bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalent Morphometrically Assessed Vertebral Fractures in Individuals With Type 2 Diabetes, Prediabetes and Normal Glucose Metabolism: The Maastricht Study
Authors: van Hulten Veerle , Sarodnik Cindy , Driessen Johanna H. M. , Schaper Nicolaas C. , Geusens Piet P. M. M. , Webers Carol A. B. , Dinant Geert-Jan , Ottenheijm Ramon P. G. , Rasmussen Nicklas H. , Viggers Rikke , Stehouwer Coen D. A. , van der Kallen Carla J. H. , Schram Miranda T. , Bours Sandrine P. G. , Dagnelie Pieter C. , van den Bergh Joop P.
Published: February 2022

Background

Type 2 diabetes (T2D) is frequently reported to be associated with an increased fracture risk. Epidemiological data on prevalent morphometric vertebral fractures (VFs) in T2D are sparse and even less is known in the prediabetic state.

Purpose

To determine the association between prevalence and severity of morphometric VFs and glucose metabolism state: normal glucose metabolism (NGM), impaired glucose metabolism (prediabetes) or T2D.

Methods

This study included cross-sectional data from 3625 participants of the Maastricht Study who had a vertebral fracture assessment on lateral Dual Energy X-Ray Absorptiometry images. VFs were classified based on morphometric assessment into mild, moderate and severe VFs (respectively 20–24%, 25–39% or ≥40% reduction in expected vertebral body height). Logistic regression models were used to investigate the association between glucose metabolism status and the prevalence and severity of VFs. Analyses were adjusted for subject characteristics and life-style factors.

Results

T2D individuals were older (62.8 ± 7.5 years old) and less often female (30.5%) compared to the NGM group (57.7 ± 8.5 years old, and 58.8% female, respectively). At least one mild, moderate or severe prevalent VF was found in 8.6% of the men and 2.2% of the women in the T2D group, in 9.4% and 8.4% in the prediabetes group and in 9.1% and 4.8% in the NGM group, respectively. After adjustment T2D in women was associated with a lower probability of having a prevalent VF compared to NGM [adjusted OR 0.25 (95% CI 0.09-0.65)], while this was not the case for prediabetes. Furthermore, women with T2D had a significantly lower probability of a prevalent moderate or severe VF [adjusted OR 0.32 (95% CI 0.11-0.96)]. In men there was no significant association between T2D or prediabetes and prevalent VFs.

Conclusion

Women with T2D had a lower probability of prevalent VFs compared to women with a normal glucose metabolism, while this was not the case for men with T2D and participants with prediabetes.
Comparative Efficacy of Xianling Gubao Capsules in Improving Bone Mineral Density in Postmenopausal Osteoporosis: A Network Meta-Analysis
Authors: Luo Ming-hui , Zhao Jin-long , Xu Nan-jun , Xiao Xiao , Feng Wen-xuan , Li Zi-ping , Zeng Ling-feng
Published: February 2022

Objective

The clinical efficacy of Xianling Gubao capsule (XLGB) and its combination therapy in the treatment of postmenopausal osteoporosis (PMOP) was systematically evaluated by frequency-based network meta-analysis.

Methods

We searched the China National Knowledge Infrastructure (CNKI), Wanfang, SinoMed, PubMed, Embase and Cochrane Library databases to identify clinical trials of XLGB for the treatment of PMOP from the establishment of each database to November 22, 2021. The quality of the included studies was evaluated by using the risk of bias assessment tool version 2.0 (Rob 2.0) recommended by Cochrane. Stata 14.0 was applied for statistical analysis of the data, and the surface under the cumulative ranking curve (SUCRA) was used to rank the intervention measures of each outcome index.

Results

This study included 22 clinical trials (including 19 RCTs and 3 non-RCTs) involving 12 drug therapies. According to the results of the network meta-analysis and SUCRA, the best three interventions for improving lumbar bone mineral density (BMD) are XLGB+BP+calcium (83.7%), XLGB+BP (68.5.7%) and XLGB+VD (67.1%). XLGB+calcium was the best combination regimen for improving femoral neck BMD and increasing bone Gla protein (BGP) and alkaline phosphatase (ALP) contents in serum. The SUCRA values of XLGB+calcium for improving the three outcome indicators were 68.0%, 59.5% and 82.1%, respectively.

Conclusions

The results of this network meta-analysis show that combined application of XLGB can effectively improve BMD and serum BGP and ALP compared to calcium alone, VD or BP. In the future, multicenter, large-sample and double-blind clinical RCTs should be carried out to supplement and verify the results of this study.
Numerical Simulations of Carbon Dioxide Storage in Selected Geological Structures in North-Western Poland
Authors: Urych Tomasz , Chećko Jarosław , Magdziarczyk Małgorzata , Smoliński Adam
Published: February 2022

In this study, dynamic simulation models of CO2 injection into saline aquifers of the Choszczno-Suliszewo structure located in north-western Poland were constructed for two scenarios with different injection rates. The injection rates of 1 Mt CO2/year and 2 Mt CO2/year were analysed for each of the injection wells. Changes in pressures, characteristic for the sequestration process, were analysed; in addition, the spatial distribution of free CO2 saturation in the structure and carbon dioxide dissolved in brine were presented in a graphical form. The observation time of changes occurring in the rock mass in the interval of up to 1,000 years after the completion of injection was assumed. During the modelling of CO2 sequestration in Lower Jurassic aquifers in the Suliszewo model, the previously assumed CO2 injection rates were achieved for both injection scenarios. The observed pressure increase does not pose any threat to the Suliszewo structure tightness. The sequestration process was found to be highly effective due to the phenomenon of the dissolution of CO2 in brine and the resulting convection motion of brine enriched with carbon dioxide. Consequently, there is an increase in CO2 storage capacity and permanent long-term trapping of the injected carbon dioxide. The process of the displacement of injected CO2 from the collector layers to the layers constituting the reservoir sealing was observed. This phenomenon takes place in the upper parts of the Choszczno structure and is caused mainly by the locally occurring worse technical parameters of seal layers in this area.
Knowledge Co-creation and Sustainable Education in the Labor Market-Driven University–Business Environment
Authors: Pocol Cristina Bianca , Stanca Liana , Dabija Dan-Cristian , Pop Ioana Delia , Mișcoiu Sergiu
Published: February 2022

Objective: The university-business partnership plays a particularly important role in society, allowing a symbiosis between socio-economic stakeholders and the university. This symbiosis is based on co-creating and sharing knowledge, creating collaborative projects, valorizing research, implementing SD principles, and on good governance. The aim of this research is to identify groups of francophone socio-economic organizations willing to engage in co-creating knowledge with universities to adapt the academic curriculum to the dynamic requirements of the labor market, supporting entrepreneurship, whilst implementing SDG principles, and ensuring sustainable education. We base our approach on the two-step cluster analysis, data being collected via questionnaires among representatives of francophone organizations in an emerging market. This allows the identification of two clusters of francophone organizations according to the extent to which they contribute to strengthening their relationship with the university by co-creating knowledge, implementing SDG principles, and supporting sustainable education.

Findings: The first cluster is represented by francophone organizations reluctant to co-create knowledge and innovate with universities. These organizations have a rather unclear long-term vision and are not actively involved in supporting SDG education or understanding the universities’ training needs. The second cluster is represented by francophone organizations willing to strengthen the relationship with universities and to co-create value, developing students’ entrepreneurial skills and cooperating on the adaptation of the academic curriculum to labor market requirements.

Originality/Implications: The originality of this paper consists in conducting exhaustive research among francophone organizations in Romania, with significant practical and social implications for strengthening the strategic university-business environment partnership and identifying solutions to improve knowledge co-creation and sustainable education within a proper university governance.
Increasing but Variable Trend of Surface Ozone in the Yangtze River Delta Region of China
Authors: Tang Keqin , Zhang Haoran , Feng Weihang , Liao Hong , Hu Jianlin , Li Nan
Published: February 2022

Surface ozone (O3) increased by ∼20% in the Yangtze River Delta (YRD) region of China during 2014–2020, but the aggravating trend is highly variable on interannual time and city-level space scales. Here, we employed multiple air quality observations and numerical simulation to describe the increasing but variable trend of O3 and to reveal the main driving factors behind it. In 2014–2017, the governmental air pollution control action plan was mostly against PM2.5 (mainly to control the emissions of SO2, NOx, and primary PM2.5) and effectively reduced the PM2.5 concentration by 18%–45%. However, O3 pollution worsened in the same period with an increasing rate of 4.9 μg m−3 yr−1, especially in the Anhui province, where the growth rate even reached 14.7 μg m−3 yr−1. After 2018, owing to the coordinated prevention and control of both PM2.5 and O3, volatile organic compound (VOC) emissions in the YRD region has also been controlled with a great concern, and the O3 aggravating trend in the same period has been obviously alleviated (1.1 μg m−3 yr−1). We further combined the precursor concentration and the corresponding O3 formation regime to explain the observed trend of O3 in 2014–2020. The leading O3 formation regime in 2014–2017 is diagnosed as VOC-limited (21%) or mix-limited (58%), with the help of a simulated indicator HCHO/NOy. Under such condition, the decreasing NO2 (2.8% yr−1) and increasing VOCs (3.6% yr−1) in 2014–2017 led to a rapid increment of O3. With the continuous reduction in NOx emission and further in ambient NOx/VOCs, the O3 production regime along the Yangtze River has been shifting from VOC-limited to mix-limited, and after 2018, the mix-limited regime has become the dominant O3 formation regime for 55% of the YRD cities. Consequently, the decreases of both NOx (3.3% yr−1) and VOCs (7.7% yr−1) in 2018–2020 obviously slowed down the aggravating trend of O3. Our study argues that with the implementation of coordinated regional reduction of NOx and VOCs, an effective O3 control is emerging in the YRD region.
Relating Country-Level Governance and Tree Cover Loss in Sub-Saharan African Protected Areas: Identifying Knowledge Gaps and a More Nuanced Perspective
Authors: Dehmel Naira , Franks Phil , Schreckenberg Kate , Beresford Alison , Buchanan Graeme , Dawson Terence P.
Published: February 2022

‘Good governance’ is highlighted by many as being essential for improving protected area (PA) management and conservation outcomes, with a growing body of evidence based on site-level governance data. Yet how exactly governance at other levels supports or hinders successful PA implementation, and how this should be considered in conservation planning and practice, remains insufficiently understood. We conducted an exploratory analysis of the relationship between the quality of country-level governance and trends in tree cover loss within sub-Saharan African PAs. For the period 2008–2017, we correlated annual governance scores from the Ibrahim Index of African Governance (IIAG) with the annual rate of tree cover loss in the total terrestrial area of PAs in 33 forested sub-Saharan African countries. Overall governance was not correlated with tree cover loss in a simple model, but there was evidence that overall governance was positively correlated with tree cover loss in PAs when the interaction with environmental governance was included. The interaction indicated that the rate of tree cover loss decreased for a given level of overall governance as environmental governance increased. Human development was negatively correlated with forest loss. Thus, the relationship between country-level ‘good governance’ and conservation success is more complex than a direct and positive cause and effect. Yet, uncertainty remains about the many possible and likely confounding pathways: whilst the quality of overall governance may be mirrored at the site-level, it may also contribute to increased anthropogenic pressures on natural resources. Through this research we found significant limitations in data quality and availability both to evaluate the effectiveness of protection beyond tree cover, as well as less conventional governance aspects, such as environmental policy and regulation or site-level governance. With an expected increase in area-based protection and conservation financing in the coming decades, such data will be vital to monitor the effectiveness of our efforts and ensure financial accountability.
Predicting EGFR and PD-L1 Status in NSCLC Patients Using Multitask AI System Based on CT Images
Authors: Wang Chengdi , Ma Jiechao , Shao Jun , Zhang Shu , Liu Zhongnan , Yu Yizhou , Li Weimin
Published: February 2022

Background

Epidermal growth factor receptor (EGFR) genotyping and programmed death ligand-1 (PD-L1) expressions are of paramount importance for treatment guidelines such as the use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) in lung cancer. Conventional identification of EGFR or PD-L1 status requires surgical or biopsied tumor specimens, which are obtained through invasive procedures associated with risk of morbidities and may be unavailable to access tissue samples. Here, we developed an artificial intelligence (AI) system that can predict EGFR and PD-L1 status in using non-invasive computed tomography (CT) images.

Methods

A multitask AI system including deep learning (DL) module, radiomics (RA) module, and joint (JO) module combining the DL, RA, and clinical features was developed, trained, and optimized with CT images to predict the EGFR and PD-L1 status. We used feature selectors and feature fusion methods to find the best model among combinations of module types. The models were evaluated using the areas under the receiver operating characteristic curves (AUCs).

Results

Our multitask AI system yielded promising performance for gene expression status, subtype classification, and joint prediction. The AUCs of DL module achieved 0.842 (95% CI, 0.825–0.855) in the EGFR mutated status and 0.805 (95% CI, 0.779–0.829) in the mutated-EGFR subtypes discrimination (19Del, L858R, other mutations). DL module also demonstrated the AUCs of 0.799 (95% CI, 0.762–0.854) in the PD-L1 expression status and 0.837 (95% CI, 0.775–0.911) in the positive-PD-L1 subtypes (PD-L1 tumor proportion score, 1%–49% and ≥50%). Furthermore, the JO module of our AI system performed well in the EGFR and PD-L1 joint cohort, with an AUC of 0.928 (95% CI, 0.909–0.946) for distinguishing EGFR mutated status and 0.905 (95% CI, 0.886–0.930) for discriminating PD-L1 expression status.

Conclusion

Our AI system has demonstrated the encouraging results for identifying gene status and further assessing the genotypes. Both clinical indicators and radiomics features showed a complementary role in prediction and provided accurate estimates to predict EGFR and PD-L1 status. Furthermore, this non-invasive, high-throughput, and interpretable AI system can be used as an assistive tool in conjunction with or in lieu of ancillary tests and extensive diagnostic workups to facilitate early intervention.
CD71+ Erythroid Cell Expansion in Adult Sepsis: Potential Causes and Role in Prognosis and Nosocomial Infection Prediction
Authors: Zhao Guang-ju , Jiang Dan-wei , Cai Wen-chao , Chen Xiao-Yan , Dong Wei , Chen Long-wang , Hong Guang-liang , Wu Bin , Yao Yong-ming , Lu Zhong-qiu
Published: February 2022

Background

Immune suppression contributes to nosocomial infections (NIs) and poor prognosis in sepsis. Recent studies revealed that CD71+ erythroid cells had unappreciated immunosuppressive functions. This study aimed to investigate the values of CD71+ erythroid cells (CECs) in predicting NIs and prognosis among adult septic patients. The potential factors associated with the expansion of CECs were also explored.

Methods

In total, 112 septic patients and 32 critically ill controls were enrolled. The frequencies of CD71+ cells, CD71+CD235a+ cells, and CD45+ CECs were measured by flow cytometry. The associations between CECs and NIs and 30-day mortality were assessed by ROC curve analysis and Cox and competing-risk regression models. Factors associated with the frequency of CECs were identified by linear regression analysis.

Results

The percentage of CD71+ cells, CECs, and CD45+ CECs were higher in septic patients than critically ill controls. In septic patients, the percentages of CD71+ cells, CECs, and CD45+ CECs were associated with NI development, while CD71+ cells and CECs were independently associated with 30-day mortality. Linear regression analysis showed that the levels of interleukin (IL)-6 and interferon (IFN)-γ were positively associated with the frequencies of CD71+ cells, CECs, and CD45+ CECs, while IL-10 was negatively associated with them. Additionally, the levels of red blood cells (RBCs) were negatively associated with the percentage of CD45+ CECs.

Conclusions

CECs were expanded in sepsis and can serve as independent predictors of the development of NI and 30-day mortality. Low levels of RBCs and high levels of IL-6 and IFN-γ may contribute to the expansion of CECs in sepsis.

Trial Registration

ChiCTR, ChiCTR1900024887. Registered 2 August 2019, http://www.chictr.org.cn/showproj.aspx?proj=38645
Blockade of the PD-1/PD-L1 Immune Checkpoint Pathway Improves Infection Outcomes and Enhances Fungicidal Host Defense in a Murine Model of Invasive Pulmonary Mucormycosis
Authors: Wurster Sebastian , Albert Nathaniel D. , Bharadwaj Uddalak , Kasembeli Moses M. , Tarrand Jeffrey J. , Daver Naval , Kontoyiannis Dimitrios P.
Published: February 2022

Anecdotal clinical reports suggested a benefit of adjunct immune checkpoint inhibitors (ICIs) to treat invasive mucormycosis. However, proof-of-concept data in animal models and mechanistic insights into the effects of ICIs on host defense against Mucorales are lacking. Therefore, we studied the effects of PD-1 and PD-L1 inhibitors (4 doses of 250 µg/kg) on outcomes and immunopathology of invasive pulmonary mucormycosis (IPM) in cyclophosphamide- and cortisone acetate-immunosuppressed mice. Rhizopus arrhizus-infected mice receiving either of the ICI treatments had significantly improved survival, less morbidity, and lower fungal burden compared to isotype-treated infected mice. While early improvement of morbidity/mortality was comparable between the ICI treatments, anti-PD-L1 provided more consistent sustained protection through day 7 post-infection than anti-PD-1. Both ICIs enhanced the fungicidal activity of ex-vivo splenocytes and effectively counteracted T-cell exhaustion; however, macrophages of ICI-treated mice showed compensatory upregulation of other checkpoint markers. Anti-PD-1 elicited stronger pulmonary release of proinflammatory cytokines and chemokines than anti-PD-L1, but also induced cytokines associated with potentially unfavorable type 2 T-helper-cell and regulatory T-cell responses. Although no signs of hyperinflammatory toxicity were observed, mice with IPM receiving ICIs, particularly anti-PD-1, had elevated serum levels of IL-6, a cytokine linked to ICI toxicities. Altogether, inhibition of the PD-1/PD-L1 pathway improved clinical outcomes of IPM in immunosuppressed mice, even without concomitant antifungals. PD-L1 inhibition yielded more favorable immune responses and more consistent protection from IPM-associated morbidity and mortality than PD-1 blockade. Future dose-effect studies are needed to define the “sweet spot” between ICI-induced augmentation of antifungal immunity and potential immunotoxicities.
Incorporation of Toll-Like Receptor Ligands and Inflammasome Stimuli in GM3 Liposomes to Induce Dendritic Cell Maturation and T Cell Responses
Authors: Nijen Twilhaar Maarten K. , Czentner Lucas , Bouma Rianne G. , Olesek Katarzyna , Grabowska Joanna , Wang Aru Zeling , Affandi Alsya J. , Belt Saskia C. , Kalay Hakan , van Nostrum Cornelus F. , van Kooyk Yvette , Storm Gert , den Haan Joke M. M.
Published: February 2022

Cancer vaccination aims to activate immunity towards cancer cells and can be achieved by delivery of cancer antigens together with immune stimulatory adjuvants to antigen presenting cells (APC). APC maturation and antigen processing is a subsequent prerequisite for T cell priming and anti-tumor immunity. In order to specifically target APC, nanoparticles, such as liposomes, can be used for the delivery of antigen and adjuvant. We have previously shown that liposomal inclusion of the ganglioside GM3, an endogenous ligand for CD169, led to robust uptake by CD169-expressing APC and resulted in strong immune responses when supplemented with a soluble adjuvant. To minimize the adverse effects related to a soluble adjuvant, immune stimulatory molecules can be incorporated in liposomes to achieve targeted delivery of both antigen and adjuvant. In this study, we incorporated TLR4 (MPLA) or TLR7/8 (3M-052) ligands in combination with inflammasome stimuli, 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine (PGPC) or muramyl dipeptide (MDP), into GM3 liposomes. Incorporation of TLR and inflammasome ligands did not interfere with the uptake of GM3 liposomes by CD169-expressing cells. GM3 liposomes containing a TLR ligand efficiently matured human and mouse dendritic cells in vitro and in vivo, while inclusion of PGPC or MDP had minor effects on maturation. Immunization with MPLA-containing GM3 liposomes containing an immunogenic synthetic long peptide stimulated CD4+ and CD8+ T cell responses, but additional incorporation of either PGPC or MDP did not translate into stronger immune responses. In conclusion, our study indicates that TLRL-containing GM3 liposomes are effective vectors to induce DC maturation and T cell priming and thus provide guidance for further selection of liposomal components to optimally stimulate anti-cancer immune responses.
Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Unresectable Hepatocellular Carcinoma: Efficacy and Systemic Immune Response
Authors: Yang Fei , Xu Gui-Li , Huang Jin-Tao , Yin Yu , Xiang Wei , Zhong Bin-Yan , Li Wan-Ci , Shen Jian , Zhang Shuai , Yang Jun , Sun Hong Peng , Wang Wan-Sheng , Zhu Xiao-Li
Published: February 2022

Background

Locoregional therapy combined with systemic therapy can further improve the prognoses for HCC. However, the efficacy of TACE combined with ICIs and TKIs for HCC and whether this triple therapy can activate systemic immune response are still unknown.

Purpose

To identify the efficacy of TACE+ICIs+TKIs for unresectable hepatocellular carcinoma (uHCC) and its effect on systemic immunity.

Materials and Methods

This single-center retrospective study was approved by the Institutional Review Board. From August 1, 2019, to March 30, 2021, patients with uHCC who received the combination therapy of TACE+ICIs+TKIs were included. Peripheral blood samples were collected at baseline and once a month for 4 months after treatment. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The dynamic change trend of circulating parameters was tested using simple linear regression.

Results

Fifty-three patients with a mean age of 59 ± 10.6 years were included. TTP was 8.0 months (95% CI, 5.5–10.5) and PFS was 8.5 months (95% CI, 5.4–11.5). ORR was 52.8% and DCR was 81.1%. Twenty patients had completed analysis of biomarkers in peripheral blood. For cellular immune response, the level of circulating CD8+, CD3+ T cells and NK cells increased, the frequency of CD4+T cells and the CD4+/CD8+ ratio decreased, and among them, CD8+ T cells increased significantly. For humoral immune response, there was a significant decrease in B cells and a significant increase in Ig G, Ig κ, and Ig λ. Moreover, Ig G, Ig κ, and Ig λ were related to tumor response.

Conclusion

TACE+ICIs+TKIs showed considerable efficacy in patients with uHCC. This triple therapy activated not only cell immune but also humoral immune activation. Circulating Ig G, Ig λ, and Ig κ can serve as potential biomarkers.
The Neglected Virome of Triatomine Insects
Authors: Cardoso Maira Arruda , Brito Tarcísio Fontenele de , Brito Ingrid Alexandre de Abreu , Berni Mateus Antonio , Coelho Vitor Lima , Pane Attilio
Published: February 2022

The Triatominae subfamily (Reduviidae) harbors some hematophagous insect species that have been firmly connected to the transmission of Trypanosoma cruzi, the causative agent of Chagas disease. Triatomines not only host and transmit trypanosomatids, but also coexist with a variety of symbiotic microorganisms that generally reside in the insect’s intestinal flora. The microbiome has profound effects on the physiology, immunity, fitness and survival of animals and plants. The interaction between triatomines and bacteria has been investigated to some extent and has revealed important bacteria symbionts. In contrast, the range of viral species that can infect triatomine insects is almost completely unknown. In some cases, genomic and metatranscriptomic approaches have uncovered sequences related to possible viral genomes, but, to date, only eight positive single-strand RNA viruses, namely Triatoma virus and Rhodnius prolixus viruses 1 - 7 have been investigated in more detail. Here, we review the literature available on triatomine viruses and the viruses-insect host relationship. The lack of broader metagenomic and metatranscriptomic studies in these medically relevant insects underscores the importance of expanding our knowledge of the triatomine virome both for surveillance purposes as well as to possibly harness their potential for insect vector population control strategies.
Estimation of Ocean Biogeochemical Parameters in an Earth System Model Using the Dual One Step Ahead Smoother: A Twin Experiment
Authors: Singh Tarkeshwar , Counillon François , Tjiputra Jerry , Wang Yiguo , Gharamti Mohamad El
Published: February 2022

Ocean biogeochemical (BGC) models utilise a large number of poorly-constrained global parameters to mimic unresolved processes and reproduce the observed complex spatio-temporal patterns. Large model errors stem primarily from inaccuracies in these parameters whose optimal values can vary both in space and time. This study aims to demonstrate the ability of ensemble data assimilation (DA) methods to provide high-quality and improved BGC parameters within an Earth system model in an idealized perfect twin experiment framework. We use the Norwegian Climate Prediction Model (NorCPM), which combines the Norwegian Earth System Model with the Dual-One-Step ahead smoothing-based Ensemble Kalman Filter (DOSA-EnKF). We aim to estimate five spatially varying BGC parameters by assimilating salinity and temperature profiles and surface BGC (Phytoplankton, Nitrate, Phosphate, Silicate, and Oxygen) observations in a strongly coupled DA framework—i.e., jointly updating ocean and BGC state-parameters during the assimilation. We show how BGC observations can effectively constrain error in the ocean physics and vice versa. The method converges quickly (less than a year) and largely reduces the errors in the BGC parameters. Some parameter error remains, but the resulting state variable error using the estimated parameters for a free ensemble run and for a reanalysis performs nearly as well as with true parameter values. Optimal parameter values can also be recovered by assimilating climatological BGC observations or sparse observational networks. The findings of this study demonstrate the applicability of the DA approach for tuning the system in a real framework.
Oxymatrine Protects TGFβ1-Induced Retinal Fibrosis in an Animal Model of Glaucoma
Authors: Das Ashmita , Kashyap Onkar , Singh Amrita , Shree Jaya , Namdeo Kamta P. , Bodakhe Surendra H.
Published: February 2022

Glaucoma has engulfed a huge population of the world into its claws of blindness as it remains asymptomatic until nearly 40% of the neurons are lost and the only option left is for patients to be subjected to symptomatic treatments or surgical methods, neither of which is completely effective in curing the disease as they do not restore the physiological dimensions at the neuronal level. Among the several factors that drive the pathophysiology of glaucoma, one is the involvement of fibrogenic factors, such as transforming growth factor β (TGFβ) which remodels the extracellular matrix (ECM) and, thus, the deposition of fibrotic material in the retina, resulting in the progression of primary open-angle glaucoma (POAG). The primary objectives of this study were to evaluate the protective effects of oxymatrine (OMT) in the steroid-induced glaucoma model in experimental rats and to determine the role of transforming growth factor β1 (TGFβ1) in the pathogenesis of glaucoma and its consequent inhibition due to the antioxidant and the antiinflammatory, and also the TGFβ1 antagonistic, behavior of OMT. To that end, we experimentally elucidated the role of OMT, a TGFβ1 antagonist, that is known to play antiinflammatory and antioxidant roles in the steroid-induced glaucoma model in experimental rats, and using the enzyme-linked immunosorbent assay (ELISA), we observed a direct inhibitory effect of OMT on the pathogenesis of glaucoma. The antioxidant and the antiinflammatory potentials of OMT were determined using several biochemical methods to determine the major antioxidants in the retinal layers, such as superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), and glutathione (GSH), along with the nitrite and the malondialdehyde (MDA) concentration levels. As a result, OMT was found to reduce the total protein content in the retinal layers, a correlation that has not been previously reported. Moreover, the impacts of OMT on the major governing ATPases, namely Na+/K+ ATPase and Ca2+ATPase, along with its impacts on the intracellular ionic concentrations of Na+, K+, and Ca2+, were determined and were found to point toward OMT, restoring homeostasis in glaucomatous animals. A clearer picture of the changes during the treatment was obtained using retinal images of the live animals and of the lenticular changes in the sacrificed animal; these images provided data on the pathological pathways leading to glaucoma inception and its consequent inhibition by OMT. The data reported in this study clearly indicate that OMT has a possible role in inhibiting the pathogenesis of glaucoma, and the data also permit the quantification of several biochemical parameters of concern.
In vitro Relative Fitness, in vivo Intestinal Colonization and Genomic Differences of Escherichia coli of ST131 Carrying blaCTX–M–15
Authors: Hertz Frederik Boëtius , Marvig Rasmus L. , Frimodt-Møller Niels , Nielsen Karen Leth
Published: February 2022

Introduction

Extended-spectrum beta-lactamase (ESBL) producing Escherichia coli have become prevalent worldwide, with E. coli of sequence type 131 (ST131) as the dominant genotype. E. coli ST131 predominantly exhibits the serotype O25, is associated with the ESBL CTX-M-15 and belongs to a well-defined subclade within the FimH30-R clade, FimH30-Rx/C2. Multidrug resistance may have fitness costs for the bacteria. The aim of the current study was to investigate the fitness burden compared to a susceptible ST131 isolate without resistance genes in vitro and in vivo and describe genetic differences between fit and less fit isolates.

Materials and methods

From a collection of clinical ESBL and non-ESBL E. coli isolates from urinary tract infection, we selected 16 blaCTX–M–15-positive isolates of ST131. The in vitro fitness was examined, and relative bacterial fitness (fitt) was determined by direct competition with a fully susceptible ST131 isolate and illustrated in percent, with <100% resulting in a lower fitness, compared to the susceptible reference isolate. The isolates were subjected to whole-genome sequencing and analyzed for resistance markers, plasmids, phage content, and serotype. In vivo competition was tested in a mouse colonization model.

Results

The majority (12 out of 16) of the CTX-M-15-producing isolates had a slightly lower relative fitness compared to the susceptible ST131 isolate (mean, 97.6%; range, 82.6–108%) in vitro. Three isolates had a better fitness than the susceptible ST131 isolate, and one isolate had an identical fitness to the susceptible ST131 isolate. The in vitro fitness showed no correlation to the number of plasmids, number of phages, number of resistances, or genome size. For the in vivo competition assays, all three ESBL-producing isolates showed better colonization of the ESBL-resistant ST131 isolates compared to the susceptible ST131 isolate.

Conclusion

This study shows that ESBL-producing ST131/H30-Rx are not necessarily burdened by multidrug resistance, however, have a better in vitro fitness than the susceptible isolate. These data contribute to the understanding of the success of ST131/H30-Rx, although they do not indicate ways to overcome this highly fit, virulent, and antimicrobial-resistant clone.
The Combination Analysis Between Bacillus thuringiensis Sip1Ab Protein and Brush Border Membrane Vesicles in Midgut of Colaphellus bowringi Baly
Authors: Cao Dengtian , Xiao Changyixin , Fu Qian , Liu Xinbo , Liu Rongmei , Li Haitao , Gao Jiguo
Published: February 2022

The secretory insecticidal protein Sip1Ab and crystal protein Cry8Ca from Bacillus thuringiensis (Bt) are widely recognized for their coleopteran insecticidal activities. It is worthwhile to investigate the insecticidal mechanisms of these two proteins against Colaphellus bowringi Baly, which is a serious pest of cruciferous vegetables in China and other Asian countries. To that end, the genes encoding the Sip1Ab and Cry8Ca proteins were amplified from the strain QZL38 genome, then expressed in Escherichia coli, after which bioassays were conducted in C. bowringi larvae. After feeding these two proteins, the histopathological changes in the midguts of C. bowringi larvae were observed using transmission electron microscopy (TEM), and the Brush Border Membrane Vesicle (BBMV) was extracted for competition binding assays. TEM showed that ingestion of Sip1Ab caused a significant reduction in growth of the larvae, disruption of midgut microvilli, and expansion of intercellular spaces. Competition binding assays demonstrated that Sip1Ab bound to C. bowringi BBMV with a high binding affinity. However, a mixture of the two proteins in equal proportions showed no significant difference in insecticidal activity from that of Sip1Ab. These results could provide a molecular basis for the application of Sip1Ab in coleopteran insect control and contribute to the study of the Sip1Ab insecticidal mechanism as well.
Insights Into the Cultivable Bacterial Fraction of Sediments From the Red Sea Mangroves and Physiological, Chemotaxonomic, and Genomic Characterization of Mangrovibacillus cuniculi gen. nov., sp. nov., a Novel Member of the Bacillaceae Family
Authors: Sefrji Fatmah O. , Marasco Ramona , Michoud Grégoire , Seferji Kholoud A. , Merlino Giuseppe , Daffonchio Daniele
Published: February 2022

Mangrove forests are dynamic and productive ecosystems rich in microbial diversity; it has been estimated that microbial cells in the mangrove sediments constitute up to 91% of the total living biomass of these ecosystems. Despite in this ecosystem many of the ecological functions and services are supported and/or carried out by microorganisms (e.g., nutrient cycling and eukaryotic-host adaptation), their diversity and function are overlooked and poorly explored, especially for the oligotrophic mangrove of the Red Sea coast. Here, we investigated the cultivable fraction of bacteria associated with the sediments of Saudi Arabian Red Sea mangrove forest by applying the diffusion-chamber-based approach in combination with oligotrophic medium and long incubation time to allow the growth of bacteria in their natural environment. Cultivation resulted in the isolation of numerous representatives of Isoptericola (n = 51) and Marinobacter (n = 38), along with several less abundant and poorly study taxa (n = 25) distributed across ten genera. Within the latest group, we isolated R1DC41T, a novel member of the Bacillaceae family in the Firmicutes phylum. It showed 16S rRNA gene similarity of 94.59–97.36% with closest relatives of Rossellomorea (which was formerly in the Bacillus genus), Domibacillus, Bacillus, and Jeotgalibacillus genera. Based on the multilocus sequence analysis (MLSA), R1DC41T strain formed a separated branch from the listed genera, representing a novel species of a new genus for which the name Mangrovibacillus cuniculi gen. nov., sp. nov. is proposed. Genomic, morphological, and physiological characterizations revealed that R1DC41T is an aerobic, Gram-stain-variable, rod-shaped, non-motile, endospore-forming bacterium. A reduced genome and the presence of numerous transporters used to import the components necessary for its growth and resistance to the stresses imposed by the oligotrophic and salty mangrove sediments make R1DC41T extremely adapted to its environment of origin and to the competitive conditions present within.
Consistent Biofilm Formation by Streptococcus pyogenes emm 1 Isolated From Patients With Necrotizing Soft Tissue Infections
Authors: Skutlaberg Dag Harald , Wiker Harald G. , Mylvaganam Haima ,   The INFECT Study Group, Norrby-Teglund Anna , Skrede Steinar
Published: February 2022

Objectives

Biofilm formation has been demonstrated in muscle and soft tissue samples from patients with necrotizing soft tissue infection (NSTI) caused by Streptococcus pyogenes, but the clinical importance of this observation is not clear. Although M-protein has been shown to be important for in vitro biofilm formation in S. pyogenes, the evidence for an association between emm type and biofilm forming capacity is conflicting. Here we characterize the biofilm forming capacity in a collection of S. pyogenes isolates causing NSTI, and relate this to emm type of the isolates and clinical characteristics of the patients.

Methods

Bacterial isolates and clinical data were obtained from NSTI patients enrolled in a multicenter prospective observational study. Biofilm forming capacity was determined using a microtiter plate assay.

Results

Among 57 cases, the three most frequently encountered emm types were emm1 (n = 22), emm3 (n = 13), and emm28 (n = 7). The distribution of biofilm forming capacity in emm1 was qualitatively (narrow-ranged normal distribution) and quantitatively (21/22 isolates in the intermediate range) different from other emm types (wide ranged, multimodal distribution with 5/35 isolates in the same range as emm1). There were no significant associations between biofilm forming capacity and clinical characteristics of the patients.

Conclusions

The biofilm forming capacity of emm1 isolates was uniform and differed significantly from other emm types. The impact of biofilm formation in NSTI caused by S. pyogenes on clinical outcomes remains uncertain.
GC-MS Analysis of Potentially Volatile Compounds of Pleurotus ostreatus Polar Extract: In vitro Antimicrobial, Cytotoxic, Immunomodulatory, and Antioxidant Activities
Authors: Hamad Doaa , El-Sayed Heba , Ahmed Wafaa , Sonbol Hana , Ramadan Mohammed Abdel Halim
Published: February 2022

One strategy to manage resistant pathogens and develop potential anticancer drugs is the search for new, promising, and cost-effective medicinal benefits in the field of bioactive metabolites derived from mushrooms. In the current study, Egyptian cultivated Pleurotus ostreatus fruiting bodies polar extract was prepared to evaluate its antimicrobial activities as well as its cytotoxic effect on various cancer cell lines. The Pleurotus ostreatus polar extract (PoPE) was characterized by its phenolic and flavonoid content. The phenolics and flavonoids of PoPE were 6.94 and 0.15 mg/g, respectively. P. ostreatus polar extract showed potent antimicrobial activity against four pathogens, including Candida albicans, Staphylococcus aureus, Micrococcus luteus, and Escherichia coli. PoPE was found to inhibit Fusarium oxysporum (47%), Fusarium solani (28%) as well as Rhizoctonia solani (21%). PoPE was found to be 13 times more selective and toxic to MCF-7 cells than Vero normal cells, with the lowest IC50 value (4.5 μg/mL), so they were selected to examine the potential cytotoxic effects of PoPE. In MCF-7 cells, PoPE appeared to promote cell cycle arrest in the sub-G1 stage, as well as apoptosis. It significantly increased TNF-α production while decreasing IL-6 levels. PoPE’s total antioxidant capacity, lipid peroxide, and glutathione reductase activity were recorded 0.14 ± 0.02 mM/L, 15.60 ± 0.015 nmol/mL, and 9.50 ± 1.30 U/L, respectively. The existence of different bioactive metabolites was investigated via GC-MS, which confirmed the presence of 15 compounds with well-known biological activity.
Clinical Significance of Composition and Functional Diversity of the Vaginal Microbiome in Recurrent Vaginitis
Authors: Kim Min Jeong , Lee Seungok , Kwon Mi Yeon , Kim Myungshin
Published: February 2022

Objective

The vaginal microbiome protects the female genital tract from various diseases, such as vaginitis, a vaginal inflammation characterized by abnormal discharge, itching, and pain. To evaluate the clinical relationship between the vaginal microbiome and the pathophysiology of recurrent vaginitis (RV), we investigated the microbiome taxonomic profile (MTP) in the vaginal samples of Korean female patients with RV.

Methods

Forty women of reproductive age diagnosed with RV were enrolled. The vaginal MTP of patients was analyzed using 16S ribosomal RNA gene sequencing, and the results were compared with that of healthy women (n = 100). Further, the association of the vaginal community state type (CST) with the clinical characteristics was analyzed.

Results

The species abundance of MTP was significantly lower in patients with RV than in healthy women (p < 0.05), whereas species evenness and diversity were significantly higher in patients with RV than in healthy individuals (p < 0.05). The proportion of the most common vaginal Lactobacillus spp. was significantly lower in the MTP of patients with RV than healthy women (p < 0.01). The beta diversity distance was also significantly different between patients with RV patients and healthy individuals (p = 0.001). Based on the CST, the MTP of 40 RV samples was categorized as follows: 21 (52.5%) for CST IV, 8 (20.0%) for CST III, 5 (12.5%) for CST I, 2 (5.0%) for CST II, 1 for (2.5%) for CST V, and 3 (7.5%) for mixed CST. Patients with underlying uterine diseases (uterine leiomyoma, adenomyosis, and endometrial polyps; n = 17) showed higher species richness and diversity than those without (n = 23; p < 0.05).

Conclusion

Changes in the species abundance and microbial diversity in the vagina were strongly associated with RV. A low proportion of Lactobacillus spp. was found in patients with RV than in healthy women. The abundance and diversity of bacterial taxa were significantly higher in patients with underlying gynecologic disease than those without. Our study offers an insight into the nature of the vaginal microbiome and proposes that surveying the vaginal microbiome is valuable for detecting and treating gynecologic diseases in the future.
A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma
Authors: Chen Naifei , He Dongsheng , Cui Jiuwei
Published: February 2022

Background: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis and immune escape of cancers. This study aimed to investigate NET-related genes, their clinical prognostic value and their correlation with immunotherapy and anticancer drugs in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Differentially expressed NET-related genes in HNSCC were identified based on multiple public databases. To improve the clinical practicability and avoid overfitting, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were used to construct a prognostic risk model. A nomogram was further used to explore the clinical value of the model. Internal and external validation were conducted to test the model. Furthermore, the immune microenvironment, immunophenoscore (IPS) and sensitivity to anticancer drugs in HNSCC patients with different prognostic risks were explored.

Results: Six NET-related genes were screened to construct the risk model. In the training cohort, Kaplan–Meier (K-M) analysis showed that the overall survival (OS) of low-risk HNSCC patients was significantly better than that of high-risk HNSCC patients (p < 0.001). The nomogram also showed a promising prognostic value with a better C-index (0.726 vs 0.640) and area under the curve (AUC) (0.743 vs 0.706 at 3 years, 0.743 vs 0.645 at 5 years) than those in previous studies. Calibration plots and decision curve analysis (DCA) also showed the satisfactory predictive capacity of the nomogram. Internal and external validation further strengthened the credibility of the clinical prognostic model. The level of tumor mutational burden (TMB) in the high-risk group was significantly higher than that in the low-risk group (p = 0.017), and the TMB was positively correlated with the risk score (R = 0.11; p = 0.019). Moreover, the difference in immune infiltration was significant in HNSCC patients with different risks (p < 0.05). Furthermore, the IPS analysis indicated that anti-PD-1 (p < 0.001), anti-CTLA4 (p < 0.001) or combining immunotherapies (p < 0.001) were more beneficial for low-risk HNSCC patients. The response to anticancer drugs was also closely correlated with the expression of NET-related genes (p < 0.001).

Conclusion: This study identified a novel prognostic model that might be beneficial to develop personalized treatment for HNSCC patients.