bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphologies and Structure of Brain Lipid Membrane Dispersions
Authors: Alfredsson Viveka , Lo Nostro Pierandrea , Ninham Barry , Nylander Tommy
Published: June 2021

This study aims to explore the variety of previously unknown morphologies that brain lipids form in aqueous solutions. We study how these structures are dependent on cholesterol content, salt solution composition, and temperature. For this purpose, dispersions of porcine sphingomyelin with varying amounts of cholesterol as well as dispersions of porcine brain lipid extracts were investigated. We used cryo-TEM to investigate the dispersions at high-salt solution content together with small-angle (SAXD) and wide-angle X-ray diffraction (WAXD) and differential scanning calorimetry (DSC) for dispersions in the corresponding salt solution at high lipid content. Sphingomyelin forms multilamellar vesicles in large excess of aqueous salt solution. These vesicles appear as double rippled bilayers in the images and as split Bragg peaks in SAXD together with a very distinct lamellar phase pattern. These features disappear with increasing temperature, and addition of cholesterol as the WAXD data shows that the peak corresponding to the chain crystallinity disappears. The dispersions of sphingomyelin at high cholesterol content form large vesicular type of structures with smooth bilayers. The repeat distance of the lamellar phase depends on temperature, salt solution composition, and slightly with cholesterol content. The brain lipid extracts form large multilamellar vesicles often attached to assemblies of higher electron density. We think that this is probably an example of supra self-assembly with a multiple-layered vesicle surrounding an interior cubic microphase. This is challenging to resolve. DSC shows the presence of different kinds of water bound to the lipid aggregates as a function of the lipid content. Comparison with the effect of lithium, sodium, and calcium salts on the structural parameters of the sphingomyelin and the morphologies of brain lipid extract morphologies demonstrate that lithium has remarkable effects also at low content.
The Implication of STEP in Synaptic Plasticity and Cognitive Impairments in Alzheimer’s Disease and Other Neurological Disorders
Authors: Mahaman Yacoubou Abdoul Razak , Huang Fang , Embaye Kidane Siele , Wang Xiaochuan , Zhu Feiqi
Published: June 2021

STriatal-Enriched protein tyrosine Phosphatase (STEP) is a tyrosine phosphatase that has been implicated in Alzheimer’s disease (AD), the most common form of dementia, and many other neurological diseases. The protein level and activity of STEP have been found to be elevated in most of these disorders, and specifically in AD as a result of dysregulation of different pathways including PP2B/DARPP32/PP1, PKA as well as impairments of both proteasomal and lysosomal systems. The upregulation in STEP leads to increased binding to, and dephosphorylation of, its substrates which are mainly found to be synaptic plasticity and thus learning and memory related proteins. These proteins include kinases like Fyn, Pyk2, ERK1/2 and both NMDA and AMPA receptor subunits GluN2B and GluA2. The dephosphorylation of these molecules results in inactivation of these kinases and internalization of NMDA and AMPA receptor complexes leading to synapse loss and cognitive impairments. In this study, we aim to review STEP regulation and its implications in AD as well as other neurological disorders and then summarize data on targeting STEP as therapeutic strategy in these diseases.
The C-X-C Motif Chemokine Ligand 1 Sustains Breast Cancer Stem Cell Self-Renewal and Promotes Tumor Progression and Immune Escape Programs
Authors: Ciummo Stefania Livia , D’Antonio Luigi , Sorrentino Carlo , Fieni Cristiano , Lanuti Paola , Stassi Giorgio , Todaro Matilde , Di Carlo Emma
Published: June 2021

Breast cancer (BC) mortality is mainly due to metastatic disease, which is primarily driven by cancer stem cells (CSC). The chemokine C-X-C motif ligand-1 (CXCL1) is involved in BC metastasis, but the question of whether it regulates breast cancer stem cell (BCSC) behavior is yet to be explored. Here, we demonstrate that BCSCs express CXCR2 and produce CXCL1, which stimulates their proliferation and self-renewal, and that CXCL1 blockade inhibits both BCSC proliferation and mammosphere formation efficiency. CXCL1 amplifies its own production and remarkably induces both tumor-promoting and immunosuppressive factors, includingSPP1/OPN,ACKR3/CXCR7,TLR4,TNFSF10/TRAILandCCL18and, to a lesser extent, immunostimulatory cytokines, includingIL15, while it downregulatesCCL2,CCL28, andCXCR4. CXCL1 downregulatesTWIST2andSNAI2, while it boostsTWIST1expression in association with the loss of E-Cadherin, ultimately promoting BCSC epithelial-mesenchymal transition. Bioinformatic analyses of transcriptional data obtained from BC samples of 1,084 patients, reveals thatCXCL1expressing BCs mostly belong to the Triple-Negative (TN) subtype, and that BC expression ofCXCL1strongly correlates with that of pro-angiogenic and cancer promoting genes, such asCXCL2-3-5-6,FGFBP1,BCL11A,PI3,B3GNT5,BBOX1, andPTX3, suggesting that the CXCL1 signaling cascade is part of a broader tumor-promoting signaling network. Our findings reveal that CXCL1 functions as an autocrine growth factor for BCSCs and elicits primarily tumor progression and immune escape programs. Targeting the CXCL1/CXCR2 axis could restrain the BCSC compartment and improve the treatment of aggressive BC.
A Novel Risk Model Based on Lipid Metabolism-Associated Genes Predicts Prognosis and Indicates Immune Microenvironment in Breast Cancer
Authors: Ye Zhimin , Zou Shengmei , Niu Zhiyuan , Xu Zhijie , Hu Yongbin
Published: June 2021

Background

Breast cancer (BRCA) is the most common tumor in women, and lipid metabolism involvement has been demonstrated in its tumorigenesis and development. However, the role of lipid metabolism-associated genes (LMAGs) in the immune microenvironment and prognosis of BRCA remains unclear.

Methods

A total of 1076 patients with BRCA were extracted from The Cancer Genome Atlas database and randomly assigned to the training cohort (n = 760) or validation cohort (n = 316). Kaplan–Meier analysis was used to assess differences in survival. Consensus clustering was performed to categorize the patients with BRCA into subtypes. Using multivariate Cox regression analysis, an LMAG-based prognostic risk model was constructed from the training cohort and validated using the validation cohort. The immune microenvironment was evaluated using the ESTIMATE and tumor immune estimation resource algorithms, CIBERSORT, and single sample gene set enrichment analyses.

Results

Consensus clustering classified the patients with BRCA into two subgroups with significantly different overall survival rates and immune microenvironments. Better prognosis was associated with high immune infiltration. The prognostic risk model, based on four LMAGs (MED10, PLA2G2D, CYP4F11, and GPS2), successfully stratified the patients into high- and low-risk groups in both the training and validation sets. High risk scores predicted poor prognosis and indicated low immune status. Subgroup analysis suggested that the risk model was an independent predictor of prognosis in BRCA.

Conclusion

This study demonstrated, for the first time, that LMAG expression plays a crucial role in BRCA. The LMAG-based risk model successfully predicted the prognosis and indicated the immune microenvironment of patients with BRCA. Our study may provide inspiration for further research on BRCA pathomechanisms.
The Biological Function Delineated Across Pan-Cancer Levels Through lncRNA-Based Prognostic Risk Assessment Factors for Pancreatic Cancer
Authors: Tang Xudong , Zhang Mengyan , Sun Liang , Xu Fengyan , Peng Xin , Zhang Yan , Deng Ying , Wu Shuliang
Published: June 2021

Long non-coding RNAs (lncRNAs) play key roles in tumors and function not only as important molecular markers for cancer prognosis, but also as molecular characteristics at the pan-cancer level. Because of the poor prognosis of pancreatic cancer, accurate assessment of prognosis is a key issue in the development of treatment plans for pancreatic cancer. Here we analyzed pancreatic cancer data from The Cancer Genome Atlas and The Genotype Tissue Expression database using Cox regression and lasso regression in analyses using a combination of the two databases as well as only The Cancer Genome Atlas database (Cancer Genome Atlas Research Network et al., 2013). A prognostic risk score model with significant correlation with pancreatic cancer survival was constructed, and two lncRNAs were investigated. Additional analysis of 33 cancers using the two lncRNAs showed that lncRNA TsPOAP1-AS1 was a prognostic marker of seven cancers, among which pancreatic cancer was the most significant, and lncRNA mi600hg was a prognostic marker of ovarian cancer and pancreatic cancer. LncRNA TsPOAP1-AS1 is associated with clinical stage and tumor mutation burden of some cancers as well as a strong degree of immune infiltration in many cancers, while a strong correlation between lncRNA mi600hg and microsatellite instability was observed in several cancers. The results of this study help further our understanding of the different functions of lncRNAs in cancer and may aid in the clinical application of lncRNAs as prognostic factors for cancer.
Detection of Mycobacterium tuberculosis Complex Bacilli and Nucleic Acids From Tongue Swabs in Young, Hospitalized Children
Authors: Ealand Christopher , Peters Julian , Jacobs Olivia , Sewcharran Astika , Ghoor Azra , Golub Jonathan , Brahmbhatt Heena , Martinson Neil , Dangor Ziyaad , Lala Sanjay G. , Kana Bavesh
Published: June 2021

Diagnosis of tuberculosis in pediatric patients remains challenging due to inherent difficulties associated with obtaining respiratory samples for molecular and culture-based testing. To address this, recent studies have highlighted the utility of tongue swabs to detect Mycobacterium tuberculosis genomic DNA in the oral epithelia of tuberculosis infected adults. It is unknown whether tongue swabs have similar utility for diagnosis of childhood tuberculosis and if the presence of DNA in these swabs was associated with whole bacilli. We therefore sought to conduct a preliminary assessment of the utility of tongue swabs to detect tubercle bacilli and their associated genetic material in young children. For this, we recruited hospitalized children with clinically diagnosed tuberculosis (n = 26) or lower respiratory tract infection (LRTI, n = 9). These categories were blinded for downstream laboratory tests, which included PCR, spoligotyping, smear microscopy, and culture. Mtb genomic DNA was detected by PCR only in clinically diagnosed TB cases [11/26 (31.4%)] and not in cases with LRTI. Of these, 5/11 [45.5%] were associated with a spoligotype. Spoligotyping also detected an additional six specimens that were negative by PCR. Using smear microscopy, 19/26 [73.1%] and 4/9 [44.4] were Mtb positive in the tuberculosis or LRTI categories respectively. We noted positive results on all three tests in 5/26 [19.2%] in the tuberculosis category and 0/9 in the LRTI category. All specimens were culture negative. Collectively, these preliminary data present a compelling case for broader testing of tongue swabs to diagnose tuberculosis in children where obtaining standard sputum specimens is not easy.
Evaluating a Novel P300-Based Real-Time Image Ranking BCI
Authors: Sutaj Ngadhnjim , Walchshofer Martin , Schreiner Leonhard , Turchet Luca , Pretl Harald , Guger Christoph
Published: June 2021

Brain–computer interfaces (BCIs) establish communication between a human brain and a computer or external devices by translating the electroencephalography (EEG) signal into computer commands. After stimulating a sensory organ, a positive deflection of the EEG signal between 250 and 700 ms can be measured. This signal component of the event-related potential (ERP) is called “P300.” Numerous studies have provided evidence that the P300 amplitude and latency are linked to sensory perception, engagement, and cognition. Combining the advances in technology, classification methods, and signal processing, we developed a novel image ranking system called the Unicorn Blondy Check. In this study, the application was tested on 21 subjects using three different visual oddball paradigms. Two consisted of female faces and gray-scale images, while the third test paradigm consisted of familiar and unfamiliar faces. The images were displayed for a duration of 150 ms in a randomized order. The system was trained using 50 trials and tested with 30 trials. The EEG data were acquired using the Unicorn Hybrid Black eight-channel BCI system. These synchronized recordings were analyzed, and the achieved classification accuracies were calculated. The EEG signal was averaged over all participants and for every paradigm separately. Analysis of the EEG data revealed a significant shift in the P300 latency dependent on the paradigm and decreased amplitude for a lower target to non-target ratio. The image ranking application achieved a mean accuracy of 100 and 95.5% for ranking female faces above gray-scale images with ratios of 1:11 and 5:11, respectively. In the case of four familiar faces to 24 unfamiliar faces, 86.4% was reached. The obtained results illustrate this novel system’s functionality due to accuracies above chance levels for all subjects.
Post-operative Right Ventricular Failure After Cardiac Surgery: A Cohort Study
Authors: Levy David , Laghlam Driss , Estagnasie Philippe , Brusset Alain , Squara Pierre , Nguyen Lee S.
Published: June 2021

Introduction: Right ventricular failure (RVF) after cardiac surgery is an important risk factor for morbidity and mortality. Its diagnosis is challenging, and thus, its incidence and predictors are not well-established. We investigated the incidence, complications, and variables associated with clinically relevant post-operative RVF.

Methods: We included all patients who underwent cardiac surgery with cardiopulmonary bypass between 2016 and 2019 in a cardiac surgery center with standardized diagnostic and therapeutic management of RVF. RVF was considered only if clinically relevant: associated with hemodynamic instability requiring catecholamine support and inhaled nitric oxide relayed by sildenafil.

Results: Overall, 3,826 patients were included, of whom, 110 (2.9%) developed post-operative RVF. Mortality was not different among patients who developed post-operative RVF, compared with the rest of the cohort (1.8 vs. 0.7%, p = 0.17). Using a composite outcome that combined death, reintubation, stroke, and prolonged intensive care unit stay (more than 14 days) yielded an incidence of 6.6%, and RVF was associated with this composite outcome with an odds ratio of 3.6 (2.2–5.8), p < 0.001. In a multivariable model, pre-operative variables independently associated with post-operative RVF were pre-operative atrial fibrillation (AF) {adjusted odds ratio (adjOR) 3.22 [95% confidence interval (95%CI) = 1.94–5.36], p < 0.001}, left ventricle ejection fraction below 50% [adjOR = 2.55 (95%CI = 1.52–4.33), p < 0.001], systolic pulmonary artery pressure above 55 mmHg [adjOR = 8.64 (95%CI = 5.27–14.1); p < 0.001], mitral valve surgery [adjOR = 2.17 CI (95%CI = 1.28–3.66), p = 0.004], and tricuspid valve surgery [adjOR = 10.33 (95%CI = 6.14–17.4), p < 0.001]. In patients who developed post-operative RVF requiring treatment, 32 (29.1%) showed RV dysfunction before surgery.

Conclusion: In this cohort study, 2.9% of patients developed clinically significant post-operative RVF. Moreover, RVF was associated with severe adverse outcomes, including death, strokes, reintubation, and prolonged intensive care unit stay.
Myocardial Work Efficiency, A Novel Measure of Myocardial Dysfunction, Is Reduced in COVID-19 Patients and Associated With In-Hospital Mortality
Authors: Minhas Anum S. , Gilotra Nisha A. , Goerlich Erin , Metkus Thomas , Garibaldi Brian T. , Sharma Garima , Bavaro Nicole , Phillip Susan , Michos Erin D. , Hays Allison G.
Published: June 2021

Background: Although troponin elevation is common in COVID-19, the extent of myocardial dysfunction and its contributors to dysfunction are less well-characterized. We aimed to determine the prevalence of subclinical myocardial dysfunction and its association with mortality using speckle tracking echocardiography (STE), specifically global longitudinal strain (GLS) and myocardial work efficiency (MWE). We also tested the hypothesis that reduced myocardial function was associated with increased systemic inflammation in COVID-19.

Methods and Results: We conducted a retrospective study of hospitalized COVID-19 patients undergoing echocardiography (n = 136), of whom 83 and 75 had GLS (abnormal >−16%) and MWE (abnormal <95%) assessed, respectively. We performed adjusted logistic regression to examine associations of GLS and MWE with in-hospital mortality. Patients were mean 62 ± 14 years old (58% men). While 81% had normal left ventricular ejection fraction (LVEF), prevalence of myocardial dysfunction was high by STE; [39/83 (47%) had abnormal GLS; 59/75 (79%) had abnormal MWE]. Higher MWE was associated with lower in-hospital mortality in unadjusted [OR 0.92 (95% CI 0.85–0.99); p = 0.048] and adjusted models [aOR 0.87 (95% CI 0.78–0.97); p = 0.009]. In addition, increased systemic inflammation measured by interleukin-6 level was associated with reduced MWE.

Conclusions: Subclinical myocardial dysfunction is common in COVID-19 patients with clinical echocardiograms, even in those with normal LVEF. Reduced MWE is associated with higher interleukin-6 levels and increased in-hospital mortality. Non-invasive STE represents a readily available method to rapidly evaluate myocardial dysfunction in COVID-19 patients and can play an important role in risk stratification.
Adaptive Governance and Resilience Capacity of Farms: The Fit Between Farmers’ Decisions and Agricultural Policies
Authors: Manevska-Tasevska Gordana , Petitt Andrea , Larsson Sara , Bimbilovski Ivan , Meuwissen Miranda P. M. , Feindt Peter H. , Urquhart Julie
Published: June 2021

Greater resilience is needed for farms to deal with shocks and disturbances originating from economic, environmental, social and institutional challenges, with resilience achieved by adequate adaptive governance. This study focuses on the resilience capacity of farms in the context of multi-level adaptive governance. We define adaptive governance as adjustments in decision-making processes at farm level and policy level, through changes in management practices and policies in response to identified challenges and the delivery of desired functions (e.g. private and public goods) to be attained. The aim of the study is twofold. First, we investigate how adaptive governance processes at farm level and policy level influence the resilience capacity of farms in terms of robustness, adaptability and transformability. Second, we investigate the “fit” between the adaptive governance processes at farm level and policy level to enable resilience. We study primary egg and broiler production in Sweden taking into consideration economic, social and environmental challenges. We use semi-structured interviews with 17 farmers to explain the adaptive processes at farm level and an analysis of policy documents from the Common Agricultural Policy program 2014–2020, to explain the intervention actions taken by the Common Agricultural Policy. Results show that neither the farm level nor policy level adaptive processes on their own have the capacity to fully enable farms to be robust, adaptable and transformable. While farm level adaptive processes are mainly directed toward securing the robustness and adaptability of farms, policy level interventions are targeted at enabling adaptability. The farm- and the policy level adaptive processes do not “fit” for attaining robustness and transformability.
Sediment Metal Contamination, Bioavailability, and Oxidative Stress Response in Mangrove Avicennia marina in Central Red Sea
Authors: Alhassan Abdullahi Bala , Aljahdali Mohammed Othman
Published: June 2021

Anthropogenic activities have been on the increase in the urban environment and have led to contamination of the environment with toxic metals. However, mangrove plants’ response to heavy metal stress due to anthropogenic activities explains the metal bioavailability and its potential ecotoxicological effect. We carried out a multi-approach study to investigate i) if the concentrations of metals (Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Mo, Cd, Pb, Sr, and V) in mangroves at the central Red Sea are due to the anthropogenic influence and are above the sediment quality guidelines and ii) if an increase in metal concentration influences height and antioxidant enzyme (catalase, CAT; glutathione S-transferase, GST; and superoxide dismutase, SOD) activities in Avicennia marina. There were significant variations (p < 0.05) in metal concentrations and antioxidants across the six mangrove ecosystems with higher concentrations at Al Lith (LT) and south Jeddah (SJ). Even though the concentrations of metals in mangrove leaves are slightly higher in LT than SJ, principal component analysis showed that higher concentrations of Cr, Co, Zn, Cd, and Pb in mangrove leaves from SJ influence higher antioxidant enzyme activities and the lowest average mangrove height (2.01 m). This suggests that higher metal concentrations be factors for the biggest stress in these mangrove ecosystems. However, among the 13 metals, Cr (82.07 mg/kg), Cu (41.29 mg/kg), and As (10.30 mg/kg) in sediments have values within the ERL range of probable effect, while Ni (53.09 mg/kg) was above the ERM threshold. Hence, there is need to focus on monitoring these metals in mangrove sediments and their anthropogenic sources.
Spatio-Temporal Variations of the PM2.5/PM10 Ratios and Its Application to Air Pollution Type Classification in China
Authors: Fan Hao , Zhao Chuanfeng , Yang Yikun , Yang Xingchuan
Published: June 2021

Particulate Matter (PM) is an important indicator of the degree of air pollution. The PM type and the ratio of coarse and fine PM particles determine the ability to affect human health and atmospheric processes. Using the observation data across the country from 2015 to 2018, this study investigates the distribution and proportion of PM2.5 and PM10 at different temporal and spatial scales in mainland China; clarifies the PM2.5, PM10 and PM2.5/PM10 ratios interrelation; and classifies the dust, mixed, and anthropogenic type aerosol. It shows that the annual average concentration of PM2.5 and PM10 decreased by 10.55 and 8.78 μg m−3 in 4 years. PM2.5, PM10, and PM2.5/PM10 ratios show obvious while different seasonal variations. PM2.5 is high in winter and low in summer, while PM10 is high in winter and spring, and low in summer and autumn. Differently, the PM2.5/PM10 ratios are the highest in winter, and the lowest in spring. PM2.5/PM10 ratios show strong independence on PM2.5 and PM10, implying that it can provide extra information about the aerosol pollution such as aerosol type. A classification method about air pollution types is then further proposed based on probability distribution function (PDF) morphology of PM2.5/PM10 ratios. The results show that dust type mainly lies in the west of Hu-Line, mixed type pollution distributes near Hu-Line, and the anthropogenic type dominates over North China Plain and cities in southern China. The results provide insights into China’s future clean air policy making and environmental research.
Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins
Authors: Mohammadnejad Afsaneh , Li Weilong , Lund Jesper Beltoft , Li Shuxia , Larsen Martin J. , Mengel-From Jonas , Michel Tanja Maria , Christiansen Lene , Christensen Kaare , Hjelmborg Jacob , Baumbach Jan , Tan Qihua
Published: June 2021

Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.
Investigation of a Hypoxia-Immune-Related Microenvironment Gene Signature and Prediction Model for Idiopathic Pulmonary Fibrosis
Authors: Li Xinyu , Cai Haozheng , Cai Yufeng , Zhang Quyan , Ding Yinghe , Zhuang Quan
Published: June 2021

Background

There is growing evidence found that the role of hypoxia and immune status in idiopathic pulmonary fibrosis (IPF). However, there are few studies about the role of hypoxia and immune status in the lung milieu in the prognosis of IPF. This study aimed to develop a hypoxia-immune-related prediction model for the prognosis of IPF.

Methods

Hypoxia and immune status were estimated with microarray data of a discovery cohort from the GEO database using UMAP and ESTIMATE algorithms respectively. The Cox regression model with the LASSO method was used for identifying prognostic genes and developing hypoxia-immune-related genes. Cibersort was used to evaluate the difference of 22 kinds of immune cell infiltration. Three independent validation cohorts from GEO database were used for external validation. Peripheral blood mononuclear cell (PBMC) and bronchoalveolar lavage fluid (BALF) were collected to be tested by Quantitative reverse transcriptase-PCR (qRT-PCR) and flow cytometry from 22 clinical samples, including 13 healthy controls, six patients with non-fibrotic pneumonia and three patients with pulmonary fibrosis.

Results

Hypoxia and immune status were significantly associated with the prognosis of IPF patients. High hypoxia and high immune status were identified as risk factors for overall survival. CD8+ T cell, activated CD4+ memory T cell, NK cell, activated mast cell, M1 and M0 macrophages were identified as key immune cells in hypoxia-immune-related microenvironment. A prediction model for IPF prognosis was established based on the hypoxia-immune-related one protective and nine risk DEGs. In the independent validation cohorts, the prognostic prediction model performed the significant applicability in peripheral whole blood, peripheral blood mononuclear cell, and lung tissue of IPF patients. The preliminary clinical specimen validation suggested the reliability of most conclusions.

Conclusions

The hypoxia-immune-based prediction model for the prognosis of IPF provides a new idea for prognosis and treatment.
Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor
Authors: Rafael Tynisha S. , de Vries Hielke M. , Ottenhof Sarah R. , Hofland Ingrid , Broeks Annegien , de Jong Jeroen , Bekers Elise , Horenblas Simon , de Menezes Renée X. , Jordanova Ekaterina S. , Brouwer Oscar R.
Published: June 2021

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV− tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV− cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.
Intra-Population Variability in Group Size of Indo-Pacific Humpback Dolphins (Sousa chinensis)
Authors: Liu Mingming , Lin Mingli , Lusseau David , Li Songhai
Published: June 2021

Group size is a key social trait influencing population dynamics of group-living animals. The Indo-Pacific humpback dolphins (IPHDs), Sousa chinensis, a shallow water delphinid species, display a fission-fusion social system. Yet little is known about how social organization of this species vary with temporal scales and behavioral state. In this study, we sampled group size estimates from the world’s second largest population of humpback dolphins (Sousa spp.), which inhabit the eastern waters of Zhanjiang, China. IPHD group sizes changed seasonally and inter-annually, but not with tidal phases. Group sizes also changed with behavioral state of IPHD groups and with number of mother-calf pairs present. IPHDs formed larger groups in the autumn than in other seasons, which might be related to seasonal changes in food availability and reproductive cycle. Of the groups observed, we recorded the presence of mother-calf pair in 85 groups (i.e., nursery groups: 47 ones with one pair, 25 ones with two pairs, and others with three pairs). Notably, nursery groups were about 2–4 times larger than non-nursery groups. In addition, group sizes greatly increased with the number of mother-calf pairs. Living in relatively large groups, more protection, food, and resources might be available for IPHD mothers and calves, and such social strategy provide higher reproduction efficiency and survival success for this species. During our observations, feeding (45.5%) and traveling (25.2%) represented the majority of IPHD’s behavioral budget, while socializing (8.4%) and resting/milling (6.8%) were not frequently observed. Resting/milling groups were approximately 50% smaller than feeding, traveling, or socializing groups, while the latter three types had a similar mean group size. Large groups when IPHDs foraged, traveled, or socialized, might provide more added group benefits. For the first time, our findings clearly revealed intra-population variability in IPHD group sizes across different behavioral and temporal variables, and provided a better understanding of IPHDs’ adaptations to various biological processes and ecological constraints.
Rationale and Design of Assessing the Effectiveness of Short-Term Low-Dose Lithium Therapy in Averting Cardiac Surgery-Associated Acute Kidney Injury: A Randomized, Double Blinded, Placebo Controlled Pilot Trial
Authors: Sharif Sairah , Chen Bohan , Brewster Pamela , Chen Tian , Dworkin Lance , Gong Rujun
Published: June 2021

Background: Burgeoning pre-clinical evidence suggests that therapeutic targeting of glycogen synthase kinase 3β (GSK3β), a convergence point of multiple cellular protective signaling pathways, confers a beneficial effect on acute kidney injury (AKI) in experimental models. However, it remains unknown if GSK3β inhibition likewise mitigates AKI in humans. Cardiac surgery associated acute kidney injury (CSA-AKI) poses a significant challenge for clinicians and currently the only treatment available is general supportive measures. Lithium, an FDA approved mood stabilizer, is the best-known GSK3β inhibitor and has been safely used for over half a century as the first line regimen to treat bipolar affective disorders. This study attempts to examine the effectiveness of short term low dose lithium on CSA-AKI in human patients.

Methods/Design: This is a single center, prospective, randomized, double blinded, placebo controlled pilot study on patients undergoing cardiac surgery with cardiopulmonary bypass. Patients will be randomized to receive a small dose of lithium or placebo treatment for three consecutive days. Renal function will be measured via creatinine as well as novel AKI biomarkers. The primary outcome is incidence of AKI according to Acute Kidney Injury Network (AKIN) criteria, and secondary outcomes include receipt of new dialysis, days on dialysis, days on mechanical ventilation, infections within 1 month of surgery, and death within 90 days of surgery.

Discussion: As a standard selective inhibitor of GSK3β, lithium has been shown to exert a beneficial effect on tissue repair and regeneration upon acute injury in multiple organ systems, including the central nervous system and hematopoietic system. In experimental AKI, lithium at small doses is able to ameliorate AKI and promote kidney repair. Successful completion of this study will help to assess the effectiveness of lithium in CSA-AKI and could potentially pave the way for large-scale randomized trials to thoroughly evaluate the efficacy of this novel regimen for preventing AKI after cardiac surgery.

Trial Registration: This study was registered prospectively on the 17th February 2017 at ClinicalTrials.gov (NCT03056248, https://clinicaltrials.gov/ct2/show/NCT03056248?term=NCT03056248&draw=2&rank=1).
Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial
Authors: Solanich Xavier , Antolí Arnau , Rocamora-Blanch Gemma , Padullés Núria , Fanlo-Maresma Marta , Iriarte Adriana , Mitjavila Francesca , Capdevila Olga , Riera-Mestre Antoni , Bas Jordi , Vicens-Zygmunt Vanesa , Niubó Jordi , Calvo Nahum , Bolivar Santiago , Rigo-Bonnin Raúl , Mensa-Vilaró Anna , Arregui Laura , Tebe Cristian , Videla Sebastià , Hereu Pilar , Corbella Xavier
Published: June 2021

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients.

Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization.

Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC.

Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19.

Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].
Revealing Microbiome Structure and Assembly Process in Three Rhizocompartments of Achyranthes bidentata Under Continuous Monoculture Regimes
Authors: Wang Juanying , Wu Hongmiao , Wu Linkun , Liu Ye , Letuma Puleng , Qin Xianjin , Chen Ting , Rensing Christopher , Lin Sheng , Lin Wenxiong
Published: June 2021

The complex composition and interaction of root-associated microbes are critical to plant health and performance. In this study, we presented a detailed characterization of three rhizocompartment (rhizosphere, rhizoplane, and root) microbiomes of Achyranthes bidentata under different years of consecutive monoculture by deep sequencing in order to determine keystone microorganisms via co-occurrence network analysis. The network analysis showed that multiple consecutive monoculture (MCM, represented 5Y and 10Y) soils generated some distinct beneficial bacterial taxa such as Bacillus, Fictibacillus, Bradyrhizobium, Shinella, and Herbaspirillum. For fungi, Mortierella substituted for Fusarium in occupying an important position in different rhizocompartments under A. bidentate monoculture. Quantitative PCR analysis confirmed a significant increase in Bacillus, Pseudomonas, and Burkholderia spp. The results of the inoculation assay showed that addition of beneficial bacteria Bacillus subtilis 74 and Bacillus halodurans 75 significantly increased the root length and fresh weight of A. bidentata. Furthermore, three types of phytosterones, as the main allochemicals, were identified both in the rhizosphere soil and in culture medium under sterile conditions by LC-MS/MS. When looking at in vitro interactions, it was found that phytosterones displayed a positive interaction with dominant beneficial species (Bacillus amyloliquefaciens 4 and B. halodurans 75) and had a negative effect on the presence of the pathogenic fungi Fusarium solani and Fusarium oxysporum. Overall, this study demonstrated that consecutive monoculture of A. bidentata can alter the bacterial and fungal community by secreting root exudates, leading to recruitment of beneficial microbes and replacement of plant-specific pathogenic fungi with plant beneficial fungi.
Massive Survey on Bacterial–Bacteriophages Biodiversity and Quality of Natural Whey Starter Cultures in Trentingrana Cheese Production
Authors: Mancini Andrea , Rodriguez Maria Cid , Zago Miriam , Cologna Nicola , Goss Andrea , Carafa Ilaria , Tuohy Kieran , Merz Andrea , Franciosi Elena
Published: June 2021

This study focused on the microbial and bacteriophages identification and characterization in cheese-production facilities that use natural whey starter (NWS) cultures for Trentingrana production. Bacterial and phage screening was carried out on cooked not acidified whey and NWS samples isolated from six dairy factories, for 4 consecutive days in four different months. By means of a combined approach, using plate counts, bacterial isolation, and metataxonomic analysis Lactobacillus helveticus was found occurring as the dominant species in NWS cultures and Levilactobacillus brevis as codominant in the cheese factories where the temperature of NWS production was mainly lower than 40°C, suggesting that the variability in the parameters of the NWS culture preparation could differently modulate the bacterial species in NWS cultures. Using turbidity test approach on 303 bacterial isolates from the NWS cultures, 120 distinct phages were identified. L. helveticus phage contamination of NWS cultures was revealed in most of the analyzed samples, but despite the great recovery of bacteriophage contamination cases, the microbial quality of NWS cultures was high. Our results support the presence of natural bacteriophage resistance mechanisms in L. helveticus. The use of NWS cultures probably creates an ideal environment for the proliferation of different L. helveticus strains balanced with their phages without a clear dominance. It is evident, from this study, that the presence of a high biodiversity of NWS bacterial strains is relevant to avoid phages dominance in NWS cultures and consequently to keep a good acidification ability.
A Novel Method for Non-invasive Estimation of Primary Productivity in Aquatic Ecosystems Using a Chlorophyll Fluorescence-Induced Dynamic Curve
Authors: Chen Hui , Li Kunfeng , Xue Chunling , Wang Qiang
Published: June 2021

Photosynthetic microalgae are a major contributor to primary productivity in aquatic ecosystems, but typical measurements of their biomass and productivity are costly and relatively inefficient. The chlorophyll fluorescence induced dynamic (OJIP) curve can reflect the original photochemical reaction and the changes to the function and structure of photosystems as well as the effects of environmental factors on photosynthetic systems. Here, we present a novel method for estimating the Chl a content and photosynthetic microalgal cell density in water samples using the integral area of the OJIP curve. We identify strong linear relationships between OJIP curve integrals and both Chl a contents and cell densities for a variety of microalgal cultures and natural communities. Based on these findings, we present a non-invasive method to estimate primary productivity in aquatic ecosystems and monitor microalgal populations. We believe that this technique will allow for widespread, rapid, and inexpensive estimating of water primary productivity and monitoring of microalgal populations in natural water. This method is potentially useful in health assessment of natural water and as an early warning indicator for algal blooms.
Efficient Secretion and Recombinant Production of a Lactobacillal α-amylase in Lactiplantibacillus plantarum WCFS1: Analysis and Comparison of the Secretion Using Different Signal Peptides
Authors: Tran Anh-Minh , Unban Kridsada , Kanpiengjai Apinun , Khanongnuch Chartchai , Mathiesen Geir , Haltrich Dietmar , Nguyen Thu-Ha
Published: June 2021

Lactic acid bacteria (LAB) have been used as starter cultures and producers of enzymes, antimicrobial peptides or metabolites that contribute to the flavor, texture and safety of food products. Lactiplantibacillus plantarum, one of the best-studied LAB, is considered as safe and effective cell factory for food applications. In this study, our aim was to use L. plantarum as the producer for high levels of a food-grade lactobacillal α-amylase, which has potential applications in food, fermentation and feed industries. The native form of an α-amylase (AmyL) from L. plantarum S21, an amylolytic LAB isolated from Thai fermented rice noodles, was expressed in L. plantarum WCFS1 using the pSIP expression system. The secretion of the α-amylase was driven by the native signal peptides of the α-amylases from L. plantarum S21 (SP_AmyL) and Lactobacillus amylovorus NRRL B-4549 (SP_AmyA), as well as by three Sec-type signal peptides derived from L. plantarum WCFS1; Lp_2145, Lp_3050, and Lp_0373. Among the tested signal peptides, Lp_2145 appears to be the best signal peptide giving the highest total and extracellular enzymatic activities of α-amylase AmyL from L. plantarum S21, which were 13.1 and 8.1 kU/L of fermentation, respectively. These yields were significantly higher than the expression and secretion in L. plantarum WCFS1 using the native signal peptide SP_AmyL, resulting in 6.2- and 5.4-fold increase in total and extracellular activities of AmyL, respectively. In terms of secretion efficiency, Lp_0373 was observed as the most efficient signal peptide among non-cognate signal peptides for the secretion of AmyL. Real-time reverse-transcriptase quantitative PCR (RT-qPCR) was used to estimate the mRNA levels of α-amylase transcript in each recombinant strain. Relative quantification by RT-qPCR indicated that the strain with the Lp_2145 signal peptide-containing construct had the highest mRNA levels and that the exchange of the signal peptide led to a change in the transcript level of the target gene.
Predicting the Specificity- Determining Positions of Receptor Tyrosine Kinase Axl
Authors: Karakulak Tülay , Rifaioglu Ahmet Sureyya , Rodrigues João P. G. L. M. , Karaca Ezgi
Published: June 2021

Owing to its clinical significance, modulation of functionally relevant amino acids in protein-protein complexes has attracted a great deal of attention. To this end, many approaches have been proposed to predict the partner-selecting amino acid positions in evolutionarily close complexes. These approaches can be grouped into sequence-based machine learning and structure-based energy-driven methods. In this work, we assessed these methods’ ability to map the specificity-determining positions of Axl, a receptor tyrosine kinase involved in cancer progression and immune system diseases. For sequence-based predictions, we used SDPpred, Multi-RELIEF, and Sequence Harmony. For structure-based predictions, we utilized HADDOCK refinement and molecular dynamics simulations. As a result, we observed that (i) sequence-based methods overpredict partner-selecting residues of Axl and that (ii) combining Multi-RELIEF with HADDOCK-based predictions provides the key Axl residues, covered by the extensive molecular dynamics simulations. Expanding on these results, we propose that a sequence-structure-based approach is necessary to determine specificity-determining positions of Axl, which can guide the development of therapeutic molecules to combat Axl misregulation.