bluuebunny/crossref_metadata_2025 huggingface dataset:
3D Printing of Acrylonitrile Butadiene Styrene by Fused Deposition Modeling: Artificial Neural Network and Response Surface Method Analyses
Authors: Moradi Mahmoud , Beygi Reza , Mohd. Yusof Noordin , Amiri Ali , da Silva L. F. M. , Sharif Safian
Published: August 2022

Additive manufacturing of acrylonitrile butadiene styrene (ABS) was investigated based on statistical analysis via an optimization method. The present article discusses the influence of the layer thickness (LT), infill percentage (IP), and contours number (C) on the maximum failure load and elastic modulus of the final product of ABS. ABS is a low-cost manufacturing thermoplastic that can be easily fabricated, thermoformed, and machined. Chemical, stress, and creep resistance is all excellent in this thermoplastic material. ABS combines a good balance of impact, heat, chemical, and abrasion resistance with dimensional stability, tensile strength, surface hardness, rigidity, and electrical properties. To comprehend the impact of additive manufacturing parameters on the build quality, both artificial neural network (ANN) and response surface method (RSM) were used to model the data. The main characteristics of the build considered for modeling were ultimate tensile strength (UTS) and elastic modulus. Main effect plots and 3d plots were extracted from ANN and RSM models to analyze the process. The two models were compared in terms of their accuracy and capability to analyze the process. It was concluded that though ANN is more accurate in the prediction of the results, both tools can be used to model the mechanical properties of ABS formed by 3D printing. Both models yielded similar results and could effectively give the effect of each variable on the mechanical properties.
Impact of wire and arc additively manufactured workpiece geometry on the milling process
Authors: Fuchs Christina , Fritz Christian , Zaeh Michael F.
Published: August 2022

In recent years, the wire and arc additive manufacturing (WAAM) process has been given attention as a possibility to save material during the production of large-scale parts. Drawbacks of the WAAM process are the relatively low surface quality and the low form accuracies, which require post-processing of all functional surfaces. The milling process is researched as a post-processing option, especially to achieve high form accuracies. While several authors presented successful applications of the milling process, the difficulties of machining wire and arc manufactured parts (WAAM-parts) due to the part geometry have not yet been researched. In the present research, the impact of the WAAM-part geometry on the milling process was analyzed by machining three sets of samples, and guidelines for a milling strategy were developed. The results show that the geometry leads to modulated cutting forces, whose frequency, in turn, has to be considered for the milling setup. Additionally, the modulated cutting force leads to a periodically changing deflection resulting in a form deviation on the final workpiece.
An investigation into directional characteristics of the rocket plane in a tailless configuration
Authors: Kwiek Agnieszka , Figat Marcin
Published: August 2022

This paper embraces result of wind tunnel tests of a rocket plane designed to space tourism application. The rocket plane is designed in a tailless configuration with a leading edge extension (LEX) and side plates on the wing’s tip which work as all moving tail. Usually for such a concept of control, movable surfaces are position in a horizontal direction while in the considered concept there is no classical rudder, and the movable surfaces are mounted with a significant dihedral angle. The research was carried out in the subsonic closed circuit wind tunnel with an open test section. Moreover, MGAERO and PANUKL package were used for numerical computations. The first research question is to investigate how the configuration of the side plate affects the directional stability of the rocket plane. The second aim is to study the efficiency of the side plates deflected like an all moving tail for both low and high angles of attack. As a result of this investigation, the directional stability derivatives and the control derivatives were obtained. Finally, the experimental results were compared with numerical outcomes to establish does software with no full flow model can be applicable for design an aircraft with all moving tail in case of low of angles of attack.
Paleoenvironmental reconstruction, paleoecology and sequence stratigraphy of some Nummulites buildups in Egypt
Authors: Ayyat Abdalla M. El
Published: August 2022

The present study deals with microfacies analysis, paleoecology and sequence stratigraphy of the Lower–Middle Eocene rocks in central Nile Valley and west-central Sinai. Four rock units were marked (Minia, Darat, Samalut and Maghagha formations). Eight facies belts were interpreted including lagoon, back bank, main bank, fore bank and open marine outer bank facies and deposited on a gently dipping platform ramp. This ramp might be further divided to three main faunal associations depending on the depth of the water and associated fauna. Four major depositional sequences (DS1–DS4), reflecting third-order cycles and separated by two prominent sequence boundaries (SB1 and SB2) were marked. The record of these sequences reflects the changes in eustatic sea level plus the regional tectonism in the area. Every sequence includes facies associations, which constitute lowstand and/or transgressive and highstand systems tracts. Based on faunal elements and facies analysis, the water salinity, water temperature, nutrients, substrate, water depth and hydrodynamic behavior were discussed. The fine-grain size of the deposits, the loss of good connectedness and the occluding of theNummulitetests by other minerals could give rise to low reservoir potential. The sedimentation was affected by the tectonic activity of the Syrian orogeny. Moreover, both external and internal mechanisms have controlled the carbonate sedimentation, basin construction and sequence bounding surfaces.
Elucidating the Effect of Antenatal Corticosteroids in the Late Preterm Period
Authors: Upadhya Rekha , Bhavana Sai , Pai Muralidhar V. , Tahlan Shweta
Published: August 2022

Aim and Objective

To determine the efficacy of antenatal corticosteroids given in the late preterm period.

Methodology

We conducted a retrospective case–control study on patients with singleton pregnancies who were at a risk of delivering in the late preterm period (34 weeks to 36 weeks 6 days). A total of 126 patients who had received antenatal corticosteroids (prenatal administration of either betamethasone or dexamethasone, minimum one dose) during the late preterm period were taken as cases, and 135 patients who had not received steroids antenatally due to various reasons, for example, who were clinically unstable, presented with active bleeding, non-reassuring foetal status that obligated an imminent delivery and those in active labour were included as controls. The various neonatal outcomes like APGAR score at one and five minutes, incidence of admission and duration of stay in neonatal intensive care unit (NICU), respiratory morbidity, requirement of assisted ventilation, intraventricular haemorrhage (IVH) necrotizing enterocolitis, transient tachypnea of the newborn, respiratory distress syndrome, use of surfactant, neonatal hypoglycaemia, hyperbilirubinemia requiring phototherapy, sepsis and neonatal mortality were compared between the two groups.

Results

The baseline characteristics of both groups were comparable. There was a lower incidence of admissions to neonatal intensive care unit (NICU) (15% vs. 26%, p = 0.05), respiratory distress syndrome (5% vs. 13%, p = 0.04), requirement of invasive ventilation (0% vs. 4%, p = 0.04) and hyperbilirubinemia requiring phototherapy (24% vs. 39%, p = 0.02) in the babies of the group that received steroids compared to the control group. The rate of overall respiratory morbidity in the neonates was lowered after giving steroids (16% vs. 28%, p = 0.04). The incidence of neonatal necrotizing enterocolitis, hypoglycaemia, IVH, TTN, sepsis and mortality between the two groups was not significant (p > 0.05).

Conclusion

Antenatal corticosteroids administered to patients between 34 and 36 weeks 6 days of gestation reduce respiratory morbidity, requirement of invasive ventilation, respiratory distress syndrome, hyperbilirubinemia requiring phototherapy and the incidence of NICU admissions in the newborns.
Investigating the introduction of e-navigation and S-100 into bridge related operations: the impact over seafarers
Authors: Palma Valentino , Giglio Davide , Tei Alessio
Published: August 2022

The present work is focused on analyzing how e-navigation will affect the daily work of seafarers involved in bridge-related operations. Within e-navigation, the International Hydrographic Organization (IHO) is currently working in the development of the new standard (S-100) whose role is to guarantee a homogeneous management of the maritime domain data. S-100 is called to act as the Common Maritime Data Structure (CMDS), it represents the technical framework required to guarantee a wider and better use of maritime data. The mission of the standard is to create a common foundation that can be used for multiple purposes; meteorologists, physicists, and whoever is interested in developing maritime related products will refer to the same standard. Not having a homogeneous type of data processed with standardized procedures will allow a better combination and processing of maritime data. Considering the perspective of Hydrographic Offices, the objective of the present document is to analyze the impact which e-navigation will have over seafarers. The study is focused on the evaluation of the risks connected to S-100-based products and on the analysis of specific bridge operations. Considering that e-navigation products are still at their design phase, being aware of the consequences for the final users is essential to make S-100-based products more customer oriented and to allow seafarers who are involved in bridge operations to get familiar with this new technology.
Long non-coding RNA IGFBP7-AS1 accelerates the odontogenic differentiation of stem cells from human exfoliated deciduous teeth by regulating IGFBP7 expression
Authors: Wang Dan , Zhu Ningxin , Xie Fei , Qin Man , Wang Yuanyuan
Published: August 2022

Stem cells from human exfoliated deciduous teeth (SHED) are attractive seed cells for dental tissue engineering. We identified the effect of the long noncoding RNA insulin-like growth factor-binding protein 7 antisense RNA 1 (lncRNA IGFBP7-AS1) in vivo and its underlying mechanism during SHED odontogenic differentiation. IGFBP7-AS1 and insulin-like growth factor-binding protein 7 (IGFBP7) were overexpressed using lentiviruses. IGFBP7 expression was knocked down with small interfering RNA. The effect of IGFBP7-AS1 in vivo was confirmed by animal experiments. The effect of IGFBP7 on SHED odontogenic differentiation was assessed with alkaline phosphatase staining, alizarin red S staining, quantitative reverse transcription-PCR, and western blotting. The relationship between IGFBP7-AS1 and IGFBP7 was confirmed by quantitative reverse transcription–PCR and western blotting. IGFBP7-AS1 promoted SHED odontogenesis in vivo, and regulated the expression of the coding gene IGFBP7 positively. Inhibiting IGFBP7 led to suppress SHED odontogenic differentiation while IGFBP7 overexpression had the opposite effect. IGFBP7-AS1 enhanced the stability of IGFBP7. IGFBP7-AS1 promoted SHED odontogenic differentiation in vivo. The underlying mechanism may involve the enhancement of IGFBP7 stability. This may provide novel potential targets for dental tissue engineering.
Understanding Farmers’ Preferences Towards Insurance Schemes that Promote Biosecurity Best Management Practices
Authors: Mato-Amboage Rosa , Touza Julia , Soliño Mario
Published: August 2022

Plant pest and disease outbreaks, which occur with increasing frequency and intensity, cause catastrophic losses and threaten food security in many areas around the world. These impacts are expected to be exacerbated by climate change. Tackling this challenge requires mechanisms that ensure the financial security of farmers while incentivizing private biosecurity efforts to prevent future outbreaks. This study explored crop producers’ preferences for a subsidized insurance scheme as an instrument to manage novel biotic risks. Specifically, we developed a choice experiment to evaluate Spanish growers’ willingness to pay for a crop insurance product that promotes compliance with best biosecurity management practices. Our results show that while growers are willing to pay more for high coverage products that increase the resilience of crops to potential catastrophic outbreaks, there is neither a strong demand nor widespread availability of such tools. Farmers required reductions in premiums before undertaking risk prevention measures; they are more willing to pay for schemes that link their eligibility to access to ad hoc funds in the eventuality of a catastrophic outbreak than they are to purchase insurance. Our findings also suggest that Spanish growers prefer expanding the eligible risks covered by insurance and envisage a role for insurance in offering biosecurity protection.
Impacts of differential mosquito control treatment regimens on insecticide susceptibility status of Aedes aegypti (Diptera: Culicidae)
Authors: Parker-Crockett Casey , Lloyd Aaron , Ramirez Daviela , Connelly C. Roxanne
Published: August 2022

Aedes aegypti (Linnaeus) is an invasive mosquito species and notable vector of several pathogens in the USA. Their cryptic and anthropophilic nature puts this species in close association with humans, where they can also be a nuisance. Mosquito control programs are the front line of defense for protecting the community from nuisance-biting and disease. However, the occurrence and prevalence of insecticide resistance in mosquitoes is a well-documented phenomenon that directly impacts the efficacy of insecticide applications. In Florida specifically, widespread resistance in Ae. aegypti has created a need for operational strategies that combat and, ideally, reverse resistance. Laboratory studies and the association between fitness costs and insecticide resistance indicate that this reversion is possible under the right conditions. For a 2.5-year period, the impact of varying operational treatment regimens on insecticide resistance in Ae. aegypti is evaluated using kdr genotyping and the CDC bottle bioassay. In an organophosphate treatment area, a decrease in frequency of a double homozygous resistant genotype was observed. CDC bottle bioassays did not reveal any clear trends in the data to indicate a reversion to insecticide susceptibility. However, the changes in genotype could indicate the first step back to insecticide susceptibility. This study provides preliminary data that has implications for resistance management in mosquito control operations.

Article Highlights

Presented study represents the first field study to evaluate how changing insecticide pressures on resistant mosquitoes affects insecticide resistance.

A decrease in the double homozygous resistance genotype was observed in Ae. aegypti from the organophosphate treatment area after a change in use patterns.

Identifiable trends in phenotypic resistance as a result of the treatment regimens were not observed.
TIGER: A Web Portal of Tumor Immunotherapy Gene Expression Resource
Authors: Chen Zhihang , Luo Ziwei , Zhang Di , Li Huiqin , Liu Xuefei , Zhu Kaiyu , Zhang Hongwan , Wang Zongping , Zhou Penghui , Ren Jian , Zhao An , Zuo Zhixiang
Published: August 2022

Immunotherapy is a promising cancer treatment method; however, only a few patients benefit from it. The development of new immunotherapy strategies and effective biomarkers of response and resistance is urgently needed. Recently, high-throughput bulk and single-cell gene expression profiling technologies have generated valuable resources. However, these resources are not well organized and systematic analysis is difficult. Here, we present TIGER, a tumor immunotherapy gene expression resource, which contains bulk transcriptome data of 1508 tumor samples with clinical immunotherapy outcomes and 11,057 tumor/normal samples without clinical immunotherapy outcomes, as well as single-cell transcriptome data of 2,116,945 immune cells from 655 samples. TIGER provides many useful modules for analyzing collected and user-provided data. Using the resource in TIGER, we identified a tumor-enriched subset of CD4+ T cells. Patients with melanoma with a higher signature score of this subset have a significantly better response and survival under immunotherapy. We believe that TIGER will be helpful in understanding anti-tumor immunity mechanisms and discovering effective biomarkers. TIGER is freely accessible at http://tiger.canceromics.org/.
The World in Dress
Authors: Calvi Giulia
Published: August 2022

In the early modern period costume books and albums participated in the shaping of a new visual culture that displayed the diversity of the people of the known world on a variety of media including maps, atlases, screens, and scrolls. At the crossroads of early anthropology, geography, and travel literature, this textual and visual production blurred the lines between art and science. Costume books and albums were not a unique European production: in the Ottoman Empire and the Far East artists and geographers also pictured the dress of men and women of their own and faraway lands hybridizing the Renaissance western tradition. Acknowledging this circulation of knowledge and people through migration, travel, missionary and diplomatic encounters, this Element contributes to the expanding field of early modern cultural studies in a global perspective.
Risk of antibiotics associated with Clostridioides difficile infection: Antibiotic stewardship in action
Authors: Dysangco Andrew T. , Pierce Tamra M. , Bravata Dawn M.
Published: August 2022

We examined risk associated with antibiotics used for Clostridioides difficile infection (CDI) at a single site from 2018 through 2020. Overall, 78 patients had nonrecurrent infections. Among inpatient antibiotics, intravenous meropenem had the highest CDI rate (3.56 per 1,000 days of therapy; n = 2 cases). Among outpatient antibiotics, metronidazole had the highest rate (0.071 per 1,000 pills dispensed; n = 3 cases).
Patient and provider perceptions of a peer-delivered intervention (‘Khanya’) to improve anti-retroviral adherence and substance use in South Africa: a mixed methods analysis
Authors: Rose Alexandra L. , Belus Jennifer M. , Hines Abigail C. , Barrie Issmatu , Regenauer Kristen S. , Andersen Lena S. , Joska John A. , Ciya Nonceba , Ndamase Sibabalwe , Myers Bronwyn , Safren Steven A. , Magidson Jessica F.
Published: August 2022

Background

Despite a high prevalence of problematic substance use among people living with HIV in South Africa, there remains limited access to substance use services within the HIV care system. To address this gap, our team previously developed and adapted a six-session, peer-delivered problem-solving and behavioral activation-based intervention (Khanya) to improve HIV medication adherence and reduce substance use in Cape Town. This study evaluated patient and provider perspectives on the intervention to inform implementation and future adaptation.

Methods

Following intervention completion, we conducted semi-structured individual interviews with patients (n = 23) and providers (n = 9) to understand perspectives on the feasibility, acceptability, and appropriateness of Khanya and its implementation by a peer. Patients also quantitatively ranked the usefulness of individual intervention components (problem solving for medication adherence ‘Life-Steps’, behavioral activation, mindfulness training, and relapse prevention) at post-treatment and six months follow-up, which we triangulated with qualitative feedback to examine convergence and divergence across methods.

Results

Patients and providers reported high overall acceptability, feasibility, and appropriateness of Khanya, although there were several feasibility challenges. Mindfulness and Life-Steps were identified as particularly acceptable, feasible, and appropriate components by patients across methods, whereas relapse prevention strategies were less salient. Behavioral activation results were less consistent across methods.

Conclusions

Findings underscore the importance of examining patients’ perspectives on specific intervention components within intervention packages. While mindfulness training and peer delivery models were positively perceived by consumers, they are rarely used within task-shared behavioral interventions in low- and middle-income countries.
Big Five Traits Based Profiles and Humor Styles in Preadolescents
Authors: Kokkinos Costantinos M. , Voulgaridou Ioanna , Michaelides Orestis
Published: August 2022

Abstract. The present study investigated the relationship between Big Five traits-based profiles and humor styles in a sample of 426 Greek preadolescents. Latent Profile Analysis yielded three distinct personality profiles: resilients, average, and undercontrollers. These profiles exhibited significant group differences in humor styles. The resilient profile displayed the highest scores on the two benign humor styles and the lowest on the two malign styles. On the contrary, the under controllers scored lowest on the two benign humor styles and highest on self-defeating humor. Findings showed that the patterns identified in the extant literature between humor, personality, and adjustment generalize to preadolescents. These are discussed with reference to prior work and relevant theoretical implications.
No Unique Scaling Law for Igneous Dikes
Authors: Gill S. P. A. , Walker R. J. , McCaffrey K. J. W. , Greenfield C.
Published: August 2022

In linear elastic fracture mechanics (LEFM), veins, dikes, and sills grow in length when the stress intensity factor at the tip reaches a critical value: the host rock fracture toughness . This criterion is applied broadly in LEFM models for crack growth and it is often assumed that the pressure inside the crack is uniform. When applied to intrusion length versus thickness scaling, a significant issue arises in that derived , which is about 100–1,000 times that of measured values for rocks at upper crustal depths. The same scaling relationships applied to comparatively short mineral vein data gives , approaching the expected range. Here we propose that intrusions preserve non‐equilibrated pressures as cracks controlled by kinetics, and therefore cannot be treated in continuum with fracture‐controlled constant pressure (equilibrium) structures such as veins, or many types of scaled analogue model. Early stages of dike growth (inflation) give rise to increasing length and thickness, but magma pressure gradients within intrusions may serve to drive late‐stage lengthening at the expense of maximum thickness (relaxation). For cracks in 2D, we find that intrusion scaling in non‐equilibrium growth is controlled by the magma injection rate and initial dike scaling, effective (2D) host rock modulus, magma viscosity and cooling rate, which are different for all individual intrusions and sets of intrusions. A solidified intrusion can therefore achieve its final dimensions via many routes, with relaxation acting as a potentially significant factor, hence there is no unique scaling law for dike intrusions.
Deep learning for non-parameterized MEMS structural design
Authors: Guo Ruiqi , Sui Fanping , Yue Wei , Wang Zekai , Pala Sedat , Li Kunying , Xu Renxiao , Lin Liwei
Published: August 2022

The geometric designs of MEMS devices can profoundly impact their physical properties and eventual performances. However, it is challenging for researchers to rationally consider a large number of possible designs, as it would be very time- and resource-consuming to study all these cases using numerical simulation. In this paper, we report the use of deep learning techniques to accelerate the MEMS design cycle by quickly and accurately predicting the physical properties of numerous design candidates with vastly different geometric features. Design candidates are represented in a nonparameterized, topologically unconstrained form using pixelated black-and-white images. After sufficient training, a deep neural network can quickly calculate the physical properties of interest with good accuracy without using conventional numerical tools such as finite element analysis. As an example, we apply our deep learning approach in the prediction of the modal frequency and quality factor of disk-shaped microscale resonators. With reasonable training, our deep learning neural network becomes a high-speed, high-accuracy calculator: it can identify the flexural mode frequency and the quality factor 4.6 × 103 times and 2.6 × 104 times faster, respectively, than conventional numerical simulation packages, with good accuracies of 98.8 ± 1.6% and 96.8 ± 3.1%, respectively. When simultaneously predicting the frequency and the quality factor, up to ~96.0% of the total computation time can be saved during the design process. The proposed technique can rapidly screen over thousands of design candidates and promotes experience-free and data-driven MEMS structural designs.
Visual system assessment for predicting a transition to psychosis
Authors: Diamond Alexander , Silverstein Steven M. , Keane Brian P.
Published: August 2022

The field of psychiatry is far from perfect in predicting which individuals will transition to a psychotic disorder. Here, we argue that visual system assessment can help in this regard. Such assessments have generated medium-to-large group differences with individuals prior to or near the first psychotic episode or have shown little influence of illness duration in larger samples of more chronic patients. For example, self-reported visual perceptual distortions—so-called visual basic symptoms—occur in up to 2/3rds of those with non-affective psychosis and have already longitudinally predicted an impending onset of schizophrenia. Possibly predictive psychophysical markers include enhanced contrast sensitivity, prolonged backward masking, muted collinear facilitation, reduced stereoscopic depth perception, impaired contour and shape integration, and spatially restricted exploratory eye movements. Promising brain-based markers include visual thalamo-cortical hyperconnectivity, decreased occipital gamma band power during visual detection (MEG), and reduced visually evoked occipital P1 amplitudes (EEG). Potentially predictive retinal markers include diminished cone a- and b-wave amplitudes and an attenuated photopic flicker response during electroretinography. The foregoing assessments are often well-described mechanistically, implying that their findings could readily shed light on the underlying pathophysiological changes that precede or accompany a transition to psychosis. The retinal and psychophysical assessments in particular are inexpensive, well-tolerated, easy to administer, and brief, with few inclusion/exclusion criteria. Therefore, across all major levels of analysis—from phenomenology to behavior to brain and retinal functioning—visual system assessment could complement and improve upon existing methods for predicting which individuals go on to develop a psychotic disorder.
Regulation of CCL2 by EZH2 affects tumor-associated macrophages polarization and infiltration in breast cancer
Authors: Wang Ya-fang , Yu Lei , Hu Zong-long , Fang Yan-fen , Shen Yan-yan , Song Min-fang , Chen Yi
Published: August 2022

Tumor associated macrophages (TAMs) play an important role in tumorigenesis, development and anti-cancer drug therapy. However, very few epigenetic compounds have been elucidated to affect tumor growth by educating TAMs in the tumor microenvironment (TME). Herein, we identified that EZH2 performs a crucial role in the regulation of TAMs infiltration and protumoral polarization by interacting with human breast cancer (BC) cells. We showed that EZH2 inhibitors-treated BC cells induced M2 macrophage polarization in vitro and in vivo, while EZH2 knockdown exhibited the opposite effect. Mechanistically, inhibition of EZH2 histone methyltransferase alone by EZH2 inhibitors in breast cancer cells could reduce the enrichment of H3K27me3 on CCL2 gene promoter, elevate CCL2 transcription and secretion, contributing to the induction of M2 macrophage polarization and recruitment in TME, which reveal a potential explanation behind the frustrating results of EZH2 inhibitors against breast cancer. On the contrary, EZH2 depletion led to DNA demethylation and subsequent upregulation of miR-124-3p level, which inhibited its target CCL2 expression in the tumor cells, causing arrest of TAMs M2 polarization. Taken together, these data suggested that EZH2 can exert opposite regulatory effects on TAMs polarization through its enzymatic or non-enzymatic activities. Our results also imply that the effect of antitumor drugs on TAMs may affect its therapeutic efficacy, and the combined application with TAMs modifiers should be warranted to achieve great clinical success.
Activation of pancreatic stellate cells attenuates intracellular Ca2+ signals due to downregulation of TRPA1 and protects against cell death induced by alcohol metabolites
Authors: Kusiak Agnieszka A. , Jakubowska Monika A. , Stopa Kinga B. , Zhang Xiaoying , Huang Wei , Gerasimenko Julia V. , Gerasimenko Oleg V. , Sutton Robert , Petersen Ole H. , Ferdek Pawel E.
Published: August 2022

Alcohol abuse, an increasing problem in developed societies, is one of the leading causes of acute and chronic pancreatitis. Alcoholic pancreatitis is often associated with fibrosis mediated by activated pancreatic stellate cells (PSCs). Alcohol toxicity predominantly depends on its non-oxidative metabolites, fatty acid ethyl esters, generated from ethanol and fatty acids. Although the role of non-oxidative alcohol metabolites and dysregulated Ca2+ signalling in enzyme-storing pancreatic acinar cells is well established as the core mechanism of pancreatitis, signals in PSCs that trigger fibrogenesis are less clear. Here, we investigate real-time Ca2+ signalling, changes in mitochondrial potential and cell death induced by ethanol metabolites in quiescent vs TGF-β-activated PSCs, compare the expression of Ca2+ channels and pumps between the two phenotypes and the consequences these differences have on the pathogenesis of alcoholic pancreatitis. The extent of PSC activation in the pancreatitis of different aetiologies has been investigated in three animal models. Unlike biliary pancreatitis, alcohol-induced pancreatitis results in the activation of PSCs throughout the entire tissue. Ethanol and palmitoleic acid (POA) or palmitoleic acid ethyl ester (POAEE) act directly on quiescent PSCs, inducing cytosolic Ca2+ overload, disrupting mitochondrial functions, and inducing cell death. However, activated PSCs acquire remarkable resistance against ethanol metabolites via enhanced Ca2+-handling capacity, predominantly due to the downregulation of the TRPA1 channel. Inhibition or knockdown of TRPA1 reduces EtOH/POA-induced cytosolic Ca2+ overload and protects quiescent PSCs from cell death, similarly to the activated phenotype. Our results lead us to review current dogmas on alcoholic pancreatitis. While acinar cells and quiescent PSCs are prone to cell death caused by ethanol metabolites, activated PSCs can withstand noxious signals and, despite ongoing inflammation, deposit extracellular matrix components. Modulation of Ca2+ signals in PSCs by TRPA1 agonists/antagonists could become a strategy to shift the balance of tissue PSCs towards quiescent cells, thus limiting pancreatic fibrosis.
Corosolic acid sensitizes ferroptosis by upregulating HERPUD1 in liver cancer cells
Authors: Peng Yingxiu , Li Ning , Tang Feifeng , Qian Chunmei , Jia Tingting , Liu Jingjin , Xu Yanfeng
Published: August 2022

Primary liver cancer is the third leading cause of cancer death in the world, and the lack of effective treatments is the main reason for the high mortality. Corosolic acid (CA) has been proved to have antitumor activity. In this study, we found that CA can sensitize liver cancer cells to ferroptosis, which is a regulated form of cell death characterized by iron-dependent lipid peroxides reaching lethal levels. Here, we revealed that CA can inhibit glutathione (GSH) synthesis via HERPUD1, decreasing the cellular GSH level and causing liver cancer cells to become more sensitive to ferroptosis. Mechanistically, further studies found that HERPUD1 reduced the ubiquitination of the GSS-associated E3 ubiquitin ligase MDM2, which promoted ubiquitination of GSS, thereby inhibiting GSH synthesis to increase ferroptosis susceptibility. Importantly, a mouse xenograft model also demonstrated that CA inhibits tumor growth via HERPUD1. Collectively, our findings suggesting that CA is a candidate component for the development of treatments against liver cancer.
Subcortical-cortical dynamical states of the human brain and their breakdown in stroke
Authors: Favaretto Chiara , Allegra Michele , Deco Gustavo , Metcalf Nicholas V. , Griffis Joseph C. , Shulman Gordon L. , Brovelli Andrea , Corbetta Maurizio
Published: August 2022

The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01–0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome.
PIF7 is a master regulator of thermomorphogenesis in shade
Authors: Burko Yogev , Willige Björn Christopher , Seluzicki Adam , Novák Ondřej , Ljung Karin , Chory Joanne
Published: August 2022

The size of plant organs is highly responsive to environmental conditions. The plant’s embryonic stem, or hypocotyl, displays phenotypic plasticity, in response to light and temperature. The hypocotyl of shade avoiding species elongates to outcompete neighboring plants and secure access to sunlight. Similar elongation occurs in high temperature. However, it is poorly understood how environmental light and temperature cues interact to effect plant growth. We found that shade combined with warm temperature produces a synergistic hypocotyl growth response that dependent on PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) and auxin. This unique but agriculturally relevant scenario was almost totally independent on PIF4 activity. We show that warm temperature is sufficient to promote PIF7 DNA binding but not transcriptional activation and we demonstrate that additional, unknown factor/s must be working downstream of the phyB-PIF-auxin module. Our findings will improve the predictions of how plants will respond to increased ambient temperatures when grown at high density.
Highly hydrated paramagnetic amorphous calcium carbonate nanoclusters as an MRI contrast agent
Authors: Dong Liang , Xu Yun-Jun , Sui Cong , Zhao Yang , Mao Li-Bo , Gebauer Denis , Rosenberg Rose , Avaro Jonathan , Wu Ya-Dong , Gao Huai-Ling , Pan Zhao , Wen Hui-Qin , Yan Xu , Li Fei , Lu Yang , Cölfen Helmut , Yu Shu-Hong
Published: August 2022

Amorphous calcium carbonate plays a key role as transient precursor in the early stages of biogenic calcium carbonate formation in nature. However, due to its instability in aqueous solution, there is still rare success to utilize amorphous calcium carbonate in biomedicine. Here, we report the mutual effect between paramagnetic gadolinium ions and amorphous calcium carbonate, resulting in ultrafine paramagnetic amorphous carbonate nanoclusters in the presence of both gadolinium occluded highly hydrated carbonate-like environment and poly(acrylic acid). Gadolinium is confirmed to enhance the water content in amorphous calcium carbonate, and the high water content of amorphous carbonate nanoclusters contributes to the much enhanced magnetic resonance imaging contrast efficiency compared with commercially available gadolinium-based contrast agents. Furthermore, the enhanced T1 weighted magnetic resonance imaging performance and biocompatibility of amorphous carbonate nanoclusters are further evaluated in various animals including rat, rabbit and beagle dog, in combination with promising safety in vivo. Overall, exceptionally facile mass-productive amorphous carbonate nanoclusters exhibit superb imaging performance and impressive stability, which provides a promising strategy to design magnetic resonance contrast agent.
Cytoplasmic forces functionally reorganize nuclear condensates in oocytes
Authors: Al Jord Adel , Letort Gaëlle , Chanet Soline , Tsai Feng-Ching , Antoniewski Christophe , Eichmuller Adrien , Da Silva Christelle , Huynh Jean-René , Gov Nir S. , Voituriez Raphaël , Terret Marie-Émilie , Verlhac Marie-Hélène
Published: August 2022

Cells remodel their cytoplasm with force-generating cytoskeletal motors. Their activity generates random forces that stir the cytoplasm, agitating and displacing membrane-bound organelles like the nucleus in somatic and germ cells. These forces are transmitted inside the nucleus, yet their consequences on liquid-like biomolecular condensates residing in the nucleus remain unexplored. Here, we probe experimentally and computationally diverse nuclear condensates, that include nuclear speckles, Cajal bodies, and nucleoli, during cytoplasmic remodeling of female germ cells named oocytes. We discover that growing mammalian oocytes deploy cytoplasmic forces to timely impose multiscale reorganization of nuclear condensates for the success of meiotic divisions. These cytoplasmic forces accelerate nuclear condensate collision-coalescence and molecular kinetics within condensates. Disrupting the forces decelerates nuclear condensate reorganization on both scales, which correlates with compromised condensate-associated mRNA processing and hindered oocyte divisions that drive female fertility. We establish that cytoplasmic forces can reorganize nuclear condensates in an evolutionary conserved fashion in insects. Our work implies that cells evolved a mechanism, based on cytoplasmic force tuning, to functionally regulate a broad range of nuclear condensates across scales. This finding opens new perspectives when studying condensate-associated pathologies like cancer, neurodegeneration and viral infections.
Invariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor
Authors: Macleod Olivia J. S. , Cook Alexander D. , Webb Helena , Crow Mandy , Burns Roisin , Redpath Maria , Seisenberger Stefanie , Trevor Camilla E. , Peacock Lori , Schwede Angela , Kimblin Nicola , Francisco Amanda F. , Pepperl Julia , Rust Steve , Voorheis Paul , Gibson Wendy , Taylor Martin C. , Higgins Matthew K. , Carrington Mark
Published: August 2022

African trypanosomes are extracellular pathogens of mammals and are exposed to the adaptive and innate immune systems. Trypanosomes evade the adaptive immune response through antigenic variation, but little is known about how they interact with components of the innate immune response, including complement. Here we demonstrate that an invariant surface glycoprotein, ISG65, is a receptor for complement component 3 (C3). We show how ISG65 binds to the thioester domain of C3b. We also show that C3 contributes to control of trypanosomes during early infection in a mouse model and provide evidence that ISG65 is involved in reducing trypanosome susceptibility to C3-mediated clearance. Deposition of C3b on pathogen surfaces, such as trypanosomes, is a central point in activation of the complement system. In ISG65, trypanosomes have evolved a C3 receptor which diminishes the downstream effects of C3 deposition on the control of infection.
Natural and anthropogenic contributions to the hurricane drought of the 1970s–1980s
Authors: Rousseau-Rizzi Raphaël , Emanuel Kerry
Published: August 2022

Atlantic hurricane activity experienced a pronounced lull during the 1970s and 1980s. The current explanation that anthropogenic aerosol radiative forcing cooled the sea surface locally fails to capture the magnitude of this large decrease in activity. To explain this hurricane drought, we propose that the radiative effects of sulfate aerosols from Europe and North-America decreased precipitation in the Sahara-Sahel region, leading to an enhancement of dust regional emissions and transport over the Atlantic. This dust in turn enhanced the local decrease of sea-surface temperature and of hurricane activity. Here, we show that dust emissions from the Sahara peaked in phase with regional sulfate aerosol optical thickness and Sahel drought conditions, and that dust optical depth variations alone can explain nearly half of the sea-surface temperature depression in the 1970s and 1980s.
Heterostrain-enabled ultrahigh electrostrain in lead-free piezoelectric
Authors: Feng Wei , Luo Bingcheng , Bian Shuaishuai , Tian Enke , Zhang Zili , Kursumovic Ahmed , MacManus-Driscoll Judith L. , Wang Xiaohui , Li Longtu
Published: August 2022

Piezoelectric materials provide high strain and large driving forces in actuators and can transform electrical energy into mechanical energy. Although they were discovered over 100 years ago, scientists are still searching for alternative lead-free piezoelectrics to reduce their environmental impact. Developing high-strain piezoelectric materials has been a long-term challenge, particularly challenging for the design of high-strain polycrystalline piezoelectrics containing no toxic lead element. In this work, we report one strategy to enhance the electrostrain via designing “heterostrain” through atomic-scale defect engineering and mesoscale domain engineering. We achieve an ultrahigh electrostrain of 2.3% at high temperature (220 °C) in lead-free polycrystalline ceramics, higher than all state-of-the-art piezoelectric materials, including lead-free and lead-based ceramics and single crystals. We demonstrate practical solutions for achieving high electrostrain in low-cost environmentally piezoelectric for various applications.
Safety analyses from the phase 3 ASCENT trial of sacituzumab govitecan in metastatic triple-negative breast cancer
Authors: Rugo Hope S. , Tolaney Sara M. , Loirat Delphine , Punie Kevin , Bardia Aditya , Hurvitz Sara A. , O’Shaughnessy Joyce , Cortés Javier , Diéras Véronique , Carey Lisa A. , Gianni Luca , Piccart Martine J. , Loibl Sibylle , Goldenberg David M. , Hong Quan , Olivo Martin , Itri Loretta M. , Kalinsky Kevin
Published: August 2022

Sacituzumab govitecan (SG) is an anti-Trop-2 antibody-drug conjugate with an SN-38 payload. In the ASCENT study, patients with metastatic triple-negative breast cancer (mTNBC) relapsed/refractory to ≥2 prior chemotherapy regimens (≥1 in the metastatic setting), received SG or single-agent treatment of physician’s choice (eribulin, vinorelbine, capecitabine, or gemcitabine). This ASCENT safety analysis includes the impact of age and UGT1A1 polymorphisms, which hinder SN-38 detoxification. SG demonstrated a manageable safety profile in patients with mTNBC, including those ≥65 years; neutropenia/diarrhea are key adverse events (AE). Patients with UGT1A1 *28/*28 genotype versus those with 1/*28 and *1/*1 genotypes had higher rates of grade ≥3 SG-related neutropenia (59% vs 47% and 53%), febrile neutropenia (18% vs 5% and 3%), anemia (15% vs 6% and 4%), and diarrhea (15% vs 9% and 10%), respectively. Individuals with UGT1A1 *28/*28 genotype should be monitored closely; active monitoring and routine AE management allow optimal therapeutic exposure of SG.
ZNF92, an unexplored transcription factor with remarkably distinct breast cancer over-expression associated with prognosis and cell-of-origin
Authors: Kamran Mohammad , Bhattacharya Udayan , Omar Mohamed , Marchionni Luigi , Ince Tan A.
Published: August 2022

Tumor phenotype is shaped both by transforming genomic alterations and the normal cell-of-origin. We identified a cell-of-origin associated prognostic gene expression signature, ET-9, that correlates with remarkably shorter overall and relapse free breast cancer survival, 8.7 and 6.2 years respectively. The genes associated with the ET-9 signature are regulated by histone deacetylase 7 (HDAC7) partly through ZNF92, a previously unexplored transcription factor with a single PubMed citation since its cloning in 1990s. Remarkably, ZNF92 is distinctively over-expressed in breast cancer compared to other tumor types, on a par with the breast cancer specificity of the estrogen receptor. Importantly, ET-9 signature appears to be independent of proliferation, and correlates with outcome in lymph-node positive, HER2+, post-chemotherapy and triple-negative breast cancers. These features distinguish ET-9 from existing breast cancer prognostic signatures that are generally related to proliferation and correlate with outcome in lymph-node negative, ER-positive, HER2-negative breast cancers. Our results suggest that ET-9 could be also utilized as a predictive signature to select patients for HDAC inhibitor treatment.
TLR agonists induce sustained IgG to hemagglutinin stem and modulate T cells following newborn vaccination
Authors: Clemens Elene A. , Holbrook Beth C. , McNeilly Brendan , Kanekiyo Masaru , Graham Barney S. , Alexander-Miller Martha A.
Published: August 2022

The newborn immune system is characterized by diminished immune responses that leave infants vulnerable to virus-mediated disease and make vaccination more challenging. Optimal vaccination strategies for influenza A virus (IAV) in newborns should result in robust levels of protective antibodies, including those with broad reactivity to combat the variability in IAV strains across seasons. The stem region of the hemagglutinin (HA) molecule is a target of such antibodies. Using a nonhuman primate model, we investigate the capacity of newborns to generate and maintain antibodies to the conserved stem region following vaccination. We find adjuvanting an inactivated vaccine with the TLR7/8 agonist R848 is effective in promoting sustained HA stem-specific IgG. Unexpectedly, HA stem-specific antibodies were generated with a distinct kinetic pattern compared to the overall response. Administration of R848 was associated with increased influenza-specific T follicular helper cells as well as Tregs with a less suppressive phenotype, suggesting adjuvant impacts multiple cell types that have the potential to contribute to the HA-stem response.