bluuebunny/crossref_metadata_2025 huggingface dataset:
Postsynaptic Neuroligin-1 Mediates Presynaptic Endocytosis During Neuronal Activity
Authors: Luo Jiaqi Keith , Melland Holly , Nithianantharajah Jess , Gordon Sarah L.
Published: October 2021

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.
Combination of Anoectochilus roxburghii Polysaccharide and Exercise Ameliorates Diet-Induced Metabolic Disorders in Obese Mice
Authors: Chen Cong , Kang Meisong , Wang Qiaowen , Liu Weilin , Yang Minguang , Liang Shengxiang , Xiang Qing , Han Xiao , Tao Jing
Published: October 2021

Metabolic syndrome is a cluster of metabolic disorders that threatens public health. Nevertheless, its exact mechanism and relative intervention remain largely obscure. Accumulating evidence indicate that tither Anoectochilus roxburghii polysaccharide (ARP) or exercise (EX) exhibited the beneficial effects on metabolic health. However, the synergetic beneficial effects of ARP and EX as a combined intervention on obesity-induced metabolic disorders remain largely obscure. Male C57BL/6 mice were fed a high-fat diet (HFD) and intervened with ARP and EX for 12 continuous weeks. The results indicated that the ARP, EX, and ARP combined with EX treatment group regulated lipogenesis by suppressing the fatty acid pathway, dampening the system oxidative stress by stimulating Nrf2-mediated phase II enzyme system, and promoting the mitochondrial function by activating the mitochondrial complexes and PGC-1α in HFD mice. More importantly, the combination of ARP and EX showed an even greater beneficial effects relative to either ARP or EX alone, especially in decreasing reactive oxygen species (ROS) level and increasing adenosine triphosphate (ATP) content. Taken together, these findings further confirmed that ARP and EX could be effective interventions on obesity-induced metabolic abnormalities, and that the combination of ARP and EX exhibited the beneficial synergetic effects.
Baicalin–Zinc Complex Alleviates Inflammatory Responses and Hormone Profiles by Microbiome in Deoxynivalenol Induced Piglets
Authors: Zha Andong , Tu Ruiqi , Cui Zhijuan , Qi Ming , Liao Simeng , Wang Jing , Tan Bie , Liao Peng
Published: October 2021

This study aimed to investigate the beneficial effect of baicalin–zinc complex (BZN) on intestinal microorganisms in deoxynivalenol (DON)-challenged piglets and the association between intestinal microorganisms and host immunity and hormone secretion. Forty weaned piglets were randomly divided into four treatments with 10 piglets in each treatment: (1) control (Con) group (pigs fed basal diet); (2) DON group (pigs fed 4 mg DON/kg basal diet); (3) BZN group (pigs fed 0.5% BZN basal diet); and (4) DBZN group (pigs fed 4 mg DON/kg and 0.5% BZN basal diet). The experiment lasted for 14 days. The BZN supplementation in DON-contaminated diets changed the intestinal microbiota composition and increased intestinal microbial richness and diversity of piglets. The BZN supplementation in DON-contaminated diets also alleviated the inflammatory responses of piglets and modulated the secretion of hormones related to the growth axis. Moreover, microbiota composition was associated with inflammatory and hormone secretion. In conclusion, BZN alleviated inflammatory response and hormone secretion in piglets, which is associated with the intestinal microbiome.
CT-Based Sarcopenic Nomogram for Predicting Progressive Disease in Advanced Non-Small-Cell Lung Cancer
Authors: Yi Xiaoping , Chen Qiurong , Yang Jingying , Jiang Dengke , Zhu Liping , Liu Haipeng , Pang Peipei , Zeng Feiyue , Chen Changyong , Gong Guanghui , Yin Hongling , Li Bin , Chen Bihong T.
Published: October 2021

Background

It is prudent to identify the risk for progressive disease (PD) in patients with non-small-cell lung cancer (NSCLC) who undergo platinum-based chemotherapy. The present study aimed to develop a CT imaging-based sarcopenic nomogram for predicting the risk of PD prior to chemotherapy treatment.

Methods

We retrospectively enrolled patients with NSCLC who underwent platinum-based chemotherapy. Imaging-based body composition parameters such as skeletal muscle index (SMI) for assessment of sarcopenia were obtained from pre-chemotherapy chest CT images at the level of the eleventh thoracic vertebral body (T11). Sarcopenic nomogram was constructed using multivariate logistic regression and performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve.

Results

Sixty (14.7%) of the 408 patients in the study cohort developed PD during chemotherapy. The prediction nomogram for developing PD achieved a moderate efficiency with an area under the curve (AUC) of 0.75 (95% CI: 0.69-0.80) for the training cohort, and 0.76 (95%CI: 0.68-0.84) for the validation cohort, as well as a good performance of consistence (bootstrap for training cohort: 0.75 ± 0.02; validation cohort: 0.74 ± 0.06). Favorable clinical application was observed in the decision curve analysis.

Conclusion

Our CT-based sarcopenic nomogram showed the potential for an individualized prediction of progression for patients with NSCLC receiving platinum-based chemotherapy.
Aberrant Metabolism as Inductor of Epigenetic Changes in Breast Cancer: Therapeutic Opportunities
Authors: Coronel-Hernández Jossimar , Pérez-Yépez Eloy Andrés , Delgado-Waldo Izamary , Contreras-Romero Carlos , Jacobo-Herrera Nadia , Cantú-De León David , Pérez-Plasencia Carlos
Published: October 2021

Aberrant metabolism is arising interest in the scientific community not only because of the role it plays in the development and establishment of the tumor mass but also the possibility of drug poisoning of key enzymes overexpressed in tumor cells. Moreover, tumor metabolism provides key molecules to maintain the epigenetic changes that are also an undisputed characteristic of each tumor type. This metabolic change includes the Warburg effect and alterations in key pathways involved in glutaminolysis, pentose phosphate, and unsaturated fatty acid biosynthesis. Modifications in all these pathways have consequences that impact genetics and epigenetics processes such as DNA methylation patterns, histone post-translational modifications, triggering oncogenes activation, and loss in tumor suppressor gene expression to lead the tumor establishment. In this review, we describe the metabolic rearrangement and its association with epigenetic regulation in breast cancer, as well as its implication in biological processes involved in cancer progression. A better understanding of these processes could help to find new targets for the diagnosis, prognosis, and treatment of this human health problem.
Construction and Validation of a Serum Albumin-to-Alkaline Phosphatase Ratio-Based Nomogram for Predicting Pathological Complete Response in Breast Cancer
Authors: Qu Fanli , Li Zongyan , Lai Shengqing , Zhong XiaoFang , Fu Xiaoyan , Huang Xiaojia , Li Qian , Liu Shengchun , Li Haiyan
Published: October 2021

Background

Breast cancer patients who achieve pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have favorable outcomes. Reliable predictors for pCR help to identify patients who will benefit most from NAC. The pretreatment serum albumin-to-alkaline phosphatase ratio (AAPR) has been shown to be a prognostic predictor in several malignancies, but its predictive value for pCR in breast cancer is still unknown. This study aims to investigate the predictive role of AAPR in breast cancer patients and develop an AAPR-based nomogram for pCR rate prediction.

Methods

A total of 780 patients who received anthracycline and taxane-based NAC from January 2012 to March 2018 were retrospectively analyzed. Univariate and multivariate analyses were performed to assess the predictive value of AAPR and other clinicopathological factors. A nomogram was developed and calibrated based on multivariate logistic regression. A validation cohort of 234 patients was utilized to further validate the predictive performance of the model. The C-index, calibration plots and decision curve analysis (DCA) were used to evaluate the discrimination, calibration and clinical value of the model.

Results

Patients with a lower AAPR (<0.583) had a significantly reduced pCR rate (OR 2.228, 95% CI 1.246-3.986, p=0.007). Tumor size, clinical nodal status, histological grade, PR, Ki67 and AAPR were identified as independent predictors and included in the final model. The nomogram was used as a graphical representation of the model. The nomogram had satisfactory calibration and discrimination in both the training cohort and validation cohort (the C-index was 0.792 in the training cohort and 0.790 in the validation cohort). Furthermore, DCA indicated a clinical net benefit from the nomogram.

Conclusions

Pretreatment serum AAPR is a potentially valuable predictor for pCR in breast cancer patients who receive NAC. The AAPR-based nomogram is a noninvasive tool with favorable predictive accuracy for pCR, which helps to make individualized treatment strategy decisions.
Prognostic Value of the Pretreatment Lung Immune Prognostic Index in Advanced Small Cell Lung Cancer Patients Treated With First-Line PD-1/PD-L1 Inhibitors Plus Chemotherapy
Authors: Li Lingling , Pi Chenghui , Yan Xin , Lu Jiangyue , Yang Xuhui , Wang Chunyu , Li Xiaoyan , Zhang Sujie , Zhang Zhibo , Sun Yi , Hu Yi
Published: October 2021

Background

Lung immune prognostic index (LIPI) refers to a biomarker combining derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH). Its prognostic effect on advanced small cell lung cancer (SCLC) patients receiving programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors plus chemotherapy as first-line treatment remains unclear. Our research investigated the relationship between pretreatment LIPI and the prognosis of patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy.

Methods

Advanced SCLC patients receiving PD-1/PD-L1 inhibitors plus chemotherapy as first-line treatment from Jan 2015 to Oct 2020 were included. Based on the values of dNLR and LDH, the study population was divided into two groups: LIPI good and LIPI intermediate/poor. The Kaplan-Meier method was used to compute the median survival time and the log-rank test was used to compare the two groups. Univariate and multivariate analyses were used to examine the correlation between the pretreatment LIPI and clinical outcomes.

Results

One hundred patients were included in this study, of which, 64% were LIPI good (dNLR < 4.0 and LDH < 283 U/L), 11% were LIPI poor (dNLR ≥ 4.0 and LDH ≥ 283 U/L), and the remaining 25% were LIPI intermediate. The LIPI good group had better progression-free survival (PFS) (median: 8.4 vs 4.7 months, p = 0.02) and overall survival (OS) (median: 23.8 vs 13.3 months, p = 0.0006) than the LIPI intermediate/poor group. Multivariate analysis showed that pretreatment LIPI intermediate/poor was an independent risk factor for OS (HR: 2.34; 95%CI, 1.13, 4.86; p = 0.02). Subgroup analysis showed that pretreatment LIPI good was associated with better PFS and OS in males, extensive disease (ED), PD-1 inhibitor treatment, smokers, and liver metastasis (p < 0.05).

Conclusions

Pretreatment LIPI could serve as a prognostic biomarker for advanced SCLC patients receiving first-line PD-1/PD-L1 inhibitors plus chemotherapy.
Risk Factors Associated With Early-Onset Colorectal Neoplasm in Chinese Youth: A Prospective Population-Based Study
Authors: Shen Jie , Wu Yiling , Mo Miao , Feng Xiaoshuang , Zhou Changming , Wang Zezhou , Cai Guoxiang , Zheng Ying
Published: October 2021

Evidence of the risk factors associated with early-onset colorectal neoplasm from prospective population-based studies is limited. We enrolled 17,293 participants younger than 50 years from the Shanghai colorectal cancer (CRC) screening program cohort. Face-to-face interviews were performed by trained primary care physicians using a standardized questionnaire to collect the information on potential risk factors at baseline entry. Furthermore, 124 cases of early-onset colorectal neoplasm, including six CRC cases and 118 colorectal adenoma (CRA) cases, were detected between 2012 and 2016. Multivariable logistic regression models and restricted cubic spline (RCS) were used to evaluate the risk factors associated with early-onset colorectal neoplasm. We found that sex, body mass index (BMI), and family history of CRC were associated with the early onset of colorectal neoplasm. The RCS model showed a positive dose–response and linear association between BMI and risk of early-onset colorectal neoplasm among young participants (p-overall = 0.19, p-nonlinear = 0.97). The findings indicated that it was beneficial for normal people younger than 50 years to start opportunistic CRC screening. As for those at high risk, increased surveillance is strongly recommended. Further close follow-up is required for research on the underlying causes of early-onset CRC.
The Addition of Peripheral Blood Inflammatory Indexes to Nomogram Improves the Predictive Accuracy of Survival in Limited-Stage Small Cell Lung Cancer Patients
Authors: Qi Jing , Zhang Jiaqi , Ge Xingping , Wang Xin , Xu Liming , Liu Ningbo , Zhao Lujun , Wang Ping
Published: October 2021

Background

Accumulated evidence for systemic inflammation response in several solid tumors prompts a possibility of prediction of patients’ prognosis in a more accessible and valuable manner. However, the prognostic value of peripheral blood inflammatory markers in limited-stage small cell lung cancer (LS-SCLC) remains unclear. Therefore, we investigated the prognostic values of pretreatment inflammatory indexes in LS-SCLC patients.

Methods

We retrospectively identified 334 patients with LS-SCLC and collected their pretreatment serum levels of neutrophil, platelet, lymphocyte, leukocyte, hemoglobin, and albumin, then neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic inflammation index (SII) were calculated. Patients were dichotomized as low-Risk or high-Risk group based on their corresponding cutoff values. Univariate and multivariate analyses were conducted with a Cox proportional hazards model. The least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to construct the inflammation-related prognostic scoring system named Risk for OS. Nomograms were established to provide prognostic information, allowing for more individualized prediction of survival.

Results

Higher pretreatment platelet, lymphocyte, and albumin were indicators of favorable overall survival (OS), whereas higher NLR and SII were accompanied by inferior OS. The prognosis of patients with high Risk was significantly worse than that with low Risk in both the training group and the validation group (both p < 0.001). Comparable area under the curve (AUC) values between the training group and the validation group were observed, yielding 1-, 3-, and 5-year OS rates of 67.3% vs. 69.2%, 66.8% vs. 69.5%, and 66.7% vs. 71.4%, respectively. Multivariate analyses revealed that Risk [hazard ratio (HR) = 0.551, p < 0.001] was an independent negative prognostic indicator for OS, which was further verified in the validation set. The addition of Risk to nomogram (C-index = 0.643) harbored improved predictive accuracy for OS when compared with that of clinical factors alone (C-index = 0.606); the AUC values of 1-, 3-, and 5-year OS rates were 71.7% vs. 66.4%, 73.5% vs. 66.6%, and 71.9% vs. 65.6%, respectively.

Conclusions

Pretreatment peripheral blood inflammatory indexes may be a noninvasive serum biomarker for poor prognosis in LS-SCLC. The addition of Risk to the nomogram model could serve as a more powerful, economical, and practical method to predict survival for patients with LS-SCLC.
The Chemokine CXCL7 Is Related to Angiogenesis and Associated With Poor Prognosis in Colorectal Cancer Patients
Authors: Li Longhai , Jiang Kai , Li Dongpeng , Li Dongxiao , Fan Zitong , Dai Guosheng , Tu Sheng , Liu Xiangyu , Wei Guangyou
Published: October 2021

Objective

The present study was designed to investigate the role of the chemokine CXCL7 in angiogenesis and explore its prognostic value in colorectal cancer (CRC).

Methods

A total of 160 CRC patients who had undergone surgery were included in this study, and staged according to the guidelines of the AJCC, 7th Edition. Expression of CXCL7 and VEGF was detected by immunohistochemical (IHC) staining and divided into high and low expression subgroups. The correlation between CXCL7 and VEGF expression was evaluated by Spearman’s rank-correlation coefficient. Prognosis based on CXCL7 and VEGF was evaluated using the Cox proportional hazards regression model and a nomogram of 5-year overall survival (OS) time.

Results

CXCL7 was highly expressed in tumor tissues (65.63% vs 25.00% in paracancerous tissue, P < 0.001), as was VEGF. CXCL7 and VEGF expression correlated well with N and TNM stage cancers (all P < 0.001). Importantly, CXCL7 was positively correlated with VEGF expression in CRC tissues. CXCL7 was an independent predictor of poor OS of CRC patients (HR = 2.216, 95% CI: 1.069-4.593, P = 0.032), and co-expression of CXCL7 and VEGF of predicted poor OS of 56.96 months.

Conclusion

Expression of CXCL7 correlated with VEGF and was associated with poor clinical outcomes in CRC patients.
The Missing Link: Cre Pigs for Cancer Research
Authors: Kalla Daniela , Flisikowski Krzysztof , Yang Kaiyuan , Sangüesa Laura Beltran , Kurome Mayuko , Kessler Barbara , Zakhartchenko Valeri , Wolf Eckhard , Lickert Heiko , Saur Dieter , Schnieke Angelika , Flisikowska Tatiana
Published: October 2021

The Cre/loxP system is a powerful tool for the generation of animal models with precise spatial and temporal gene expression. It has proven indispensable in the generation of cancer models with tissue specific expression of oncogenes or the inactivation of tumor suppressor genes. Consequently, Cre-transgenic mice have become an essential prerequisite in basic cancer research. While it is unlikely that pigs will ever replace mice in basic research they are already providing powerful complementary resources for translational studies. But, although conditionally targeted onco-pigs have been generated, no Cre-driver lines exist for any of the major human cancers. To model human pancreatic cancer in pigs, Cre-driver lines were generated by CRISPR/Cas9-mediated insertion of codon-improved Cre (iCre) into the porcine PTF1A gene, thus guaranteeing tissue and cell type specific function which was proven using dual fluorescent reporter pigs. The method used can easily be adapted for the generation of other porcine Cre-driver lines, providing a missing tool for modeling human cancers in large animals.
Invasive Pneumococcal Disease in Latvia in PCV10 Vaccination Era, 2012–2018
Authors: Savrasova Larisa , Krumina Angelika , Cupeca Hedija , Zeltina Indra , Villerusha Anita , Grope Ilze , Viksna Ludmila , Dimina Elina , Balasegaram Sooria
Published: October 2021

In 2010 in Latvia, invasive pneumococcal disease (IPD) became a cause for concern and vaccination of infants with four doses of 7–valent pneumococcal conjugate vaccine (PCV7) commenced. In 2012, 10–valent pneumococcal conjugate vaccine (PCV10) (three doses at 2, 4, and 12–15 month of age) vaccination was introduced. We described incidence and serotype distribution of IPD in Latvia and investigated serotypes associated with death from IPD based on surveillance data. Adult vaccination against pneumococcal infection is not included in the national immunization program. Laboratory confirmed IPD cases are passively notified to the Center for Disease Prevention and Control of Latvia (CDPC) by laboratories and clinicians. We calculated incidence by age, sex, case fatality, and trend in serotypes by conducting a retrospective population-based cross-sectional study based on national IPD surveillance data. From 2012 to 2018 466 cases of IPD were reported. The highest notified incidence was in 2015 at 4.4/100,000, which fell to 3.9 in 2018. The highest mean annual IPD incidence was in infants (4.8) and in the elderly (6.0). PCV10 vaccine serotypes were the most prevalent in IPD cases up to 2015 with a decreasing trend from 50% (20/40) in 2012 to 19% (14/74) in 2018 (chi2 test for trend of odds = 0.000). PCV23nonPCV13 vaccine serotypes had an increasing trend and rose from 18% (7/40) to 34% (25/74) (chi2 test for trend of odds = 0.000). Non-Vaccine serotypes had an increasing trend and rose from 13% (5/40) to 27% (20/74) (chi2 test for trend of odds = 0.038). Reported total case fatality was 19% (87/466). The highest, at 36% (20/56), was reported in 2013. After adjusting for age, Streptococcus pneumoniae serotype 3 was associated with death from IPD (adjusted OR 2.3 95%CI 1.25–4.12 p 0.007). Surveillance data indicate evidence of serotype replacement with an increasing trend of serotype 19A and PPV23nonPCV13 and Non-Vaccine serotypes. Serotype 3 and age were associated with fatal IPD outcome. Further studies of S. pneumoniae carriage would be useful in providing more evidence to characterize serotypes' circulation.
Outcomes of Pediatric Patients With Sepsis Related to Staphylococcus aureus and Methicillin-Resistant Staphylococcus aureus Infections Requiring Extracorporeal Life Support: An ELSO Database Study
Authors: Foster Cortney , Bagdure Dayanand , Custer Jason , Holloway Adrian , Rycus Peter , Day Jenni , Bhutta Adnan
Published: October 2021

Background: Extracorporeal membrane oxygenation (ECMO) is increasingly utilized for pediatric sepsis unresponsive to steroids and inotropic support. Outcomes of children with sepsis are influenced by the type of pathogen causing their illness.

Objective: To determine if the outcomes of children with Staphylococcus aureus sepsis receiving ECMO differed according to microbial sensitivity (Methicillin-resistant Staphylococcus aureus [MRSA] vs. Methicillin-sensitive Staphylococcus aureus [MSSA]).

Methods: Retrospective case-matched cohort study of children (0–<18 years) with Staphylococcus aureus sepsis reported to the ELSO registry from more than 995 centers. Inclusion criteria were age 0–18 years, laboratory diagnosis of Staphylococcal infection, clinical diagnosis of sepsis, and ECMO deployment. Exclusion criteria were no laboratory diagnosis of Staphylococcal infection. We compared patient demographics, pre-ECMO management and outcomes of those with MRSA vs. MSSA using Chi-Square test, with independent samples t-test used to test to compare continuous variables.

Results: In our study cohort of 308 patients, 160 (52%) had MSSA and 148 (48%) MRSA with an overall survival rate of 41.5%. There were no differences in the age group (p = 0.76), gender distribution (p = 0.1) or racial distribution (p = 0.58) between the two groups. P value for racial distribution should be 0.058. There were 91 (56.8%) deaths in the MSSA group and 89 (60.1%) deaths (p = 0.56) in the MRSA group. Duration on ECMO (p = 0.085) and the time from intubation to ECMO (p = 0.37) were also similar in the two groups. Survival with MSSA sepsis and MRSA sepsis did not improve significantly over the 20 years evaluated despite an increase in ECMO utilization.

Conclusion: In this multi-center retrospective study, there were no differences in outcomes for children receiving ECMO support with Staphylococcus aureus sepsis according to microbial methicillin sensitivity. There was no significant increase in survival among patients with MRSA and MSSA infections receiving ECMO in the last 20 years.
Efficacy and Safety of Rifaximin Versus Placebo or Other Active Drugs in Critical ill Patients With Hepatic Encephalopathy
Authors: Han Xianghui , Luo Zhanyang , Wang Wenyi , Zheng Peiyong , Li Tian , Mei Zubing , Wang Jianyi
Published: October 2021

Objective: Rifaximin has been approved for use as a first-line therapy for secondary prophylaxis of hepatic encephalopathy (HE). This article is to update existing evidence on efficacy and safety of rifaximin treatment and prevention for HE.

Methods: We systematically searched multiple databases until January 31 2021. The studies compared rifaximin vs. placebo or other active drugs (i.e., nonabsorbable disaccharides, other antibiotics, L-ornithine-L-aspartate (LOLA), and probiotics) for patients with overt HE (OHE), minimal HE (MHE), and recurrent HE.

Results: Twenty-eight randomized controlled trials with a total of 2979 patients were included. Compared with the controls, rifaximin significantly reduced HE grade (OHE: RR = 1.11, 95% CI = 1.02–1.21), improved the cognitive impairments (MHE: RR = 1.82, 95% CI = 1.12–2.93) and prevented the risk of HE recurrent episodes (RR = 1.33, 95% CI = 1.18–1.49). No statistical difference was observed in mortality between rifaximin and their controls (RR = 0.82, 95% CI = 0.54–1.24). The incidence of total adverse events in rifaximin-treated groups was significantly lower than that in the controls during the treatment period (RR = 0.73, 95% CI = 0.54–0.98). In addition, rifaximin treatment was better than other active drugs in improving psychometric indicators (mental state, flapping tremor and portosystemic encephalopathy (PSE) index) and reducing the risk of rehospitalization in HE patients.

Conclusion: Rifaximin therapy is effective and well-tolerated in different types of HE, which might be recommended as an alternative to conventional oral drugs in clinical settings.
Integrated Network Pharmacology Analysis and Experimental Validation to Investigate the Mechanism of Zhi-Zi-Hou-Po Decoction in Depression
Authors: Bai Yongtao , Zhang Yingchun , Li Shuolei , Zhang Wenzhou , Wang Xinhui , He Baoxia , Ju Wenzheng
Published: October 2021

Zhi-Zi-Hou-Po Decoction (ZZHPD) is a well-known traditional Chinese medicine (TCM) that has been widely used in depression. However, the antidepressant mechanism of ZZHPD has not yet been fully elucidated. The purpose of this study was to explore the pharmacological mechanisms of ZZHPD acting on depression by combining ultra flow liquid chromatography with quadrupole time-of-flight mass spectrometry (UFLC-Q-TOF/MS) and network pharmacology strategy. The chemical components of ZZHPD were identified using UFLC-Q-TOF/MS, while the potential drug targets and depression-related targets were collected from databases on the basis of the identified compounds of ZZHPD. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were used to unravel potential antidepressant mechanisms. The predicted antidepressant targets from the pharmacology-based analysis were further verified in vivo. As a result, a total of 31 chemical compounds were identified by UFLC-Q-TOF/MS; 514 promising drug targets were mined by using the Swiss Target Prediction; and 527 depression-related target genes were pinpointed by the GeneCards and OMIM databases. STRING database and Cytoscape’s topological analysis revealed 80 potential targets related to the antidepressant mechanism of ZZHPD. The KEGG pathway analysis revealed that the antidepressant targets of ZZHPD were mainly involved in dopaminergic synapse, serotonin synapse, cAMP, and mTOR signaling pathways. Furthermore, based on the animal model of depression induced by chronic corticosterone, the regulatory effects of ZZHPD on the expression of MAOA, MAOB, DRD2, CREBBP, AKT1, MAPK1, HTR1A, and GRIN2B mRNA levels as well as the cAMP signaling pathway and monoaminergic metabolism were experimentally verified in rats. Our study revealed that ZZHPD is expounded to target various genes and pathways to perform its antidepressant effect.
Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
Authors: Tate Mitchel , Perera Nimna , Prakoso Darnel , Willis Andrew M. , Deo Minh , Oseghale Osezua , Qian Hongwei , Donner Daniel G , Kiriazis Helen , De Blasio Miles J. , Gregorevic Paul , Ritchie Rebecca H.
Published: October 2021

Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.
A Fatty Acid Fraction Purified From Sea Buckthorn Seed Oil Has Regenerative Properties on Normal Skin Cells
Authors: Dudau Maria , Codrici Elena , Tarcomnicu Isabela , Mihai Simona , Popescu Ionela Daniela , Albulescu Lucian , Constantin Nicoleta , Cucolea Iulia , Costache Teodor , Rambu Dan , Enciu Ana-Maria , Hinescu Mihail E. , Tanase Cristiana
Published: October 2021

In recent years, natural product's research gained momentum, fueled by technological advancement and open availability of research data. To date, sea buckthorn (Hippophae rhamnoides L. [Elaeagnaceae]) plant parts, especially berries, are well characterized and repeatedly tested for antioxidant activity and regenerative properties, in various cell types and tissues. However, fatty acids (FA) have been less investigated in term of biological effects, although, they are important bioactive components of the sea buckthorn fruit and oil. The aim of our work was to determine whether sea buckthorn seed oil is a suitable source of FA with regenerative properties on normal skin cells. Using high-performance liquid chromatography (HPLC) and liquid chromatography – mass spectrometry (LC-MS), we purified and characterized four fractions enriched in saturated (palmitic) and non-saturated (linoleic, alfa-linolenic, oleic) FA, which were tested for cytotoxicity, cytokine and growth factor production, and regenerative effect on normal keratinocytes and skin fibroblasts. Evidence is presented that the palmitic acid enriched fraction was a suitable sea buckthorn seed oil derived product with cell proliferation properties on both skin cell types.
Allium victorialis L. Extracts Promote Activity of FXR to Ameliorate Alcoholic Liver Disease: Targeting Liver Lipid Deposition and Inflammation
Authors: Cui Zhen-Yu , Han Xin , Jiang Yu-Chen , Dou Jia-Yi , Yao Kun-Chen , Hu Zhong-He , Yuan Ming-Hui , Bao Xiao-Xue , Zhou Mei-Jie , Liu Yue , Lian Li-Hua , Zhang Xian , Nan Ji-Xing , Wu Yan-Ling
Published: October 2021

Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber–DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.
Gaboxadol in Fragile X Syndrome: A 12-Week Randomized, Double-Blind, Parallel-Group, Phase 2a Study
Authors: Budimirovic Dejan B. , Dominick Kelli C. , Gabis Lidia V. , Adams Maxwell , Adera Mathews , Huang Linda , Ventola Pamela , Tartaglia Nicole R. , Berry-Kravis Elizabeth
Published: October 2021

Background: Fragile X syndrome (FXS), the most common single-gene cause of intellectual disability and autism spectrum disorder (ASD), is caused by a >200-trinucleotide repeat expansion in the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Individuals with FXS can present with a range of neurobehavioral impairments including, but not limited to: cognitive, language, and adaptive deficits; ASD; anxiety; social withdrawal and avoidance; and aggression. Decreased expression of the γ-aminobutyric acid type A (GABAA) receptor δ subunit and deficient GABAergic tonic inhibition could be associated with symptoms of FXS. Gaboxadol (OV101) is a δ-subunit–selective, extrasynaptic GABAA receptor agonist that enhances GABAergic tonic inhibition, providing the rationale for assessment of OV101 as a potential targeted treatment of FXS. No drug is approved in the United States for the treatment of FXS.

Methods: This 12-weeks, randomized (1:1:1), double-blind, parallel-group, phase 2a study was designed to assess the safety, tolerability, efficacy, and optimal daily dose of OV101 5 mg [once (QD), twice (BID), or three-times daily (TID)] when administered for 12 weeks to adolescent and adult men with FXS. Safety was the primary study objective, with key assessments including treatment-emergent adverse events (TEAEs), treatment-related adverse events leading to study discontinuation, and serious adverse events (SAEs). The secondary study objective was to evaluate the effect of OV101 on a variety of problem behaviors.

Results: A total of 23 participants with FXS (13 adolescents, 10 adults) with moderate-to-severe neurobehavioral phenotypes (Full Scale Intelligence Quotient, 41.5 ± 3.29; ASD, 82.6%) were randomized to OV101 5 mg QD (n = 8), 5 mg BID (n = 8), or 5 mg TID (n = 7) for 12 weeks. OV101 was well tolerated across all 3 treatment regimens. The most common TEAEs were upper respiratory tract infection (n = 4), headache (n = 3), diarrhea (n = 2), and irritability (n = 2). No SAEs were reported. Improvements from baseline to end-of-treatment were observed on several efficacy endpoints, and 60% of participants were identified as treatment responders based on Clinical Global Impressions-Improvement.

Conclusions: Overall, OV101 was safe and well tolerated. Efficacy results demonstrate an initial signal for OV101 in individuals with FXS. These results need to be confirmed in a larger, randomized, placebo-controlled study with optimal outcomes and in the most appropriate age group.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03697161
3D Mueller Matrix Reconstruction of the Optical Anisotropy Parameters of Myocardial Histopathology Tissue Samples
Authors: Hogan Benjamin T. , Ushenko Volodimyr A. , Syvokorovskaya Anastasia-Vira , Dubolazov Alexander V. , Vanchulyak Oleg Ya. , Ushenko Alexander G. , Ushenko Yuriy A. , Gorsky Mykhailo P. , Tomka Yuriy , Kuznetsov Sergey L. , Bykov Alexander , Meglinski Igor
Published: October 2021

Diseases affecting myocardial tissues are currently a leading cause of death in developed nations. Fast and reliable techniques for analysing and understanding how tissues are affected by disease and respond to treatment are fundamental to combating the effects of heart disease. A 3D Mueller matrix method that reconstructs the linear and circular birefringence and dichroism parameters has been developed to image the biological structures in myocardial tissues. The required optical data is gathered using a Stokes polarimeter and then processed mathematically to recover the individual optical anisotropy parameters, expanding on existing 2D Mueller matrix implementations by combining with a digital holography approach. Changes in the different optical anisotropy parameters are rationalised with reference to the general tissue structure, such that the structures can be identified from the anisotropy distributions. The first to fourth order statistical moments characterising the distribution of the parameters of the optical anisotropy of the polycrystalline structure of the partially depolarising layer of tissues in different phase sections of their volumes are investigated and analysed. The third and fourth order statistical moments are found to be the most sensitive to changes in the phase and amplitude anisotropy. The possibility of forensic medical differentiation of death in cases of acute coronary insufficiency (ACI) and coronary heart disease (CHD) is considered as a diagnostic application. The optimal phase plane (θ∗=0.7rad) has been found, in which excellent differentiation accuracy is achieved ACI and CHD -Ac(ΔZ4(θ∗,ΦL,ΔL))=93.05%÷95.8%. A comparative analysis of the accuracy of the Mueller-matrix reconstruction of the parameters of the optical anisotropy of the myocardium in different phase planes (θ=0.9radandθ=1.2rad), as well as the 2D Mueller-matrix reconstruction method was carried out. This work demonstrates that a 3D Mueller matrix method can be used to effectively analyse the optical anisotropy parameters of myocardial tissues with potential for definitive diagnostics in forensic medicine.
Dual-Band Antenna Integrated With Solar Cells for WLAN Applications
Authors: An Wenxing , Wang Hui , Luo Yu
Published: October 2021

A single-port dual-band antenna integrated with solar cells is reported for the 2.4/5-GHz wireless local area network (WLAN) applications. Thirty solar cells are adopted and integrated into the antenna structure for both energy harvesting and wireless communication. The solar cells can act as a director for the lower band, and the main radiation structure for the higher band. The slot and microstrip antennas are incorporated into the compact structure and multiple resonant modes are utilized for dual-band performance. The measurement results show that the lower band is from 2.27 to 2.5 GHz with an omnidirectional radiation pattern and the upper band is from 4.8 to 6.9 GHz with a directional radiation pattern. The proposed solar cell antenna can provide a dual-band performance with the ability of DC power generation, which can be a potential candidate for future green low-carbon communication.
Thermal Acclimation to the Highest Natural Ambient Temperature Compromises Physiological Performance in Tadpoles of a Stream-Breeding Savanna Tree Frog
Authors: Longhini Leonardo S. , Zena Lucas A. , Polymeropoulos Elias T. , Rocha Aline C. G. , da Silva Leandro Gabriela , Prado Cynthia P. A. , Bícego Kênia C. , Gargaglioni Luciane H.
Published: October 2021

Amphibians may be more vulnerable to climate-driven habitat modification because of their complex life cycle dependence on land and water. Considering the current rate of global warming, it is critical to identify the vulnerability of a species by assessing its potential to acclimate to warming temperatures. In many species, thermal acclimation provides a reversible physiological adjustment in response to temperature changes, conferring resilience in a changing climate. Here, we investigate the effects of temperature acclimation on the physiological performance of tadpoles of a stream-breeding savanna tree frog (Bokermannohyla ibitiguara) in relation to the thermal conditions naturally experienced in their microhabitat (range: 18.8–24.6°C). We quantified performance measures such as routine and maximum metabolic rate at different test (15, 20, 25, 30, and 34°C) and acclimation temperatures (18 and 25°C). We also measured heart rate before and after autonomic blockade with atropine and sotalol at the respective acclimation temperatures. Further, we determined the critical thermal maximum and warming tolerance (critical thermal maximum minus maximum microhabitat temperature), which were not affected by acclimation. Mass-specific routine and mass-specific maximum metabolic rate, as well as heart rate, increased with increasing test temperatures; however, acclimation elevated mass-specific routine metabolic rate while not affecting mass-specific maximum metabolic rate. Heart rate before and after the pharmacological blockade was also unaffected by acclimation. Aerobic scope in animals acclimated to 25°C was substantially reduced, suggesting that physiological performance at the highest temperatures experienced in their natural habitat is compromised. In conclusion, the data suggest that the tadpoles ofB. ibitiguara, living in a thermally stable environment, have a limited capacity to physiologically adjust to the highest temperatures found in their micro-habitat, making the species more vulnerable to future climate change.
Cigarette Smoke Promotes Interleukin-8 Production in Alveolar Macrophages Through the Reactive Oxygen Species/Stromal Interaction Molecule 1/Ca2+ Axis
Authors: Zhu Xianying , Zhan Yuan , Gu Yiya , Huang Qian , Wang Ting , Deng Zhesong , Xie Jungang
Published: October 2021

Chronic obstructive pulmonary disease (COPD), primarily attributed to cigarette smoke (CS), is characterized by multiple pathophysiological changes, including oxidative stress and inflammation. Stromal interaction molecule 1 (STIM1) is a Ca2+ sensor that regulates Ca2+ entry in different types of cells. The present study aimed to explore the relationship between CS-induced oxidative stress and inflammation, as well as the functional role of STIM1 thereinto. Our results showed that the reactive oxygen species (ROS)/STIM1/Ca2+ axis played a critical role in CS-induced secretion of interleukin (IL)-8 in human alveolar macrophages. Specifically, smokers with COPD (SC) showed higher levels of ROS in the lung tissues compared with healthy non-smokers (HN). STIM1 was upregulated in the lung tissues of COPD patients. The expression of STIM1 was positively associated with ROS levels and negatively correlated with pulmonary function. The expression of STIM1 was also increased in the bronchoalveolar lavage fluid (BALF) macrophages of COPD patients and PMA-differentiated THP-1 macrophages stimulated by cigarette smoke extract (CSE). Additionally, CSE-induced upregulation of STIM1 in PMA-differentiated THP-1 macrophages was inhibited by pretreatment with N-acetylcysteine (NAC), a ROS scavenger. Transfection with small interfering RNA (siRNA) targeting STIM1 and pretreatment with NAC alleviated CSE-induced increase in intracellular Ca2+ levels and IL-8 expression. Furthermore, pretreatment with SKF-96365 and 2-APB, the inhibitors of Ca2+ influx, suppressed CSE-induced secretion of IL-8. In conclusion, our study demonstrates that CSE-induced ROS production may increase the expression of STIM1 in macrophages, which further promotes the release of IL-8 by regulating Ca2+ entry. These data suggest that STIM1 may play a crucial role in CSE-induced ROS production and inflammation, and participate in the pathogenesis of COPD.
Modulation of Adaptive Immunity and Viral Infections by Ion Channels
Authors: Bohmwald Karen , Gálvez Nicolás M. S. , Andrade Catalina A. , Mora Valentina P. , Muñoz José T. , González Pablo A. , Riedel Claudia A. , Kalergis Alexis M.
Published: October 2021

Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca2+) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+concentrations and the mobilization of this cation through Ca2+channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+channels in the context of viral infections and their contribution to the modulation of adaptive immune responses.