bluuebunny/crossref_metadata_2025 huggingface dataset:
Type 1 interferon suppresses expression and glucocorticoid induction of glucocorticoid-induced leucine zipper (GILZ)
Authors: Dankers Wendy , Northcott Melissa , Bennett Taylah , D’Cruz Akshay , Sherlock Rochelle , Gearing Linden J. , Hertzog Paul , Russ Brendan , Miceli Iolanda , Scheer Sebastian , Fujishiro Maki , Hayakawa Kunihiro , Ikeda Keigo , Morand Eric F. , Jones Sarah A.
Published: November 2022

SLE is a systemic multi-organ autoimmune condition associated with reduced life expectancy and quality of life. Glucocorticoids (GC) are heavily relied on for SLE treatment but are associated with detrimental metabolic effects. Type 1 interferons (IFN) are central to SLE pathogenesis and may confer GC insensitivity. Glucocorticoid-induced leucine zipper (GILZ) mediates many effects of GC relevant to SLE pathogenesis, but the effect of IFN on GC regulation of GILZ is unknown. We performed in vitro experiments using human PBMC to examine the effect of IFN on GILZ expression. JAK inhibitors tofacitinib and tosylate salt were used in vivo and in vitro respectively to investigate JAK-STAT pathway dependence of our observations. ChiP was performed to examine glucocorticoid receptor (GR) binding at the GILZ locus. Several public data sets were mined for correlating clinical data. High IFN was associated with suppressed GILZ and reduced GILZ relevant to GC exposure in a large SLE population. IFN directly reduced GILZ expression and suppressed the induction of GILZ by GC in vitro in human leukocytes. IFN actions on GILZ expression were dependent on the JAK1/Tyk2 pathway, as evidenced by loss of the inhibitory effect of IFN on GILZ in the presence of JAK inhibitors. Activation of this pathway led to reduced GR binding in key regulatory regions of the GILZ locus. IFN directly suppresses GILZ expression and GILZ upregulation by GC, indicating a potential mechanism for IFN-induced GC resistance. This work has important implications for the ongoing development of targeted GC-sparing therapeutics in SLE.
Persistent expression of NLRP3 in spinal microglia promotes development of lumbar disc degeneration
Authors: Wang Peng , Zhang Jing
Published: November 2022

Introduction

Activated microglia play a critical role in the development of lumbar disc degeneration (LDD), which is a severe disease that causes neuropathic pain in affected people. Interleukin 1β (IL-1β) is a proinflammatory cytokine produced and secreted by activated microglia to induce the inflammation and the subsequent degradation of the disease discs. Recent findings suggest that activation of IL-1β in cells usually requires the involvement of NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-induced formation of inflammasome. However, the importance of NLRP3 in spinal microglia in LDD is not known and thus addressed in the current study.

Methods

NLRP3 expression was examined in the spinal discs. Correlation of NLRP3 levels in microglia with the pain score of the LDD patients or Thompson classification of the degeneration level of the patients was determined. The effects of persistent expression or depletion of NLRP3 on phagocytosis potential and production of proinflammatory cytokines in microglia were tested in vitro, while their effects on the severity of LDD and LDD-associated neuropathic pain were assessed in a mouse model for LDD.

Results

NLRP3 was exclusively expressed in microglia in the spinal discs. NLRP3 levels in microglia strongly correlated with the pain score of the LDD patients, and modestly correlated with the Thompson classification of the degeneration level of the patients. Persistent NLRP3 expression in microglia increased both their phagocytosis potential and production of proinflammatory cytokines, while NLRP3-depleted microglia decreased both their phagocytosis potential and production of proinflammatory cytokines. In a mouse model for LDD, persistent NLRP3 activation in microglia significantly increased the severity of LDD and LDD-associated neuropathic pain, while specific depletion of NLRP3 in microglia significantly attenuated the severity of LDD and reduced the LDD-associated neuropathic pain.

Conclusions

Persistent activation of NLRP3 in spinal microglia promotes development of LDD, while suppression of NLRP3 in microglia could be a promising strategy for LDD therapy.
The ecosystem approach to marine management in the Arctic: Opportunities and challenges for integration
Authors: Wienrich Nicole , Buschman Victoria Qutuuq , Coon Catherine , Fuller Susanna , Hennicke Janos , Humrich Christoph , Prip Christian , Wenzel Lauren
Published: November 2022

Climate change is strongly impacting Arctic marine ecosystems, and the Arctic coastal communities whose identities, traditions and livelihoods are closely interconnected with the marine environment. The Ecosystem Approach (EA) is a promising approach for understanding and managing the occurring shifts in the Arctic marine ecosystems. Based on our analysis, we find that assessments conducted by international and regional instruments and institutions, most notably the Arctic Council, as well as the wealth of Indigenous knowledge present in the region, provide valuable starting points for the implementation of EA in the Arctic. Yet, mechanisms for translating knowledge into joint coordinated and integrated action in accordance with EA are currently lacking. Our analysis suggests that incremental steps can be taken now to promote the implementation of EA, while working to establish a more comprehensive governance framework. In our view, bottom-up initiatives may provide the most promising avenue for promoting the application of EA in the region under the current geopolitical circumstances. Support by civil society, Indigenous and conservation organizations, as well as global momentum will be necessary to coordinate, finance and elevate community-driven initiatives. Other opportunities we identify for advancing EA is to engage with sectoral management bodies and to advance EA through climate change adaptation measures.
Isobaric sampling apparatus and key techniques for deep sea macro-organisms: A brief review
Authors: Wang Hao , Chen Jiawang , Zhou Qixiao , Hu Xiaohui , Gao Qiaoling , Guo Jin , Wang Ying , Li Haonan
Published: November 2022

The study of deep-sea fauna is one of the essential themes of marine scientific research. For all that, the biology of deep animals remains largely unknown, such as their behaviors, metabolic characteristics, and mechanisms of adaptation to the deep-sea environment. Obtaining samples in good condition is an essential prerequisite for these investigations. The isobaric samplers were created to keep the organisms as much as possible in the in-situ environment during recovery. This report reviews the history and the application of isobaric samplers for deep-sea animals established by researchers worldwide over the past hundred years. Also, the crucial technologies of isobaric samplers are analyzed and summarized, including pressure compensation, insulation, sealing, etc. Finally, prospects for the future development of isobaric sampling technologies from the aspects of high fidelity, function integration, and real-time communication and integration operation. This review can provide a reference for future design and optimization of fidelity samplers for deep-sea animals.
Post-operative delirium in the patient with hip fracture: The journey from hospital arrival to discharge
Authors: Ní Chróinín Danielle , Chuan Alwin
Published: November 2022

Delirium- an acute disorder of attention and cognition- is the commonest complication following hip fracture. Patients with hip fracture are particularly vulnerable to delirium, and many of the lessons from the care of the patient with hip fracture will extend to other surgical cohorts. Prevention and management of delirium for patients presenting with hip fracture, extending along a continuum from arrival through to the post-operative setting. Best practice guidelines emphasize multidisciplinary care including management by an orthogeriatric service, regular delirium screening, and multimodal interventions. The evidence base for prevention is strongest in terms of multifaceted interventions, while once delirium has set in, early recognition and identification of the cause are key. Integration of effective strategies is often suboptimal, and may be supported by approaches such as interactive teaching methodologies, routine feedback, and clear protocol dissemination. Partnering with patients and carers will support person centered care, improve patient experiences, and may improve outcomes. Ongoing work needs to focus on implementing recognized best practice, in order to minimize the health, social and economic costs of delirium.
Different maturation of gut microbiome in Korean children
Authors: Kim Jieun , Kim Erin , Kim Bongyoung , Kim Jinsup , Lee Hyun Ju , Park Jun-Sun , Hwang Sehee , Rho Mina , Pai Hyunjoo
Published: November 2022

Introduction

Gut microbiome plays a crucial role in maintaining human health and is influenced by food intake, age, and other factors.

Methods

In this study based in Korea, we examined the bacterial taxonomic composition of the gut microbiota in infants (≤ 1 year), toddlers (1–<4 years), and school-aged children (4–13 years) and compared them with those of healthy adults to investigate the microbiota changes in early life and their association with the resistome. We used whole metagenome sequences obtained by Illumina HiSeq sequencing and clinical information of 53 healthy children, and sequence data of 61 adults from our previous study.

Results

Our results indicate that the bacterial proportion of the gut in the population ranging from infants to adults forms three clusters: the Ruminococcus-Eubacterium (G1), Bifidobacterium-Escherichia (G2), and Bacteroides-Faecalibacterium (G3) groups. The gut microbiota of infants and toddlers (100% of infants and 85% of toddlers) constituted mostly of G2 and G3 groups, whereas 90% of adults showed G1-type gut microbiota. School-aged children showed a transitional gut microbiota composition of both infants and adults (31%, 38%, and 31% in G1, G2, and G3, respectively). Notably, the three clusters of microbiota showed significantly different patterns of bacterial diversity (p < 0.001): G2 showed the lowest Shannon index, followed by G3 and G1 (1.41, 2.08, and 2.48, respectively; median Shannon index). When combined with the adult group, alpha diversity showed a positive correlation with age (R2 = 0.3). Furthermore, clustering the composition of antibiotic resistance genes (ARG) identified two clusters (A1 and A2), and most of G1 (95%) and G3 (80%) belonged to A1. However, G2 showed the least diversity and the highest abundance of ARGs. Nine ARG families showed a significant difference among age groups; three tetracycline resistance genes, tet32, tetO, and tetW, showed a positive correlation, and six other genes, ampC, TEM, ileS, bacA, pmr transferase, and cepA, showed a negative correlation with age.

Discussion

In conclusion, our results highlighted that a delayed persistence of the Bifidobacterium-dominant enterotype with a lower bacterial diversity was observed in Korean children up to 13 years of age, which suggests a different maturation process with a delayed maturation time.
Molecular etiology study of hearing loss in 13 Chinese Han families
Authors: Sun Lianhua , Lin Zhengyu , Wang Xiaowen , Shen Jiali , Li Yue , Huang Yuyu , Yang Jun
Published: November 2022

Hearing loss affecting about 2/1000 newborns is the most common congenital disease. Genetic defects caused approximately 70% of patients who have non-syndromic hearing loss. We recruited 13 Chinese Han deafness families who tested negative for GJB2, SLC26A4, and mitochondrial 12S rRNA. The probands of each family were performed whole-exome sequencing (WES) or targeted next-generation sequencing (NGS) for known deafness genes to study for pathogenic causes. We found four novel mutations of CDH23, one novel mutation of MYO15A, one novel mutation of TMC1, one novel mutation of PAX3, and one novel mutation of ADGRV1, one novel CNV of ADGRV1, and one novel CNV of STRC. Hearing loss is a highly hereditary and heterogeneous disease. The results in the limited samples of this study show that Usher and Waardenburg syndrome-related genes account for a major proportion are strongly associated with Chinese Han hearing loss patients negative for GJB2, SLC26A4, and mitochondrial 12S rRNA, followed by STRC resulting in mild to moderate deafness.
Focal vibrations enhance somatosensory facilitation in healthy subjects: A pilot study on Equistasi® and high-frequency oscillations
Authors: Cruciani Alessandro , Lanzone Jacopo , Musumeci Gabriella , Di Lazzaro Vincenzo , Marano Massimo
Published: November 2022

Background

Equistasi® is a vibrotactile device composed of nanotechnology fibers that converts temperature change into mechanical energy by self-producing a focal vibration. It is used in non-pharmacological rehabilitation in patients with movement disorders and multiple sclerosis sequelae. Nonetheless, the mechanism underlying such an improvement in motor functions is still poorly understood.

Objectives

We designed a small uncontrolled pilot trial to explore the effect of Equistasi® on the somatosensory pathway through the analysis of high-frequency oscillations (HFOs).

Methods

For all the included subjects, we recorded somatosensory-evoked potentials (SEPs) at the baseline (T0) and at 60 min after the application of Equistasi® (T1) on the seventh cervical vertebra level and at the forearm over each flexor carpi radialis, bilaterally. Then, we extracted the HFOs from the N20 signal and compared the HFO duration and area under the curve pre- and post-Equistasi® application.

Results

In a head-to-head comparison of T0 to T1 data, there was a statistically significant reduction in the total HFO area (p < 0.01), which was prominent for the late component (p = 0.025). No statistical differences have been found between T0 and T1 HFO duration (p > 0.05). We further evaluated the N20 amplitude from the onset to the N20 peak to avoid possible interpretational bias. No statistical differences have been found between T0 and T1 (p = 0.437).

Conclusion

Our clinical hypothesis, supported by preliminary data, is that vibrotactile afference delivered by the device could work by interfering with the somatosensory processing, rather than by peripheral effects.
A novel link between silent information regulator 1 and autophagy in cerebral ischemia-reperfusion
Authors: Tang Yingying , Xie Jiaqian , Chen Xiaoping , Sun Lihong , Xu Lili , Chen Xinzhong
Published: November 2022

Cerebral ischemia is one of the leading causes of death and disability worldwide. Although revascularization via reperfusion combined with advanced anticoagulant therapy is currently a gold standard treatment for patients, the reperfusion itself also results in a serious dysfunction termed cerebral ischemia-reperfusion (I/R) injury. Silent information regulator 1 (sirtuin 1, SIRT1), is a classic NAD+-dependent deacetylase, which has been proposed as an important mediator in the alleviation of cerebral ischemia through modulating multiple physiological processes, including apoptosis, inflammation, DNA repair, oxidative stress, and autophagy. Recent growing evidence suggests that SIRT1-mediated autophagy plays a key role in the pathophysiological process of cerebral I/R injury. SIRT1 could both activate and inhibit the autophagy process by mediating different autophagy pathways, such as the SIRT1-FOXOs pathway, SIRT1-AMPK pathway, and SIRT1-p53 pathway. However, the autophagic roles of SIRT1 in cerebral I/R injury have not been systematically summarized. Here, in this review, we will first introduce the molecular mechanisms and effects of SIRT1 in cerebral ischemia and I/R injury. Next, we will discuss the involvement of autophagy in the pathogenesis of cerebral I/R injury. Finally, we will summarize the latest advances in the interaction between SIRT1 and autophagy in cerebral I/R injury. A good understanding of these relationships would serve to consolidate a framework of mechanisms underlying SIRT1’s neuroprotective effects and provides evidence for the development of drugs targeting SIRT1.
Predictions of task using neural modeling
Authors: Fox Elizabeth L. , Ugolini Margaret , Houpt Joseph W.
Published: November 2022

Introduction

A well-designed brain-computer interface (BCI) can make accurate and reliable predictions of a user's state through the passive assessment of their brain activity; in turn, BCI can inform an adaptive system (such as artificial intelligence, or AI) to intelligently and optimally aid the user to maximize the human-machine team (HMT) performance. Various groupings of spectro-temporal neural features have shown to predict the same underlying cognitive state (e.g., workload) but vary in their accuracy to generalize across contexts, experimental manipulations, and beyond a single session. In our work we address an outstanding challenge in neuroergonomic research: we quantify if (how) identified neural features and a chosen modeling approach will generalize to various manipulations defined by the same underlying psychological construct, (multi)task cognitive workload.

Methods

To do this, we train and test 20 different support vector machine (SVM) models, each given a subset of neural features as recommended from previous research or matching the capabilities of commercial devices. We compute each model's accuracy to predict which (monitoring, communications, tracking) and how many (one, two, or three) task(s) were completed simultaneously. Additionally, we investigate machine learning model accuracy to predict task(s) within- vs. between-sessions, all at the individual-level.

Results

Our results indicate gamma activity across all recording locations consistently outperformed all other subsets from the full model. Our work demonstrates that modelers must consider multiple types of manipulations which may each influence a common underlying psychological construct.

Discussion

We offer a novel and practical modeling solution for system designers to predict task through brain activity and suggest next steps in expanding our framework to further contribute to research and development in the neuroergonomics community. Further, we quantified the cost in model accuracy should one choose to deploy our BCI approach using a mobile EEG-systems with fewer electrodes—a practical recommendation from our work.
Association between blood selenium levels and gestational diabetes mellitus: A systematic review and meta-analysis
Authors: Yan Shuai , Su Han , Xia Yang , Yan Zixuan , Gao Yitao , Shi Mengyuan , Liu Huiyuan , Wen Yu , Zhao Yuhong , Chang Qing
Published: November 2022

Introduction

The association between blood (serum or plasma) selenium concentrations and gestational diabetes mellitus (GDM) has been evaluated in some studies. However, the reported findings are debatable, and only case-control and cross-sectional studies were included.

Objective

This research aimed to assess the association between blood selenium levels and GDM by analyzing existing literature. To provide a reference for the prevention and treatment of GDM, we included prospective studies which are not included in previous studies to collate more high-quality evidence and better test the etiological hypothesis between blood Se concentrations and GDM.

Methods

The PubMed, EMBASE, and Web of Science databases were retrieved for literature up to September 2022, and relevant references were manually searched. Raw data from relevant studies were extracted, and a random effect model was adopted for meta-analysis. The total effects were reported as weighted mean differences. All data were analyzed using Stata 16.0 software.

Results

Fourteen studies involving 890 pregnant women with GDM and 1618 healthy pregnant women were incorporated in the meta-analysis. Pregnancies with GDM had significantly lower blood selenium levels than those with normal glucose tolerance (weighted mean difference = −8.11; 95% confidence interval: −12.68 to −3.54, P = 0.001). Subgroup analyses showed that the association between blood selenium levels and GDM was consistent in the residents of Asia and Africa, but not in European. This trend was significant in the second and third trimester subgroups, but not in the first trimester subgroup. Articles published in 2006–2015 also showed this trend, but those published before 2005 and 2016–2019 did not show significant results. This difference was evident in non-prospective studies, but not significant in prospective studies. Studies using the Carpenter and Coustan diagnostic criteria were consistent with this trend, whereas studies using other diagnostic criteria found no differences. In addition, in terms of blood selenium measurement methods, atomic absorption spectrometry showed more significant differences than other methods. In the subgroup analysis based on the sample size of included studies and the quality of the studies, each subgroup showed statistical differences.

Conclusion

Lower blood selenium concentrations are associated with GDM as shown in our study. Therefore, supplementing an appropriate amount of selenium may be helpful for GDM prevention and treatment.
Improvement in nutritional quality of traditional unleavened flat bread using Quality Protein Maize
Authors: Kaur Navjot , Kumar Ramesh , Singh Alla , Shobha D. , Das Abhijit Kumar , Chaudhary Dharampaul , Kaur Yashmeet , Kumar Pardeep , Sharma Priti , Singh Baljit
Published: November 2022

Maize grains are consumed majorly in the form of unleavened flat bread (chapatti) in the South East Asian region. The landraces are better accepted for their chapatti-making attributes such as grain color and good organoleptic properties. However, these cultivars are low in essential amino acids, particularly lysine and tryptophan content. Hence, an investigation was performed to identify maize genotypes with high nutritional value coupled with good chapatti-making qualities. Seven genotypes, comprising two Quality Protein Maize (QPM) hybrids, two normal maize hybrids, and three normal white maize landraces were assessed for their physical characteristics, proximate composition, and chapatti-making quality. Landrace 593 showed the highest protein and ash content. Flours obtained from different genotypes were significantly different (p ≤ 0.001) in terms of protein content, color value, textural, as well as mineral content. PMH 10 and IQMH 203 exhibited the highest and lowest hydration index, respectively. Two QPM hybrids showed significantly higher lysine and tryptophan content as compared to other genotypes. QPM hybrids were identified as the promising material with improved nutritional quality with respect to chapatti making. In combination with mustard greens, maize chapatti constitutes an important traditional delicacy in north India. The enhanced nutritional quality of QPM chapattis is an added advantage. We show the differentiation of chapattis made from QPM and normal maize using a rapid protocol developed previously. This is expected to enable the development and quality control of commercial enterprises based on high protein quality QPM.
Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma
Authors: Shaikh Saba S. , Zang Yan , Hanmer Janel , Wang Hong , Lin Yan , Davar Diwakar , Zarour Hassane M. , Kirkwood John M. , Najjar Yana G.
Published: November 2022

Background

Preclinical and translational evidence suggest BRAF/MEK inhibitors modulate the tumor microenvironment (TME), providing rationale for combination with immunotherapy.

Methods

This investigator-initiated, phase I trial evaluated pembrolizumab, vemurafenib, and cobimetinib in patients with untreated, BRAFV600E/K mutant advanced melanoma. The first 4 patients received vemurafenib with pembrolizumab, and the next 5 patients received vemurafenib and cobimetinib with pembrolizumab. Primary endpoints: safety and maximum tolerated dose of the triplet.

Secondary endpoints

objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). The trial was closed after enrollment of 9 (planned 30) patients due to dose-limiting toxicity (DLT). Study NCT02818023 was approved by the IRB, and all patients provided informed consent.

Results

Patients received a median of 6 cycles of therapy. 8 of 9 experienced drug-related grade 3/4 AEs. DLTs included dermatitis (n=8), hepatitis (n=1), QTc prolongation (n=1), and arthralgias (n=1 each). QoL assessments identified a clinically significant decrease in self assessed QoL at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vemurafenib with pembrolizumab. Median PFS and OS were not reached for patients receiving triple therapy. ORR in the overall cohort was 78% (7/9). 2 patients experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease. 4 patients had ongoing responses at data analysis. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline, not corresponding to clinical response.

Conclusions

Triple therapy with vemurafenib, cobimetinib and pembrolizumab is associated with high response rates but significant adverse events, leading to early study closure.
A novel prognostic model based on cellular senescence-related gene signature for bladder cancer
Authors: Luo Lianmin , Li Fenghua , Gong Binbin , Xi Ping , Xie Wenjie
Published: November 2022

Background

Cellular senescence plays crucial role in the progression of tumors. However, the expression patterns and clinical significance of cellular senescence-related genes in bladder cancer (BCa) are still not clearly clarified. This study aimed to establish a prognosis model based on senescence-related genes in BCa.

Methods

The transcriptional profile data and clinical information of BCa were downloaded from TCGA and GEO databases. The least absolute shrinkage and selection operator (LASSO), univariate and multivariate Cox regression analyses were performed to develop a prognostic model in the TCGA cohort. The GSE13507 cohort were used for validation. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were performed to investigate underlying mechanisms.

Results

A six-gene signature (CBX7, EPHA3, STK40, TGFB1I1, SREBF1, MYC) was constructed in the TCGA databases. Patients were classified into high risk and low risk group in terms of the median risk score. Survival analysis revealed that patients in the higher risk group presented significantly worse prognosis. Receiver operating characteristic (ROC) curve analysis verified the moderate predictive power of the risk model based on the six senescence-related genes signature. Further analysis indicated that the clinicopathological features analysis were significantly different between the two risk groups. As expected, the signature presented prognostic significance in the GSE13507 cohort. Functional analysis indicated that immune-related pathways activity, immune cell infiltration and immune-related function were different between two risk groups. In addition, risk score were positively correlated with multiple immunotherapy biomarkers.

Conclusion

Our study revealed that a novel model based on senescence-related genes could serve as a reliable predictor of survival for patients with BCa.
Preoperative differentiation of hepatocellular carcinoma with peripheral rim-like enhancement from intrahepatic mass-forming cholangiocarcinoma on contrast-enhanced MRI
Authors: Zhang Sisi , Huo Lei , Feng Yayuan , Zhang Juan , Wu Yuxian , Liu Yiping , Lu Lun , Jia Ningyang , Liu Wanmin
Published: November 2022

Purpose

The present study aimed to determine the reliable imaging features to distinguish atypical hepatocellular carcinoma (HCC) with peripheral rim-like enhancement from intrahepatic mass-forming cholangiocarcinoma (IMCC) on contrast-enhanced magnetic resonance imaging (MRI).

Methods

A total of 168 patients (130 male, 57.10 ± 10.53 years) pathological confirmed HCC or IMCC who underwent contrast-enhanced MRI between July 2019 and February 2022 were retrospectively included. Univariate and multivariate logistic regression analyses were used to determine independent differential factors for distinguishing HCC from IMCC, and the model was established. Bootstrap resampling 1000 times was used to verify the model, which was visualized by nomograms. The predictive performance of the model was evaluated based on discrimination, calibration, and clinical utility.

Results

Radiological capsule (OR 0.024, 95% CI: 0.006, 0.095, P<0.001), heterogeneous signal intensity (SI) on T1WI (OR 0.009, 95%CI: 0.001,0.056, P<0.001) were independent differential factors for predicting HCC over IMCC. A lobulated contour (OR 11.732, 95%CI: 2.928,47.007, P = 0.001), target sign on DP (OR 14.269, 95%CI: 2.849,82.106, P = 0.007), bile duct dilatation (OR 12.856, 95%CI: 2.013, P = 0.001) were independent differential factors for predicting IMCCs over HCCs. The independent differential factors constituted a model to distinguish atypical HCCs and IMCCs. The area under receiver operating characteristic (ROC) curve, sensitivity, and specificity values of the model were 0.964(0.940,0.987), 0.88, and 0.906, indicating that the model had an excellent differential diagnostic performance. The decision curve analysis (DCA) curve showed that the model obtained a better net clinical benefit.

Conclusion

The present study identified reliable imaging features for distinguishing atypical HCCs with peripheral rim-like enhancement from IMCCs on contrast-enhanced MRI. Our findings may help radiologists provide clinicians with more accurate preoperative imaging diagnoses to select appropriate treatment options.
Ethnobotanical study of endemic and non-endemic medicinal plants used by indigenous people in environs of Gullele botanical garden Addis Ababa, central Ethiopia: A major focus on Asteraceae family
Authors: Woldeamanuel Melaku Masresha , Geda Mohammed Kasso , Mohapatra Shibani , Bastia Tapan Kumar , Rath Prasanta , Panda Alok Kumar
Published: November 2022

Gullele Botanical Garden (GBG) in Addis Ababa, Ethiopia is a joint venture of Addis Ababa government and the university. The garden has been built mainly to conserve the endemic plants and to advance the research on the endemic and non-endemic plants collected from different part of Ethiopia. Many traditional healers from the environs of GBG and different subcities of Addis Ababa depend on the garden for their practice of traditional medicine but there is no systematic documentation of the traditional medicinal knowledge of these healers. The main objective of the present study is to comprehensively document the ethnobotanical and ethnomedicinal information from the traditional healers of different ethnic and cultural groups depending on GBG and to create a database of the endemic plants used by these healers. The ethnobotanical and ethnomedicinal data obtained from 60 traditional healers have been analyzed both qualitatively and quantitatively. A total of 81 medicinal plants belonging to 47 families have been identified. Majority of the plants used belonged to Asteraceae (12) family. The most frequently used plant form and plant parts are herbs and leaves. The major method adopted by the healers for preparation and administration of traditional medicine is crushing and topical, respectively. Skin and general diseases are the most important ailments treated by the healers. The three most cited plants used to treat diseases areEchinops keberichoMesfin (60),Hagenia abyssinica(Bruce) J.F.Gmel (60) and Laggera tomentosa (A.Rich.) Sch.Bip. ex Oliv. & Hiern (58). The present study is the first systematic, qualitative, and quantitative ethnobotanical analysis and documentation done on the use of the medicinal plants from GBG for traditional medicine. In addition, our study reveals thatE. keberichois endemic and endangered plant and is highly used in traditional medicine. Therefore, GBG authorities should take steps for the propagation and restoration of this plant. Further it is suggested that the pharmacological properties of the roots and leaves ofE. keberichoshould be compared to find the possibility of use of leaves in place of roots for the preparation of traditional medicine which would help in conserving this endemic plant of Ethiopia.
The differential in vivo contribution of spinal α2A- and α2C-adrenoceptors in tonic and acute evoked nociception in the rat
Authors: López-Córdoba Gustavo , Martínez-Lorenzana Guadalupe , Lozano-Cuenca Jair , Condés-Lara Miguel , González-Hernández Abimael
Published: November 2022

Spinal α2-adrenoceptor induces analgesia by neuronal inhibition of primary afferent fibers. This family receptor coupled to Gi/o proteins can be subdivided into three functional subtypes: α2A, α2B, and α2C-adrenoceptors, and current evidence on spinal analgesia supports the relevance of α2A and seems to exclude the role of α2B, but the functional contribution of α2C-adrenoceptors remains elusive. The present study was designed to pharmacologically dissect the contribution of spinal α2-adrenoceptor subtypes modulating tonic or acute peripheral nociception. Using male Wistar rats, we analyzed the effect of spinal clonidine (a non-selective α2A/α2B/α2C-adrenoceptor agonist) and/or selective subtype α2-adrenoceptor antagonists on: 1) tonic nociception induced by subcutaneous formalin (flinching behavior) or 2) acute nociception induced by peripheral electrical stimulus in in vivo extracellular recordings of spinal dorsal horn second-order wide dynamic range (WDR) neurons. Clonidine inhibited the nocifensive behavior induced by formalin, an effect blocked by BRL 44408 (α2A-adrenoceptor antagonist) but not by imiloxan (α2B-adrenoceptor antagonist) or JP 1302 (α2C-adrenoceptor antagonist). Similarly, spinal BRL 44408 reversed the clonidine-induced inhibition of nociceptive WDR activity. Interestingly, spinal JP 1302 per se produced behavioral antinociception (an effect blocked by bicuculline, a preferent GABAA channel blocker), but no correlation was found with the electrophysiological experiments. These data imply that, at the spinal level, 1) presynaptic α2A-adrenoceptor activation produces antinociception during acute or tonic nociceptive stimuli; and 2) under tonic nociceptive (inflammatory) input, spinal α2C-adrenoceptors are pronociceptive, probably by the inactivation of GABAergic transmission. This result supports a differential role of α2A and α2C-adrenoceptors modulating nociception.
Protective effects of mefunidone on ischemia-reperfusion injury/Folic acid-induced acute kidney injury
Authors: Li Jiajia , Jiang Yupeng , Dai Qin , Yu Yue , Lv Xin , Zhang Yan , Liao Xiaohua , Ao Liyun , Hu Gaoyun , Meng Jie , Peng Zhangzhe , Tao Lijian , Xie Yanyun
Published: November 2022

Renal ischemia-reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). It poses a significant threat to public health, and effective therapeutic drugs are lacking. Mefunidone (MFD) is a new pyridinone drug that exerts a significant protective effect on diabetic nephropathy and the unilateral ureteral obstruction (UUO) model in our previous study. However, the effects of mefunidone on ischemia-reperfusion injury-induced acute kidney injury remain unknown. In this study, we investigated the protective effect of mefunidone against ischemia-reperfusion injury-induced acute kidney injury and explored the underlying mechanism. These results revealed that mefunidone exerted a protective effect against ischemia-reperfusion injury-induced acute kidney injury. In an ischemia-reperfusion injury-induced acute kidney injury model, treatment with mefunidone significantly protected the kidney by relieving kidney tubular injury, suppressing oxidative stress, and inhibiting kidney tubular epithelial cell apoptosis. Furthermore, we found that mefunidone reduced mitochondrial damage, regulated mitochondrial-related Bax/bcl2/cleaved-caspase3 apoptotic protein expression, and protected mitochondrial electron transport chain complexes III and V levels both in vivo and in vitro, along with a protective effect on mitochondrial membrane potential in vitro. Given that folic acid (FA)-induced acute kidney injury is a classic model, we used this model to further validate the efficacy of mefunidone in acute kidney injury and obtained the same conclusion. Based on the above results, we conclude that mefunidone has potential protective and therapeutic effects in both ischemia-reperfusion injury- and folic acid-induced acute kidney injury.
Population pharmacokinetics and dosing optimization of unbound teicoplanin in Chinese adult patients
Authors: Fu Wen-Qian , Tian Ting-Ting , Zhang Min-Xin , Song Hong-Tao , Zhang Li-Li
Published: November 2022

Objectives: To develop a population pharmacokinetic (PopPK) model describing unbound teicoplanin concentrations in Chinese adult patients and perform Monte Carlo simulations to optimize the dosing regimens.

Methods: The raw data for PopPK analysis in this study were collected from Chinese adult patients. A PopPK model of unbound teicoplanin was developed and Monte Carlo simulations were used to optimize the dosing regimens. The trough concentrations of unbound teicoplanin were targeted at 0.75 mg/L and 1.13 mg/L for most infection induced by Gram-positive bacteria and endocarditis or severe infections, respectively.

Results: A total of 103 teicoplanin unbound concentrations were collected from 72 Chinese adult patients. A one-compartment pharmacokinetic model with first-order elimination was established. The typical values of clearance and the volume of distribution were 11.7 L/h and 811 L, respectively. The clearance and volume of distribution of unbound teicoplanin were positively correlated with estimated glomerular filtration rate (eGFR) and serum albumin concentrations, respectively. Dosing simulation results showed that standard dosing regimens were unable to meet the treatment needs of all patients, and the dosing regimen need optimize based on eGFR and serum albumin concentrations. The high eGFR and serum albumin concentration were associated with reduced probability of achieving target unbound trough concentrations.

Conclusion: We successfully characterized the pharmacokinetics of unbound teicoplanin in Chinese adult patients. Importantly, we further highlight the importance of guiding dosing through unbound drugs. To achieve safe and effective treatment, the dosing regimens need to be adjusted according to eGFR and serum albumin concentrations.
Discovery of the key active compounds in Citri Reticulatae Pericarpium (Citrus reticulata “Chachi”) and their therapeutic potential for the treatment of COVID-19 based on comparative metabolomics and network pharmacology
Authors: Wang Fu , Chen Lin , Chen Hongping , Yan Zhuyun , Liu Youping
Published: November 2022

Edible herbal medicines contain macro- and micronutrients and active metabolites that can take part in biochemical processes to help achieve or maintain a state of well-being. Citri Reticulatae Pericarpium (CRP) is an edible and medicinal herb used as a component of the traditional Chinese medicine (TCM) approach to treating COVID-19 in China. However, the material basis and related mechanistic research regarding this herb for the treatment of COVID-19 are still unclear. First, a wide-targeted UPLC-ESI-MS/MS-based comparative metabolomics analysis was conducted to screen for the active metabolites of CRP. Second, network pharmacology was used to uncover the initial linkages among these metabolites, their possible targets, and COVID-19. Each metabolite was then further studied via molecular docking with the identified potential SARS-CoV-2 targets 3CL hydrolase, host cell target angiotensin-converting enzyme II, spike protein, and RNA-dependent RNA polymerase. Finally, the most potential small molecule compound was verified by in vitro and in vivo experiments, and the mechanism of its treatment of COVID-19 was further explored. In total, 399 metabolites were identified and nine upregulated differential metabolites were screened out as potential key active metabolites, among which isorhamnetin have anti-inflammatory activity in vitro validation assays. In addition, the molecular docking results also showed that isorhamnetin had a good binding ability with the key targets of COVID-19. Furthermore, in vivo results showed that isorhamnetin could significantly reduced the lung pathological injury and inflammatory injury by regulating ATK1, EGFR, MAPK8, and MAPK14 to involve in TNF signaling pathway, PI3K-Akt signalling pathway, and T cell receptor signaling pathway. Our results indicated that isorhamnetin, as screened from CRP, may have great potential for use in the treatment of patients with COVID-19. This study has also demonstrated that comparative metabolomics combined with network pharmacology strategy could be used as an effective approach for discovering potential compounds in herbal medicines that are effective against COVID-19.
Halofuginone inhibits tumor migration and invasion by affecting cancer-associated fibroblasts in oral squamous cell carcinoma
Authors: Wang Danni , Tian Mei , Fu Yong , Sun Yawei , Ding Liang , Zhang Xiaoxin , Jing Yue , Sun Guowen , Ni Yanhong , Song Yuxian
Published: November 2022

Oral squamous cell carcinoma (OSCC) is the most common malignant tumor in the oral and maxillofacial regions, with a high rate of metastasis. Cancer-associated fibroblasts (CAFs) play critical roles in tumor growth, metastasis and invasion, making them attractive therapeutic targets for cancer treatment. As an old anti-coccidiosis drug for poultry, Halofuginone (HF) has also been reported to possess anti-fibrosis and anti-cancer activities in the recent decades. However, whether it works by targeting CAFs in OSCC, and the mechanisms involved remain unclear. In the present study, we observed HF dose-dependently inhibits OSCC-derived CAF viability and proliferation. Meanwhile, HF decreased the expressions of α-SMA, FSP-1 and PDGFRβ, markers of the malignant phenotype of CAFs, both at mRNA and protein levels. Furthermore, functional studies demonstrated that HF dramatically attenuates the promotion effect of CAFs on OSCC cell migration and invasion. Mechanistically, the inhibition of MMP2 secretion and the upstream TGF-β/Smad2/3 signaling pathway played an important role in these processes. In the orthotopic transplanted tongue carcinoma in mice model, we confirmed that HF administration inhibited tumor growth and lymph node metastasis (LNM) with reduced CAF population, MMP2 expression and collagen deposition in tumor. Altogether, these results indicate that HF can inhibit the migration and invasion of OSCC by targeting CAFs, which will provide new ideas for the treatment of OSCC.
Apol9a regulates myogenic differentiation via the ERK1/2 pathway in C2C12 cells
Authors: Jiang Xuan , Ji Siyu , Cui Siyuan , Wang Rong , Wang Wei , Chen Yongquan , Zhu Shenglong
Published: November 2022

Background: The rising prevalence of obesity and its complications is a big challenge for the global public health. Obesity is accompanied by biological dysfunction of skeletal muscle and the development of muscle atrophy. The deep knowledge of key molecular mechanisms underlying myogenic differentiation is crucial for discovering novel targets for the treatment of obesity and obesity-related muscle atrophy. However, no effective target is currently known for obesity-induced skeletal muscle atrophy.

Methods: Transcriptomic analyses were performed to identify genes associated with the regulation of myogenic differentiation and their potential mechanisms of action. C2C12 cells were used to assess the myogenic effect of Apol9a through immunocytochemistry, western blotting, quantitative polymerase chain reaction, RNA interference or overexpression, and lipidomics.

Results: RNA-seq of differentiated and undifferentiated C2C12 cells revealed that Apol9a expression significantly increased following myogenic differentiation and decreased during obesity-induced muscle atrophy. Apol9a silencing in these C2C12 cells suppressed the expression of myogenesis-related genes and reduced the accumulation of intracellular triglycerides. Furthermore, RNA-seq and western blot results suggest that Apol9a regulates myogenic differentiation through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This assumption was subsequently confirmed by intervention with PD98059.

Conclusion: In this study, we found that Apol9a regulates myogenic differentiation via the ERK1/2 pathway. These results broaden the putative function of Apol9a during myogenic differentiation and provide a promising therapeutic target for intervention in obesity and obesity-induced muscle atrophy.
Remarkable consistency of spinal cord microvasculature in highly adapted diving odontocetes
Authors: Miller Megan L. , Glandon Hillary L. , Tift Michael S. , Pabst D. Ann , Koopman Heather N.
Published: November 2022

Odontocetes are breath-hold divers with a suite of physiological, anatomical, and behavioral adaptations that are highly derived and vastly different from those of their terrestrial counterparts. Because of these adaptations for diving, odontocetes were originally thought to be exempt from the harms of nitrogen gas embolism while diving. However, recent studies have shown that these mammals may alter their dive behavior in response to anthropogenic sound, leading to the potential for nitrogen supersaturation and bubble formation which may cause decompression sickness in the central nervous system (CNS). We examined the degree of interface between blood, gases, and neural tissues in the spinal cord by quantifying its microvascular characteristics in five species of odontocetes (Tursiops truncatus, Delphinus delphis, Grampus griseus, Kogia breviceps, and Mesoplodon europaeus) and a model terrestrial species (the pig-Sus scrofa domesticus) for comparison. This approach allowed us to compare microvascular characteristics (microvascular density, branching, and diameter) at several positions (cervical, thoracic, and lumbar) along the spinal cord from odontocetes that are known to be either deep or shallow divers. We found no significant differences (p < 0.05 for all comparisons) in microvessel density (9.30–11.18%), microvessel branching (1.60–2.12 branches/vessel), or microvessel diameter (11.83–16.079 µm) between odontocetes and the pig, or between deep and shallow diving odontocete species. This similarity of spinal cord microvasculature anatomy in several species of odontocetes as compared to the terrestrial mammal is in contrast to the wide array of remarkable physio-anatomical adaptations marine mammals have evolved within their circulatory system to cope with the physiological demands of diving. These results, and other studies on CNS lipids, indicate that the spinal cords of odontocetes do not have specialized features that might serve to protect them from Type II DCS.