bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipidcsökkentő kezelés hypertoniában: mit, mennyit, mikor?
Authors: Harangi Mariann , Kovács Beáta
Published: September 2023

A hypertonia és a lipidanyagcsere-eltérések a cardiovascularis megbetegedések két legfontosabb kockázati tényezője. A hypertoniás és hyperlipidaemiás beteg cardiovascularis kockázata nagyobb, mint a csak hypertoniás vagy csak hyperlipidaemiás betegé. Ezért a hyperlipidaemia megfelelő kezelése fontos szempont a hypertoniás beteg gondozása során, mivel megelőzheti az érelmeszesedés és az ehhez társuló macrovascularis események, köztük a myocardialis infarctus és a stroke kialakulását. A korábbi vizsgálatok azt igazolták, hogy a hidroxi-metil-glutaril-koenzim-A-reduktáz-gátló sztatinok hypertoniás betegek esetén nem várt vérnyomáscsökkentő hatással is rendelkeznek. Emellett a fibrátok és az omega-3 zsírsav készítmények is fokozhatják a vérnyomáscsökkentő kezelés hatékonyságát. E farmakológiai ágensek segítségével, a lipidszintekre és a vérnyomásértékekre kifejtett kedvező hatásuknak köszönhetően, nagyobb cardiovascularis kockázatcsökkenés érhető el ebben a speciális betegcsoportban.
Macaristan ve Polonya demokrasilerindeki gerilemenin siyasi kurumlar ve uluslararası aktörler çerçevesinde değerlendirilmesi
Authors: KÜÇÜKŞAHİN Muhammed Emre
Published: September 2023

Günümüzde pek çok ülke insan hakları, hukukun üstünlüğü, serbest ve adil seçimler ve çoğulculuk gibi demokratik değerleri kısıtlayan yasal ve idari girişimlerde bulunmaktadır. Bu bağlamda demokrasi uzun yıllardır küresel anlamda gerileme içindedir. Bu durum demokratik gerilemenin ampirik olarak tespit edilmesini ve nedenlerinin araştırılmasını teşvik etmektedir.

Avrupa Birliği demokratik değerleri Birlik içinde yasal norm olarak kabul etmesine rağmen birden fazla üyesi hakkında demokratik gerileme içinde oldukları yönünde tartışmalar yürütülmektedir. Söz konusu üyelerden ikisi Macaristan ve Polonya olup iki ülkede hem Birlik içinde hem de uluslararası alanda anti demokratik uygulamaları nedeniyle eleştirilmektedir.

Bu çalışmada da Macaristan ve Polonya’nın demokratik gerileme içinde oldukları ampirik veriler ile ortaya konulmakta ve bunun nedenleri siyasal kurumlar ve uluslararası faktörler çerçevesinde açıklanmaktadır.
Zocalos pintados de época islámica en la Plaza de San Pedro (Huelva)
Authors: López Domínguez Miguel Ángel
Published: September 2023

Durante las actividades arqueológicas realizadas en los solares nº 6 y 7 de la Plaza de San Pedro de Huelva, se localizó un edificio de época islámica del que se pudo documentar un total de siete estancias. Entre ellas destaca la denominada Estancia 1, que se desarrolla entre los dos solares, es en este espacio donde se localizan los zócalos pintados que decoraban sus paredes norte y oeste.
El poblamiento romano y Tardoantiguo de El Cuervo (Sevilla, SW de España)
Authors: Pérez Aguilar Luis Gethsemani , Ruiz Prieto Enrique , Guillén Rodríguez Livia , Gómez Peña Álvaro
Published: September 2023

En el año 2013 se llevó a cabo una campaña de prospección arqueológica superficial en el término municipal de El Cuervo (Sevilla). Esta intervención arqueológica tenía en origen una finalidad científica y académica. Su objetivo fue la revisión sobre el terreno de trabajos de campo anteriores, junto a la posible documentación de nuevos yacimientos, de cara a la comprensión evolutiva del poblamiento humano desde la gran diacronía y los parámetros de la arqueología del territorio. En este artículo nos centraremos, no obstante, en presentar los datos y analizar la evolución del poblamiento romano y tardoantiguo.
Introduction to Arabic Literary Journalism: A Critical Study
Authors: Jumaa Abu Marzouk Samah
Published: September 2023

This paper examines Al Adab Al Sahafi: (Arabic literary journalism) as a possible branch of Anglo-American literary journalism, analyzing extracts from works of Al Jahith, Abu: Hayan Al Tawhedi:, Yacaqub Sanu:c and Ghassan Kanafany according to the criteria set out by a number of Anglo-American literary journalism scholars such as Thomas Connery, Kevin Kerrane, Ben Yagoda, and Norman Sims. This paper also briefly surveys humor in Al Adab Al Sahafi: to the end of understanding its role at overcoming challenges of limited freedom of expression in the Arab world..
Contextual Considerations in the Use of Synonymous Verbs: The Case of Cease, End, Finish and Stop
Authors: Thabit Saeed Aziz
Published: September 2023

This corpus-based study endeavors to explore the semantic differences among the verbs cease, finish, end and stop when used in different contexts. The author analyzed a set of data that comprised 500 contextualized instances in which these verbs are used. The data were culled from different sources including BNC, novels and spontaneous speech. In addition to the syntactic constraints that govern the use of these verbs, the findings of the study reveal a number of contextual features that distinguish them from one another, including completeness, finality, conclusiveness, animacy, abruptness, gradualness, among others. .
Measure Terms in Rural Jordanian Spoken Arabic
Authors: Mohammad Al-Harahsheh Ahmad
Published: September 2023

The use of measure terms can be socially and culturally determined, as every speech society may have its own unique measure terms. This study aims to shed light on the sociolinguistic usage of measure terms in Jordanian Spoken Arabic (JSA). The researcher collected the data from everyday conversations in the rural dialect of the north of Jordan. The participants of the study were 15 men and women who were in their fifties and sixties. The ethnography of communication and Interactional Sociolinguistic (IS) approaches are adopted as the theoretical framework for this study. The study concluded that measure terms in JSA are culturally and socially inherited and transmitted, and Jordanians tend to use body parts (i.e. finger, hand, foot and leg related expressions) as measure terms for heights, lengths and weights..
English-Cairene Arabic Classroom Code Switching:An Interactional-Sociolinguistic Approach
Authors: Youssef Islam
Published: September 2023

This is a data-oriented study of code switching in the context of Cairene Arabic-English bilinguals in university classrooms. Data were collected through in-class observations of bilingual Egyptian professors in a program where English is the language of instruction. The observed code-switches are grouped into a structural typology based on their syntax and into a functional typology based on the communicative activities they perform. Each category is exemplified, and the examples are analyzed from an interactional-sociolinguistic perspective. I entertain both the hypothesis that certain verbal activities are associated with a given language during the switch, and the hypothesis that the code switching behavior is itself a contextual cue associated with certain activities, and contend that a synthesis of the two is needed. Patterns, tendencies, and attitudes of the participants are thoroughly discussed. By providing a careful treatment of code switching, the paper promotes the idea that it is a natural linguistic strategy which bilinguals employ to enrich their communication, not least in the classroom setting..
The mind of the artist/the mind of the leader: what neuroscience can teach us about the training of arts managers and leaders
Authors: Edelman David , Green Jennifer
Published: September 2023

This research paper will triangulate neuroscience with performing artist cognitive traits and the training of arts leaders. The authors will examine current research in the burgeoning field of neuro-cognition and its pedagogical implications for teaching future arts leaders who come to the study from a performing arts background. The paper will present several discoveries on how the mind works and how this research helps us understand the parallels between the habits of mind utilized by performing artists and the training of the arts leader. Leadership training for future arts leaders is a critical component of their education, but we often rely on pedagogical tools created for the business world or generic nonprofit education modified to suit the realities of arts organizations. This presentation will illustrate a new pedagogical model that draws from research into how the brain works, our understanding of the mind and practice of the performing artist. Using new research on the practice of thinking and learning to inform leadership models in arts management and applying the habits of the artistic mind to the training of arts leaders points to a broadening of our pedagogical toolbox and may indeed be a new way forward in the field.
Current advances in the structural biology and molecular engineering of PETase
Authors: Liu Fei , Wang Tao , Yang Wentao , Zhang Yingkang , Gong Yuming , Fan Xinxin , Wang Guocheng , Lu Zhenhua , Wang Jianmin
Published: September 2023

Poly(ethylene terephthalate) (PET) is a highly useful synthetic polyester plastic that is widely used in daily life. However, the increase in postconsumer PET as plastic waste that is recalcitrant to biodegradation in landfills and the natural environment has raised worldwide concern. Currently, traditional PET recycling processes with thermomechanical or chemical methods also result in the deterioration of the mechanical properties of PET. Therefore, it is urgent to develop more efficient and green strategies to address this problem. Recently, a novel mesophilic PET-degrading enzyme (IsPETase) from Ideonella sakaiensis was found to streamline PET biodegradation at 30°C, albeit with a lower PET-degrading activity than chitinase or chitinase-like PET-degrading enzymes. Consequently, the molecular engineering of more efficient PETases is still required for further industrial applications. This review details current knowledge on IsPETase, MHETase, and IsPETase-like hydrolases, including the structures, ligand‒protein interactions, and rational protein engineering for improved PET-degrading performance. In particular, applications of the engineered catalysts are highlighted, including metabolic engineering of the cell factories, enzyme immobilization or cell surface display. The information is expected to provide novel insights for the biodegradation of complex polymers.
Cigarette smoke restricts the ability of mesenchymal cells to support lung epithelial organoid formation
Authors: Khedoe P. P. S. J. , van Schadewijk W. A. A. M. , Schwiening M. , Ng-Blichfeldt J. P. , Marciniak S. J. , Stolk J. , Gosens R. , Hiemstra P. S.
Published: September 2023

Adequate lung epithelial repair relies on supportive interactions within the epithelial niche, including interactions with WNT-responsive fibroblasts. In fibroblasts from patients with chronic obstructive pulmonary disease (COPD) or upon in vitro cigarette smoke exposure, Wnt/β-catenin signalling is distorted, which may affect interactions between epithelial cells and fibroblasts resulting in inadequate lung repair. We hypothesized that cigarette smoke (CS), the main risk factor for COPD, interferes with Wnt/β-catenin signalling in fibroblasts through induction of cellular stress responses, including oxidative- and endoplasmic reticulum (ER) stress, and thereby alters epithelial repair support potential. Therefore, we assessed the effect of CS-exposure and the ER stress inducer Thapsigargin (Tg) on Wnt/β-catenin signalling activation in MRC-5 fibroblasts, and on their ability to support lung epithelial organoid formation. Exposure of MRC-5 cells for 15 min with 5 AU/mL CS extract (CSE), and subsequent 6 h incubation induced oxidative stress (HMOX1). Whereas stimulation with 100 nM Tg increased markers of both the integrated stress response (ISR - GADD34/PPP1R15A, CHOP) and the unfolded protein response (UPR - XBP1spl, GADD34/PPP1R15A, CHOP and HSPA5/BIP), CSE only induced GADD34/PPP1R15A expression. Strikingly, although treatment of MRC-5 cells with the Wnt activator CHIR99021 upregulated the Wnt/β-catenin target gene AXIN2, this response was diminished upon CSE or Tg pre-exposure, which was confirmed using a Wnt-reporter. Furthermore, pre-exposure of MRC-5 cells to CSE or Tg, restricted their ability to support organoid formation upon co-culture with murine pulmonary EpCam+ cells in Matrigel at day 14. This restriction was alleviated by pre-treatment with CHIR99021. We conclude that exposure of MRC-5 cells to CSE increases oxidative stress, GADD34/PPP1R15A expression and impairs their ability to support organoid formation. This inhibitory effect may be restored by activating the Wnt/β-catenin signalling pathway.
Azetidine synthesis by La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines
Authors: Kuriyama Yuse , Sasano Yusuke , Iwabuchi Yoshiharu
Published: September 2023

Azetidine is a prevalent structural motif found in various biologically active compounds. In this research paper, we report La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines to afford azetidines. This reaction proceeded in high yields even in the presence of acid-sensitive and Lewis basic functional groups.
Diagnostic yield of genetic testing in a multinational heterogeneous cohort of 2088 DCM patients
Authors: Heliö Krista , Cicerchia Marcos , Hathaway Julie , Tommiska Johanna , Huusko Johanna , Saarinen Inka , Koskinen Lotta , Muona Mikko , Kytölä Ville , Djupsjöbacka Janica , Gentile Massimiliano , Salmenperä Pertteli , Alastalo Tero-Pekka , Steinberg Christian , Heliö Tiina , Paananen Jussi , Myllykangas Samuel , Koskenvuo Juha
Published: September 2023

Background

Familial dilated cardiomyopathy (DCM) causes heart failure and may lead to heart transplantation. DCM is typically a monogenic disorder with autosomal dominant inheritance. Currently disease-causing variants have been reported in over 60 genes that encode proteins in sarcomeres, nuclear lamina, desmosomes, cytoskeleton, and mitochondria. Over half of the patients undergoing comprehensive genetic testing are left without a molecular diagnosis even when patient selection follows strict DCM criteria.

Methods and results

This study was a retrospective review of patients referred for genetic testing at Blueprint Genetics due to suspected inherited DCM. Next generation sequencing panels included 23–316 genes associated with cardiomyopathies and other monogenic cardiac diseases. Variants were considered diagnostic if classified as pathogenic (P) or likely pathogenic (LP). Of the 2,088 patients 514 (24.6%) obtained a molecular diagnosis; 534 LP/P variants were observed across 45 genes, 2.7% (14/514) had two diagnostic variants in dominant genes. Nine copy number variants were identified: two multigene and seven intragenic. Diagnostic variants were observed most often in TTN (45.3%), DSP (6.7%), LMNA (6.7%), and MYH7 (5.2%). Clinical characteristics independently associated with molecular diagnosis were: a lower age at diagnosis, family history of DCM, paroxysmal atrial fibrillation, absence of left bundle branch block, and the presence of an implantable cardioverter-defibrillator.

Conclusions

Panel testing provides good diagnostic yield in patients with clinically suspected DCM. Causative variants were identified in 45 genes. In minority, two diagnostic variants were observed in dominant genes. Our results support the use of genetic panels in clinical settings in DCM patients with suspected genetic etiology.
Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans
Authors: Chavkin Nicholas W. , Vippa Tanvi , Jung Changhee , McDonnell Stephanie , Hirschi Karen K. , Gokce Noyan , Walsh Kenneth
Published: September 2023

Introduction

Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue.

Methods

Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45−CD31−Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals.

Results

Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFβ signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-β1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT.

Discussion

These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..
Ultrasound-guided microwave ablation in the treatment of recurrent primary hyperparathyroidism in a patient with MEN1: a case report
Authors: Liu Zhoujun , Zhao Yueting , Han Xue , Hu Xin , Zhang Yuzhi , Xu Lan , Chen Guofang , Liu Chao , Xu Shuhang
Published: September 2023

Background

Multiple endocrine neoplasia type 1 (MEN1) is an inherited endocrine syndrome caused by the mutation in the tumor suppressor gene MEN1. The recurrence rate of primary hyperparathyroidism (PHPT) in patients with MEN1 after parathyroidectomy remains high, and the management of recurrent hyperparathyroidism is still challenging.

Case presentation

We reported a 44-year-old woman with MEN1 combined with PHPT who was diagnosed through genetic screening of the patient and her family members. After parathyroidectomy to remove one parathyroid gland, the patient suffered from persistent high levels of serum calcium and parathyroid hormone, which returned to normal at up to 8 months after ultrasound-guided microwave ablation (MWA) for bilateral parathyroid glands, suggesting an acceptable short-term prognosis.

Conclusion

Ultrasound-guided MWA for parathyroid nodules may be an effective therapeutic strategy for recurrent PHPT in MEN1 patients.
The roles of protein ubiquitination in tumorigenesis and targeted drug discovery in lung cancer
Authors: Ye Zhen , Yang Jingru , Jiang Hanming , Zhan Xianquan
Published: September 2023

The malignant lung cancer has a high morbidity rate and very poor 5-year survival rate. About 80% - 90% of protein degradation in human cells is occurred through the ubiquitination enzyme pathway. Ubiquitin ligase (E3) with high specificity plays a crucial role in the ubiquitination process of the target protein, which usually occurs at a lysine residue in a substrate protein. Different ubiquitination forms have different effects on the target proteins. Multiple short chains of ubiquitination residues modify substrate proteins, which are favorable signals for protein degradation. The dynamic balance adapted to physiological needs between ubiquitination and deubiquitination of intracellular proteins is beneficial to the health of the organism. Ubiquitination of proteins has an impact on many biological pathways, and imbalances in these pathways lead to diseases including lung cancer. Ubiquitination of tumor suppressor protein factors or deubiquitination of tumor carcinogen protein factors often lead to the progression of lung cancer. Ubiquitin proteasome system (UPS) is a treasure house for research and development of new cancer drugs for lung cancer, especially targeting proteasome and E3s. The ubiquitination and degradation of oncogene proteins with precise targeting may provide a bright prospect for drug development in lung cancer; Especially proteolytic targeted chimerism (PROTAC)-induced protein degradation technology will offer a new strategy in the discovery and development of new drugs for lung cancer.
Study on mechanical properties and microscopic damage mechanism of tight sandstone reservoir under uniaxial compression
Authors: Huang Jin , Xing Jiacheng , Liao Xingchuan , Ren Yixing , Ding Keer , Tan Jin
Published: September 2023

Due to the characteristics of low porosity, low permeability and serious anisotropy in tight reservoirs, it is difficult for conventional hydraulic fracturing theory to accurately guide the efficient exploitation of tight reservoirs. It has been shown that the reservoir rock mechanical properties are the key factor impacting the fracturing effect, but the current research on the damage properties of tight reservoir rocks is not comprehensive enough. Therefore, in order to improve the fracturing theory of tight reservoirs, this paper first explores the evolution mechanism of rock fractures through uniaxial compression experiments. Secondly, based on the particle discrete element method, the damage and failure process of tight sandstone under uniaxial compression is simulated from the microscopic scale. The test results show that the rock failure mainly includes tensile failure, shear failure, and tensile-shear failure; Internal micro-fractures will interconnect during rock destruction to form primary fractures through the rock mass, while secondary micro-fractures will also be generated. The numerical simulation results show that when the rock is subjected to tensile-shear failure, with the increase of load, tensile micro-fractures are mainly produced in the specimen, accompanied by a few shear fractures. Under the joint action of shear failure and tensile failure, V-shaped cracks are easily formed in rock. The tensile strength of rock is mainly affected by the microscopic tensile strength, and the cohesive force, modulus, stiffness ratio, friction coefficient and friction angle have significant effects on the compressive strength of rock. Therefore, a reasonable choice of microscopic parameters can realistically simulate the compression-tensile strength ratio of the rock. The research results of this paper can provide the theoretical basis of rock mechanics for the efficient exploitation of tight reservoirs.
Geography, climate and shifts in host plants distribution explain the genomic variation in the cactus moth
Authors: Poveda-Martínez Daniel , Noguerales Víctor , Hight Stephen D. , Logarzo Guillermo , Emerson Brent C. , Varone Laura , Hasson Esteban
Published: September 2023

Landscape heterogeneity and the host plant use are factors suggested to play determinant roles in shaping the evolutionary history of herbivorous insects. However, the role of the reconfiguration of host plants distributions linked to Quaternary climate oscillations as drivers of contemporary population genetic structure is still poorly understood. Here, we formally examine the relative contribution of such factors on intraspecific diversification using the South American cactus moth, Cactoblastis cactorum, an herbivore insect specialized in the use of cacti as host plants. We assessed genomic variation using genome-wide SNPs and mitochondrial data in populations sampled across a broad geographical gradient where moths feed on different cactus species. We integrated demographic simulations and ecological niche modeling into a landscape genomics framework, to test alternative hypotheses of past and current population connectivity for both C. cactorum and its host plants. Regions exhibiting higher genomic diversity were evaluated for congruence with areas where suitable climatic conditions remained stable through time. Our results revealed that past spatial configuration of suitable habitat conditions and shifts of host plants distributions are the factors that better explain the intraspecific diversification. Genomic data also supported the hypothesis that areas of long-term habitat stability served as refugia for C. cactorum, enabling the maintenance of high levels of genetic diversity over time. Overall, our study highlights the importance of integrating inter-specific interactions and their spatio-temporal dynamics to better understand the relative importance of abiotic and biotic factors driving the diversification processes in herbivorous insects with broad geographical and restricted host ranges.
Causal association between common rheumatic diseases and glaucoma: a Mendelian randomization study
Authors: Meng Yang , Tan Zongbiao , Su Yu , Li Lu , Chen Changzheng
Published: September 2023

Background

Autoimmunity and inflammation are the main characteristics of rheumatic diseases and have both been found to be related to glaucoma. However, it remains unclear whether rheumatic diseases increase the risk of glaucoma. Here, we performed a Mendelian randomization (MR) analysis to investigate the causal effects of six common rheumatic diseases on glaucoma.

Methods

Six rheumatic diseases were included: ankylosing spondylitis (AS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sicca syndrome/Sjögren’s sydrome (SS), dermatomyositis (DM), and gout. Glaucoma included primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG). Genetic variants associated with these rheumatic diseases and glaucoma were extracted from the genome-wide association studies and FinnGen8 database, respectively. First, a two-sample MR was used to investigate the potential causal association. Then, a multivariable MR was conducted to further verify the results. Inverse-variance weighted MR analysis was used as the main method, together with several sensitivity analyses.

Results

Two-sample MR suggests that AS is related to a higher risk of both POAG [odds ratio (OR): 1.28, 95% confidence interval (CI) 1.13–1.44; p = 1.1 × 10−4] and PACG (OR: 1.55, 95% CI: 1.09–2.09, p = 1.4 × 10−2). Multivariable MR shows a similar trend of the effect of AS on POAG (OR: 1.52, 95% CI: 1.22–1.90, p = 1.9 × 10−4) and PACG (OR: 2.05, 95% CI: 1.06–3.95, p = 3.2 × 10−2). No significant association was observed between the other five rheumatic diseases and glaucoma.

Conclusions

AS is related to an increased risk of POAG and PACG. We stress the importance of glaucoma screening for AS patients.
Optimization of universal allogeneic CAR-T cells combining CRISPR and transposon-based technologies for treatment of acute myeloid leukemia
Authors: Calviño Cristina , Ceballos Candela , Alfonso Ana , Jauregui Patricia , Calleja-Cervantes Maria E. , San Martin-Uriz Patxi , Rodriguez-Marquez Paula , Martin-Mallo Angel , Iglesias Elena , Abizanda Gloria , Rodriguez-Diaz Saray , Martinez-Turrillas Rebeca , Illarramendi Jorge , Viguria Maria C. , Redondo Margarita , Rifon Jose , Villar Sara , Lasarte Juan J. , Inoges Susana , Lopez-Diaz de Cerio Ascension , Hernaez Mikel , Prosper Felipe , Rodriguez-Madoz Juan R.
Published: September 2023

Despite the potential of CAR-T therapies for hematological malignancies, their efficacy in patients with relapse and refractory Acute Myeloid Leukemia has been limited. The aim of our study has been to develop and manufacture a CAR-T cell product that addresses some of the current limitations. We initially compared the phenotype of T cells from AML patients and healthy young and elderly controls. This analysis showed that T cells from AML patients displayed a predominantly effector phenotype, with increased expression of activation (CD69 and HLA-DR) and exhaustion markers (PD1 and LAG3), in contrast to the enriched memory phenotype observed in healthy donors. This differentiated and more exhausted phenotype was also observed, and corroborated by transcriptomic analyses, in CAR-T cells from AML patients engineered with an optimized CAR construct targeting CD33, resulting in a decreased in vivo antitumoral efficacy evaluated in xenograft AML models. To overcome some of these limitations we have combined CRISPR-based genome editing technologies with virus-free gene-transfer strategies using Sleeping Beauty transposons, to generate CAR-T cells depleted of HLA-I and TCR complexes (HLA-IKO/TCRKO CAR-T cells) for allogeneic approaches. Our optimized protocol allows one-step generation of edited CAR-T cells that show a similar phenotypic profile to non-edited CAR-T cells, with equivalent in vitro and in vivo antitumoral efficacy. Moreover, genomic analysis of edited CAR-T cells revealed a safe integration profile of the vector, with no preferences for specific genomic regions, with highly specific editing of the HLA-I and TCR, without significant off-target sites. Finally, the production of edited CAR-T cells at a larger scale allowed the generation and selection of enough HLA-IKO/TCRKO CAR-T cells that would be compatible with clinical applications. In summary, our results demonstrate that CAR-T cells from AML patients, although functional, present phenotypic and functional features that could compromise their antitumoral efficacy, compared to CAR-T cells from healthy donors. The combination of CRISPR technologies with transposon-based delivery strategies allows the generation of HLA-IKO/TCRKO CAR-T cells, compatible with allogeneic approaches, that would represent a promising option for AML treatment.
Extreme marine heatwaves and cold-spells events in the Southern North Sea: classifications, patterns, and trends
Authors: Mohamed Bayoumy , Barth Alexander , Alvera-Azcárate Aida
Published: September 2023

In this study, we examined the long-term spatiotemporal trend of marine heatwaves (MHW) and marine cold spells (MCS) characteristics in the southern North Sea over the last four decades (1982-2021). We then estimated the difference between their annual mean values and the possible relationship with the large-scale climate modes of natural sea surface temperature (SST) and atmospheric variability using satellite SST data. The SST warming rate was 0.33 ± 0.06°C/decade and was associated with an increase in MHW frequency (0.85 ± 0.39 events/decade) and a decrease in MCS frequency (-0.92 ± 0.40 events/decade) over the entire period. We found a distinct difference between the annual mean values of MHW and MCS characteristics, with a rapid increase in total MHW days (14.36 ± 8.16 days/decade), whereas MCS showed an opposite trend (-16.54 ± 9.06 days/decade). The highest MHW frequency was observed in the last two decades, especially in 2014 (8 events), 2020 (5 events), and 2007 (4 events), which were also the warmest years during the study period. Only two years (2010 and 2013) in the last two decades had higher MCS frequency, which was attributed to the strong negative phase of the North Atlantic Oscillation (NAO). Our results also show that on the annual scale, both the East Atlantic Pattern (EAP) and the Atlantic Multidecadal Oscillation (AMO) play a more important role in the formation of the MHW in the southern North Sea than the other teleconnections (e.g., the NAO). However, the NAO made the largest contribution only in the winter. Strong significant (p < 0.05) positive/negative correlations were found between oceanic and atmospheric temperatures and the frequency of MHW/MCS. This suggests that with global warming, we can expect an increase/decrease in MHW/MCS occurrences in the future.
Crack propagation and strain-induced α’-martensite transformation in selective laser melting 316L stainless steels
Authors: Tan Zhiheng , Gui Maolei , Zhou Zhiping , Lv Jinlong , Zhang Shuye , Wang Zhuqing
Published: September 2023

At present, in-situ monitoring of metal cracking and propagation is still a challenge. In this work, we used in-situ tensile tests with precast cracks of selective laser melting (SLM) and conventionally manufactured (CM) 316L stainless steels (SSs) to study crack propagation and strain-induced α′-martensite transformation. During in-situ tensile, cracks initiate at the concentration of slip lines at the precast crack, and the strong stress at the crack tip will tear apart the grain boundaries causing the crack to propagate until the samples are completely fractured. After in-situ tensile, abnormal grain growth was observed in the plastic zone at the crack tip of the SLMed 316L SS sample, while austenite to α′-martensite transformation was appeared at the grain boundaries of the SLMed 316L SS sample, and martensitic patches generated by severe plastic deformation induced in the CM 316L SS were also observed. The SLMed 316L SS shows higher strength and resistance to deformation than CM 316L SS. In addition, the stress concentration at the crack tip in crack propagation has a significant effect on the transformation of strain-induced α′-martensite.
Ball-milling of titanium dioxide and zinc oxide for enhanced UV protection
Authors: Yang Panpan , Wang Hongxia , Chen Yuyan , Li Yanan , Zhang Jun , Zhang Chunxiao , Lin Bao , Wei Xiaolan
Published: September 2023

Among various sunscreen materials, zinc oxide and titanium dioxide are excellent physical sunscreen components; however, these two materials tend to aggregate and form micrometer-sized particles that may impact their performance. This study utilizes fine grinding techniques to break up the aggregated oxide particles into small nanoparticles with a narrow size distribution averaging around 200 nm in diameter. The ground zinc oxide and titanium dioxide particles exhibit enhanced ability in absorbing and scattering ultraviolet radiation compared to their original state before grinding. Consequently, this research offers innovative concepts as well as approaches towards developing highly efficient yet low-toxic physical sunscreen components while significantly contributing to the preparation process optimization for mixed material performance.
Sleep and critical illness: a review
Authors: Eschbach Erin , Wang Jing
Published: September 2023

Critical illness and stays in the Intensive Care Unit (ICU) have significant impact on sleep. Poor sleep is common in this setting, can persist beyond acute critical illness, and is associated with increased morbidity and mortality. In the past 5 years, intensive care clinical practice guidelines have directed more focus on sleep and circadian disruption, spurring new initiatives to study and improve sleep complications in the critically ill. The global SARS-COV-2 (COVID-19) pandemic and dramatic spikes in patients requiring ICU level care also brought augmented levels of sleep disruption, the understanding of which continues to evolve. This review aims to summarize existing literature on sleep and critical illness and briefly discuss future directions in the field.
Ochronotic arthropathy effectively treated with total hip and total knee arthroplasty: a case report
Authors: Liu Yikai , Li Chenkai , Zhang Zian , Lu Xinzhe , Zhang Haining
Published: September 2023

Ochronosis is a rare autosomal recessive disorder of tyrosine metabolism characterized by multilevel spinal degeneration and arthritis of large weight-bearing joints, which is referred to as ochronotic arthropathy. In this case report, we describe diagnosis and treatment of ochronotic arthropathy in a patient who underwent total hip arthroplasty (THA) and total knee arthroplasty (TKA). The Harris hip score was 26 preoperatively and 45, 68, 76, 90, 92, and 94 at 1, 3, 6, 9, 11, and 14 months, respectively, postoperatively. The forgotten joint score (FJS) of the hip was 27.8, 52.8, 81.1, 89.0, 90.6, and 92.4 at 1, 3, 6, 9, 11, and 14 months, respectively, postoperatively. TKA was performed 8 months after THA. The Knee Society Score was 36 before TKA and 74, 82, and 90 at 1, 3, and 6 months, respectively, after TKA. The FJS of the knee was 36.6, 63.9, and 84.5 at 1, 3, and 6 months, respectively, after TKA. The patient’s knee range of motion returned to normal, with significant reduction in pain and improved satisfaction levels after TKA. THA and TKA can achieve good clinical outcomes in patients with ochronosis accompanied by severe joint pain.
Current management and future challenges in salivary glands cancer
Authors: Locati Laura D. , Ferrarotto Renata , Licitra Lisa , Benazzo Marco , Preda Lorenzo , Farina Davide , Gatta Gemma , Lombardi Davide , Nicolai Piero , Vander Poorten Vincent , Chua Melvin Lee Kiang , Vischioni Barbara , Sanguineti Giuseppe , Morbini Patrizia , Fonseca Isabel , Sozzi Davide , Merlotti Anna , Orlandi Ester
Published: September 2023

Salivary gland cancers (SGCs) are rare, accounting for less than 5% of all malignancies of the head and neck region, and are morphologically heterogeneous. The diagnosis is mainly based on histology, with the complementary aid of molecular profiling, which is helpful in recognizing some poorly differentiated, borderline, or atypical lesions. Instrumental imaging defines the diagnosis, representing a remarkable tool in the treatment plan. Ultrasound and magnetic resonance are the most common procedures used to describe the primary tumour. The treatment of SGCs is multimodal and consists of surgery, radiotherapy, and systemic therapy; each treatment plan is, however, featured on the patient and disease’s characteristics. On 24 June 2022, in the meeting “Current management and future challenges in salivary gland cancers” many experts in this field discussed the state of the art of SGCs research, the future challenges and developments. After the meeting, the same pool of experts maintained close contact to keep these data further updated in the conference proceedings presented here. This review collects the insights and suggestions that emerged from the discussion during and after the meeting per se.
Insight of novel biomarkers for papillary thyroid carcinoma through multiomics
Authors: Liu Wei , Zhu Junkan , Wu Zhen , Yin Yongxiang , Wu Qiao , Wu Yiming , Zheng Jiaojiao , Wang Cong , Chen Hongyan , Qazi Talal Jamil , Wu Jun , Zhang Yuqing , Liu Houbao , Yang Jingmin , Lu Daru , Zhang Xumin , Ai Zhilong
Published: September 2023

Introduction

The overdiagnosing of papillary thyroid carcinoma (PTC) in China necessitates the development of an evidence-based diagnosis and prognosis strategy in line with precision medicine. A landscape of PTC in Chinese cohorts is needed to provide comprehensiveness.

Methods

6 paired PTC samples were employed for whole-exome sequencing, RNA sequencing, and data-dependent acquisition mass spectrum analysis. Weighted gene co-expression network analysis and protein-protein interactions networks were used to screen for hub genes. Moreover, we verified the hub genes' diagnostic and prognostic potential using online databases. Logistic regression was employed to construct a diagnostic model, and we evaluated its efficacy and specificity based on TCGA-THCA and GEO datasets.

Results

The basic multiomics landscape of PTC among local patients were drawn. The similarities and differences were compared between the Chinese cohort and TCGA-THCA cohorts, including the identification of PNPLA5 as a driver gene in addition to BRAF mutation. Besides, we found 572 differentially expressed genes and 79 differentially expressed proteins. Through integrative analysis, we identified 17 hub genes for prognosis and diagnosis of PTC. Four of these genes, ABR, AHNAK2, GPX1, and TPO, were used to construct a diagnostic model with high accuracy, explicitly targeting PTC (AUC=0.969/0.959 in training/test sets).

Discussion

Multiomics analysis of the Chinese cohort demonstrated significant distinctions compared to TCGA-THCA cohorts, highlighting the unique genetic characteristics of Chinese individuals with PTC. The novel biomarkers, holding potential for diagnosis and prognosis of PTC, were identified. Furthermore, these biomarkers provide a valuable tool for precise medicine, especially for immunotherapeutic or nanomedicine based cancer therapy.
Prophylactic intravenous norepinephrine for the prevention of hypotension during spinal anesthesia for elective cesarean section: a systematic review and dose–response meta-analysis of randomized controlled trials
Authors: Li Yuan , Shuai Bingxing , Huang Han
Published: September 2023

Introduction: In this study, we aimed to evaluate the potential dose–response relationship between prophylactic norepinephrine (NE) infusion rates and the risks of hypotension during cesarean section following spinal anesthesia.

Methods: Randomized controlled trials with two or more NE doses for post-spinal hypotension prophylaxis during cesarean section were systematically searched in the MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and US Clinical Trials Registry databases until 31 July 2022. The primary outcome was the relative risk of maternal hypotension with different NE regimens (infusion rates or bolus doses). Secondary outcomes included the relative risks of maternal and fetal adverse events with different NE regimens.

Results: Ten studies with 1,144 parturients were included for final analysis using restricted cubic splines and random-effects dose–response meta-analysis models. A significant dose–response relationship existed between NE infusion rates and the relative risks of maternal hypotension. Every 0.01 μg/kg/min increment in the NE infusion rate was associated with a 14% decrease in the incidence of post-spinal hypotension. ED50 and ED95 of NE infusion rates for post-spinal hypotension prophylaxis were estimated to be 0.046 (95% CI from 0.032 to 0.085) and 0.2 (95% CI from 0.14 to 0.37) μg/kg/min, respectively. However, a higher NE infusion rate was associated with a higher incidence of maternal hypertension.

Conclusion: An increased NE infusion rate was associated with a decreased incidence of post-spinal hypotension but an increased incidence of hypertension. Therefore, 0.07 μg/kg/min was recommended as the initial NE infusion rate for clinical practice, as it was associated with the lowest risk of physician intervention for unstable hemodynamics after spinal anesthesia for cesarean delivery.

Systematic Review Registration: (https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349934), identifier (CRD42022349934).
Comprehensive deep learning-based framework for automatic organs-at-risk segmentation in head-and-neck and pelvis for MR-guided radiation therapy planning
Authors: Czipczer Vanda , Kolozsvári Bernadett , Deák-Karancsi Borbála , Capala Marta E. , Pearson Rachel A. , Borzási Emőke , Együd Zsófia , Gaál Szilvia , Kelemen Gyöngyi , Kószó Renáta , Paczona Viktor , Végváry Zoltán , Karancsi Zsófia , Kékesi Ádám , Czunyi Edina , Irmai Blanka H. , Keresnyei Nóra G. , Nagypál Petra , Czabány Renáta , Gyalai Bence , Tass Bulcsú P. , Cziria Balázs , Cozzini Cristina , Estkowsky Lloyd , Ferenczi Lehel , Frontó András , Maxwell Ross , Megyeri István , Mian Michael , Tan Tao , Wyatt Jonathan , Wiesinger Florian , Hideghéty Katalin , McCallum Hazel , Petit Steven F. , Ruskó László
Published: September 2023

Introduction: The excellent soft-tissue contrast of magnetic resonance imaging (MRI) is appealing for delineation of organs-at-risk (OARs) as it is required for radiation therapy planning (RTP). In the last decade there has been an increasing interest in using deep-learning (DL) techniques to shorten the labor-intensive manual work and increase reproducibility. This paper focuses on the automatic segmentation of 27 head-and-neck and 10 male pelvis OARs with deep-learning methods based on T2-weighted MR images.

Method: The proposed method uses 2D U-Nets for localization and 3D U-Net for segmentation of the various structures. The models were trained using public and private datasets and evaluated on private datasets only.

Results and discussion: Evaluation with ground-truth contours demonstrated that the proposed method can accurately segment the majority of OARs and indicated similar or superior performance to state-of-the-art models. Furthermore, the auto-contours were visually rated by clinicians using Likert score and on average, 81% of them was found clinically acceptable.
Effect of isokinetic muscle strength training on knee muscle strength, proprioception, and balance ability in athletes with anterior cruciate ligament reconstruction: a randomised control trial
Authors: Wang Kun , Cheng Liang , Wang Bingcheng , He Benxiang
Published: September 2023

Objective: This study aimed to investigate the effects of regular isokinetic muscle strength training on knee muscle strength, proprioception, and balance ability in athletes after anterior cruciate ligament (ACL) reconstruction.

Methods: Forty-one athletes who underwent ACL reconstruction were randomly divided into the experimental (n = 21) and control (n = 20) groups. The experimental group used an isokinetic muscle strength tester for 4 weeks (five times/ week) of knee flexion and extension isokinetic muscle strength training. The control group used the knee joint trainer (pneumatic resistance) for the same exercise regimen as the experimental group.

Results: 1) Four weeks when compared with the baseline. Experimental group: the knee flexion and extension PT (60°/s and 240°/s) increased by 31.7%, 40.3%, 23.4%, and 42.9% (p < 0.01), and the flexion muscular endurance increased by 21.4% and 19.7% (p < 0.01). The flexion and extension kinaesthesia and the 30° and 60° position sense decreased by 36.2%, 32.3%, 40.0%, and 18.9% (p < 0.05). The anterior–posterior and medial–lateral displacement and speed decreased by 30.2%, 44.2%, 38.4%, and 24.0% (p < 0.05). Control group: the knee peak torque (60°/s) increased by 18.8% (p < 0.01). The anterior–posterior and medial–lateral displacement and speed decreased by 14.9%, 40.0%, 26.8%, and 19.5% (p < 0.01). 2) After 4 weeks, compared with the control group, the knee flexion and extension peak torque (60°/s), extension, peak torque (240°/s), and extension muscular endurance of the treatment group increased to varying degrees (p < 0.05). However, the kinaesthesia, 30° position sense, and anterior–posterior displacement decreased to varying degrees (p < 0.05).

Conclusion: Adding regular isokinetic muscle strength training to rehabilitation training further improved the knee flexion and extensor strength and extensor endurance of athletes with ACL reconstruction, as well as enhanced the kinaesthesia and 30° position sense and the balance between the anterior and posterior directions. However, the treatment had limited effects on knee flexion kinaesthesia and muscle endurance.
Inferior plant competitor allocates more biomass to belowground as a result of greater competition for resources in heterogeneous habitats
Authors: Zhou Jian , Ma Ziwen , Jia Yuehui , Liu Jie , Yang Yuping , Li Wei , Cui Lijuan
Published: September 2023

Nutrient heterogeneity in soil widely exists in nature and can have significant impacts on plant growth, biomass allocation, and competitive interactions. However, limited research has been done to investigate the interspecific competitive intensity between two clonal species in a heterogeneous habitat. Therefore, this greenhouse experiment was conducted with two clonal species, Phragmites australis and Scirpus planiculumis, exposed to heterogeneous and homogeneous patches of soil nutrients at five different planting ratios (0:4, 1:3, 2:2, 3:1 and 4:0), to assess the effects of both soil heterogeneity and interspecific competition on plant growth. It was found that soil nutrient heterogeneity significantly enhanced P. australis’ interspecific competitive capacity and biomass by promoting a 20% increase in belowground allocation. Interestingly, the planting ratio did not affect the magnitude of this net outcome. In contrast, the superior competitor S. planiculumis did not exhibit significant change of growth indicators to the heterogeneous soil patches. These findings imply that the uncertainties associated with human-induced redistribution of plant species may lead to a shift in dominance from other species to those like P. australis, which have strong nutrient foraging abilities in response to heterogeneity in emergent wetland plant communities.