bluuebunny/crossref_metadata_2025 huggingface dataset:
Regional activity alterations in Parkinson’s disease patients with anxiety disorders: A resting-state functional magnetic resonance imaging study
Authors: Zhang Peiyao , Zhang Yanling , Luo Yuan , Wang Lu , Wang Kang
Published: December 2022

Background

Previous studies have revealed alteration of functional connectivity (FC) in Parkinson’s disease patients with anxiety (PD-A), but local brain activities associated with anxiety in Parkinson’s disease (PD) patients remain to be elucidated. Regional homogeneity (ReHo) analysis was employed to investigate alterations of regional brain activities in PD-A patients.

Methods

Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 42 PD-A patients, 41 PD patients without anxiety (PD-NA), and 40 age-and gender-matched healthy control (HC) subjects. ReHo analysis was used to investigate the synchronization of neuronal activities in brain regions in the three groups. The relationship between ReHo value and anxiety score in the PD-A group was also investigated.

Results

Parkinson’s disease patients with anxiety showed increased ReHo values in the bilateral frontal lobes, caudate nucleus, and anterior cingulate gyrus [Gaussian random field (GRF) correction, voxel size p < 0.01, cluster size p < 0.05], compared with PD-NA patients and HC subjects, but the ReHo values of the right cerebellar hemisphere and posterior cerebellar lobe decreased (GRF correction, voxel size p < 0.01, cluster size p < 0.05). The increased ReHo values of the right superior frontal gyrus (r = 0.633, p = 0.001) and anterior cingulate gyrus (r = 0.45, p = 0.01) were positively correlated with anxiety scores in PD-A patients.

Conclusion

The development of PD-A may be associated with dysfunctional local activities in multiple brain regions, including the frontal cortex, cerebella, basal ganglia, and limbic system. Abnormal ReHo values in these brain regions may serve as neuroimaging markers for the early diagnosis of PD-A. The results suggest that using ReHo analysis to identify functional changes in core regions may advance our understanding of the pathophysiological mechanisms underlying PD-A.
What does a “good life” mean for people living with dementia? A protocol for a think-aloud study informing the value of care
Authors: Kinchin Irina , Leroi Iracema , Kennelly Sean P. , Kochovska Slavica , Brady Conor , Fitzhenry Deborah , McHale Cathy , Kinghorn Philip , Coast Joanna
Published: December 2022

Introduction

Economic evaluation currently focuses almost exclusively on the maximization of health, using the Quality-Adjusted Life-Year (QALY) framework with instruments such as the EQ-5D, with a limited number of health-focused dimensions providing the assessment of health benefit. This evaluative framework is likely to be insufficient for setting priorities in dementia care because of its exclusive concern with health. Data are also often collected from the perspective of a proxy, limiting the voice of those living with dementia in decision-making. This protocol describes a research project that aims to gather the perspectives of people living with dementia, their insights, and preferences for assessing their quality of life to inform economic evaluation outcome measurement and design with a goal of creating a more robust evidence base for the value of healthcare services. Specifically, this study will elucidate what a “good life” means to people living with dementia and how well instruments currently used in economic evaluation meet this description. This project will further test the acceptability of capability wellbeing instruments as self-report instruments and compare them to generic and dementia-specific preference-based instruments.

Methods and analysis

People living with dementia, diagnosed, or waiting to receive a formal diagnosis and with the capacity to participate in research, will be invited to participate in an hour “think aloud” interview. Participants will be purposefully selected to cover a range of dementia diagnoses, age, and sex, recruited through the integrated care, geriatric, and post-diagnostic clinics at St James’ and Tallaght University Hospitals and dementia support groups in the Ireland. During the interview, participants will be invited to reflect on a “good life” and “think aloud” while completing four economic quality of life instruments with a perspective that goes beyond health (AD-5D/QOL-AD, AQOL-4D, ICECAP-O, ICECAP-SCM). An interviewer will then probe areas of difficulty when completing the instruments in a semi-structured way. The analysis will identify the frequency of errors in comprehension, retrieval, judgment, and response from verbatim transcripts. Qualitative data will be analyzed using constant comparison.

Ethics

The St James’s Hospital and Tallaght University Hospital Joint Research Ethics Committee approved the study (Approval Date: 11 April 2022).
Longitudinal relations between parenting stress and child internalizing and externalizing behaviors: Testing within-person changes, bidirectionality and mediating mechanisms
Authors: Dijk Willeke Van , de Moor Marleen H. M. , Oosterman Mirjam , Huizink Anja C. , Matvienko-Sikar Karen
Published: December 2022

Introduction

Parenthood can be experienced as a pleasant but challenging period for parents, possibly accompanied by parenting stress. Early parenthood in particular is a vulnerable period as many parents experience biological and psychosocial changes related to new parenthood. Previous studies have shown that parenting stress is related to child behavior problems, but few studies have investigated the transactional relations across time between parenting stress and child internalizing and externalizing outcomes separately, examining within-person changes. The first aim of this study was to examine the transactional within-person associations of parenting stress and child internalizing and externalizing behavior problems across childhood from age 9 months to 9 years. As a second aim, we examined parenting as a possible underlying mechanism of the transactional associations by testing whether parental warmth and hostility mediate within-person associations of parenting stress and child behavior across time.

Method

Data were analyzed from the Growing Up in Ireland longitudinal child cohort study including 7,208 caregiver-child dyads at wave 1 (child’s age 9 months), who were followed at child’s age three (wave 2), five (wave 3), and 9 years (wave 5). Primary caregiver’s and child’s age and gender, household income, occupational status, educational status, partner status, and cultural background were covariates assessed at all waves. Data were analyzed using a random intercept cross-lagged panel model (CLPM) in R-lavaan.

Results

Bidirectional relations between parenting stress and child behavior were found for both internalizing and externalizing behavior from age 5 to 9, but not for earlier time points.

Discussion

Our results did not indicate mediating effects of parental warmth or parental hostility in the associations between parenting stress and child behavior problems. Therefore, we conclude that parenting stress and child internalizing as well as parenting stress and child externalizing behaviors have transactional associations from child’s age 5 to 9 years. Future research examining transactional associations of parenting stress and child behaviors should investigate possible other mediations taking a within-person approach by utilizing the RI-CLPM.
Loss of TMEM106B exacerbates C9ALS/FTD DPR pathology by disrupting autophagosome maturation
Authors: Bauer Claudia S. , Webster Christopher P. , Shaw Allan C. , Kok Jannigje R. , Castelli Lydia M. , Lin Ya-Hui , Smith Emma F. , Illanes-Álvarez Francisco , Higginbottom Adrian , Shaw Pamela J. , Azzouz Mimoun , Ferraiuolo Laura , Hautbergue Guillaume M. , Grierson Andrew J. , De Vos Kurt J.
Published: December 2022

Disruption to protein homeostasis caused by lysosomal dysfunction and associated impairment of autophagy is a prominent pathology in amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). The most common genetic cause of ALS/FTD is a G4C2 hexanucleotide repeat expansion in C9orf72 (C9ALS/FTD). Repeat-associated non-AUG (RAN) translation of G4C2 repeat transcripts gives rise to dipeptide repeat (DPR) proteins that have been shown to be toxic and may contribute to disease etiology. Genetic variants in TMEM106B have been associated with frontotemporal lobar degeneration with TDP-43 pathology and disease progression in C9ALS/FTD. TMEM106B encodes a lysosomal transmembrane protein of unknown function that is involved in various aspects of lysosomal biology. How TMEM106B variants affect C9ALS/FTD is not well understood but has been linked to changes in TMEM106B protein levels. Here, we investigated TMEM106B function in the context of C9ALS/FTD DPR pathology. We report that knockdown of TMEM106B expression exacerbates the accumulation of C9ALS/FTD-associated cytotoxic DPR proteins in cell models expressing RAN-translated or AUG-driven DPRs as well as in C9ALS/FTD-derived iAstrocytes with an endogenous G4C2 expansion by impairing autophagy. Loss of TMEM106B caused a block late in autophagy by disrupting autophagosome to autolysosome maturation which coincided with impaired lysosomal acidification, reduced cathepsin activity, and juxtanuclear clustering of lysosomes. Lysosomal clustering required Rab7A and coincided with reduced Arl8b-mediated anterograde transport of lysosomes to the cell periphery. Increasing Arl8b activity in TMEM106B-deficient cells not only restored the distribution of lysosomes, but also fully rescued autophagy and DPR protein accumulation. Thus, we identified a novel function of TMEM106B in autophagosome maturation via Arl8b. Our findings indicate that TMEM106B variants may modify C9ALS/FTD by regulating autophagic clearance of DPR proteins. Caution should therefore be taken when considering modifying TMEM106B expression levels as a therapeutic approach in ALS/FTD.
A deep learning framework for classifying microglia activation state using morphology and intrinsic fluorescence lifetime data
Authors: Mukherjee Lopamudra , Sagar Md Abdul Kader , Ouellette Jonathan N. , Watters Jyoti J. , Eliceiri Kevin W.
Published: December 2022

Microglia are the immune cell in the central nervous system (CNS) and exist in a surveillant state characterized by a ramified form in the healthy brain. In response to brain injury or disease including neurodegenerative diseases, they become activated and change their morphology. Due to known correlation between this activation and neuroinflammation, there is great interest in improved approaches for studying microglial activation in the context of CNS disease mechanisms. One classic approach has utilized Microglia's morphology as one of the key indicators of its activation and correlated with its functional state. More recently microglial activation has been shown to have intrinsic NADH metabolic signatures that are detectable via fluorescence lifetime imaging (FLIM). Despite the promise of morphology and metabolism as key fingerprints of microglial function, they has not been analyzed together due to lack of an appropriate computational framework. Here we present a deep neural network to study the effect of both morphology and FLIM metabolic signatures toward identifying its activation status. Our model is tested on 1, 000+ cells (ground truth generated using LPS treatment) and provides a state-of-the-art framework to identify microglial activation and its role in neurodegenerative diseases.
A comprehensive approach to modeling maternal immune activation in rodents
Authors: Bucknor Morgan C. , Gururajan Anand , Dale Russell C. , Hofer Markus J.
Published: December 2022

Prenatal brain development is a highly orchestrated process, making it a very vulnerable window to perturbations. Maternal stress and subsequent inflammation during pregnancy leads to a state referred to as, maternal immune activation (MIA). If persistent, MIA can pose as a significant risk factor for the manifestation of neurodevelopmental disorders (NDDs) such as autism spectrum disorder and schizophrenia. To further elucidate this association between MIA and NDD risk, rodent models have been used extensively across laboratories for many years. However, there are few uniform approaches for rodent MIA models which make not only comparisons between studies difficult, but some established approaches come with limitations that can affect experimental outcomes. Here, we provide researchers with a comprehensive review of common experimental variables and potential limitations that should be considered when designing an MIA study based in a rodent model. Experimental variables discussed include: innate immune stimulation using poly I:C and LPS, environmental gestational stress paradigms, rodent diet composition and sterilization, rodent strain, neonatal handling, and the inclusion of sex-specific MIA offspring analyses. We discuss how some aspects of these variables have potential to make a profound impact on MIA data interpretation and reproducibility.
Improved gesturing in left-hemispheric stroke by right inferior parietal theta burst stimulation
Authors: Pastore-Wapp Manuela , Gyurkó Dávid M. , Vanbellingen Tim , Lehnick Dirk , Cazzoli Dario , Pflugshaupt Tobias , Pflugi Stefanie , Nyffeler Thomas , Walther Sebastian , Bohlhalter Stephan
Published: December 2022

Objectives

Apraxia is a common syndrome of left hemispheric stroke. A parieto-premotor-prefrontal network has been associated with apraxia, in which the left inferior parietal lobe (IPL-L) plays a major role. We hypothesized that transcranial continuous theta burst stimulation (cTBS) over the right inferior parietal lobe (IPL-R) improves gesturing by reducing its inhibition on the contralateral IPL in left hemispheric stroke patients. It was assumed that this effect is independent of lesion volume and that transcallosal connectivity is predictive for gestural effect after stimulation.

Materials and methods

Nineteen stroke patients were recruited. Lesion volume and fractional anisotropy of the corpus callosum were acquired with structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI). Each patient had pseudorandomised sessions with sham or with stimulation over the IPL-R or over the right inferior frontal gyrus IFG-R. Gesturing was assessed in a double-blinded manner before and after each session. We tested the effects of stimulation on gesture performance using a linear mixed-effects model.

Results

Pairwise treatment contrasts showed, that, compared to sham, the behavioral effect was higher after stimulation over IPL-R (12.08, 95% CI 6.04 – 18.13, p < 0.001). This treatment effect was approximately twice as high as the contrasts for IFG-R vs. sham (6.25, 95% CI –0.20 – 12.70, p = 0.058) and IPL-R vs. IFG-R vs. sham (5.83, 95% CI –0.49 – 12.15, p = 0.071). Furthermore, higher fractional anisotropy in the splenium (connecting the left and right IPL) were associated with higher behavioral effect. Relative lesion volume did not affect the changes after sham or stimulation over IPL-R or IFG-R.

Conclusion

One single session of cTBS over the IPL-R improved gesturing after left hemispheric stroke. Denser microstructure in the corpus callosum correlated with favorable gestural response. We therefore propose the indirect transcallosal modulation of the IPL-L as a promising model of restoring interhemispheric balance, which may be useful in rehabilitation of apraxia.
Age-specific reference values for low psoas muscle index at the L3 vertebra level in healthy populations: A multicenter study
Authors: Kong Ming , Lin Ning , Wang Lili , Geng Nan , Xu Manman , Li Shanshan , Song Wenyan , Zhou Ying , Piao Yuetong , Han Zuoqing , Guo Rong , Yang Chao , Luo Nan , Wang Zhong , Xu Quanxiao , Shi Daimeng , Qiu Wanchun , Li Junfeng , Cheung Eddie C. , Ma Lei , Chen Yu , Duan Zhongping
Published: December 2022

Background and aims

The progressive and generalized loss of skeletal muscle mass, strength and physical function is defined as sarcopenia. Sarcopenia is closely related to the prognosis of patients. Accurate diagnosis and adequate management of sarcopenia are crucial. The psoas muscle mass index taken at the third lumbar vertebra (L3-PMI, cm2/m2) is one of the established methods for evaluating skeletal muscle mass. However, the cutoff values of L3-PMI for diagnosis of sarcopenia are not yet to be clarified in Asian populations. We attempted to establish reference values for low L3-PMI that would be suitable for defining sarcopenia in the Northern Chinese population.

Methods

This was a retrospective, multicenter cross-sectional study. A search of abdominal CT imaging reports was conducted in four representative cities in northern China. Transverse CT images were measured using the analysis software Slice-O-Matic. Low psoas muscle index was defined as the 5th percentile or mean-2SD of the study group.

Results

1,787 healthy individuals in the study were grouped by age. The sex and number of people in each group were similar. L3-PMI had a negative linear correlation with age, and a strong correlation with the skeletal muscle index taken at the third lumbar vertebrae (L3-SMI, cm2/m2). The L3-PMI reference values in males were 5.41 cm2/m2 for 20–29 years, 4.71 cm2/m2 for 30–39 years, 4.65 cm2/m2 for 40–49 years, 4.10 cm2/m2 for 50–59 years and 3.68 cm2/m2 for over 60 years by using 5th percentile threshold. Similarly, the reference values in females were 3.32, 3.40, 3.18, 2.91, and 2.62 cm2/m2. When using mean-2SD as the reference, the values for each age group were 4.57, 4.16, 4.03, 3.37, and 2.87 cm2/m2 for males and 2.79, 2.70, 2.50, 2.30, and 2.26 cm2/m2 for females, respectively.

Conclusion

We defined the reference values of age-specific low skeletal muscle mass when simply evaluated by L3-PMI. Further studies about the association of sarcopenia using these reference values with certain clinical outcomes or diseases are needed.
Comparing the outcome between multicentric/multifocal breast cancer and unifocal breast cancer: A systematic review and meta-analysis
Authors: Zhang Yalan , Liu Fan , Gao Qianqian , Chai Yahui , Ren Yan , Tian Hongyou , Ma Bin , Song Ailin
Published: December 2022

Objective

This systematic review and meta-analysis compares the outcome between MMBC and unifocal breast cancer (UFBC), in order to provide a theoretical basis for the design of an appropriate clinical therapeutic strategy of MMBC patients.

Methods

PubMed, Embase, The Cochrane Library, Web of science, CNKI, WanFang Data, CBM and VIP database were searched from inception to July 2021, and observational studies reporting the outcome of patients with MMBC and UFBC were included. We extracted or calculated the mortality rates of MMBC and UFBC patients; and obtained the hazard ratios; odds ratios; relative risks; and the corresponding 95% confidence intervals from the eligible studies. All the meta-analyses were conducted by using the Stata 15.0 software.

Results

31 eligible studies comprising a total of 15,703 individuals were included. The meta-analysis revealed that MMBC did not have a significant association with poor overall survival (HR=1.04, 95% CI=0.96-1.12), disease-free survival (HR= 1.07, 95% CI= 0.84-1.36), breast cancer-specific survival (HR=1.42, 95% CI= 0.89-2.27), recurrence-free survival (HR= 0.878, 95% CI= 0.652-1.182), local recurrence-free survival (HR= 0.90, 95% CI= 0.57-1.42), and contralateral breast cancer risk (RR= 0.908, 95% CI= 0.667-1.234). However, MMBC appeared to have a correlation with a slightly higher risk of death (OR=1.31, 95% CI=1.18-1.45).

Conclusion

Patients with MMBC appeared to have a higher risk of death, however, it may not be independently associated with poorer outcomes. Considering the inter-study heterogeneity and other limitations, our results need to be validated by further multicenter prospective studies with a large sample size in the future.
Diagnostic and surgical management of primary central nervous system angioleiomyoma: A case report and literature review
Authors: Rubiu Emanuele , La Corte Emanuele , Bonomo Giulio , Restelli Francesco , Falco Jacopo , Mazzapicchi Elio , Broggi Morgan , Schiariti Marco Paolo , Pollo Bianca , Pinzi Valentina , Bruzzone Maria Grazia , Di Meco Francesco , Acerbi Francesco , Ferroli Paolo
Published: December 2022

Angioleiomyoma (ALM) is a benign smooth muscle neoplasm that mainly occurs in lower extremities subcutaneous tissue and generally affects middle-aged adults. This tumor histotype may rarely localize intracranially, although only a few cases have been described in the literature. We report a case of intracranial ALM, whose differential diagnosis has been particularly challenging, and firstly provide a comprehensive radiological and intra-operative evaluation of a such rare entity. This represents also the first report of the use of intraoperative confocal microscopy in ALM and the first documented short-term recurrence. At this regard, a scoping literature review has been conducted with the aim of presenting the major clinical and diagnostic features along with the proposed therapeutic strategies.
Predictive modelling for late rectal and urinary toxicities after prostate radiotherapy using planned and delivered dose
Authors: Ong Ashley Li Kuan , Knight Kellie , Panettieri Vanessa , Dimmock Mathew , Tuan Jeffrey Kit Loong , Tan Hong Qi , Wright Caroline
Published: December 2022

Background and purpose

Normal tissue complication probability (NTCP) parameters derived from traditional 3D plans may not be ideal in defining toxicity outcomes for modern radiotherapy techniques. This study aimed to derive parameters of the Lyman-Kutcher-Burman (LKB) NTCP model using prospectively scored clinical data for late gastrointestinal (GI) and genitourinary (GU) toxicities for high-risk prostate cancer patients treated using volumetric-modulated-arc-therapy (VMAT). Dose-volume-histograms (DVH) extracted from planned (DP) and accumulated dose (DA) were used.

Material and methods

DP and DA obtained from the DVH of 150 prostate cancer patients with pelvic-lymph-nodes irradiation treated using VMAT were used to generate LKB-NTCP parameters using maximum likelihood estimations. Defined GI and GU toxicities were recorded up to 3-years post RT follow-up. Model performance was measured using Hosmer-Lemeshow goodness of fit test and the mean area under the receiver operating characteristics curve (AUC). Bootstrapping method was used for internal validation.

Results

For mild-severe (Grade ≥1) GI toxicity, the model generated similar parameters based on DA and DP DVH data (DA-D50:71.6 Gy vs DP-D50:73.4; DA-m:0.17 vs DP-m:0.19 and DA/P-n 0.04). The 95% CI for DA-D50 was narrower and achieved an AUC of >0.6. For moderate-severe (Grade ≥2) GI toxicity, DA-D50 parameter was higher and had a narrower 95% CI (DA-D50:77.9 Gy, 95% CI:76.4-79.6 Gy vs DP-D50:74.6, 95% CI:69.1-85.4 Gy) with good model performance (AUC>0.7). For Grade ≥1 late GU toxicity, D50 and n parameters for DA and DP were similar (DA-D50: 58.8 Gy vs DP-D50: 59.5 Gy; DA-n: 0.21 vs DP-n: 0.19) with a low AUC of<0.6. For Grade ≥2 late GU toxicity, similar NTCP parameters were attained from DA and DP DVH data (DA-D50:81.7 Gy vs DP-D50:81.9 Gy; DA-n:0.12 vs DP-n:0.14) with an acceptable AUCs of >0.6.

Conclusions

The achieved NTCP parameters using modern RT techniques and accounting for organ motion differs from QUANTEC reported parameters. DA-D50 of 77.9 Gy for GI and DA/DP-D50 of 81.7-81.9 Gy for GU demonstrated good predictability in determining the risk of Grade ≥2 toxicities especially for GI derived D50 and are recommended to incorporate as part of the DV planning constraints to guide dose escalation strategies while minimising the risk of toxicity.
Adjuvant chemotherapy and survival outcomes in rectal cancer patients with good response (ypT0-2N0) after neoadjuvant chemoradiotherapy and surgery: A retrospective nationwide analysis
Authors: Kuo Yu-Hsuan , Lin Yun-Tzu , Ho Chung-Han , Chou Chia-Lin , Cheng Li-Chin , Tsai Chia-Jen , Hong Wei-Ju , Chen Yi-Chen , Yang Ching-Chieh
Published: December 2022

Background

For rectal cancer, it remains unclear how to incorporate tumor response to neoadjuvant chemoradiotherapy (nCRT) when deciding whether to give adjuvant chemotherapy. In this study, we aim to determinate the survival benefit of adjuvant chemotherapy for rectal cancer patients with good response (ypT0-2N0) after nCRT and surgery.

Methods

The study cohort included 720 rectal cancer patients who had good response (ypT0-2N0) after nCRT and surgery, who did or did not receive adjuvant chemotherapy between January 2007 and December 2017, from the Taiwan Cancer Registry and National Health Insurance Research database. The Kaplan–Meier method, log-rank tests, and Cox regression analysis were performed to investigate the effect of adjuvant chemotherapy on 5-year overall survival (OS) and disease-free survival (DFS).

Results

Of 720 patients, 368 (51.1%) received adjuvant chemotherapy and 352 (48.9%) did not. Patients who received adjuvant chemotherapy were more likely to be female, younger (≤ 65), with advanced clinical T (3-4)/N (1-2) classification and ypT2 classification. No significant difference in 5-year OS (p=0.681) or DFS (p=0.942) were observed by receipt of adjuvant chemotherapy or not. Multivariable analysis revealed adjuvant chemotherapy was not associated with better OS (adjusted hazard ratio [aHR], 1.03; 95% Confidence Interval [CI], 0.88-1.21) or DFS (aHR, 1.05; 95% CI, 0.89-1.24). Stratified analysis for OS and DFS found no significant protective effect in the use of adjuvant chemotherapy, even for those with advanced clinical T or N classification.

Conclusion

Adjuvant chemotherapy may be omitted in rectal cancer patients with good response (ypT0-2N0) after nCRT and surgery.
Nanotechnology in cervical cancer immunotherapy: Therapeutic vaccines and adoptive cell therapy
Authors: Zhou Xuyan , Lian Haiying , Li Hongpeng , Fan Meiling , Xu Wei , Jin Ye
Published: December 2022

Immunotherapy is an emerging method for the treatment of cervical cancer and is more effective than surgery and radiotherapy, especially for recurrent cervical cancer. However, immunotherapy is limited by adverse effects in clinical practice. In recent years, nanotechnology has been widely used for tumor diagnosis, drug delivery, and targeted therapy. In the setting of cervical cancer, nanotechnology can be used to actively or passively target immunotherapeutic agents to tumor sites, thereby enhancing local drug delivery, reducing drug adverse effects, achieving immunomodulation, improving the tumor immune microenvironment, and optimizing treatment efficacy. In this review, we highlight the current status of therapeutic vaccines and adoptive cell therapy in cervical cancer immunotherapy, as well as the application of lipid carriers, polymeric nanoparticles, inorganic nanoparticles, and exosomes in this context.
The emerging roles of TLR and cGAS signaling in tumorigenesis and progression of ovarian cancer
Authors: Zhang Zhen , Zhao Hong , Chu Chu , Fu Xiaoxiao , Liu Yonglin , Wang Li , Wei Ran , Xu Ke , Li Lihua , Li Xia
Published: December 2022

Ovarian cancer is fatal to women and has a high mortality rate. Although on-going efforts are never stopped in identifying diagnostic and intervention strategies, the disease is so far unable to be well managed. The most important reason for this is the complexity of pathogenesis for OC, and therefore, uncovering the essential molecular biomarkers accompanied with OC progression takes the privilege for OC remission. Inflammation has been reported to participate in the initiation and progression of OC. Both microenvironmental and tumor cell intrinsic inflammatory signals contribute to the malignancy of OC. Inflammation responses can be triggered by various kinds of stimulus, including endogenous damages and exogenous pathogens, which are initially recognized and orchestrated by a series of innate immune system related receptors, especially Toll like receptors, and cyclic GMP-AMP synthase. In this review, we will discuss the roles of innate immune system related receptors, including TLRs and cGAS, and responses both intrinsic and exogenetic in the development and treatment of OC.
Stimulation of hair growth by Tianma Gouteng decoction: Identifying mechanisms based on chemical analysis, systems biology approach, and experimental evaluation
Authors: Zhang Yanyan , Zhang Shiqian , Long Yunluan , Wang Wuji , Du Fanpan , Li Jingjie , Jin Feng , Li Zheng
Published: December 2022

Hair serves important physiological functions, including temperature regulation and scalp protection. However, excessive shedding not only impacts these functions but can also significantly affect mental health and quality of life. Tianma Gouteng decoction (TGD) is a traditional Chinese medicine used for the treatment of various conditions, including hair loss. However, the associated mechanism underlying its anti-alopecia effect remains unknown. Therefore, this study aims to elucidate these mechanisms by employing systematic biology approaches, as well as in vitro and in vivo experimental validation. The chemical constituents of Tianma Gouteng decoction were identified using UHPLC-MS/MS, from which 39 potential bioactive components were screened, while an additional 131 putative Tianma Gouteng decoction beneficial components were extracted from the Traditional Chinese Medicine Database and Analysis Platform (TCMSP) database. We then applied a dual-dimensional network pharmacology approach to analyze the data, followed by validation studies combining molecular docking techniques with in vivo and in vitro experiments. From the 39 bioactive components, including quercetin, luteolin, fisetin, wogonin, oroxylin A, boldine, tetrahydroalstonine, and galangin A, 782 corresponding targets were identified. In particular, GSK3β and β-catenin exhibited strong binding activity with the bioactive compounds. Hence, construction of a bioactive component-target network revealed that the mechanism underlying the anti-alopecia mechanism of Tianma Gouteng decoction primarily involved the Wnt/β-catenin signaling pathway. Moreover, C57BL/6J mice exhibited measurable improvements in hair follicle regeneration following treatment with Tianma Gouteng decoction. Additionally, β-catenin and p-GSK3β levels were upregulated, while GSK3β was downregulated in Tianma Gouteng decoction-treated animals and dermal papilla cells compared to control group. These in vivo and in vitro outcomes validated the targets and pathways predicted in the network pharmacology analysis of Tianma Gouteng decoction. This study provides a systematic analysis approach to identify the underlying anti-alopecia mechanisms of Tianma Gouteng decoction, further providing theoretical support for clinical assessment of Tianma Gouteng decoction.
Ginseng glycoprotein and ginsenoside facilitate anti UV damage effects in diabetic rats
Authors: Hu Shuang , Huo Lulu , He Jing , Jin Ye , Deng Yongzhi , Liu Da
Published: December 2022

Diabetes mellitus combined with ultraviolet (UV) radiation damage not only brings great mental stress to patients, but also seriously impairs their quality of life. A UV-irradiated diabetic rat trauma skin model was established by us to investigate the effects and possible mechanisms of ginsenoside and glycoprotein on skin trauma repair in UV-irradiated diabetic rats. In the study, ginsenosides and ginseng glycoproteins were extracted from different parts of ginseng roots. It found that it’s easier to prepare saponins in ginseng bark and proteins in ginseng core in large quantities. Since glycoprotein-like metabolites are relatively novel ginseng extracts, specifically characterized its structures. It was verified that the ginseng glycoproteins are not toxic to HaCaT cells and can significantly increase the survival of HaCaT cells after UV damage at the in vitro cellular level. Experiments in vivo were conducted to evaluate the therapeutic effects of ginsenoside and ginseng glycoprotein in a rat model of diabetes mellitus combined with UV irradiation injury. Histopathological changes on rat skin after treatment with ginsenoside and ginseng glycoprotein were evaluated by hematoxylin and eosin (H&E) staining and aldehyde fuchsine staining. The expression levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), matrix metalloproteinases (MMPs), hydroxyproline (HYP), interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) were measured. The results indicate that both ginsenoside and ginseng glycoprotein could improve skin damage and ulcers caused by diabetes combined with UV irradiation and could alleviate a range of skin damage caused by the combination of diabetes and UV irradiation, including peroxidation and collagen fiber loss. Ginsenoside and ginseng glycoproteins can be considered as natural product candidates for the development of new drugs to treat diabetes combined with UV irradiation-induced skin damage.
Hyperglycemia-associated Alzheimer’s-like symptoms and other behavioral effects attenuated by Plumeria obtusa L. Extract in alloxan-induced diabetic rats
Authors: Naz Sumeera , Imran Imran , Farooq Muhammad Asad , Shah Syed Adil Hussain , Ajmal Iqra , Zahra Zartash , Aslam Aqsa , Sarwar Muhammad Irfan , Shah Jaffer , Aleem Ambreen
Published: December 2022

Diabetes mellitus is a chronic metabolic complaint with numerous short- and long-term complications that harm a person’s physical and psychological health. Plumeria obtusa L. is a traditional medicine used in the treatment of diabetes to reduce complications related to behavior. Plumeria is a genus with antipsychotic activities. The objective of this study was to examine the effects of a methanolic extract of Plumeria obtusa L. in the attenuation of diabetes, on symptoms of Alzheimer disease, and on other associated behavioral aspects. A single dose of alloxan was administered to an experimental group of rats to induce development of diabetes (150 mg/kg, intraperitoneal) and the rats were then administered selected doses of methanolic extract of Plumeria obtusa L. (Po.Cr) or glibenclamide (0.6 mg/kg) for 45 consecutive days. Behavioral effects were evaluated using three validated assays of anxiety-related behavior: the open field test, the light and dark test, and the elevated plus maze. Anti-depressant effects of Plumeria obtusa L. were evaluated using the forced swim test (FST) and memory and learning were assessed using the Morris water maze (MWM) task. Po.Cr was also evaluated for phytochemicals using total phenolic content (TPC), total flavonoid content (TFC), and high-performance liquid chromatography assays, and antioxidant capability was assessed through assays of DPPH radical scavenging, total oxidation capacity, and total reducing capacity. In the alloxan-induced model of diabetes, the administration of Po.Cr and glibenclamide for 45 days produced a marked decrease (p < 0.001) in hyperglycemia compared to control animals. Po.Cr treatment also resulted in improvement in indicators, such as body weight and lipid profile (p < 0.05), as well as restoration of normal levels of alanine transaminase (ALT) (p < 0.001), a biomarker of liver function. Diabetic rats presented more Alzheimer-like symptoms, with greater impairment of memory and learning, and increased anxiety and depression compared to non-diabetic normal rats, whereas treated diabetic rats showed significant improvements in memory and behavioral outcomes. These results demonstrate that Po.Cr reversed alloxan-induced hyperglycemia and ameliorated Alzheimer-related behavioral changes, which supports additional study and assessment of conventional use of the plant to treat diabetes and associated behavioral complications.
The adenosine A2A receptor antagonist KW6002 distinctly regulates retinal ganglion cell morphology during postnatal development and neonatal inflammation
Authors: Hu Shisi , Li Yaoyao , Zhang Yuanjie , Shi Ruyi , Tang Ping , Zhang Di , Kuang Xiuli , Chen Jiangfan , Qu Jia , Gao Ying
Published: December 2022

Adenosine A2A receptors (A2ARs) appear early in the retina during postnatal development, but the roles of the A2ARs in the morphogenesis of distinct types of retinal ganglion cells (RGCs) during postnatal development and neonatal inflammatory response remain undetermined. As the RGCs are rather heterogeneous in morphology and functions in the retina, here we resorted to the Thy1-YFPH transgenic mice and three-dimensional (3D) neuron reconstruction to investigate how A2ARs regulate the morphogenesis of three morphologically distinct types of RGCs (namely Type I, II, III) during postnatal development and neonatal inflammation. We found that the A2AR antagonist KW6002 did not change the proportion of the three RGC types during retinal development, but exerted a bidirectional effect on dendritic complexity of Type I and III RGCs and cell type-specifically altered their morphologies with decreased dendrite density of Type I, decreased the dendritic field area of Type II and III, increased dendrite density of Type III RGCs. Moreover, under neonatal inflammation condition, KW6002 specifically increased the proportion of Type I RGCs with enhanced the dendrite surface area and volume and the proportion of Type II RGCs with enlarged the soma area and perimeter. Thus, A2ARs exert distinct control of RGC morphologies to cell type-specifically fine-tune the RGC dendrites during normal development but to mainly suppress RGC soma and dendrite volume under neonatal inflammation.
Role of 5-HT1A-mediated upregulation of brain indoleamine 2,3 dioxygenase 1 in the reduced antidepressant and antihyperalgesic effects of fluoxetine during maintenance treatment
Authors: Dai Jiajia , Kim Hyangin , You Zerong , McCabe Michael F. , Zhang Shuzhuo , Wang Shiyu , Lim Grewo , Chen Lucy , Mao Jianren
Published: December 2022

The reduced antidepressant and antihyperalgesic effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine during maintenance treatment has been reported, but little is known about the molecular mechanism of this phenomenon. In three comorbid pain and depression animal models (genetic predisposition, chronic social stress, arthritis), we showed that the fluoxetine’s antidepressant and antihyperalgesic effects were reduced during the maintenance treatment. Fluoxetine exposure induced upregulation of the 5-hydroxytryptamine 1A (5-HT1A) auto-receptor and indoleamine 2,3 dioxygenase 1 (IDO1, a rate-limiting enzyme of tryptophan metabolism) in the brainstem dorsal raphe nucleus (DRN), which shifted the tryptophan metabolism away from the 5-HT biosynthesis. Mechanistically, IDO1 upregulation was downstream to fluoxetine-induced 5-HT1A receptor expression because 1) antagonism of the 5-HT1A receptor with WAY100635 or 5-HT1A receptor knockout blocked the IDO1 upregulation, and 2) inhibition of IDO1 activity did not block the 5-HT1A receptor upregulation following fluoxetine exposure. Importantly, inhibition of either the 5-HT1A receptor or IDO1 activity sustained the fluoxetine’s antidepressant and antihyperalgesic effects, indicating that 5-HT1A-mediated IDO1 upregulation in the brainstem DRN contributed to the reduced antidepressant and antihyperalgesic effects of fluoxetine. These results suggest a new strategy to improving the therapeutic efficacy of SSRI during maintenance treatment.
Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae
Authors: Yu Zhenwei , Liu Xiaofen , Du Xiaoxing , Chen Huiying , Zhao Feng , Zhou Zhihui , Wang Yu , Zheng Yang , Bergen Phillip J. , Li Xi , Sun Renhua , Fang Li , Li Wanzhen , Fan Yaxin , Wu Hailan , Guo Beining , Li Jian , Yu Yunsong , Zhang Jing
Published: December 2022

Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.

Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.

Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.

Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.
Polarization-multiplexed dual-comb fiber laser based on an all-polarization-maintaining cavity configuration
Authors: Rao Bingjie , Li Mingkun , Yang Xiguang , Yan Lulu , Chen Xin , Yuan Ru , Zhang Pan , Zhang Shougang
Published: December 2022

In this study, we present a polarization-multiplexed, erbium-doped dual-comb fiber laser based on an all-polarization-maintaining cavity configuration. We observed that the dual-comb fiber laser easily realized the self-starting mode-locking operation due to the non-linear amplifying loop mirror (NALM) with a non-reciprocal phase shifter. Furthermore, owing to the sharing of the NALM part, the two outputs from this laser configuration had similar center wavelengths, with small different repetition rates (∆frep). In the free-running operation, the standard deviation of relative stability for Δfrep of 2.09 kHz was measured to be 1.59 Hz, and the full width at half-maximum of the relative beat note between the two frequency combs in the optical frequency domain was approximately 1 kHz. These results show that the two frequency combs from this laser configuration have high relative stability and mutual coherence.
Comprehensive investigation and regulatory function of lncRNAs engaged in western honey bee larval immune response to Ascosphaera apis invasion
Authors: Ye Yaping , Fan Xiaoxue , Long Qi , Wang Jie , Zhang Wende , Cai Zongbing , Sun Minghui , Gu Xiaoyu , Zou Peiyuan , Chen Dafu , Guo Rui
Published: December 2022

Ascosphaera apis is a fungal pathogen that exclusively infects bee larvae, causing chalkbrood disease, which results in severe damage for beekeeping industry. Long non-coding RNAs (lncRNAs) are versatile regulators in various biological processes such as immune defense and host-pathogen interaction. However, expression pattern and regulatory role of lncRNAs involved in immune response of bee host to A. apis invasion is still very limited. Here, the gut tissues of Apis mellifera ligustica 4-, 5-, and 6-day-old larvae inoculated by A. apis spores (AmT1, AmT2, and AmT3 groups) and corresponding un-inoculated larval guts (AmCK1, AmCK2, and AmCK3 groups) were prepared and subjected to deep sequencing, followed by identification of lncRNAs, analysis of differentially expressed lncRNAs (DElncRNAs), and investigation of competing endogenous RNA (ceRNA) network. In total, 3,746 A. m. ligustica lncRNAs were identified, including 78 sense lncRNAs, 891 antisense lncRNAs, 1,893 intergenic lncRNAs, 346 bidirectional lncRNAs, and 210 intronic lncRNAs. In the 4-, 5-, and 6- comparison groups, 357, 236, and 505 DElncRNAs were discovered. Additionally, 217, 129, and 272 DElncRNAs were respectively predicted to regulate neighboring genes via cis-acting manner, and these targets were associated with a series of GO terms and KEGG pathways of great importance, such as response to stimulus and Jak-STAT signaling pathway. Moreover, 197, 95, and 356 DElncRNAs were observed to target 10, eight, and 21 DEmiRNAs and further target 147, 79, and 315 DEmRNAs, forming complex regulatory networks. Further investigation suggested that these targets were engaged in several key cellular and humoral immune pathways, such as phagosome and MAPK signaling pathway. Ultimately, the expression trends of nine randomly selected DElncRNAs were verified by RT-qPCR, confirming the authenticity and reliability of our transcriptome data. Findings in this current work not only provide candidate DElncRNAs for functional study, but also lay a foundation for unclosing the mechanism underlying DElncRNA-regulated larval immune responses to A. apis invasion.
A novel sulfur dioxide probe inhibits high glucose-induced endothelial cell senescence
Authors: Ren Hui , Han WenWen , Wang Shuo , Zhao BaoXiang , Miao JunYing , Lin ZhaoMin
Published: December 2022

Sulfur dioxide (SO2) is an important gas signal molecule produced in the cardiovascular system, so it has an important regulatory effect on human umbilical vascular endothelial cells (HUVECs). Studies have shown that high glucose (HG) has become the main cause of endothelial dysfunction and aging. However, the mechanism by which SO2 regulates the senescence of vascular endothelial cells induced by HG has not yet been clarified, so it is necessary to find effective tools to elucidate the effect of SO2 on senescence of HUVECs. In this paper, we identified a novel sulfur dioxide probe (2-(4-(dimethylamino)styryl)-1,1,3-trimethyl-1H-benzo [e]indol-3-ium, DLC) that inhibited the senescence of HUVECs. Our results suggested that DLC facilitated lipid droplets (LDs) translocation to lysosomes and triggered upregulation of LAMP1 protein levels by targeting LDs. Further study elucidated that DLC inhibited HG-induced HUVECs senescence by promoting the decomposition of LDs and protecting the proton channel of V-ATPase on lysosomes. In conclusion, our study revealed the regulatory effect of lipid droplet-targeted sulfur dioxide probes DLC on HG-induced HUVECs senescence. At the same time, it provided the new experimental evidence for elucidating the regulatory mechanism of intracellular gas signaling molecule sulfur dioxide on vascular endothelial fate.