bluuebunny/crossref_metadata_2025 huggingface dataset:
The Association Between Quantitative Flow Ratio and Intravascular Imaging-defined Vulnerable Plaque Characteristics in Patients With Stable Angina and Non-ST-segment Elevation Acute Coronary Syndrome
Authors: Zuo Wenjie , Sun Renhua , Zhang Xiaoguo , Qu Yangyang , Ji Zhenjun , Su Yamin , Zhang Rui , Ma Genshan
Published: June 2021

Background: This study aimed to examine whether quantitative flow ratio (QFR), an angiography-based computation of fractional flow reserve, was associated with intravascular imaging-defined vulnerable plaque features, such as thin cap fibroatheroma (TCFA) in patients with stable angina, and non-ST-segment elevation acute coronary syndrome.

Methods: Patients undergoing optical coherence tomography (OCT) or intravascular ultrasound (IVUS) examinations were identified from two prospective studies and their interrogated vessels were assessed with QFR. Lesions in the OCT cohort were classified into tertiles: QFR-T1 (QFR ≤ 0.85), QFR-T2 (0.85 < QFR ≤ 0.93), and QFR-T3 (QFR > 0.93). Lesions in the IVUS cohort were classified dichotomously as low or high QFR groups.

Results: This post-hoc analysis included 132 lesions (83 for OCT and 49 for IVUS) from 126 patients. The prevalence of OCT-TCFA was significantly higher in QFR-T1 (50%) than in QFR-T2 (14%) and QFR-T3 (19%) (p = 0.003 and 0.018, respectively). Overall significant differences were also observed among tertiles in maximum lipid arc, thinnest fibrous cap thickness, and minimal lumen area (p = 0.017, 0.040, and <0.001, respectively). Thrombus was more prevalent in QFR-T1 (39%) than in QFR-T2 (3%), and QFR-T3 (12%) (p = 0.001 and 0.020, respectively). In the multivariable analysis, QFR ≤ 0.80 remained as a significant determinant of OCT-TCFA regardless of the presence of NSTE-ACS and the level of low-density lipoprotein cholesterol (adjusted OR: 4.387, 95% CI 1.297–14.839, p = 0.017). The diagnostic accuracy of QFR was moderate in identifying lesions with OCT-TCFA (area under the curve: 0.72, 95% CI 0.58–0.86, p = 0.003). In the IVUS cohort, significant differences were found between two groups in minimal lumen area and plaque burden but not in the distribution of virtual histology (VH)-TCFA (p = 0.025, 0.036, and 1.000, respectively).

Conclusions: Lower QFR was related to OCT-defined plaque vulnerability in angiographically mild-to-intermediate lesions. The QFR might be a useful tool for ruling out high-risk plaques without using any pressure wire or vasodilator.
Agreement Between Invasive Wire-Based and Angiography-Based Vessel Fractional Flow Reserve Assessment on Intermediate Coronary Stenoses
Authors: Chang Chun-Chin , Lee Yin-Hao , Chuang Ming-Ju , Hsueh Chien-Hung , Lu Ya-Wen , Tsai Yi-Lin , Chou Ruey-Hsing , Wu Cheng-Hsueh , Lu Tse-Min , Huang Po-Hsun , Lin Shing-Jong , van Geuns Robert-Jan
Published: June 2021

Background: Angiography-based functional assessment of coronary stenoses emerges as a novel approach to assess coronary physiology. We sought to investigate the agreement between invasive coronary wire-based fractional flow reserve (FFR), resting full-cycle ratio (RFR), and angiography-based vessel FFR (vFFR) for the functional assessment of coronary stenoses in patients with coronary artery disease.

Materials and Methods: Between Jan 01, 2018, and Dec 31, 2020, 298 patients with 385 intermediate lesions received invasive coronary wire-based functional assessment (FFR, RFR or both) at a single tertiary medical center. Coronary lesions involving ostium or left main artery were excluded. vFFR analysis was performed retrospectively based on aortic root pressure and two angiographic projections.

Results: In total, 236 patients with 291 lesions were eligible for vFFR analysis. FFR and RFR were performed in 258 and 162 lesions, respectively. The mean FFR, RFR and vFFR value were 0.84 ± 0.08, 0.90 ± 0.09, and 0.83 ± 0.10. vFFR was significantly correlated with FFR (r = 0.708, P < 0.001) and RFR (r = 0.673, P < 0.001). The diagnostic performance of vFFR vs. FFR was accuracy 81.8%, sensitivity 77.4%, specificity 83.9%, positive predictive value 69.9%, and negative predictive value 88.5%. The discriminative power of vFFR for FFR ≤ 0.80 or RFR ≤ 0.89 was excellent. Area under the receiver operating characteristic curve (AUC) was 0.87 (95% CI:0.83–0.92) for FFR and 0.80 (95% CI:0.73–0.88) for RFR.

Conclusion: Angiography-based vFFR has a substantial agreement with invasive wire-based FFR and RFR in patients with intermediate coronary stenoses. vFFR can be utilized to assess coronary physiology without a pressure wire in a post hoc manner.
Academic Self-Regulation, Chronotype and Personality in University Students During the Remote Learning Phase due to COVID-19
Authors: Staller Naomi , Großmann Nadine , Eckes Alexander , Wilde Matthias , Müller Florian H. , Randler Christoph
Published: June 2021

During the COVID-19 shutdown phase in Germany, universities stopped presence teaching and students had to turn to digital instruction. To examine their capability to cope with the changed learning situation, we assessed how basic psychological need satisfaction and frustration, motivational regulation, vitality, and self-efficacy of 228 German biology-teaching students (75% female) relate to their chronotype and personality (Big Five). Specifically, we were interested in possible effects of chronotype and personality dimensions on variables related to successful remote learning. Since the pandemic and remote learning will accompany teaching and learning at university in 2021, predictors of successful remote learning need to be identified to support student learning optimally in digital learning environments. In our study, morning-oriented, conscientious, and open students with low neuroticism seem to better cope with the shutdown environment due to vitality, self-efficacy, and partly their self-determined motivation. Moreover, our findings implicate students might need different support depending on their chronotype and personality during the digital learning phase.
Attraction of Trichogramma Wasps to Butterfly Oviposition-Induced Plant Volatiles Depends on Brassica Species, Wasp Strain and Leaf Necrosis
Authors: Afentoulis Dimitrios G. , Cusumano Antonino , Greenberg Liana O. , Caarls Lotte , Fatouros Nina E.
Published: June 2021

Within the Brassicaceae, wild as well as crop species are challenged by specialist herbivores including cabbage white butterflies (Pieris spp.). The wild crucifer Brassica nigra responds to oviposition by Pieris butterflies by the synergistic expression of two egg-killing traits. Genotypes that express a hypersensitive response (HR)-like necrosis (direct egg-killing) also emit oviposition-induced plant volatiles (OIPVs) attracting Trichogramma egg parasitoids (indirect egg-killing). This so-called double defense line can result in high butterfly egg mortalities. It remains unknown whether this strategy is unique to B. nigra or more common in Brassica species. To test this, we examined the response of different Trichogramma evanescens lines to OIPVs emitted by B. nigra and three close relatives (Brassica napus, Brassica rapa, and Brassica oleracea). Furthermore, we evaluated whether HR-like necrosis played a role in the attraction toward plant volatiles. Our results show a specificity in wasp attraction to different plant species. Three out of four plant species attracted a specific T. evanescens strain, including the crops B. rapa and B. napus. Parasitoid attraction was positively affected by presence of HR-like necrosis in one plant species. Our findings imply that, despite being a true generalist in terms of host range, T. evanescens shows intraspecific variation during host searching, which should be taken into account when selecting parasitoid lines for biocontrol of certain crops. Finally, we conclude that also crop plants within the Brassicaceae family possess egg-killing traits and can exert the double-defense line which may enable effective selection of egg-killing defense traits by cabbage breeders.
ACP-DA: Improving the Prediction of Anticancer Peptides Using Data Augmentation
Authors: Chen Xian-gan , Zhang Wen , Yang Xiaofei , Li Chenhong , Chen Hengling
Published: June 2021

Anticancer peptides (ACPs) have provided a promising perspective for cancer treatment, and the prediction of ACPs is very important for the discovery of new cancer treatment drugs. It is time consuming and expensive to use experimental methods to identify ACPs, so computational methods for ACP identification are urgently needed. There have been many effective computational methods, especially machine learning-based methods, proposed for such predictions. Most of the current machine learning methods try to find suitable features or design effective feature learning techniques to accurately represent ACPs. However, the performance of these methods can be further improved for cases with insufficient numbers of samples. In this article, we propose an ACP prediction model called ACP-DA (Data Augmentation), which uses data augmentation for insufficient samples to improve the prediction performance. In our method, to better exploit the information of peptide sequences, peptide sequences are represented by integrating binary profile features and AAindex features, and then the samples in the training set are augmented in the feature space. After data augmentation, the samples are used to train the machine learning model, which is used to predict ACPs. The performance of ACP-DA exceeds that of existing methods, and ACP-DA achieves better performance in the prediction of ACPs compared with a method without data augmentation. The proposed method is available at http://github.com/chenxgscuec/ACPDA.
Lymphocyte-Related Immunological Indicators for Stratifying Mycobacterium tuberculosis Infection
Authors: Luo Ying , Xue Ying , Tang Guoxing , Cai Yimin , Yuan Xu , Lin Qun , Song Huijuan , Liu Wei , Mao Liyan , Zhou Yu , Chen Zhongju , Zhu Yaowu , Liu Weiyong , Wu Shiji , Wang Feng , Sun Ziyong
Published: June 2021

Background

Easily accessible tools that reliably stratify Mycobacterium tuberculosis (MTB) infection are needed to facilitate the improvement of clinical management. The current study attempts to reveal lymphocyte-related immune characteristics of active tuberculosis (ATB) patients and establish immunodiagnostic model for discriminating ATB from latent tuberculosis infection (LTBI) and healthy controls (HC).

Methods

A total of 171 subjects consisted of 54 ATB, 57 LTBI, and 60 HC were consecutively recruited at Tongji hospital from January 2019 to January 2021. All participants were tested for lymphocyte subsets, phenotype, and function. Other examination including T-SPOT and microbiological detection for MTB were performed simultaneously.

Results

Compared with LTBI and HC, ATB patients exhibited significantly lower number and function of lymphocytes including CD4+ T cells, CD8+ T cells and NK cells, and significantly higher T cell activation represented by HLA-DR and proportion of immunosuppressive cells represented by Treg. An immunodiagnostic model based on the combination of NK cell number, HLA-DR+CD3+ T cells, Treg, CD4+ T cell function, and NK cell function was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.920 (95% CI, 0.867-0.973) in distinguishing ATB from LTBI, while the cut-off value of 0.676 produced a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and specificity of 91.23% (95% CI, 81.06%-96.20%). Meanwhile, AUC analysis between ATB and HC according to the diagnostic model was 0.911 (95% CI, 0.855-0.967), with a sensitivity of 81.48% (95% CI, 69.16%-89.62%) and a specificity of 90.00% (95% CI, 79.85%-95.34%).

Conclusions

Our study demonstrated that the immunodiagnostic model established by the combination of lymphocyte-related indicators could facilitate the status differentiation of MTB infection.
Increased Frequency of Activated Switched Memory B Cells and Its Association With the Presence of Pulmonary Fibrosis in Diffuse Cutaneous Systemic Sclerosis Patients
Authors: Simon Diána , Balogh Péter , Erdő-Bonyár Szabina , Böröcz Katalin , Minier Tünde , Czirják László , Berki Tímea
Published: June 2021

Disease-associated, high-affinity pathological autoantibody production is a well-described consequence of immune dysregulation affecting B cells in systemic sclerosis (SSc), including the distribution of B-cell subsets. We have previously shown that the increased relative frequency of CD19+CD27+IgD− switched memory B cells is associated with the severe form of SSc. This study sought to analyze memory B cell subsets using an extended range of markers for further subdivision based on CD19, IgD, CD27, CD38 and CD95 phenotype, to define relationship between the alterations of memory B cell subsets and the clinical features of SSc. Peripheral blood samples were obtained from 21 SSc patients, including 14 diffuse (dcSSc) and 7 limited (lcSSc) cutaneous SSc patients, with disease duration of 2.7 ( ± 1.6) years. After purification of CD19+ B cells, multiparametric flow cytometry was performed and the frequencies of CD19+IgD−CD27−CD38+ double negative (DN) 1, CD19+IgDloCD27+CD38+ unswitched, CD19+IgD−CD27+CD38+CD95− resting switched and CD19+IgD−CD27+CD38−CD95+ activated switched memory (ASM) B cells were determined, and correlated with clinical features of SSc. The dcSSc patients had a higher frequency of ASM B cells (p = 0.028) compared to lcSSc patients. The percentage of ASM B cells was elevated in anti-Scl-70 (anti-topoisomerase I) antibody positive patients compared to negative patients (p = 0.016). Additionally, the frequency of ASM B cells was also increased in patients with pulmonary fibrosis (p = 0.003) suggesting that patients with severe form of SSc have higher ASM B cell ratios. Furthermore, the ratio of DN1 B cells was decreased (p = 0.029), while the level of anti-citrate synthase IgG natural autoantibody was elevated (p = 0.028) in patients with active disease. Our observations on the increase of ASM B cells in dcSSc and in patients with pulmonary fibrosis may point to the association of this alteration with the severe form of the disease. Functionally the correlation of ASM B cells as effector memory-plasma cell precursors with anti-topoisomerase I antibody positivity could reflect their contribution to pathological autoantibody production, whereas the decrease of memory precursor DN B cells and the increase of anti-citrate synthase IgG autoantibody may have potential significance in the assessment of disease activity.
T-Cell Mediated Inflammation in Postmenopausal Osteoporosis
Authors: Wu Di , Cline-Smith Anna , Shashkova Elena , Perla Ajit , Katyal Aditya , Aurora Rajeev
Published: June 2021

Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause – the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.
Comparison of Surrogate Markers of the Type I Interferon Response and Their Ability to Mirror Disease Activity in Systemic Lupus Erythematosus
Authors: Enocsson Helena , Wetterö Jonas , Eloranta Maija-Leena , Gullstrand Birgitta , Svanberg Cecilia , Larsson Marie , Bengtsson Anders A. , Rönnblom Lars , Sjöwall Christopher
Published: June 2021

Objectives

Type I interferons (IFNs) are central and reflective of disease activity in systemic lupus erythematosus (SLE). However, IFN-α levels are notoriously difficult to measure and the type I IFN gene signature (IGS) is not yet available in clinical routine. This study evaluates galectin-9 and an array of chemokines/cytokines in their potential as surrogate markers of type I IFN and/or SLE disease activity.

Methods

Healthy controls and well-characterized Swedish SLE patients from two cross-sectional cohorts (n=181; n=59) were included, and a subgroup (n=21) was longitudinally followed. Chemokine/cytokine responses in immune complex triggered IFN-α activity was studied in healthy donor peripheral blood mononuclear cells (PBMC). Levels of chemokines/cytokines and galectin-9 were measured by immunoassays. Gene expression was quantified by qPCR.

Results

The IGS was significantly (p<0.01) correlated with galectin-9 (rho=0.54) and CXCL10 (rho=0.37) levels whereas serum IFN-α correlated with galectin-9 (rho=0.36), CXCL10 (rho=0.39), CCL19 (rho=0.26) and CCL2 (rho=0.19). The strongest correlation was observed between galectin-9 and TNF (rho=0.56). IFN-α and disease activity (SLEDAI-2K) were correlated (rho=0.20) at cross-sectional analysis, but no significant associations were found between SLEDAI-2K and galectin-9 or chemokines. Several inflammatory mediators increased at disease exacerbation although CCL19, CXCL11, CXCL10, IL-10 and IL-1 receptor antagonist were most pronounced. Immune complex-stimulation of PBMC increased the production of CCL2, CXCL8 and TNF.

Conclusion

Galectin-9 and CXCL10 were associated with type I IFN in SLE but correlated stronger with TNF. None of the investigated biomarkers showed a convincing association with disease activity, although CXCL10 and CCL19 performed best in this regard.
Immunogenicity of COVID-19 Tozinameran Vaccination in Patients on Chronic Dialysis
Authors: Schrezenmeier Eva , Bergfeld Leon , Hillus David , Lippert Joerg-Detlev , Weber Ulrike , Tober-Lau Pinkus , Landgraf Irmgard , Schwarz Tatjana , Kappert Kai , Stefanski Ana-Luisa , Sattler Arne , Kotsch Katja , Dörner Thomas , Sander Leif Erik , Budde Klemens , Halleck Fabian , Kurth Florian , Corman Victor Max , Choi Mira
Published: June 2021

Patients with kidney failure have notoriously weak responses to common vaccines. Thus, immunogenicity of novel SARS-CoV-2 vaccines might be impaired in this group. To determine immunogenicity of SARS-CoV-2 vaccination in patients with chronic dialysis, we analyzed the humoral and T-cell response after two doses of mRNA vaccine Tozinameran (BNT162b2 BioNTech/Pfizer). This observational study included 43 patients on dialysis before vaccination with two doses of Tozinameran 21 days apart. Overall, 36 patients completed the observation period until three weeks after the second dose and 32 patients were further analyzed at week 10. Serum samples were analyzed by SARS-CoV-2 specific IgG and IgA antibodies ~1, ~3–4 and ~10 weeks after the second vaccination. In addition, SARS-CoV-2-specific T-cell responses were assessed at ~3–4 weeks by an interferon-gamma release assay (IGRA). Antibody and T cell outcomes at this timepoint were compared to a group of 44 elderly patients not on dialysis, after immunization with Tozinameran. Median age of patients on chronic dialysis was 74.0 years (IQR 66.0, 82.0). The proportion of males was higher (69.4%) than females. Only 20/36 patients (55.6%, 95%CI: 38.29–71.67) developed SARS-CoV-2-IgG antibodies at the first sampling, whereas 32/36 patients (88.9%, 95%CI: 73.00–96.38) demonstrated IgG detection at the second sampling. In a longitudinal follow-up at ~10 weeks after the second dose, the proportion of dialysis patients reactive for anti-SARS-CoV-2-IgG decreased to 27/32 (84.37%, 95%CI: 66.46–94.10) The proportion of anti-SARS-CoV-2 S1 IgA decreased from 33/36 (91.67%; 95%CI: 76.41–97.82) at weeks 3–4 down to 19/32 (59.38; 95%CI: 40.79–75.78). Compared to a cohort of vaccinees with similar age but not on chronic dialysis seroconversion rates and antibody titers were significantly lower. SARS-CoV-2-specific T-cell responses 3 weeks after second vaccination were detected in 21/31 vaccinated dialysis patients (67.7%, 95%CI: 48.53–82.68) compared to 42/44 (93.3%, 95%CI: 76.49–98.84) in controls of similar age. Patients on dialysis demonstrate a delayed, but robust immune response three to four weeks after the second dose, which indicates effective vaccination of this vulnerable group. However, the lower immunogenicity of Tozinameran in these patients needs further attention to develop potential countermeasures such as an additional booster vaccination.
Regulatory B Cells (Bregs) Inhibit Osteoclastogenesis and Play a Potential Role in Ameliorating Ovariectomy-Induced Bone Loss
Authors: Sapra Leena , Bhardwaj Asha , Mishra Pradyumna Kumar , Garg Bhavuk , Verma Bhupendra , Mishra Gyan C. , Srivastava Rupesh K.
Published: June 2021

Increasing evidence in recent years has suggested that regulatory B cells (Bregs) are one of the crucial modulators in various inflammatory disease conditions. However, no study to date has investigated the significance of Bregs in modulating osteoclastogenesis. To the best of our knowledge, in the present study, we for the first time examined the anti-osteoclastogenic potential of Bregs under in vitro conditions and observed that Bregs suppress RANKL-induced osteoclastogenesis in a dose-dependent manner. We further elucidated the mechanism behind the observed suppression of osteoclasts differentiation via Bregs. Our results clearly suggested that the observed anti-osteoclastogenic property of Bregs is mediated via the production of IL-10 cytokine. Next, we explored whether Bregs have any role in mediating inflammatory bone loss under post-menopausal osteoporotic conditions in ovx mice. Remarkably, our in vivo data clearly suggest that the frequencies of both CD19+IL-10+ Bregs and CD19+CD1dhiCD5+IL-10+ “B10” Bregs were significantly reduced in case of osteoporotic mice model. Moreover, we also found a significant reduction in serum IL-10 cytokine levels in osteoporotic mice, thereby further supporting our observations. Taken together, the present study for the first time establishes the direct role of regulatory B cells in modulating osteoclastogenesis in vitro. Further, our in vivo data suggest that modulations in the percentage of Bregs population along with its reduced potential to produce IL-10 might further exacerbate the observed bone loss in ovx mice.
Serum Amyloid A1 Induces Classically Activated Macrophages: A Role for Enhanced Fibril Formation
Authors: Gaiser Ann-Kathrin , Bauer Shanna , Ruez Stephanie , Holzmann Karlheinz , Fändrich Marcus , Syrovets Tatiana , Simmet Thomas
Published: June 2021

AA amyloidosis belongs to the group of amyloid diseases which can follow chronic inflammatory conditions of various origin. The disease is characterized by the deposition of insoluble amyloid fibrils formed by serum amyloid A1 (SAA1) leading eventually to organ failure. Macrophages are intimately involved in the fibrillogenesis as well as in the clearance of amyloid fibrils. In vivo, macrophages may occur as classically (M1) or alternatively activated (M2) macrophages. We investigate here how SAA1 might affect the macrophage phenotype and function. Gene microarray analysis revealed upregulation of 64 M1-associated genes by SAA1. M1-like polarization was further confirmed by the expression of the M1-marker MARCO, activation of the NF-κB transcription factor, and secretion of the M1-cytokines TNF-α, IL-6, and MCP-1. Additionally, we demonstrate here that M1-polarized macrophages exhibit enhanced fibrillogenic activity towards SAA1. Based on our data, we propose reconsideration of the currently used cellular amyloidosis models towards an in vitro model employing M1-polarized macrophages. Furthermore, the data suggest macrophage repolarization as potential intervention strategy in AA amyloidosis.
Th2 Modulation of Transient Receptor Potential Channels: An Unmet Therapeutic Intervention for Atopic Dermatitis
Authors: Meng Jianghui , Li Yanqing , Fischer Michael J. M. , Steinhoff Martin , Chen Weiwei , Wang Jiafu
Published: June 2021

Atopic dermatitis (AD) is a multifaceted, chronic relapsing inflammatory skin disease that affects people of all ages. It is characterized by chronic eczema, constant pruritus, and severe discomfort. AD often progresses from mild annoyance to intractable pruritic inflammatory lesions associated with exacerbated skin sensitivity. The T helper-2 (Th2) response is mainly linked to the acute and subacute phase, whereas Th1 response has been associated in addition with the chronic phase. IL-17, IL-22, TSLP, and IL-31 also play a role in AD. Transient receptor potential (TRP) cation channels play a significant role in neuroinflammation, itch and pain, indicating neuroimmune circuits in AD. However, the Th2-driven cutaneous sensitization of TRP channels is underappreciated. Emerging findings suggest that critical Th2-related cytokines cause potentiation of TRP channels, thereby exaggerating inflammation and itch sensation. Evidence involves the following: (i) IL-13 enhances TRPV1 and TRPA1 transcription levels; (ii) IL-31 sensitizes TRPV1 via transcriptional and channel modulation, and indirectly modulates TRPV3 in keratinocytes; (iii) The Th2-cytokine TSLP increases TRPA1 synthesis in sensory neurons. These changes could be further enhanced by other Th2 cytokines, including IL-4, IL-25, and IL-33, which are inducers for IL-13, IL-31, or TSLP in skin. Taken together, this review highlights that Th2 cytokines potentiate TRP channels through diverse mechanisms under different inflammatory and pruritic conditions, and link this effect to distinct signaling cascades in AD. This review strengthens the notion that interrupting Th2-driven modulation of TRP channels will inhibit transition from acute to chronic AD, thereby aiding the development of effective therapeutics and treatment optimization.
Beyond Just Peptide Antigens: The Complex World of Peptide-Based Cancer Vaccines
Authors: Stephens Alexander J. , Burgess-Brown Nicola A. , Jiang Shisong
Published: June 2021

Peptide-based cancer vaccines rely upon the strong activation of the adaptive immune response to elicit its effector function. They have shown to be highly specific and safe, but have yet to prove themselves as an efficacious treatment for cancer in the clinic. This is for a variety of reasons, including tumour heterogeneity, self-tolerance, and immune suppression. Importance has been placed on the overall design of peptide-based cancer vaccines, which have evolved from simple peptide derivatives of a cancer antigen, to complex drugs; incorporating overlapping regions, conjugates, and delivery systems to target and stimulate different components of antigen presenting cells, and to bolster antigen cross-presentation. Peptide-based cancer vaccines are increasingly becoming more personalised to an individual’s tumour antigen repertoire and are often combined with existing cancer treatments. This strategy ultimately aids in combating the shortcomings of a more generalised vaccine strategy and provides a comprehensive treatment, taking into consideration cancer cell variability and its ability to avoid immune interrogation.
Dysregulation of the Immune Environment in the Airways During HIV Infection
Authors: Bunjun Rubina , Soares Andreia P. , Thawer Narjis , Müller Tracey L. , Kiravu Agano , Ginbot Zekarias , Corleis Björn , Murugan Brandon D. , Kwon Douglas S. , von Groote-Bidlingmaier Florian , Riou Catherine , Wilkinson Robert J. , Walzl Gerhard , Burgers Wendy A.
Published: June 2021

HIV-1 increases susceptibility to pulmonary infection and disease, suggesting pathogenesis in the lung. However, the lung immune environment during HIV infection remains poorly characterized. This study examined T cell activation and the cytokine milieu in paired bronchoalveolar lavage (BAL) and blood from 36 HIV-uninfected and 32 HIV-infected participants. Concentrations of 27 cytokines were measured by Luminex, and T cells were phenotyped by flow cytometry. Blood and BAL had distinct cytokine profiles (p=0.001). In plasma, concentrations of inflammatory cytokines like IFN-γ (p=0.004) and TNF-α (p=0.004) were elevated during HIV infection, as expected. Conversely, BAL cytokine concentrations were similar in HIV-infected and uninfected individuals, despite high BAL viral loads (VL; median 48,000 copies/ml epithelial lining fluid). HIV-infected individuals had greater numbers of T cells in BAL compared to uninfected individuals (p=0.007); and BAL VL positively associated with CD4+ and CD8+ T cell numbers (p=0.006 and p=0.0002, respectively) and CXCL10 concentrations (p=0.02). BAL T cells were highly activated in HIV-infected individuals, with nearly 2-3 fold greater frequencies of CD4+CD38+ (1.8-fold; p=0.007), CD4+CD38+HLA-DR+ (1.9-fold; p=0.0006), CD8+CD38+ (2.8-fold; p=0.0006), CD8+HLA-DR+ (2-fold; p=0.022) and CD8+CD38+HLA-DR+ (3.6-fold; p<0.0001) cells compared to HIV-uninfected individuals. Overall, this study demonstrates a clear disruption of the pulmonary immune environment during HIV infection, with readily detectable virus and activated T lymphocytes, which may be driven to accumulate by local chemokines.
Influence of the Calcium Carbonate Shell of Coccolithophores on Ingestion and Growth of a Dinoflagellate Predator
Authors: Haunost Mathias , Riebesell Ulf , D’Amore Francesco , Kelting Ole , Bach Lennart T.
Published: June 2021

Coccolithophores are an important group of ∼200 marine phytoplankton species which cover themselves with a calcium carbonate shell called “coccosphere.” Coccolithophores are ecologically and biogeochemically important but the reason why they calcify remains elusive. One key function may be that the coccosphere offers protection against microzooplankton predation, which is one of the main causes of phytoplankton death in the ocean. Here, we investigated the effect of the coccosphere on ingestion and growth of the heterotrophic dinoflagellate Oxyrrhis marina. Calcified and decalcified cells of the coccolithophore species Emiliania huxleyi, Pleurochrysis carterae, and Gephyrocapsa oceanica were offered separately to the predator as well as in an initial ∼1:1 mixture. The decrease of the prey concentrations and predator abundances were monitored over a period of 48–72 h. We found that O. marina did not actively select against calcified cells, but rather showed a size selective feeding behavior. Thus, the coccosphere does not provide a direct protection against grazing by O. marina. However, O. marina showed slower growth when calcified coccolithophores were fed. This could be due to reduced digestion rates of calcified cells and/or increased swimming efforts when ballasted with heavy calcium carbonate. Furthermore, we show that the coccosphere reduces the ingestion capacity simply by occupying much of the intracellular space of the predator. We speculate that the slower growth of the grazer when feeding on calcified cells is of limited benefit to the coccolithophore population because other co-occurring phytoplankton species within the community that do not invest energy in the formation of a calcite shell could also benefit from the reduced growth of the predators. Altogether, these new insights constitute a step forward in our understanding of the ecological relevance of calcification in coccolithophores.
Early Detection of Legionella pneumophila and Aspergillus by mNGS in a Critically Ill Patient With Legionella Pneumonia After Extracorporeal Membrane Oxygenation Treatment: Case Report and Literature Review
Authors: Yue Ruiming , Wu Xiaoxiao , Li Tianlong , Chang Li , Huang Xiaobo , Pan Lingai
Published: June 2021

Legionella pneumophilacan cause pneumonia, leading to severe acute respiratory distress syndrome (ARDS). Because of its harsh growth requirements, limited detection methods, and non-specific clinical manifestations, diagnosingLegionellapneumonia remains still challenging. Metagenomic next-generation sequencing (mNGS) technology has increased the rate of detection ofLegionella. This study describes a patient who rapidly progressed to severe ARDS during the early stage of infection and was treated with extracorporeal membrane oxygenation (ECMO). Although his bronchoalveolar lavage fluid (BALF) was negative for infection and his serum was negative for anti-Legionellaantibody, mNGS of his BALF and blood showed only the presence ofLegionella pneumophila(blood mNGS reads 229, BALF reads 656). After antibiotic treatment and weaning from ECMO, however, he developed a secondaryAspergillusandKlebsiella pneumoniaeinfection as shown by mNGS. Mechanical ventilation and antibiotic treatment were effective. A search of PubMed showed few reports of secondaryAspergillusinfections afterLegionellainfection. Severe pneumonia caused by any type of pathogenic bacteria may be followed byAspergillusinfection, sometimes during extremely early stages of infection. Patients with severe pneumonia caused byLegionellainfection should undergo early screening for secondary infections using methods such as mNGS, enabling early and precise treatment, thereby simplifying the use of antibiotics and improving patient prognosis.
Malaria in Europe: A Historical Perspective
Authors: Boualam Mahmoud A. , Pradines Bruno , Drancourt Michel , Barbieri Rémi
Published: June 2021

Endemic malaria, which claimed 229 million new cases and 409,000 deaths in 2019 mainly in Africa, was eradicated from Europe by the mid-20th century. Historical descriptions of intermittent tertian and quartan fever reported in texts of Hippocrates in Greece and Celsus in Italy suggest malaria. A few paleomicrobiology investigations have confirmed the presence of malarial parasite Plasmodium falciparum in 1st, 2nd, and 5th century infected individuals in diverse regions of Italy, and Plasmodium sp. later in Bavaria. The causative Plasmodium pathogens, discovered in the 19th century in Algeria, were controversially used as therapeutic agents in the European pharmacopeia more than two centuries after effective quinine-based treatments had been introduced in Europe. How Europe managed to eradicate malaria and what the history of malaria was in Europe are of medical interest, and this review traces research pathways for a renewed understanding of malaria eradication in Europe through combined historical and paleomicrobiological investigations.
The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms
Authors: Salvatore Teresa , Pafundi Pia Clara , Galiero Raffaele , Albanese Gaetana , Di Martino Anna , Caturano Alfredo , Vetrano Erica , Rinaldi Luca , Sasso Ferdinando Carlo
Published: June 2021

Individuals with diabetes mellitus (DM) disclose a higher incidence and a poorer prognosis of heart failure (HF) than non-diabetic people, even in the absence of other HF risk factors. The adverse impact of diabetes on HF likely reflects an underlying “diabetic cardiomyopathy” (DM–CMP), which may by exacerbated by left ventricular hypertrophy and coronary artery disease (CAD). The pathogenesis of DM-CMP has been a hot topic of research since its first description and is still under active investigation, as a complex interplay among multiple mechanisms may play a role at systemic, myocardial, and cellular/molecular levels. Among these, metabolic abnormalities such as lipotoxicity and glucotoxicity, mitochondrial damage and dysfunction, oxidative stress, abnormal calcium signaling, inflammation, epigenetic factors, and others. These disturbances predispose the diabetic heart to extracellular remodeling and hypertrophy, thus leading to left ventricular diastolic and systolic dysfunction. This Review aims to outline the major pathophysiological changes and the underlying mechanisms leading to myocardial remodeling and cardiac functional derangement in DM-CMP.
Calcium Phosphate-Based Bioceramics in the Treatment of Osteosarcoma: Drug Delivery Composites and Magnetic Hyperthermia Agents
Authors: Oliveira Tiê Menezes , Berti Fernanda Costa Brandão , Gasoto Sidney Carlos , Schneider Bertoldo , Stimamiglio Marco Augusto , Berti Lucas Freitas
Published: June 2021

The use of biomaterials in medicine is not recent, and in the last few decades, the research and development of biocompatible materials had emerged. Hydroxyapatite (HAp), a calcium phosphate that constitutes a large part of the inorganic composition of human bones and teeth, has been used as an interesting bioceramic material. Among its applications, HAp has been used to carry antitumor drugs, such as doxorubicin, cisplatin, and gemcitabine. Such HAp-based composites have an essential role in anticancer drug delivery systems, including the treatment of osteosarcoma. In addition, the association of this bioceramic with magnetic nanoparticles (MNPs) has also been used as an effective agent of local magnetic hyperthermia. Further, the combined approach of the aforementioned techniques (HAp scaffolds combined with anti-tumor drugs and MNPs) is also an attractive therapeutical alternative. Considering the promising role of the use of bioceramics in modern medicine, we proposed this review, presenting an updated perspective on the use of HAp in the treatment of cancer, especially osteosarcoma. Finally, after giving the current progress in this field, we highlight the urgent need for efforts to provide a better understanding of their potential applications.
Mining Public Metagenomes for Environmental Surveillance of Parasites: A Proof of Principle
Authors: Franssen Frits F. J. , Janse Ingmar , Janssen Dennis , Caccio Simone M. , Vatta Paolo , van der Giessen Joke W. B. , van Passel Mark W. J.
Published: June 2021

Parasites often have complex developmental cycles that account for their presence in a variety of difficult-to-analyze matrices, including feces, water, soil, and food. Detection of parasites in these matrices still involves laborious methods. Untargeted sequencing of nucleic acids extracted from those matrices in metagenomic projects may represent an attractive alternative method for unbiased detection of these pathogens. Here, we show how publicly available metagenomic datasets can be mined to detect parasite specific sequences, and generate data useful for environmental surveillance. We use the protozoan parasite Cryptosporidium parvum as a test organism, and show that detection is influenced by the reference sequence chosen. Indeed, the use of the whole genome yields high sensitivity but low specificity, whereas specificity is improved through the use of signature sequences. In conclusion, querying metagenomic datasets for parasites is feasible and relevant, but requires optimization and validation. Nevertheless, this approach provides access to the large, and rapidly increasing, number of datasets from metagenomic and meta-transcriptomic studies, allowing unlocking hitherto idle signals of parasites in our environments.
Application of 23 Novel Serological Markers for Identifying Recent Exposure to Plasmodium vivax Parasites in an Endemic Population of Western Thailand
Authors: Chotirat Sadudee , Nekkab Narimane , Kumpitak Chalermpon , Hietanen Jenni , White Michael T. , Kiattibutr Kirakorn , Sa-angchai Patiwat , Brewster Jessica , Schoffer Kael , Takashima Eizo , Tsuboi Takafumi , Harbers Matthias , Chitnis Chetan E. , Healer Julie , Tham Wai-Hong , Nguitragool Wang , Mueller Ivo , Sattabongkot Jetsumon , Longley Rhea J.
Published: June 2021

Thailand is aiming for malaria elimination by the year 2030. However, the high proportion of asymptomatic infections and the presence of the hidden hypnozoite stage of Plasmodium vivax are impeding these efforts. We hypothesized that a validated surveillance tool utilizing serological markers of recent exposure to P. vivax infection could help to identify areas of ongoing transmission. The objective of this exploratory study was to assess the ability of P. vivax serological exposure markers to detect residual transmission “hot-spots” in Western Thailand. Total IgG levels were measured against a panel of 23 candidate P. vivax serological exposure markers using a multiplexed bead-based assay. A total of 4,255 plasma samples from a cross-sectional survey conducted in 2012 of endemic areas in the Kanchanaburi and Ratchaburi provinces were assayed. We compared IgG levels with multiple epidemiological factors that are associated with an increased risk of P. vivax infection in Thailand, including age, gender, and spatial location, as well as Plasmodium infection status itself. IgG levels to all proteins were significantly higher in the presence of a P. vivax infection (n = 144) (T-test, p < 0.0001). Overall seropositivity rates varied from 2.5% (PVX_097625, merozoite surface protein 8) to 16.8% (PVX_082670, merozoite surface protein 7), with 43% of individuals seropositive to at least 1 protein. Higher IgG levels were associated with older age (>18 years, p < 0.05) and males (17/23 proteins, p < 0.05), supporting the paradigm that men have a higher risk of infection than females in this setting. We used a Random Forests algorithm to predict which individuals had exposure to P. vivax parasites in the last 9-months, based on their IgG antibody levels to a panel of eight previously validated P. vivax proteins. Spatial clustering was observed at the village and regional level, with a moderate correlation between PCR prevalence and sero-prevalence as predicted by the algorithm. Our data provides proof-of-concept for application of such surrogate markers as evidence of recent exposure in low transmission areas. These data can be used to better identify geographical areas with asymptomatic infection burdens that can be targeted in elimination campaigns.
Effect of Protein O-Mannosyltransferase (MSMEG_5447) on M. smegmatis and Its Survival in Macrophages
Authors: Jia Liqiu , Sha Shanshan , Yang Shufeng , Taj Ayaz , Ma Yufang
Published: June 2021

Protein O-mannosyltransferase (PMT) catalyzes an initial step of protein O-mannosylation of Mycobacterium tuberculosis (Mtb) and plays a crucial role for Mtb survival in the host. To better understand the role of PMT in the host innate immune response during mycobacterial infection, in this study, we utilized Mycobacterium smegmatis pmt (MSMEG_5447) gene knockout strain, ΔM5447, to infect THP-1 cells. Our results revealed that the lack of MSMEG_5447 not only impaired the growth of M. smegmatis in 7H9 medium but also reduced the resistance of M. smegmatis against lysozyme and acidic stress in vitro. Macrophage infection assay showed that ΔM5447 displayed attenuated growth in macrophages at 24 h post-infection. The production of TNF-α and IL-6 and the activation of transcription factor NF-κB were decreased in ΔM5447-infected macrophages, which were further confirmed by transcriptomic analysis. Moreover, ΔM5447 failed to inhibit phagosome–lysosome fusion in macrophages. These findings revealed that PMT played a role in modulating the innate immune responses of the host, which broaden our understanding for functions of protein O-mannosylation in mycobacterium–host interaction.
Characterizing Expression and Regulation of Gamma-Herpesviral Circular RNAs
Authors: Tagawa Takanobu , Oh Daniel , Santos Jerico , Dremel Sarah , Mahesh Guruswamy , Uldrick Thomas S. , Yarchoan Robert , Kopardé Vishal N. , Ziegelbauer Joseph M.
Published: June 2021

Multiple herpesviruses have been recently found to encode viral circular RNAs. Like cellular circular RNAs, these RNAs lack poly-A tails and their 5′ and 3′ ends have been joined, which confers protection from RNA exonucleases. We examined the expression patterns of circular RNAs from Kaposi’s sarcoma herpesvirus (KSHV) in various environments. We performed deep sequencing of circRNA-enriched total RNA from a KSHV-positive patient lymph node for comparison with previous circRNA-Seq results. We found that circvIRF4 is highly expressed in the KSHV-positive patient sample relative to both B cell lines and de novo infected primary vascular and lymphatic endothelial cells (LECs). Overall, this patient sample showed a viral circRNA expression pattern more similar to the pattern from B cell lines, but we also discovered new back-spliced junctions and additional viral circular RNAs in this patient sample. We validated some of these back-spliced junctions as circular RNAs with standard assays. Differential expression patterns of circular RNAs in different cell types led us to investigate what cellular factors might be influencing the ratio of viral linear mRNAs to circular RNAs. We found that repression of certain RNA-binding proteins shifted the balance between viral linear mRNAs and circular RNAs. Taken together, examining viral circular RNA expression patterns may become useful tools for discovering their functions, the regulators of their expression, and determining the stage and cell types of infection in humans.
Profiling the Virulence and Antibiotic Resistance Genes of Cronobacter sakazakii Strains Isolated From Powdered and Dairy Formulas by Whole-Genome Sequencing
Authors: Parra-Flores Julio , Holý Ondrej , Riffo Francisca , Lepuschitz Sarah , Maury-Sintjago Eduard , Rodríguez-Fernández Alejandra , Cruz-Córdova Ariadnna , Xicohtencatl-Cortes Juan , Mancilla-Rojano Jetsi , Troncoso Miriam , Figueroa Guillermo , Ruppitsch Werner , Forsythe Stephen
Published: June 2021

Cronobacter sakazakii is an enteropathogen that causes neonatal meningitis, septicemia, and necrotizing enterocolitis in preterm infants and newborns with a mortality rate of 15 to 80%. Powdered and dairy formulas (P-DF) have been implicated as major transmission vehicles and subsequently the presence of this pathogen in P-DF led to product recalls in Chile in 2017. The objective of this study was to use whole genome sequencing (WGS) and laboratory studies to characterize Cronobacter strains from the contaminated products. Seven strains were identified as C. sakazakii, and the remaining strain was Franconibacter helveticus. All C. sakazakii strains adhered to a neuroblastoma cell line, and 31 virulence genes were predicted by WGS. The antibiograms varied between strains. and included mcr-9.1 and blaCSA genes, conferring resistance to colistin and cephalothin, respectively. The C. sakazakii strains encoded I-E and I-F CRISPR-Cas systems, and carried IncFII(pECLA), Col440I, and Col(pHHAD28) plasmids. In summary, WGS enabled the identification of C. sakazakii strains and revealed multiple antibiotic resistance and virulence genes. These findings support the decision to recall the contaminated powdered and dairy formulas from the Chilean market in 2017.
Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit
Authors: Bernier Louis-Philippe , Brunner Clément , Cottarelli Azzurra , Balbi Matilde
Published: June 2021

The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.