bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and validation of a muscle failure index to predict prognosis and immunotherapy in lung adenocarcinoma through integrated analysis of bulk and single-cell RNA sequencing data
Authors: Gu Xuyu , Cai Lubing , Luo Zhiwen , Shi Luze , Peng Zhen , Sun Yaying , Chen Jiwu
Published: January 2023

Background

It was previously reported that the production of exerkines is positively associated with the beneficial effects of exercise in lung adenocarcinoma (LUAD) patients. This study proposes a novel scoring system based on muscle failure-related genes, to assist in clinical decision making.

Methods

A comprehensive analysis of bulk and single cell RNA sequencing (scRNA-seq) of early, advanced and brain metastatic LUAD tissues and normal lung tissues was performed to identify muscle failure-related genes in LUAD and to determine the distribution of muscle failure-related genes in different cell populations. A novel scoring system, named MFI (Muscle failure index), was developed and validated. The differences in biological functions, immune infiltration, genomic alterations, and clinical significance of different subtypes were also investigated.

Results

First, we conducted single cell analysis on the dataset GSE131907 and identified eight cell subpopulations. We found that four muscle failure-related genes (BDNF, FNDC5, IL15, MSTN) were significantly increased in tumor cells. In addition, IL15 was widely distributed in the immune cell population. And we have validated it in our own clinical cohort. Then we created the MFI model based on 10 muscle failure-related genes using the LASSO algorithm, and MFI remained an independent prognostic factor of OS in both the training and validation cohorts. Moreover, we generated MFI in the single-cell dataset, in which cells with high MFI received and sent more signals compared to those with low MFI. Biological function analysis of both subtypes revealed stronger anti-tumor immune activity in the low MFI group, while tumor cells with high MFI had stronger metabolic and proliferative activity. Finally, we systematically assessed the immune cell activity and immunotherapy responses in LUAD patients, finding that the low MFI group was more sensitive to immunotherapy.

Conclusion

Overall, our study can improve the understanding of the role of muscle failure-related genes in tumorigenesis and we constructed a reliable MFI model for predicting prognosis and guiding future clinical decision making.
Immunogenicity and reactogenicity of accelerated regimens of fractional intradermal COVID-19 vaccinations
Authors: Niyomnaitham Suvimol , Atakulreka Suparat , Wongprompitak Patimaporn , Copeland Katherine Kradangna , Toh Zheng Quan , Licciardi Paul V. , Srisutthisamphan Kanjana , Jansarikit Laddawan , Chokephaibulkit Kulkanya
Published: January 2023

Introduction

This phase I study explored the immunogenicity and reactogenicity of accelerated, Q7 fractional, intradermal vaccination regimens for COVID-19.

Methods

Participants (n = 60) aged 18-60 years, naïve to SARS-CoV-2 infection or vaccination, were randomly allocated into one of four homologous or heterologous accelerated two-dose, two-injection intradermal regimens seven days apart:(1) BNT162b2-BNT162b2(n= 20),(2) ChAdOx1- BNT162b2 (n = 20), (3) CoronaVac-ChAdOx1 (n = 10), and (4) ChAdOx1-ChAdOx1 (n = 10). CoronaVac and ChAdOx1 were 20%, and BNT162b2 17%, of their standard intramuscular doses (0.1 mL and 0.05 mL per injection, respectively). Humoral immune responses were measured through IgG response towards receptor binding domains (RBD-IgG) of ancestral SARS-CoV-2 spike protein and pseudovirus neutralization tests (PVNT50). Cellular immune responses were measured using ELISpot for ancestral protein pools.

Results

Immunogenicity was highest in regimen (2), followed by (1), (4), and (3) 2 weeks after the second dose (P < 0.001 for anti-RBD-IgG and P= 0.01 for PVNT50). Each group had significantly lower anti-RBD IgG (by factors of 5.4, 3.6, 11.6, and 2.0 for regimens (1) to (4), respectively) compared to their respective standard intramuscular regimens (P < 0.001 for each). Seroconversion rates for PVNT50 against the ancestral strain were 75%, 90%, 57% and 37% for regimens (1) to (4), respectively. All participants elicited ELISpot response to S-protein after vaccination. Adverse events were reportedly mild or moderate across cohorts.

Discussion

We concluded that accelerated, fractional, heterologous or homologous intradermal vaccination regimens of BNT162b2 and ChAdOx1 were well tolerated, provided rapid immune priming against SARS-CoV-2, and may prove useful for containing future outbreaks.
A multi-epitope vaccine GILE against Echinococcus Multilocularis infection in mice
Authors: Zhou Pei , Zhou Zhen , Huayu Meiduo , Wang Lei , Feng Lin , Xiao Yang , Dai Yao , Xin Mingyuan , Tang Feng , Li Runle
Published: January 2023

Introduction

The objective of this study is to construct a multi-epitope vaccine GILE containing B-cell and T-cell epitopes against Echinococcus Multilocularis (E. multilocularis) infection based on the dominant epitopes of E. multilocularis EMY162, LAP, and GLUT1.

Methods

The structure and hydrophobicity of GILE were predicted by SWISSMODEL, pyMOL, SOPMA and VMD, and its sequence was optimized by Optimum™ Codon. The GILE gene was inserted into pCzn1 and transformed into Escherichia coli Arctic express competent cells. IPTG was added to induce the expression of recombinant proteins. High-purity GILE recombinant protein was obtained by Ni-NTA Resin. BALB/c mice were immunized with GILE mixed with Freund’s adjuvant, and the antibody levels and dynamic changes in the serum were detected by ELISA. Lymphocyte proliferation was detected by MTS. The levels of IFN-g and IL-4 were detected by ELISpot and flow cytometry (FCM). T cells were detected by FCM. The growth of hepatic cysts was evaluated by Ultrasound and their weights were measured to evaluate the immune protective effect of GILE.

Results

The SWISS-MODEL analysis showed that the optimal model was EMY162 95-104―LAP464-479―LAP495-510―LAP396-410―LAP504-518―EMY162112-126. The SOPMA results showed that there were Alpha helix (14.88%), Extended strand (26.25%), Beta turn (3.73%) and Random coil (45.82%) in the secondary structure of GILE. The restriction enzyme digestion and sequencing results suggested that the plasmid pCzn1-GILE was successfully constructed. The SDSPAGE results indicated that the recombinant protein was 44.68 KD. The ELISA results indicated that mice immunized with GILE showed higher levels of serum antibodies compared to the PBS group. The FCM and ELISpot results indicated that mice immunized with GILE secreted more IFN-g and IL-4. Immunization with GILE also led to a significant decrease in the maximum diameter and weight of cysts and stimulated the production of CD4+ and CD8+ T Cell.

Discussion

A multi-epitope vaccine GILE with good immunogenicity and antigenicity has been successfully constructed in this study, which may provide important theoretical and experimental bases for the prevention and treatment of E. multilocularis infection.
Effect of immunostimulation with bacterial lysate on the clinical course of allergic rhinitis and the level of γδT, iNKT and cytotoxic T cells in children sensitized to grass pollen allergens: A randomized controlled trial
Authors: Janeczek Kamil , Kowalska Wioleta , Zarobkiewicz Michał , Suszczyk Dorota , Mikołajczyk Marek , Markut-Miotła Ewa , Morawska-Michalska Izabela , Bakiera Adrian , Tomczak Aleksandra , Kaczyńska Agnieszka , Emeryk Andrzej , Roliński Jacek , Piotrowska-Weryszko Krystyna
Published: January 2023

Background

There are many drugs for allergic rhinitis (AR), however, these drugs show variable clinical effectiveness and some side effects. Therefore, new methods of AR pharmacotherapy are being sought.

Objectives

The objectives of this study were to evaluate the efficacy of polyvalent mechanical bacterial lysate (PMBL) therapy in improving the clinical course of grass pollen-induced AR (seasonal AR, SAR) in children and its effect on changes in the blood level of the γδT, iNKT and cytotoxic T cell subsets.

Methods

Fifty children with SAR were enrolled in this study and were randomly assigned to either the PMBL group or the placebo group. The severity of SAR symptoms was assessed using the total nasal symptom score (TNSS) and visual analogue scale (VAS). During two visits (V1, V2), peak nasal inspiratory flow (PNIF) was measured and peripheral blood was collected for immunological analyses. The study also included 2 telephone contacts (TC1, TC2).

Results

The severity of the nasal symptoms of SAR on the TNSS scale was revealed to have a significantly lower impact in the PMBL group vs the placebo group at measuring points TC1 and V2 (p = 0.01, p = 0.009, respectively). A statistically significantly lower mean severity of nasal symptoms of SAR on the VAS scale was recorded for children in the PMBL group compared to the placebo group at measuring points TC1, V2 and TC2 (p = 0.04, p = 0.04, p = 0.03, respectively). The compared groups do not show significant differences in terms of PNIF values at individual measuring points. There were no statistically significant changes in immune variables. For both groups, there was a statistically significant association between the level of Th1-like γδT cells and the severity of SAR symptoms expressed on the TNSS scale (p = 0.03) – the lower the level of Th1-like γδT cells, the higher the TNSS value.

Conclusion

Administration of sublingual PMBL tablets during the grass pollen season proves to have a high efficacy in alleviating SAR symptoms in children sensitized to grass pollen allergens. Th1-like γδT cells may be used as potential markers for SAR severity in children.

Clinical trial registration

ClinicalTrials.gov, identifier (NCT04802616).
Bone-marrow derived cells do not contribute to new beta-cells in the inflamed pancreas
Authors: Jiang Yinan , Wiersch John , Wu Wei , Qian Jieqi , Adama Maharana Prathap R. , Wu Nannan , Yang Weixia , Chen Congde , Zhu Lingyan , Prasadan Krishna , Gittes George K. , Xiao Xiangwei
Published: January 2023

The contribution of bone-marrow derived cells (BMCs) to a newly formed beta-cell population in adults is controversial. Previous studies have only used models of bone marrow transplantation from sex-mismatched donors (or other models of genetic labeling) into recipient animals that had undergone irradiation. This approach suffers from the significant shortcoming of the off-target effects of irradiation. Partial pancreatic duct ligation (PDL) is a mouse model of acute pancreatitis with a modest increase in beta-cell number. However, the possibility that recruited BMCs in the inflamed pancreas may convert into beta-cells has not been examined. Here, we used an irradiation-free model to track the fate of the BMCs from the donor mice. A ROSA-mTmG red fluorescent mouse was surgically joined to an INS1Cre knock-in mouse by parabiosis to establish a mixed circulation. PDL was then performed in the INS1Cre mice 2 weeks after parabiosis, which was one week after establishment of the stable blood chimera. The contribution of red cells from ROSA-mTmG mice to beta-cells in INS1Cre mouse was evaluated based on red fluorescence, while cell fusion was evaluated by the presence of green fluorescence in beta-cells. We did not detect any red or green insulin+ cells in the INS1Cre mice, suggesting that there was no contribution of BMCs to the newly formed beta-cells, either by direct differentiation, or by cell fusion. Thus, the contribution of BMCs to beta-cells in the inflamed pancreas should be minimal, if any.
Discovery of pyrazolopyrrolidinones as potent, broad-spectrum inhibitors of Leishmania infection
Authors: Kavouris John A. , McCall Laura-Isobel , Giardini Miriam A. , De Muylder Geraldine , Thomas Diane , Garcia-Pérez Adolfo , Cantizani Juan , Cotillo Ignacio , Fiandor Jose M. , McKerrow James H. , De Oliveira Camila I. , Siqueira-Neto Jair L. , González Silvia , Brown Lauren E. , Schaus Scott E.
Published: January 2023

Introduction

Leishmaniasis is a parasitic disease that affects more than 1 million people worldwide annually, predominantly in resource-limited settings. The challenge in compound development is to exhibit potent activity against the intracellular stage of the parasite (the stage present in the mammalian host) without harming the infected host cells. We have identified a compound series (pyrazolopyrrolidinones) active against the intracellular parasites of Leishmania donovani and L. major; the causative agents of visceral and cutaneous leishmaniasis in the Old World, respectively.

Methods

In this study, we performed medicinal chemistry on a newly-discovered antileishmanial chemotype, with over 100 analogs tested. Studies included assessments of antileishmanial potency, toxicity towards host cells, and in vitro ADME screening of key drug properties.

Results and discussion

Members of the series showed high potency against the deadliest form, visceral leishmaniasis (approximate EC50 ≥ 0.01 µM without harming the host macrophage up to 10.0 µM). In comparison, the most efficient monotherapy treatment for visceral leishmaniasis is amphotericin B, which presents similar activity in the same assay (EC50 = 0.2 µM) while being cytotoxic to the host cell at 5.0 µM. Continued development of this compound series with the Discovery Partnership with Academia (DPAc) program at the GlaxoSmithKline Diseases of the Developing World (GSK DDW) laboratories found that the compounds passed all of GSK’s criteria to be defined as a potential lead drug series for leishmaniasis.

Conclusion

Here, we describe preliminary structure-activity relationships for antileishmanial pyrazolopyrrolidinones, and our progress towards the identification of candidates for future in vivo assays in models of visceral and cutaneous leishmaniasis.
A sustainable shipping management framework in the marine environment: Institutional pressure, eco-design, and cross-functional perspectives
Authors: Wang Lu , Yao Jinge , Zhang Haikuo , Pang Qiwei , Fang Mingjie
Published: January 2023

The shipping industry plays a vital role in the world trading system and in maintaining the stability of global supply chains. However, we cannot ignore the damage it brings to the marine environment. With a focus on protecting the marine environment, the sustainable development of shipping companies has also drawn growing attention. This study examines the sustainable shipping management practice system and develops a comprehensive framework to evaluate the significance of influencing elements and prioritizes those factors. This paper adopts a fuzzy analytic hierarchy process method. It establishes a total of 11 sub-index systems from three aspects: the external policy pressure of shipping companies, the ecological design of shipping services, and the cross-functional green management within shipping companies. We used the fuzzy analytic hierarchy process (FAHP) to analyze data collected from 37 experts in the Chinese shipping industry. The findings show that external policy pressure is the most critical factor influencing sustainable shipping management, followed by eco-design and cross-functional green management. These factors have a big impact and provide management references for shipping company managers and policymakers. They also give the government a company perspective when creating pertinent regulations.
Heterogeneity in diagnostic characters across ecoregions: A case study with Botrynema (Hydrozoa: Trachylina: Halicreatidae)
Authors: Montenegro Javier , Collins Allen G. , Hopcroft Russell R. , Questel Jennifer M. , Thuesen Erik V. , Bachtel Tiffany S. , Bergman Leah A. , Sangekar Mehul N. , Drazen Jeffrey C. , Lindsay Dhugal J.
Published: January 2023

Introduction

Botrynema, a genus of medusozoans in the trachyline family Halicreatidae, currently contains two species: B. brucei and B. ellinorae, distinguished by the presence or absence, respectively, of an apical knob as a diagnostic character. However, no study has corroborated if these taxonomic diagnoses have a biological and evolutionary basis. Therefore, in this study we attempted to address the question “do the two nominal species in the genus Botrynema represent independent phylogenetic lineages, or two phenotypic variants of a single species?

Methods

In this study we took advantage of legacy collections from different research expeditions across the globe from 2000 to 2021 to study the phylogenetics and taxonomy of the genus Botrynema.

Results

B. brucei and B. ellinorae present partially overlapping vertical distributions in the Arctic and as a whole in the Arctic the genus seems to be limited to the Atlantic water masses. The phylogenetic reconstruction based on the concatenated alignment corroborates the validity of the family Halicreatidae and of genus Botrynema as monophyletic groups. However no clear differentiation was found between the two presently accepted species, B. ellinorae and B. brucei.

Discussion

Based on the evidence we gathered, we conclude that while the genus Botrynema does contain at least two species lineages, these lineages are not concordant with current species definitions. The species B. ellinorae is reassigned as a subspecies of B. brucei and diagnostic characters are provided.
Comparative transcriptome analysis of rainbow trout gonadal cells (RTG-2) infected with U and J genogroup infectious hematopoietic necrosis virus
Authors: Zhao Jing-Zhuang , Xu Li-Ming , Ren Guang-Ming , Shao Yi-Zhi , Liu Qi , Teng Chun-Bo , Lu Tong-Yan
Published: January 2023

Infectious hematopoietic necrosis virus (IHNV) is the causative pathogen of infectious hematopoietic necrosis, outbreaks of which are responsible for significant losses in rainbow trout aquaculture. Strains of IHNV isolated worldwide have been classified into five major genogroups, J, E, L, M, and U. To date, comparative transcriptomic analysis has only been conducted individually for the J and M genogroups. In this study, we compared the transcriptome profiles in U genogroup and J genogroup IHNV-infected RTG-2 cells with mock-infected RTG-2 cells. The RNA-seq results revealed 17,064 new genes, of which 7,390 genes were functionally annotated. Differentially expressed gene (DEG) analysis between U and J IHNV-infected cells revealed 2,238 DEGs, including 1,011 downregulated genes and 1,227 upregulated genes. Among the 2,238 DEGs, 345 new genes were discovered. The DEGs related to immune responses, cellular signal transduction, and viral diseases were further analyzed. RT-qPCR validation confirmed that the changes in expression of the immune response-related genes trpm2, sting, itgb7, ripk2, and irf1, cellular signal transduction-related genes irl, cacnb2, bmp2l, gadd45α, and plk2, and viral disease-related genes mlf1, mtor, armc5, pik3r1, and c-myc were consistent with the results of transcriptome analysis. Taken together, our findings provide a comprehensive transcriptional analysis of the differential virulence of the U and J genogroups of IHNV, and shed new light on the pathogenic mechanisms of IHNV strains.
Facial expression recognition method based on PSA—YOLO network
Authors: Ma Ruoling , Zhang Ruoyuan
Published: January 2023

In order to improve the recognition speed and accuracy of face expression recognition, we propose a face expression recognition method based on PSA—YOLO (Pyramids Squeeze Attention—You Only Look Once). Based on CSPDarknet53, the Focus structure and pyramid compression channel attention mechanism are integrated, and the network depth reduction strategy is adopted to build a PSA-CSPDarknet-1 lightweight backbone network with small parameters and high accuracy, which improves the speed of face expression recognition. Secondly, in the neck of the network, a spatial pyramid convolutional pooling module is built, which enhances the spatial information extraction ability of deep feature maps with a very small computational cost, and uses the α—CIoU loss function as the bounding box loss function to improve the recognition accuracy of the network for targets under high IoU threshold and improve the accuracy of face expression recognition. The proposed method is validated on the JAFFE, CK+, and Cohn-Kanade datasets. The experimental results show that the running time of the proposed method and the comparison method is reduced from 1,800 to 200 ms, and the recognition accuracy is increased by 3.11, 2.58, and 3.91%, respectively, so the method proposed in this paper has good applicability.
An analysis of neurovascular disease markers in the hippocampus of Tupaia chinensis at different growth stages
Authors: Ouyang Yiqiang , Zhang Ying , Guo Xiaoping , Li Jiafu , Ao Qingqing , Guo Songchao , Zhang Mingyuan , Sun Junming
Published: January 2023

Introduction

It is considered thatTupaia chinensiscan replace laboratory primates in the study of nervous system diseases. To date, however, protein expression in the brain ofTupaia chinensishas not been fully understood.

Method

Three age groups ofT. chinensis-15 days, 3 months and 1.5 years—were selected to study their hippocampal protein expression profiles.

Results

A significant difference was observed between the 15-day group and the other two age groups, where as there were no significant differences between the 3-month and 1.5-year age groups. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that differentially expressed proteins could be enriched in several pathways related to neurovascular diseases, such as metabolic pathways for Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and other diseases. The KEGG enrichment also showed that relevant protein involved in oxidative phosphorylation in the hippocampus ofT. chinensisfor 15days were downregulated, and ribosomal proteins (RPs) were upregulated, compared to those in the hippocampus of the other two age groups.

Discussion

It was suggested that when the hippocampus ofT. chinensisdeveloped from day 15 to 3 months, the expression of oxidatively phosphorylated proteins and RPs would vary over time. Meanwhile, the hippocamppal protein expression profile ofT. chinensisafter 3 months had become stable. Moreover, the study underlines that, during the early development of the hippocampus ofT. chinensis, energy demand increases while protein synthesis decreases. The mitochondria ofT. chinensischanges with age, and the oxidative phosphorylation metabolic pathway of mitochondria is closely related to neurovascular diseases, such as stroke and cerebral ischemia.
Spatial rehabilitation using virtual auditory space training paradigm in individuals with sensorineural hearing impairment
Authors: Nisha Kavassery Venkateswaran , Uppunda Ajith Kumar , Kumar Rakesh Trinesh
Published: January 2023

Purpose

The present study aimed to quantify the effects of spatial training using virtual sources on a battery of spatial acuity measures in listeners with sensorineural hearing impairment (SNHI).

Methods

An intervention-based time-series comparison design involving 82 participants divided into three groups was adopted. Group I (n = 27, SNHI-spatially trained) and group II (n = 25, SNHI-untrained) consisted of SNHI listeners, while group III (n = 30) had listeners with normal hearing (NH). The study was conducted in three phases. In the pre-training phase, all the participants underwent a comprehensive assessment of their spatial processing abilities using a battery of tests including spatial acuity in free-field and closed-field scenarios, tests for binaural processing abilities (interaural time threshold [ITD] and level difference threshold [ILD]), and subjective ratings. While spatial acuity in the free field was assessed using a loudspeaker-based localization test, the closed-field source identification test was performed using virtual stimuli delivered through headphones. The ITD and ILD thresholds were obtained using a MATLAB psychoacoustic toolbox, while the participant ratings on the spatial subsection of speech, spatial, and qualities questionnaire in Kannada were used for the subjective ratings. Group I listeners underwent virtual auditory spatial training (VAST), following pre-evaluation assessments. All tests were re-administered on the group I listeners halfway through training (mid-training evaluation phase) and after training completion (post-training evaluation phase), whereas group II underwent these tests without any training at the same time intervals.

Results and discussion

Statistical analysis showed the main effect of groups in all tests at the pre-training evaluation phase, with post hoc comparisons that revealed group equivalency in spatial performance of both SNHI groups (groups I and II). The effect of VAST in group I was evident on all the tests, with the localization test showing the highest predictive power for capturing VAST-related changes on Fischer discriminant analysis (FDA). In contrast, group II demonstrated no changes in spatial acuity across timelines of measurements. FDA revealed increased errors in the categorization of NH as SNHI-trained at post-training evaluation compared to pre-training evaluation, as the spatial performance of the latter improved with VAST in the post-training phase.

Conclusion

The study demonstrated positive outcomes of spatial training using VAST in listeners with SNHI. The utility of this training program can be extended to other clinical population with spatial auditory processing deficits such as auditory neuropathy spectrum disorder, cochlear implants, central auditory processing disorders etc.
The relationship between intake of fruits, vegetables and dairy products with overweight and obesity in a large sample in Iran: Findings of STEPS 2016
Authors: Nouri Mehran , Shateri Zainab , Faghih Shiva
Published: January 2023

Background

The present study aimed to investigate the association between fruits and vegetables (FVs) and dairy product intake with body weight based on the data from the nationwide Stepwise approach to surveillance (STEPS) survey in Iran.

Methods

STEPS is a national-based cross-sectional study conducted on 3,0541 people selected by stratified cluster random sampling in Iran from April to November 2016. The outcome of the current study was body mass index (BMI) which was classified as normal weight, underweight, overweight, and obese. Also, as exposure variables, dietary intakes of fruits, vegetables and dairy products were extracted from the STEPS questionnaires. Multinomial logistic regression was used to evaluate the association between dairy products, FVs consumption, and BMI category in the crude and adjusted models.

Results

In the adjusted model, we observed 41% [odd ratio (OR) = 0.59; 95% confidence intervals (CI): 0.50, 0.68, P < 0.001], 27% (OR = 0.73; 95% CI: 0.62, 0.84,P< 0.001), and 26% (OR = 0.74; 95% CI: 0.63, 0.87,P< 0.001) lower odds of being overweight, and 46% (OR = 0.54; 95% CI: 0.46, 0.64,P< 0.001), 29% (OR = 0.71; 95% CI: 0.60, 0.84,P< 0.001), and 21% (OR = 0.79; 95% CI: 0.65, 0.95,P= 0.014) decrease in obesity odds among the participants who consumed 1, 2, and more than 2 servings of fruits per day in comparison to less than one serving, respectively. Also, we observed participants who consumed 1, 2, and more than 2 servings in comparison to less than one serving of dairy products per day had 31% (OR = 0.69; 95% CI: 0.58, 0.81,P< 0.001), 23% (OR = 0.77; 95 %CI: 0.65, 0.91,P= 0.002), and 21% (OR = 0.79; 95% CI: 0.67, 0.94,P= 0.011) lower odds of being overweight and 47% (OR = 0.53; 95% CI: 0.44, 0.64,P< 0.001), 36% (OR = 0.64; 95% CI: 0.53, 0.77,P< 0.001), and 32% (OR = 0.68; 95% CI: 0.56, 0.83,P< 0.001) lower odds of obesity, respectively. In addition, compared to participants who consumed less than 2 servings of vegetables per day, participants who consumed 2, 3, and more than 3 servings had 40% (OR = 0.60; 95% CI: 0.47, 0.76,P< 0.001), 29% (OR = 0.71; 95% CI: 0.56, 0.90,P= 0.006), and 26% (OR = 0.74; 95% CI: 0.57, 0.96,P= 0.027) lower odds of being overweight, respectively. Furthermore, we observed 36% lower odds of obesity among participants who ate 2 servings of vegetables per day compared to less than 2 serving (OR = 0.64; 95% CI: 0.49, 0.84,P= 0.002).

Conclusion

Our findings showed that intake of FVs and dairy products is associated with a healthier weight status in adults. Further studies are needed to confirm these findings.
CCKAR is a biomarker for prognosis and asynchronous brain metastasis of non-small cell lung cancer
Authors: Liang Nan , Sun Suohui , Li Zheng , Wu Tao , Zhang Chunpu , Xin Tao
Published: January 2023

Background

Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, and brain metastasis (BM) is the most lethal complication of NSCLC. The predictive biomarkers and risk factors of asynchronous BM are still unknown.

Materials and methods

A total of 203 patients with NSCLC were enrolled into our cohort and followed up. The clinicopathological factors such as tumor size, T stage, lymphatic invasion, metastasis and asynchronous BM were investigated. CCKAR expression in NSCLC and resected BM was assessed by IHC, and CCKAR mRNAs in NSCLC and para-tumor tissues were estimated by qRT-PCR. The correlations between CCKAR expression, BM and other clinicopathological factors were assessed by chi-square test, and prognostic significance of CCKAR was estimated by univariate and multivariate analyses.

Results

CCKAR was highly expressed in NSCLC tissues compared with para-tumor tissues. CCKAR expression in NSCLC was significantly associated with asynchronous BM. The BM percentages for NSCLC patients with low and high CCKAR were surprisingly 5.2% and 66.6%, respectively. CCKAR expression and BM were unfavorable factors predicting unfavorable outcome of NSCLC. Moreover, CCKAR expression in NSCLC was an independent risk factor of asynchronous BM.

Conclusions

CCKAR is a prognostic biomarker of NSCLC. CCKAR expression in NSCLC is positively associated with asynchronous BM, and is a risk factor of asynchronous BM from NSCLC.
A novel homozygous SLC39A14 variant in an infant with hypermanganesemia and a review of the literature
Authors: Zhang Meijiao , Zhu Liping , Wang Huiping , Hao Ying , Zhang Qingping , Zhao Chunyan , Bao Xinhua
Published: January 2023

Background

Manganese (Mn) is an essential trace metal necessary for good health; however, excessive amounts in the body are neurotoxic. To date, three genes (SLC30A10, SLC39A8, and SLC39A14) have been discovered to cause inborn errors in Mn metabolism in humans. As very rare diseases, the clinical features require further clarification.

Methods

A male Chinese patient who mainly presented with hypermanganesemia and progressive parkinsonism–dystonia was recruited for this study. We collected and analyzed clinical information, performed whole-exome sequencing (WES), and reviewed the relevant literature.

Results

The motor-developmental milestones of the patient were delayed at the age of 4 months, followed by rapidly progressive dystonia. The patient displayed elevated Mn concentrations in blood and urine, and brain magnetic resonance imaging (MRI) showed symmetrical hyperintensity on T1-weighted images and hypointensity on T2-weighted images in multiple regions. A novel homozygous variant of the SLC39A14 gene (c.1058T > G, p.L353R) was identified. The patient was treated with disodium calcium edetate chelation (Na2CaEDTA). Three months later, mild improvement in clinical manifestation, blood Mn levels, and brain MRI was observed. To date, 15 patients from 10 families have been reported with homozygous mutations of SLC39A14, with a mean age of onset of 14.9 months. The common initial symptom is motor regression or developmental milestone delay, with a disease course for nearly all patients involving development of progressive generalized dystonia and loss of ambulation before treatment. Additionally, hypermanganesemia manifests as Mn values ranging from 4- to 25-fold higher than normal baseline levels, along with brain MRI results similar to those observed in the recruited patient. Nine SLC39A14 variants have been identified. Seven patients have been treated with Na2CaEDTA, and only one patient achieved obvious clinical improvement.

Conclusion

We identified a novel SLC39A14 mutation related to autosomal recessive hypermanganesemia with dystonia-2, which is a very rare disease. Patients present motor regression or delay of developmental milestones and develop progressive generalized dystonia. Chelation therapy with Na2CaEDTA appears to effectively chelate Mn and increase urinary Mn excretion in some cases; however, clinical response varies. The outcome of the disease was unsatisfactory. This study expands the genetic spectrum of this disease.
Natural products from plants and microorganisms: Novel therapeutics for chronic kidney disease via gut microbiota regulation
Authors: Zheng Lin , Luo Mingjing , Zhou Haokui , Chen Jianping
Published: January 2023

Dysbiosis of gut microbiota plays a fundamental role in the pathogenesis and development of chronic kidney disease (CKD) and its complications. Natural products from plants and microorganisms can achieve recognizable improvement in renal function and serve as an alternative treatment for chronic kidney disease patients with a long history, yet less is known on its beneficial effects on kidney injury by targeting the intestinal microbiota. In this review, we summarize studies on the effects of natural products from plants and microorganisms, including herbal medicines and their bioactive extracts, polysaccharides from plants and microorganisms, and phytochemicals, on the prevention and treatment of chronic kidney disease through targeting gut microflora. We describe the strategies of these anti-CKD effects in animal experiments including remodulation of gut microbiota structure, reduction of uremic toxins, enhancement of short-chain fatty acid (SCFA) production, regulation of intestinal inflammatory signaling, and improvement in intestinal integrity. Meanwhile, the clinical trials of different natural products in chronic kidney disease clinical practice were also analyzed and discussed. These provide information to enable a better understanding of the renoprotective effects of these effective natural products from plants and microorganisms in the treatment of chronic kidney disease. Finally, we propose the steps to prove the causal role of the intestinal microflora in the treatment of chronic kidney disease by natural products from plants and microorganisms. We also assess the future perspective that natural active products from plants and microorganisms can beneficially delay the onset and progression of kidney disease by targeting the gut flora and highlight the remaining challenges in this area. With the continuous deepening of studies in recent years, it has been proved that gut microbiota is a potential target of natural active products derived from plants and microorganisms for chronic kidney disease treatment. Fully understanding the functions and mechanisms of gut microbiota in these natural active products from plants and microorganisms is conducive to their application as an alternative therapeutic in the treatment of chronic kidney disease.
Investigating bile acid-mediated cholestatic drug-induced liver injury using a mechanistic model of multidrug resistance protein 3 (MDR3) inhibition
Authors: Beaudoin James J. , Yang Kyunghee , Adiwidjaja Jeffry , Taneja Guncha , Watkins Paul B. , Siler Scott Q. , Howell Brett A. , Woodhead Jeffrey L.
Published: January 2023

Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population (n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans.
Protective effect of Saussurea involucrata polysaccharide against skin dryness induced by ultraviolet radiation
Authors: Wang Lusheng , Yang Kaiye , Jing Rongrong , Zhao Wengang , Guo Keke , Hu Zhenlin , Liu Guangrong , Xu Nuo , Zhao Jungang , Lin Li , Gao Shuang
Published: January 2023

Background: Exposure to ultraviolet B (UVB) radiation can damage the epidermis barrier function and eventually result in skin dryness. At present, little work is being devoted to skin dryness. Searching for active ingredients that can protect the skin against UVB-induced dryness will have scientific significance.

Methods:Saussurea involucrata polysaccharide (SIP) has been shown to have significant antioxidant and anti-photodamage effects on the skin following UVB irradiation. To evaluate the effect of SIP on UVB-induced skin dryness ex vivo, SIP-containing hydrogel was applied in a mouse model following exposure to UVB and the levels of histopathological changes, DNA damage, inflammation, keratinocyte differentiation, lipid content were then evaluated. The underlying mechanisms of SIP to protect the cells against UVB induced-dryness were determined in HaCaT cells.

Results: SIP was found to lower UVB-induced oxidative stress and DNA damage while increasing keratinocyte differentiation and lipid production. Western blot analysis of UVB-irradiated skin tissue revealed a significant increase in peroxisome proliferator-activated receptor-α (PPAR-α) levels, indicating that the underlying mechanism may be related to PPAR-α signaling pathway activation.

Conclusions: By activating the PPAR-α pathway, SIP could alleviate UVB-induced oxidative stress and inhibit the inflammatory response, regulate proliferation and differentiation of keratinocytes, and mitigate lipid synthesis disorder. These findings could provide candidate active ingredients with relatively clear mechanistic actions for the development of skin sunscreen moisturizers.
Multiple sensor theory in cardiovascular mechanosensory units
Authors: Yu Jerry
Published: January 2023

Multiple sensor theory (MST) has advanced our understanding of how lung mechanosensors operate. That is, single lung units contain multiple homogeneous or heterogeneous sensors. Each detects sensor-specific mechanical information and interacts with other sensors lying within the unit sending integrated information to the brain to evoke reflexes. MST explains numerous controversial issues in the respiratory system. Recent studies in baroreceptors (BRs), along with reinterpretation of recordings appearing in the literature, indicate MST also operates in the cardiovascular (CV) system. This review outlines evidence supporting MST in the CV system and provides examples to apply the theory. Longstanding controversies surrounding the CV sensors are also considered.
Revisiting differential control of sympathetic outflow by the rostral ventrolateral medulla
Authors: Kulkarni Soumya S. , Mischel Nicholas A. , Mueller Patrick J.
Published: January 2023

The rostral ventrolateral medulla (RVLM) is an important brain region involved in both resting and reflex regulation of the sympathetic nervous system. Anatomical evidence suggests that as a bilateral structure, each RVLM innervates sympathetic preganglionic neurons on both sides of the spinal cord. However, the functional importance of ipsilateral versus contralateral projections from the RVLM is lacking. Similarly, during hypotension, the RVLM is believed to rely primarily on withdrawal of tonic gamma aminobutyric acid (GABA) inhibition to increase sympathetic outflow but whether GABA withdrawal mediates increased activity of functionally different sympathetic nerves is unknown. We sought to test the hypothesis that activation of the ipsilateral versus contralateral RVLM produces differential increases in splanchnic versus adrenal sympathetic nerve activities, as representative examples of functionally different sympathetic nerves. We also tested whether GABA withdrawal is responsible for hypotension-induced increases in splanchnic and adrenal sympathetic nerve activity. To test our hypothesis, we measured splanchnic and adrenal sympathetic nerve activity simultaneously in Inactin-anesthetized, male Sprague-Dawley rats during ipsilateral or contralateral glutamatergic activation of the RVLM. We also produced hypotension (sodium nitroprusside, i.v.) before and after bilateral blockade of GABAA receptors in the RVLM (bicuculline, 5 mM 90 nL). Glutamate (100 mM, 30 nL) injected into the ipsilateral or contralateral RVLM produced equivalent increases in splanchnic sympathetic nerve activity, but increased adrenal sympathetic nerve activity by more than double with ipsilateral injections versus contralateral injections (p < 0.05; n = 6). In response to hypotension, increases in adrenal sympathetic nerve activity were similar after bicuculline (p > 0.05), but splanchnic sympathetic nerve activity responses were eliminated (p < 0.05; n = 5). These results provide the first functional evidence that the RVLM has predominantly ipsilateral innervation of adrenal nerves. In addition, baroreflex-mediated increases in splanchnic but not adrenal sympathetic nerve activity are mediated by GABAA receptors in the RVLM. Our studies provide a deeper understanding of neural control of sympathetic regulation and insight towards novel treatments for cardiovascular disease involving sympathetic nervous system dysregulation.
Meta-analysis of the intervention effects of taekwondo on metabolic syndrome indicators
Authors: Han Zhengfa , Ju Hanyu
Published: January 2023

Objective: To quantify the effect of taekwondo as an intervention on the indicators of metabolic syndrome and identify an intervention plan with the optimal effects.

Methods: Combining the Cnki.net, Wanfang, PubMed, Web of Science, Embase, KISS, RISS, and DBPIA databases, this paper retrieved relevant references in Chinese, English, and Korean, applied Review Manager 5.4 software to evaluate the methodological quality of the included references according to the Cochrane manual, and utilized Comprehensive Meta-Analysis version 3.7 to perform statistical analyses.

Result: A total of 45 references and 1079 related subjects were included in the analysis. The results of the meta-analysis showed that taekwondo has a beneficial effect on all indicators of metabolic syndrome (Hedges’ g [effect size] = −0.615, −0.672, −0.497, −0.785, −0.591, and 0.435; p < 0.05). Subgroup analysis revealed the superior intervention effect of taekwondo on metabolic syndrome in women compared to men, middle-aged and elderly compared to other age groups, and abnormal metabolic syndrome indicators compared to normal values. Moreover, the best results were obtained for longer intervention durations—12 weeks—three times per week, for 40–50 min per session. In addition, the combination of intervention types (poomsae, kick, and taekwondo gymnastics) showed optimal effects. The exercise intensity should consider the characteristics of the intervention object and be generally set to medium or high intensity.

Conclusion: Taekwondo can effectively improve metabolic syndrome, as evidenced by decreased body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose (FBG), and triglyceride (TG) levels and increased high-density lipoprotein cholesterol (HDL-C) level. Taekwondo had the greatest effect on quinquagenarian women with abnormal levels of metabolic syndrome indicators. To maximize the intervention effect of taekwondo on metabolic syndrome, an exercise prescription of high-intensity poomsae, kick, and taekwondo gymnastics performed in 40–50 min sessions, three times weekly for 12 weeks is recommended.
Generation of multi-layered protein bodies in N. benthamiana for the encapsulation of vaccine antigens
Authors: Schwestka Jennifer , Zeh Lukas , Tschofen Marc , Schubert Fabian , Arcalis Elsa , Esteve-Gasent Maria , Pedrazzini Emanuela , Vitale Alessandro , Stoger Eva
Published: January 2023

The ability of plants to assemble particulate structures such as virus-like particles and protein storage organelles allows the direct bioencapsulation of recombinant proteins during the manufacturing process, which holds promise for the development of new drug delivery vehicles. Storage organelles found in plants such as protein bodies (PBs) have been successfully used as tools for accumulation and encapsulation of recombinant proteins. The fusion of sequences derived from 27-kDa-γ-zein, a major storage protein of maize, with a protein of interest leads to the incorporation of the chimeric protein into the stable and protected environment inside newly induced PBs. While this procedure has proven successful for several, but not all recombinant proteins, the aim of this study was to refine the technology by using a combination of PB-forming proteins, thereby generating multi-layered protein assemblies in N. benthamiana. We used fluorescent proteins to demonstrate that up to three proteinaceous components can be incorporated into different layers. In addition to 27-kDa-γ-zein, which is essential for PB initiation, 16-kDa-γ-zein was identified as a key element to promote the incorporation of a third zein-component into the core of the PBs. We show that a vaccine antigen could be incorporated into the matrix of multi-layered PBs, and the protein microparticles were characterized by confocal and electron microscopy as well as flow cytometry. In future, this approach will enable the generation of designer PBs that serve as drug carriers and integrate multiple components that can be functionalized in different ways.