bluuebunny/crossref_metadata_2025 huggingface dataset:
ANALISIS DIMENSI PENGETAHUAN, DIMENSI PROSES KOGNITIF DAN SOAL HIGHER ORDER THINKING SKILL DALAM SOAL USP KIMIA SMAN 3 TAHUN PELAJARAN 2022/2023
Authors: Mustofa
Published: October 2023

The Education Unit Examination (USP) as a continuation of the progress of the National Examination moratorium regulation has strategic functions, including as a determinant of student graduation, being a means of empowering teacher working groups or subject teacher deliberations as a compiler of USP question scripts in all subjects. Analysis of the dimensions of knowledge, cognitive processes and HOTS questions on USP Chemistry questions is very important to determine the proportion of knowledge dimensions, cognitive process dimensions, and HOTS questions in the USP Chemistry questions of SMAN 3 Mojokerto City for the 2022/2023 academic year. This research method includes qualitative descriptive research on document analysis, because the data collected in this study was sourced from one form of official school documents, namely the USP Chemistry question script tested at SMAN 3 Mojokerto City in March - April 2023. Data obtained through analysis of knowledge dimensions, cognitive process dimensions and HOTS questions on each question item asked in the USP Chemistry questions for the 2022/2023 academic year. The validity test of the data used in this study includes: credibility test using triangulation technique, and reliability test with observation reliability method involving 2 senior chemistry teachers. With a deal coefficient of 0.80 in the very good category. Based on the results of the study, it can be concluded that: (1) the proportion of knowledge dimensions in the USP Chemistry questions of SMAN 3 Mojokerto City for the 2022/2023 academic year is dominated by procedural knowledge (59.5%) and the rest is factual knowledge (26.2%) and conceptual knowledge (14.3%);(2) the proportion of cognitive process dimensions is dominated by cognitive process application by 45.2% and the rest understanding (19.05%), analysis (19.05%), remembering (9.52%) and evaluation (7.14%); and (3) the proportion of HOTS questions reached 26.2%.
A Joint Data- and Model-Driven Approach Simulating the Behaviour of a Walkalong Glider
Authors: Alblas Dieuwertje , Bosch Mark van den , Feigl Zoro , Jansen Klomp Lucas , Rottschäfer Vivi , Schwenninger Felix , Spek Len , Weedage Lotte , Zeijlemaker Sjanne
Published: October 2023

Properly flying a walkalong glider is a challenging control problem, involving internal and external influences. We approach this problem from both a model-driven and data-driven viewpoint. We construct a mathematical model, based on well-established theory, which is used to derive both optimal paddle angle and distance between the paddle and the glider for steady level flight. Moreover, we derive parameters of the glider during uniform circular flight, as well as their relation to movement of the paddle from our model. As the glider is in practice very sensitive to airflow disturbances, we develope a data-driven model that tracks the status of the glider using video data, recorded by a camera mounted on the paddle. We use image processing and deep learning to automatically detect glider position with respect to the paddle and its yaw. Both approaches could be jointly used for feedback controlling an automatically operating walkalong glider.
The Potential of Cassava Peel Waste as a Material of Biodegradable Plastic using Calcium Silicate Filler
Authors: Noor Isnaini Azkiya  , S. Sigit Udjiana  , Arya Rizqy Irangga  , Anatasya Tania Febiyanti
Published: October 2023

Biodegradable plastics are plastics that can be degraded and decomposed quickly by microorganisms in the soil. In this study, biodegradable plastic was made with starch from cassava peel waste, sorbitol as a plasticizer, and calcium silicate as a filler. This research was conducted to determine the effect of the amount of filler and the amount of plasticizer on biodegradation properties, tensile and elongation strength, and water absorption properties. The variables used in the plasticizer are 30%, 40%, and 50% (w/w) of the weight of cassava peel starch. While the variables used for filler are 1%, 3%, 5%, and 7% (w/w) of the weight of cassava peel starch. The results of the study showed that the highest biodegradation test results were 81.7% with 7% calcium silicate filler variables and 50% plasticizer sorbitol, tensile strength test obtained the highest value of 0.767 MPa on 3% calcium silicate filler variables and 30% sorbitol, elongation test with the highest value on the filler variable calcium silicate 7% and sorbitol 30% that is equal to 5.20% and the water adsorption test obtained the smallest value is 10.33% on the filler variable calcium silicate 1% and sorbitol 30%. The biodegradable plastic as a result of this research has met the standards for degradation ability based on the ASTM 6400 standard but has not met the standards for tensile strength, elongation, and water adsorption.
Reducing Sugar Production by Cellulose Immobilized Enzyme from the Oil Palm Empty Fruit Brunch (OPEFB) Treated by Organosolv Pretreatment
Authors: Pardeny Vini Ivania , Nurfadiya Alvanissa , Hidayatulloh Irwan , Haq Muhammad Umair Ul , Permanasari Ayu Ratna
Published: October 2023

Oil Palm Empty Fruit Bunches (OPEFB) is lignocellulosic that consists of 13.20-25.31% lignin, 42.70-65.00% cellulose, and 17.10-33.50% hemicellulose. Cellulose can be used as a material for a new renewable energy source in the term of reducing sugar through a combination of organosolv pretreatment and hydrolysis process using immobilized enzymes. Organosolv pretreatment was used for lignin degradation, by using ethanol as solvent, which are environmentally friendly and easy to recover, with a concentration S/L 10%(w/w), in 160°C for 90-150 min. The following process is to produce crude enzyme from Aspergillus niger and Trichoderma viride. The resulting crude enzyme cellulase activity of 0.774 U/mL. Then, the crude enzyme is immobilized by Chitosan-GDA. OPEFB hydrolysis process with immobilized cellulase was carried out for 5, 7 and 9 days at 37°C. The best result of lignin degradation reaches out 56.68% lignin removal at 160°C for 150 min, while the hydrolysis of cellulose gives the highest yield, 47.59%, in the 9 days processing time.
Evaluation and Management of B3 Waste Sludge via the Sludge Oil Recovery (SOR) Program at PT. X Plaju
Authors: Nurdiasna Widya Reza , Septiariva Iva Yenis , Suryawan I Wayan Koko , Sari Mega Mutiara , Ulhasanah Nova
Published: October 2023

With the ever-increasing need for waste management solutions, PT. X Plaju is one of the entities that contribute to B3 waste production, a waste type characterized by its explosive, flammable, reactive, corrosive, and toxic properties. This research centers on the evaluation and management of B3 waste sludge, particularly at PT. X Plaju. The institution implements two licensed B3 waste control programs: the Sludge Oil Recovery (SOR) and used lubricant utilization programs. The SOR program, which focuses on recovering components from oil deposits or sludge, operates under the recovery principle. This study showcases the importance of the oil component in the oil sludge, emphasizing that it must constitute more than 20% of the total volume to be deemed suitable for refinery production. Our findings highlighted a water content of 28.32% within the waste oil sludge. Additionally, the ultimate analysis showcased carbon, hydrogen, and nitrogen compositions of 85.99%, 13.42%, and 0.21%, respectively, while the density was measured at 0.85 gr/cc. This research offers insights into the waste management practices of PT. X Plaju, emphasizing the potential of the SOR program in managing B3 waste effectively.
Simulation of Furfural and Levulinic Acid Production from Lignocellulosic Biomass
Authors: Panjaitan Jabosar Ronggur Hamonangan
Published: October 2023

Furfural and levulinic acid are chemicals that can be produced from lignocellulosic biomass. In this research, mass balance simulation of furfural and levulinic acid production at scale of 100 tons of biomass/year was examined. This research using various models of kinetic reaction and biomass to solvent ratio from lignocellulosic biomass raw materials consisting of cellulose, hemicellulose, lignin, ash, and water composition of 35%, 30%, 25%, 3%, and 7%. The kinetic models used in this research were separate kinetic models and simultaneous model (model-3). The separate kinetic models were divided into two models which separate kinetic model 1 (model-1) and separate kinetic model 2 (model-2). SuperPro Designer 9.0 software was used to calculate mass balance simulation. From the research, it was found that variations in kinetic reaction model affected furfural and levulinic acid production. Higher biomass to solvent ratio produced higher furfural and levulinic acid production. The highest furfural produced from simulation process was kinetic reaction model-2 with a biomass to solvent ratio of 1:30 and 0.67 liter furfural/hour. While the highest levulinic acid produced from the simulation process was kinetic reaction model-1 with a biomass to solvent ratio of 1:30 and 2.37 liter levulinic acid/hour.
Simulating time-to-event data under the Cox proportional hazards model: assessing the performance of the non-parametric Flexible Hazards Method
Authors: Delzeit Jennifer L. , Koestler Devin C.
Published: October 2023

Numerous methods and approaches have been developed for generating time-to-event data from the Cox Proportional Hazards (CPH) model; however, they often require specification of a parametric distribution for the baseline hazard even though the CPH model itself makes no assumptions on the distribution of the baseline hazards. In line with the semi-parametric nature of the CPH model, a recently proposed method called the Flexible Hazards Method generates time-to-event data from a CPH model using a non-parametric baseline hazard function. While the initial results of this method are promising, it has not yet been comprehensively assessed with increasing covariates or against data generated under parametric baseline hazards. To fill this gap, we conducted a comprehensive study to benchmark the performance of the Flexible Hazards Method for generating data from a CPH model against parametric methods. Our results showed that with a single covariate and large enough assumed maximum time, the bias in the Flexible Hazards Method is 0.02 (with respect to the log hazard ratio) with a 95% confidence interval having coverage of 84.4%. This bias increases to 0.054 when there are 10 covariates under the same settings and the coverage of the 95% confidence interval decreases to 46.7%. In this paper, we explain the plausible reasons for this observed increase in bias and decrease in coverage as the number of covariates are increased, both empirically and theoretically, and provide readers and potential users of this method with some suggestions on how to best address these issues. In summary, the Flexible Hazards Method performs well when there are few covariates and the user wishes to simulate data from a non-parametric baseline hazard.
Improving the stimulation selectivity in the human cochlea by strategic selection of the current return electrode
Authors: Cakmak Ozan , Pal Saikat , Sahin Mesut
Published: October 2023

The hearing quality provided by cochlear implants is poorly predicted by computer simulations. A high-resolution, human-specific cochlear anatomy is crucial for the accuracy of predictions. In this study, the standard multipolar stimulation paradigms are revisited and Rattay's Activating Function is evaluated in a finite element model of a realistic cochlear geometry that is based on μ-CT images and a commercial lead. The stimulation thresholds across the cochlear fibers were investigated for monopolar, bipolar, tripolar, and a novel (distant) bipolar electrode configuration using an active compartmental nerve model based on Schwartz-Eikhof-Frijns membrane dynamics. The results suggest that jumping of the stimulation point from the vicinity of the cathodic electrode to distant fibers, especially to the low frequency (apical) region of the basilar membrane that is most critical to hearing, occurs more often with monopolar stimulation than other electrode configurations. Bipolar and tripolar electrodes near the apical region did not provide a large threshold margin either. On the other hand, the threshold margin could be improved by proper selection of the electrode for the return current with bipolar stimulation, a technique named here as distant bipolar. The results also demonstrate the significance of having a realistic cochlear geometry in computer models for accurate interpretation for multipolar stimulation paradigms. More selective and focal stimulation may be possible by designing the electrode carrier shape and positioning of the current return electrodes more strategically. This is needed particularly in the apical turn of the cochlea where the current stimulation methods are the least selective.
Implications of LDH in patients with coronavirus disease 2019 pneumonia
Authors: Mu Tong , Wang Xingguang , Lu Zhiming , Tong Jia
Published: October 2023

Objective

The objective of this study was to explore the value of serum lactic dehydrogenase (LDH) in the early diagnosis and prognostic evaluation of pneumonia associated with the novel coronavirus infection.

Methods

A total of 101 patients with coronavirus disease 2019 (COVID-19) pneumonia were included in the study. According to the severity of the initial chest computed tomography (CT), the patients were divided into the ordinary pneumonia group and the severe pneumonia group and then divided into the remission group and the nonremission group according to the changes of the chest CT after medication treatment. The differences in general characteristics, underlying diseases, clinical symptoms, laboratory findings, and imaging examination outcomes between groups were observed retrospectively. To analyze the diagnostic performance of LDH, receiver operating characteristic (ROC) curves were constructed and the area under the curve (AUC) was calculated.

Results

Compared with ordinary pneumonia patients, patients in the severe group presented with significantly higher LDH, neutrophil count, high-sensitivity troponin T (HS-TnT), C-reactive protein (CRP), human serum amyloid A (SAA), N-terminal pro-brain natriuretic peptide (NTproBNP), and D-dimer. Compared with remission patients, non-remission patients presented with significantly higher LDH, neutrophil count, HS-TnT, CRP, SAA, procalcitonin (PCT), creatine kinase–MB mass (CKMB_M), NTproBNP, and D-dimer. In multivariate logistic regression analysis, we found that LDH [odds ratio (OR), 1.015; 95% confidence interval (CI), 1.006–1024; p = 0.001] and neutrophil count (OR, 1.352; 95% CI, 1.008–1.811; p = 0.044) were independently associated with exacerbation in COVID-19 patients. For ROC analysis, the AUC was 0.833 (95% CI, 0.729–0.936; p < 0.001) when we use the LDH value of 256.69 U/L to discriminate the ordinary pneumonia and severe pneumonia patients. The AUC was 0.759 (95% CI, 0.603–0.914; p = 0.008) and the sensitivity is 92.3% when we combined the LDH (cutoff value 258.46 U/L) and the neutrophil count (cutoff value 6.76 × 109/L) to discriminate remission and non-remission patients.

Conclusion

The level of LDH is associated with the severity of COVID-19 pneumonia and can be used as important indicators to evaluate the prognosis of patients.
Plant-human entanglements in buildings: designing for care infrastructuring with office occupants and pot plants
Authors: Loh Susan , Santo Yasu , Foth Marcus
Published: October 2023

The current outsourcing of maintenance and the use of technological devices to automatically care for plants in buildings change the spatial experience between human office occupants and plants. This caretaker system distances people from plants, inclining us to regard them more as decorative objects. The relationship between humans and plants in a building is often unidirectional, with plants providing humans multiple benefits such as improved health and well-being, and increased worker productivity. In our human-plant interaction study, we developed a layer of care infrastructure within an office building that gives agency to people as a collective to interact with and take care of other non-human beings; that is, plants. In re-imagining mediated human-building interaction, we employed technology as an ambient mediator where people, plants and technology comprised the plant care system in a typical office building. A year-long design intervention was introduced within a typical office floor using artifacts (pots, shelves, and digital system) which we fabricated for the plants. From the results of an 8 week participation experiment together with data from qualitative interviews of 6 study participants, we identified five themes: Technology, Object/Thing, Infrastructuring, Commoning, and Care. Our analysis of these themes informs a care infrastructuring approach where both humans and plants become interdependent office co-inhabitants. By entangling with technology, care, and others, we present an infrastructuring layer to mediate human-building interactions with plants.
Identification and analysis of differential miRNA–mRNA interactions in coronary heart disease: an experimental screening approach
Authors: Wang Jie , Liu Lanchun , Liu Chao , Cheng Nuo , Mao Qiyuan , Chen Cong , Hu Jun , He Haoqiang , Hui Xiaoshan , Qu Peirong , Lian Wenjing , Duan Lian , Dong Yan , Liu Yongmei , Li Jun
Published: October 2023

Objective

This aim of this study is to screen the differential molecules of kidney deficiency and blood stasis (KDBS) syndrome in coronary heart disease by high-throughput sequencing. In addition, the study aims to verify the alterations in the expression levels of miR-4685-3p and its regulated downstream, namely, C1QC, C4, and C5, using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA), and to determine whether the complement and coagulation cascade pathway is the specific pathogenic pathway.

Methods

Patients diagnosed with unstable angina pectoris with KDBS syndrome, patients with non-kidney deficiency blood stasis (NKDBS) syndrome, and a Normal group were recruited. The clinical symptoms of each group were further analyzed. Illumina's NextSeq 2000 sequencing platform and FastQC software were used for RNA sequencing and quality control. DESeq software was used for differential gene expression (DGE) analysis. qPCR and ELISA verification were performed on DGE analysis.

Results

The DGE profiles of 77 miRNA and 331 mRNA were selected. The GO enrichment analysis comprised 43 biological processes, 49 cell components, and 42 molecular functions. The KEGG enrichment results included 40 KEGG pathways. The PCR results showed that, compared with the Normal group, the miR-4685-3p levels decreased in the CHD_KDBS group (P = 0.001), and were found to be lower than those observed in the CHD_NKDBS group. The downstream mRNA C1 regulated by miR-4685-3p showed an increasing trend in the CHD_KDBS group, which was higher than that in the Normal group (P = 0.0019). The mRNA C4 and C5 in the CHD_KDBS group showed an upward trend, but the difference was not statistically significant. ELISA was utilized for the detection of proteins associated with the complement and coagulation cascade pathway. It was found that the expression level of C1 was significantly upregulated in the CHD_KDBS group compared with the Normal group (P < 0.0001), which was seen to be higher than that in the CHD_NKDBS group (P < 0.0001). The expression levels of C4 and C5 in the CHD_KDBS group were significantly lower than the Normal group, and were lower than that in the CHD_NKDBS group (P < 0.0001).

Conclusion

The occurrence of CHD_KDBS might be related to the activation of the complement and coagulation cascade pathway, which is demonstrated by the observed decrease in miR-4685-3p and the subsequent upregulation of its downstream C1QC. In addition, the expression levels of complement C4 and C5 were found to be decreased, which provided a research basis for the prevention and treatment of this disease.
Unraveling the role of VLDL in the relationship between type 2 diabetes and coronary atherosclerosis: a Mendelian randomization analysis
Authors: Feng Wenshuai , Guo Liuli , Liu Yiman , Ren Ming
Published: October 2023

Background

The causal link between Type 2 diabetes (T2D) and coronary atherosclerosis has been established through wet lab experiments; however, its analysis with Genome-wide association studies (GWAS) data remains unexplored. This study aims to validate this relationship using Mendelian randomization analysis and explore the potential mediation of VLDL in this mechanism.

Methods

Employing Mendelian randomization analysis, we investigated the causal connection between T2D and coronary atherosclerosis. We utilized GWAS summary statistics from European ancestry cohorts, comprising 23,363 coronary atherosclerosis patients and 195,429 controls, along with 32,469 T2D patients and 183,185 controls. VLDL levels, linked to SNPs, were considered as a potential mediating causal factor that might contribute to coronary atherosclerosis in the presence of T2D. We employed the inverse variance weighted (IVW), Egger regression (MR-Egger), weighted median, and weighted model methods for causal effect estimation. A leave-one-out sensitivity analysis was conducted to ensure robustness.

Results

Our Mendelian randomization analysis demonstrated a genetic association between T2D and an increased coronary atherosclerosis risk, with the IVW estimate at 1.13 [95% confidence interval (CI): 1.07–1.20]. Additionally, we observed a suggestive causal link between T2D and VLDL levels, as evidenced by the IVW estimate of 1.02 (95% CI: 0.98–1.07). Further supporting lipid involvement in coronary atherosclerosis pathogenesis, the IVW-Egger estimate was 1.30 (95% CI: 1.06–1.58).

Conclusion

In conclusion, this study highlights the autonomous contributions of T2D and VLDL levels to coronary atherosclerosis development. T2D is linked to a 13.35% elevated risk of coronary atherosclerosis, and within T2D patients, VLDL concentration rises by 2.49%. Notably, each standard deviation increase in VLDL raises the likelihood of heart disease by 29.6%. This underscores the significant role of lipid regulation, particularly VLDL, as a mediating pathway in coronary atherosclerosis progression.
Role of inflammation and immunity in vascular calcification: a bibliometric and visual analysis, 2000–2022
Authors: Wang Chen , Liang Qingchun , He Siyi , Zhu Jie , Lin Xiafei , Lin Guanwen , Wu Duozhi , Zhang Wenqi , Wang Zhihua
Published: October 2023

Background

In recent years, a great deal of research has been done on vascular calcification (VC), and inflammation and immunity have been displayed to play important roles in the mechanism of VC. However, to date, no comprehensive or systematic bibliometric analyses have been conducted on this topic.

Methods

Articles and reviews on the roles of inflammation and immunity in VC were obtained from the Web of Science Core Collection on August 5, 2022. Four scientometric software packages—HistCite, CiteSpace, VOSviewer, and R-bibliometrix—were used for the bibliometric and knowledge mapping analyses.

Results

The obtained 1,868 papers were published in 627 academic journals by 9,595 authors of 2,217 institutions from 69 countries. The annual number of publications showed a clear growth trend. The USA and China were the most productive countries. Karolinska Institutet, Harvard University, and the University of Washington were the most active institutions. Stenvinkel P published the most articles, whereas Demer LL received the most citations. Atherosclerosis published the most papers, while Circulation was the most highly cited journal. The largest cluster among the 22 clusters, based on the analysis of co-citations, was osteo-/chondrogenic transdifferentiation. “Vascular calcification,” “inflammation,” “chronic kidney disease,” and “expression” were the main keywords in the field. The keyword “extracellular vesicle” attracted great attention in recent years with the strongest citation burst.

Conclusions

Osteo-/chondrogenic transdifferentiation is the primary research topic in this field. Extracellular vesicles are expected to become a new research focus for exploring the inflammatory and immune mechanisms of VC.
Full waveform inversion with combined misfit functions and application in land seismic data
Authors: Song Jianyong , Yang Zhifang , Cao Hong , He Weiguang , Pan Wenyong , Li Meng , Tian Na
Published: October 2023

Full waveform inversion reconstructs subsurface structures by matching the synthetic waveform to the observed waveform. Inaccuracy of the source wavelets can, thus, easily lead to an inaccurate model. Simultaneously updating source wavelets and model parameters is a conventionally used strategy. However, when the initial model is very far from the true model, cycle skipping exists, and estimating a reliable source wavelet is very difficult. We propose a combinatory inversion workflow based on seismic events. We apply a Gaussian time window around the first break and gradually increase its width to include more seismic events. The influence of inaccurate source wavelets is alleviated by applying a Gaussian time window around the first break to evaluate the normalized cross-correlation-based objective function. There are inevitable small model artifacts caused by inter-event interactions when calculating cross-correlations. As a result, we switch to the optimal transport function to clean the model and update the source wavelets simultaneously. The combinatory strategy has been applied to models with different types of geological structures. Starting from a crude initial model, we recovered a high-resolution and high-fidelity model and the source wavelets in two synthetic experiments. Finally, we apply our inversion strategy to a real-land seismic dataset in Southeast China and obtain a higher-resolution velocity model. By comparing an inversion velocity profile with well log information and the recorded data with the simulated data, we conclude that our inversion results for the field data are accurate and this new strategy is effective.
The intersection of learning difficulties and behavior problems – a scoping review of intervention research
Authors: Gabriel Taina , Börnert-Ringleb Moritz
Published: October 2023

Learning difficulties (LDif) and behavioral problems (BP) frequently co-occur. Affected students typically require interventions targeting learning-, social-, as well as emotional and behavioral-domains. The goal of this scoping review is therefore to provide an overview of the research on interventions that target these critical areas for students with or at-risk of disabilities. In total, 48 relevant studies were identified and analyzed regarding addressed competencies, target groups, the setting of the interventions as well as underlying causal assumptions. The review identified a variety of interventions and approaches designed to address LDif and BP, which makes it impossible to draw conclusions on a single best approach. Co-occurring LDif and BP reflect a plurality of difficulties that are incompatible with a ‘one size fits all’ approach. The vast majority of studies assumed that the relationship between LDif and BP are reciprocal/unidirectional. Few studies focused common variables that potentially affect both LDif and BP. In addition, the majority of studies addressed child-level variables. Future research should be conducted to focus on variables at the environmental or institutional level that might impact both LDif and BP.
The real teacher arrives: toward a modern education of children and adults
Authors: Saar Sven
Published: October 2023

In this article I will examine the role of traditional paradigms in developing systematic education. I will then offer a modern alternative, expanding on the question what learners need from their teachers and focusing on the gestures of intention, implementation, and impact. Finally, I will look at how Teacher Education can respond to the changed and changing needs of modern learners. Here, the holistic Steiner/Waldorf approach offers a particularly attractive alternative to mainstream Teacher Education in its focus on the self-education of the teacher.
Clinical characteristics of a large familial cohort with Medullary thyroid cancer and germline Cys618Arg RET mutation in an Israeli multicenter study
Authors: Rosenblum Rachel Chava , Hirsch Dania , Grozinsky-Glasberg Simona , Benbassat Carlos , Yoel Uri , Ishay Avraham , Zolotov Sagit , Bachar Gideon , Banne Ehud , Levy Sigal , Twito Orit
Published: October 2023

Objective

To determine genealogical, clinical and pathological characteristics of a cohort with Cys618Arg mutation from an Israeli multicenter MTC study.

Methods

Retrospective database analysis examining RET mutations and comparing Cys618Arg and Cys634Arg/Thr/Tyr subgroups.

Results

Genetic testing was performed in 131/275 MTC patients (47.6%). RET mutations were found in 50/131 (38.2%), including Cys618Arg (28/50 cases,56%), and Cys634Arg/Thr/Tyr (15/50,30%). Through genealogical study, 31 MTC patients were found descendants of one family of Jewish Moroccan descent, accounting for 27/28 patients with documented Cys618Arg mutation and 4 patients without available genetic testing. Familial Cys618Arg cases (n=31) and Cys634Arg/Thr/Tyr cases (n=15, from 6 families) were compared. Although surgical age was similar (25.7 vs 31.3 years, p=0.19), the Cys618Arg group had smaller tumors (8.9mm vs 18.5mm, p=0.004) and lower calcitonin levels (33.9 vs 84.5 X/ULN, p=0.03). Youngest ages at MTC diagnosis were 8 and 3 years in Cys618Arg and Cys634Arg/Thr/Tyr cohorts, respectively. Long-term outcome was similar between groups. The Cys618Arg cohort had lower rates of pheochromocytoma (6.5% vs 53.3%, p=0.001) and primary hyperparathyroidism (3.2% vs 33.3%, p=0.01).

Conclusion

This is the first description of RET mutation distribution in Israel. Of 131 tested MTC patients, Cys618Arg was the predominant mutation. To the best of our knowledge, this is the largest cohort of Cys618Arg mutation described. For Cys618Arg and Cys634Arg/Thr/Tyr cohorts, MTC was diagnosed earlier than expected, likely due to familial genetic screening, and MTC outcomes were similar between groups. International studies are necessary to further characterize the clinical features of Cys618 mutations due to their relative rarity.
RNA sequencing profiles reveals progressively reduced spermatogenesis with progression in adult cryptorchidism
Authors: Sun Weihao , Zhang Xinhui , Wang Lei , Ren Guanyu , Piao Shuguang , Yang Chenghua , Liu Zhiyong
Published: October 2023

Introduction

The fertility of cryptorchidism patients who didn’t perform corrective surgery will decrease with age. Herein, we elucidate the histological alterations and underlying molecular mechanism in patients with an increase in the disease duration from 20 to 40 years.

Methods

Testicular tissues were obtained from three patients with cryptorchidism, ranging in age from 22 to 44 years. Three benign paracancerous testicular samples of matched ages were used as controls. The normal and undescended testicular tissues were stained with hematoxylin and eosin (HE) and immunofluorescence and all six testicular samples were subjected to RNA sequencing. RNA sequencing data were subjected to gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI) network analysis, and Gene Ontology (GO) searches. Real-time reverse transcriptase polymerase chain reaction was used to confirm the DEGs.

Results

The seminiferous tubules’ basement membrane thickens with age in healthy testes. As the period of cryptorchidism in the cryptorchid testis extended, the seminiferous tubules significantly atrophy, the number of spermatogenic cells declines, and the amount of interstitial fibrous tissue increases in comparison to normal tissues. The number of germ cells per cross-section of seminiferous tubules was significantly lower in cryptorchidism than in normal testicular tissues, according to immunofluorescence staining, but the number of Sertoli cells remained stable. RNA sequencing analysis identified 1150 differentially expressed genes (DEGs) between cryptorchidism and normal testicular tissues (fold change >2 and p<0.05), of which 61 genes were noticeably upregulated and 1089 were significantly downregulated. These genes were predominantly linked to sperm development and differentiation, and fertilization, according to GO analysis. Meiosis pathways were significantly downregulated in cryptorchidism, according to KEGG pathway analysis and GSEA (P<0.001). PPI analysis was used to identify the top seven downregulated hub genes (PLCZ1, AKAP4, IZUMO1, SPAG6, CAPZA3, andROPN1L), which were then further verified by qPCR.

Discussion

By describing the histological changes and differential gene expression patterns in adult cryptorchid patients of different age groups, we discovered the progression mechanisms of undescended testes in adults with aging and identified seven significantly downregulated hub genes (PLCZ1, AKAP4, IZUMO1, SPAG6, CAPZA3, andROPN1L) in cryptorchid testis compared to normal testicular tissues. These genes played a role in the process of spermgenesis and are directly linked to the steady decline in fertility caused by cryptorchidism. Our study provided a better understanding of the molecular mechanisms underlying the loss of spermatogenesis in adult cryptorchidism, and give support for the development of adult cryptorchidism treatments.
Risk factor analysis and prediction model for papillary thyroid carcinoma with lymph node metastasis
Authors: Lu Juerong , Liao Jintang , Chen Yunhao , Li Jie , Huang Xinyue , Zhang Huajun , Zhang Bo
Published: October 2023

Objective

We aimed to identify the clinical factors associated with lymph node metastasis (LNM) based on ultrasound characteristics and clinical data, and develop a nomogram for personalized clinical decision-making.

Methods

A retrospective analysis was performed on 252 patients with papillary thyroid carcinoma (PTC). The patient’s information was subjected to univariate and multivariate logistic regression analyses to identify risk factors. A nomogram to predict LNM was established combining the risk factors. The performance of the nomogram was evaluated using receiver operating characteristic (ROC) curve, calibration curve, cross-validation, decision curve analysis (DCA), and clinical impact curve.

Results

There are significant differences between LNM and non-LNM groups in terms of age, sex, tumor size, hypoechoic halo around the nodule, thyroid capsule invasion, lymph node microcalcification, lymph node hyperechoic area, peak intensity of contrast (PI), and area under the curve (AUC) of the time intensity curve of contrast (P<0.05). Age, sex, thyroid capsule invasion, lymph node microcalcification were independent predictors of LNM and were used to establish the predictive nomogram. The ROC was 0.800, with excellent discrimination and calibration. The predictive accuracy of 0.757 and the Kappa value was 0.508. The calibration curve, DCA and calibration curve demonstrated that the prediction model had excellent net benefits and clinical practicability.

Conclusion

Age, sex, thyroid capsule invasion, and lymph node microcalcification were identified as significant risk factors for predicting LNM in patients with PTC. The visualized nomogram model may assist clinicians in predicting the likelihood of LNM in patients with PTC prior to surgery.
Case Report: Labor induced coccydynia associated with Modic I changes successfully treated with platelet-rich plasma
Authors: Vuković Miloš , Nosek Igor , Vuković Jelena , Ilić Đorđe , Kozić Duško , Boban Jasmina
Published: October 2023

Imaging can aid in determining potential causes of coccygeal pain and therefore guide clinicians to carry out individualized treatment. We represent a case of postpartum coccydynia treated by platelet-rich plasma (PRP) which was assessed and followed by MRI. A primipara with uncomplicated labor developed coccygeal pain after delivery that significantly limited her postpartum recovery. On the first MR scan, recorded 6 months after delivery, there were edematous changes of the vertebral endplates of Co1-4 level (Modic type I) with the presence of pronounced precoccygeal venous drainage. Degenerative changes with signs of edema in the area of the pubic symphysis were recorded. The sacroiliac joints had regular morphological features. Since the patient was breastfeeding, PRP therapy was applied with a total of three injections in the area of the coccyx subcutaneously, once every 3 months. The subjective feeling of pain reduction after each injection was about 30%, with the complete withdrawal of pain after one year and still pain-free at the two-year follow-up. One year after the initial MR imaging, a follow-up MR examination was performed, where almost complete resolution of edematous changes in the previously present zones was observed, with residual minor edema of the vertebral endplates at the Co2-3 level. Edema of the pubic bones in the area of the pubic symphysis also subsided. A case of labor-induced coccydynia that was represented as Modic type I changes without neither fracture or luxation was successfully treated with PRP with complete resolution of symptoms.
The prognostic value of the histological shape of tumor negative sentinel nodes in breast cancer
Authors: Kooreman Loes F. S. , Dieleman Sabine , van Kuijk Sander M. J. , zur Hausen Axel , Smidt Marjolein L. , Grabsch Heike I.
Published: October 2023

Introduction

Sentinel lymph node (SLN) metastasis is an important predictor of prognosis in breast cancer (BC) patients, guiding treatment decisions. However, patients with the same BC subtype and tumor negative SLN (SLNneg) can have different survival outcomes. We hypothesized that the host anti-tumor immune reaction in SLNneg is important and results in morphometrically measurable changes in SLN size or shape which are related to patient prognosis.

Methods

Surface area, circumference, long axis and short axis were histologically measured in 694 SLNneg from 356 cases of invasive BC and 67 ductal carcinoma in situ cases. The area occupied by fat was categorized as less or more than 50%. The long to short axis (L/S) ratio was calculated. The relationship between SLNneg morphometries and clinicopathological variables like tumor-infiltrating lymphocytes (TILs) within the primary tumor, as well as prognosis at 10 years follow up were analyzed.

Results

The mean SLNneg surface area was 78.7mm2, circumference 40.3mm, long axis 13.1mm, short axis 8.2mm and L/S ratio 1.7. Larger surface area, long axis and short axis, including age >55 years were associated with higher body mass index (BMI) and SLN fat over 50% (p<0.003). In invasive BC, a high SLNneg L/S ratio (≥1.9) was related to poorer disease-free (HR=1.805, 95%CI 1.182-2.755, p=0.006) and overall (HR=2.389, 95%CI 1.481-3.851, p<0.001) survival. A low SLNneg L/S ratio (<1.9) was associated with high TILs in the primary BC (≥10%) (p=0.005). However a high TIL count was not of prognostic relevance.

Conclusions

This is the first study to suggest that morphometric characteristics of axillary SLNneg, like L/S ratio, could be used to predict prognosis in patients with SLNneg invasive BC of all subtypes. The association between low L/S ratio and high TILs suggest that SLN shape is related to immunological functioning of the SLN and could be used in addition to TIL evaluation. Regarding the dubious role of TILs in hormone receptor positive breast cancer, SLNneg morphometry to gain information about host immune status could especially be of benefit in this subtype. Further studies are warranted to better understand the underlying biological mechanisms.
Tumour immune escape via P2X7 receptor signalling
Authors: Sainz Ricardo M. , Rodriguez-Quintero Jorge Humberto , Maldifassi Maria Constanza , Stiles Brendon M. , Wennerberg Erik
Published: October 2023

While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.
Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling
Authors: Moll Guido , Luecht Christian , Gyamfi Michael Adu , da Fonseca Dennyson L. M. , Wang Pinchao , Zhao Hongfan , Gong Zexian , Chen Lei , Ashraf Muhamad Imtiaz , Heidecke Harald , Hackel Alexander Maximilian , Dragun Duska , Budde Klemens , Penack Olaf , Riemekasten Gabriela , Cabral-Marques Otávio , Witowski Janusz , Catar Rusan
Published: October 2023

Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses.
Mosquito-borne flaviviruses and type I interferon: catch me if you can!
Authors: Zoladek Jim , Nisole Sébastien
Published: October 2023

Mosquito-borne flaviviruses include many viruses that are important human pathogens, including Yellow fever virus, Dengue virus, Zika virus and West Nile virus. While these viruses have long been confined to tropical regions, they now pose a global public health concern, as the geographical distribution of their mosquito vectors has dramatically expanded. The constant threat of flavivirus emergence and re-emergence underlines the need for a better understanding of the relationships between these viruses and their hosts. In particular, unraveling how these viruses manage to bypass antiviral immune mechanisms could enable the design of countermeasures to limit their impact on human health. The body’s first line of defense against viral infections is provided by the interferon (IFN) response. This antiviral defense mechanism takes place in two waves, namely the induction of type I IFNs triggered by viral infection, followed by the IFN signaling pathway, which leads to the synthesis of interferon-stimulated genes (ISGs), whose products inhibit viral replication. In order to spread throughout the body, viruses must race against time to replicate before this IFN-induced antiviral state hinders their dissemination. In this review, we summarize our current knowledge on the multiple strategies developed by mosquito-borne flaviviruses to interfere with innate immune detection and signaling pathways, in order to delay, if not prevent, the establishment of an antiviral response.
The absence of surface D-alanylation, localized on lipoteichoic acid, impacts the Clostridioides difficile way of life and antibiotic resistance
Authors: Lacotte Pierre-Alexandre , Denis-Quanquin Sandrine , Chatonnat Eva , Le Bris Julie , Leparfait David , Lequeux Thierry , Martin-Verstraete Isabelle , Candela Thomas
Published: October 2023

Introduction

The dlt operon encodes proteins responsible for the esterification of positively charged D-alanine on the wall teichoic acids and lipoteichoic acids of Gram-positive bacteria. This structural modification of the bacterial anionic surface in several species has been described to alter the physicochemical properties of the cell-wall. In addition, it has been linked to reduced sensibilities to cationic antimicrobial peptides and antibiotics.

Methods

We studied the D-alanylation of Clostridioides difficile polysaccharides with a complete deletion of the dltDABCoperon in the 630 strain. To look for D-alanylation location, surface polysaccharides were purified and analyzed by NMR. Properties of the dltDABCmutant and the parental strains, were determined for bacterial surface’s hydrophobicity, motility, adhesion, antibiotic resistance.

Results

We first confirmed the role of the dltDABCoperon in D-alanylation. Then, we established the exclusive esterification of D-alanine on C. difficile lipoteichoic acid. Our data also suggest that D-alanylation modifies the cell-wall’s properties, affecting the bacterial surface’s hydrophobicity, motility, adhesion to biotic and abiotic surfaces,and biofilm formation. In addition, our mutant exhibitedincreased sensibilities to antibiotics linked to the membrane, especially bacitracin. A specific inhibitor DLT-1 of DltA reduces the D-alanylation rate in C. difficile but the inhibition was not sufficient to decrease the antibiotic resistance against bacitracin and vancomycin.

Conclusion

Our results suggest the D-alanylation of C. difficile as an interesting target to tackle C. difficile infections.
Current and future research on the association between gut microbiota and breast cancer
Authors: Liu Kuan , Jia Nan , Shi Hongyun , Ran Yuge
Published: October 2023

Breast cancer (BC) is a prevalent malignancy. There exists a strong association between gut microbiota (GM) and the development of BC. The GM composition in individuals with BC significantly differs from that in their healthy counterparts. Furthermore, the distribution of GM varies significantly among individuals with different types of BC. The GM can impact BC through metabolite secretion, the gut-mammary axis, and other pathways. Modulating the GM can serve as a very promising potential therapeutic strategy in the treatment of BC. This article will summarize existing research, focusing on the relationship between intestinal microbiota and BC. At the same time, the project will also analyze the application value of intestinal microorganisms in BC intervention work, so as to provide a reference for the further development of BC prevention and treatment work.