bluuebunny/crossref_metadata_2025 huggingface dataset:
LINC01798/miR-17-5p axis regulates ITGA8 and causes changes in tumor microenvironment and stemness in lung adenocarcinoma
Authors: Li Xuanguang , Zhu Guangsheng , Li Yongwen , Huang Hua , Chen Chen , Wu Di , Cao Peijun , Shi Ruifeng , Su Lianchun , Zhang Ruihao , Liu Hongyu , Chen Jun
Published: February 2023

Integrins are closely related to the occurrence and development of tumors. ITGA8 encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1. Studies on the role of this gene in the occurrence and development of lung cancer are scarce. The examination of public databases revealed that ITGA8 expression was significantly lower in tumor tissue than that in normal tissue, especially in lung cancer, renal carcinoma, and prostate cancer. Survival analysis of patients with lung adenocarcinoma revealed that higher ITGA8 expression had better prognosis. ITGA8 was positively related to immune checkpoints and immunomodulators, whereas B cell, CD4+ T cell, CD8+ T cell, neutrophil, macrophage, and dendritic cell infiltration had the same correlation. Moreover, ITGA8 was negatively related to cancer stemness. We used an online database to predict the miRNAs and lncRNAs that regulate ITGA8 and obtained the regulatory network of ITGA8 through correlation analysis and Kaplan–Meier survival analysis. Quantitative real-time PCR and western blot analyses showed that LINC01798 regulates ITGA8 expression through miR-17-5p. Therefore, the regulatory network of ITGA8 may serve as a new therapeutic target to improve the prognosis of patients with lung cancer.
Identification of a glutamine metabolism reprogramming signature for predicting prognosis, immunotherapy efficacy, and drug candidates in bladder cancer
Authors: Xu Yan , Xia Zhixiu , Sun Xiaoyu , Wei Baojun , Fu Yang , Shi Du , Zhu Yuyan
Published: February 2023

Background

Bladder cancer is the most common malignancy of the urinary system. However, patient prognosis and treatment outcomes in bladder cancer are difficult to predict owing to high tumor heterogeneity. Given that abnormal glutamine metabolism has been identified as a key factor driving the progression of bladder cancer, it is necessary to assess the prognosis and therapeutic efficacy of bladder cancer treatments based on an analysis of glutamine metabolism-related genes.

Methods

We used bladder cancer sample data downloaded from The Cancer Genome Atlas to identify glutamine metabolism-related genes as prognostic markers, and established a novel Glutamine Metabolism Immunity Index (GMII) based on univariate and multivariate COX regression analyses. On the basis of GMII values, bladder cancer patients were divided into high- and low-risk groups, and systematic analysis was conducted for clinical features, somatic mutations, immune cell infiltration, chemotherapeutic response, and immunotherapeutic efficacy. Candidate small-molecule drugs targeting the GMII core target proteins were identified based on molecular docking analysis.

Results

The GMII consisting of eight independent prognostic genes was established to be an excellent tool for predicting the survival in patients with bladder cancer and was validated using multiple datasets. Compared with patients in the high-risk group, those in the low-risk group had significantly better responses to gemcitabine and immune checkpoint blockade. In addition, we predicted 12 potential small-molecule drugs that could bind to three of the GMII core target proteins.

Conclusions

The GMII can be used to accurately predict the prognosis and immunotherapeutic response of bladder cancer patients, as well as candidate small-molecule drugs. Furthermore, the novel “Glutamine Metabolism-related Gene”-guided strategy for predicting survival and chemo-immunotherapeutic efficacy may also be applicable for cancers other than bladder cancer.
Unmet needs in ANCA-associated vasculitis: Physicians’ and patients’ perspectives
Authors: Quartuccio Luca , Treppo Elena , Urso Livio , Del Frate Giulia , Mescia Federica , Alberici Federico , Vaglio Augusto , Emmi Giacomo
Published: February 2023

In recent years, clinical research has increased significantly and therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have improved. However, there are still unanswered questions and unmet needs about AAV patients. The purpose of this review is to examine the frontiers of research related to emerging biomarkers eventually predicting relapse, and new therapeutic approaches, not to mention new quality of life assessment tools. Identifying predictors of relapse may help optimize therapeutic strategies, minimize disease recurrence, and reduce treatment-related side effects. In addition, it is important to recognize that patients may suffer long-term consequences of the disease and its treatment, which, although life-saving, is often associated with significant side effects. Our goal, therefore, is to highlight what has been achieved, the pitfalls, and what still needs to be done, comparing the views of physicians and patients.
An arginase1- and PD-L1-derived peptide-based vaccine for myeloproliferative neoplasms: A first-in-man clinical trial
Authors: Grauslund Jacob Handlos , Holmström Morten Orebo , Martinenaite Evelina , Lisle Thomas Landkildehus , Glöckner Hannah Jorinde , El Fassi Daniel , Klausen Uffe , Mortensen Rasmus E. J. , Jørgensen Nicolai , Kjær Lasse , Skov Vibe , Svane Inge Marie , Hasselbalch Hans Carl , Andersen Mads Hald
Published: February 2023

Introduction

Arginase-1 (ARG1) and Programed death ligand-1 (PD-L1) play a vital role in immunosuppression in myeloproliferative neoplasms (MPNs) and directly inhibit T-cell activation and proliferation. We previously identified spontaneous T-cell responses towards PD-L1 and ARG1 derived peptide epitopes in patients with MPNs. In the present First-in-Man study we tested dual vaccinations of ARG1- derived and PD-L1-derived peptides, combined with Montanide ISA-51 as adjuvant, in patients with Janus Kinase 2 (JAK2) V617F-mutated MPN.

Methods

Safety and efficacy of vaccination with ARG1- derived and PD-L1-derived peptides with montanide as an adjuvant was tested in 9 patients with MPN The primary end point was safety and toxicity evaluation. The secondary end point was assessment of the immune response to the vaccination epitope (www.clinicaltrials.gov identifier NCT04051307).

Results

The study included 9 patients with JAK2-mutant MPN of which 8 received all 24 planned vaccines within a 9-month treatment period. Patients reported only grade 1 and 2 vaccine related adverse events. No alterations in peripheral blood counts were identified, and serial measurements of the JAK2V617F allelic burden showed that none of the patients achieved a molecular response during the treatment period. The vaccines induced strong immune responses against both ARG1 and PD-L1- derived epitopes in the peripheral blood of all patients, and vaccine-specific skin-infiltrating lymphocytes from 5/6 patients could be expanded in vitro after a delayed-type hypersensitivity test. In two patients we also detected both ARG1- and PD-L1-specific T cells in bone marrow samples at the end of trial. Intracellular cytokine staining revealed IFNγ and TNFγ producing CD4+- and CD8+- T cells specific against both vaccine epitopes. Throughout the study, the peripheral CD8/CD4 ratio increased significantly, and the CD8+ TEMRA subpopulation was enlarged. We also identified a significant decrease in PD-L1 mRNA expression in CD14+ myeloid cells in the peripheral blood in all treated patients and a decrease in ARG1 mRNA expression in bone marrow of 6 out of 7 evaluated patients.

Conclusion

Overall, the ARG1- and PD-L1-derived vaccines were safe and tolerable and induced strong T-cell responses in all patients. These results warrant further studies of the vaccine in other settings or in combination with additional immune-activating treatments.
Glycan masking of a non-neutralising epitope enhances neutralising antibodies targeting the RBD of SARS-CoV-2 and its variants
Authors: Carnell George W. , Billmeier Martina , Vishwanath Sneha , Suau Sans Maria , Wein Hannah , George Charlotte L. , Neckermann Patrick , Del Rosario Joanne Marie M. , Sampson Alexander T. , Einhauser Sebastian , Aguinam Ernest T. , Ferrari Matteo , Tonks Paul , Nadesalingam Angalee , Schütz Anja , Huang Chloe Qingzhou , Wells David A. , Paloniemi Minna , Jordan Ingo , Cantoni Diego , Peterhoff David , Asbach Benedikt , Sandig Volker , Temperton Nigel , Kinsley Rebecca , Wagner Ralf , Heeney Jonathan L.
Published: February 2023

The accelerated development of the first generation COVID-19 vaccines has saved millions of lives, and potentially more from the long-term sequelae of SARS-CoV-2 infection. The most successful vaccine candidates have used the full-length SARS-CoV-2 spike protein as an immunogen. As expected of RNA viruses, new variants have evolved and quickly replaced the original wild-type SARS-CoV-2, leading to escape from natural infection or vaccine induced immunity provided by the original SARS-CoV-2 spike sequence. Next generation vaccines that confer specific and targeted immunity to broadly neutralising epitopes on the SARS-CoV-2 spike protein against different variants of concern (VOC) offer an advance on current booster shots of previously used vaccines. Here, we present a targeted approach to elicit antibodies that neutralise both the ancestral SARS-CoV-2, and the VOCs, by introducing a specific glycosylation site on a non-neutralising epitope of the RBD. The addition of a specific glycosylation site in the RBD based vaccine candidate focused the immune response towards other broadly neutralising epitopes on the RBD. We further observed enhanced cross-neutralisation and cross-binding using a DNA-MVA CR19 prime-boost regime, thus demonstrating the superiority of the glycan engineered RBD vaccine candidate across two platforms and a promising candidate as a broad variant booster vaccine.
Dysregulated low-density granulocyte contributes to early spontaneous abortion
Authors: Ye Hongxia , Li Lan , Dong Yajun , Zheng Qu , Sha Yulin , Li Li , Yang Panyu , Jia Yan , Gu Jiang
Published: February 2023

Spontaneous abortion (SA) is a common adverse pregnancy event with unclarified pathogenesis and limited therapeutic efficiency. Although most SA cases with the euploid embryo(s) are associated with immunological factors, the contribution of low-density granulocyte (LDG) in SA pathogenesis is rarely reported. This study aimed to investigate the serial characteristics and possible contribution of LDG and their subpopulations in early pregnancy, especially in early SA. Unpregnant (UP), normally pregnant (NP), and SA women were recruited, and the peripheral blood and endometrium/decidua were collected for LDG isolation and histological observation. The percentage, phenotype, and subpopulations of LDG were analyzed via flow cytometric analysis, and the ability of Nets formation was assessed by immunofluorescent and immunohistochemical assays. As a result, 43 participants were enrolled, including 10 UP, 15 NP, and 18 SA women. Compared with the UP group, the LDG percentage in peripheral blood mononuclear cells (PBMCs) and decidual immune cells (DICs) increased in the NP group, while the loss of this increase was observed in the SA group. Meanwhile, CD16int/− cell percentage in peripheral blood LDG (PB-LDG) increased in the NP and SA groups, and insufficient activation of CD16hi PB-LDG characterized by reduced CD11b expression was discovered in the SA group. Moreover, the LDG percentage in DICs was higher than that in PBMCs, and the decidual LDG (D-LDG) showed a surface marker expression profile that is easier to be activated in the pregnant cohort (NP + SA women). Finally, increased decidual Nets formation was observed in the SA group compared with the NP group, and more Nets formation was detected in D-LDG of NP and SA women following PMA stimulation. Overall, LDG participates in the maintenance of early pregnancy, while dysregulated LDG is responsible for early SA, providing novel potential targets for further exploration of SA pathogenesis and therapeutics.
E3-ubiquitin ligases and recent progress in osteoimmunology
Authors: Asano Yosuke , Matsumoto Yoshinori , Wada Jun , Rottapel Robert
Published: February 2023

Ubiquitin-mediated proteasomal degradation is a post-transcriptional protein modification that is comprised of various components including the 76-amino acid protein ubiquitin (Ub), Ub-activating enzyme (E1), Ub-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzyme (DUB) and proteasome. We and others have recently provided genetic evidence showing that E3-ubiquitin ligases are associated with bone metabolism, the immune system and inflammation through ubiquitylation and subsequent degradation of their substrates. Dysregulation of the E3-ubiquitin ligase RNF146-mediated degradation of the adaptor protein 3BP2 (SH3 domain-binding protein 2) causes cherubism, an autosomal dominant disorder associated with severe inflammatory craniofacial dysmorphia syndrome in children. In this review, on the basis of our discoveries in cherubism, we summarize new insights into the roles of E3-ubiquitin ligases in the development of human disorders caused by an abnormal osteoimmune system by highlighting recent genetic evidence obtained in both human and animal model studies.
Orally administered Lactiplantibacillus plantarum OLL2712 decreased intestinal permeability, especially in the ileum: Ingested lactic acid bacteria alleviated obesity-induced inflammation by collaborating with gut microbiota
Authors: Wang Yimei , Takano Tomohiro , Zhou Yingyu , Wang Rong , Toshimitsu Takayuki , Sashihara Toshihiro , Tanokura Masaru , Miyakawa Takuya , Nakajima-Adachi Haruyo , Hachimura Satoshi
Published: February 2023

Introduction

Chronic inflammation caused by dietary obesity has been considered to induce lifestyle-related diseases and functional ingredients with anti-inflammatory effects are attracting attention. Although multiple studies on obesity had proved the anti-inflammatory effects of ingestion of lactic acid bacteria (LAB) and other functional ingredients on adipose tissue, the precise effects on the intestine, especially on the individual intestinal segments have not been made clear. In this study, we elucidated the mechanisms of Lactiplantibacillus plantarum (basonym: Lactobacillus plantarum) OLL2712 in suppressing obesity-induced inflammation using high fat diet (HFD)-fed mice obesity model.

Methods

We orally administered heat-treated LAB to HFD-fed mice model, and investigated the inflammatory changes in adipose tissue and intestinal immune cells. We also analyzed gut microbiota, and evaluated the inflammation and permeability of the duodenum, jejunum, ileum and colon; four intestinal segments differing in gut bacteria composition and immune response.

Results

After 3-week LAB administration, the gene expression levels of proinflammatory cytokines were downregulated in adipose tissue, colon, and Peyer’s patches (PP)-derived F4/80+ cells. The LAB treatment alleviated obesity-related gut microbiota imbalance. L. plantarum OLL2712 treatment helps maintain intestinal barrier function, especially in the ileum, possibly by preventing ZO-1 and Occludin downregulation.

Discussion

Our results suggest that the oral administration of the LAB strain regulated the gut microbiota, suppressed intestinal inflammation, and improved the gut barrier, which could inhibit the products of obesity-induced gut dysbiosis from translocating into the bloodstream and the adipose tissue, through which the LAB finally alleviated the inflammation caused by dietary obesity. Barrier improvement was observed, especially in the ileum, suggesting collaborative modulation of the intestinal immune responses by ingested LAB and microbiota.
Understanding fibroblast-immune cell interactions via co-culture models and their role in asthma pathogenesis
Authors: Thiam F. , Yazeedi S. Al , Feng K. , Phogat S. , Demirsoy E. , Brussow J. , Abokor F. A. , Osei E. T.
Published: February 2023

Asthma is a chronic lung disease involving airway inflammation and fibrosis. Fibroblasts are the main effector cells important for lung tissue production which becomes abnormal in asthmatics and is one of the main contributors to airway fibrosis. Although fibroblasts were traditionally viewed solely as structural cells, they have been discovered to be highly active, and involved in lung inflammatory and fibrotic processes in asthma. In line with this, using 2D and 3D in vitro co-culture models, a complex interaction between lung fibroblasts and various immune cells important for the pathogenesis of asthma have been recently uncovered. Hence, in this review, we provide the first-ever summary of various studies that used 2D and 3D in vitro co-culture models to assess the nature of aberrant immune cell-fibroblast interactions and their contributions to chronic inflammation and fibrotic mechanisms in asthma pathogenesis.
NF-κB in monocytes and macrophages – an inflammatory master regulator in multitalented immune cells
Authors: Mussbacher Marion , Derler Martina , Basílio José , Schmid Johannes A.
Published: February 2023

Nuclear factor κB (NF-κB) is a dimeric transcription factor constituted by two of five protein family members. It plays an essential role in inflammation and immunity by regulating the expression of numerous chemokines, cytokines, transcription factors, and regulatory proteins. Since NF-κB is expressed in almost all human cells, it is important to understand its cell type-, tissue-, and stimulus-specific roles as well as its temporal dynamics and disease-specific context. Although NF-κB was discovered more than 35 years ago, many questions are still unanswered, and with the availability of novel technologies such as single-cell sequencing and cell fate-mapping, new fascinating questions arose. In this review, we will summarize current findings on the role of NF-κB in monocytes and macrophages. These innate immune cells show high plasticity and dynamically adjust their effector functions against invading pathogens and environmental cues. Their versatile functions can range from antimicrobial defense and antitumor immune responses to foam cell formation and wound healing. NF-κB is crucial for their activation and balances their phenotypes by finely coordinating transcriptional and epigenomic programs. Thereby, NF-κB is critically involved in inflammasome activation, cytokine release, and cell survival. Macrophage-specific NF-κB activation has far-reaching implications in the development and progression of numerous inflammatory diseases. Moreover, recent findings highlighted the temporal dynamics of myeloid NF-κB activation and underlined the complexity of this inflammatory master regulator. This review will provide an overview of the complex roles of NF-κB in macrophage signal transduction, polarization, inflammasome activation, and cell survival.
Prognostic model for predicting outcome and guiding treatment decision for unresectable hepatocellular carcinoma treated with lenvatinib monotherapy or lenvatinib plus immunotherapy
Authors: Guo De-Zhen , Zhang Shi-Yu , Dong San-Yuan , Yan Jia-Yan , Wang Yu-Peng , Cao Ya , Rao Sheng-Xiang , Fan Jia , Yang Xin-Rong , Huang Ao , Zhou Jian
Published: February 2023

Background

Lenvatinib monotherapy and combination therapy with immune checkpoint inhibitors (ICI) were widely applied for unresectable hepatocellular carcinoma (uHCC). However, many patients failed to benefit from the treatments. A prognostic model was needed to predict the treatment outcomes and guide clinical decisions.

Methods

304 patients receiving lenvatinib monotherapy or lenvatinib plus ICI for uHCC were retrospectively included. The risk factors derived from the multivariate analysis were used to construct the predictive model. The C-index and area under the receiver-operating characteristic curve (AUC) were calculated to assess the predictive efficiency.

Results

Multivariate analysis revealed that protein induced by vitamin K absence or antagonist-II (PIVKA-II) (HR, 2.05; P=0.001) and metastasis (HR, 2.07; P<0.001) were independent risk factors of overall survival (OS) in the training cohort. Herein, we constructed a prognostic model called PIMET score and stratified patients into the PIMET-low group (without metastasis and PIVKA-II<600 mAU/mL), PIMET-int group (with metastasis or PIVKA-II>600 mAU/mL) and PIMET-high group (with metastasis and PIVKA-II>600 mAU/mL). The C-index of PIMET score for the survival prediction was 0.63 and 0.67 in the training and validation cohort, respectively. In the training cohort, the AUC of 12-, 18-, and 24-month OS was 0.661, 0.682, and 0.744, respectively. The prognostic performances of the model were subsequently validated. The AUC of 12-, 18-, and 24-month OS was 0.724, 0.726, and 0.762 in the validation cohort. Subgroup analyses showed consistent predictive value for patients receiving lenvatinib monotherapy and patients receiving lenvatinib plus ICI. The PIMET score could also distinguish patients with different treatment responses. Notably, the combination of lenvatinib and ICI conferred survival benefits to patients with PIMET-int or PIMET-high, instead of patients with PIMET-low.

Conclusion

The PIMET score comprising metastasis and PIVKA-II could serve as a helpful prognostic model for uHCC receiving lenvatinib monotherapy or lenvatinib plus ICI. The PIMET score could guide the treatment decision and facilitate precision medicine for uHCC patients.
The long-term observation of the rotation of implantable collamer lens as the management of high postoperative vault
Authors: Jiang Yang , Luo Yan , Li Ying , Lu Thomas
Published: February 2023

Purpose

This study aimed to describe the effectiveness and stability of implantable collamer lens (ICL) rotation in reducing high postoperative vault.

Setting

This study was conducted in the Peking Union Medical College Hospital, Chinese Academy of Medical Sciences.

Design

This is a retrospective case series.

Methods

Twenty-two eyes from 22 patients who had ICL (V4c EVO) implantation with high postoperative vault (>=750 μm) were recruited for our study. All the lenses were rotated from a horizontal to an oblique position. The vault, SSA, AOD500, AOD750, TISA500, and TISA750 at 180° and 0° were measured pre-rotation, 1-week post-rotation, and in the at-least 1-year-follow-up.

Results

Twenty female patients and two male patients were recruited, with a mean age of 28.68 ± 6.08 years. The mean vault had declined significantly from 951.81 ± 154.26 μm pre-rotation to 772.27 ± 119.40 μm 1 week post-rotation (p < 0.001). The SSA, AOD500, AOD750, TISA500, and TISA750 at 180° and 0° pre-rotation and 1-week post-rotation were 30.40 ± 7.91° and 45.14 ± 6.75°, 32.37 ± 7.48° and 46.23 ± 6.39°, 303.27 ± 87.99 and 522.45 ± 122.16 μm, 323.81 ± 89.15 and 536.13 ± 121.66 μm, 387.95 ± 99.43 and 630.81 ± 133.59 μm, 435.68 ± 106.72 and 643.36 ± 132.82 μm, 0.109 ± 0.034 and 0.202 ± 0.053 mm2, 0.123 ± 0.034 and 0.212 ± 0.051 mm2, 0.194 ± 0.056 and 0.345 ± 0.083 mm2, and 0.216 ± 0.055 and 0.358 ± 0.079 mm2 (all p < 0.001). The mean vault value had changed from 747.50 ± 116.07 μm 1-week post-rotation to 586.87 ± 132.65 μm in the 1-year follow-up. However, the SSA, AOD500, AOD750, TISA500, and TISA750 at 180° and 0° had remained stable (p > 0.05).

Conclusion

Non-toric ICL rotation is a novel and effective technique in the treatment of high postoperative vault. Our results are more robust given the extended period of follow-up.
Effectiveness and safety of cataract surgery in laminar air flow device versus traditional scrubs: A 1-year non-inferiority pilot study
Authors: Artus Arnaud , Fabro Filippo , Cochereau Isabelle , Caputo Georges , Tadayoni Ramin , Vignal Catherine , Galatoire Olivier , Salviat Flore , Gatinel Damien , Panthier Christophe
Published: February 2023

Purpose

The study aimed to assess the safety and the non-inferiority of cataract surgery outside an operating room using the Surgicube®, a mobile laminar airflow (LAF) device.

Settings

This single-center study was conducted at the Rothschild Foundation, Paris, France.

Design

This is a retrospective cross-sectional study.

Methods

All patients operated on for cataracts using the Surgicube® between February 2020 and February 2021 were included and controlled by a cohort of patients operated on for cataracts in the traditional theater during the same period. Patients with a postoperative follow-up of less than 1 month were excluded. Data collection was carried out using the patient’s medical record. The primary endpoint was the evaluation of the number of endophthalmitis in the two groups. The secondary judgment criteria were the analysis of the various complications and the Logmar visual acuity at 1 month in the two groups. All the patients underwent an OCT retinal examination.

Results

A total of 923 randomized patients who underwent cataract surgery between 2020 and 2021 have been included in the study. Among them, 448 patients were operated on using the Surgicube, and 475 patients underwent surgery in the traditional operating room using the same lens phacoemulsification technique. There are no significant differences between the two groups (p > 0.05).

Conclusion

Cataract surgery using the Surgicube® outside a conventional operating room seems non-inferior to conventional scrub.
Persistent flocks of diverse motile bacteria in long-term incubations of electron-conducting cable bacteria, Candidatus Electronema aureum
Authors: Lustermans Jamie J. M. , Bjerg Jesper J. , Burdorf Laurine D. W. , Nielsen Lars Peter , Schramm Andreas , Marshall Ian P. G.
Published: February 2023

Cable bacteria are centimeters-long filamentous bacteria that oxidize sulfide in anoxic sediment layers and reduce oxygen at the oxic-anoxic interface, connecting these reactions via electron transport. The ubiquitous cable bacteria have a major impact on sediment geochemistry and microbial communities. This includes diverse bacteria swimming around cable bacteria as dense flocks in the anoxic zone, where the cable bacteria act as chemotactic attractant. We hypothesized that flocking only appears when cable bacteria are highly abundant and active. We set out to discern the timing and drivers of flocking over 81 days in an enrichment culture of the freshwater cable bacterium Candidatus Electronema aureum GS by measuring sediment microprofiles of pH, oxygen, and electric potential as a proxy of cable bacteria activity. Cable bacterial relative abundance was quantified by 16S rRNA amplicon sequencing, and microscopy observations to determine presence of flocking. Flocking was always observed at some cable bacteria, irrespective of overall cable bacteria rRNA abundance, activity, or sediment pH. Diverse cell morphologies of flockers were observed, suggesting that flocking is not restricted to a specific, single bacterial associate. This, coupled with their consistent presence supports a common mechanism of interaction, likely interspecies electron transfer via electron shuttles. Flocking appears exclusively linked to the electron conducting activity of the individual cable bacteria.
Diet and high altitude strongly drive convergent adaptation of gut microbiota in wild macaques, humans, and dogs to high altitude environments
Authors: Zhao Junsong , Yao Yongfang , Dong Mengmeng , Xiao Hongtao , Xiong Ying , Yang Shengzhi , Li Diyan , Xie Meng , Ni Qingyong , Zhang Mingwang , Xu Huailiang
Published: February 2023

Animal gut microbiota plays an indispensable role in host adaptation to different altitude environments. At present, little is known about the mechanism of animal gut microbiota in host adaptation to high altitude environments. Here, we selected wild macaques, humans, and dogs with different levels of kinship and intimate relationships in high altitude and low altitude environments, and analyzed the response of their gut microbiota to the host diet and altitude environments. Alpha diversity analysis found that at high altitude, the gut microbiota diversity of wild macaques with more complex diet in the wild environments is much higher than that of humans and dogs with simpler diet (p < 0.05), and beta diversity analysis found that the UniFrac distance between humans and dogs was significantly lower than between humans and macaques (p < 0.05), indicating that diet strongly drive the convergence of gut microbiota among species. Meanwhile, alpha diversity analysis found that among three subjects, the gut microbiota diversity of high altitude population is higher than that of low altitude population (ACE index in three species, Shannon index in dog and macaque and Simpson index in dog, p < 0.05), and beta diversity analysis found that the UniFrac distances among the three subjects in the high altitude environments were significantly lower than in the low altitude environments (p < 0.05). Additionally, core shared ASVs analysis found that among three subjects, the number of core microbiota in high altitude environments is higher than in low altitude environments, up to 5.34 times (1,105/207), and the proportion and relative abundance of the core bacteria types in each species were significantly higher in high altitude environments than in low altitude environments (p < 0.05). The results showed that high altitude environments played an important role in driving the convergence of gut microbiota among species. Furthermore, the neutral community model trial found that the gut microbiota of the three subjects was dispersed much more at high altitude than at low altitude, implying that the gut microbiota convergence of animals at high altitudes may be partly due to the microbial transmission between hosts mediated by human activities.
Research progress and hotspot analysis of rhizosphere microorganisms based on bibliometrics from 2012 to 2021
Authors: Sun Shangsheng , Xue Ruipeng , Liu Mengyue , Wang Liqing , Zhang Wei
Published: February 2023

Rhizosphere microorganisms are important organisms for plant growth promotion and bio-control. To understand the research hot topics and frontier trends of rhizosphere microorganisms comprehensively and systematically, we collected 6,056 publications on rhizosphere microorganisms from Web of Science and performed a bibliometric analysis by CiteSpace 6.1.3 and R 5.3.1. The results showed that the total number of references issued in this field has been on the rise in the past decades. China, India, and Pakistan are the top three countries in terms of the number of articles issued, while Germany, the United States, and Spain were the countries with the highest number of co-published papers with other countries. The core research content in this field were the bio-control, bacterial community, ACC deaminase, phytoremediation, induced systematic resistance, and plant growth promotion. Seeding growth, Bacillus velezensis, plant-growth, and biological-control were currently and may be the highlights in the field of rhizosphere microorganisms research for a long time in the future. The above study results quantitatively, objectively, and scientifically described the research status and research focus of rhizosphere microorganisms from 2012 to 2021 from the perspective of referred papers, with a view to promoting in-depth research in this field and providing reference information for scholars in related fields to refine research trends and scientific issues.
Metabolomics-based response of Salmonella to desiccation stress and skimmed milk powder storage
Authors: Li Shaoting , Chen Yingqi , Zeng Ji , Zeng Haiyan , Ma Zhuolin , Chen Siyi , Yang Yuheng , Zhang Hongmei
Published: February 2023

The strong survival ability of Salmonella in low-moisture foods (LMFs) has been of public concern, and is considered a threat to people’s health. Recently, the development of omics technology has promoted research on the molecular mechanisms of the desiccation stress response of pathogenic bacteria. However, multiple analytical aspects related to their physiological characteristics remain unclear. We explored the physiological metabolism changes of S. enterica Enteritidis exposed to a 24 h-desiccation treatment and a subsequent 3-month desiccation storage in skimmed milk powder (SMP) with an approach of gas chromatography–mass spectrometry (GC–MS) and ultra-performance liquid chromatography-Q Exactive-mass spectrometry (UPLC-QE-MS). A total of 8,292 peaks were extracted, of which 381 were detected by GC–MS and 7,911 peaks were identified by LC–MS/MS, respectively. Through analyses of differentially expressed metabolites (DEMs) and key pathways, a total of 58 DEMs emerged from the 24 h-desiccation treatment, which exhibited the highest relevance for five metabolic pathways, involving glycine, serine, and threonine metabolism, pyrimidine metabolism, purine metabolism, vitamin B6 metabolism, and pentose phosphate pathway. After 3-month SMP storage, 120 DEMs were identified, which were related to several regulatory pathways including arginine and proline metabolism, serine and threonine metabolism, β-alanine metabolism, glycerolipid metabolism, and glycolysis. The analyses of key enzyme activities of XOD, PK, and G6PDH and ATP content provided further evidence that supported the metabolic responses such as nucleic acid degradation, glycolysis, and ATP production played an important role in Salmonella’s adaptation to desiccation stress. This study enables a better understanding of metabolomics-based responses of Salmonella at the initial stage of desiccation stress and the following long-term adaptive stage. Meanwhile, the identified discriminative metabolic pathways may serve as potentially useful targets in developing strategies for the control and prevention of desiccation-adapted Salmonella in LMFs.
A rapid, accurate, and low-cost method for detecting Mycobacterium tuberculosis and its drug-resistant genes in pulmonary tuberculosis: Applications of MassARRAY DNA mass spectrometry
Authors: Yang Han , Li Aifang , Dang Liyun , Kang Tao , Ren Fei , Ma Jinbao , Zhou Yong , Yang Yuanli , Lei Jing , Zhang Tao
Published: February 2023

Introduction

Mycobacterium tuberculosis (MTB) identification and drug resistance diagnosis are very important for treatment of drug-resistant tuberculosis (DR-TB). Therefore, high throughput, accurate and low-cost molecular detection techniques are urgently needed. This study aimed to evaluate the clinical application value of MassARRAY in tuberculosis diagnosis and drug resistance screening.

Methods

The limit of detection (LOD) and clinical application value of MassARRAY were evaluated using reference strains and clinical isolates. MTB in bronchoalveolar lavage fluid (BALF) and sputum samples were detected using MassARRAY, quantitative real-time polymerase chain reaction (qPCR) and MGIT960 liquid culture (culture). Using culture as the standard, the efficacy of MassARRAY and qPCR for the detection of TB was analyzed. Mutation of drug resistance genes in MTB clinical isolates was tested using MassARRAY, high-resolution melting curve (HRM), and Sanger sequencing. Using sequencing as the standard, the efficacy of MassARRAY, and HRM for the detection of each drug resistance site of MTB was analyzed. Simultaneously, the mutation of drug resistance genes by the MassARRAY method was compared with the results of drug susceptibility testing (DST), and the genotype–phenotype relationship was analyzed. The ability of MassARRAY to discriminate mixed infections was detected using mixtures of standard strains (M. tuberculosis H37Rv) and drug-resistant clinical isolates and mixtures of wild-type and mutant plasmids.

Results

In MassARRAY, 20 related gene mutations could be detected by two PCR systems. All genes could be accurately detected when the bacterial load was 104 CFU/mL. When the load of wild-type and drug-resistant MTB mixture was 105 CFU/mL (respectively reached 104 CFU/mL), variants and wild-type genes could be detected simultaneously. The sensitivity of MassARRAY (96.9%) for identification was higher than that of qPCR (87.5%) (p < 0.001). The sensitivity and specificity of MassARRAY for all drug resistance gene mutations were 100.0%, with higher accuracy and consistency than HRM (sensitivity = 89.3% and specificity = 96.9%, p = 0.001). Analyzing the relationship between MassARRAY genotype and DST phenotype, the accuracy of katG_315, rpoB_531, rpsL_43, rpsL_88, and rrs_513 sites was 100.0%, and embB_306 and rpoB_526 were inconsistent with the DST results when the base changes were different.

Discussion

MassARRAY can obtain base mutation information and identify heteroresistance infections simultaneously when the mutant proportion was at least 5–25%. It has good application prospects in the diagnosis of DR-TB with high throughput, accurate and low-cost.
Impacts of meteorological factors on the risk of scrub typhus in China, from 2006 to 2020: A multicenter retrospective study
Authors: Han Ling , Sun Zhaobin , Li Ziming , Zhang Yunfei , Tong Shilu , Qin Tian
Published: February 2023

Scrub typhus is emerging as a global public health threat owing to its increased prevalence and remarkable geographic expansion. However, it remains a neglected disease, and possible influences of meteorological factors on its risk are poorly understood. We conducted the largest-scale research to assess the impact of meteorological factors on scrub typhus in China. Weekly data on scrub typhus cases and meteorological factors were collected across 59 prefecture-level administrative regions from 2006 to 2020. First, we divided these regions into 3 regions and analyzed the epidemiological characteristics of scrub typhus. We then applied the distributed lag nonlinear model, combined with multivariate meta-analysis, to examine the associations between meteorological factors and scrub typhus incidence at the total and regional levels. Subsequently, we identified the critical meteorological predictors of scrub typhus incidence and extracted climate risk windows. We observed distinct epidemiological characteristics across regions, featuring obvious clustering in the East and Southwest with more even distribution and longer epidemic duration in the South. The mean temperature and relative humidity had profound effects on scrub typhus with initial-elevated-descendent patterns. Weather conditions of weekly mean temperatures of 25–33°C and weekly relative humidity of 60–95% were risk windows for scrub typhus. Additionally, the heavy rainfall was associated with sharp increase in scrub typhus incidence. We identified specific climatic signals to detect the epidemic of scrub typhus, which were easily monitored to generalize. Regional heterogeneity should be considered for targeted monitoring and disease control strategies.
Mutation-driven parallel evolution in emergence of ACE2-utilizing sarbecoviruses
Authors: Gao Bin , Zhu Shunyi
Published: February 2023

Mutation and recombination are two major genetic mechanisms that drive the evolution of viruses. They both exert an interplay during virus evolution, in which mutations provide a first ancestral source of genetic diversity for subsequent recombination. Sarbecoviruses are a group of evolutionarily related β-coronaviruses including human severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 and a trove of related animal viruses called SARS-like CoVs (SL-CoVs). This group of members either use or not use angiotensin-converting enzyme 2 (ACE2) as their entry receptor, which has been linked to the properties of their spike protein receptor binding domains (RBDs). This raises an outstanding question regarding how ACE2 binding originated within sarbecoviruses. Using a combination of analyses of phylogenies, ancestral sequences, structures, functions and molecular dynamics, we provide evidence in favor of an evolutionary scenario, in which three distinct ancestral RBDs independently developed the ACE2 binding trait via parallel amino acid mutations. In this process, evolutionary intermediate RBDs might be firstly formed through loop extensions to offer key functional residues accompanying point mutations to remove energetically unfavorable interactions and to change the dynamics of the functional loops, all required for ACE2 binding. Subsequent optimization in the context of evolutionary intermediates led to the independent emergence of ACE2-binding RBDs in the SARS-CoV and SARS-CoV-2 clades of Asian origin and the clade comprising SL-CoVs of European and African descent. These findings will help enhance our understanding of mutation-driven evolution of sarbecoviruses in their early history.
Environment or genetic isolation? An atypical intestinal microbiota in the Maltese honey bee Apis mellifera spp. ruttneri
Authors: Gaggìa Francesca , Jakobsen Rasmus Riemer , Alberoni Daniele , Baffoni Loredana , Cutajar Simone , Mifsud David , Nielsen Dennis Sandris , Di Gioia Diana
Published: February 2023

Introduction

Apis mellifera evolved mainly in African, Asian, and European continents over thousands of years, leading to the selection of a considerable number of honey bees subspecies that have adapted to various environments such as hot semi-desert zones and cold temperate zones. With the evolution of honey bee subspecies, it is possible that environmental conditions, food sources, and microbial communities typical of the colonized areas have shaped the honey bee gut microbiota.

Methods

In this study the microbiota of two distinct lineages (mitochondrial haplotypes) of bees Apis mellifera ruttneri (lineage A) and Apis mellifera ligustica and carnica (both lineage C) were compared. Honey bee guts were collected in a dry period in the respective breeding areas (the island of Malta and the regions of Emilia-Romagna and South Tyrol in Italy). Microbial DNA from the honey bee gut was extracted and amplified for the V3-V4 regions of the 16S rRNA gene for bacteria and for ITS2 for fungi.

Results

The analyses carried out show that the Maltese lineage A honey bees have a distinctive microbiota when compared to Italian lineage C honey bees, with the most abundant genera being Bartonellaceae and Lactobacillaceae, respectively. Lactobacillaceae in Maltese Lineage A honey bees consist mainly of Apilactobacillus instead of Lactobacillus and Bombilactobacillus in the lineage C. Lineage A honey bee gut microbiota also harbors higher proportions of Arsenophonus, Bombella, Commensalibacter, and Pseudomonas when compared to lineage C.

Discussion

The environment seems to be the main driver in the acquisition of these marked differences in the gut microbiota. However, the influence of other factors such as host genetics, seasonality or geography may still play a significant role in the microbiome shaping, in synergy with the environmental aspects.
Bacterial taxonomic and functional profiles from Bohai Sea to northern Yellow Sea
Authors: Niu Tianyi , Xu Yongqian , Chen Jinni , Qin Liangyun , Li Zhicong , Yang Yating , Liang Jiayuan
Published: February 2023

Microbial distribution patterns are the result of a combination of biotic and abiotic factors, which are the core issues in microbial ecology research. To better understand the biogeographic pattern of bacteria in water environments from the Bohai Sea to the northern Yellow Sea, the effects of environmental factors, and spatial distance on the structure of bacterial communities in marine water were investigated using high-throughput sequencing technology based on 16S rRNA genes. The results showed that Proteobacteria, Bacteroidetes, Actinobacteri, Desulfobacterota, and Bdellovibrionota were the dominant phyla in the study area. A clear spatial pattern in the bacterial community was observed, and environmental factors, including salinity, nutrient concentration, carbon content, total phosphorus, dissolved oxygen, and seawater turbidity emerged as the central environmental factors regulating the variation in bacterial communities. In addition, the study provides direct evidence of the existence of dispersal limitation in this strongly connected marine ecological system. Therefore, these results revealed that the variation in bacterial community characteristics was attributed to environmental selection, accompanied by the regulation of stochastic diffusion. The network analysis demonstrated a nonrandom co-occurrence pattern in the microbial communities with distinct spatial distribution characteristics. It is implied that the biogeography patterns of bacterial community may also be associated with the characteristics of co-occurrence characterize among bacterial species. Furthermore, the PICRUSt analysis indicated a clear spatial distribution of functional characteristics in bacterial communities. This functional variation was significantly modulated by the environmental characteristics of seawater but uncoupled from the taxonomic characteristics of bacterial communities (e.g., diversity characteristics, community structure, and co-occurrence relationships). Together, this findings represent a significant advance in linking seawater to the mechanisms underlying bacterial biogeographic patterns and community assembly, co-occurrence patterns, and ecological functions, providing new insights for identifying the microbial ecology as well as the biogeochemical cycle in the marine environment.
Lipid environment determines the drug-stimulated ATPase activity of P-glycoprotein
Authors: Tran Nghi N. B. , Bui A. T. A. , Jaramillo-Martinez Valeria , Weber Joachim , Zhang Qinghai , Urbatsch Ina L.
Published: February 2023

P-glycoprotein (Pgp) is a multidrug transporter that uses the energy from ATP binding and hydrolysis to export from cells a wide variety of hydrophobic compounds including anticancer drugs, and mediates the bioavailability and pharmacokinetics of many drugs. Lipids and cholesterol have been shown to modulate the substrate-stimulated ATPase activity of purified Pgp in detergent solution and the substrate transport activity after reconstitution into proteoliposomes. While lipid extracts from E. coli, liver or brain tissues generally support well Pgp’s functionality, their ill-defined composition and high UV absorbance make them less suitable for optical biophysical assays. On the other hand, studies with defined synthetic lipids, usually the bilayer-forming phosphatidylcholine with or without cholesterol, are often plagued by low ATPase activity and low binding affinity of Pgp for drugs. Drawing from the lipid composition of mammalian plasma membranes, we here investigate how different head groups modulate the verapamil-stimulated ATPase activity of purified Pgp in detergent-lipid micelles and compare them with components of E. coli lipids. Our general approach was to assay modulation of verapamil-stimulation of ATPase activity by artificial lipid mixtures starting with the bilayer-forming palmitoyloyl-phosphatidylcholine (POPC) and -phosphatidylethanolamine (POPE). We show that POPC/POPE supplemented with sphingomyelin (SM), cardiolipin, or phosphatidic acid enhanced the verapamil-stimulated activity (Vmax) and decreased the concentration required for half-maximal activity (EC50). Cholesterol (Chol) and more so its soluble hemisuccinate derivative cholesteryl hemisuccinate substantially decreased EC50, perhaps by supporting the functional integrity of the drug binding sites. High concentrations of CHS (>15%) resulted in a significantly increased basal activity which could be due to binding of CHS to the drug binding site as transport substrate or as activator, maybe acting cooperatively with verapamil. Lastly, Pgp reconstituted into liposomes or nanodiscs displayed higher basal activity and sustained high levels of verapamil stimulated activity. The findings establish a stable source of artificial lipid mixtures containing either SM and cholesterol or CHS that restore Pgp functionality with activities and affinities similar to those in the natural plasma membrane environment and will pave the way for future functional and biophysical studies.