bluuebunny/crossref_metadata_2025 huggingface dataset:
General practitioner residents’ experiences and perceptions of outpatient training in primary care settings in China: a qualitative study
Authors: Wu Lingyan , Tong Yuling , Yu Yingying , Yu Xinyan , Zhou Yening , Xu Meiqun , Guo Yi , Song Zhenya , Xu Zhijie
Published: September 2023

Objectives

The implementation of outpatient training in primary care settings is an essential part of residency training for general practitioner (GP) residents. However, limited research exists on their experiences and perceptions of this training. This study aimed to explore the experiences and perceptions of GP residents regarding outpatient training in primary care settings in China and provide insights and recommendations to enhance training quality.

Design

A qualitative descriptive study employing in-depth interviews.

Setting

Two community healthcare centres (CHCs) that implement outpatient training programmes for GP residents in Zhejiang Province, China.

Participants

In total, 20 GP residents affiliated with 14 CHCs and two hospitals across Zhejiang Province and Guizhou Province who had completed outpatient training in either CHC for over 1 month.

Results

Of the 20 participants in this study, 11 (55%) were women, and the mean age was 28 years. GP residents completed the process of consultation, physical examination and therapy independently; subsequently, the community preceptors provided feedback based on their clinical performance and modelled their clinical skills. The benefits perceived by GP residents included improved clinical skills and confidence in practice, and they learned approaches to maintaining good relationships with patients. They preferred dealing with complex cases, discussions with peers and the indirect supervision of community preceptors in the training session. Residents recommended that measures be taken to improve the training quality regarding patient selection and recruitment, clinical skills in the training session, and assessment of clinical performance.

Conclusions

The outpatient training in primary care settings provides constructive opportunities for GP residents to improve their professional competencies. Although the current training sessions and the abilities of community preceptors largely satisfy the needs of GP residents, further research is needed to evaluate the effectiveness of training and explore approaches to improve its quality.
Antenatal and early childhood exposures associated with non-fatal infant injury: evidence from a longitudinal birth cohort in New Zealand
Authors: Ghebreab Luam , Kool Bridget , Lee Arier , Morton Susan
Published: September 2023

Objective

To identify antenatal and early childhood exposures of unintentional injury among infants in New Zealand (NZ).

Method

The theoretical life-course framework of child injury prevention domains was utilised to analyse data from a prospective longitudinal NZ birth cohort (Growing Up in NZ). Risk and protective factors for injury were identified using Robust Poisson regression models.

Result

Among children included for the analysis(n=6304), 52% were male, 55% were born to European mothers, and 37% lived in a household with high levels of deprivation. Mothers reported that 6% of infants (n=406) had sustained at least one injury by 9 months. Multivariate analysis showed injury risk among single mothers with antenatal depression were more than twice that (IRR=2.20) of children of mothers with partners and without depression.

Conclusion

Understanding antenatal risk and protective factors for infant injury will assist in implementing injury prevention programmes or modifying the existing policies that affect these vulnerable age groups.
High glycemia and resistin normalized in children with double burden of malnutrition: a cross-sectional study
Authors: Pereira Joicy Karla Grangeiro , de Moraes Rúbia Cartaxo Squizato , Sawaya Ana Lydia , Alves José Luiz de Brito , Filgueiras Andrea Rocha , Franco Maria do Carmo Pinho , Martins Vinicius José Baccin
Published: September 2023

The coexistence of stunting and excess weight in the same individual is defined as a double burden of malnutrition (DBM) and is associated with noncommunicable diseases. In this study, we evaluated the impact of DBM on adipokine concentrations and metabolic profiles in children compared with weight excess alone. Children were allocated to the weight excess group ( n = 23) (height-for-age (HAZ) > 0.0 and < 2.0 Z-score and body mass index-for-age (BMI/A) > 1.0 Z-score) or DBM ( n = 22) group (HAZ < −1.0 Z-score (including mild stunting) and BMI/A > 1.0 Z-score). Lipid, glycemic profile, resistin, plasminogen activator inhibitor-1, leptin, and adiponectin concentrations were analyzed. Glycemia was significantly higher in the DBM group compared to the weight excess group (5.05 (4.76–5.31) mmol/L vs. 4.57 (4.35–4.81) mmol/L), although no differences were found in insulin and homeostasis model assessment of insulin resistance (HOMA-IR). Adipokine concentrations did not differ between the groups. However, the DBM group showed higher resistin concentrations normalized by body fat mass than those of the weight excess group (1.44 (0.98–1.93) ng/mL vs. 0.76 (0.55–1.45) ng/mL). Insulin and HOMA-IR showed a negative correlation with adiponectin ( r = −0.590 and −0.624, respectively, both p < 0.01). DBM was associated with increased glucose and resistin concentrations adjusted by fat mass compared to that associated with excess weight alone. Therefore, this association between mild stunting and weight excess has deleterious potential for long-term metabolic function, highlighting an additional precaution against weight gain in children, especially in those with stunting.
PARALiA: A Performance Aware Runtime for Auto-tuning Linear Algebra on Heterogeneous Systems
Authors: Anastasiadis Petros , Papadopoulou Nikela , Goumas Georgios , Koziris Nectarios , Hoppe Dennis , Zhong Li
Published: September 2023

Dense linear algebra operations appear very frequently in high-performance computing (HPC) applications, rendering their performance crucial to achieve optimal scalability. As many modern HPC clusters contain multi-GPU nodes, BLAS operations are frequently offloaded on GPUs, necessitating the use of optimized libraries to ensure good performance. Unfortunately, multi-GPU systems are accompanied by two significant optimization challenges: data transfer bottlenecks as well as problem splitting and scheduling in multiple workers (GPUs) with distinct memories. We demonstrate that the current multi-GPU BLAS methods for tackling these challenges target very specific problem and data characteristics, resulting in serious performance degradation for any slightly deviating workload. Additionally, an even more critical decision is omitted because it cannot be addressed using current scheduler-based approaches: the determination of which devices should be used for a certain routine invocation. To address these issues we propose a model-based approach: using performance estimation to provide problem-specific autotuning during runtime. We integrate this autotuning into an end-to-end BLAS framework named PARALiA. This framework couples autotuning with an optimized task scheduler, leading to near-optimal data distribution and performance-aware resource utilization. We evaluate PARALiA in an HPC testbed with 8 NVIDIA-V100 GPUs, improving the average performance of GEMM by 1.7× and energy efficiency by 2.5× over the state-of-the-art in a large and diverse dataset and demonstrating the adaptability of our performance-aware approach to future heterogeneous systems.
Flows Over Rotating Disks and Cones
Authors: Alfredsson P. Henrik , Kato Kentaro , Lingwood R.J.
Published: September 2023

Rotating-disk flows were first considered by von Kármán in a seminal paper in 1921, where boundary layers in general were discussed and, in two of the nine sections, results for the laminar and turbulent boundary layers over a rotating disk were presented. It was not until in 1955 that flow visualization discovered the existence of stationary cross-flow vortices on the disk prior to the transition to turbulence. The rotating disk can be seen as a special case of rotating cones, and recent research has shown that broad cones behave similarly to disks, whereas sharp cones are susceptible to a different type of instability. Here, we provide a review of the major developments since von Kármán's work from 100 years ago, regarding instability, transition, and turbulence in the boundary layers, and we include some analysis not previously published.
Can't Believe It Went By So Fast
Authors: Kamp Hans
Published: September 2023

This autobiographical sketch starts with my arrival as a PhD student at UCLA in 1965. It focuses on the most prominent line of my intellectual development, from work in Priorean tense logic for my dissertation and essays intended to fit within the framework of Montague Grammar to the discourse-oriented framework of Discourse Representation Theory (DRT) and eventually to the unequivocally cognitive approach of Mental State Discourse Representation Theory (MSDRT), which is the core of my present view and work.
Structural Insights into Type III Secretion Systems of the Bacterial Flagellum and Injectisome
Authors: Worrall Liam J. , Majewski Dorothy D. , Strynadka Natalie C.J.
Published: September 2023

Two of the most fascinating bacterial nanomachines—the broadly disseminated rotary flagellum at the heart of cellular motility and the eukaryotic cell–puncturing injectisome essential to specific pathogenic species—utilize at their core a conserved export machinery called the type III secretion system (T3SS). The T3SS not only secretes the components that self-assemble into their extracellular appendages but also, in the case of the injectisome, subsequently directly translocates modulating effector proteins from the bacterial cell into the infected host. The injectisome is thought to have evolved from the flagellum as a minimal secretory system lacking motility, with the subsequent acquisition of additional components tailored to its specialized role in manipulating eukaryotic hosts for pathogenic advantage. Both nanomachines have long been the focus of intense interest, but advances in structural and functional understanding have taken a significant step forward since 2015, facilitated by the revolutionary advances in cryo-electron microscopy technologies. With several seminal structures of each nanomachine now captured, we review here the molecular similarities and differences that underlie their diverse functions.
License to Clump: Secretory IgA Structure–Function Relationships Across Scales
Authors: Hockenberry Alyson , Slack Emma , Stadtmueller Beth M.
Published: September 2023

Secretory antibodies are the only component of our adaptive immune system capable of attacking mucosal pathogens topologically outside of our bodies. All secretory antibody classes are ( a) relatively resistant to harsh proteolytic environments and ( b) polymeric. Recent elucidation of the structure of secretory IgA (SIgA) has begun to shed light on SIgA functions at the nanoscale. We can now begin to unravel the structure–function relationships of these molecules, for example, by understanding how the bent conformation of SIgA enables robust cross-linking between adjacent growing bacteria. Many mysteries remain, such as the structural basis of protease resistance and the role of noncanonical bacteria–IgA interactions. In this review, we explore the structure–function relationships of IgA from the nano- to the metascale, with a strong focus on how the seemingly banal “license to clump” can have potent effects on bacterial physiology and colonization.
Tissue-specific mitochondrial toxicity of cigarette smoke concentrate: consequence to oxidative phosphorylation
Authors: Decker Stephen T. , Matias Alexs A. , Cuadra Adolfo E. , Bannon Sean T. , Madden Jack P. , Erol M. Enes , Serviente Corinna , Fenelon Karine , Layec Gwenael
Published: September 2023

Despite numerous investigations into the mechanisms underlying cigarette smoke-induced mitochondrial dysfunction, no studies have investigated the tissue-specific mitochondrial toxicity to cigarette smoke. We demonstrate that, while aorta is least sensitive and susceptible to cigarette smoke-induced toxicity, the degree of cigarette smoke-induced toxicity in striated muscle depends on the tissue-specific mitochondrial content. We conclude that while the mitochondrial content influences cigarette smoke-induced toxicity in striated muscles, aorta is intrinsically protected against cigarette smoke-induced mitochondrial toxicity.
Isolated cardiac muscle contracting against a real-time model of systemic and pulmonary cardiovascular loads
Authors: Garrett Amy S. , Dowrick Jarrah , Taberner Andrew J. , Han June-Chiew
Published: September 2023

We present the use of a “closed-loop” model of systemic and pulmonary circulations to apply, for the first time, real-time model-calculated preload and afterload to isolated cardiac muscle preparations. This method extends current experimental protocols where only afterload has been considered. The extension to include preload provides the opportunity to investigate ventricular muscle response to hemodynamic coupling and as a pump source across a wider range of cardiovascular loads.
Tissue transglutaminase: a multifunctional and multisite regulator in health and disease
Authors: Yao Zhouzhou , Fan Yuhua , Lin Lizhen , Kellems Rodney E. , Xia Yang
Published: September 2023

Tissue transglutaminase (TG2) is a widely distributed multifunctional protein involved in a broad range of cellular and metabolic functions carried out in a variety of cellular compartments. In addition to transamidation, TG2 also functions as a Gα signaling protein, a protein disulfide isomerase (PDI), a protein kinase, and a scaffolding protein. In the nucleus, TG2 modifies histones and transcription factors. The PDI function catalyzes the trimerization and activation of heat shock factor-1 in the nucleus and regulates the oxidation state of several mitochondrial complexes. Cytosolic TG2 modifies proteins by the addition of serotonin or other primary amines and in this way affects cell signaling. Modification of protein-bound glutamines reduces ubiquitin-dependent proteasomal degradation. At the cell membrane, TG2 is associated with G protein-coupled receptors (GPCRs), where it functions in transmembrane signaling. TG2 is also found in the extracellular space, where it functions in protein cross-linking and extracellular matrix stabilization. Of particular importance in transglutaminase research are recent findings concerning the role of TG2 in gene expression, protein homeostasis, cell signaling, autoimmunity, inflammation, and hypoxia. Thus, TG2 performs a multitude of functions in multiple cellular compartments, making it one of the most versatile cellular proteins. Additional evidence links TG2 with multiple human diseases including preeclampsia, hypertension, cardiovascular disease, organ fibrosis, cancer, neurodegenerative diseases, and celiac disease. In conclusion, TG2 provides a multifunctional and multisite response to physiological stress.
Application of an Endodontic Static Guide in Fiber Post Removal from a Compromised Tooth
Authors: Farajollahi Mehran , Dianat Omid , Gholami Samaneh , Saber Tahan Shima
Published: September 2023

Removing a fiber post from a root canal that requires endodontic retreatment is often very challenging. Conventional freehand techniques for removing fiber posts are time-consuming, sometimes result in iatrogenic errors, and heavily rely on the practitioner’s experience. The endodontic static guide can be an alternative method. While the use of an endodontic 3D-printed static guide for fiber post removal has been reported as highly successful, it can also cause complications. Skipping any critical steps during the guide construction or its clinical application can lead to errors. This case report presents the saving of a compromised tooth with a fractured fiber post and a periapical lesion around the apex through the use of an endodontic static guide for fiber post removal. This study describes possible sources of error that may happen during construction and clinical use of the guide.
In Vitro Investigation of the Anticancer Activity of Peucedanum praeruptorum Dunn Extract on HepG2 Human Hepatoma Cells
Authors: Hu Shiwen , Wang Pan , Chen Yongchun , Kuang Gang , Wang Cun , Luo Jing , Chen Shaocheng
Published: September 2023

The anticancer activity of Peucedanum praeruptorum Dunn extract (PPDE) was investigated in vitro in the HepG2 human hepatoma cell line and compared to normal human liver cells (L02 cells). The effect of the PPDE on the proliferation of the cells was measured by MTT assays, and the levels of enzymes and small molecules implicated in oxidative stress regulation were measured using specific reagent kits. The expression levels of genes implicated in apoptosis (Bax, Bcl-2, caspase-3, caspase-8, and caspase-9) and oxidative stress (SOD1 and SOD2) were quantified by RT-qPCR. Lastly, HPLC was employed to analyze the composition of the PPDE. PPDE was found to significantly inhibit the proliferation of HepG2 cells but had little effect on the proliferation of normal liver cells. PPDE increased the levels of reactive oxygen species and malonaldehyde, a lipid peroxidation product, in HepG2 cells, and it reduced the activities of antioxidant enzymes, as well as the levels of γ-GCS and reduced glutathione (GSH), suggesting that it inhibited the ability of cancer cells to regulate intracellular oxidative stress. PPDE also increased the expression of the genes encoding Bax, caspase-3, caspase-8, and caspase-9 and decreased the expression of Bcl-2, SOD1, and SOD2 in HepG2 cells, suggesting that PPDE induced the apoptosis of the liver cancer cells. HPLC analysis identified that the components of PPDE included caffeic acid, isochlorogenic acid C, myricetin, baicalin, luteolin, and kaempferol, all of which have demonstrated antioxidant properties.
Experimental Study on Dust Removal Performance of Electrostatic Water Film Cyclone Dust Collector
Authors: Zhang Di , Chen Zuyun , Zhong Fangquan , Zhou Ziyi
Published: September 2023

Due to their limitations, conventional electric and water film dust removal methods struggle to handle fine dust. This study presented information on and examined the electrostatic water film cyclone dust collector (EWFCDC). By using the variable control approach, the impacts of inlet flow speed, water film flow rate, and corona pole form on dust removal performance were investigated. At EWFCDC, an orthogonal test was carried out to improve the test design and operating parameters based on the single-factor experiment. The pressure loss in the cyclone cylinder, when there is no water film and no corona pole, is a quadratic function of the inlet flow speed, and it is 2418.10 Pa at a 21.25 m/s inlet flow speed. The effectiveness of dust removal may be increased by increasing the water film flow rate. The effectiveness of dust removal is greatly influenced by the type of corona pole used, and cage needling thread is the optimal type. The electrostatic water film cyclone’s multimechanism coupling significantly increases the effectiveness of dust removal.
Data from Oncogenic ASPM is a regulatory hub of developmental and stemness signaling in cancers
Authors: Tsai Kelvin K. , Bae Byoung-Il , Hsu Chung-Chi , Cheng Li-Hsin , Shaked Yuval
Published: September 2023

Abstract
Despite recent advances in molecularly targeted therapies and immunotherapies, the effective treatment of advanced-stage cancers remains a largely unmet clinical need. Identifying driver mechanisms of cancer aggressiveness can lay the groundwork for the development of breakthrough therapeutic strategies. Assembly factor for spindle microtubules (ASPM) was initially identified as a centrosomal protein that regulates neurogenesis and brain size. Mounting evidence has demonstrated the pleiotropic roles of ASPM in mitosis, cell cycle progression, and DNA double-strand breaks (DSB) repair. Recently, the exon-18-preserved isoform 1 of ASPM has emerged as a critical regulator of cancer stemness and aggressiveness in various malignant tumor types. Here, we describe the domain compositions of ASPM and its transcript variants and overview their expression patterns and prognostic significance in cancers. A summary is provided of recent progress in the molecular elucidation of ASPM as a regulatory hub of development- and stemness-associated signaling pathways, such as the Wnt, Hedgehog, and Notch pathways, and of DNA DSB repair in cancer cells. The review emphasizes the potential utility of ASPM as a cancer-agnostic and pathway-informed prognostic biomarker and therapeutic target.
Data from Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer
Authors: Marín Arnaldo , Mamun Abdullah Al , Patel Hima , Akamatsu Hiroaki , Ye Dan , Sudhan Dhivya R. , Eli Lisa , Marcelain Katherine , Brown Benjamin P. , Meiler Jens , Arteaga Carlos L. , Hanker Ariella B.
Published: September 2023

Abstract
HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer.
Significance:
HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.
Data from Intratumoral Microbiota Composition Regulates Chemoimmunotherapy Response in Esophageal Squamous Cell Carcinoma
Authors: Wu Hong , Leng Xuefeng , Liu Qianshi , Mao Tianqin , Jiang Tao , Liu Yiqiang , Li Feifei , Cao Chenhui , Fan Jun , Chen Liang , Chen Yaqi , Yao Quan , Lu Shun , Liang Renchuan , Hu Lanlin , Liu Mingxin , Wan Yejian , Li Zhaoshen , Peng Jun , Luo Qiyu , Zhou Hang , Yin Jun , Xu Ke , Lan Mei , Peng Xinhao , Lan Haitao , Li Gang , Han Yongtao , Zhang Xia , Xiao Zhi-Xiong Jim. , Lang Jinyi , Wang Guihua , Xu Chuan
Published: September 2023

Abstract
Neoadjuvant chemoimmunotherapy (NACI) has shown promise in the treatment of resectable esophageal squamous cell carcinoma (ESCC). The microbiomes of patients can impact therapy response, and previous studies have demonstrated that intestinal microbiota influences cancer immunotherapy by activating gut immunity. Here, we investigated the effects of intratumoral microbiota on the response of ESCC patients to NACI. Intra-tumoral microbiota signatures of β-diversity were disparate and predicted the treatment efficiency of NACI. The enrichment of Streptococcus positively correlated with GrzB+ and CD8+ T cell infiltration in tumor tissues. The abundance of Streptococcus could predict prolonged disease-free survival in ESCC. Single-cell RNA sequencing (scRNA-seq) demonstrated that responders displayed a higher proportion of CD8+ effector memory T cells but a lower proportion of CD4+ Treg cells. Mice that underwent fecal microbial transplantation (FMT) or intestinal colonization with Streptococcus from responders showed enrichment of Streptococcus in tumor tissues, elevated tumor-infiltrating CD8+ T cells, and a favorable response to anti-PD-1 treatment. Collectively, this study suggests that intratumoral Streptococcus signatures could predict NACI response and sheds light on the potential clinical utility of intratumoral microbiota for cancer immunotherapy. 
Data from Mutant KRAS Mediates circARFGEF2 Biogenesis to Promote Lymphatic Metastasis of Pancreatic Ductal Adenocarcinoma
Authors: Kong Yao , Luo Yuming , Zheng Shangyou , Yang Jiabin , Zhang Dingwen , Zhao Yue , Zheng Hanhao , An Mingjie , Lin Yan , Ai Le , Diao Xiayao , Lin Qing , Chen Changhao , Chen Rufu
Published: September 2023

Abstract
Circular RNAs (circRNA) contribute to cancer stemness, proliferation, and metastasis. The biogenesis of circRNAs can be impacted by the genetic landscape of tumors. Herein, we identified a novel circRNA, circARFGEF2 (hsa_circ_0060665), which was upregulated in KRASG12D pancreatic ductal adenocarcinoma (PDAC) and positively associated with KRASG12D PDAC lymph node (LN) metastasis. CircARFGEF2 overexpression significantly facilitated KRASG12D PDAC LN metastasis in vitro and in vivo. Mechanistically, circARFGEF2 biogenesis in KRASG12D PDAC was significantly activated by the alternative splicing factor QKI-5, which recruited U2AF35 to facilitate spliceosome assembly. QKI-5 bound the QKI binding motifs and neighboring reverse complement sequence in intron 3 and 6 of ARFGEF2 pre-mRNA to facilitate circARFGEF2 biogenesis. CircARFGEF2 sponged miR-1205 and promoted the activation of JAK2, which phosphorylated STAT3 to trigger KRASG12D PDAC lymphangiogenesis and LN metastasis. Importantly, circARFGEF2 silencing significantly inhibited LN metastasis in the KrasG12D/+Trp53R172H/+Pdx-1-Cre (KPC) mouse PDAC model. These findings provide insight into the mechanism and metastasis-promoting function of mutant KRAS-mediated circRNA biogenesis.
Significance:
Increased splicing-mediated biogenesis of circARFGEF2 in KRAS-mutant pancreatic ductal adenocarcinoma activates JAK2–STAT3 signaling and triggers lymph node metastasis, suggesting circARFGEF2 could be a therapeutic target to inhibit pancreatic cancer progression.
Supplementary Table S1 from Evaluation of Somatic Mutations in Urine Samples as a Noninvasive Method for the Detection and Molecular Classification of Endometrial Cancer
Authors: Costas Laura , Onieva Irene , Pelegrina Beatriz , Marin Fátima , Carmona Álvaro , López-Querol Marta , Frias-Gomez Jon , Peremiquel-Trillas Paula , Martínez José Manuel , Dorca Eduard , Brunet Joan , Pineda Marta , Ponce Jordi , Matias-Guiu Xavier , de Sanjosé Silvia , Bosch Francesc Xavier , Alemany Laia , Paytubi Sonia
Published: September 2023

Descriptive characteristics of participants
Data from Estrogen Therapy Induces Receptor-Dependent DNA Damage Enhanced by PARP Inhibition in ER+ Breast Cancer
Authors: Traphagen Nicole A. , Schwartz Gary N. , Tau Steven , Roberts Alyssa M. , Jiang Amanda , Hosford Sarah R. , Marotti Jonathan D. , Goen Abigail E. , Romo Bianca A. , Johnson Anneka L. , Duffy Emily-Claire K. , Demidenko Eugene , Heverly Paul , Mosesson Yaron , Soucy Shannon M. , Kolling Fred , Miller Todd W.
Published: September 2023

AbstractPurpose:
Clinical evidence indicates that treatment with estrogens elicits anticancer effects in ∼30% of patients with advanced endocrine-resistant estrogen receptor α (ER)-positive breast cancer. Despite the proven efficacy of estrogen therapy, its mechanism of action is unclear and this treatment remains underused. Mechanistic understanding may offer strategies to enhance therapeutic efficacy.
Experimental Design:
We performed genome-wide CRISPR/Cas9 screening and transcriptomic profiling in long-term estrogen-deprived ER+ breast cancer cells to identify pathways required for therapeutic response to the estrogen 17β-estradiol (E2). We validated findings in cell lines, patient-derived xenografts (PDX), and patient samples, and developed a novel combination treatment through testing in cell lines and PDX models.
Results:
Cells treated with E2 exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops). Pharmacologic suppression of the DNA damage response via PARP inhibition with olaparib enhanced E2-induced DNA damage. PARP inhibition synergized with E2 to suppress growth and prevent tumor recurrence in BRCA1/2-mutant and BRCA1/2-wild-type cell line and PDX models.
Conclusions:
E2-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells. Inhibition of the DNA damage response using drugs such as PARP inhibitors can enhance therapeutic response to E2. These findings warrant clinical exploration of the combination of E2 with DNA damage response inhibitors in advanced ER+ breast cancer, and suggest that PARP inhibitors may synergize with therapeutics that exacerbate transcriptional stress.
EGFR Inhibition Overcomes Resistance to FGFR4 Inhibition and Potentiates FGFR4 Inhibitor Therapy in Hepatocellular Carcinoma
Authors: Shen Bin , Shi Jue-Ping , Zhu Zhi-Xuan , He Zhi-Dong , Liu Shen-Yan , Shi Wan , Zhang Yong-Xian , Ying Hai-Yan , Wang Jie , Xu Rui-Feng , Fang Fei , Chang Harrison Xuesong , Chen Zhui , Zhang Nan-Nan
Published: September 2023

Aberrant activation of the FGF19-FGFR4 signaling pathway plays an essential role in the tumorigenesis of hepatocellular carcinoma (HCC). As such, FGFR4 inhibition has emerged as a novel therapeutic option for the treatment of HCC and has shown preliminary efficacy in recent clinical trials for patients exhibiting aberrant FGF19 expression. Resistance to kinase inhibitors is common in oncology, presenting a major challenge in the clinical treatment process. Hence, we investigated the potential mechanisms mediating and causing resistance to FGFR4 inhibition in HCC. Upon the successful establishment of a battery of cellular models developing resistance to FGFR4 inhibitors, we have identified the activation of EGFR, MAPK, and AKT signaling as the primary mechanisms mediating the acquired resistance. Combination of inhibitors against EGFR or its downstream components restored sensitivity to FGFR4 inhibitors. In parental HCC cell lines, EGF treatment also resulted in resistance to FGFR4 inhibitors. This resistance was effectively reverted by inhibitors of the EGFR signaling pathway, suggesting that EGFR activation is a potential cause of intrinsic resistance. We further confirmed the above findings in vivo in mouse xenograft tumor models. Genomic analysis of patient samples from The Cancer Genome Atlas confirmed that a segment of patients with HCC harboring FGF19 overexpression indeed exhibited increased activation of EGFR signaling. These findings conclusively indicate that both induced and innate activation of EGFR could mediate resistance to FGFR4 inhibition, suggesting that dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for the treatment of FGF19-FGFR4 altered HCC.
Hemorrhagic Safety of Magnetic Resonance-Guided Focused Ultrasound Thalamotomy for Tremor without Interruption of Antiplatelet or Anticoagulant Therapy
Authors: Caston Rose M. , Campbell Justin M. , Rahimpour Shervin , Moretti Paolo , Alexander Matthew D. , Rolston John D.
Published: September 2023

Introduction: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is an incision-less ablative technique used to treat medically refractory tremor. Although intracerebral hemorrhage has not been reported with MRgFUS thalamotomy for the treatment of movement disorders, clinicians commonly interrupt active blood thinning medications prior to the procedure or offer gamma knife radiosurgery instead. However, MRgFUS uses focal thermoablation, and bleeding risk is likely minimal. This study aimed to evaluate the safety of MRgFUS thalamotomy in patients with essential tremor (ET) and tremor-dominant Parkinson’s disease (PD) without interrupting anticoagulant or antiplatelet therapies. Methods: This was a single-center retrospective case series of all patients with ET or PD undergoing MRgFUS from February 2019 through December 2022 (n = 96). Demographic variables and medications taken at the time of surgery were obtained. Our primary outcome was the type and frequency of hemorrhagic complications noted on the operative report or postoperative imaging. Results: The mean age of patients was 74.2 years, and 26% were female. Forty patients were taking ≥1 antiplatelet or anticoagulant medications. No patient actively taking anticoagulant or antiplatelet therapies had a hemorrhagic complication during or <48 h after the procedure. Conclusion: The frequency of intra- or postoperative complications from MRgFUS was not higher in patients actively taking anticoagulant or antiplatelet therapies relative to those who were not. Our findings suggest that MRgFUS thalamotomy does not necessitate interrupting anticoagulant or antiplatelet therapies. However, given the limited number of patients actively taking these therapies in our cohort (n = 40), additional testing in large, prospective studies should be conducted to further establish safety.
Método da energia potencial total na análise numérica de estruturas : primeiras noções sobre o método dos elementos finitos
Authors:   Universidade de São Paulo. Escola de Engenharia de São Carlos, Savassi Walter
Published: September 2023

O texto decorre da experiência docente do autor na área da mecânica das estruturas e, particularmente, por várias décadas, na disciplina Método dos Elementos Finitos, na graduação e pós-graduação. É dirigido principalmente aos alunos de graduação para oferecer-lhes um primeiro contato com o emprego do método dos elementos finitos na mecânica das estruturas, seguindo a versão baseada no princípio da energia potencial estacionária. Intencionalmente, os exemplos abordados nos dois primeiros capítulos são simples e, obviamente, passíveis de solução clássica, mediante abordagem via equações diferenciais. São casos unidimensionais. Foram assim escolhidos justamente para dirigir o foco sobre a apresentação das etapas da aplicação do MEPT e para demonstrar potencialidades quanto à possibilidade de se obter respostas numéricas com excelente aproximação, quando comparadas com as respostas analíticas. Dois outros capítulos tratam de elementos estruturais bi e tridimensionais. No caso bidimensional são apresentados os estados planos de tensão e de deformação, detalhando-se a formulação de elemento triangular e, para a flexão de placas, segundo a teoria de Kirchhoff, detalha-se o elemento retangular com 12 parâmetros nodais e mencionam-se os elementos triangulares com 9 e 21 parâmetros nodais. Resultados obtidos por outros autores são apresentados. Finalmente, é feito aceno sobre os elementos tridimensionais.
Wing pattern variation and DNA barcodes defy taxonomic splitting in the New Zealand Pimelea Looper Notoreas perornata (Walker) (Lepidoptera: Geometridae: Larentiinae): the importance of populations as conservation units
Authors: HOARE ROBERT J.B. , PATRICK BRIAN H. , BUCKLEY THOMAS R. , BRAV-CUBITT TALIA
Published: September 2023

The endemic Notoreas perornata (Walker, 1863) complex (Lepidoptera: Geometridae: Larentiinae) from the North Island and northern South Island of New Zealand is reviewed. Larvae feed on Pimelea spp. (Thymelaeaceae), frequently in highly fragmented and threatened shrubland habitats. Allopatric populations tend to differ in size and wing pattern characteristics, but not in genitalia; moreover extensive variation renders recognition of subspecies / allopatric species based on any species concept problematic. A mitochondrial DNA gene tree is not congruent with morphology and indicates rapid recent divergence that has not ‘settled’ into diagnosable lineages. Based on our results, we synonymise Notoreas simplex Hudson, 1898 with N. perornata (Walker, 1863), and retain N. perornata as a single, highly diverse but monotypic species. All known populations are illustrated to display variation. For conservation purposes, we recommend the continued recognition within the species of 10 populations or groups of populations that appear to be on the way to diverging at subspecific level based on morphological and/or DNA data. The conservation status of all these populations is reviewed. One conservation unit, comprising the populations from Westland, has not been seen since 1998 and is feared possibly extinct.
On the identity of Conisania leuconephra Draudt, 1950 with a description of a new species from Xizang, China (Lepidoptera: Noctuidae: Noctuinae)
Authors: PAN ZHAOHUI , ZHENG WEILIE , VOLYNKIN ANTON V. , SALDAITIS AIDAS , GYULAI PÉTER , TÓTH BALÁZS
Published: September 2023

The identity of Conisania leuconephra (Draudt, 1950) from Yunnan (China) is revised. A new species Conisania sejilaensis sp. nov. is described from Xizang (China). The adults as well as the male and the female genitalia of the new and related species are illustrated.
At Home in the World: Two Western Models of Mindfulness
Authors: Hadjioannou Christos
Published: September 2023

This article offers a schematic description of two models for mindfulness, a Stoic and a Heideggerian one, focusing on the different ways they theorize well-being, emotions, and the role of unhomelikeness and homelikeness. It shows that Stoic mindfulness would have to aim at well-being qua oikeiōsis through a form of attention, which would involve the extirpation of passions. On the contrary, Heideggerian mindfulness would have to aim at well-being as an interplay of unhomelikeness and homelikeness, through anticipatory resoluteness. Heideggerian mindfulness would not only not aim at the extirpation of passions but would rather be motivated by a passion (angst) and embrace the passion. Heideggerian mindfulness is shown to involve not the sovereign prevalence of unhomelikeness (and angst) but rather a reconnection that involves a certain rehabilitation of homelikeness, expressed through “unshakable joy.” Heideggerian mindfulness is shown to involve a certain reversal of Stoic mindfulness with respect to homelikeness. However, it is also shown that in some respects, Heideggerian authenticity and mindfulness would involve a rehabilitation of the Stoic idea of oikeiōsis, as is revealed for example by the homology between oikeiōsis and Befindlichkeit, where both non-conceptually disclose the organism’s constitution to itself.
Rats prefer condensed milk to strawberry jam – a new possibility for voluntary oral drug administration
Authors: Ferreira-Duarte Mariana , Lopes Igor Moreira , Morato Manuela , Duarte-Araújo Margarida
Published: September 2023

Voluntary oral drug administration using sweet substances promotes rodents’ therapeutic compliance while reducing stress induced by forced drug administration. We aimed to test whether rats would willingly eat strawberry jam or condensed milk from a syringe, and which one they would prefer. Our results show that rats prefer condensed milk, demonstrating its potential as a vehicle for the voluntary oral administration of drugs in experimental protocols.
Synoptic Singularity? The Chronicler’s Redaction of Samuel-Kings and Gospel Composition
Authors: Myers Jimmy
Published: September 2023

One of the puzzles facing scholarship on gospel relationships is explaining the high yet varying degree of verbatim agreement among the Synoptics. On antiquity’s compositional spectrum, this high but inconsistent verbatim agreement appears anomalous to many. Some scholars point to the Synoptists’ scribal education to make sense of the data. This article highlights the fact that the Chronicler’s use of Samuel-Kings exhibits a similar dynamic, a phenomenon that has received little attention from scholars investigating the use of sources among ancient authors. Given this compositional overlap, I propose that the Synoptists, having been immersed for years in the warp and weft of sacred Jewish texts in a Greek-speaking synagogal school, took note of and ultimately imitated the Chronicler’s redaction of Samuel-Kings in composing their gospels. After presenting the evidence of the Chronicler’s varying compositional technique, the study concludes with implications and indicates further how attention to the Chronicler’s redaction of Samuel-Kings sheds light on the question of the feasibility of scribal reordering of sources in antiquity.
The reliability and validity of the cone evasion walk test in patients with hip osteoarthritis
Authors: Sevik Kacmaz Kevser , Unver Bayram , Karatosun Vasfi
Published: September 2023

Background:

Hip osteoarthritis (OA) can result in joint pain, stiffness, compromised balance, hindered mobility, and decreased functional independence. The Cone Evasion Walk Test (CEW) was designed for evaluating balance by evaluating the capacity to evade obstacles. Consequently, the study’s objective was to assess the validity and reliability of the CEW in hip OA patients.

Methods:

A total of 24 patients with hip OA were enrolled. Patients performed trials for the CEW and the timed up and go test (TUG). Between the trials, patients rested for an hour. The falls within the previous 12-month period were reported.

Results:

The analysis showed that the CEW has excellent reliability and high validity in hip OA. ( p < 0.001). The relative (intraclass correlation [ICC] coefficient) and absolute (SEM and SRD95) reliability of the CEW were 0.96 (0.88–0.98 95% CI), 0.56, and 1.54, respectively. The Spearman correlation coefficient between the CEW and the TUG was 0.74 ( p < 0.001) and between the CEW and the falls in the last 12 months was 0.51 ( p > 0.05).

Conclusions:

The CEW is effective for evaluating the function, dynamic balance, and mobility in patients with hip OA and could be a more accurate measure of the dynamic balance activities in the community.
Measuring Hispanic Optimism and Personal Expectancy
Authors: Cervantes Richard C. , Gonzalez-Guarda Rosa M. , McCabe Brian E. , Nagy Gabriela A.
Published: September 2023

The purpose of this study was to develop the Hispanic Optimism and Personal Expectancy (HOPE), a measure of optimism related to the concept of the American Dream. This measure assesses beliefs that are shared by Hispanic/Latinx immigrants and non-immigrants about opportunities for advancement in the United States. Based on focus groups consisting of both immigrant and non-immigrant Hispanic/Latinx participants ( n = 93), twenty four (24) items for the measure were created from qualitative interviews. Separate exploratory ( n = 174) and confirmatory ( n = 181) factor analysis supported three factors: Hope for a better life, for freedom & security, and for economic opportunity. Results provided empirical support for the HOPE. A final set of sixteen (16) items are included in the HOPE measure. This measure can benefit researchers or counselors who work with Hispanic/Latinx immigrants to understand individual expectancies and barriers toward achieving their American Dream. We discuss implications for research and potential conceptions of U.S. meritocracy as a potential myth for minority and immigrant groups.
Entropy generation analysis on EMHD non-Newtonian hybrid nanofluid flow over a permeable rotating disk through semi analytical and numerical approaches
Authors: Gunisetty Ramasekhar , Reddy P Bala Anki , A Divya
Published: September 2023

In the present study, the effect of entropy production on electromagnetohydrodynamic hybrid nanofluid (Gold- alumina/Blood) flow owing to a rotating disk in the presence of an electric field and thermal radiation are investigated. By applying the self-similarity variables, the PDE is converted into ODEs. After that, by using the Homotopy Perturbation Method (HPM). The Homotopy Perturbation Method (HPM) yields more efficient and reliable results than the numerical (Runge-Kutta) approach. To highlight their physical significance, a unique characteristic graph is shown for the profiles of temperature, velocity, and entropy generation, along with an appropriate explanation. The main findings are the velocity profile is increased by amplifying the Weissenberg, while the porosity and magnetic field reduce it. The temperature profile enhances due to rise in the electric field and radiation parameters. Entropy generation and Bejan number profiles increase due to an increment in Weissenberg and Brinkman numbers. The focus of this research can be applicable in the treatment of atherosclerosis without surgery, as well as to minimize medical expenditures and post-surgical problems. It has far-reaching significance in the treatment of cancers and diseases, as well as the elimination of blood clots.
An undercarriage image driven anomaly detection method for metro vehicle based on adversarial memory enhancement
Authors: Wang Lei , Zhang Kai , Zheng Qing , Ding Guofu , Zhang Weihua , Chen Dejun , Liu Bin
Published: September 2023

Anomaly detection is essential to ensure metro vehicles' safe operation. Error reconstruction-based anomaly detection methods have been widely studied because they only need to be trained by normal data and do not require much anomaly data, which is challenging to obtain. However, sometimes the auto-encoder network for error reconstructing “generalizes” so well that it also rebuilds the anomaly well, leading to missed anomaly detection. Therefore, this paper proposes an undercarriage image-driven anomaly detection method for metro vehicles based on adversarial memory enhancement. Firstly, this study performs component segmentation based on YOLOv5 detection results and constructs a component anomaly detection dataset. Secondly, an anomaly detection method based on memory enhancement and adversarial training of encoding-decoding-encoding structure is proposed for component anomaly detection. It enables the auto-encoder to reconstruct the image better. Thirdly, the combined indicator of the difference between potential features and reconstruction error is used as an anomaly indicator for anomaly detection of metro components, reducing the rate of fault misses. The experimental results on the established dataset demonstrate that the proposed method reduces false negative rates of 92.4%, 92.6%, 74.6%, and 59.1% compared with [Formula: see text], [Formula: see text], GANomaly, and MemAE, respectively.
Modelling the rate of trainees transitioning to Fellowship before achieving competence under the RANZCP’s Alternative Assessment Pathway to the Objective Structured Clinical Examination
Authors: Amos Andrew , Weightman Michael James , Miller Edward
Published: September 2023

Objective

The Objective Structured Clinical Examination (OSCE) has been removed from the Royal Australian and New Zealand College of Psychiatrists’ (RANZCP) training pathway. This decision occurred in the context of an Alternative Assessment Pathway (AAP) necessitated by Covid-19, justified by logistical, methodological and equity concerns. The false positive rate of trainees progressing to Fellowship before achieving competence is a key indicator for evaluating any assessment leading to psychiatric Fellowship. Variations in the statistical properties of the AAP and OSCE were analysed for their impact on pre-competent trainees progressing to Fellowship.

Method

Starting with the false positive scenario presented to justify discontinuing the OSCE, false positive rates associated with the AAP and OSCE were calculated based on different assumptions about reliability and accuracy.

Results

The analyses suggest that less reliable and less accurate alternatives to the OSCE, such as the AAP, increase the number of pre-competent trainees progressing to Fellowship.

Conclusions

Given possible increases in pre-competent trainees progressing to Fellowship while alternatives to the OSCE are finalised, confidence in the RANZCP's training program demands robust public analyses of those alternatives.