bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systems pharmacology-based approach to investigate the mechanisms of Danggui-Shaoyao-san prescription for treatment of Alzheimer’s disease
Authors: Wu Qihui , Chen Yunbo , Gu Yong , Fang Shuhuan , Li Weirong , Wang Qi , Fang Jiansong , Cai Chuipu 
Published: September 2020

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia in the elderly, characterized by a progressive and irreversible loss of memory and cognitive abilities. Currently, the prevention and treatment of AD still remains a huge challenge. As a traditional Chinese medicine (TCM) prescription, Danggui-Shaoyao-san decoction (DSS) has been demonstrated to be effective for alleviating AD symptoms in animal experiments and clinical applications. However, due to the complex components and biological actions, its underlying molecular mechanism and effective substances are not yet fully elucidated.MethodsIn this study, we firstly systematically reviewed and summarized the molecular effects of DSS against AD based on current literatures of in vivo studies. Furthermore, an integrated systems pharmacology framework was proposed to explore the novel anti-AD mechanisms of DSS and identify the main active components. We further developed a network-based predictive model for identifying the active anti-AD components of DSS by mapping the high-quality AD disease genes into the global drug-target network.ResultsWe constructed a global drug-target network of DSS consisting 937 unique compounds and 490 targets by incorporating experimental and computationally predicted drug–target interactions (DTIs). Multi-level systems pharmacology analyses revealed that DSS may regulate multiple biological pathways related to AD pathogenesis, such as the oxidative stress and inflammatory reaction processes. We further conducted a network-based statistical model, drug-likeness analysis, human intestinal absorption (HIA) and blood-brain barrier (BBB) penetration prediction to uncover the key ani-AD ingredients in DSS. Finally, we highlighted 9 key ingredients and validated their synergistic role against AD through a subnetwork.ConclusionOverall, this study proposed an integrative systems pharmacology approach to disclose the therapeutic mechanisms of DSS against AD, which also provides novel in silico paradigm for investigating the effective substances of complex TCM prescription.
Positive association between triglyceride glucose index and arterial stiffness in hypertensive patients: the China H-type Hypertension Registry Study
Authors: Li Minghui , Zhan Aihua , Huang Xiao , Hu Lihua , Zhou Wei , Wang Tao , Zhu Lingjuan , Bao Huihui , Cheng Xiaoshu 
Published: September 2020

Abstract
Background
Data are limited on whether TyG index is an independent predictor of arterial stiffness in hypertensive patients. The purpose of this study was to assess the association between the TyG index and arterial stiffness, and examined whether there were effect modifiers, in hypertensive patients.

Methods
This study included 4718 hypertensive adults, a subset of the China H-type Hypertension Registry Study. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Arterial stiffness was determined by measuring brachial-ankle pulse wave velocity (baPWV).

Results
The overall mean TyG index was 8.84. Multivariate linear regression analyses showed that TyG index was independently and positively associated with baPWV (β, 1.02; 95% confidence interval [CI] 0.83, 1.20). Consistently, Multiple logistic analyses showed a positive association between TyG index risk of elevated baPWV (> 75th percentile) (odds ratio [OR], 2.12; 95% CI 1.80, 2.50). Analyses using restricted cubic spline confirmed that the associations of TyG index with baPWV and elevated baPWV were linear. Subgroup analyses showed that stronger associations between TyG index and baPWV were detected in men (all P for interaction < 0.05).

Conclusion
TyG index was independently and positively associated with baPWV and elevated baPWV among hypertensive patients, especially in men. The data suggest that TyG index may serve as a simple and effective tool for arterial stiffness risk assessment in daily clinical practice.
Rabies virus phosphoprotein P5 binding to BECN1 regulates self-replication by BECN1-mediated autophagy signaling pathway
Authors: Liu Juan , Liao Min , Yan Yan , Yang Hui , Wang Hailong , Zhou Jiyong 
Published: September 2020

Abstract
Background
Rabies virus (RABV) is reported to encode five phosphoproteins (P), which are involved in viral genomic replication, axonal transport, oxidative stress, interferon antagonism, and autophagy induction. However, the functions of the different P proteins are poorly understood.

Methods
Immunofluorescence staining and western blot were performed to detect the autophagy activity, the form of ring-like structure, and the colocalization of BECN1 and P. Co-immunoprecipitation was performed to detect the interaction between P and BECN1. QRT-PCR and TCID50 assay were performed to detect the replication level of RABV. Small interfering RNA was used to detect the autophagy signaling pathway.

Results
We found that P5 attaches to N-terminal residues 1–139 of BECN1 (beclin1) on the BECN1 ring-like structure through amino acid residues 173–222 of P5. Subsequently, we found that P5-induced autophagosomes did not fuse with lysosomes. Becn1 silencing did not recover P5 overexpression-induced promotion of RABV replication. Mechanistically, RABV protein PΔN82 (P5) induced incomplete autophagy via the BECN1-mediated signaling pathway.

Conclusions
Our data indicate that P5 binding to the BECN1 ring benefits RABV replication by inducing BECN1 signaling pathway-dependent incomplete autophagy, which provides a potential target for antiviral drugs against RABV.

Graphical abstract
National physical activity and sedentary behaviour policies in 76 countries: availability, comprehensiveness, implementation, and effectiveness
Authors: Klepac Pogrmilovic Bojana , Ramirez Varela Andrea , Pratt Michael , Milton Karen , Bauman Adrian , Biddle Stuart J. H. , Pedisic Zeljko 
Published: September 2020

Abstract
Background
Evidence on current, national physical activity (PA) and sedentary behaviour (SB) policies is limited. We, therefore, analysed availability, comprehensiveness, implementation, and effectiveness of PA and SB policies internationally.

Methods
In this cross-sectional study, Global Observatory for Physical Activity (GoPA!) Country Contacts from 173 countries were asked to provide data on their national PA and SB policies by completing GoPA! Policy Inventory. Data were collected for 76 countries (response rate = 44%).

Results
Formal written policies for PA and SB were found in 92% (95% confidence interval [CI]: 86, 98) and 62% (95% CI: 50, 75) of countries, respectively. Sixty-two percent (95% CI: 51, 73) of countries have national PA guidelines, while 40% (95% CI: 29, 52) have SB guidelines. Fifty-two (95% CI: 40, 64) and 11% (95% CI: 3, 19) of countries have quantifiable national targets for PA and SB, respectively. The most represented ministries/departments involved in the promotion of more PA and/or less SB were in the sport (reported by 99% countries; 95% CI: 96, 100), health (97%; 95% CI: 94, 100), education (94%; 95% CI: 88, 100), and recreation and leisure (85%; 95% CI: 71, 99) sectors. The median score (0–10) for the comprehensiveness of PA and SB policies was 4 (95% CI: 4, 5) and 2 (95% CI: 2, 3), respectively. For PA and SB policy implementation it was 6 (95% CI: 5, 6). For the effectiveness of PA and SB policies it was 4 (95% CI: 3, 5) and 3 (95% CI: 2, 4), respectively. PA and SB policies were generally best developed in high-income countries and countries of European and Western-Pacific regions.

Conclusions
Most of the included countries have PA policies, but their comprehensiveness, implementation, and effectiveness are generally low-to-moderate. SB policies are less available, comprehensive, implemented, and effective than PA policies. PA and SB policies are better developed in high-income countries, compared with low- and lower-middle-income countries, and in countries of European and Western-Pacific regions, compared with other world regions. More investment is needed in development and implementation of comprehensive and effective PA and SB policies, particularly in low- and lower-middle-income countries.
Development of a CD19 PET tracer for detecting B cells in a mouse model of multiple sclerosis
Authors: Stevens Marc Y. , Cropper Haley C. , Lucot Katherine L. , Chaney Aisling M. , Lechtenberg Kendra J. , Jackson Isaac M. , Buckwalter Marion S. , James Michelle L. 
Published: September 2020

Abstract
Background
B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE).

Methods
Female C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1–125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted.

Results
Radiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/μmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry—providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice.

Conclusion
CD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.
NanoPASS: an easy-to-use user interface for nanoparticle dosimetry with the 3DSDD model
Authors: Frenzel Falko , König-Mattern Laura , Stock Valerie , Voss Linn , Paul Maxi B. , Sieg Holger , Braeuning Albert , Voigt Andreas , Böhmert Linda 
Published: September 2020

AbstractNanoparticles exhibit a specific diffusion and sedimentation behavior under cell culture conditions as used in nantoxicological in vitro testing. How a particular particle suspension behaves depends on the particular physicochemical characteristics of the particles and the cell culture system. Only a fraction of the nanoparticles applied to a cell culture will thus reach the cells within a given time frame. Therefore, dosimetric calculations are essential not only to determine the exact fraction of nanoparticles that has come into contact with the cells, but also to ensure experimental comparability and correct interpretation of results, respectively. Yet, the use of published dosimetry models is limited. Not the least because the correct application of these in silico tools usually requires bioinformatics knowledge, which often is perceived a hurdle. Moreover, not all models are freely available and accessible. In order to overcome this obstacle, we have now developed an easy-to-use interface for our recently published 3DSDD dosimetry model, called NanoPASS (NanoParticle Administration Sedimentation Simulator). The interface is freely available to all researchers. It will facilitate the use of in silico dosimetry in nanotoxicology and thus improve interpretation and comparability of in vitro results in the field.
Cost-utility analysis of extensile lateral approach versus sinus tarsi approach in Sanders type II/III calcaneus fractures
Authors: Li Zihua , Wu Xinbo , Zhou Haichao , Xu Shaochen , Xiao Fajiao , Huang Hui , Yang Yunfeng 
Published: September 2020

Abstract
Background
Extensile lateral approach had been recognized as the gold standard technique for displaced intra-articular calcaneus fractures (DIACFs) while sinus tarsi approach had been increasingly valued by surgeons and comparative clinical outcome was shown in both techniques. Appropriate decisions could be made by the clinicians with the help of cost-utility analysis (CUA) about optimal healthcare for type II/III calcaneus fracture.

Method
A single-center, retrospective study was conducted in which basic characteristics, clinical outcomes, and health care costs of 109 patients had been obtained and analyzed. Changes in health-related quality of life (HRQoL) scores, validated by EuroQol five-dimensional-three levels (EQ-5D-3L), were used to enumerate quality-adjusted life years (QALYs). Cost-effectiveness was determined by the incremental cost per QALY.

Results
One hundred nine patients were enrolled in our study including 62 in the ELA group and 47 in the STA group. There were no significant differences between these two groups in mean total cost, laboratory, and radiographic evaluation expense, surgery, anesthesia, and antibiotic expense. The expense of internal fixation materials ($3289.0 ± 543.9) versus ($2630.6 ± 763.7) and analgesia ($145.8 ± 85.6) versus ($102.9 ± 62.7) in ELA group were significantly higher than in the STA group (P < .001, P = .008, respectively). Visual Analogue Scale (VAS) scores showed significant difference at postoperative 3 and 5 days (P < .001). American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scores and the Bohlers’ and Gissane angle showed no significant differences between the two groups before and after the operation. The cost-effectiveness ratios of ELA and STA were $8766.8 ± 2835.2/QALY and $7914.9 ± 1822.0/QALY respectively, and incremental cost-effectiveness ratio (ICERs) of ELA over STA was $32110.00/QALY, but both showed no significant difference.

Conclusion
Both ELA and STA techniques are effective operative procedures for the patients with calcaneus fracture. Moreover, STA seems to be more reasonable for its merits including less postoperative pain, and less expense of analgesia as well as internal fixation materials.

Level of evidence
5
Prevalence of coat colour traits and congenital disorders of South American camelids in Austria, Germany and Switzerland
Authors: Jost Stéphanie Mali , Knoll Andrea , Lühken Gesine , Drögemüller Cord , Zanolari Patrik 
Published: September 2020

Abstract
Background
The increasing popularity of alpacas and llamas outside of South America is undeniable. The associated limited genetic diversity raises questions about health and other genetically determined traits like coat colour. Therefore, a survey studying the prevalence of congenital disorders and coat colours and patterns in South American camelids was performed in Austria, Germany and Switzerland. Moreover, the motivation for keeping these animals, the herd size and breeds was assessed.

Results
A total of 146 questionnaires were returned corresponding to 16 farms from Austria, 69 farms from Germany, and 61 farms from Switzerland. In total, the returned surveys reported data on 2770 animals including ~ 85% alpacas and ~ 15% llamas. The most common alpaca breed was Huacaya (87.7%), the most common llama breed was Wooly (15.6%). Breeding (69.4%), wool production (63.3%) and keeping them as pets (53.7%) were the most common motivations to keep these animals, although this varied among countries. The three coat colour groups, solid white (24.8%), brown and black (64.8%) and grey (10.4%), occurred at different frequencies. About 7% of the South American camelids with solid white coat showed blue-pigmented eyes, corresponding to the known blue-eyed white phenotype, of which more than every second animal was apparently deaf. Uniform solid coloured animals occurred predominantly (81.4%), whereas pinto (8.8%), speckled (6.4%) and spotted (3.4%), also known as appaloosa, were comparably less prevalent. In total 161 observations of congenital disorders occurring during a 5-year-period were reported. The most prevalent disorders were in the group of musculoskeletal disorders such as spiral toe growth (16.4%), hyperextension of the fetlock joint (12.3%), angular limb deformities (11.0%) and axial rotation of the limbs (8.2%).

Conclusions
This survey revealed first insights into the occurrence of different traits and disorders in the current South American camelid population of Austria, Germany, and Switzerland. The identification of the most common musculoskeletal disorders might encourage the breeders to eliminate affected animals from their breeding program to decrease the incidence although traits such as spiral toe growth might also represent phenocopies.
Implementation of external quality assessment of microscopy for improved parasite detection and confirmatory diagnosis of malaria in Tanzanian Military health facilities
Authors: Kalinga Akili K. , Mgata Saidi , Kavishe Reginald A. , Mahikwano Lucas , Temu Lucky , Mswanya Christopher , Mwanziva Charles , Amoo George , Kamau Edwin , Vesely Brian , Ishengoma Deus S. 
Published: September 2020

Abstract
Objective
Good quality microscopy is critical for accurate detection and confirmation of malaria parasite infections. Microscopy relies on the skills of technicians to prepare and read slides, high quality reagents, and a good program of internal and external quality control (EQA), which are lacking in most malaria endemic settings. This study was undertaken between January 2016 and December 2018 to pilot an EQA of microscopy for improved diagnosis of malaria and patient care in Tanzanian Military health facilities.

Results
Of all blood smears crosschecked (n = 4000) at baseline, only 38.5% were incorrectly diagnosed by laboratory staff with false positive and negative rates of 46.7% and 16.4%, respectively. During the implementation of EQA, false positive and negative results decreased due to increased quality index of slide preparation and reading through supportive supervision, and retraining of laboratory personnel. There was a gradual increase of quarterly and annual total quality index for all laboratories, from 60% in 2016 to 78% in 2017 and 90% in 2018. The mean proficiency testing performance scores also increased from 75% in 2016 to 82% in 2017 and to 90% in 2018. Poor blood smear preparation and staining contributed to high false positive and negative rates while EQA helped in improvement of diagnostics.
Early-stage bilayer tissue-engineered skin substitute formed by adult skin progenitor cells produces an improved skin structure in vivo
Authors: Zhang Qun , Wen Jie , Liu Chang , Ma Chuan , Bai Fuxiang , Leng Xue , Chen Zhihong , Xie Zhiwei , Mi Jun , Wu Xunwei 
Published: September 2020

Abstract
Background
In recent years, significant progress has been made in developing highly complex tissue-engineered skin substitutes (TESSs) for wound healing. However, the lack of skin appendages, such as hair follicles and sweat glands, and the time required, are two major limitations that hinder its broad application in the clinic. Therefore, it is necessary to develop a competent TESS in a short time to meet the needs for clinical applications.

Methods
Adult scalp dermal progenitor cells and epidermal stem cells together with type I collagen as a scaffold material were used to reconstitute bilayer TESSs in vitro. TESSs at 4 different culture times (5, 9, 14, and 21 days) were collected and then grafted onto full-thickness wounds created in the dorsal skin of athymic nude/nude mice. The skin specimens formed from grafted TESSs were collected 4 and 8 weeks later and then evaluated for their structure, cell organization, differentiation status, vascularization, and formation of appendages by histological analysis, immunohistochemistry, and immunofluorescent staining.

Results
Early-stage bilayer TESSs after transplantation had a better efficiency of grafting. A normal structure of stratified epidermis containing multiple differentiated layers of keratinocytes was formed in all grafts from both early-stage and late-stage TESSs, but higher levels of the proliferation marker Ki-67 and the epidermal progenitor marker p63 were found in the epidermis formed from early-stage TESSs. Interestingly, the transplantation of early-stage TESSs produced a thicker dermis that contained more vimentin- and CD31-positive cells, and importantly, hair follicle formation was only observed in the skin grafted from early-stage TESSs. Finally, early-stage TESSs expressed high levels of p63 but had low expression levels of genes involved in the activation of the apoptotic pathway compared to the late-stage TESSs in vitro.

Conclusions
Early-stage bilayer TESSs reconstituted from skin progenitor cells contained more competent cells with less activation of the apoptotic pathway and produced a better skin structure, including hair follicles associated with sebaceous glands, after transplantation, which should potentially provide better wound healing when applied in the clinic in the future.
Sex differences in severity and mortality from COVID-19: are males more vulnerable?
Authors: Pradhan Ajay , Olsson Per-Erik 
Published: September 2020

AbstractCoronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.