bluuebunny/crossref_metadata_2025 huggingface dataset:
Akkermansia muciniphila Enhances Egg Quality and the Lipid Profile of Egg Yolk by Improving Lipid Metabolism
Authors: Wei Fuxiao , Yang Xinyue , Zhang Meihong , Xu Chang , Hu Yongfei , Liu Dan
Published: July 2022

Akkermansia muciniphila (A. muciniphila) has shown potential as a probiotic for the prevention and treatment of non-alcoholic fatty liver disease in both humans and mice. However, relatively little is known about the effects of A. muciniphila on lipid metabolism, productivity, and product quality in laying hens. In this study, we explored whether A. muciniphila supplementation could improve lipid metabolism and egg quality in laying hens and sought to identify the underlying mechanism. In the first experiment, 80 Hy-Line Brown laying hens were divided into four groups, one of which was fed a normal diet (control group), while the other three groups were administered a high-energy, low-protein diet to induce fatty liver hemorrhagic syndrome (FLHS). Among the three FLHS groups, one was treated with phosphate-buffered saline, one with live A. muciniphila, and one with pasteurized A. muciniphila. In the second experiment, 140 Hy-Line Brown laying hens were divided into two groups and respectively fed a basal diet supplemented or not with A. muciniphila lyophilized powder. The results showed that, in laying hens with FLHS, treatment with either live or pasteurized A. muciniphila efficiently decreased body weight, abdominal fat deposition, and lipid content in both serum and the liver; downregulated the mRNA expression of lipid synthesis-related genes and upregulated that of lipid transport-related genes in the liver; promoted the growth of short-chain fatty acids (SCFAs)-producing microorganisms and increased the cecal SCFAs content; and improved the yolk lipid profile. Additionally, the supplementation of lyophilized powder of A. muciniphila to aged laying hens reduced abdominal fat deposition and total cholesterol (TC) levels in both serum and the liver, suppressed the mRNA expression of cholesterol synthesis-related genes in the liver, reduced TC content in the yolk, increased eggshell thickness, and reshaped the composition of the gut microbiota. Collectively, our findings demonstrated that A. muciniphila can modulate lipid metabolism, thereby, promoting laying hen health as well as egg quality and nutritive value. Live, pasteurized, and lyophilized A. muciniphila preparations all have the potential for use as additives for improving laying hen production.
The Response of Fecal Microbiota and Host Metabolome in Dairy Cows Following Rumen Fluid Transplantation
Authors: Huang Shuai , Zheng Gang , Men Hongkai , Wang Wei , Li Shengli
Published: July 2022

Rumen fluid transplantation (RFT) has been used to rebuild rumen bacterial homeostasis, reshape rumen function, and restore rumen fermentation, whereas the effect of RFT on fecal microbiota and host metabolism in cows remains poorly understood. In our study, a combination of 16S rRNA sequencing and serum non-targeted metabolomics was performed to investigate the response of fecal microbiota and serum metabolome in dairy cows following RFT. Twenty-four prepartum dairy cows were randomly assigned to 3 groups (n = 8) for infusion of either saline (Con), fresh rumen fluid (FR), or sterilized rumen fluid (SR) after calving. Fourteen days after calving, fecal microbiota and serum metabolome were analyzed. The sequencing data of fecal samples revealed no changes in alpha diversity and relative abundance of dominant genera such as Ruminococcaceae UCG-005, Rikenellaceae RC9 gut and Eubacterium coprostanoligenes. However, the other genus level taxa, such as Eubacterium oxidoreducens, Anaerorhabdus furcosa, Bacillus and Selenomonas, showed distinct changes following RFT. Serum metabolome analysis showed that FR or SR infusion affected amino acids metabolism, bile acids metabolism and fatty acids metabolism (including linoleic acid, oleic acid and palmitic acid). Furthermore, correlation analysis showed that taxa from genera Clostridiales were positively correlated with metabolites involved in tryptophan and bile acid metabolisms, such as OTU1039 from genera unclassified o_Clostridiales was positively correlated to indoleacetic acid and taurolithocholic acid. These results suggest that RFT altered the composition of the fecal microbiota and modulated microbial metabolic pathways, which is vital for the development and safety assessment of rumen microbial intervention strategies.
Comorbid depressive symptoms can aggravate the functional changes of the pain matrix in patients with chronic back pain: A resting-state fMRI study
Authors: Zhang Guangfang , Ma Junqin , Lu Weirong , Zhan Hongrui , Zhang Xuefei , Wang Kangling , Hu Yingxuan , Wang Xianglong , Peng Weiwei , Yue Shouwei , Cai Qingxiang , Liang Wen , Wu Wen
Published: July 2022

Objective

The purposes of this study are to explore (1) whether comorbid depressive symptoms in patients with chronic back pain (CBP) affect the pain matrix. And (2) whether the interaction of depression and CBP exacerbates impaired brain function.

Methods

Thirty-two patients with CBP without comorbid depressive symptoms and thirty patients with CBP with comorbid depressive symptoms were recruited. All subjects underwent functional magnetic resonance imaging (fMRI) scans. The graph theory analysis, mediation analysis, and functional connectivity (FC) analysis were included in this study. All subjects received the detection of clinical depressive symptoms and pain-related manifestations.

Result

Compared with the CBP group, subjects in the CBP with comorbid depressive symptoms (CBP-D) group had significantly increased FC in the left medial prefrontal cortex and several parietal cortical regions. The results of the graph theory analyses showed that the area under the curve of small-world property (t = −2.175, p = 0.034), gamma (t = −2.332, p = 0.023), and local efficiency (t = −2.461, p = 0.017) in the CBP-D group were significantly lower. The nodal efficiency in the ventral posterior insula (VPI) (t = −3.581, p = 0.0007), and the network efficiency values (t = −2.758, p = 0.008) in the pain matrix were significantly lower in the CBP-D group. Both the topological properties and the FC values of these brain regions were significantly correlated with self-rating depression scale (SDS) scores (all FDR corrected) but not with pain intensity. Further mediation analyses demonstrated that pain intensity had a mediating effect on the relationship between SDS scores and Pain Disability Index scores. Likewise, the SDS scores mediated the relationship between pain intensity and PDI scores.

Conclusion

Our study found that comorbid depressive symptoms can aggravate the impairment of pain matrix function of CBP, but this impairment cannot directly lead to the increase of pain intensity, which may be because some brain regions of the pain matrix are the common neural basis of depression and CBP.
Side-Scan Sonar Image Segmentation Based on Multi-Channel CNN for AUV Navigation
Authors: Yang Dianyu , Cheng Chensheng , Wang Can , Pan Guang , Zhang Feihu
Published: July 2022

The AUV (Autonomous Underwater Vehicle) navigation process relies on the interaction of a variety of sensors. The side-scan sonar can collect underwater images and obtain semantic underwater environment information after processing, which will help improve the ability of AUV autonomous navigation. However, there is no practical method to utilize the semantic information of side scan sonar image. A new convolutional neural network model is proposed to solve this problem in this paper. The model is a standard codec structure, which extracts multi-channel features from the input image and then fuses them to reduce parameters and strengthen the weight of feature channels. Then, a larger convolution kernel is used to extract the features of large-scale sonar images more effectively. Finally, a parallel compensation link with a small-scale convolution kernel is added and spliced with features extracted from a large convolution kernel in the decoding part to obtain features of different scales. We use this model to conduct experiments on self-collected sonar data sets, which were uploaded on github. The experimental results show that ACC and MIoU reach 0.87 and 0.71, better than other classical small-order semantic segmentation networks. Furthermore, the 347.52 g FOLP and the number of parameters around 13 m also ensure the computing speed and portability of the network. The result can extract the semantic information of the side-scan sonar image and assist with AUV autonomous navigation and mapping.
Does Executive Function Influence Walking in Acutely Hospitalized Patients With Advanced Parkinson's Disease: A Quantitative Analysis
Authors: Geritz Johanna , Welzel Julius , Hansen Clint , Maetzler Corina , Hobert Markus A. , Elshehabi Morad , Sobczak Alexandra , Kudelka Jennifer , Stiel Christopher , Hieke Johanne , Alpes Annekathrin , Bunzeck Nico , Maetzler Walter
Published: July 2022

Introduction

It is well-known that, in Parkinson's disease (PD), executive function (EF) and motor deficits lead to reduced walking performance. As previous studies investigated mainly patients during the compensated phases of the disease, the aim of this study was to investigate the above associations in acutely hospitalized patients with PD.

Methods

A total of seventy-four acutely hospitalized patients with PD were assessed with the delta Trail Making Test (ΔTMT, TMT-B minus TMT-A) and the Movement Disorder Society-revised version of the motor part of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS III). Walking performance was assessed with wearable sensors under single (ST; fast and normal pace) and dual-task (DT; walking and checking boxes as the motor secondary task and walking and subtracting seven consecutively from a given three-digit number as the cognitive secondary task) conditions over 20 m. Multiple linear regression and Bayes factor BF10 were performed for each walking parameter and their dual-task costs while walking (DTC) as dependent variables and also included ΔTMT, MDS-UPDRS III, age, and gender.

Results

Under ST, significant negative effects of the use of a walking aid and MDS-UPDRS III on gait speed and at a fast pace on the number of steps were observed. Moreover, depending on the pace, the use of a walking aid, age, and gender affected step time variability. Under walking-cognitive DT, a resolved variance of 23% was observed in the overall model for step time variability DTC, driven mainly by age (β = 0.26, p = 0.09). Under DT, no other significant effects could be observed. ΔTMT showed no significant associations with any of the walking conditions.

Discussion

The results of this study suggest that, in acutely hospitalized patients with PD, reduced walking performance is mainly explained by the use of a walking aid, motor symptoms, age, and gender, and EF deficits surprisingly do not seem to play a significant role. However, these patients with PD should avoid walking-cognitive DT situations, as under this condition, especially step time variability, a parameter associated with the risk of falling in PD worsens.
An Exploratory Analysis of the Neural Correlates of Human-Robot Interactions With Functional Near Infrared Spectroscopy
Authors: Yorgancigil Emre , Yildirim Funda , Urgen Burcu A. , Erdogan Sinem Burcu
Published: July 2022

Functional near infrared spectroscopy (fNIRS) has been gaining increasing interest as a practical mobile functional brain imaging technology for understanding the neural correlates of social cognition and emotional processing in the human prefrontal cortex (PFC). Considering the cognitive complexity of human-robot interactions, the aim of this study was to explore the neural correlates of emotional processing of congruent and incongruent pairs of human and robot audio-visual stimuli in the human PFC with fNIRS methodology. Hemodynamic responses from the PFC region of 29 subjects were recorded with fNIRS during an experimental paradigm which consisted of auditory and visual presentation of human and robot stimuli. Distinct neural responses to human and robot stimuli were detected at the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC) regions. Presentation of robot voice elicited significantly less hemodynamic response than presentation of human voice in a left OFC channel. Meanwhile, processing of human faces elicited significantly higher hemodynamic activity when compared to processing of robot faces in two left DLPFC channels and a left OFC channel. Significant correlation between the hemodynamic and behavioral responses for the face-voice mismatch effect was found in the left OFC. Our results highlight the potential of fNIRS for unraveling the neural processing of human and robot audio-visual stimuli, which might enable optimization of social robot designs and contribute to elucidation of the neural processing of human and robot stimuli in the PFC in naturalistic conditions.
Comprehensive mutations analyses of FTO (fat mass and obesity-associated gene) and their effects on FTO’s substrate binding implicated in obesity
Authors: Kumar Rakesh , Ningombam Somorjit Singh , Kumar Rahul , Goel Harsh , Gogia Ajay , Khurana Sachin , Deo S. V. S. , Mathur Sandeep , Tanwar Pranay
Published: July 2022

An excessive amount of fat deposition in the body leads to obesity which is a complex disease and poses a generic threat to human health. It increases the risk of various other diseases like diabetes, cardiovascular disease, and multiple types of cancer. Genomic studies have shown that the expression of the fat mass obesity (FTO) gene was highly altered and identified as one of the key biomarkers for obesity. This study has been undertaken to investigate the mutational profile of the FTO gene and elucidates its effect on the protein structure and function. Harmful effects of various missense mutations were predicted using different independent tools and it was observed that all mutations were highly pathogenic. Molecular dynamics (MD) simulations were performed to study the structure and function of FTO protein upon different mutations and it was found that mutations decreased the structure stability and affected protein conformation. Furthermore, a protein residue network analysis suggested that the mutations affected the overall residues bonding and topology. Finally, molecular docking coupled with MD simulation suggested that mutations affected FTO substrate binding by changing the protein-ligand affinity. Hence, the results of this finding would help in an in-depth understanding of the molecular biology of the FTO gene and its variants and lead to the development of effective therapeutics against associated diseases and disorders.
Preoperative Non-Invasive Prediction of Breast Cancer Molecular Subtypes With a Deep Convolutional Neural Network on Ultrasound Images
Authors: Li Chunxiao , Huang Haibo , Chen Ying , Shao Sihui , Chen Jing , Wu Rong , Zhang Qi
Published: July 2022

Purpose

This study aimed to develop a deep convolutional neural network (DCNN) model to classify molecular subtypes of breast cancer from ultrasound (US) images together with clinical information.

Methods

A total of 1,012 breast cancer patients with 2,284 US images (center 1) were collected as the main cohort for training and internal testing. Another cohort of 117 breast cancer cases with 153 US images (center 2) was used as the external testing cohort. Patients were grouped according to thresholds of nodule sizes of 20 mm and age of 50 years. The DCNN models were constructed based on US images and the clinical information to predict the molecular subtypes of breast cancer. A Breast Imaging-Reporting and Data System (BI-RADS) lexicon model was built on the same data based on morphological and clinical description parameters for diagnostic performance comparison. The diagnostic performance was assessed through the accuracy, sensitivity, specificity, Youden’s index (YI), and area under the receiver operating characteristic curve (AUC).

Results

Our DCNN model achieved better diagnostic performance than the BI-RADS lexicon model in differentiating molecular subtypes of breast cancer in both the main cohort and external testing cohort (all p < 0.001). In the main cohort, when classifying luminal A from non-luminal A subtypes, our model obtained an AUC of 0.776 (95% CI, 0.649–0.885) for patients older than 50 years and 0.818 (95% CI, 0.726–0.902) for those with tumor sizes ≤20 mm. For young patients ≤50 years, the AUC value of our model for detecting triple-negative breast cancer was 0.712 (95% CI, 0.538–0.874). In the external testing cohort, when classifying luminal A from non-luminal A subtypes for patients older than 50 years, our DCNN model achieved an AUC of 0.686 (95% CI, 0.567–0.806).

Conclusions

We employed a DCNN model to predict the molecular subtypes of breast cancer based on US images. Our model can be valuable depending on the patient’s age and nodule sizes.
Indoleamine 2,3-Dioxygenase Immune Status as a Potential Biomarker of Radioiodine Efficacy for Advanced Distant Metastatic Differentiated Thyroid Cancer
Authors: Shi Liang , Duan Rui , Jia Qiong , Wu Wenyu , Zhou Jianming , Li Shaohua , Zhang Hao , Xue Xue
Published: July 2022

Purpose

Host immunity influences the impact of cancer therapy but the effect of immune status in radioiodine (RAI)-treated differentiated thyroid cancer (DTC) remains obscure. Here we investigated indoleamine 2,3-dioxygenase (IDO) activity as a biomarker of response to RAI in patients with distant metastatic DTC (dmDTC).

Methods

Patients with dmDTC receiving RAI were evaluated for serum IDO activity (kynurenine and kynurenine:tryptophan ratio) at baseline and 3 months after RAI. The optimal cut-off value for these biomarkers to predict response was established by receiver operating characteristic analysis. The relationship between disease outcomes, overall survival (OS) and progression-free survival (PFS), and IDO activity levels was studied.

Results

Higher baseline kynurenine:tryptophan ratio (>2.46) was correlated with poorer RAI response as well as shorter median PFS (45 mo versus not reached, p=0.002) and OS (78 mo versus not reached, p=0.035). High baseline kynurenine:tryptophan ratio was also correlated with a reduced number of tumor-infiltrating lymphocytes. Higher post/pre-kynurenine ratio (>1.69) was associated with survival endpoints: shorter median PFS (48 mo versus not reached, p=0.002) and OS (68 mo versus not reached, p=0.010). Favorable baseline and favorable change corresponded with better PFS and OS.

Conclusions

Our results suggest that RAI also alters IDO activity in dmDTC patients. IDO activity could predict progression and survival outcomes for advanced dmDTC patients. Serum IDO biomarker levels could be used to select dmDTC likely to benefit from RAI therapy, although further studies are necessary.
Radiomic Features From Diffusion-Weighted MRI of Retroperitoneal Soft-Tissue Sarcomas Are Repeatable and Exhibit Change After Radiotherapy
Authors: Thrussell Imogen , Winfield Jessica M. , Orton Matthew R. , Miah Aisha B. , Zaidi Shane H. , Arthur Amani , Thway Khin , Strauss Dirk C. , Collins David J. , Koh Dow-Mu , Oelfke Uwe , Huang Paul H. , O’Connor James P. B. , Messiou Christina , Blackledge Matthew D.
Published: July 2022

Background

Size-based assessments are inaccurate indicators of tumor response in soft-tissue sarcoma (STS), motivating the requirement for new response imaging biomarkers for this rare and heterogeneous disease. In this study, we assess the test–retest repeatability of radiomic features from MR diffusion-weighted imaging (DWI) and derived maps of apparent diffusion coefficient (ADC) in retroperitoneal STS and compare baseline repeatability with changes in radiomic features following radiotherapy (RT).

Materials and Methods

Thirty patients with retroperitoneal STS received an MR examination prior to treatment, of whom 23/30 were investigated in our repeatability analysis having received repeat baseline examinations and 14/30 patients were investigated in our post-treatment analysis having received an MR examination after completing pre-operative RT. One hundred and seven radiomic features were extracted from the full manually delineated tumor region using PyRadiomics. Test–retest repeatability was assessed using an intraclass correlation coefficient (baseline ICC), and post-radiotherapy variance analysis (post-RT-IMS) was used to compare the change in radiomic feature value to baseline repeatability.

Results

For the ADC maps and DWI images, 101 and 102 features demonstrated good baseline repeatability (baseline ICC > 0.85), respectively. Forty-three and 2 features demonstrated both good baseline repeatability and a high post-RT-IMS (>0.85), respectively. Pearson correlation between the baseline ICC and post-RT-IMS was weak (0.432 and 0.133, respectively).

Conclusions

The ADC-based radiomic analysis shows better test–retest repeatability compared with features derived from DWI images in STS, and some of these features are sensitive to post-treatment change. However, good repeatability at baseline does not imply sensitivity to post-treatment change.
Apogossypolone Inhibits Cell Proliferation and Epithelial-Mesenchymal Transition in Cervical Cancer via Activating DKK3
Authors: Li Yuling , Qu Jinfeng , Liu Lu , Sun Yu , Zhang Junhua , Han Sai , Zhang Youzhong
Published: July 2022

Apogossypolone (ApoG2), a novel derivative of gossypol lacking of two aldehyde groups, exhibits anti-tumor effects. However, the mechanisms by which ApoG2 regulates cervical cancer (CC) cells remain unclear. In this study, we treated two CC cell lines (CaSki and HeLa) with an increasing concentration of ApoG2 for 24 h. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, flow cytometry and transwell invasion assay were utilized to detect cell proliferation, apoptosis and invasion in vitro. We first observed that ApoG2 inhibited cell proliferation, invasion and epithelial-to-mesenchymal transition (EMT) process in CC cells, along with upregulation of Dickkopf Wnt signaling pathway inhibitor 3 (DKK3) in a dose-dependent manner. The immunohistochemistry confirmed the downregulation of DKK3 in tumor tissues. Moreover, DKK3 was correlated with FIGO stage and lymph node metastasis. Functionally, DKK3 overexpression significantly suppressed cell viability, colony formation and invasion, but promoted apoptosis in CaSki and HeLa cells. Overexpression of DKK3 upregulated the protein levels of cleaved caspase-3 and E-cadherin, but downregulated the protein levels of Bcl-2, N-cadherin and Vimentin. Furthermore, DKK3 knockdown reversed the suppressive effects of ApoG2 on CaSki cell proliferation, invasion and EMT markers, while DKK3 overexpression enhanced these effects. In addition, ApoG2 treatment inhibited CC xenograft tumor growth and upregulated the protein levels of DKK3, cleaved caspase-3 and E-cadherin. In conclusions, these findings suggested that ApoG2 could effectively inhibit the growth and invasion of CC cells at least partly by activating DKK3.
Nutritional Supplementation to Increase Influenza Vaccine Response in Children Living With HIV: A Pilot Clinical Trial
Authors: Sainz Talía , Casas Inmaculada , González-Esguevillas Mónica , Escosa-Garcia Luis , Muñoz-Fernández María Ángeles , Prieto Luis , Gosalbes María José , Jiménez-Hernández Nuria , Ramos José Tomas , Navarro María Luisa , Mellado María José , Serrano-Villar Sergio , Calvo Cristina
Published: July 2022

Aims

Vaccine response is poor among children living with HIV. The gut microbiota has been identified as a potential target to improve vaccine immunogenicity, but data are scarce in the context of HIV infection.

Methods

Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected children were randomized to receive a mixture of symbiotics, omega-3/6 fatty acids, and amino acids or placebo for 4 weeks, each in combination with ART, and were then immunized against influenza. Vaccine response and safety of the nutritional supplementation were the primary outcomes.

Results

Eighteen HIV-infected children completed the follow-up period (mean age 11.5 ± 4.14 years, 61% female). The nutritional supplement was safe but did not enhance the response to the influenza vaccine. A 4-fold rise in antibody titers was obtained in only 37.5% of participants in the intervention arm vs. 40% in the placebo. No immunological or inflammatory predictors of vaccine response were identified.

Conclusions

In this exploratory study, a 4-week course of symbiotics did not increase influenza vaccine immunogenicity in HIV-infected children. Larger studies are warranted to address the potential of modulating the microbiome in children living with HIV.
Associations Between Antithrombosis and Ventilator-Associated Events, ICU Stays, and Mortality Among Mechanically Ventilated Patients: A Registry-Based Cohort Study
Authors: Wang Mingqi , Wang Wen , Jia Xue , He Qiao , Zhu Shichao , Kang Yan , Zhang Rui , Ren Yan , Li Ling , Zou Kang , Zong Zhiyong , Sun Xin
Published: July 2022

Background: The effect of thromboembolism prophylaxis on clinical outcomes, such as ventilator-associated events (VAEs), ICU stays, and mortality, remains controversial. This study was conducted to evaluate the effect of pharmacological thromboprophylaxis on VAEs, ICU stays, and ICU mortality among patients receiving mechanical ventilation (MV).

Materials and Methods: A retrospective cohort study was conducted based on a well-established registry of healthcare-associated infections at ICUs in the West China Hospital system. Patients who consistently received MV for at least 4 days from 1 April 2015 to 31 December 2018 were included. Hazard ratios (HRs) were compared for three tiers of VAEs, ICU stays, and ICU mortality among patients receiving pharmacological thromboprophylaxis versus those without using the time-dependent Cox model. For the analyses of ICU stays and ICU mortality, we also used Fine-Gray models to disentangle the competing risks and outcomes of interest.

Results: Overall, 6,140 patients were included. Of these, 3,805 received at least one prescription of antithrombosis agents. Treatments with antithrombosis agents were associated with lower risk of VAEs (HR: 0.87, 95% CI: 0.77, 0.98) and ICU mortality (HR: 0.72, 95% CI: 0.61, 0.86) than those without. Anticoagulants but not antiplatelet agents were associated with decreased risk of VAEs (HR: 0.86, 95% CI: 0.75, 0.98), ICU mortality (HR: 0.62, 95% CI: 0.51, 0.76), and less time to ICU discharge (HR: 1.15, 95% CI: 1.04, 1.28). Antithrombosis may be associated with decreased risk of VAEs in patients with D-dimer >5 mg/LFEU (HR: 0.84, 95%CI: 0.72, 0.98).

Conclusions: Pharmacological thromboprophylaxis was associated with lower risk of VAEs and ICU mortality. Similar effects were observed between unfractionated heparins versus low-molecular-weight heparins.
Kangfuxiaoyanshuan alleviates uterine inflammation and adhesion via inhibiting NF-κB p65 and TGF-β/MMP-2 signaling pathway in pelvic inflammatory disease rats
Authors: Fan Linyuan , Liu Zhaohui , Zhang Zhan , Li Ting , Zong Xiaonan , Bai Huihui
Published: July 2022

Background and aims: Pelvic inflammatory disease (PID) is infection-induced inflammation of the female upper reproductive tract that results in high fever, ectopic pregnancy, infertility, and varying degrees of chronic pelvic pain. Recent clinical studies have shown that Kangfuxiaoyanshuan (KFXYS), a Traditional Chinese Medicine (TCM) formulation, may short the course of the disease and reduce the occurrence of PID sequelae, but its pharmacological action and potential mechanism have not been fully elucidated. Here, we aimed to investigate the therapeutic effects and mechanism of KFXYS in rats with PID.

Materials and Methods: A PID rat model was constructed through endometrial mechanical injury and pathogen infection. The rectal temperature was measured during the 14-days course of treatment, and the white blood cell (WBC) count in the blood and the levels of cytokines (IFN-γ, IL-1β, IL-4, TNF-α) in the serum were evaluated by ELISA. Hematoxylin and eosin (HE) staining was performed to analyze pathological changes, and transmission electron microscopy (TEM) was used to observe ultrastructural changes. The p-p65/p65 protein expression was evaluated by western blotting and the levels of MMP-2 and TGF-β in adhesion tissues were assessed by immunohistochemistry.

Results: KFXYS lowered the rectal temperature and the WBC counts in the blood in the acute stage of PID and alleviated inflammatory cell infiltration of the uterus, especially when combined with levofloxacin. KFXYS significantly decreased the levels of proinflammatory cytokines (IFN-γ, IL-1β, IL-4) and adhesion-related factors (TNF-α) and protected the ultrastructure of endometrial epithelial cells. Mechanistically, KFXYS inhibited the NF-κB activation by decreasing phosphorylation of p65, thus the alleviation of inflammation further reduced the expression of TGF-β and MMP-2, and inhibited the occurrence of uterine adhesions.

Conclusion: These results revealed that KFXYS alleviated pelvic inflammation and effectively inhibits inflammation-associated adhesion, which indicated the potential role of KFXYS for treatment of PID and the prevention of PID sequelae.
How Can We Optimize the Value Assessment and Appraisal of Orphan Drugs for Reimbursement Purposes? A Qualitative Interview Study Across European Countries
Authors: Blonda Alessandra , Denier Yvonne , Huys Isabelle , Kawalec Pawel , Simoens Steven
Published: July 2022

Introduction: The expansion of orphan drug treatment at increasing prices, together with uncertainties regarding their (cost-)effectiveness raises difficulties for decision-makers to assess these drugs for reimbursement. The present qualitative study aims to gain better insight into current value assessment and appraisal frameworks for orphan drugs, and provides guidance for improvement.

Methods: 22 European experts from 19 different countries were included in a qualitative survey, followed by in-depth semi-structured interviews. These experts were academics, members of reimbursement agencies or health authorities, or members of regulatory or health/social insurance institutions. Adopting a Grounded Theory approach, transcripts were analysed according to the QUAGOL method, supported by the qualitative data analysis software Nvivo.

Results: Although participants indicated several good practices (e.g., the involvement of patients and the presence of structure and consistency), several barriers (e.g., the lack of transparency) lead to questions regarding the efficiency of the overall reimbursement process. In addition, the study identified a number of “contextual” determinants (e.g., bias, perverse effects of the orphan drug legislation, and an inadequate consideration of the opportunity cost), which may undermine the legitimacy of orphan drug reimbursement decisions.

Conclusion: The present study provides guidance for decision-makers to improve the efficiency of orphan drug reimbursement. In particular, decision-makers can generate quick wins by limiting the impact of contextual determinants rather than improving the methods included in the HTA. When implemented into a framework that promotes “Accountability for Reasonableness” (A4R), this allows decision-makers to improve the legitimacy of reimbursement decisions concerning future orphan drugs.
PPARα: A potential therapeutic target of cholestasis
Authors: Ye Xiaoyin , Zhang Tong , Han Han
Published: July 2022

The accumulation of bile acids in the liver leads to the development of cholestasis and hepatocyte injury. Nuclear receptors control the synthesis and transport of bile acids in the liver. Among them, the farnesoid X receptor (FXR) is the most common receptor studied in treating cholestasis. The activation of this receptor can reduce the amount of bile acid synthesis and decrease the bile acid content in the liver, alleviating cholestasis. Ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) have a FXR excitatory effect, but the unresponsiveness of some patients and the side effect of pruritus seriously affect the results of UDCA or OCA treatment. The activator of peroxisome proliferator-activated receptor alpha (PPARα) has emerged as a new target for controlling the synthesis and transport of bile acids during cholestasis. Moreover, the anti-inflammatory effect of PPARα can effectively reduce cholestatic liver injury, thereby improving patients’ physiological status. Here, we will focus on the function of PPARα and its involvement in the regulation of bile acid transport and metabolism. In addition, the anti-inflammatory effects of PPARα will be discussed in some detail. Finally, we will discuss the application of PPARα agonists for cholestatic liver disorders.
Effects of an Armillaria mellea Polysaccharide on Learning and Memory of D-Galactose-Induced Aging Mice
Authors: Li Hongyu , Xu Guangyu , Yuan Guangxin
Published: July 2022

Armillaria mellea has been known and used in traditional medicine in East Asia for hundreds of years. It has already been reported that A. mellea extracts have various pharmacological effects, and the polysaccharides of A. mellea exhibit antioxidant and anti-apoptotic activities. In this study, a water-soluble polysaccharide (AMP-N-a-1), with an average molecular weight of 17 kD, was isolated and purified from the water extract of A. mellea using DEAE-52, Sepharose CL-4B, and Sephadex G-100 column chromatography. AMP-N-a-1 was mainly composed of Man (1.65%), Glca (1.64%), Rha (1.82%), Gala (2.49%), Glc (90.48%), Gal (0.89%), Xyl (0.42%), and Ara (0.61%). AMP-N-a-1 was used to study the effect on the learning and memory of mice and its underlying mechanisms. The results showed that AMP-N-a-1 could significantly increase the activities of catalase (CAT) and superoxide dismutase (SOD) and reduce the content of nitric oxide (NO) in mouse brain tissue. Meanwhile, AMP-N-a-1 could reduce the contents of norepinephrine (NE) and dopamine (DA) but could increase the content of 5-hydroxytryptamine (5-HT) in mouse brain tissue. In addition, the immunofluorescence experiment showed that AMP-N-a-1 could promote the proliferation of hippocampal dentate gyrus neurons. The above results indicate that AMP-N-a-1 can significantly improve the learning and memory of mice, and the mechanism may be that AMP-N-a-1 can participate in the regulation of learning and memory through a variety of ways.
A Multicenter Study of 239 Patients Aged Over 70 Years With Diffuse Large B-Cell Lymphoma in China
Authors: Yang Chunli , Li Qiaoer , Xie Ke , Zhang Yakun , Xiang Dania , Han Yunwei , Zou Liqun
Published: July 2022

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma subtype worldwide and occurs frequently in the elderly population. However, there are limited data on the clinical profiles of patients with DLBCL over 70 years of age. Our objective was to summarize the clinical characteristics, treatment strategies and survival outcomes of this population in China.

Methods: This multicenter retrospective study was conducted in China from January 2012 to July 2020 to investigate the clinical characteristics and survival outcomes. A total of 239 patients with DLBCL aged over 70 years underwent pretreatment evaluations, treatment, and follow-up at local hospitals. The primary endpoints were the progression-free survival (PFS) and the overall survival (OS) rates at 2 years. Secondary endpoints included median PFS and OS, the estimated PFS and OS rates at 5 years, and adverse events during treatment.

Results: With a median follow-up of 50 months (range, 1–102 months), the 2-year PFS and OS rates were 53.0% and 65.5%, respectively. The median PFS and OS were 42.1 and 96.4 months, respectively; and the estimated 5-year PFS and OS rates were 44.7% and 56.1%, respectively. Hematological toxicities were the most common adverse effects in this study, accounting for 90.4%; and leukopenia was the most frequently observed ≥ grade 3 event. Furthermore, we found that regimens without rituximab and chemotherapy cycles < 6 were significantly associated with worse survival. Additionally, in the 70–80-year group, reduction in chemotherapy dose was associated with a significantly shorter OS, with a 2-year OS rate of 74.4% in the full dose group, compared to 67.1% for the decreased-dose group (p = 0.044).

Conclusion: Our study presents the clinical profiles and survival outcomes of elderly patients with DLBCL in China. Treatment of these patients requires careful evaluation of toxicities and benefits. To this end, a prognosis model, such as comprehensive geriatric assessment, is required in clinical practice to optimally manage elderly patients with DLBCL.
Population pharmacokinetics model for escitalopram in Chinese psychiatric patients: effect of CYP2C19 and age
Authors: Liu Shujing , Xiao Tao , Huang Shanqing , Li Xiaolin , Kong Wan , Yang Ye , Zhang Zi , Ni Xiaojia , Lu Haoyang , Zhang Ming , Shang Dewei , Wen Yuguan
Published: July 2022

Objective: To establish a population pharmacokinetic model in Chinese psychiatric patients to characterize escitalopram pharmacokinetic profile to identify factors influencing drug exposure, and through simulation to compare the results with the established therapeutic reference range.

Methods: Demographic information, dosing regimen, CYP2C19 genotype, concomitant medications, and liver and kidney function indicators were retrospectively collected for inpatients taking escitalopram with therapeutic drug monitoring from 2018 to 2021. Nonlinear mixed-effects modeling was used to model the pharmacokinetic characteristics of escitalopram. Goodness-of-fit plots, bootstrapping, and normalized prediction distribution errors were used to evaluate the model. Simulation for different dosing regimens was based on the final estimations.

Results: The study comprised 106 patients and 337 measurements of serum sample. A structural model with one compartment with first-order absorption and elimination described the data adequately. The population-estimated apparent volume of distribution and apparent clearance were 815 and 16.3 L/h, respectively. Age and CYP2C19 phenotype had a significant effect on the apparent clearance (CL/F). CL/F of escitalopram decreased with increased age, and CL/F of poor metabolizer patients was significantly lower than in extensive and immediate metabolizer patients. The final model-based simulation showed that the daily dose of adolescents with poor metabolizer might be as high as 15 mg or 20 mg and referring to the therapeutic range for adults may result in overdose and a high risk of adverse effects in older patients.

Conclusion: A population pharmacokinetics model of escitalopram was successfully created for the Chinese population. Depending on the age of the patients, CYP2C19 genotype and serum drug concentrations throughout treatment are required for adequate individualization of dosing regimens. When developing a regimen for older patients, especially those who are poor metabolizers, vigilance is required.
SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice
Authors: Shi Chunxia , Jiao Fangzhou , Wang Yao , Chen Qian , Wang Luwen , Gong Zuojiong
Published: July 2022

The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1β) were measured by ELISA and Western blotting. The cell type expression of IL-1β in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.
A Phosphoproteomics Study of the Soybean root necrosis 1 Mutant Revealed Type II Metacaspases Involved in Cell Death Pathway
Authors: Wang Feifei , Das Priyanka , Pal Narinder , Bhawal Ruchika , Zhang Sheng , Bhattacharyya Madan K.
Published: July 2022

The soybean root necrosis 1 (rn1) mutation causes progressive browning of the roots soon after germination and provides increased tolerance to the soil-borne oomycete pathogen Phytophthora sojae in soybean. Toward understanding the molecular basis of the rn1 mutant phenotypes, we conducted tandem mass tag (TMT)-labeling proteomics and phosphoproteomics analyses of the root tissues of the rn1 mutant and progenitor T322 line to identify potential proteins involved in manifestation of the mutant phenotype. We identified 3,160 proteins. When the p-value was set at ≤0.05 and the fold change of protein accumulation between rn1 and T322 at ≥1.5 or ≤0.67, we detected 118 proteins that showed increased levels and 32 proteins decreased levels in rn1 as compared to that in T322. The differentially accumulated proteins (DAPs) are involved in several pathways including cellular processes for processing environmental and genetic information, metabolism and organismal systems. Five pathogenesis-related proteins were accumulated to higher levels in the mutant as compared to that in T322. Several of the DAPs are involved in hormone signaling, redox reaction, signal transduction, and cell wall modification processes activated in plant–pathogen interactions. The phosphoproteomics analysis identified 22 phosphopeptides, the levels of phosphorylation of which were significantly different between rn1 and T322 lines. The phosphorylation levels of two type II metacaspases were reduced in rn1 as compared to T322. Type II metacaspase has been shown to be a negative regulator of hypersensitive cell death. In absence of the functional Rn1 protein, two type II metacaspases exhibited reduced phosphorylation levels and failed to show negative regulatory cell death function in the soybean rn1 mutant. We hypothesize that Rn1 directly or indirectly phosphorylates type II metacaspases to negatively regulate the cell death process in soybean roots.
Spray drift evaluation with point clouds data of 3D LiDAR as a potential alternative to the sampling method
Authors: Li Longlong , Zhang Ruirui , Chen Liping , Liu Boqin , Zhang Linhuan , Tang Qing , Ding Chenchen , Zhang Zhen , Hewitt Andrew J.
Published: July 2022

Spray drift is an inescapable consequence of agricultural plant protection operation, which has always been one of the major concerns in the spray application industry. Spray drift evaluation is essential to provide a basis for the rational selection of spray technique and working surroundings. Nowadays, conventional sampling methods with passive collectors used in drift evaluation are complex, time-consuming, and labor-intensive. The aim of this paper is to present a method to evaluate spray drift based on 3D LiDAR sensor and to test the feasibility of alternatives to passive collectors. Firstly, a drift measurement algorithm was established based on point clouds data of 3D LiDAR. Wind tunnel tests included three types of agricultural nozzles, three pressure settings, and five wind speed settings were conducted. LiDAR sensor and passive collectors (polyethylene lines) were placed downwind from the nozzle to measure drift droplets in a vertical plane. Drift deposition volume on each line and the number of LiDAR droplet points in the corresponding height of the collecting line were calculated, and the influencing factors of this new method were analyzed. The results show that 3D LiDAR measurements provide a rich spatial information, such as the height and width of the drift droplet distribution, etc. High coefficients of determination (R2 > 0.75) were observed for drift points measured by 3D LiDAR compared to the deposition volume captured by passive collectors, and the anti-drift IDK12002 nozzle at 0.2 MPa spray pressure has the largest R2 value, which is 0.9583. Drift assessment with 3D LiDAR is sensitive to droplet density or drift mass in space and nozzle initial droplet spectrum; in general, larger droplet density or drift mass and smaller droplet size are not conducive to LiDAR detection, while the appropriate threshold range still needs further study. This study demonstrates that 3D LiDAR has the potential to be used as an alternative tool for rapid assessment of spray drift.
Temperature- and light stress adaptations in Zygnematophyceae: The challenges of a semi-terrestrial lifestyle
Authors: Permann Charlotte , Becker Burkhard , Holzinger Andreas
Published: July 2022

Streptophyte green algae comprise the origin of land plants and therefore life on earth as we know it today. While terrestrialization opened new habitats, leaving the aquatic environment brought additional abiotic stresses. More-drastic temperature shifts and high light levels are major abiotic stresses in semi-terrestrial habitats, in addition to desiccation, which has been reviewed elsewhere. Zygnematophyceae, a species-rich class of streptophyte green algae, is considered a sister-group to embryophytes. They have developed a variety of avoidance and adaptation mechanisms to protect against temperature extremes and high radiation in the form of photosynthetically active and ultraviolet radiation (UV) radiation occurring on land. Recently, knowledge of transcriptomic and metabolomic changes as consequences of these stresses has become available. Land-plant stress-signaling pathways producing homologs of key enzymes have been described in Zygnematophyceae. An efficient adaptation strategy is their mat-like growth habit, which provides self-shading and protects lower layers from harmful radiation. Additionally, Zygnematophyceae possess phenolic compounds with UV-screening ability. Resting stages such as vegetative pre-akinetes tolerate freezing to a much higher extent than do young cells. Sexual reproduction occurs by conjugation without the formation of flagellated male gametes, which can be seen as an advantage in water-deficient habitats. The resulting zygospores possess a multilayer cell wall, contributing to their resistance to terrestrial conditions. Especially in the context of global change, understanding temperature and light tolerance is crucial.