bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a novel cord blood NK cell subpopulation expressing functional programmed death receptor-1
Authors: Greppi Marco , Obino Valentina , Goda Rayan , Rebaudi Federico , Carlomagno Simona , Della Chiesa Mariella , Sivori Simona , Ubezio Gianluca , Agostini Vanessa , Bo Alessandra , Pesce Silvia , Marcenaro Emanuela
Published: June 2023

Background

Natural Killer cells (NKs) represent the innate counterpart of TCRαβ lymphocytes and are characterized by a high anti-tumor and an anti-viral cytotoxic activity. Recently, it has been demonstrated that NKs can express PD-1 as an additional inhibitory receptor. Specifically, PD-1 was identified on a subpopulation of terminally differentiated NKs from healthy adults with previous HCMV infection. So far it is unknown whether PD-1 appears during NK-cell development and whether this process is directly or indirectly related to HCMV infection.

Methods

In this study, we analyzed the expression and function of PD-1 on Cord Blood derived NKs (CB-NKs) on a large cohort of newborns through multiparametric cytofluorimetric analysis.

Results

We identified PD-1 on CB-NKs in more than of half the newborns analyzed. PD-1 was present on CD56dim NKs, and particularly abundant on CD56neg NKs, but only rarely present on CD56bright NKs. Importantly, unlike in adult healthy donors, in CB-NKs PD-1 is co-expressed not only with KIR, but also with NKG2A. PD-1 expression was independent of HCMV mother seropositivity and occurs in the absence of HCMV infection/reactivation during pregnancy. Notably, PD-1 expressed on CB-NKs was functional and mediated negative signals when triggered.

Conclusion

To our understanding, this study is the first to report PD-1 expression on CB derived NKs and its features in perinatal conditions. These data may prove important in selecting the most suitable CB derived NK cell population for the development of different immunotherapeutic treatments.
Anti-dense fine speckled 70 (DFS70) autoantibodies: correlates and increasing prevalence in the United States
Authors: Dinse Gregg E. , Zheng Bing , Co Caroll A. , Parks Christine G. , Weinberg Clarice R. , Miller Frederick W. , Chan Edward K. L.
Published: June 2023

Objective

Recent studies report high-titer anti-dense fine speckled 70 (DFS70) autoantibodies in persons with inflammatory conditions, but the clinical significance remains unclear. Our goals were to estimate anti-DFS70 autoantibody prevalence, identify correlates, and assess time trends.

Methods

Serum antinuclear antibodies (ANA) were measured by indirect immunofluorescence assay on HEp-2 cells in 13,519 participants ≥12 years old from three time periods (1988–1991, 1999–2004, 2011–2012) of the National Health and Nutrition Examination Survey. ANA-positive participants with dense fine speckled staining were evaluated for anti-DFS70 antibodies by enzyme-linked immunosorbent assay. We used logistic models adjusted for survey-design variables to estimate period-specific anti-DFS70 antibody prevalence in the US, and we further adjusted for sex, age, and race/ethnicity to identify correlates and assess time trends.

Results

Women were more likely than men (odds ratio (OR)=2.97), black persons were less likely than white persons (OR=0.60), and active smokers were less likely than nonsmokers (OR=0.28) to have anti-DFS70 antibodies. The prevalence of anti-DFS70 antibodies increased from 1.6% in 1988-1991 to 2.5% in 1999-2004 to 4.0% in 2011-2012, which corresponds to 3.2 million, 5.8 million, and 10.4 million seropositive individuals, respectively. This increasing time trend in the US population (P<0.0001) was modified in some subgroups and was not explained by concurrent changes in tobacco smoke exposure. Some, but not all, anti-DFS70 antibody correlates and time trends resembled those reported for total ANA.

Conclusion

More research is needed to elucidate anti-DFS70 antibody triggers, their pathologic or potentially protective influences on disease, and their possible clinical implications.
Prognostic impact of peripheral natural killer cells in primary central nervous system lymphoma
Authors: Lin Zhiguang , Ma Jingjing , Ma Yan , Li Qing , Kang Hui , Zhang Mengxue , Chen Bobin , Xia Rong
Published: June 2023

Background

Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma with a poor prognosis. We aimed to evaluate the prognostic impact of circulating NK cells in PCNSL.

Materials and methods

Patients diagnosed with PCNSL who were treated at our institution between December 2018 and December 2019 were retrospectively screened. Patient variables including age, sex, Karnofsky performance status, diagnostic methods, location of lesions, lactate dehydrogenase, cerebrospinal fluids (CSF), and vitreous fluids involvement or not were documented. NK cell count and NK cell proportion (NK cell count/lymphocyte count) in the peripheral blood were evaluated by flow cytometry. Some patients underwent two consecutive NK cell tests before and three weeks after chemotherapy (before the next chemotherapy). The fold change in NK cell proportion and NK cell counts were calculated. CD56-positive NK cells in tumor tissue were assessed by immunohistochemistry. NK cell cytotoxicity assay was performed using flow cytometry.

Results

A total of 161 patients with PCNSL were included in this study. The median NK cell count of all NK cell tests was 197.73/μL (range 13.11–1889.90 cells/μL). The median proportion of NK cells was 14.11% (range 1.68–45.15%) for all. Responders had a higher median NK cell count (p<0.0001) and NK cell proportion (p<0.0001) than non-responders. Furthermore, Responders had a higher median fold change in NK cell proportion than non-responders (p=0.019) or patients in complete remission/partial remission (p<0.0001). A higher median fold change in NK cell count was observed in responders than in non-responders (p=0.0224) or patients in complete remission/partial remission (p=0.0002). For newly diagnosed PCNSL, patients with a high NK cell count (>165 cells/μL) appeared to have a longer median overall survival than those with a low NK cell count (p=0.0054). A high fold change in the proportion of NK cells (>0.1957; p=0.0367) or NK cell count (>0.1045; p=0.0356) was associated with longer progression-free survival. Circulating NK cells from newly-diagnosed PCNSL demonstrated an impaired cytotoxicity capacity compared to those from patients with PCNSL in complete remission or healthy donors.

Conclusion

Our study indicated that circulating NK cells had some impact on the outcome of PCNSL.
TMEM123 a key player in immune surveillance of colorectal cancer
Authors: Pesce Elisa , Cordiglieri Chiara , Bombaci Mauro , Eppenberger-Castori Serenella , Oliveto Stefania , Manara Cristina , Crosti Mariacristina , Ercan Caner , Coto Mairene , Gobbini Andrea , Campagnoli Susanna , Donnarumma Tiziano , Martinelli Manuele , Bevilacqua Valeria , De Camilli Elisa , Gruarin Paola , Sarnicola Maria L. , Cassinotti Elisa , Baldari Ludovica , Viale Giuseppe , Biffo Stefano , Abrignani Sergio , Terracciano Luigi M. , Grifantini Renata
Published: June 2023

Colorectal cancer (CRC) is a leading cause of cancer-associated death. In the tumor site, the interplay between effector immune cells and cancer cells determines the balance between tumor elimination or outgrowth. We discovered that the protein TMEM123 is over-expressed in tumour-infiltrating CD4 and CD8 T lymphocytes and it contributes to their effector phenotype. The presence of infiltrating TMEM123+ CD8+ T cells is associated with better overall and metastasis-free survival. TMEM123 localizes in the protrusions of infiltrating T cells, it contributes to lymphocyte migration and cytoskeleton organization. TMEM123 silencing modulates the underlying signaling pathways dependent on the cytoskeletal regulator WASP and the Arp2/3 actin nucleation complex, which are required for synaptic force exertion. Using tumoroid-lymphocyte co-culture assays, we found that lymphocytes form clusters through TMEM123, anchoring to cancer cells and contributing to their killing. We propose an active role for TMEM123 in the anti-cancer activity of T cells within tumour microenvironment.
Inflammation in multiple system atrophy
Authors: Leńska-Mieciek Marta , Madetko-Alster Natalia , Alster Piotr , Królicki Leszek , Fiszer Urszula , Koziorowski Dariusz
Published: June 2023

Misfolding protein aggregation inside or outside cells is the major pathological hallmark of several neurodegenerative diseases. Among proteinopathies are neurodegenerative diseases with atypical Parkinsonism and an accumulation of insoluble fibrillary alpha-synuclein (synucleinopathies) or hyperphosphorylated tau protein fragments (tauopathies). As there are no therapies available to slow or halt the progression of these disea ses, targeting the inflammatory process is a promising approach. The inflammatory biomarkers could also help in the differential diagnosis of Parkinsonian syndromes. Here, we review inflammation’s role in multiple systems atrophy pathogenesis, diagnosis, and treatment.
Combination of thalidomide and Clostridium butyricum relieves chemotherapy-induced nausea and vomiting via gut microbiota and vagus nerve activity modulation
Authors: Zhao Xuanqi , Wu Heng , Zhu Ruizhe , Shang Gaishuang , Wei Jing , Shang Haitao , Tian Puyuan , Chen Tingtao , Wei Hong
Published: June 2023

Nausea and vomiting (CINV) are distressful and widespread side effects of chemotherapy, and additional efficient regimens to alleviate CINV are urgently needed. In the present study, colorectal cancer (CRC) mice model induced by Azoxymethane (AOM)/Dextran Sodium Sulfate (DSS) was employed to evaluate the cancer suppression and CINV amelioration effect of the combination of thalidomide (THD) and Clostridium butyricum. Our results suggested that the combination of THD and C. butyricum abundantly enhanced the anticancer effect of cisplatin via activating the caspase-3 apoptosis pathway, and also ameliorated CINV via inhibiting the neurotransmitter (e.g., 5-HT and tachykinin 1) and its receptor (e.g., 5-HT3R and NK-1R) in brain and colon. Additionally, the combination of THD and C. butyricum reversed the gut dysbacteriosis in CRC mice by increasing the abundance of Clostridium, Lactobacillus, Bifidobacterium, and Ruminococcus at the genus level, and also led to increased expression of occludin and Trek1 in the colon, while decreased expression of TLR4, MyD88, NF-κB, and HDAC1, as well as the mRNA level of IL-6, IL-1β, and TNF-α. In all, these results suggest that the combination of THD and C. butyricum had good efficacy in enhancing cancer treatments and ameliorating CINV, which thus provides a more effective strategy for the treatment of CRC.
The modulating effect of lexical predictability on perceptual learning of degraded speech
Authors: Li Yumeng , Fan Chen , Liu Chang , Li Xiaoqing
Published: June 2023

Predictive coding is considered to be an important mechanism for perceptual learning. Posterior prediction-error minimization can lead to higher rates of lasting changes in the representational hierarchy, and hence is likely to enhance the process of learning. In the field of speech processing, although considerable studies have demonstrated that a highly predictive sentence context can facilitate the perception of forthcoming word, it remains to be examined that how this type of predictability affects the perceptual learning of speech (especially degraded speech). The present study, therefore, aimed to examine whether and how the lexical predictability of spoken sentences modulates perceptual learning of speech embedded in noise, by using spoken sentences as training stimuli and strictly controlling the semantic-context constraint of these training sentences. The current study adopted a “pretest-training-posttest” procedure. Two groups of subjects participated in this perceptual learning study, with cognitive and language abilities matched across these two groups. For one group, the spoken sentences used for training all have a highly predictive semantic context; for another group, the training sentences all have a low predictive context. The results showed that both the reaction time and accuracy of the speech-in-noise intelligibility test were significantly improved in the post-training phase compared to the pre-training phase; moreover, the learning-related improvement was significantly enhanced in participants with weak-constraint sentences as training stimuli (compared to those with strong-constraint sentences as training stimuli). This enhancement effect of low lexical predictability on learning-related improvement supports a prediction-error based account of perceptual learning.
Ladderane and lipid biomarker estimate of the sources and distributions of anammox activities in Laizhou Bay of the Bohai Sea, China
Authors: Shi Mingwei , Xiao Xiaotong , Ma Haili , Li Li , Wang Yujue , Dong Caixia , Ding Yang , Zhao Meixun
Published: June 2023

Anaerobic ammonium oxidation (anammox) plays an important role in nitrogen removal in coastal seas, and ladderanes, as specific biomarkers of anammox bacteria, can be used to indicate the anammox activity. However, the origins of ladderanes and their controlling factors in the coastal seas influenced by anthropogenic activities are still not well constrained. To address this, we reported ladderanes, long-chain n-alkanols (terrestrial biomarker) and sterols (marine biomarker) in suspended particulates from the estuaries and inner area of Laizhou Bay in North China, to study ladderane sources and its distribution patterns. This study proposed a novel index, Rlad, using ladderane ratio of ladderane III to ladderane IV, and by correlating this index with other biomarker distributions to evaluate the source of ladderanes. High Rlad values (> 0.9) indicated biosynthesis by terrestrial anammox bacteria Ca. Brocadia and Ca. Kuenenia, while low Rlad values (< 0.9) indicated biosynthesis by marine anammox bacteria Ca. Scalindua. High Rlad values and high ladderane concentrations in particulates from the estuaries and nearshore area of Laizhou Bay revealed sources from the terrestrial input via riverine inflow as well as in situ production in oxygen-depleted estuaries, supported by high concentrations of terrestrial biomarkers; Low Rlad values and low ladderane concentrations in particulates from offshore area indicated sources from marine environment via the cold hypoxia water input by the Bohai circulation. Comparison of ladderane concentrations of our study with previously published results from a wide range of environments with human influences from Chinese coastal area revealed that high ladderane concentrations synthesized by terrestrial anammox bacteria could contribute significantly to coastal seas, and the anammox process in river-estuary-bay system might be underestimated. This study provides new understandings about the evaluation of the source and distribution of ladderanes under anthropogenic influences in coastal seas.
Area effect during the fracture process of high-Niobium-Titanium-Aluminum alloys under continuous tension loading-unloading
Authors: Zhong Mingjie , Lin Youzhi
Published: June 2023

Based on the extracted results of the continuous tension loading-unloading testing, and observations of the corresponding cracks and fracture surfaces for the high-Niobium-Titanium-Aluminum alloys, both tensile damage and fracture mechanism were systematically studied. From the acquired results, it was demonstrated that the continuous tension loading-unloading did not affect the elastic modulus of the alloy. However, it decreased in fracture stress, fracture strain, and fracture work per unit area, and increased in irreversible strain. This result shows that the irreversible strain is not mainly caused by the volume effect of microcracks, but by the plastic strain of the materials. Although the density of the micro-cracks produced by multi-loading and unloading was small, most of the micro-cracks were concentrated on a certain section area, which results in an obvious area effect caused by the damage of the microcrack. In addition, the further propagation of the main crack under lower re-loading stress was not caused by the application of higher normal stress but by the residual tensile stress, which depends on the deterioration of the material at the crack tip during the unloading process of the alloy. These small amounts of microcracks are usually concentrated on the cross-sectional area, and the area effect caused by the microcracks damage is also obvious, which leads to a reduction of the fracture performance. Therefore, the area effect ultimately induces a decrease in fracture stress.
Three-dimensional microstructure reconstruction for two-phase materials from three orthogonal surface maps
Authors: Eshlaghi G. Tolooei , Egels G. , Benito S. , Stricker M. , Weber S. , Hartmaier A.
Published: June 2023

Introduction: A full three-dimensional (3D) microstructure characterization that captures the essential features of a given material is oftentimes desirable for determining critical mechanisms of deformation and failure and for conducting computational modeling to predict the material’s behavior under complex thermo-mechanical loading conditions. However, acquiring 3D microstructure representations is costly and time-consuming, whereas 2D surface maps taken from orthogonal perspectives can be readily produced by standard microscopic procedures. We present a robust and comprehensive approach for such 3D microstructure reconstructions based on three electron backscatter diffraction (EBSD) maps from orthogonal surfaces of two-phase materials.

Methods: It is demonstrated that processing surface maps by spatial correlation functions combined with principal component analysis (PCA) results in a small set of unique descriptors that serve as a representative fingerprint of the 2D maps. In this way, the differences between surface maps of the real microstructure and virtual surface maps of a reconstructed 3D microstructure can be quantified and iteratively minimized by optimizing the 3D reconstruction.

Results: To demonstrate the applicability of the method, the microstructure of a metastable austenitic steel in the two-phase region, where austenite and deformation-induced martensite coexist at room temperature, was characterized and reconstructed. After convergence, the synthetic 3D microstructure accurately describes the experimental system in terms of physical parameters such as volume fractions and phase shapes.

Discussion: The resulting 3D microstructures represent the real microstructure in terms of their characteristic features such that multiple realizations of statistically equivalent microstructures can be generated easily. Thus, the presented approach ensures that the 3D reconstructed sample and the associated 2D surface maps are statistically equivalent.
Assessment of the prognostic value of preoperative high-sensitive troponin T for myocardial injury and long-term mortality for groups at high risk for cardiovascular events following noncardiac surgery: a retrospective cohort study
Authors: Zhu Yingchao , Bi Yaodan , Yu Qian , Liu Bin
Published: June 2023

Background

Few studies explored the association between high-sensitive cardiac troponin T (hs-cTnT) and long-term mortality for patients after surgery. This study was conducted to assess the association of hs-cTnT with long-term mortality and to investigate the extent to which this association is mediated via myocardial injury after noncardiac surgery (MINS).

Methods

This retrospective cohort study included all patients with hs-cTnT measurements who underwent non-cardiac surgery at Sichuan University West China Hospital. Data were collected from February 2018 and November 2020, with follow-up through February 2022. The primary outcome was all-cause mortality within 1 year. As secondary outcomes, MINS, length of hospital stay (LOS), and ICU admission were analyzed.

Results

The cohort included 7,156 patients (4,299 [60.1%] men; 61.0 [49.0–71.0] years). Among 7,156 patients, there were 2,151 (30.05%) with elevated hs-cTnT(>14 ng/L). After more than 1 year of follow-up, more than 91.8% of mortality information was available. During one-year follow-up after surgery, there were 308 deaths (14.8%) with a preoperative hs-cTnT >14 ng/L, compared with 192 deaths (3.9%) with a preoperative hs-cTnT <=14 ng/L(adjusted hazard ratio [aHR] 1.93, 95% CI 1.58–2.36; p < 0.001). Elevated preoperative hs-cTnT was also associated with several other adverse outcomes (MINS: adjusted odds ratio [aOR] 3.01; 95% CI, 2.46–3.69; p < 0.001; LOS: aOR 1.48, 95%CI 1.34–1.641; p < 0.001; ICU admission: aOR 1.52, 95%CI 1.31–1.76; p < 0.001). MINS explained approximately 33.6% of the variance in mortality due to preoperative hs-cTnT levels.

Conclusion

Preoperative elevated hs-cTnT concentrations have a significant association with long-term mortality after noncardiac surgery, one-third of which may by accounted for by MINS.
Ischemia/reperfusion-activated ferroptosis in the early stage triggers excessive inflammation to aggregate lung injury in rats
Authors: Liu Xiujie , Pan Binhui , Wang Xiaoting , Xu Junpeng , Wang Xinyu , Song Zhengyang , Zhang Eryao , Wang Fangyan , Wang Wantie
Published: June 2023

Objective

Lung ischemia/reperfusion injury (LIRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. Ferroptosis and inflammation are involved in the pathogenesis of LIRI according to the results of several studies on animal models. However, the interactive mechanisms between ferroptosis and inflammation contributing to LIRI remain unclear.

Methods

HE staining and indicators of oxidative stress were used to evaluated the lung injury. The reactive oxygen species (ROS) level was examined by DHE staining. The quantitative Real-time PCR (qRT-PCR) and western blot analysis were employed to detect the level of inflammation and ferroptosis, and deferoxamine (DFO) was used to assess the importance of ferroptosis in LIRI and its effect on inflammation.

Results

In the present study, the link of ferroptosis with inflammation was evaluated at reperfusion 30-, 60- and 180-minute time points, respectively. As the results at reperfusion 30-minute point shown, the pro-ferroptotic indicators, especially cyclooxygenase (COX)-2 and acyl-CoA synthetase long-chain family member 4 (ACSL4), were upregulated while the anti-ferroptotic factors glutathione peroxidase 4 (GPX4), cystine-glumate antiporter (XCT) and ferritin heavy chain (FTH1) were downregulated. Meanwhile, the increased level of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α) and IL-1β were observed beginning at reperfusion 60-minute point but mostly activated at reperfusion 180-minute point. Furthermore, deferoxamine (DFO) was employed to block ferroptosis, which can alleviate lung injury. Expectedly, the survival rate of rats was increased and the lung injury was mitigated containing the improvement of type II alveolar cells ultrastructure and ROS production. In addition, at the reperfusion 180-minute point, the inflammation was observed to be dramatically inhibited after DFO administration as verified by IL-6, TNF-α and IL-1β detection.

Conclusion

These findings suggest that ischemia/reperfusion-activated ferroptosis plays an important role as the trigger for inflammation to further deteriorate lung damages. Inhibiting ferroptosis may have therapeutic potential for LIRI in clinical practice.
Quantification of Torque Teno Virus (TTV) in plasma and saliva of individuals with liver cirrhosis: a cross sectional study
Authors: Falabello de Luca Ana Clara , Marinho Gabriella Bueno , Franco Juliana Bertoldi , Tenório Jefferson da Rocha , Andrade Natália Silva , Batista Alexandre Mendes , Mamana Ana Carolina , Tozetto-Mendoza Tânia Regina , Pérez Sayáns Mário , Braz-Silva Paulo Henrique , Ortega Karem L.
Published: June 2023

Introduction

Torque teno virus (TTV) has been pointed as an endogenous marker of immune function, the objective of this study was to investigate the TTV viral load in plasma and saliva of cirrhotic individuals and correlate it with clinical characteristics.

Methods

Blood, saliva, clinical data from records and laboratory tests were collected from 72 cirrhotic patients. Plasma and saliva were submitted to real-time polymerase chain reaction for quantification of TTV viral load.

Results

The majority of the patients presented decompensated cirrhosis (59.7%) and 47.2% had alterations in the white blood series. TTV was identified in 28 specimens of plasma (38.8%) and in 67 specimens of saliva (93.0%), with median values of TTV copies/mL of 90.6 in plasma and 245.14 in saliva. All the patients who were positive for TTV in plasma were also positive in saliva, with both fluids having a moderately positive correlation for the presence of TTV. There was no correlation between TTV viral load, either in plasma or in saliva, and any of the variables studied.

Conclusion

TTV is more frequently found and in greater amount in the saliva than in the plasma of cirrhotic patients. There was no correlation between TTV viral load and clinical parameters.
Association of x-ray velocimetry (XV) ventilation analysis compared to spirometry
Authors: Kirkness Jason P. , Dusting Jonathan , Eikelis Nina , Pirakalathanan Piraveen , DeMarco John , Shiao Stephen L. , Fouras Andreas
Published: June 2023

Introduction

X-ray Velocimetry (XV) ventilation analysis is a 4-dimensional imaging-based method for quantifying regional ventilation, aiding in the assessment of lung function. We examined the performance characteristics of XV ventilation analysis by examining correlation to spirometry and measurement repeatability.

Methods

XV analysis was assessed in 27 patients receiving thoracic radiotherapy for non-lung cancer malignancies. Measurements were obtained pre-treatment and at 4 and 12-months post-treatment. XV metrics such as ventilation defect percent (VDP) and regional ventilation heterogeneity (VH) were compared to spirometry at each time point, using correlation analysis. Repeatability was assessed between multiple runs of the analysis algorithm, as well as between multiple breaths in the same patient. Change in VH and VDP in a case series over 12 months was used to determine effect size and estimate sample sizes for future studies.

Results

VDP and VH were found to significantly correlate with FEV1 and FEV1/FVC (range: −0.36 to −0.57; p < 0.05). Repeatability tests demonstrated that VDP and VH had less than 2% variability within runs and less than 8% change in metrics between breaths. Three cases were used to illustrate the advantage of XV over spirometry, where XV indicated a change in lung function that was either undetectable or delayed in detection by spirometry. Case A demonstrated an improvement in XV metrics over time despite stable spirometric values. Case B demonstrated a decline in XV metrics as early as 4-months, although spirometric values did not change until 12-months. Case C demonstrated a decline in XV metrics at 12 months post-treatment while spirometric values remained normal throughout the study. Based on the effect sizes in each case, sample sizes ranging from 10 to 38 patients would provide 90% power for future studies aiming to detect similar changes.

Conclusions

The performance and safety of XV analysis make it ideal for both clinical and research applications across most lung indications. Our results support continued research and provide a basis for powering future studies using XV as an endpoint to examine lung health and determine therapeutic efficacy.
Surface proteins of Shiga toxin-producing Escherichia coli mediate association with milk fat globules in raw milk
Authors: Bagel Arthur , Bouvier-Crozier Marion , Canizares Mélissa , Hamadou Badis , Courcol Louise , Lopez Christelle , Michel Valérie , Douellou Thomas , Sergentet Delphine
Published: June 2023

Introduction

By adhering to host cells and colonizing tissues, bacterial pathogens can successfully establish infection. Adhesion is considered the first step of the infection process and bacterial adhesion to anti-adhesive compounds is now seen as a promising strategy to prevent infectious diseases. Among the natural sources of anti-adhesive molecules, the membrane of milk fat globules (MFGs) is of interest because of its compositional diversity of proteins and glycoconjugates. However, few studies have focused on the bacterial molecules involved in MFG- mediated inhibition of bacterial adhesion to enterocytes.

Methods

We used three pathogenic Shiga toxin-producing Escherichia coli (STEC) strains (O26:H11 str. 21765, O157:H7 str. EDL933, and O103:H3 str. PMK5) as models to evaluate whether STEC surface proteins are involved in the affinity of STEC for MFG membrane proteins (MFGMPs). The affinity of STEC for MFGMPs was assessed both indirectly by a natural raw milk creaming test and directly by an adhesion test. Mass spectrometry was used to identify enriched STEC proteins within the protein fraction of MFGMs. Bacterial mutants were constructed and their affinity to MFGs were measured to confirm the role of the identified proteins.

Results

We found that free STEC surface proteins inhibit the concentration of the pathogen in the MFG-enriched cream in a strain-dependent manner. Moreover, the OmpA and FliC proteins were identified within the protein fraction of MFGMs. Our results suggest that FliC protein participates in STEC adhesion to MFGMPs but other STEC molecules may also participate.

Discussion

For the first time, this study highlighted, the involvement of STEC surface proteins in the affinity for MFGs. The mechanism of STEC-MFG association is still not fully understood but our results confirm the existence of receptor/ligand type interactions between the bacteria and MFGs. Further studies are needed to identify and specify the molecules involved in this interaction. These studies should consider the likely involvement of several factors, including adhesion molecules, and the diversity of each STEC strain.
Genomic changes underpinning the emergence of a successful Mycobacterium tuberculosis Latin American and Mediterranean clonal complex
Authors: Dekhil Naira , Mardassi Helmi
Published: June 2023

Introduction

The Latin American and Mediterranean sublineage (L4.3/LAM) is the most common generalist sublineage of Mycobacterium tuberculosis lineage 4 (L4), yet certain L4.3/LAM genotypes appear to be confined to particular geographic regions. This is typically the case of a L4.3/LAM clonal complex (CC), TUN4.3_CC1, which is the most preponderant in Tunisia (61.5% of L4.3/LAM).

Methods

Here, we used whole-genome sequencing data of 346 globally distributed L4 clinical strains, including 278 L4.3/LAM isolates, to reconstruct the evolutionary history of TUN4.3_CC1 and delineate critical genomic changes underpinning its success.

Results and Discussion

Phylogenomic coupled to phylogeographic analyses indicated that TUN4.3_CC1 has evolved locally, being confined mainly to North Africa. Maximum likelihood analyses using the site and branch-site models of the PAML package disclosed strong evidence of positive selection in the gene category “cell wall and cell processes” of TUN4.3_CC1. Collectively, the data indicate that TUN4.3_CC1 has inherited several mutations, which could have potentially contributed to its evolutionary success. Of particular interest are amino acid replacements at the esxK and eccC2 genes of the ESX/Type VII secretion system, which were found to be specific to TUN4.3_CC1, being common to almost all isolates. Because of its homoplastic nature, the esxK mutation could potentially have endowed TUN4.3_CC1 with a selective advantage. Moreover, we noticed the occurrence of additional, previously described homoplasic nonsense mutations in ponA1 and Rv0197. The mutation in the latter gene, a putative oxido-reductase, has previously been shown to be correlated with enhanced transmissibility in vivo. In sum, our findings unveiled several features underpinning the success of a locally evolved L4.3/LAM clonal complex, lending further support to the critical role of genes encoded by the ESX/type VII secretion system.
Human beta defensin-3 mediated activation of β-catenin during human respiratory syncytial virus infection: interaction of HBD3 with LDL receptor-related protein 5
Authors: Pokharel Swechha M. , Mohanty Indira , Mariasoosai Charles , Miura Tanya A. , Maddison Lisette A. , Natesan Senthil , Bose Santanu
Published: June 2023

Respiratory Syncytial Virus (RSV) is a non-segmented negative-sense RNA virus belonging to the paramyxovirus family. RSV infects the respiratory tract to cause pneumonia and bronchiolitis in infants, elderly, and immunocompromised patients. Effective clinical therapeutic options and vaccines to combat RSV infection are still lacking. Therefore, to develop effective therapeutic interventions, it is imperative to understand virus-host interactions during RSV infection. Cytoplasmic stabilization of β-catenin protein results in activation of canonical Wingless (Wnt)/β-catenin signaling pathway that culminates in transcriptional activation of various genes regulated by T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors. This pathway is involved in various biological and physiological functions. Our study shows RSV infection of human lung epithelial A549 cells triggering β-catenin protein stabilization and induction of β-catenin mediated transcriptional activity. Functionally, the activated β-catenin pathway promoted a pro-inflammatory response during RSV infection of lung epithelial cells. Studies with β-catenin inhibitors and A549 cells lacking optimal β-catenin activity demonstrated a significant loss of pro-inflammatory chemokine interleukin-8 (IL-8) release from RSV-infected cells. Mechanistically, our studies revealed a role of extracellular human beta defensin-3 (HBD3) in interacting with cell surface Wnt receptor LDL receptor-related protein-5 (LRP5) to activate the non-canonical Wnt independent β-catenin pathway during RSV infection. We showed gene expression and release of HBD3 from RSV-infected cells and silencing of HBD3 expression resulted in reduced stabilization of β-catenin protein during RSV infection. Furthermore, we observed the binding of extracellular HBD3 with cell surface localized LRP5 protein, and our in silico and protein–protein interaction studies have highlighted a direct interaction of HBD3 with LRP5. Thus, our studies have identified the β-catenin pathway as a key regulator of pro-inflammatory response during RSV infection of human lung epithelial cells. This pathway was induced during RSV infection via a non-canonical Wnt-independent mechanism involving paracrine/autocrine action of extracellular HBD3 activating cell surface Wnt receptor complex by directly interacting with the LRP5 receptor.
Molecular epidemiological characteristics of Brucella in Guizhou Province, China, from 2009 to 2021
Authors: Tan Qinqin , Wang Yue , Liu Ying , Tao Zhongfa , Yu Chun , Huang Yan , Yang Xinggui , Ying Xia , Hu Yong , Li Shijun
Published: June 2023

Introduction

Brucellosis was made statutorily notifiable in 1955, in China, while in Guizhou Province, the pathogen of human brucellosis was isolated for the first time in 2011. However, currently, the brucellosis epidemic is becoming more and more severe in Guizhou Province. The type distribution and genetic characteristics of Brucella in Guizhou Province, as well as its evolutionary relationship with domestic and foreign strains, are still unclear.

Methods

MLST, MLVA, and rpoB typing techniques were used for the molecular epidemiological study of the 83 Brucella isolates in Guizhou province.

Results

Among the 83 Brucella strains, MLST identified three ST genotypes, of which ST39 is a newly reported type in China. MLVA-16 generated 49 genotypes, and MLVA-11 generated 5 known genotypes and 2 unreported genotypes. Six genotypes were identified by rpoB technology.

Discussion

MLVA has a high resolution, but differences at the Bruce 04 and 16 loci cannot exclude associations between epidemics, and combining MLST and rpoB typing methods for epidemiologic tracing can avoid erroneous judgments. Moreover, through the combined analysis of the three typing techniques, the possible origin of the new Brucella can be reasonably inferred, which is also conducive to promoting the subsequent research of the novel Brucella.
Causal relationship between gut microbiota and urticaria: a bidirectional two-sample mendelian randomization study
Authors: Shi Yun-Zhou , Tao Qing-Feng , Qin Hai-Yan , Li Ying , Zheng Hui
Published: June 2023

Background

Cumulative evidence showed an association between gut microbiota and urticaria, but the causal relationship between them is unclear. We aimed to verify whether there is a causal relationship between the composition of gut microbiota and urticaria and explore whether the causal effect was bidirectional.

Methods

We obtained genome-wide association studies (GWAS) summary data of 211 gut microbiota and urticaria from the most extensive available GWAS database. A bidirectional two-sample mendelian randomization (MR) study was used to test the causal relationship between the gut microbiota and urticaria. The MR analysis was primarily performed with the inverse variance weighted (IVW) method, and MR-Egger, weighted median (WM), and MR-PRESSO were performed as sensitivity analyses.

Results

The Phylum Verrucomicrobia (OR 1.27, 95%CI 1.01 to 1.61; p = 0.04), Genus Defluviitaleaceae UCG011 (OR 1.29, 95%CI 1.04 to 1.59; p = 0.02), and Genus Coprococcus 3 (OR 1.44, 95%CI 1.02 to 2.05; p = 0.04) was a risk effect against urticaria. And Order Burkholderiales (OR 0.68, 95%CI 0.49 to 0.99; p = 0.04) and Genus Eubacterium xylanophilum group (OR 0.78, 95%CI 0.62 to 0.99; p = 0.04) were negatively associated with urticaria, suggesting a protective effect. At the same time, urticaria had a positively causal effect on gut microbiota (Genus Eubacterium coprostanoligenes group) (OR 1.08, 95%CI 1.01 to 1.16; p = 0.02). These findings showed no influence by heterogeneity or horizontal pleiotropy. Moreover, most sensitivity analyses showed results consistent with those of IVW analysis.

Conclusion

Our MR study confirmed the potential causal relationship between gut microbiota and urticaria, and the causal effect was bidirectional. Nevertheless, these findings warrant further examination owing to the unclear mechanisms.
Comprehensive analysis of the microbiome and metabolome in pus from pyogenic liver abscess patients with and without diabetes mellitus
Authors: Guo Yawen , Wang Hairui , Liu Zhaoyu , Chang Zhihui
Published: June 2023

Introduction

Pyogenic liver abscess (PLA) patients combined with diabetes mellitus (DM) tend to have more severe clinical manifestations than without DM. The mechanism responsible for this phenomenon is not entirely clear. The current study therefore aimed to comprehensively analyze the microbiome composition and metabolome in pus from PLA patients with and without DM, to determine the potential reasons for these differences.

Methods

Clinical data from 290 PLA patients were collected retrospectively. We analyzed the pus microbiota using 16S rDNA sequencing in 62 PLA patients. In addition, the pus metabolomes of 38 pus samples were characterized by untargeted metabolomics analysis. Correlation analyses of microbiota, metabolites and laboratory findings were performed to identify significant associations.

Results

PLA patients with DM had more severe clinical manifestations than PLA patients without DM. There were 17 discriminating genera between the two groups at the genus level, among which Klebsiella was the most discriminating taxa. The ABC transporters was the most significant differential metabolic pathway predicted by PICRUSt2. Untargeted metabolomics analysis showed that concentrations of various metabolites were significantly different between the two groups and seven metabolites were enriched in the ABC transporters pathway. Phosphoric acid, taurine, and orthophosphate in the ABC transporters pathway were negatively correlated with the relative abundance of Klebsiella and the blood glucose level.

Discussion

The results showed that the relative abundance of Klebsiella in the pus cavity of PLA patients with DM was higher than those without DM, accompanied by changes of various metabolites and metabolic pathways, which may be associated with more severe clinical manifestations.
Investigation of antibiotic resistance genotypic and phenotypic characteristics of marine aquaculture fish carried in the Dalian area of China
Authors: Gao Zihui , Piao Yongzhe , Hu Bing , Yang Chunhua , Zhang Xiaobo , Zheng Qiuyue , Cao Jijuan
Published: June 2023

Due to the long-term and irrational use of antibiotics for the prevention and control of bacterial diseases in aquaculture, antibiotic resistance genes have become a new source of pollution in aquatic products. Factors such as the spread of drug-resistant strains and the horizontal transfer of drug-resistant genes have led to multi-drug resistance in fish-infecting bacteria, which seriously affects the quality and safety of aquatic products. In this study, 50 samples of horse mackerel and puffer fish sold in Dalian aquatic products market and seafood supermarket were collected, and the phenotypic characteristics of the bacteria carried by the fish for drugs such as sulfonamides, amide alcohols, quinolones, aminoglycosides and tetracyclines were tested and analyzed, and the resistance genes carried by fish samples were detected by SYBG qPCR. Our statistical analyses demonstrated that the drug resistance phenotypes and genotypes of bacteria carried by mariculture horse mackerel and puffer fish in the Dalian area of China were complex, and the multi-drug resistance rate reached 80%. Among the examined antibiotics, the resistance rates to cotrimoxazole, tetracycline, chloramphenicol, ciprofloxacin, norfloxacin, levofloxacin, kanamycin, and florfenicol exceeded 50%, whereas the resistance rates to gentamicin and tobramycin were 26 and 16%, respectively. The detection rate of the drug resistance genes tetA, sul1, sul2, qnrA, qnrS, and floR exceeded 70% and all samples carried more than three drug resistance genes. The correlation analysis of drug resistance genes and drug resistance phenotypes showed that the detection of the drug resistance genes sul1, sul2, floR, and qnrD was correlated with the detection of drug resistance phenotypes (p < 0.01). However, the correlation between the resistance genes cmlA, cfr, tetA, qnrA, qnrS, and aac(6′)-Ib-cr and the corresponding resistance phenotype was not significant (p > 0.05). In general, our findings indicated that the multi-drug resistance of bacteria carried by marine horse mackerel and puffer fish in the Dalian area was serious. From the perspective of drug resistance rate and drug resistance gene detection rate, the aminoglycosides gentamicin and tobramycin are still considered effective in controlling bacterial infection in marine fish in the study area. Collectively, our findings provide a scientific basis for the management of drug use in mariculture, which can prevent the transmission of drug resistance through the food chain and minimize the associated human health risks.
Sequence- and structure-specific RNA oligonucleotide binding attenuates heterogeneous nuclear ribonucleoprotein A1 dysfunction
Authors: Clarke Joseph P. , Thibault Patricia A. , Fatima Sakina , Salapa Hannah E. , Kalyaanamoorthy Subha , Ganesan Aravindhan , Levin Michael C.
Published: June 2023

The RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (A1) regulates RNA metabolism, which is crucial to maintaining cellular homeostasis. A1 dysfunction mechanistically contributes to reduced cell viability and loss, but molecular mechanisms of how A1 dysfunction affects cell viability and loss, and methodologies to attenuate its dysfunction, are lacking. Utilizing in silico molecular modeling and an in vitro optogenetic system, this study examined the consequences of RNA oligonucleotide (RNAO) treatment on attenuating A1 dysfunction and its downstream cellular effects. In silico and thermal shift experiments revealed that binding of RNAOs to the RNA Recognition Motif 1 of A1 is stabilized by sequence- and structure-specific RNAO-A1 interactions. Using optogenetics to model A1 cellular dysfunction, we show that sequence- and structure-specific RNAOs significantly attenuated abnormal cytoplasmic A1 self-association kinetics and A1 cytoplasmic clustering. Downstream of A1 dysfunction, we demonstrate that A1 clustering affects the formation of stress granules, activates cell stress, and inhibits protein translation. With RNAO treatment, we show that stress granule formation is attenuated, cell stress is inhibited, and protein translation is restored. This study provides evidence that sequence- and structure-specific RNAO treatment attenuates A1 dysfunction and its downstream effects, thus allowing for the development of A1-specific therapies that attenuate A1 dysfunction and restore cellular homeostasis.
Pyridylnidulin exerts anti-diabetic properties and improves non-alcoholic fatty liver disease in diet-induced obesity mice
Authors: Likitnukul Sutharinee , Tepaarmorndech Surapun , Kaewamatawong Theerayuth , Yangchum Arunrat , Duangtha Chanathip , Jongjang Pimrapat , Mangmool Supachoke , Pinthong Darawan , Isaka Masahiko
Published: June 2023

Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the metabolic disorders related to the pathophysiology of type 2 diabetes mellitus (T2DM). Therapeutic strategies are focused on the improvement of energy balance and lifestyle modification. Additionally, the derivative of the bioactive fungal metabolite is of interest to provide health benefits, especially in obese and pre-diabetic conditions. In our screening of anti-diabetic compounds from fungal metabolites and semisynthetic derivatives, a depsidone derivative, namely pyridylnidulin (PN), showed potent glucose uptake-inducing activity. The present study aimed to investigate the liver lipid metabolism and anti-diabetic properties of PN in diet-induced obesity mice.

Methods: Male C57BL/6 mice were induced obesity and pre-diabetic conditions by dietary intervention with a high-fat diet (HFD) for 6 weeks. These obese mice were orally administered with PN (40 or 120 mg/kg), metformin (150 mg/kg), or vehicle for 4 weeks. Glucose tolerance, plasma adipocytokines, hepatic gene and protein expressions were assessed after treatment.

Results: Improved glucose tolerance and reduced fasting blood glucose levels were found in the PN and metformin-treated mice. Additionally, hepatic triglyceride levels were consistent with the histopathological steatosis score regarding hepatocellular hypertrophy in the PN and metformin groups. The levels of plasma adipocytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were reduced in the PN (120 mg/kg) and metformin-treated mice. In addition, hepatic gene expression involved in lipid metabolism, including lipogenic enzymes was significantly reduced in the PN (120 mg/kg) and metformin-treated mice. The increased protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) was also found in PN and metformin-treated mice.

Discussion: Considering the increased p-AMPK protein expression levels in PN and metformin-treated mice were revealed as the underlying mechanisms to improve metabolic parameters. These results suggested that PN provided the health benefit to slow the progression of NAFLD and T2DM in obese and pre-diabetic conditions.