bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional verification and characterization of a type-III geranylgeranyl diphosphate synthase gene from Sporobolomyces pararoseus NGR
Authors: Yan Jianyu , Li Chunji , Zhang Ning , Li Chunwang , Wang Yunjiao , Li Bingxue
Published: November 2022

Carotenoids, a group of natural pigments, have strong antioxidant properties and act as precursors to vitamin A, which have garnered attention from industry and researchers. Sporobolomyces pararoseus represents a hyper-producer of carotenoids, mainly including β–carotene, torulene, and torularhodin. Geranylgeranyl diphosphate synthase (GGPPS) is regarded as a key enzyme in the carotenoid biosynthesis pathway. However, the precise nature of the gene encoding GGPPS in S. pararoseus has not been reported yet. Here, we cloned a cDNA copy of the GGPPS protein-encoding gene crtE from S. pararoseus NGR. The crtE full-length genomic DNA and cDNA are 1,722 and 1,134 bp, respectively, which consist of 9 exons and 8 introns. This gene encodes 377 amino acids protein with a predicted molecular mass of 42.59 kDa and a PI of 5.66. Identification of the crtE gene encoding a functional GGPPS was performed using heterologous complementation detection in Escherichia coli. In vitro enzymatic activity experiments showed that CrtE utilized farnesyl diphosphate (FPP) as an allylic substrate for the condensation reaction with isopentenyl diphosphate (IPP), generating more of the unique product GGPP compared to other allylic substrates. The predicted CrtE 3D-model was analyzed in comparison with yeast GGPPS. The condensation reaction occurs in the cavity of the subunit, and three bulky amino acids (Tyr110, Phe111, and His141) below the cavity prevent further extension of the product. Our findings provide a new source of genes for carotenoid genetic engineering.
Structural insights into the PrpTA toxin–antitoxin system in Pseudoalteromonas rubra
Authors: Wang Chenchen , Niu Chuanying , Hidayatullah Khan Muhammad , Xue Lu , Zhu Zhongliang , Niu Liwen
Published: November 2022

Bacteria could survive stresses by a poorly understood mechanism that contributes to the emergence of bacterial persisters exhibiting multidrug tolerance (MDT). Recently, Pseudoalteromonas rubra prpAT module was found to encode a toxin PrpT and corresponding cognate antidote PrpA. In this study, we first reported multiple individual and complex structures of PrpA and PrpT, which uncovered the high-resolution three-dimensional structure of the PrpT:PrpA2:PrpT heterotetramer with the aid of size exclusion chromatography-multi-angle light scattering experiments (SEC-MALS). PrpT:PrpA2:PrpT is composed of a PrpA homodimer and two PrpT monomers which are relatively isolated from each other and from ParE family. The superposition of antitoxin monomer structures from these structures highlighted the flexible C-terminal domain (CTD). A striking conformational change in the CTDs of PrpA homodimer depolymerized from homotetramer was provoked upon PrpT binding, which accounts for the unique PrpT-PrpARHH mutual interactions and further neutralizes the toxin PrpT. PrpA2–54-form I and II crystal structures both contain a doughnut-shaped hexadecamer formed by eight homodimers organized in a cogwheel-like form via inter-dimer interface dominated by salt bridges and hydrogen bonds. Moreover, PrpA tends to exist in solution as a homodimer other than a homotetramer (SEC-MALS) in the absence of flexible CTD. Multiple multi-dimers, tetramer and hexamer included, of PrpA2–54 mediated by the symmetric homodimer interface and the complicated inter-dimer interface could be observed in the solution. SEC-MALS assays highlighted that phosphate buffer (PB) and the increase in the concentration appear to be favorable for the PrpA2–54 oligomerization in the solution. Taken together with previous research, a model of PrpA2–54 homotetramer in complex with prpAT promoter and the improved mechanism underlying how PrpTA controls the plasmid replication were proposed here.
Consumption of the cell-free or heat-treated fractions of a pitched kefir confers some but not all positive impacts of the corresponding whole kefir
Authors: Bourrie Benjamin C. T. , Forgie Andrew J. , Ju Tingting , Richard Caroline , Cotter Paul D. , Willing Benjamin P.
Published: November 2022

Introduction

Kefir consumption can have many metabolic health benefits, including, in the case of specific kefirs, improvements in plasma and liver lipid profiles. Our group has previously shown that these health benefits are dependent on the microbial composition of the kefir fermentation, and that a pitched kefir (PK1) containing specific traditional microbes can recapitulate the health benefits of a traditional kefir. In this study we investigated how different preparations of kefir impact cholesterol and lipid metabolism and circulating markers of cardiovascular disease risk and determine if freeze-drying impacts health benefits relative to past studies.

Materials and methods

Eight-week-old male and female C57Bl/6 mice were fed a high fat diet (40% kcal from fat) supplemented with one of 3 freeze-dried kefir preparations (whole kefir, cell-free kefir, or heat-treated kefir) for 8 weeks prior to analysis of plasma and liver lipid profiles, circulating cardiovascular disease (CVD) biomarkers, cecal microbiome composition, and cecal short-chain fatty acid levels. These groups of mice were compared to others that were fed a control low-fat diet, control high fat diet or high fat diet supplemented with milk, respectively.

Results

All kefir preparations lowered plasma cholesterol in both male and female mice, while only whole kefir lowered liver cholesterol and triglycerides. Plasma vascular cell adhesion molecule 1 (VCAM-1) was lowered by both whole kefir and heat-treated kefir in male mice but not females, while c-reactive protein (CRP) was unchanged across all high fat diet fed groups in males and females.

Conclusion

These results indicate that some of the metabolic benefits of consumption of this kefir do not require whole kefir while also indicating that there are multiple compounds or components responsible for the different benefits observed.
Natural detoxification of antibiotics in the environment: A one health perspective
Authors: Baquero Fernando , Coque Teresa M. , Martínez José-Luis
Published: November 2022

The extended concept of one health integrates biological, geological, and chemical (bio-geo-chemical) components. Anthropogenic antibiotics are constantly and increasingly released into the soil and water environments. The fate of these drugs in the thin Earth space (“critical zone”) where the biosphere is placed determines the effect of antimicrobial agents on the microbiosphere, which can potentially alter the composition of the ecosystem and lead to the selection of antibiotic-resistant microorganisms including animal and human pathogens. However, soil and water environments are highly heterogeneous in their local composition; thus the permanence and activity of antibiotics. This is a case of “molecular ecology”: antibiotic molecules are adsorbed and eventually inactivated by interacting with biotic and abiotic molecules that are present at different concentrations in different places. There are poorly explored aspects of the pharmacodynamics (PD, biological action) and pharmacokinetics (PK, rates of decay) of antibiotics in water and soil environments. In this review, we explore the various biotic and abiotic factors contributing to antibiotic detoxification in the environment. These factors range from spontaneous degradation to the detoxifying effects produced by clay minerals (forming geochemical platforms with degradative reactions influenced by light, metals, or pH), charcoal, natural organic matter (including cellulose and chitin), biodegradation by bacterial populations and complex bacterial consortia (including “bacterial subsistence”; in other words, microbes taking antibiotics as nutrients), by planktonic microalgae, fungi, plant removal and degradation, or sequestration by living and dead cells (necrobiome detoxification). Many of these processes occur in particulated material where bacteria from various origins (microbiota coalescence) might also attach (microbiotic particles), thereby determining the antibiotic environmental PK/PD and influencing the local selection of antibiotic resistant bacteria. The exploration of this complex field requires a multidisciplinary effort in developing the molecular ecology of antibiotics, but could result in a much more precise determination of the one health hazards of antibiotic production and release.
Cultivable endophytic fungal community associated with the karst endemic plant Nervilia fordii and their antimicrobial activity
Authors: Zhou Ya-Qin , Yao Shao-Chang , Wang Jie , Xie Xin-Yi , Tan Xiao-Ming , Huang Rong-Shao , Yang Xin-Feng , Tan Yong , Yu Li-Ying , Fu Peng
Published: November 2022

Endophytic fungi from medicinal plants with specific pharmacological functions attract much attention to provide the possibility of discovering valuable natural drugs with novel structures and biological activities. Nervilia fordii is a rare and endangered karst endemic plant that is used as medicine and food homology in Guangxi, China. These plants have been reported to have antimicrobial, antitumor, antiviral, and anti-inflammatory activities. However, few studies have focused on the diversity and antibacterial activity of endophytic fungi from N. fordii. In the present study, 184 endophytic fungi were isolated from the healthy tissues of N. fordii, and their molecular diversity and antimicrobial activities were analyzed for the first time. These fungi were categorized into 85 different morphotypes based on the morphological characteristics and the similarity between the target sequence and the reference sequence in the GenBank database. With the exception of 18 unidentified fungi, the fungal isolates belonged to at least 2 phyla, 4 classes, 15 orders, 45 known genera, and 45 different species, which showed high abundance, rich diversity, and obvious tissue specificity. All isolates were employed to screen for their antimicrobial activities via the agar diffusion method against Escherichia coli, Staphylococcus aureus, and Candida tropicalis. Among these endophytes, eight strains (9.41%) displayed inhibitory activity against E. coli, 11 strains (12.94%) against S. aureus, and two strains (2.35%) against C. tropicalis, to some extent. In particular, our study showed for the first time that the fungal agar plugs of Penicillium macrosclerotiorum 1151# exhibited promising antibacterial activity against E. coli and S. aureus. Moreover, the ethyl acetate (EA) extract of P. macrosclerotiorum 1151# had antibacterial effects against E. coli and S. aureus with a minimum inhibitory concentration (MIC) of 0.5 mg ml–1. Further research also confirmed that one of the antimicrobial compounds of P. macrosclerotiorum 1151# was methyl chloroacetate and exhibited excellent antibacterial activity against E. coli and S. aureus up to 1.71-fold and 1.13-fold compared with tetracycline (TET) (5 mg ml–1), respectively. Taken together, the present data suggest that various endophytic fungi of N. fordii could be exploited as sources of novel natural antimicrobial agents.
Formic acid, an organic acid food preservative, induces viable-but-non-culturable state, and triggers new Antimicrobial Resistance traits in Acinetobacter baumannii and Klebsiella pneumoniae
Authors: Yadav Manisha , Dhyani Samridhi , Joshi Pooja , Awasthi Sakshi , Tanwar Subhash , Gupta Vishal , Rathore Deepak K. , Chaudhuri Susmita
Published: November 2022

Numerous human pathogens, especially Gram-negative bacteria, are able to enter the viable-but-non-culturable (VBNC) state when they are exposed to environmental stressors and pose the risk of being resuscitated and causing infection after the removal of the trigger. Widely used food preservatives like weak organic acids are potential VBNC inducers in food processing and packaging facilities but have only been reported for food-borne pathogens. In the present study, it is demonstrated for the first time that one such agent, formic acid (FA), can induce a VBNC state at food processing, storage, and distribution temperatures (4, 25, and 37°C) with a varied time of treatment (days 4–10) in pathogenic Gram-negative bacteria Acinetobacter baumannii and Klebsiella pneumoniae. The use of hospital-associated pathogens is critical based on the earlier reports that demonstrated the presence of these bacteria in hospital kitchens and commonly consumed foods. VBNC induction was validated by multiple parameters, e.g., non-culturability, metabolic activity as energy production, respiratory markers, and membrane integrity. Furthermore, it was demonstrated that the removal of FA was able to resuscitate VBNC with an increased expression of multiple virulence and Antimicrobial Resistance (AMR) genes in both pathogens. Since food additives/preservatives are significantly used in most food manufacturing facilities supplying to hospitals, contamination of these packaged foods with pathogenic bacteria and the consequence of exposure to food additives emerge as pertinent issues for infection control, and control of antimicrobial resistance in the hospital setting.
Screening of bioflocculant and cellulase-producing bacteria strains for biofloc culture systems with fiber-rich carbon source
Authors: Wu Jinping , Chen Yifeng , Xu Xueni , Ren Wei , Zhang Xiang , Cai Xiaoni , Huang Aiyou , Zeng Yanhua , Long Hao , Xie Zhenyu
Published: November 2022

The biofloc technology (BFT) system has been widely applied in the shrimp and fish culture industry for its advantages in water-saving, growth improvement, and water quality purification. However, The BFT system usually takes a long time to establish, and the extra carbon source input increases the maintenance cost of the system. In this study, we aimed to develop a low-cost and high-efficient BFT system for Litopenaeus vannamei by applying bacteria that could promote the formation of BFT and utilize cheap carbon sources. Three bioflocculant-producing bacteria strains (M13, M15, and M17) have been screened from a cellulolytic strain collection. All three strains have been identified as Bacillus spp. and can use sugarcane bagasse (SB) as a carbon source, which is a cheap byproduct of the sucrose industry in the tropic area of China. Compared to sucrose, the addition of SB and the three strains could improve the biofloc formation rate, biofloc size distribution, ammonia removal rate, and the growth performance of the shrimps. These results suggest that the bioflocculant and cellulase-producing bacteria strains could promote the biofloc formation and the growth of shrimps by using SB as an economic substitute carbon source in the BFT shrimp culture system.
Untargeted metabolomics screening reveals unique secondary metabolite production from Alternaria section Alternaria
Authors: Witte Thomas E. , Villenueve Nicolas , Shields Samuel W. , Sproule Amanda , Eggertson Quinn , Kim Natalie E. , Boddy Christopher N. , Dettman Jeremy R. , Overy David P.
Published: November 2022

Alternaria section Alternaria is comprised of many species that infect a broad diversity of important crop plants and cause post-harvest spoilage. Alternaria section Alternaria species, such as A. alternata and A. arborescens, are prolific producers of secondary metabolites that act as virulence factors of disease and are mycotoxins that accumulate in infected tissues—metabolites that can vary in their spectrum of production between individuals from the same fungal species. Untargeted metabolomics profiling of secondary metabolite production using mass spectrometry is an effective means to detect phenotypic anomalies in secondary metabolism within a species. Secondary metabolite phenotypes from 36 Alternaria section Alternaria isolates were constructed to observe frequency of production patterns. A clear and unique mass feature pattern was observed for three of the strains that were linked with the production of the dehydrocurvularin family of toxins and associated detoxification products. Examination of corresponding genomes revealed the presence of the dehydrocurvularin biosynthesis gene cluster associated with a sub-telomeric accessory region. A comparison of sequence similarity and occurrences of the dehydrocurvularin biosynthetic gene cluster within Pleosporalean fungi is presented and discussed.
Endothelial-mesenchymal transition induced by metastatic 4T1 breast cancer cells in pulmonary endothelium in aged mice
Authors: Smeda Marta , Jasztal Agnieszka , Maleki Ebrahim H , Bar Anna , Sternak Magdalena , Kwiatkowski Grzegorz , Suraj-Prażmowska Joanna , Proniewski Bartosz , Kieronska-Rudek Anna , Wojnar-Lason Kamila , Skrzypek Klaudia , Majka Marcin , Chrabaszcz Karolina , Malek Kamilla , Chlopicki Stefan
Published: November 2022

Ageing is a major risk factor for cancer metastasis but the underlying mechanisms remain unclear. Here, we characterised ageing effects on cancer-induced endothelial-mesenchymal transition (EndMT) in the pulmonary circulation of female BALB/c mice in a metastatic 4T1 breast cancer model. The effect of intravenously injected 4T1 cells on pulmonary endothelium, pulmonary metastasis, lung tissue architecture, and systemic endothelium was compared between 40-week-old and 20-week-old mice. The 40-week-old mice showed features of ongoing EndMT in their lungs before 4T1 breast cancer cell injection. Moreover, they had preexisting endothelial dysfunction in the aorta detected by in vivo magnetic resonance imaging (MRI) compared to 20-week-old mice. The injection of 4T1 breast cancer cells into 40-week-old mice resulted in rapid EndMT progression in their lungs. In contrast, injection of 4T1 breast cancer cells into 20-week-old mice resulted in initiation and less pronounced EndMT progression. Although the number of metastases did not differ significantly between 20-week-old and 40-week-old mice, the lungs of older mice displayed altered lung tissue architecture and biochemical content, reflected in higher Amide II/Amide I ratio, higher fibronectin levels, and hypoxia-inducible factor 1 subunit alpha (HIF1α) levels as well as lower nitric oxide (NO) production. Our results indicate that age-dependent pre-existing endothelial dysfunction in the pulmonary endothelium of 40-week-old mice predisposed them to rapid EndMT progression in the presence of circulating 4T1 breast cancer cells what might contribute to a more severe metastatic breast cancer phenotype in these ageing mice compared to younger mice.
Predicting the brain age of children with cerebral palsy using a two-dimensional convolutional neural networks prediction model without gray and white matter segmentation
Authors: Zhang Chun-yu , Yan Bao-feng , Mutalifu Nurehemaiti , Fu Ya-wei , Shao Jiang , Wu Jun-jie , Guan Qi , Biedelehan Song-hai , Tong Ling-xiao , Luan Xin-ping
Published: November 2022

Background

Abnormal brain development is common in children with cerebral palsy (CP), but there are no recent reports on the actual brain age of children with CP.

Objective

Our objective is to use the brain age prediction model to explore the law of brain development in children with CP.

Methods

A two-dimensional convolutional neural networks brain age prediction model was designed without segmenting the white and gray matter. Training and testing brain age prediction model using magnetic resonance images of healthy people in a public database. The brain age of children with CP aged 5–27 years old was predicted.

Results

The training dataset mean absolute error (MAE) = 1.85, r = 0.99; test dataset MAE = 3.98, r = 0.95. The brain age gap estimation (BrainAGE) of the 5- to 27-year-old patients with CP was generally higher than that of healthy peers (p < 0.0001). The BrainAGE of male patients with CP was higher than that of female patients (p < 0.05). The BrainAGE of patients with bilateral spastic CP was higher than those with unilateral spastic CP (p < 0.05).

Conclusion

A two-dimensional convolutional neural networks brain age prediction model allows for brain age prediction using routine hospital T1-weighted head MRI without segmenting the white and gray matter of the brain. At the same time, these findings suggest that brain aging occurs in patients with CP after brain damage. Female patients with CP are more likely to return to their original brain development trajectory than male patients after brain injury. In patients with spastic CP, brain aging is more serious in those with bilateral cerebral hemisphere injury than in those with unilateral cerebral hemisphere injury.
Stroke thrombolysis in a middle-income country: A case study exploring the determinants of its implementation
Authors: Hwong Wen Yea , Ng Sock Wen , Tong Seng Fah , Ab Rahman Norazida , Law Wan Chung , Kaman Zurainah , Wong Sing Keat , Puvanarajah Santhi Datuk , Sivasampu Sheamini
Published: November 2022

Introduction

Translation of evidence into clinical practice for use of intravenous thrombolysis in acute stroke care has been slow, especially across low- and middle-income countries. In Malaysia where the average national uptake was poor among the public hospitals in 2018, one hospital intriguingly showed comparable thrombolysis rates to high-income countries. This study aimed to explore and provide in-depth understanding of factors and explanations for the high rates of intravenous stroke thrombolysis in this hospital.

Methods

This single case study sourced data using a multimethod approach: (1) semi-structured in-depth interviews and focus group discussions, (2) surveys, and (3) review of medical records. The Tailored Implementation of Chronic Diseases (TICD) framework was used as a guide to understand the determinants of implementation. Twenty-nine participants comprising the Hospital Director, neurologists, emergency physicians, radiologists, pharmacists, nurses and medical assistants (MAs) were included. Thematic analyses were conducted inductively before triangulated with quantitative analyses and document reviews.

Results

Favorable factors contributing to the uptake included: (1) cohesiveness of team members which comprised of positive interprofessional team dynamics, shared personal beliefs and values, and passionate leadership, and (2) facilitative work process through simplification of workflow and understanding the rationale of the sense of urgency. Patient factors was a limiting factor. Almost two third of ischemic stroke patients arrived at the hospital outside the therapeutic window time, attributing patients' delayed presentation as a main barrier to the uptake of intravenous stroke thrombolysis. One other barrier was the availability of resources, although this was innovatively optimized to minimize its impact on the uptake of the therapy. As such, potential in-hospital delays accounted for only 3.8% of patients who missed the opportunity to receive thrombolysis.

Conclusions

Despite the ongoing challenges, the success in implementing intravenous stroke thrombolysis as standard of care was attributed to the cohesiveness of team members and having facilitative work processes. For countries of similar settings, plans to improve the uptake of intravenous stroke thrombolysis should consider the inclusion of interventions targeting on these modifiable factors.
Protective role of butyrate in obesity and diabetes: New insights
Authors: Mayorga-Ramos Arianna , Barba-Ostria Carlos , Simancas-Racines Daniel , Guamán Linda P.
Published: November 2022

Studies in human microbiota dysbiosis have shown that short-chain fatty acids (SCFAs) like propionate, acetate, and particularly butyrate, positively affect energy homeostasis, behavior, and inflammation. This positive effect can be demonstrated in the reduction of butyrate-producing bacteria observed in the gut microbiota of individuals with type 2 diabetes (T2DM) and other energy-associated metabolic alterations. Butyrate is the major end product of dietary fiber bacterial fermentation in the large intestine and serves as the primary energy source for colonocytes. In addition, it plays a key role in reducing glycemia and improving body weight control and insulin sensitivity. The major mechanisms involved in butyrate regulation include key signaling pathways such as AMPK, p38, HDAC inhibition, and cAMP production/signaling. Treatment strategies using butyrate aim to increase its intestine levels, bioavailability, and improvement in delivery either through direct supplementation or by increasing dietary fiber in the diet, which ultimately generates a higher production of butyrate in the gut. In the final part of this review, we present a summary of the most relevant studies currently being carried out in humans.
The role of tumor microenvironment reprogramming in primary liver cancer chemotherapy resistance
Authors: Zhao Chunyu , Liu Shanshuo , Gao Feng , Zou Yawen , Ren Zhigang , Yu Zujiang
Published: November 2022

Primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and other rare tumours, is the second leading cause of cancer-related mortality. It has been a major contributor to the cancer burden worldwide. Of all primary liver cancer, HCC is the most common type. Over the past few decades, chemotherapy, immunotherapy and other therapies have been identified as applicable to the treatment of HCC. However, evidence suggests that chemotherapy resistance is associated with higher mortality rates in liver cancer. The tumour microenvironment (TME), which includes molecular, cellular, extracellular matrix(ECM), and vascular signalling pathways, is a complex ecosystem. It is now increasingly recognized that the tumour microenvironment plays a pivotal role in PLC prognosis, progression and treatment response. Cancer cells reprogram the tumour microenvironment to develop resistance to chemotherapy drugs distinct from normal differentiated tissues. Chemotherapy resistance mechanisms are reshaped during TME reprogramming. For this reason, TME reprogramming can provide a powerful tool to understand better both cancer-fate processes and regenerative, with the potential to develop a new treatment. This review discusses the recent progress of tumour drug resistance, particularly tumour microenvironment reprogramming in tumour chemotherapy resistance, and focuses on its potential application prospects.
Machine-learning classifiers based on non-enhanced computed tomography radiomics to differentiate anterior mediastinal cysts from thymomas and low-risk from high-risk thymomas: A multi-center study
Authors: Shang Lan , Wang Fang , Gao Yan , Zhou Chaoxin , Wang Jian , Chen Xinyue , Chughtai Aamer Rasheed , Pu Hong , Zhang Guojin , Kong Weifang
Published: November 2022

Background

This study aimed to investigate the diagnostic value of machine-learning (ML) models with multiple classifiers based on non-enhanced CT Radiomics features for differentiating anterior mediastinal cysts (AMCs) from thymomas, and high-risk from low risk thymomas.

Methods

In total, 201 patients with AMCs and thymomas from three centers were included and divided into two groups: AMCs vs. thymomas, and high-risk vs low-risk thymomas. A radiomics model (RM) was built with 73 radiomics features that were extracted from the three-dimensional images of each patient. A combined model (CM) was built with clinical features and subjective CT finding features combined with radiomics features. For the RM and CM in each group, five selection methods were adopted to select suitable features for the classifier, and seven ML classifiers were employed to build discriminative models. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of each combination.

Results

Several classifiers combined with suitable selection methods demonstrated good diagnostic performance with areas under the curves (AUCs) of 0.876 and 0.922 for the RM and CM in group 1 and 0.747 and 0.783 for the RM and CM in group 2, respectively. The combination of support vector machine (SVM) as the feature-selection method and Gradient Boosting Decision Tree (GBDT) as the classification algorithm represented the best comprehensive discriminative ability in both group. Comparatively, assessments by radiologists achieved a middle AUCs of 0.656 and 0.626 in the two groups, which were lower than the AUCs of the RM and CM. Most CMs exhibited higher AUC value compared to RMs in both groups, among them only a few CMs demonstrated better performance with significant difference in group 1.

Conclusion

Our ML models demonstrated good performance for differentiation of AMCs from thymomas and low-risk from high-risk thymomas. ML based on non-enhanced CT radiomics may serve as a novel preoperative tool.
Models including preoperative plasma levels of angiogenic factors, leptin and IL-8 as potential biomarkers of endometrial cancer
Authors: Roškar Luka , Pušić Maja , Roškar Irena , Kokol Marko , Pirš Boštjan , Smrkolj Špela , Rižner Tea Lanišnik
Published: November 2022

Background

The diversity of endometrial cancer (EC) dictates the need for precise early diagnosis and pre-operative stratification to select treatment options appropriately. Non-invasive biomarkers invaluably assist clinicians in managing patients in daily clinical practice. Currently, there are no validated diagnostic or prognostic biomarkers for EC that could accurately predict the presence and extent of the disease.

Methods

Our study analyzed 202 patients, of whom 91 were diagnosed with EC and 111 were control patients with the benign gynecological disease. Using Luminex xMAP™ multiplexing technology, we measured the pre-operative plasma concentrations of six previously selected angiogenic factors – leptin, IL-8, sTie-2, follistatin, neuropilin-1, and G-CSF. Besides basic statistical methods, we used a machine-learning algorithm to create a robust diagnostic model based on the plasma concentration of tested angiogenic factors.

Results

The plasma levels of leptin were significantly higher in EC patients than in control patients. Leptin was higher in type 1 EC patients versus control patients, and IL-8 was higher in type 2 EC versus control patients, particularly in poorly differentiated endometrioid EC grade 3. IL-8 plasma levels were significantly higher in EC patients with lymphovascular or myometrial invasion. Among univariate models, the model based on leptin reached the best results on both training and test datasets. A combination of age, IL-8, leptin and G-CSF was determined as the most important feature for the multivariate model, with ROC AUC 0.94 on training and 0.81 on the test dataset. The model utilizing a combination of all six AFs, BMI and age reached a ROC AUC of 0.89 on both the training and test dataset, strongly indicating the capability for predicting the risk of EC even on unseen data.

Conclusion

According to our results, measuring plasma concentrations of angiogenic factors could, provided they are confirmed in a multicentre validation study, represent an important supplementary diagnostic tool for early detection and prognostic characterization of EC, which could guide the decision-making regarding the extent of treatment.
Assessing chemotherapy dosing strategies in a spatial cell culture model
Authors: Deb Dhruba , Zhu Shu , LeBlanc Michael J. , Danino Tal
Published: November 2022

Predicting patient responses to chemotherapy regimens is a major challenge in cancer treatment. Experimental model systems coupled with quantitative mathematical models to calculate optimal dose and frequency of drugs can enable improved chemotherapy regimens. Here we developed a simple approach to track two-dimensional cell colonies composed of chemo-sensitive and resistant cell populations via fluorescence microscopy and coupled this to computational model predictions. Specifically, we first developed multiple 4T1 breast cancer cell lines resistant to varying concentrations of doxorubicin, and demonstrated how heterogeneous populations expand in a two-dimensional colony. We subjected cell populations to varied dose and frequency of chemotherapy and measured colony growth. We then built a mathematical model to describe the dynamics of both chemosensitive and chemoresistant populations, where we determined which number of doses can produce the smallest tumor size based on parameters in the system. Finally, using an in vitro model we demonstrated multiple doses can decrease overall colony growth as compared to a single dose at the same total dose. In the future, this system can be adapted to optimize dosing strategies in the setting of heterogeneous cell types or patient derived cells with varied chemoresistance.
Ultrasound image intelligent diagnosis in community-acquired pneumonia of children using convolutional neural network-based transfer learning
Authors: Fang Xiaohui , Li Wen , Huang Junjie , Li Weimei , Feng Qingzhong , Han Yanlin , Ding Xiaowei , Zhang Jinping
Published: November 2022

Background

Studies show that lung ultrasound (LUS) can accurately diagnose community-acquired pneumonia (CAP) and keep children away from radiation, however, it takes a long time and requires experienced doctors. Therefore, a robust, automatic and computer-based diagnosis of LUS is essential.

Objective

To construct and analyze convolutional neural networks (CNNs) based on transfer learning (TL) to explore the feasibility of ultrasound image diagnosis and grading in CAP of children.

Methods

89 children expected to receive a diagnosis of CAP were prospectively enrolled. Clinical data were collected, a LUS images database was established comprising 916 LUS images, and the diagnostic values of LUS in CAP were analyzed. We employed pre-trained models (AlexNet, VGG 16, VGG 19, Inception v3, ResNet 18, ResNet 50, DenseNet 121 and DenseNet 201) to perform CAP diagnosis and grading on the LUS database and evaluated the performance of each model.

Results

Among the 89 children, 24 were in the non-CAP group, and 65 were finally diagnosed with CAP, including 44 in the mild group and 21 in the severe group. LUS was highly consistent with clinical diagnosis, CXR and chest CT (kappa values = 0.943, 0.837, 0.835). Experimental results revealed that, after k-fold cross-validation, Inception v3 obtained the best diagnosis accuracy, PPV, sensitivity and AUC of 0.87 ± 0.02, 0.90 ± 0.03, 0.92 ± 0.04 and 0.82 ± 0.04, respectively, for our dataset out of all pre-trained models. As a result, best accuracy, PPV and specificity of 0.75 ± 0.03, 0.89 ± 0.05 and 0.80 ± 0.10 were achieved for severity classification in Inception v3.

Conclusions

LUS is a reliable method for diagnosing CAP in children. Experiments showed that, after transfer learning, the CNN models successfully diagnosed and classified LUS of CAP in children; of these, the Inception v3 achieves the best performance and may serve as a tool for the further research and development of AI automatic diagnosis LUS system in clinical applications.

Registration

www.chictr.org.cn ChiCTR2200057328.
The association between statin use and osteoarthritis-related outcomes: An updated systematic review and meta-analysis
Authors: Zhang Zhan , Deng Chunbo , Ma Xun , Wu Qijun , Zhou Fenghua , Liu Xueyong
Published: November 2022

Objective: Findings among studies evaluating the effect of statin use and OA development in a 2020 meta-analysis of data from 11 observational studies of statin use and osteoarthritis (OA) revealed controversial results. We aimed to determine the associations between statin use and OA-related outcomes in an updated meta-analysis.

Methods: The protocol was registered with PROSPERO (CRD42020163983). A systematic literature retrieval was performed in the online databases, including PubMed, Cochrane Library, Embase, Web of Science, and Scopus, from inception to 1 June 2022, for clinical studies that compared the effects of statin users vs. nonusers on OA-related outcomes risks. Systematic reviews and meta-analyses were performed to estimate the correlations between statin use and OA-related outcomes. Tendency analysis was also used to estimate dose-response effects. The risk of bias was evaluated with the Newcastle–Ottawa scale.

Results: We included 23 studies involving more than 6,000,000 participants. Statin use was associated with increased OA risk (OR 1.099 [95%CI 1.002–1.206, p = 0.045]). Higher statin doses had higher OA risk (simvastatin equivalent daily of >40 mg). OA and related surgery risks were significantly reduced in statin users using antihypertensive drugs (AHDs). No significant differences were seen in other outcomes.

Conclusion: This meta-analysis inferred that statin use might be associated with increased OA development, especially at higher doses. The present study highlights the importance of recognizing potential OA risk in the population with long-term and/or high-dose statin use, especially in older populations. In addition, AHDs are associated with lower OA risk and fewer surgeries in hypertensive statin users. Due to limitations of heterogeneity and confounders, more rigorous studies are needed to define the correlations between statin use and OA-related outcomes.
Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients
Authors: Campos-Staffico Alessandra M. , Dorsch Michael P. , Barnes Geoffrey D. , Zhu Hao-Jie , Limdi Nita A. , Luzum Jasmine A.
Published: November 2022

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy.

Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding.

Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients.

Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant.

Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019–1.900); p = 0.038] but not from apixaban (p = 0.487).

Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.
Research progress in traditional Chinese medicine in the treatment of Alzheimer’s disease and related dementias
Authors: Tan Wanying , Qi Lingjun , Hu Xiaoyu , Tan Zhenghuai
Published: November 2022

Alzheimer’s disease (AD) is the world’s leading cause of dementia and has become a huge economic burden on nations and families. However, the exact etiology of AD is still unknown, and there are no efficient medicines or methods to prevent the deterioration of cognition. Traditional Chinese medicine (TCM) has made important contributions in the battle against AD based on the characteristics of multiple targets of TCM. This study reviewed the treatment strategies and new discoveries of traditional Chinese medicine in current research, which may be beneficial to new drug researchers.
Finite-time synchronization of Kuramoto-oscillator networks with a pacemaker based on cyber-physical system
Authors: Rao Pengchun , Guo Xiufeng
Published: November 2022

In this paper, we study the finite-time synchronization problem of a Kuramoto-oscillator network with a pacemaker. By constructing a cyber-physical system (CPS), the finite-time phase agreement and frequency synchronization of the network are explored for identical and non-identical oscillators, respectively. According to the Lyapunov stability analysis, sufficient conditions are deduced for ensuring the phase agreement and frequency synchronization for arbitrary initial phases and/or frequencies under distributed strategies. Furthermore, the upper bound estimations of convergence time are obtained accordingly, which is related to the initial phases and/or frequencies of oscillators. Finally, numerical examples are presented to verify the effectiveness of the theoretical results.
The prediction and verification of outcome of extracardiac conduits fontan based on computational fluid dynamics simulation
Authors: Zhang Yong , Fang Minhua , Wang Zengwei , Liu Yu , Zhang Chunzhen , Wang Zhenlong , Wang Huishan
Published: November 2022

Objective: This study applied preoperative computed tomography angiography (CTA) and computational fluid dynamics (CFD) simulation to predicte and verify the outcome of Y-shaped extracardiac conduits Fontan for functional single ventricle.

Methods: Based on the preoperative CTA data of functional single ventricle (FSV), 4 types of spatial structures of extracardiac conduits were designed for 4 experimental groups: Group A, a traditional TCPC group (20 mm); Group B, a diameter-preserving Y-shaped TCPC (YCPC) group (branch 10 mm); Group C, YCPC group (branch 12 mm); and Group D, an area-preserving YCPC group (branch14 mm). Four indicators including flow velocity, pressure gradient (PG), energy efficiency and inferior vena cava (IVC) blood flow distribution were compared. The optimal procedure was applied. The radionuclide lung perfusion, CTA, echocardiography, cardiovascular angiography and catheterization were performed postoperatively.

Results: There were the lowest PG, the lowest flow velocity of branches, the highest energy efficiency, and a relatively balanced and stable distribution of IVC flow for group D. Subsequently, the group D, a handcrafted Y-shaped conduit (14 mm) was used for the YCPC procedure. There was no postoperative PG between the conduit and pulmonary artery with normal pressure and resistance. IVC flow was distributed uniformly.

Conclusion: CTA-based CFD provided more guidance for the clinical application of TCPC. A comprehensive surgical design could bring good postoperative outcome. Area-preserving YCPC has more advantages than TCPC and the diameter-preserving YCPC. The study effectively improved the feasibility of clinical applications of YCPC.
Efficacy of cinnamon supplementation on glycolipid metabolism in T2DM diabetes: A meta-analysis and systematic review
Authors: Zhou Qian , Lei Xingxing , Fu Shunlian , Li Zinan , Chen Yiding , Long Cong , Li Suwen , Chen Qiu
Published: November 2022

Background: Cinnamon is a spice used in cooking and in large quantities as a medical complement with hypoglycemic and lipid-lowering properties. The potential pharmacological mechanisms underlying cinnamon’s anti-diabetic properties and its active ingredients have not been adequately determined. The current meta-analysis aims to systematically review the potential pharmacological mechanisms underlying the hypoglycemic and hypolipidemic efficacy of cinnamon administration and summarize clinical recommendations of cinnamon and its active ingredients.

Method: Relevant randomized clinical trials (RCTs) were identified through a literature search that spanned the years January 2005 to April 2022. Retrieve electronic databases including Web of Science, PubMed, Embase, Medline, and the Cochrane Library. To obtain standardized mean differences (SMDs), continuous outcomes were pooled and 95 percent confidence intervals (CIs) were provided. Categorical outcomes were aggregated to calculate relative risks (RRs) and were accompanied by 95% CIs. Heterogeneity was measured using the Cochrane Q-test and I2 statistics, with a p < 0.05 considered as substantial heterogeneity. If I2 was less than 50%, a fixed effect model was employed; otherwise, a random effect model was used. Subgroup analyses and sensitivity analyses were performed to identify the origins of heterogeneity. Publication bias was retrieved by means of a funnel-plot analysis and Egger’s test. The data were analyzed using revman (V.5.3) and stata (V.15) software packages.

Results: These 16 RCTs included a total of 1,020 patients who were followed for a duration ranging from 40 days to 4 months. According to the current meta-analysis results, glycolipid levels in diabetic individuals who received cinnamon were significantly improved as compared to those who got placebo (All p < 0.05). An adverse effect was only detected in one patient.

Conclusion: These findings imply that cinnamon has a significant influence on lipid and glucose metabolism regulation. An even more pronounced effect was observed in patients with HbA1c of 8%. The results of this study suggested that cinnamon may be utilized as hypoglycemic and lipid-lowering supplement in clinical settings with a guaranteed safety profile.Systematic Review Registration: [PROSPERO], identifier [CRD42022322735].
Screening of cold hardiness-related indexes and establishment of a comprehensive evaluation method for grapevines (V. vinifera)
Authors: Wang Zhi-Lei , Wu Dong , Hui Miao , Wang Ying , Han Xing , Yao Fei , Cao Xiao , Li Yi-Han , Li Hua , Wang Hua
Published: November 2022

The goals of this work were to screen physiological and biochemical indexes to assess a set of V. vinifera germplasm resources, to compare evaluation methods for cold hardiness, and to establish a comprehensive method that can be used for more accurate screening for cold hardiness in V. vinifera. Four single methods were used to evaluate the cold hardiness of 20 germplasms resources and 18 physiological and biochemical indexes related to cold hardiness were determined. The LT50 values determined by electrical conductivity (EL), 2,3,5-triphenyltetrazolium chloride staining (TTC), differential thermal analysis (DTA), and recovery growth (RG) methods showed extremely significant positive correlation. Bound water content (BW), proline content (Pro), total soluble sugar content (TSS), malondialdehyde content (MDA), catalase content (CAT), and ascorbic acid content (ASA) exhibited significant correlation with LT50 values measured by different evaluation methods. The comprehensive cold hardiness index calculated by principal component analysis (PCA) combined with subordinate function (SF) was negatively correlated with LT50 values measured by different evaluation methods. Meili and Ecolly exhibited the highest cold hardiness, indicating their potential for use as parents for cold hardiness breeding. EL, DTA, TTC, and RG methods successfully distinguished cold hardiness among different V. vinifera germplasm lines. Measurements of BW, Pro, TSS, MDA, CAT, and ASA in dormant shoots also can be used as main physiological and biochemical indexes related to cold hardiness of V. vinifera. Comprehensive evaluation by PCA combined with SF can accurately screen cold hardiness in V. vinifera. This study provides a reference and accurate identification method for the selection of cold hardiness parents and the evaluation of cold hardiness of germplasm of V. vinifera.