bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronically Elevated Interleukin-6 Disturbs the Coagulation Cascade in Mice
Authors: Knopp Tanja , Lagrange Jeremy , Jung Rebecca , Wild Johannes , Rossmann Heidi , Spronk Henri M.H. , Wunderlich Thomas , Hoevelmeyer Nadine , Münzel Thomas , Lämmle Bernhard , Ruf Wolfram , Wenzel Philip , Waisman Ari , Karbach Susanne Helena
Published: November 2021

Introduction: Pro-inflammatory cytokines play an essential role as activators of the hemostatic system and in the regulation of physiological antithrombotic mechanisms. Interleukin-6 (IL-6) influences platelet production and platelet activation. It was associated with accelerated clotting and intravascular coagulation in tissue factor (TF)-driven murine thrombosis models. However, the precise role of myeloid cell-derived IL-6 on thrombosis formation and the hemostatic system is still unknown.

Methods and Results:

To better understand the role of IL-6 in thrombosis and the hemostatic system, we developed a new mouse strain with Cre-recombinase driven constitutive IL-6 expression specifically in myeloid cells (LysM-IL-6 OE, Control mice: IL-6 OE). LysM-IL-6 OE mice had a prolonged tail bleeding time and lacked venous thrombus formation induced by inferior vena cava (IVC) stenosis. There were no differences in D-Dimer levels in LysM-IL-6 OE mice neither on baseline level nor after IVC ligation. However, we found unstoppable post-operative bleedings in LysM-IL-6 OE. They showed a prolonged aPTT, a significantly increased INR and a prolonged thrombin converting time. The Factor V and IX expression were reduced, but von Willebrand factor, antithrombin and fibrinogen expression were up-regulated and could not explain the missing thrombus formation. We found significantly elevated erythrocyte sedimentation in line with erythrocytes aggregates, which seemed to be mediated by IL-6 and α2M. Most importantly, hepatic levels of thrombin inhibitor α2 macroglobulin (α2M) mRNA and protein were increased in LysM-IL-6 OE/+ mice compared to control mice. In parallel, Platelet erythrocyte interaction seemed to be essential in the development of the bleeding phenotype.

Conclusions: These findings show the role of chronically elevated IL-6 in driving the accumulation of A2m on the surface of erythrocytes, thereby mediating a phenotype of increased bleeding complications.

This work was supported by the DFG KA4035/1-1 and by the German Ministry for Education and Research (BMBF 01EO1503)

Disclosures

Lämmle: Takeda: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Speakers Bureau; Baxter: Other: Travel Support, Speakers Bureau; Alexion: Other: Travel Support, Speakers Bureau; Siemens: Other: Travel Support, Speakers Bureau; Bayer: Other: Travel Support, Speakers Bureau; Roche: Other: Travel Support, Speakers Bureau; Sanofi: Other: Travel Support, Speakers Bureau. Ruf: ARCA bioscience: Consultancy, Patents & Royalties; ICONIC Therapeutics: Consultancy; MeruVasimmune: Current holder of individual stocks in a privately-held company.
Analysis and comparison of traffic flow models: a new hybrid traffic flow model vs benchmark models
Authors: Storani Facundo , Di Pace Roberta , Bruno Francesca , Fiori Chiara
Published: November 2021

Background

This paper compares a hybrid traffic flow model with benchmark macroscopic and microscopic models. The proposed hybrid traffic flow model may be applied considering a mixed traffic flow and is based on the combination of the macroscopic cell transmission model and the microscopic cellular automata.

Modelled variables

The hybrid model is compared against three microscopic models, namely the Krauß model, the intelligent driver model and the cellular automata, and against two macroscopic models, the Cell Transmission Model and the Cell Transmission Model with dispersion, respectively. To this end, three main applications were considered: (i) a link with a signalised junction at the end, (ii) a signalised artery, and (iii) a grid network with signalised junctions.

Results

The numerical simulations show that the model provides acceptable results. Especially in terms of travel times, it has similar behaviour to the microscopic model. By contrast, it produces lower values of queue propagation than microscopic models (intrinsically dominated by stochastic phenomena), which are closer to the values shown by the enhanced macroscopic cell transmission model and the cell transmission model with dispersion. The validation of the model regards the analysis of the wave propagation at the boundary region.
“Stomach mass” as the first manifestation of IgG4-related disease: a case report
Authors: Zhang Fulong , Xu Jing , Zhu Yuandong , Wu Qianneng , Xie Xincheng , Shi Yan
Published: November 2021

Background

IgG4-related disease mainly manifests as organomegaly and is accompanied by tissue fibrosis (Mimori, Mod Rheumatol 29(2):213, 2019) which is frequently confused with tumour (Dawei et al., J Gastroenterol Hepatol 29(12):1375–8, 2020). There are few reports with of IgG4-related disease with the first clinical manifestation involving the stomach.

Case presentation

We present the case of 46-year-old male patient with a “stomach tumour” as the first manifestation of IgG4-related disease. Gastroscopy showed a mass in the stomach, however, the pathology result was chronic inflammation with IgG4 positivity. CT scans of abdomen showed that the stomach wall was thick, the head of the pancreas was swollen, and retroperitoneal fibrosis was severe.The serum IgG4 level was 75 g/L (normal range 0.03–2.01 g/L).After treatment with methylprednisolone for one month, the symptoms were greatly relieved.

Conclusions

To reduce the suffering of patients and relieve their financial burden, we should consider the possibility of IgG4-related disease when the initial manifestation is a stomach mass.
Disseminated lymph node tuberculosis after splenectomy: an unusual case report in an adolescent
Authors: Cheng Moxin , Chen Yu
Published: November 2021

Background

Splenectomized patients are at an increased risk for overwhelming post-splenectomy infections typically with encapsulated bacteria. The clinical association between splenectomy and lymph-node tuberculosis is unclear.

Case presentation

We describe a rare case of disseminated tuberculous lymphadenitis in an 18-year-old woman with history of splenectomy because of hereditary sherocytosis. She was admitted with enlargement of bilateral-cervical and left-axillary lymph nodes and fever. A diagnosis of probable tuberculosis was made based on the findings of fine-needle aspiration. Histology showed granulomas and extensive caseous necrosis, with the site of puncture located at an enlarged lymph node on the right side. The diagnosis was confirmed via nucleic-acid amplification tests following excisional biopsy of the left axillary lymph node. Disseminated tuberculous lymphadenitis was localized in the bilateral neck, right lung hilum, left sub-axillary region, and mediastinum, as detected from contrast-enhanced computed tomography of the neck.

Conclusions

Mycobacterium tuberculosis infection should be considered in children and adolescents with extensive enlargement of lymph nodes after splenectomy.
A study of generalization and compatibility performance of 3D U-Net segmentation on multiple heterogeneous liver CT datasets
Authors: He Baochun , Yin Dalong , Chen Xiaoxia , Luo Huoling , Xiao Deqiang , He Mu , Wang Guisheng , Fang Chihua , Liu Lianxin , Jia Fucang
Published: November 2021

Background

Most existing algorithms have been focused on the segmentation from several public Liver CT datasets scanned regularly (no pneumoperitoneum and horizontal supine position). This study primarily segmented datasets with unconventional liver shapes and intensities deduced by contrast phases, irregular scanning conditions, different scanning objects of pigs and patients with large pathological tumors, which formed the multiple heterogeneity of datasets used in this study.

Methods

The multiple heterogeneous datasets used in this paper includes: (1) One public contrast-enhanced CT dataset and one public non-contrast CT dataset; (2) A contrast-enhanced dataset that has abnormal liver shape with very long left liver lobes and large-sized liver tumors with abnormal presets deduced by microvascular invasion; (3) One artificial pneumoperitoneum dataset under the pneumoperitoneum and three scanning profiles (horizontal/left/right recumbent position); (4) Two porcine datasets of Bama type and domestic type that contains pneumoperitoneum cases but with large anatomy discrepancy with humans. The study aimed to investigate the segmentation performances of 3D U-Net in: (1) generalization ability between multiple heterogeneous datasets by cross-testing experiments; (2) the compatibility when hybrid training all datasets in different sampling and encoder layer sharing schema. We further investigated the compatibility of encoder level by setting separate level for each dataset (i.e., dataset-wise convolutions) while sharing the decoder.

Results

Model trained on different datasets has different segmentation performance. The prediction accuracy between LiTS dataset and Zhujiang dataset was about 0.955 and 0.958 which shows their good generalization ability due to that they were all contrast-enhanced clinical patient datasets scanned regularly. For the datasets scanned under pneumoperitoneum, their corresponding datasets scanned without pneumoperitoneum showed good generalization ability. Dataset-wise convolution module in high-level can improve the dataset unbalance problem. The experimental results will facilitate researchers making solutions when segmenting those special datasets.

Conclusions

(1) Regularly scanned datasets is well generalized to irregularly ones. (2) The hybrid training is beneficial but the dataset imbalance problem always exits due to the multi-domain homogeneity. The higher levels encoded more domain specific information than lower levels and thus were less compatible in terms of our datasets.
MRI-based radiomics and ADC values are related to recurrence of endometrial carcinoma: a preliminary analysis
Authors: Zhang Kaiyue , Zhang Yu , Fang Xin , Dong Jiangning , Qian Liting
Published: November 2021

Background

To identify predictive value of apparent diffusion coefficient (ADC) values and magnetic resonance imaging (MRI)-based radiomics for all recurrences in patients with endometrial carcinoma (EC).

Methods

One hundred and seventy-four EC patients who were treated with operation and followed up in our institution were retrospectively reviewed, and the patients were divided into training and test group. Baseline clinicopathological features and mean ADC (ADCmean), minimum ADC (ADCmin), and maximum ADC (ADCmax) were analyzed. Radiomic parameters were extracted on T2 weighted images and screened by logistic regression, and then a radiomics signature was developed to calculate the radiomic score (radscore). In training group, Kaplan–Meier analysis was performed and a Cox regression model was used to evaluate the correlation between clinicopathological features, ADC values and radscore with recurrence, and verified in the test group.

Results

ADCmean showed inverse correlation with recurrence, while radscore was positively associated with recurrence. In univariate analyses, FIGO stage, pathological types, myometrial invasion, ADCmean, ADCmin and radscore were associated with recurrence. In the training group, multivariate Cox analysis showed that pathological types, ADCmean and radscore were independent risk factors for recurrence, which were verified in the test group.

Conclusions

ADCmean value and radscore were independent predictors of recurrence of EC, which can supplement prognostic information in addition to clinicopathological information and provide basis for individualized treatment and follow-up plan.
No differences in the long-term prognosis of iris and choroidal melanomas when adjusting for tumor thickness and diameter
Authors: Sabazade Shiva , Herrspiegel Christina , Gill Viktor , Stålhammar Gustav
Published: November 2021

Objective

To assess the long-term prognosis for patients with iris melanomas and compare it with the prognosis for small choroidal melanomas.

Design

Retrospective observational case series.

Methods

All patients treated for iris melanomas at a single referral institution between January 1st 1986 and January 1st 2016 were included. Patients treated for small choroidal melanomas during the same period were included for comparison. The cumulative incidence of melanoma-related mortality was calculated. Patient and tumor characteristics and size-adjusted hazard ratio (HR) for melanoma-related mortality were compared between iris and small choroidal melanomas.

Results

Forty-five iris melanomas and 268 small choroidal melanomas were included. Twenty-four iris melanomas (53%) had been treated with local resection, 12 (27%) with Ruthenium-106 brachytherapy, 7 (16%) with enucleation and 2 (4%) with proton beam irradiation. Twenty-one (68%), 7 (16%) and 2 (4%) of the iris melanomas were of the spindle, mixed and epithelioid cell types, respectively. Twenty-three patients had deceased before the end of follow-up. Median follow-up for the 22 survivors was 13.3 years (SD 9.4). Patients with iris melanomas were more often asymptomatic at presentation and had a trend towards significantly lower age (59 versus 63 years, Student’s T-testsp = 0.057). Further, iris melanomas had significantly smaller basal diameter (5.8 versus 8.0 mm,p < 0.0001) and tumor volume (79 mm3versus 93 mm mm3,p < 0.0001) but greater thickness (3.0 versus 2.5 mm,p < 0.0001). The cumulative incidence of iris melanoma-related mortality was 5% at 5 years after diagnosis, and 8% at 10, 15 and 20 years. The incidence was not significantly different to small choroidal melanomas (Wilcoxonp = 0.46). In multivariate Cox regression with tumor diameter and thickness as covariates, patients with choroidal melanomas did not have increased HR for melanoma-related mortality (HR 2.2, 95% CI 0.5–9.6,p = 0.29). Similarly, there were no significant survival differences in matched subgroups (Wilcoxonp = 0.82).

Conclusions

There are no survival differences between iris and choroidal melanomas when adjusting for tumor size. The reason for the relatively favorable prognosis of iris melanomas compared to melanomas of the choroid and ciliary body is likely that they are diagnosed at a smaller size.
Impacts of two-year multisectoral cash plus programs on young adolescent girls’ education, health and economic outcomes: Adolescent Girls Initiative-Kenya (AGI-K) randomized trial
Authors: Austrian Karen , Soler-Hampejsek Erica , Kangwana Beth , Wado Yohannes Dibaba , Abuya Benta , Maluccio John A.
Published: November 2021

Background

Early adolescence is a critical window for intervention when it is possible to lay a foundation for a safe transition to adulthood, before negative outcomes occur. The Adolescent Girls Initiative–Kenya randomized trial tested the effects of combinations of interventions for young adolescent girls in two sites – the Kibera informal settlement in Nairobi and rural Wajir County in the Northeastern region.

Methods

The interventions included community dialogues on the role and value of girls (violence prevention), a conditional cash transfer (education), weekly group meetings for girls with health and life skills training (health), and training and incentives for financial literacy and savings activities (wealth creation). Participants were randomized to one of four study arms: 1) violence prevention only, 2) violence prevention and education, 3) violence prevention, education and health or 4) violence prevention, education, health and wealth creation. An intent-to-treat (ITT) analysis was conducted using longitudinal data to estimate the impact of each combination of interventions and various sensitivity analyses conducted addressing potential attrition bias and multiple hypothesis testing concerns.

Results

In Kibera, the education conditional cash transfer had small effects on grade attainment but larger impacts on completion of primary school and the transition to secondary school in the most comprehensive arm; the health intervention improved sexual and reproductive health knowledge and condom self-efficacy; and the wealth intervention improved financial literacy and savings behavior. In Wajir, the education conditional cash transfer increased school enrollment and grade attainment, and the wealth intervention improved savings behavior.

Conclusions

The results indicate that when trying to improve a range of outcomes related to adolescent wellbeing for young girls, a multisectoral intervention with components addressing household economic constraints is a promising approach.

Trial registration

Trial Registry: ISRCTN,ISRCTN77455458. Registered 24/12/2015 - Retrospectively registered.
Pretic-I was a safe and effective artificial cervical disc prosthesis--a retrospective and comparative study with 5-year follow-up
Authors: Guo Yingjun , Liu Hao , Xu Jianzhong , Deng Yuxiao , Tao Xiaoliang , Meng Yang , Wang Xiaofei , Hong Ying , Wang Beiyu , Ding Chen , Wu Wenjie
Published: November 2021

Background

The newly designed cervical disc prosthesis, Pretic-I, had been finished its limited clinical use for over 5 years. At a short-term follow-up of 2 years, we obtained satisfactory clinical results. The long-term clinical efficacy and safety of Pretic-I will now be analyzed.

Methods

Peri-operative parameters included intra-operative blood loss, operation time, off-bed time. Clinical parameters included visual analogue scale (VAS) for arm and neck, neck disability index (NDI), and Japanese Orthopaedic Association (JOA) score. Radiological parameters included C2–7 Cobb angle, Shell angle, and the range of motion (ROM) of C2–7, functional segment unit (FSU), and adjacent FSU. The CDA-related complications included adjacent segment degeneration (ASDeg), adjacent segment disease (ASDis), heterotopic ossification (HO), prosthesis subsidence, prosthesis displacement, and dysphagia.

Results

A total 64 patients from two independent centers received a single-level CDA with Discover (n = 32) and Pretic-I (n = 32), and all of patients finished a 5-year follow-up. There’re no significant differences between two groups in peri-operative parameters. The clinical parameters improved greatly in Pretic-I group (p<0.0001), and there’s no statistical difference from Discover group. Furthermore, Pretic-I could slightly improve the cervical curvature (15.08 ± 11.75 to 18.00 ± 10.61, p = 0.3079) and perfectly maintain the Shell angle (3.03 ± 3.68 to 2.23 ± 4.10, p = 0.1988), cervical ROM (52.48 ± 14.31 to 53.30 ± 11.71, p = 0.8062) and FSU ROM (12.20 ± 4.52 to 10.73 ± 4.45, p = 0.2002). The incidence of high-grade HO (Grade III-IV) at the final follow-up was significantly lower in Pretic-I group than in Discover group (12.50% vs. 34.38%, p = 0.0389, Statistical Power = 95.36%). The incidences of other CDA-related complications in Pretic-I group were also well-accepted, comparable to the Discover group, without significant differences.

Conclusion

CDA with Pretic-I demonstrated a well-accepted and sustained clinical outcome, with a significantly lower incidence of high-grade HO. This newly designed prosthesis is expected to become an alternative choice for cervical disc prosthesis in the future.
Activity of antifungal drugs and Brazilian red and green propolis extracted with different methodologies against oral isolates of Candida spp.
Authors: Sokolonski Ana Rita , Fonseca Maísa Santos , Machado Bruna Aparecida Souza , Deegan Kathleen Ramos , Araújo Roberto Paulo Correia , Umsza-Guez Marcelo Andrés , Meyer Roberto , Portela Ricardo W.
Published: November 2021

Background

Oral candidiasis is an opportunistic disease caused by fungi of the Candida genus. The occurrence of Candida spp. resistance to the commercial antifungal drugs points to the search for alternative treatments. Propolis has been successfully used in the treatment of infectious diseases for centuries. It has been proposed that an ultrasound pretreatment in the propolis extraction protocol can enhance the concentrations of molecules with antimicrobial activities in the final extract. Thus, this study aimed to compare the antifungal activity against oral Candida spp. isolates of green and red propolis extracts submitted or not to an ultrasound pretreatment before the extraction procedure.

Methods

Candida spp. were isolated from denture stomatitis lesions and identified by sequencing. Oral Candida spp. isolates and reference strains were submitted to broth microdilution assays using commercial antifungals and Brazilian green and red propolis extracts submitted or not to an ultrasound pretreatment. Minimal Inhibitory Concentrations (MIC) and Minimal Fungicide Concentrations (MFC) were determined and biofilm formation interference was evaluated for resistant isolates.

Results

C. albicans, Candida tropicalis and Candida dubliniensis were isolated from denture stomatitis lesions. Growth inhibition was observed in all Candida isolates incubated with all green and red propolis extracts. At lower doses, red propolis extracts presented significant antifungal activity. The ultrasound pretreatment did not promote an increase in the antifungal activity of green or red propolis. Three isolates, which were highly resistant to fluconazole and itraconazole, were susceptible to low doses of red propolis extracts. These same three specimens had their biofilm formation inhibted by red propolis ethanolic extract.

Conclusions

Thus, red propolis can be faced as a promising natural product to be used in the auxiliary antifungal therapy of denture stomatitis.
Factors influencing the degree of physician-pharmacists collaboration within governmental hospitals of Jigjiga Town, Somali National Regional State, Ethiopia, 2020
Authors: Gemmechu Workineh Diriba , Eticha Endalkachew Mekonnen
Published: November 2021

Background

Collaboration is the way to deliver the desired health outcome for the patients or service users in the healthcare. Inter-professional collaboration can improve medication safety, patient outcome and minimize healthcare costs. This study aimed to explore the degree of collaboration and factors influencing collaboration between physicians and pharmacists within the public hospitals of Jigjiga town, Somali National Regional State, Ethiopia, 2020.

Methods

A cross-sectional study qualitative was conducted among 149 participants in the two governmental hospitals of the Jigjiga town with a response rate of 79.87%. The collaborative working relationship model and the physician-pharmacist collaborative instrument with three main exchange domains (trustworthiness, role specification, and relationship initiation) and collaborative care items were used. An independent sample t-test was used to compute the differences of the mean scores of physician-pharmacist collaborative instrument domains and collaborative care. Separate multiple regression was employed to assess factors influencing collaborative care for pharmacists and physicians.

Results

This study showed that pharmacists reported higher mean of collaborative care (10.66 ± 4.75) than physicians (9.17 ± 3.92). The multiple regression indicated that area of practice influence both professionals’ collaborative practice. A significant association between collaborative care and the two PPCI domains (trustworthiness and relationship initiation for the physicians; role specification and relationship initiation for pharmacists) was established.

Conclusions

The study showed that the collaboration between the physicians and pharmacists was sub-optimal and the exchange variables had a significant influence on their collaboration.

Recommendation

Physicians and pharmacists need to exert more efforts to enhance this collaboration. Further qualitative study might be needed to search for factors affecting, barriers and how to develop collaborative practice.
Predicting the hosts of prokaryotic viruses using GCN-based semi-supervised learning
Authors: Shang Jiayu , Sun Yanni
Published: November 2021

Background

Prokaryotic viruses, which infect bacteria and archaea, are the most abundant and diverse biological entities in the biosphere. To understand their regulatory roles in various ecosystems and to harness the potential of bacteriophages for use in therapy, more knowledge of viral-host relationships is required. High-throughput sequencing and its application to the microbiome have offered new opportunities for computational approaches for predicting which hosts particular viruses can infect. However, there are two main challenges for computational host prediction. First, the empirically known virus-host relationships are very limited. Second, although sequence similarity between viruses and their prokaryote hosts have been used as a major feature for host prediction, the alignment is either missing or ambiguous in many cases. Thus, there is still a need to improve the accuracy of host prediction.

Results

In this work, we present a semi-supervised learning model, named HostG, to conduct host prediction for novel viruses. We construct a knowledge graph by utilizing both virus-virus protein similarity and virus-host DNA sequence similarity. Then graph convolutional network (GCN) is adopted to exploit viruses with or without known hosts in training to enhance the learning ability. During the GCN training, we minimize the expected calibrated error (ECE) to ensure the confidence of the predictions. We tested HostG on both simulated and real sequencing data and compared its performance with other state-of-the-art methods specifically designed for virus host classification (VHM-net, WIsH, PHP, HoPhage, RaFAH, vHULK, and VPF-Class).

Conclusion

HostG outperforms other popular methods, demonstrating the efficacy of using a GCN-based semi-supervised learning approach. A particular advantage of HostG is its ability to predict hosts from new taxa.
Highly flexible metabolism of the marine euglenozoan protist Diplonema papillatum
Authors: Škodová-Sveráková Ingrid , Záhonová Kristína , Juricová Valéria , Danchenko Maksym , Moos Martin , Baráth Peter , Prokopchuk Galina , Butenko Anzhelika , Lukáčová Veronika , Kohútová Lenka , Bučková Barbora , Horák Aleš , Faktorová Drahomíra , Horváth Anton , Šimek Petr , Lukeš Julius
Published: November 2021

Background

The phylum Euglenozoa is a group of flagellated protists comprising the diplonemids, euglenids, symbiontids, and kinetoplastids. The diplonemids are highly abundant and speciose, and recent tools have rendered the best studied representative, Diplonema papillatum, genetically tractable. However, despite the high diversity of diplonemids, their lifestyles, ecological functions, and even primary energy source are mostly unknown.

Results

We designed a metabolic map of D. papillatum cellular bioenergetic pathways based on the alterations of transcriptomic, proteomic, and metabolomic profiles obtained from cells grown under different conditions. Comparative analysis in the nutrient-rich and nutrient-poor media, as well as the absence and presence of oxygen, revealed its capacity for extensive metabolic reprogramming that occurs predominantly on the proteomic rather than the transcriptomic level. D. papillatum is equipped with fundamental metabolic routes such as glycolysis, gluconeogenesis, TCA cycle, pentose phosphate pathway, respiratory complexes, β-oxidation, and synthesis of fatty acids. Gluconeogenesis is uniquely dominant over glycolysis under all surveyed conditions, while the TCA cycle represents an eclectic combination of standard and unusual enzymes.

Conclusions

The identification of conventional anaerobic enzymes reflects the ability of this protist to survive in low-oxygen environments. Furthermore, its metabolism quickly reacts to restricted carbon availability, suggesting a high metabolic flexibility of diplonemids, which is further reflected in cell morphology and motility, correlating well with their extreme ecological valence.
Flexible and stretchable polymer optical fibers for chronic brain and vagus nerve optogenetic stimulations in free-behaving animals
Authors: Cao Yi , Pan Suwan , Yan Mengying , Sun Chongyang , Huang Jianyu , Zhong Cheng , Wang Liping , Yi Lu
Published: November 2021

Background

Although electrical stimulation of the peripheral and central nervous systems has attracted much attention owing to its potential therapeutic effects on neuropsychiatric diseases, its non-cell-type-specific activation characteristics may hinder its wide clinical application. Unlike electrical methodologies, optogenetics has more recently been applied as a cell-specific approach for precise modulation of neural functions in vivo, for instance on the vagus nerve. The commonly used implantable optical waveguides are silica optical fibers, which for brain optogenetic stimulation (BOS) are usually fixed on the skull bone. However, due to the huge mismatch of mechanical properties between the stiff optical implants and deformable vagal tissues, vagus nerve optogenetic stimulation (VNOS) in free-behaving animals continues to be a great challenge.

Results

To resolve this issue, we developed a simplified method for the fabrication of flexible and stretchable polymer optical fibers (POFs), which show significantly improved characteristics for in vivo optogenetic applications, specifically a low Young’s modulus, high stretchability, improved biocompatibility, and long-term stability. We implanted the POFs into the primary motor cortex of C57 mice after the expression of CaMKIIα-ChR2-mCherry detected frequency-dependent neuronal activity and the behavioral changes during light delivery. The viability of POFs as implantable waveguides for VNOS was verified by the increased firing rate of the fast-spiking GABAergic interneurons recorded in the left vagus nerve of VGAT-ChR2 transgenic mice. Furthermore, VNOS was carried out in free-moving rodents via chronically implanted POFs, and an inhibitory influence on the cardiac system and an anxiolytic effect on behaviors was shown.

Conclusion

Our results demonstrate the feasibility and advantages of the use of POFs in chronic optogenetic modulations in both of the central and peripheral nervous systems, providing new information for the development of novel therapeutic strategies for the treatment of neuropsychiatric disorders.
Emergence of a novel recombinant of CV-A5 in HFMD epidemics in Xiangyang, China
Authors: Yu Yuting , Luo Zhiyu , Jin Weiping , Mai Jianyi , Qian Shasha , Lu Jia , Wei Zhenni , Meng Shengli , Wang Zejun , Guan Xuhua , Tong Yeqing , Shen Shuo
Published: November 2021

Background

Hand, foot and mouth disease (HFMD) is caused by a variety of enterovirus serotypes and the etiological spectrum worldwide has changed since a large scale of outbreaks occurred in 1997.

Methods

A large number of clinical specimens of HFMD patients were collected in Xiangyang and genotyping was performed by qRT-PCR, conventional PCR amplification and sequencing. Among the 146 CV-A5 detected cases, the complete genome sequences of representative strains were determined for genotyping and for recombination analysis.

Results

It was found that CV-A5 was one of the six major serotypes that caused the epidemic from October 2016 to December 2017. Phylogenetic analyses based on the VP1 sequences showed that these CV-A5 belonged to the genotype D which dominantly circulated in China. Recombination occurred between the CV-A5 and CV-A2 strains with a breakpoint in the 2A region at the nucleotide 3791.

Conclusions

The result may explain the emergence of CV-A5 as one of the major pathogens of HFMD. A multivalent vaccine against HFMD is urgently needed to control the disease and to prevent emerging and spreading of new recombinants.
Are we there yet? A machine learning architecture to predict organotropic metastases
Authors: Skaro Michael , Hill Marcus , Zhou Yi , Quinn Shannon , Davis Melissa B. , Sboner Andrea , Murph Mandi , Arnold Jonathan
Published: November 2021

Background & Aims

Cancer metastasis into distant organs is an evolutionarily selective process. A better understanding of the driving forces endowing proliferative plasticity of tumor seeds in distant soils is required to develop and adapt better treatment systems for this lethal stage of the disease. To this end, we aimed to utilize transcript expression profiling features to predict the site-specific metastases of primary tumors and second, to identify the determinants of tissue specific progression.

Methods

We used statistical machine learning for transcript feature selection to optimize classification and built tree-based classifiers to predict tissue specific sites of metastatic progression.

Results

We developed a novel machine learning architecture that analyzes 33 types of RNA transcriptome profiles from The Cancer Genome Atlas (TCGA) database. Our classifier identifies the tumor type, derives synthetic instances of primary tumors metastasizing to distant organs and classifies the site-specific metastases in 16 types of cancers metastasizing to 12 locations.

Conclusions

We have demonstrated that site specific metastatic progression is predictable using transcriptomic profiling data from primary tumors and that the overrepresented biological processes in tumors metastasizing to congruent distant loci are highly overlapping. These results indicate site-specific progression was organotropic and core features of biological signaling pathways are identifiable that may describe proliferative plasticity in distant soils.
Elp1 facilitates RAD51-mediated homologous recombination repair via translational regulation
Authors: Chen Wei-Ting , Tseng Huan-Yi , Jiang Chung-Lin , Lee Chih-Ying , Chi Peter , Chen Liuh-Yow , Lo Kai-Yin , Wang I-Ching , Lin Fu-Jung
Published: November 2021

Background

RAD51-dependent homologous recombination (HR) is one of the most important pathways for repairing DNA double-strand breaks (DSBs), and its regulation is crucial to maintain genome integrity. Elp1 gene encodes IKAP/ELP1, a core subunit of the Elongator complex, which has been implicated in translational regulation. However, how ELP1 contributes to genome maintenance is unclear.

Methods

To investigate the function of Elp1, Elp1-deficient mouse embryonic fibroblasts (MEFs) were generated. Metaphase chromosome spreading, immunofluorescence, and comet assays were used to access chromosome abnormalities and DSB formation. Functional roles of Elp1 in MEFs were evaluated by cell viability, colony forming capacity, and apoptosis assays. HR-dependent DNA repair was assessed by reporter assay, immunofluorescence, and western blot. Polysome profiling was used to evaluate translational efficiency. Differentially expressed proteins and signaling pathways were identified using a label-free liquid chromatography–tandem mass spectrometry (LC–MS/MS) proteomics approach.

Results

Here, we report that Elp1 depletion enhanced genomic instability, manifested as chromosome breakage and genotoxic stress-induced genomic DNA fragmentation upon ionizing radiation (IR) exposure. Elp1-deficient cells were hypersensitive to DNA damage and exhibited impaired cell proliferation and defective HR repair. Moreover, Elp1 depletion reduced the formation of IR-induced RAD51 foci and decreased RAD51 protein levels. Polysome profiling analysis revealed that ELP1 regulated RAD51 expression by promoting its translation in response to DNA damage. Notably, the requirement for ELP1 in DSB repair could be partially rescued in Elp1-deficient cells by reintroducing RAD51, suggesting that Elp1-mediated HR-directed repair of DSBs is RAD51-dependent. Finally, using proteome analyses, we identified several proteins involved in cancer pathways and DNA damage responses as being differentially expressed upon Elp1 depletion.

Conclusions

Our study uncovered a molecular mechanism underlying Elp1-mediated regulation of HR activity and provides a novel link between translational regulation and genome stability.
Parsed synthesis of pyocyanin via co-culture enables context-dependent intercellular redox communication
Authors: Chun Kayla , Stephens Kristina , Wang Sally , Tsao Chen-Yu , Payne Gregory F. , Bentley William E.
Published: November 2021

Background

Microbial co-cultures and consortia are of interest in cell-based molecular production and even as “smart” therapeutics in that one can take advantage of division of labor and specialization to expand both the range of available functions and mechanisms for control. The development of tools that enable coordination and modulation of consortia will be crucial for future application of multi-population cultures. In particular, these systems would benefit from an expanded toolset that enables orthogonal inter-strain communication.

Results

We created a co-culture for the synthesis of a redox-active phenazine signaling molecule, pyocyanin (PYO), by dividing its synthesis into the generation of its intermediate, phenazine carboxylic acid (PCA) from the first strain, followed by consumption of PCA and generation of PYO in a second strain. Interestingly, both PCA and PYO can be used to actuate gene expression in cells engineered with the soxRS oxidative stress regulon, although importantly this signaling activity was found to depend on growth media. That is, like other signaling motifs in bacterial systems, the signaling activity is context dependent. We then used this co-culture’s phenazine signals in a tri-culture to modulate gene expression and production of three model products: quorum sensing molecule autoinducer-1 and two fluorescent marker proteins, eGFP and DsRed. We also showed how these redox-based signals could be intermingled with other quorum-sensing (QS) signals which are more commonly used in synthetic biology, to control complex behaviors. To provide control over product synthesis in the tri-cultures, we also showed how a QS-induced growth control module could guide metabolic flux in one population and at the same time guide overall tri-culture function. Specifically, we showed that phenazine signal recognition, enabled through the oxidative stress response regulon soxRS, was dependent on media composition such that signal propagation within our parsed synthetic system could guide different desired outcomes based on the prevailing environment. In doing so, we expanded the range of signaling molecules available for coordination and the modes by which they can be utilized to influence overall function of a multi-population culture.

Conclusions

Our results show that redox-based signaling can be intermingled with other quorum sensing signaling in ways that enable user-defined control of microbial consortia yielding various outcomes defined by culture medium. Further, we demonstrated the utility of our previously designed growth control module in influencing signal propagation and metabolic activity is unimpeded by orthogonal redox-based signaling. By exploring novel multi-modal strategies for guiding communication and consortia outcome, the concepts introduced here may prove to be useful for coordination of multiple populations within complex microbial systems.
miR-30b-5p inhibits proliferation, invasion, and migration of papillary thyroid cancer by targeting GALNT7 via the EGFR/PI3K/AKT pathway
Authors: Wang Ye , Wang Congjun , Fu Zhao , Zhang Siwen , Chen Junqiang
Published: November 2021

Background

Papillary thyroid carcinoma (PTC) is a common endocrine tumor. Increasing evidence has shown that microRNA dysfunction is involved in the occurrence and development of cancer. The expression of MicroRNA-30b-5p (miR-30b-5p) was down-regulated in PTC; however, its role in the development of PTC is not clear. Hence, this study aimed to explore the role and mechanism of miR-30b-5p in the occurrence and development of PTC.

Methods

The qRT-PCR assay was used to detect the expression of miR-30b-5p in 60 cases of papillary thyroid carcinoma along with their matched non-cancerous tissues. This study explored the biological function of miR-30b-5p by the functional gain and loss experiments in vitro and vivo. The direct target gene of miR-30b-5p and its signaling pathway was identified through bioinformatics analysis, qRT-PCR, western blot, rescue experiments, and double luciferase 3'-UTR report analysis.

Results

This study demonstrated that the low expression of miR-30b-5p is related to poor clinicopathological features. Functionally, the overexpression of miR-30b-5p inhibited the proliferation, invasion, and migration of PTC cells. Bioinformatics and luciferase analysis showed that GALNT7 is the direct and functional target of miR-30b-5p. Moreover, miR-30b-5p inhibited the proliferation of PTC in vivo by inhibiting the expression of GALNT7. The studies on the mechanism have shown that GALNT7 promotes cell proliferation and invasion by activating EGFR/PI3K/AKT kinase pathway, which can be attenuated by the kinase inhibitors.

Conclusions

Overall, miR-30b-5p inhibited the progression of papillary thyroid carcinoma by targeting GALNT7 and inhibiting the EGFR/PI3K/AKT pathway.
Effects of gold nanoparticles combined with human β-defensin 3 on the alveolar bone loss of periodontitis in rat
Authors: Zhou Jing , Li Lingjun , Cui Di , Xie Xiaoting , Yang Wenrong , Yan Fuhua
Published: November 2021

Background

Nanomaterials of biomedicine and tissue engineering have been proposed for the treatment of periodontitis in recent years. This study aimed to investigate the effects of gold nanoparticles (AuNPs) combined with human β-defensin 3 (hBD3) on the repair of the alveolar bones of experimental periodontitis in rats.

Methods

A model of experimental periodontitis was established by ligation of the maxillary second molars with silk thread in rats, which were treated with or without AuNPs combined with hBD3. Micro‐computerized tomography (micro-CT) scanning, enzyme-linked immunosorbent assay, and histological and immunohistochemical staining, including alkaline phosphatase (ALP), osteoprotegerin (OPG), tartrate-resistant acid phosphatase (TRAP), and receptor activator of NF-κB ligand (RANKL), were used to analyze the samples.

Results

Micro-CT demonstrated that the alveolar bone resorption was significantly reduced after the treatment with AuNPs combined with hBD3. Levels of TNF-α and IL-6 were decreased markedly compared with the ligation group. H&E and Masson staining showed that AuNPs combined with hBD3 group had less inflammatory cell infiltration, collagen fibrosis and fracture, but higher calcification in the new bone tissue. Moreover, the administration of AuNPs combined with hBD3 increased the expression levels of ALP and OPG (related to bone formation) while decreasing the expression levels of TRAP and RANKL (related to bone resorption) expression.

Conclusions

AuNPs combined with hBD3 had a protective effect on the progression of experimental periodontitis in rats and played a certain role in suppressing osteoclastogenesis and alleviating the inflammatory destruction of periodontitis along with the promotion of bone repair.
The Ebola crisis and people with disabilities’ access to healthcare and government services in Liberia
Authors: Kett Maria , Cole Ellie , Beato Lucila , Carew Mark , Ngafuan Richard , Konneh Sekkoh , Colbourn Tim
Published: November 2021

Background

There has been little research on the impact of the 2014-2015 West African Ebola crisis on people with disabilities. This paper outlines the way in which the Ebola Virus Disease (EVD) outbreak in Liberia in 2015 highlighted existing inequalities and exclusion of people with disabilities and their households.

Methods

The results presented here are part of a larger ESRC/DFID-funded mixed methods research project in Liberia (2014-2017) which included a quantitative household survey undertaken in five counties, complemented by qualitative focus group discussions and interviews with people with disabilities and other key stakeholders. Uniquely, this research gathered information about people with disabilities’ experience of the EVD outbreak, as well as additional socioeconomic and inclusion data, that compared their experience with non-disabled community members.

Results

Reflections by people with disabilities themselves show knowledge, preparation, and responses to the EVD epidemic was often markedly different among people with disabilities due to limited resources, lack of inclusion by many mainstream public health and medical interventions and pre-existing discrimination, marginalisation and exclusion. Interviews with other key stakeholder revealed a lack of awareness of disability issues or sufficient training to include this population systematically in both Ebola response activities and general health services.

Key findings include the need to understand and mitigate direct and indirect health consequences of unequal responses to the epidemic, as well as the limited capacity of healthcare and social services to respond to people with disabilities.

Conclusion

There are lessons to be learned from Ebola outbreak around inclusion of people with disabilities, relevant to the current COVID-19 pandemic. Now is the time to undertake measures to ensure that people with disabilities do not continue to be marginalised and excluded during global public health emergencies.
Intermediate-to-therapeutic versus prophylactic anticoagulation for coagulopathy in hospitalized COVID-19 patients: a systemic review and meta-analysis
Authors: Zhang Sirui , Li Yupei , Liu Guina , Su Baihai
Published: November 2021

Background

Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal anticoagulant strategy has not yet been defined. The objective of this meta-analysis was to investigate the effect of intermediate-to-therapeutic versus prophylactic anticoagulation for thromboprophylaxis on the primary outcome of in-hospital mortality and other patient-centered secondary outcomes in COVID-19 patients.

Methods

MEDLINE, EMBASE, and Cochrane databases were searched from inception to August 10th 2021. Cohort studies and randomized clinical trials that assessed the efficacy and safety of intermediate-to-therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients were included. Baseline characteristics and relevant data of each study were extracted in a pre-designed standardized data-collection form. The primary outcome was all-cause in-hospital mortality and the secondary outcomes were incidence of thrombotic events and incidence of any bleeding and major bleeding. Pooled analysis with random effects models yielded relative risk with 95 % CIs.

Results

This meta-analysis included 42 studies with 28,055 in-hospital COVID-19 patients totally. Our pooled analysis demonstrated that intermediate-to-therapeutic anticoagulation was not associated with lower in-hospital mortality (RR=1.12, 95 %CI 0.99-1.25, p=0.06, I2=77 %) and lower incidence of thrombotic events (RR=1.30, 95 %CI 0.79-2.15, p=0.30, I2=88 %), but increased the risk of any bleeding events (RR=2.16, 95 %CI 1.79-2.60, p<0.01, I2=31 %) and major bleeding events significantly (RR=2.10, 95 %CI 1.77-2.51, p<0.01, I2=11 %) versus prophylactic anticoagulation. Moreover, intermediate-to-therapeutic anticoagulation decreased the incidence of thrombotic events (RR=0.71, 95 %CI 0.56-0.89, p=0.003, I2=0 %) among critically ill COVID-19 patients admitted to intensive care units (ICU), with increased bleeding risk (RR=1.66, 95 %CI 1.37-2.00, p<0.01, I2=0 %) and unchanged in-hospital mortality (RR=0.94, 95 %CI 0.79-1.10, p=0.42, I2=30 %) in such patients. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from very low to moderate.

Conclusions

We recommend the use of prophylactic anticoagulation against intermediate-to-therapeutic anticoagulation among unselected hospitalized COVID-19 patients considering insignificant survival benefits but higher risk of bleeding in the escalated thromboprophylaxis strategy. For critically ill COVID-19 patients, the benefits of intermediate-to-therapeutic anticoagulation in reducing thrombotic events should be weighed cautiously because of its association with higher risk of bleeding.

Trial registration

The protocol was registered at PROSPERO on August 17th 2021 (CRD42021273780).

Graphical abstract