan Ibrahim , Budaichieva Asel , ElHayek Bilal , AlWabel Linda , AlWahbi Abdullah
Published: July 2023

End-stage renal disease patients with arteriovenous fistula (AVF) encounter many vascular risks related to reduced or increased arteriovenous fistula flow. Dialysis access-associated steal syndrome is one of the devastating complications that may lead to limb loss. Multiple vascular techniques (surgical and endovascular) can be used to correct this complication. In this article, we present two endovascular approaches. One approach uses a stent graft covering two thirds of anastomosis for arteriovenous fistulas to generate artificial stenosis and divert more flow to the hand. The other approach applies Supera® stent jailing to the arteriovenous fistula to divert more flow to the hand. Over 12 months of follow up, there was no clinical manifestation of dialysis access-associated steal syndrome and the AV fistula continued to function.
Religious Innovation in the Hellenistic and Roman Periods
Authors: Hammer Olav , Rothstein Mikael
Published: July 2023

The scholarly study of new religious movements focuses on the contemporary period, but religious innovation is nothing new. This Element explores a historical epoch characterized by a multitude of emergent religious concepts and practices – the Hellenistic and Roman periods. A precondition for the intense degree of religious innovation during this time was a high level of cultural exchange. Religious elements crossed porous cultural borders and were adapted to suit new purposes. The resulting amalgams were presented in a vast corpus of texts, largely produced by a literate elite. Charismatic leaders played a particularly important role in creating new religious options and were described in genres that were infused with ideological agendas. Novel religious developments were accepted by the Roman authorities unless suspected of undermining the social order. The rise of one of the many new religions of the period, Christianity, ultimately changed the religious landscape in profound ways.
Does Monsoon Itself Cause Health Risks? Lessons From the Flash Flood of Imamzadeh Davood, Iran 2022
Authors: Aghababaeian Hamidreza , Khosravifar Ahmadreza , Mohammadi Janbazloufar Kamran
Published: July 2023

During the summer of 2022, several regions worldwide, including Iran, were subjected to intense monsoon rains, resulting in significant adverse impacts on the health, economy, and social well-being of affected populations. However, by focusing on adaptation and resilience measures, not only could the negative consequences of this phenomenon be mitigated, but as evidenced by other countries, the opportunity presented by rainwater could be utilized to promote development, health, and socioeconomic welfare in these areas. This concise report aims to explore the lessons learned from this phenomenon, including its strengths and weaknesses.
Improving the feel of 3D printed prototypes for new product development: A feasibility study of emulating mass properties by optimising infill structures and materials
Authors: Felton Harry , Yon Jason , Hicks Ben
Published: July 2023

Product prototypes and particularly those that are 3D printed will have mass properties that are significantly different from the product they represent. This affects both functional performance and stakeholder perception of the prototype. Within this work, computational emulation of mass properties for a primitive object (a cube) is considered, developing a baseline numerical method and parameter set with the aim of demonstrating the means of improving feel in 3D printed prototypes. The method is then applied and tuned for three case study products – a games controller, a hand drill and a laser pointer – demonstrating that product mass properties could be numerically emulated to within ~1% of the target values. This was achieved using typical material extrusion technology with no physical or process modification. It was observed that emulation accuracy is dependent on the relative offset of the centre of mass from the geometric centre. A sensitivity analysis is further undertaken to demonstrate that product-specific parameters can be beneficial. With tuning of these values, and with some neglect of practical limitations, emulation accuracy as high as ~99.8% can be achieved. This was shown to be a reduction in error of up to 99.6% relative to a conventional fabrication.
Orbits closeness for slowly mixing dynamical systems
Authors: ROUSSEAU JÉRÔME , TODD MIKE
Published: July 2023

Given a dynamical system, we prove that the shortest distance between two n-orbits scales like n to a power even when the system has slow mixing properties, thus building and improving on results of Barros, Liao and the first author [On the shortest distance between orbits and the longest common substring problem. Adv. Math.344 (2019), 311–339]. We also extend these results to flows. Finally, we give an example for which the shortest distance between two orbits has no scaling limit.
Large-scale motions in a turbulent natural convection boundary layer immersed in a stably stratified environment
Authors: Maryada K.R. , Armfield S.W. , Dhopade P. , Norris S.E.
Published: July 2023

This study investigates the coherence of turbulent fluctuations in a turbulent vertical natural convection boundary layer immersed in a stably stratified medium (turbulent buoyancy layer). A turbulent buoyancy layer of a fluid having a Prandtl number of

$0.71$

at a Reynolds number of

$800$

is numerically simulated using direct numerical simulation. The two-point correlations reveal that the streamwise velocity fluctuations are coherent over large streamwise distances, with the length scale of the streamwise coherence being greater than the boundary layer thickness. This is due to large-scale motions (LSMs), similar to the LSMs observed in canonical wall-bounded turbulence despite the stark differences in flow dynamics. Both high-speed (positive) and low-speed (negative) streamwise velocity fluctuations form LSMs, with their streamwise length scales increasing with increasing wall-normal distance. High-speed LSMs are composed of upwash flow with high temperatures, while low-speed LSMs are composed of downwash flow with low temperatures. Both high-speed and low-speed LSMs meander appreciably in the streamwise direction, with the degree of meandering being correlated with the sign of the spanwise velocity fluctuations. The LSMs exhibit coherence across significant wall-normal distances and contribute significantly to the turbulence production in the outer layer. Examining the one-dimensional energy spectra of the turbulent buoyancy layer shows that the LSMs are the dominant energy-containing motions, implying that the length scale of the energy-containing range is of the order of boundary layer thickness. Notably, wall-normal velocity, spanwise velocity and buoyancy fluctuations do not form LSMs with streamwise length scales comparable to streamwise velocity fluctuations.
Does reading about fictional minds make us more curious about real ones?
Authors: Eekhof Lynn S. , Mar Raymond A.
Published: July 2023

Although there is a large body of research assessing whether exposure to narratives boosts social cognition immediately afterward, not much research has investigated the underlying mechanism of this putative effect. This experiment investigates the possibility that reading a narrative increases social curiosity directly afterward, which might explain the short-term boosts in social cognition reported by some others. We developed a novel measure of state social curiosity and collected data from participants (N = 222) who were randomly assigned to read an excerpt of narrative fiction or expository nonfiction. Contrary to our expectations, we found that those who read a narrative exhibited less social curiosity afterward than those who read an expository text. This result was not moderated by trait social curiosity. An exploratory analysis uncovered that the degree to which texts present readers with social targets predicted less social curiosity. Our experiment demonstrates that reading narratives, or possibly texts with social content in general, may engage and fatigue social-cognitive abilities, causing a temporary decrease in social curiosity. Such texts might also temporarily satisfy the need for social connection, temporarily reducing social curiosity. Both accounts are in line with theories describing how narratives result in better social cognition over the long term.
From the Heart of the Country to the European Core: J. M. Coetzee andlos polacos
Authors: Kusek Robert
Published: July 2023

The aim of this article is to investigate Coetzee’s decades-long, multifaceted, and, essentially, transnational dialogue with Poland and its cultural production—from Coetzee’s encounter of Polish poetry in the early 1960s until his 2022 novelEl polaco.It intends to argue that Coetzee’s preoccupation with Polish literature and culture is part of a larger strategy of seeking new alliances and partnerships across the north-south/east-west divide, of building an alternative “affective community,” and of, simultaneously, de- and reprovincializing oneself and one’s oeuvre. Most importantly, Coetzee’s dialogue with Poland will be interpreted as an attempt to seek one’s rightful ancestry: literary and cultural, as well as genetic. The article will argue that the figure of the Pole is not simply a literary trope or the subject of Coetzee’s scholarly/readerly interest, but an instrument of both: self-defacement and identification with his Polish heritage.
THE SYMBIOSIS OF LICHENOMETRY AND RADIOCARBON DATING: A BAYESIAN CHRONOLOGY OF ALPINE HUNTING IN COLORADO’S SOUTHERN ROCKY MOUNTAINS, USA
Authors: Meyer Kelton A
Published: July 2023

Archaeologists keep a limited arsenal of methods for dating stone features at alpine sites. Radiocarbon (14C) dating is rarely possible, and it is common that dates do not accurately represent the activity of interest (stone feature construction). In this paper I review a legacy set of 89 14C dates for stone driveline sites built by hunter-gatherers in Colorado’s Southern Rocky Mountains. I amend the sample of dates using chronometric hygiene and focus on dates with direct association to hunting features. I then present a newly calibrated set of 29 lichenometric dates for rock features at these sites and use hygiene protocols to remove inaccurate dates. Size-frequency lichenometry, though poorly known in archaeology, provides a way to date stone features indirectly by measuring the growth of long-lived lichens that colonize rock surfaces after construction events. Bayesian modeling of the combined set of dates suggests that the tradition of alpine game driving spans over 6000 years BP, with abundant use over the last 2000 years. Archaeologists must use multiple methods for dating stone features in alpine environments. This Bayesian analysis is a formal effort to combine lichenometry and 14C dating for archaeological interpretation.
Living on the edge: forest edge effects on microclimate and terrestrial mammal activity in disturbed lowland forest in Sumatra, Indonesia
Authors: Slater Helen D. , Gillingham Phillipa K. , Pratt Victoria , Eaton Ben , Fletcher Simon , Abdullah Abdullah , Supriadi  , Korstjens Amanda H.
Published: July 2023

Species–environment relationships are often studied at large spatial scales, but effective conservation requires an understanding of local-scale environmental drivers and pressures. Widespread degradation and fragmentation of forests have increased the proportion of tropical mammal habitat that is affected by edge effects. Edge effects include greater exposure to anthropogenic disturbance and abiotic changes that synergistically influence how well populations can cope with climate change. We investigated relationships between distance to the forest edge, forest structure, microclimate and terrestrial mammal detections in a selectively logged forest at the boundary of Gunung Leuser National Park in Sumatra, Indonesia. We collected mammal detection data from motion-activated camera traps, microclimate data from automated climate data loggers and forest structure data from vegetation plots. Daily mean and maximum temperatures significantly decreased with distance from the forest edge, whereas tree height and minimum temperature increased. Mammal diversity was lower at the forest edge compared to the interior. Mammals were detected less frequently at the forest edge, although this relationship varied between mammal orders. Mammal detections were best explained by temperature, tree height and tree diameter at breast height. These results demonstrate that abiotic changes in forests brought on by edge effects have negative impacts on mammals, but these effects vary between mammal taxa because of differing sensitivities to human disturbance. Our findings highlight the importance of considering local-scale environmental drivers in determining species–environment relationships to identify key habitat features such as microclimate refuges that should be prioritized in ecosystem management.
A marginal structural model to estimate the effect of antidepressant medication treatment on major cardiovascular events among people with post-traumatic stress disorder
Authors: Kim Kwanghyun , Kang Sunghyuk , Nam Chung Mo , Stewart Robert , Tsai Alexander C. , Jung Sun Jae
Published: July 2023

Background

Previous evidence on antidepressant medication and cardiovascular disease (CVD) among patients with posttraumatic stress disorder (PTSD) has been inconclusive. We estimated the association between antidepressant medication and CVD by applying a marginal structural model.

Methods

We analyzed medical utilization records of 27 170 people with PTSD without prior major cardiovascular events in the Korean National Health Insurance Database (NHID). PTSD and CVD were defined in accordance with the recorded ICD-10 diagnostic codes. We acquired information on antidepressant use from the NHID and categorized them by medication type. A composite major adverse cardiovascular events (MACE) outcome was defined as coronary artery disease with revascularization, ischaemic stroke, and/or haemorrhagic stroke. We used inverse probability of treatment weighting to estimate the parameters of a marginal structural discrete-time survival analysis regression model, comparing the resulting estimates to those derived from traditional time-fixed and time-varying Cox proportional hazards regression. We calculated cumulative daily defined doses to test for a dose–response relationship.

Results

People exposed to antidepressants showed a higher hazard of MACE [hazard ratio (HR) 1.34, 95% confidence interval (CI) 1.18–1.53]. The estimated effects were strongest for selective serotonin reuptake inhibitors (HR 1.24, 95% CI 1.08–1.44) and TCAs (HR 1.33, 95% CI 1.13–1.56). Exposure to serotonin-norepinephrine reuptake inhibitors did not appear to increase the risk of MACE. People exposed to higher doses of antidepressants showed higher risk of MACE.

Conclusions

In a national cohort of people with PTSD, exposure to antidepressant medications increased the risk of MACE in a dose–response fashion.
Modeling and validation of a novel tracked robot via multibody dynamics
Authors: Grazioso Andrea , Ugenti Angelo , Galati Rocco , Mantriota Giacomo , Reina Giulio
Published: July 2023

This article focuses on a multibody model of a new passive articulated suspension tracked robot. The model of the vehicle is developed using the multibody software MSC Adams (acronym for automatic dynamic analysis of mechanical systems) in conjunction with the Adams Tracked Vehicle toolkit. The various subsystems that make up the vehicle assembly are described, with particular attention to the modeling strategies of the swing arms that constitute the suspension system and the characterization of the track belt. The multibody model allows the system performance to be evaluated in advance for fine-tuning of the design parameters and using different configurations, for example, with active and locked suspension. Efforts are also presented to validate the multibody twin against the real prototype, showing a good agreement with field experiments. Once validated, the digital twin is used to assess the performance of the innovative suspension system in various challenging environments.
Computational analysis of Finnish nonfinite clauses
Authors: Brattico Pauli
Published: July 2023

Finnish nonfinite clauses constitute a complex grammatical class with a seemingly chaotic mix of verbal and nominal properties. Thirteen nonfinite constructions, their selection, control, thematic role assignment, nonfinite agreement, embedded subjects, and syntactic status were targeted for analysis. An analysis is proposed which derives their syntactic and semantic properties by relying on a computational model of human information processing. The model analyzes Finnish nonfinite constructions as truncated clauses with one functional layer above the verb phrase. Research methods from naturalistic cognitive science and computational linguistics are considered as potentially useful tools for linguistics.
The Russian origin of Karelian cow names
Authors: Massinen Henna
Published: July 2023

This article provides an overview of the Russian origin of Karelian cow names. It explores what the Russian-origin names mean, what the most common principles of naming are, and whether Russian names have Karelian equivalents. Attention is also paid to the spatial and temporal variation of the names. The data were collected in the 2010s by means of interviews. The data are compared with the name data recorded in the Dictionary of Karelian (KKS). The KKS data reveal extensive adaptation to the Karelian language, whereas in the interview data there is less adaptation to Karelian and the names are often thoroughly Russian. In the KKS data the most common principle of naming is the time of birth, and names based on colouration are also common. According to both data sets, the principles of naming have remained relatively consistent, and the data reveal no great spatial differences in the occurrence of names.
Habitat associations and conservation opportunities for priority birds on small, diversified farms in the northeastern USA
Authors: Brofsky Isabel R. , King David I. , Peters Kimberly
Published: July 2023

Although the impacts of intensive agriculture on biodiversity and strategies for mitigating these effects have been widely described, small-scale, diversified farms and the opportunities they present for bird conservation have been less thoroughly examined. This omission is potentially significant, because this form of agriculture represents a growing sector of the industry in the populous northeastern USA, and the diverse habitats on these farms contrast with larger, structurally homogeneous intensive agriculture. To evaluate bird-habitat associations and conservation opportunities for supporting species of conservation concern on these small, diversified farms, we conducted avian point count and vegetation surveys across 23 farms in western Massachusetts during the summers of 2017 and 2018. We used Poisson-binomial mixture models and canonical correspondence analysis to assess the effects of a suite of microhabitat-, field- and landscape-scale (1 km buffer around the field) variables on the abundance of bird species. Our results confirmed that shrubland birds, a group of species of elevated conservation concern, accounted for 52% of the total observations, including song sparrow (Melospiza melodia), gray catbird (Dumatella carolinensis), common yellowthroat (Geothlypis trichas) and American goldfinch (Spinus tristis). Species–habitat relationships were diverse; however, smaller field sizes, and increased cover of tall, dense, woody or non-productive vegetation types were associated with higher abundance of shrubland species as well as lower abundance of crop pests such as European starling (Sturnus vulgaris) and house sparrow (Passer domesticus). These findings support the hypothesis that small, diversified farms are supporting birds of high conservation concern, and we provide species-specific guidelines for farmers interested in conserving birds on their land.
The 2022 Eruption of Wolf Volcano, Galápagos: The Role of Caldera Ring‐Faults During Magma Transfer From InSAR Deformation Data
Authors: Xu Wenbin , Xie Lei , Bürgmann Roland , Liu Xiaoge , Wang Jiageng
Published: July 2023

The basaltic caldera volcanoes in the Galápagos Islands characteristically erupt lavas via summit circumferential and radial flank dike intrusions, but the underlying magma plumbing systems remain enigmatic. Here, we document surface displacements of Wolf volcano using interferometric synthetic aperture radar (InSAR) data from 2015 to 2022. We show that Wolf volcano experienced 6‐years of continuous inflation after the 2015 eruption, followed by a shallow flank eruption in January 2022. The deformation is modeled with a vertical caldera ring‐fault and a radial dike on the southeast flank. The ring‐fault underwent opening and reverse faulting during the inflation period, and closure and normal faulting during and after the eruption. Stress interactions between the ring‐fault and the flank dike suggest the asymmetric opening of the ring‐fault promotes flank eruptions. The best‐fit deformation model differs from the previous models and offers an alternative view of how magma is fed into radial dikes during flank eruptions.
Asymmetry Between Positive and Negative Phases of the Pacific Meridional Mode: A Contributor to ENSO Transition Complexity
Authors: Fan Hanjie , Wang Chunzai , Yang Song
Published: July 2023

The Pacific Meridional Mode (PMM) plays a critical role in affecting El Niño‐Southern Oscillation (ENSO). This study examines the phase asymmetry of PMM events triggered by tropical and extratropical forcings, namely successive and stochastic events, respectively. It is shown that successive events exhibit negative asymmetry due to stronger trigger in the negative phase, while stochastic events display positive asymmetry due to stronger growth in the positive phase. The opposite phase asymmetry of two types of events respectively results in more frequent persistent La Niña events than El Niño events and more frequent episodic El Niño events than La Niña events, which increase ENSO transition complexity. This research provides a comprehensive understanding of PMM asymmetry and reconciles conflicting perspectives from previous studies. Additionally, the newly proposed contribution of positively asymmetric stochastic PMM events to more frequent episodic El Niño events in this study may enhance our comprehension of ENSO transition complexity.
A Gradient Boosting Decision Tree Based Correction Model for AIRS Infrared Water Vapor Product
Authors: Xu Jiafei , Liu Zhizhao
Published: July 2023

High‐quality precipitable water vapor (PWV) measurements have an essential role in climate change and weather prediction studies. The Atmospheric Infrared Sounder (AIRS) instrument provides an opportunity to measure PWV at infrared (IR) bands twice daily with nearly global coverage. However, AIRS IR PWV products are easily affected by the presence of clouds. We propose a Gradient Boosting Decision Tree (GBDT) based correction model (GBCorM) to enhance the accuracy of PWV products from AIRS IR observations in both clear‐sky and cloudy‐sky conditions. The GBCorM considers many dependence factors that are in association with the AIRS IR PWV's performance. The results show that the GBCorM greatly improves the all‐weather quality of AIRS IR PWV products, especially in dry atmospheric conditions. The GBCorM‐estimated PWV result in the presence of clouds shows an accuracy comparable with that of official AIRS IR PWV products in clear‐sky conditions, demonstrating the capability of the GBCorM model.
Focus on perovskite emitters in blue light-emitting diodes
Authors: Yang Xiaoyu , Ma Li , Yu Maotao , Chen Hao-Hsin , Ji Yongqiang , Hu An , Zhong Qixuan , Jia Xiaohan , Wang Yanju , Zhang Yuzhuo , Zhu Rui , Wang Xinqiang , Lu Changjun
Published: July 2023

Blue perovskite light-emitting diodes (PeLEDs) are essential in pixels of perovskite displays, while their progress lags far behind their red and green counterparts. Here, we focus on recent advances of blue PeLEDs and systematically review the noteworthy strategies, which are categorized into compositional engineering, dimensional control, and size confinement, on optimizing microstructures, energy landscapes, and charge behaviors of wide-bandgap perovskite emitters (bandgap >2.5 eV). Moreover, the stability of perovskite blue emitters and related devices is discussed. In the end, we propose a technical roadmap for the fabrication of state-of-the-art blue PeLEDs to chase and achieve comparable performance with the other two primary-color devices.
Auger effect in weakly confined nanocrystals
Authors: Liu Jiawen , Coolen Laurent
Published: July 2023

An extensive analysis of biexciton luminescence in high-quality, large perovskite CsPbBr3 nanocrystals shows how the biexciton Auger decay rate deviates from the “universal” volume scaling as the exciton confinement becomes weaker.
Associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease: a Mendelian randomization study
Authors: Huang Liang-Yu , Ou Ya-Nan , Yang Yu-Xiang , Wang Zuo-Teng , Tan Lan , Yu Jin-Tai
Published: July 2023

Previous observational studies reported that midlife clustering of cardiovascular risk factors and lifestyle behaviors were associated with neurodegenerative disease; however, these findings might be biased by confounding and reverse causality. This study aimed to investigate the causal associations of cardiovascular risk factors and lifestyle behaviors with neurodegenerative disease, using the two-sample Mendelian randomization design. Genetic variants for the modifiable risk factors and neurodegenerative disease were extracted from large-scale genome-wide association studies. The inverse-variance weighted method was used as the main analysis method, and MR-Egger regression and leave-one-out analyses were performed to identify potential violations. Genetically predicted diastolic blood pressure (DBP: OR per 1 mmHg, 0.990 [0.979–1.000]), body mass index (BMI: OR per 1 SD, 0.880 [0.825–0.939]), and educational level (OR per 1 SD, 0.698 [0.602–0.810]) were associated with lower risk of late-onset Alzheimer’s disease (LOAD), while genetically predicted low-density lipoprotein (LDL: OR per 1 SD, 1.302 [1.066–1.590]) might increase LOAD risk. Genetically predicted exposures (including LDL and BMI) applied to familial AD showed the same effect. The association of LDL was also found with Amyotrophic lateral sclerosis (ALS) (LDL: OR per 1 SD, 1.180 [1.080–1.289]). This MR analysis showed that LDL, BMI, BP, and educational level were causally related to AD; a significant association between LDL and ALS risk, as well as the potential effect of sleep duration on PD risk, were also revealed. Targeting these modifiable factors was a promising strategy of neurodegenerative disease prevention.
A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma
Authors: Lopez Juanita , Lai-Kwon Julia , Molife Rhoda , Welsh Liam , Tunariu Nina , Roda Desamparados , Fernández-García Paula , Lladó Victoria , McNicholl Adrian G. , Rosselló Catalina A. , Taylor Richard J. , Azaro Analía , Rodón Jordi , Sludden Julieann , Veal Gareth J. , Plummer Ruth , Urruticoechea Ander , Lahuerta Ainhara , Mujika Karmele , Escribá Pablo V.
Published: July 2023

Background

The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy.

Methods

We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D).

Results

In total, 32 recurrent patients were enrolled in the dose-escalation phase (500–16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1–2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years.

Conclusions

2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies.

Clinical trial registration

EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.
Atopic allergic conditions and prostate cancer risk and survival in the Multiethnic Cohort study
Authors: Wang Anqi , Wan Peggy , Hebert James R. , Le Marchand Loic , Wilkens Lynne R. , Haiman Christopher A.
Published: July 2023

Background

Previous studies investigating relationship between atopic allergic conditions (AACs)—a highly reactive immune state—and prostate cancer (PCa) risk were inconclusive, and few have studied diverse racial/ethnic populations.

Methods

We analysed 74,714 men aged ≥45 years at enrollment in Multiethnic Cohort study. Using multivariable Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for self-reported AAC status on PCa outcomes.

Results

Through 2017, 8697 incident PCa and 1170 related deaths occurred. Twenty-one percent of men reported a history of AACs. AACs were not associated with incident PCa (HR = 0.98, 95% CI: 0.93–1.03) but were significantly inversely associated with PCa mortality (HR = 0.79, 95% CI: 0.67–0.92). This inverse association was consistently observed across all racial/ethnic groups (HR range: 0.60–0.90). Among men diagnosed with PCa, AACs were inversely associated with PCa-specific death (HR = 0.75, 95% CI: 0.63–0.89). Adjusting for potential confounding effect of PSA screening did not meaningfully change the results. No significant heterogeneity was observed in the effect of AACs on PCa incidence or mortality by Dietary Inflammatory Index.

Conclusions

Hyper-allergic conditions were not associated with PCa incidence but were inversely associated with PCa mortality, suggesting a potential role in reducing tumour progression. Further aetiological research is warranted to understand underlying mechanisms.
GANT-61 induces cell cycle resting and autophagy by down-regulating RNAP III signal pathway and tRNA-Gly-CCC synthesis to combate chondrosarcoma
Authors: Sun Yifeng , Fang Qiongxuan , Liu Wei , Liu Yi , Zhang Chunming
Published: July 2023

Chondrosarcoma is ineffective for conventional radiotherapy and chemotherapy with a poor prognosis. Hedgehog (Hh) signal pathway plays a crucial role in tumor growth and progression, which is constitutive activated in chondrosarcoma. GLI transcription factors as targets for new drugs or interference technology for the treatment of chondrosarcoma are of great significance. In this study, we indicated that the Hedgehog-GLI1 signal pathway is activated in chondrosarcoma, which further enhances the RNAP III signal pathway to mediate endogenous tRNA fragments synthesis. Downstream oncology functions of endogenous tRNA fragments, such as “cell cycle” and “death receptor binding”, are involved in malignant chondrosarcoma. The GANT-61, as an inhibitor of GLI1, could inhibit chondrosarcoma tumor growth effectively by inhibiting the RNAP III signal pathway and tRNA-Gly-CCC synthesis in vivo. Induced G2/M cell cycle resting, apoptosis, and autophagy were the main mechanisms for the inhibitory effect of GANT-61 on chondrosarcoma, which correspond with the above-described downstream oncology functions of endogenous tRNA fragments. We also identified the molecular mechanism by which GANT-61-induced autophagy is involved in ULK1 expression and MAPK signaling pathway. Thus, GANT-61 will be an ideal and promising strategy for combating chondrosarcoma.
Ferroptosis as a potential target for cancer therapy
Authors: Chen Zhen , Wang Weilong , Abdul Razak Siti Razila , Han Tao , Ahmad Nor Hazwani , Li Xiumin
Published: July 2023

Ferroptosis is a recently discovered essential type of cell death that is mainly characterized by iron overload and lipid peroxidation. Emerging evidence suggests that ferroptosis is a double-edged sword in human cancer. However, the precise underlying molecular mechanisms and their differential roles in tumorigenesis are unclear. Therefore, in this review, we summarize and briefly present the key pathways of ferroptosis, paying special attention to the regulation of ferroptosis as well as its dual role as an oncogenic and as a tumor suppressor event in various human cancers. Moreover, multiple pharmacological ferroptosis activators are summarized, and the prospect of targeting ferroptosis in cancer therapy is further elucidated.
A general model-based causal inference method overcomes the curse of synchrony and indirect effect
Authors: Park Se Ho , Ha Seokmin , Kim Jae Kyoung
Published: July 2023

To identify causation, model-free inference methods, such as Granger Causality, have been widely used due to their flexibility. However, they have difficulty distinguishing synchrony and indirect effects from direct causation, leading to false predictions. To overcome this, model-based inference methods that test the reproducibility of data with a specific mechanistic model to infer causality were developed. However, they can only be applied to systems described by a specific model, greatly limiting their applicability. Here, we address this limitation by deriving an easily testable condition for a general monotonic ODE model to reproduce time-series data. We built a user-friendly computational package, General ODE-Based Inference (GOBI), which is applicable to nearly any monotonic system with positive and negative regulations described by ODE. GOBI successfully inferred positive and negative regulations in various networks at both the molecular and population levels, unlike existing model-free methods. Thus, this accurate and broadly applicable inference method is a powerful tool for understanding complex dynamical systems.
Giant uniaxial negative thermal expansion in FeZr2 alloy over a wide temperature range
Authors: Xu Meng , Li Qiang , Song Yuzhu , Xu Yuanji , Sanson Andrea , Shi Naike , Wang Na , Sun Qiang , Wang Changtian , Chen Xin , Qiao Yongqiang , Long Feixiang , Liu Hui , Zhang Qiang , Venier Alessandro , Ren Yang , d’Acapito Francesco , Olivi Luca , De Souza Danilo Oliveira , Xing Xianran , Chen Jun
Published: July 2023

Negative thermal expansion (NTE) alloys possess great practical merit as thermal offsets for positive thermal expansion due to its metallic properties. However, achieving a large NTE with a wide temperature range remains a great challenge. Herein, a metallic framework-like material FeZr2 is found to exhibit a giant uniaxial (1D) NTE with a wide temperature range (93-1078 K, $${\bar{\alpha }}_{l}=-34.01\times {10}^{-6}\,{{{{{{\rm{K}}}}}}}^{-1}$$

α

¯

l

=
−
34.01
×

10

−
6

K

−
1

). Such uniaxial NTE is the strongest in all metal-based NTE materials. The direct experimental evidence and DFT calculations reveal that the origin of giant NTE is the couple with phonons, flexible framework-like structure, and soft bonds. Interestingly, the present metallic FeZr2 excites giant 1D NTE mainly driven by high-frequency optical branches. It is unlike the NTE in traditional framework materials, which are generally dominated by low energy acoustic branches. In the present study, a giant uniaxial NTE alloy is reported, and the complex mechanism has been revealed. It is of great significance for understanding the nature of thermal expansion and guiding the regulation of thermal expansion.
Unlocking full and fast conversion in photocatalytic carbon dioxide reduction for applications in radio-carbonylation
Authors: Monticelli Serena , Talbot Alex , Gotico Philipp , Caillé Fabien , Loreau Olivier , Del Vecchio Antonio , Malandain Augustin , Sallustrau Antoine , Leibl Winfried , Aukauloo Ally , Taran Frédéric , Halime Zakaria , Audisio Davide
Published: July 2023

Harvesting sunlight to drive carbon dioxide (CO2) valorisation represents an ideal concept to support a sustainable and carbon-neutral economy. While the photochemical reduction of CO2 to carbon monoxide (CO) has emerged as a hot research topic, the full CO2-to-CO conversion remains an often-overlooked criterion that prevents a productive and direct valorisation of CO into high-value-added chemicals. Herein, we report a photocatalytic process that unlocks full and fast CO2-to-CO conversion (<10 min) and its straightforward valorisation into human health related field of radiochemistry with carbon isotopes. Guided by reaction-model-based kinetic simulations to rationalize reaction optimisations, this manifold opens new opportunities for the direct access to 11C- and 14C-labeled pharmaceuticals from their primary isotopic sources [11C]CO2 and [14C]CO2.
Diversity-oriented synthesis of P-stereogenic and axially chiral monodentate biaryl phosphines enabled by C-P bond cleavage
Authors: Pang Liangzhi , Huang Zhan , Sun Qilin , Li Gen , Liu Jiaojiao , Li Baoli , Ma Congyue , Guo Jiaxu , Yao Chuanzhi , Yu Jie , Li Qiankun
Published: July 2023

Chiral monodentate biaryl phosphines (MOPs) have attracted intense attention as chiral ligands over the past decades. However, the creation of structurally diverse chiral MOPs with both P- and axial chirality is still in high demand but challenging. Here, we show a distinct strategy for diversity-oriented synthesis of structurally diverse MOPs containing both P- and axial chirality enabled by enantioselective C-P bond cleavage. The key chiral PdII intermediates, generated through the stereoselective oxidative addition of C-P bond, could be trapped by alkynes, R3Si-Bpin, diboron esters or reduced by H2O/B2pin2, leading to enantioenriched structurally diverse MOPs in excellent diastereo- and enantioselectivities. Based on the outstanding properties of the parent scaffolds, the P- and axially chiral monodentate biaryl phosphines serve as excellent catalysts in asymmetric [3 + 2] annulation of MBH carbonate affording the chiral functionalized bicyclic imide.
Drought exposure decreases altruism with salient group identities as key moderator
Authors: Döring Stefan , Hall Jonathan
Published: July 2023

Previous research on climate change impact regularly considers conflict outcomes, thereby disregarding cooperative behaviour such as altruism. Drought has the potential to fuel inter-ethnic cleavages, thus contributing to conflicts. Yet this runs against resilience arguments suggesting people who experience environmental hardship are more cooperative. Here we examine altruism in survey experiments in a natural setting among refugees from Syria and Iraq. We match survey responses to observational data on drought and socioeconomic variables. Our findings speak to both arguments. First, we show that drought exposure is associated with decreased altruism for survey respondents generally. We further show how group identity moderates the relationship between drought and altruism. Our results suggest a decrease in altruism due to drought is much larger when the target of altruism is presented as a member of an antagonistic ethno-religious outgroup.
Carbonate compensation depth drives abyssal biogeography in the northeast Pacific
Authors: Simon-Lledó Erik , Amon Diva J. , Bribiesca‐Contreras Guadalupe , Cuvelier Daphne , Durden Jennifer M. , Ramalho Sofia P. , Uhlenkott Katja , Arbizu Pedro Martinez , Benoist Noëlie , Copley Jonathan , Dahlgren Thomas G. , Glover Adrian G. , Fleming Bethany , Horton Tammy , Ju Se-Jong , Mejía-Saenz Alejandra , McQuaid Kirsty , Pape Ellen , Park Chailinn , Smith Craig R. , Jones Daniel O. B.
Published: July 2023

Abyssal seafloor communities cover more than 60% of Earth’s surface. Despite their great size, abyssal plains extend across modest environmental gradients compared to other marine ecosystems. However, little is known about the patterns and processes regulating biodiversity or potentially delimiting biogeographical boundaries at regional scales in the abyss. Improved macroecological understanding of remote abyssal environments is urgent as threats of widespread anthropogenic disturbance grow in the deep ocean. Here, we use a new, basin-scale dataset to show the existence of clear regional zonation in abyssal communities across the 5,000 km span of the Clarion–Clipperton Zone (northeast Pacific), an area targeted for deep-sea mining. We found two pronounced biogeographic provinces, deep and shallow-abyssal, separated by a transition zone between 4,300 and 4,800 m depth. Surprisingly, species richness was maintained across this boundary by phylum-level taxonomic replacements. These regional transitions are probably related to calcium carbonate saturation boundaries as taxa dependent on calcium carbonate structures, such as shelled molluscs, appear restricted to the shallower province. Our results suggest geochemical and climatic forcing on distributions of abyssal populations over large spatial scales and provide a potential paradigm for deep-sea macroecology, opening a new basis for regional-scale biodiversity research and conservation strategies in Earth’s largest biome.
Climate change impacts on planned supply–demand match in global wind and solar energy systems
Authors: Liu Laibao , He Gang , Wu Mengxi , Liu Gang , Zhang Haoran , Chen Ying , Shen Jiashu , Li Shuangcheng
Published: July 2023

Climate change modulates both energy demand and wind and solar energy supply but a globally synthetic analysis of supply–demand match (SDM) is lacking. Here, we use 12 state-of-the-art climate models to assess climate change impacts on SDM, quantified by the fraction of demand met by local wind or solar supply. For energy systems with varying dependence on wind or solar supply, up to 32% or 44% of non-Antarctic land areas, respectively, are projected to experience robust SDM reductions by the end of this century under an intermediate emission scenario. Smaller and more variable supply reduces SDM at northern middle-to-high latitudes, whereas reduced heating demand alleviates or reverses SDM reductions remarkably. By contrast, despite supply increases at low latitudes, raised cooling demand reduces SDM substantially. Changes in climate extremes and climate mean make size-comparable contributions. Our results provide early warnings for energy sectors in climate change adaptation.
Neoadjuvant adebrelimab in locally advanced resectable esophageal squamous cell carcinoma: a phase 1b trial
Authors: Yin Jun , Yuan Jingnan , Li Yunjin , Fang Yong , Wang Ruoxi , Jiao Heng , Tang Han , Zhang Shaoyuan , Lin Siyun , Su Feng , Gu Jianmin , Jiang Tian , Lin Dong , Huang Zhiliang , Du Chaoxiang , Wu Kui , Tan Lijie , Zhou Qing
Published: July 2023

Overall survival (OS) benefits of neoadjuvant immunotherapy remain elusive in locally advanced esophageal squamous cell carcinomas (ESCC). Here, we reported the results of a phase 1b trial of neoadjuvant PD-L1 blockade with adebrelimab in resectable ESCC. Patients received two neoadjuvant doses of adebrelimab followed by surgery. The primary endpoints were safety and feasibility; secondary endpoints included pathologic complete response (pCR) and OS. Our data showed the primary endpoints of safety and feasibility had been met. Common treatment-related adverse events were anorexia (32%) and fatigue (16%), without grade 3 or more adverse events. Of the 30 patients enrolled in the trial, 25 underwent successful resection without surgery delay and 24% had major pathologic responses including a pCR rate of 8%. The 2-year OS was 92%. Responsive patients had an immune-enriched tumor microenvironment phenotype, whereas nonresponsive patients had greater infiltration of cancer-associated fibroblasts at baseline. Clonotypic dynamics of pre-existing intratumoral T cells was a hallmark of responsive patients. These findings provide a rational for neoadjuvant anti-PD-L1 monotherapy as a therapeutic strategy for patients with resectable ESCC. ClinicalTrials.gov identifier: NCT04215471.