bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and validation of polyamines metabolism-associated gene signatures to predict prognosis and immunotherapy response in lung adenocarcinoma
Authors: Wang Ning , Chai Mengyu , Zhu Lingye , Liu Jingjing , Yu Chang , Huang Xiaoying
Published: June 2023

Background

Polyamines metabolism is closely related to tumor development and progression, as well as tumor microenvironment (TME). In this study, we focused on exploring whether polyamines metabolism-associated genes would provide prognosis and immunotherapy response prediction in lung adenocarcinoma (LUAD).

Methods

The expression profile data of polyamines metabolism-associated genes were acquired from the Cancer Genome Atlas (TCGA) database. Utilizing the least absolute shrinkage and selection operator (LASSO) algorithm, we created a risk score model according to polyamines metabolism-associated gene signatures. Meanwhile, an independent cohort (GSE72094) was employed to validate this model. Through the univariate and multivariate Cox regression analyses, the independent prognostic factors were identified. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect their expression in LUAD cells. By consensus clustering analysis, polyamines metabolism-associated subgroups were determined in LUAD patients, with differential gene expression, prognosis, and immune characteristics analyses explored.

Results

A total of 59 polyamines metabolism genes were collected for this study, of which 14 genes were identified for the construction of risk score model using LASSO method. High- and low- risk groups of LUAD patients in TCGA cohort were distinguished via this model, and high-risk group presented dismal clinical outcomes. The same prognostic prediction of this model had been also validated in GSE72094 cohort. Meanwhile, three independent prognostic factors (PSMC6, SMOX, SMS) were determined for constructing the nomogram, and they were all upregulated in LUAD cells. In addition, two distinct subgroups (C1 and C2) were identified in LUAD patients. Comparing the two subgroups, 291 differentially expressed genes (DEGs) were acquired, mainly enriching in organelle fission, nuclear division, and cell cycle. Comparing to C1 subgroup, the patients in C2 subgroup had favorable clinical outcomes, increased immune cells infiltration, and effective immunotherapy response.

Conclusion

This study identified polyamines metabolism-associated gene signatures for predicting the patients’ survival, and they were also linked to immune cells infiltration and immunotherapy response in LUAD patients.
IL-27-containing exosomes secreted by innate B-1a cells suppress and ameliorate uveitis
Authors: Kang Minkyung , Yadav Manoj Kumar , Mbanefo Evaristus C. , Yu Cheng-Rong , Egwuagu Charles E.
Published: June 2023

Introduction

IL-27 is a heterodimeric cytokine composed of Ebi3 and IL-27p28 and can exert proinflammatory or immune suppressive effects depending on the physiological context. Ebi3 does not contain membrane-anchoring motifs, suggesting that it is a secreted protein while IL-27p28 is poorly secreted. How IL-27p28 and Ebi3 dimerize in-vivo to form biologically active IL-27 is unknown. Major impediment to clinical use of IL-27 derives from difficulty of determining exact amount of bioavailable heterodimeric IL-27 needed for therapy.

Methods

To understand how IL-27 mediates immune suppression, we characterized an innate IL-27-producing B-1a regulatory B cell population (i27-Breg) and mechanisms i27-Bregs utilize to suppress neuroinflammation in mouse model of uveitis. We also investigated biosynthesis of IL-27 and i27-Breg immunobiology by FACS, immunohistochemical and confocal microscopy.

Results

Contrary to prevailing view that IL-27 is a soluble cytokine, we show that i27-Bregs express membrane-bound IL-27. Immunohistochemical and confocal analyses co-localized expression of IL-27p28 at the plasma membrane in association with CD81 tetraspanin, a BCR-coreceptor protein and revealed that IL-27p28 is a transmembrane protein in B cells. Most surprising, we found that i27-Bregs secrete IL-27-containing exosomes (i27-exosomes) and adoptive transfer of i27-exosomes suppressed uveitis by antagonizing Th1/Th17 cells, up-regulating inhibitory-receptors associated with T-cell exhaustion while inducing Treg expansion.

Discussion

Use of i27-exosomes thus obviates the IL-27 dosing problem, making it possible to determine bioavailable heterodimeric IL-27 needed for therapy. Moreover, as exosomes readily cross the blood-retina-barrier and no adverse effects were observed in mice treated with i27-exosome, results of this study suggest that i27-exosomes might be a promising therapeutic approach for CNS autoimmune diseases.
SAPrIm, a semi-automated protocol for mid-throughput immunopeptidomics
Authors: Lim Kam Sian Terry C. C. , Goncalves Gabriel , Steele Joel R. , Shamekhi Tima , Bramberger Liesl , Jin Dongbin , Shahbazy Mohammad , Purcell Anthony W. , Ramarathinam Sri , Stoychev Stoyan , Faridi Pouya
Published: June 2023

Human leukocyte antigen (HLA) molecules play a crucial role in directing adaptive immune responses based on the nature of their peptide ligands, collectively coined the immunopeptidome. As such, the study of HLA molecules has been of major interest in the development of cancer immunotherapies such as vaccines and T-cell therapies. Hence, a comprehensive understanding and profiling of the immunopeptidome is required to foster the growth of these personalised solutions. We herein describe SAPrIm, an Immunopeptidomics tool for the Mid-Throughput era. This is a semi-automated workflow involving the KingFisher platform to isolate immunopeptidomes using anti-HLA antibodies coupled to a hyper-porous magnetic protein A microbead, a variable window data independent acquisition (DIA) method and the ability to run up to 12 samples in parallel. Using this workflow, we were able to concordantly identify and quantify ~400 - 13000 unique peptides from 5e5 - 5e7 cells, respectively. Overall, we propose that the application of this workflow will be crucial for the future of immunopeptidome profiling, especially for mid-size cohorts and comparative immunopeptidomics studies.
Frequent IgE recognition of Blomia tropicalis allergen molecules in asthmatic children and young adults in equatorial Africa
Authors: Pauli Gabrielle , Wurmser Carole , Roos Antoine , Kokou Cosme , Huang Huey-Jy , D’souza Nishelle , Lupinek Christian , Zakzuk Josefina , Regino Ronald , Acevedo Nathalie , Caraballo Luis , Vrtala Susanne , Valenta Rudolf
Published: June 2023

Background

Asthma is not well investigated in equatorial Africa and little is known about the disease-associated allergen molecules recognized by IgE from patients in this area. The aim was to study the molecular IgE sensitization profile of asthmatic children and young adults in a semi-rural area (Lambaréné) of an equatorial African country (Gabon), to identify the most important allergen molecules associated with allergic asthma in equatorial Africa.

Methods

Fifty-nine asthmatic patients, mainly children and few young adults, were studied by skin prick testing to Dermatophagoides pteronyssinus (Der p), D. farinae (Der f), cat, dog, cockroach, grass, Alternaria and peanut. Sera were obtained from a subset of 35 patients, 32 with positive and 3 with negative skin reaction to Der p and tested for IgE reactivity to 176 allergen molecules from different allergen sources by ImmunoCAP ISAC microarray technology and to seven recombinant Blomia tropicalis (Blo t) allergens by IgE dot blot assay.

Results

Thirty-three of the 59 patients (56%) were sensitized to Der p and 23 of them (39%) were also sensitized to other allergen sources, whereas 9 patients (15%) were only sensitized to allergen sources other than Der p. IgE serology analyses (n=35) showed high IgE-binding frequencies to the Blo t allergens Blo t 5 (43%), Blo t 21 (43%) and Blo t 2 (40%), whereas the Der p allergens rDer p 2, rDer p 21 and rDer p 5 (34%, 29% and 26%) were less frequently recognized. Only few patients showed IgE reactivity to allergens from other allergen sources, except to allergens containing carbohydrate determinants (CCDs) or to wasp venom allergens (i.e., antigen 5).

Conclusion

Our results thus demonstrate that IgE sensitization to mite allergens is very prevalent in asthmatics in Equatorial Africa with B. tropicalis allergen molecules representing the most important ones associated with allergic asthma.
Schlafen4+-MDSC in Helicobacter-induced gastric metaplasia reveals role for GTPases
Authors: Ding Lin , Sheriff Sulaiman , Sontz Ricky A. , Merchant Juanita L.
Published: June 2023

Introduction

MDSCs express SCHLAFEN 4 (SLFN4) in Helicobacter-infected stomachs coincident with spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of gastric cancer. We aimed to characterize SLFN4+ cell identity and the role of Slfn4 in these cells.

Methods

Single-cell RNA sequencing was performed on immune cells sorted from PBMCs and stomachs prepared from uninfected and 6-month H. felis-infected mice. Knockdown of Slfn4 by siRNA or PDE5/6 inhibition by sildenafil were performed in vitro. Intracellular ATP/GTP levels and GTPase activity of immunoprecipitated Slfn4 complexes were measured using the GTPase-Glo assay kit. The intracellular level of ROS was quantified by the DCF-DA fluorescent staining, and apoptosis was determined by cleaved Caspase-3 and Annexin V expression. Gli1CreERT2 x Slfn4fl/fl mice were generated and infected with H. felis. Sildenafil was administered twice over 2 weeks by gavaging H. felis infected mice ~4 months after inoculation once SPEM had developed.

Results

Slfn4 was highly induced in both monocytic and granulocytic MDSCs from infected stomachs. Both Slfn4+-MDSC populations exhibited strong transcriptional signatures for type-I interferon responsive GTPases and exhibited T cell suppressor function. SLFN4-containing protein complexes immunoprecipitated from myeloid cell cultures treated with IFNa exhibited GTPase activity. Knocking down Slfn4 or PDE5/6 inhibition with sildenafil blocked IFNa induction of GTP, SLFN4 and NOS2. Moreover, IFNa induction of Slfn+-MDSC function was inhibited by inducing their reactive oxygen species (ROS) production and apoptosis through protein kinase G activation. Accordingly, in vivo disruption of Slfn4 in Gli1CreERT2 x Slfn4fl/fl mice or pharmacologic inhibition by sildenafil after Helicobacter infection also suppressed SLFN4 and NOS2, reversed T cell suppression and mitigated SPEM development.

Conclusion

Taken together, SLFN4 regulates the activity of the GTPase pathway in MDSCs and precludes these cells from succumbing to the massive ROS generation when they acquire MDSC function.
Case Report: Localized bullous pemphigoid induced by local triggers: a case series and a proposal for diagnostic criteria based on a literature review
Authors: Corbella-Bagot Lluís , Gil-Lianes Javier , Fernández-Vela Javier , Martí-Martí Ignasi , Alegre-Fernández Marta , Fuertes Irene , Garbayo-Salmons Patricia , Bosch-Amate Xavier , Guilabert Antonio , Mascaró José M.
Published: June 2023

Introduction

Localized bullous pemphigoid (LBP) is an infrequent bullous pemphigoid (BP) variant restricted to a body region. According to the most compelling evidence, LBP occurs in patients with pre-existent serum antibodies against the basement membrane zone, which occasionally acquire the capacity to induce disease after the influence of different local factors acting as triggers.

Methods

We hereby present a multicenter cohort of 7 patients with LBP developed after local triggers: radiotherapy, thermal burns, surgery, rosacea, edema and a paretic leg. In addition, we conducted a review of the literature, and we propose a set of diagnostic criteria for LBP, also based on our case series and the 2022 BP guidelines from the European Academy of Dermatology and Venereology.

Results

During follow-up, three of the patients from our series evolved to a generalized BP, with only one requiring hospitalization. Our literature search retrieved 47 articles including a total of 108 patients with LBP, with a 63% with a potential local precipitating factor previous to their diagnosis. LBP mostly affected older females, and a subsequent generalized progression occurred in 16.7% of the cases. The most frequently involved areas were the lower limbs. Radiation therapy and surgery were responsible for the inducement of nearly 2 in 3 cases of LBP. We observed a significantly higher risk of generalization in cases where the trigger led to the developing of LBP earlier (p=0.016). Our statistical analysis did not detect any other prognosis factor for generalization when assessing direct immunofluorescence, histological and serological results, or other patient related factors.

Conclusion

LBP should be suspected in patients with recurrent localized bullous eruptions. The presence of a trauma history in the same anatomic area is reported in most cases.
Identification of heterogeneous subtypes and a prognostic model for gliomas based on mitochondrial dysfunction and oxidative stress-related genes
Authors: Li Junsheng , Wang Siyu , Chi Xiaojing , He Qiheng , Tao Chuming , Ding Yaowei , Wang Jia , Zhao Jizong , Wang Wen
Published: June 2023

Objective

Mitochondrial dysfunction and oxidative stress are known to involved in tumor occurrence and progression. This study aimed to explore the molecular subtypes of lower-grade gliomas (LGGs) based on oxidative stress-related and mitochondrial-related genes (OMRGs) and construct a prognostic model for predicting prognosis and therapeutic response in LGG patients.

Methods

A total of 223 OMRGs were identified by the overlap of oxidative stress-related genes (ORGs) and mitochondrial-related genes (MRGs). Using consensus clustering analysis, we identified molecular subtypes of LGG samples from TCGA database and confirmed the differentially expressed genes (DEGs) between clusters. We constructed a risk score model using LASSO regression and analyzed the immune-related profiles and drug sensitivity of different risk groups. The prognostic role of the risk score was confirmed using Cox regression and Kaplan-Meier curves, and a nomogram model was constructed to predict OS rates. We validated the prognostic role of OMRG-related risk score in three external datasets. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining confirmed the expression of selected genes. Furthermore, wound healing and transwell assays were performed to confirm the gene function in glioma.

Results

We identified two OMRG-related clusters and cluster 1 was significantly associated with poor outcomes (P<0.001). The mutant frequencies of IDH were significantly lower in cluster 1 (P<0.05). We found that the OMRG-related risk scores were significantly correlated to the levels of immune infiltration and immune checkpoint expression. High-risk samples were more sensitive to most chemotherapeutic agents. We identified the prognostic role of OMRG-related risk score in LGG patients (HR=2.665, 95%CI=1.626-4.369, P<0.001) and observed that patients with high-risk scores were significantly associated with poor prognosis (P<0.001). We validated our findings in three external datasets. The results of qRT-PCR and IHC staining verified the expression levels of the selected genes. The functional experiments showed a significant decrease in the migration of glioma after knockdown of SCNN1B.

Conclusion

We identified two molecular subtypes and constructed a prognostic model, which provided a novel insight into the potential biological function and prognostic significance of mitochondrial dysfunction and oxidative stress in LGG. Our study might help in the development of more precise treatments for gliomas.
The application and research progress of anti-angiogenesis therapy in tumor immunotherapy
Authors: Tu Jingyao , Liang Hang , Li Chunya , Huang Yongbiao , Wang Ziqi , Chen Xinyi , Yuan Xianglin
Published: June 2023

Tumor immunotherapy, as the focus of scientific research and clinical tumor treatment in recent years, has received extensive attention. Due to its remarkable curative effect and fewer side effects than traditional treatments, it has significant clinical benefits for the treatment of various advanced cancers and can improve cancer patient survival in the long term. Currently, most patients cannot benefit from immunotherapy, and some patients may experience tumor recurrence and drug resistance even if they achieve remission overcome. Numerous studies have shown that the abnormal angiogenesis state of tumors can lead to immunosuppressive tumor microenvironment, which affects the efficacy of immunotherapy. Actually, to improve the efficacy of immunotherapy, the application of anti-angiogenesis drugs to normalize abnormal tumor vessel has been widely confirmed in basic and clinical research. This review not only discusses the risk factors, mechanisms, and effects of abnormal and normalized tumor angiogenesis state on the immune environment, but summarizes the latest progress of immunotherapy combined with anti-angiogenic therapy. We hope this review provides an applied reference for anti-angiogenesis drugs and synergistic immunotherapy therapy.
miR-10a-3p modulates adiposity and suppresses adipose inflammation through TGF-β1/Smad3 signaling pathway
Authors: Kiran Sonia , Mandal Mousumi , Rakib Ahmed , Bajwa Amandeep , Singh Udai P.
Published: June 2023

Background

Obesity is a multifactorial disease characterized by an enhanced amount of fat and energy storage in adipose tissue (AT). Obesity appears to promote and maintain low-grade chronic inflammation by activating a subset of inflammatory T cells, macrophages, and other immune cells that infiltrate the AT. Maintenance of AT inflammation during obesity involves regulation by microRNAs (miRs), which also regulate the expression of genes implicated in adipocyte differentiation. This study aims to use ex vivo and in vitro approaches to evaluate the role and mechanism of miR-10a-3p in adipose inflammation and adipogenesis.

Methods

Wild-type BL/6 mice were placed on normal (ND) and high-fat diet (HFD) for 12 weeks and their obesity phenotype, inflammatory genes, and miRs expression were examined in the AT. We also used differentiated 3T3-L1 adipocytes for mechanistic in vitro studies.

Results

Microarray analysis allowed us to identify an altered set of miRs in the AT immune cells and Ingenuity pathway analysis (IPA) prediction demonstrated that miR-10a-3p expression was downregulated in AT immune cells in the HFD group as compared to ND. A molecular mimic of miR-10a-3p reduced expression of inflammatory M1 macrophages, cytokines, and chemokines, including transforming growth factor-beta 1 (TGF-β1), transcription factor Krüppel-like factor 4 (KLF4), and interleukin 17F (IL-17F) and induced expression of forkhead box P3 (FoxP3) in the immune cells isolated from AT of HFD-fed mice as compared to ND. In differentiated 3T3-L1 adipocytes, the miR-10a-3p mimics also reduced expression of proinflammatory genes and lipid accumulation, which plays a role in the dysregulation of AT function. In these cells, overexpression of miR-10a-3p reduced the expression of TGF-β1, Smad3, CHOP-10, and fatty acid synthase (FASN), relative to the control scramble miRs.

Conclusion

Our findings suggest that miR-10a-3p mimic mediates the TGF-β1/Smad3 signaling to improve metabolic markers and adipose inflammation. This study provides a new opportunity for the development of miR-10a-3p as a novel therapeutic for adipose inflammation, and its associated metabolic disorders.
Multiscale analyses of the damage of composite rocket motor cases
Authors: Liu Zai , Hui Weiwei , Chen Guoqing , Cao Peng
Published: June 2023

As one of the key components of solid rocket motors (SRMs) and launch vehicles (LVs), the deformation and damage of the composite rocket motor case (CRMC) can directly affect the effectiveness of the SRMs. Therefore, it is particularly important to analyze the damage failure of composite cases. As the analysis remains complex due to the different failure modes of composites at different scales, this paper applies multiscale analysis methods to CRMC damage. A multiscale mechanical model of CRMC is established, and data transfer between the microscale, mesoscale, and macroscale models is achieved using submodel techniques. In this paper, CRMC was finely modeled, and the thickness and carbon fiber angle of each fiber winding layer were accurately described. Additionally, the results of hydrostatic tests and numerical calculations were compared to verify the validity of the modeling method. The stress levels of the material at macroscale, mesoscale, and microscale scales were obtained through numerical calculations, and the microscale damage failure behavior of the material under the internal pressure load of the composite shell was predicted by combining the strength assessment criterion.
New and personalized ventilatory strategies in patients with COVID-19
Authors: Rodrigues de Moraes Lucas , Robba Chiara , Battaglini Denise , Pelosi Paolo , Rocco Patricia R. M. , Silva Pedro Leme
Published: June 2023

Coronavirus disease (COVID-19) is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus and may lead to severe respiratory failure and the need for mechanical ventilation (MV). At hospital admission, patients can present with severe hypoxemia and dyspnea requiring increasingly aggressive MV strategies according to the clinical severity: noninvasive respiratory support (NRS), MV, and the use of rescue strategies such as extracorporeal membrane oxygenation (ECMO). Among NRS strategies, new tools have been adopted for critically ill patients, with advantages and disadvantages that need to be further elucidated. Advances in the field of lung imaging have allowed better understanding of the disease, not only the pathophysiology of COVID-19 but also the consequences of ventilatory strategies. In cases of refractory hypoxemia, the use of ECMO has been advocated and knowledge on handling and how to personalize strategies have increased during the pandemic. The aims of the present review are to: (1) discuss the evidence on different devices and strategies under NRS; (2) discuss new and personalized management under MV based on the pathophysiology of COVID-19; and (3) contextualize the use of rescue strategies such as ECMO in critically ill patients with COVID-19.
Current understanding of the genomic abnormities in premature ovarian failure: chance for early diagnosis and management
Authors: Yang Xu , Yang Lin
Published: June 2023

Premature ovarian failure (POF) is an insidious cause of female infertility and a devastating condition for women. POF also has a strong familial and heterogeneous genetic background. Management of POF is complicated by the variable etiology and presentation, which are generally characterized by abnormal hormone levels, gene instability and ovarian dysgenesis. To date, abnormal regulation associated with POF has been found in a small number of genes, including autosomal and sex chromosomal genes in folliculogenesis, granulosa cells, and oocytes. Due to the complex genomic contributions, ascertaining the exact causative mechanisms has been challenging in POF, and many pathogenic genomic characteristics have yet to be elucidated. However, emerging research has provided new insights into genomic variation in POF as well as novel etiological factors, pathogenic mechanisms and therapeutic intervention approaches. Meanwhile, scattered studies of transcriptional regulation revealed that ovarian cell function also depends on specific biomarker gene expression, which can influence protein activities, thus causing POF. In this review, we summarized the latest research and issues related to the genomic basis for POF and focused on insights gained from their biological effects and pathogenic mechanisms in POF. The present integrated studies of genomic variants, gene expression and related protein abnormalities were structured to establish the role of etiological genes associated with POF. In addition, we describe the design of some ongoing clinical trials that may suggest safe, feasible and effective approaches to improve the diagnosis and therapy of POF, such as Filgrastim, goserelin, resveratrol, natural plant antitoxin, Kuntai capsule et al. Understanding the candidate genomic characteristics in POF is beneficial for the early diagnosis of POF and provides appropriate methods for prevention and drug treatment. Additional efforts to clarify the POF genetic background are necessary and are beneficial for researchers and clinicians regarding genetic counseling and clinical practice. Taken together, recent genomic explorations have shown great potential to elucidate POF management in women and are stepping from the bench to the bedside.
Effects of helical centerline stent vs. straight stent placement on blood flow velocity
Authors: Kohata Yutaro , Ohta Makoto , Jin Kazuyoshi , Anzai Hitomi
Published: June 2023

As an approach to maintain patency in femoropopliteal stenting, a helical stent configuration was proposed, which showed improved patency in clinical trials. However, the effects of helical stent placement on the flow have not been quantitatively analyzed. The purpose of this study was to estimate flow velocities to quantify the influence of helical stent placement. Helical and straight stents were implanted in three healthy pigs, and the flow velocities were estimated using the time-intensity curve (TIC) in the angiography images. The angiographic images indicated thinning of the leading edge of the contrast medium through the helically deformed artery, which was not observed in the straight stent. The slower rise of the TIC peak in the helical stent indicated faster travel of this thinner edge. Arterial expansion due to stenting was observed in all cases, and the expansion rate varied according to location. All cases of helical stent implantation showed that velocity was maintained (55.0%–71.3% velocity retention), unlike for straight stent implantation (43.0%–68.0% velocity retention); however, no significant difference was observed.
Expression of Human ACE2 N-terminal Domain, Part of the Receptor for SARS-CoV-2, in Fusion With Maltose-Binding Protein, E. coli Ribonuclease I and Human RNase A
Authors: Xu Shuang-yong , Fomenkov Alexey , Chen Tien-Hao , Yigit Erbay
Published: June 2023

Graphical Abstract

Cartoon illustration part of this work (Human ACE2 N-terminal domain tethered to RNase A and RNA degradation by the fusion enzyme).
BrevicidineB, a New Member of the Brevicidine Family, Displays an Extended Target Specificity
Authors: Zhao Xinghong , Kuipers Oscar P.
Published: June 2023

Graphical Abstract

The antimicrobial mode of action of brevicidines. Brevicidines are potent antimicrobial cyclic lipopeptides active against Gram-negative pathogens. They have low hemolytic activity and cytotoxicity. BrevicidineB, a single amino acid residue mutant of brevicidine, displays an altered antimicrobial spectrum, showing also antimicrobial activity against Gram-positive pathogens. Due to disruption of the proton motive force of Gram-negative pathogens, brevicidines act as bactericidal antibiotics. In addition, brevicidineB acts as a bactericidal antibiotic against Gram-positive pathogens, because of its disruption capacity of the cellular membrane.
Whole-genome sequencing analysis of Klebsiella aerogenes among men who have sex with men in Guangzhou, China
Authors: Cheng Qi , Ma Zheng , Gong Zijun , Liang Yuelang , Guo Jiajia , Ye Xiaohua , Han Zhigang , Yao Zhenjiang
Published: June 2023

Klebsiella aerogenes is a common infectious bacterium that poses a threat to human health. Nevertheless, there are limited data on the population structure, genetic diversity, and pathogenicity of K. aerogenes, especially among men who have sex with men (MSM). The present study aimed to clarify the sequence types (STs), clonal complexes (CCs), resistance genes, and virulence factors of popular strains. Multilocus sequence typing was used to describe the population structure of K. aerogenes. The Virulence Factor Database and Comprehensive Antibiotic Resistance Database were used to assess the virulence and resistance profiles. In this study, next-generation sequencing was performed on nasal swabs specimens collected in an HIV Voluntary Counseling Testing outpatient department in Guangzhou, China, from April to August 2019. The identification results showed that a total of 258 K. aerogenes isolates were collected from 911 participants. We found that the isolates were most resistant to furantoin (89.53%, 231/258) and ampicillin (89.15%, 230/258), followed by imipenem (24.81%, 64/258) and cefotaxime (18.22%, 47/258). The most common STs in carbapenem-resistant K. aerogenes were ST4, ST93, and ST14. The population has at least 14 CCs, including several novel ones identified in this study (CC11-CC16). The main mechanism of drug resistance genes was antibiotic efflux. Based on the presence of the iron carrier production genes irp and ybt, we identified two clusters according to virulence profiles. In cluster A, CC3 and CC4 carry the clb operator encoding the toxin. Increased monitoring is needed for the three main ST type strains carried by MSM. The main clone group CC4 has a large number of toxin genes, and it spreads among MSM. Caution is needed to prevent further spread of this clone group in this population. In sum, our results may provide a foundation for the development of new therapeutic and surveillance strategies for treating MSM.
Whole-genome sequencing and phylogenetic analysis capture the emergence of a multi-drug resistant Salmonella enterica serovar Infantis clone from diagnostic animal samples in the United States
Authors: Srednik Mariela E. , Morningstar-Shaw Brenda R. , Hicks Jessica A. , Tong Christopher , Mackie Tonya A. , Schlater Linda K.
Published: June 2023

Introduction

Salmonella enterica is a major cause of foodborne illness in the United States. A multi-drug resistant (MDR) emergent Salmonella Infantis (ESI) with a megaplasmid (pESI) was first identified in Israel and Italy and subsequently reported worldwide. The ESI clone carrying an extended spectrum β-lactamase blaCTX-M-65 on a pESI-like plasmid and a mutation in the gyrA gene has recently been found in the United States in poultry meat.

Methods

We analyzed the phenotypic and genotypic antimicrobial resistance, genomics and phylogeny of 200 S. infantis isolates from animal diagnostic samples.

Results

Of these, 33.5% were resistant to at least one antimicrobial and 19.5% were multi-drug resistant (MDR). Eleven isolates from different animal sources were phenotypically and genetically similar to the ESI clone. These isolates had a D87Y mutation in the gyrA gene conferring reduced susceptibility to ciprofloxacin and harbored a combination of 6–10 resistance genes: blaCTX-M-65, aac(3)-IVa, aadA1, aph(4)-Ia, aph(3′)-Ia, floR, sul1, dfrA14, tetA, and fosA. These 11 isolates carried class I and class II integrons and three virulence genes: sinH, involved in adhesion and invasion, ybtQ and ybtP, associated with iron transport. These isolates were also closely related to each other (separated by 7 to 27 SNPs) and phylogenetically related to the ESI clone recently found in the U.S.

Discussion

This dataset captured the emergence of the MDR ESI clone in multiple animal species and the first report of a pESI-like plasmid in isolates from horses in the U.S.
The role of individual exopolysaccharides in antibiotic tolerance of Pseudomonas aeruginosa aggregates
Authors: Liang Ziwei , Nilsson Martin , Kragh Kasper Nørskov , Hedal Ida , Alcàcer-Almansa Júlia , Kiilerich Rikke Overgaard , Andersen Jens Bo , Tolker-Nielsen Tim
Published: June 2023

The bacterium Pseudomonas aeruginosa is involved in chronic infections of cystic fibrosis lungs and chronic wounds. In these infections the bacteria are present as aggregates suspended in host secretions. During the course of the infections there is a selection for mutants that overproduce exopolysaccharides, suggesting that the exopolysaccharides play a role in the persistence and antibiotic tolerance of the aggregated bacteria. Here, we investigated the role of individual P. aeruginosa exopolysaccharides in aggregate-associated antibiotic tolerance. We employed an aggregate-based antibiotic tolerance assay on a set of P. aeruginosa strains that were genetically engineered to over-produce a single, none, or all of the three exopolysaccharides Pel, Psl, and alginate. The antibiotic tolerance assays were conducted with the clinically relevant antibiotics tobramycin, ciprofloxacin and meropenem. Our study suggests that alginate plays a role in the tolerance of P. aeruginosa aggregates toward tobramycin and meropenem, but not ciprofloxacin. However, contrary to previous studies we did not observe a role for Psl or Pel in the tolerance of P. aeruginosa aggregates toward tobramycin, ciprofloxacin, and meropenem.
Genomic characterization of SARS-CoV-2 in Egypt: insights into spike protein thermodynamic stability
Authors: Jalal Deena , Samir Omar , Elzayat Mariam G. , El-Shqanqery Hend E. , Diab Aya A. , ElKaialy Lamiaa , Mohammed Aya M. , Hamdy Donia , Matar Islam K. , Amer Khaled , Elnakib Mostafa , Hassan Wael , Mansour Tarek , Soliman Sonia , Hassan Reem , Al-Toukhy Ghada M. , Hammad Mahmoud , Abdo Ibrahim , Sayed Ahmed A.
Published: June 2023

The overall pattern of the SARS-CoV-2 pandemic so far has been a series of waves; surges in new cases followed by declines. The appearance of novel mutations and variants underlie the rises in infections, making surveillance of SARS-CoV-2 mutations and prediction of variant evolution of utmost importance. In this study, we sequenced 320 SARS-CoV-2 viral genomes isolated from patients from the outpatient COVID-19 clinic in the Children’s Cancer Hospital Egypt 57357 (CCHE 57357) and the Egypt Center for Research and Regenerative Medicine (ECRRM). The samples were collected between March and December 2021, covering the third and fourth waves of the pandemic. The third wave was found to be dominated by Nextclade 20D in our samples, with a small number of alpha variants. The delta variant was found to dominate the fourth wave samples, with the appearance of omicron variants late in 2021. Phylogenetic analysis reveals that the omicron variants are closest genetically to early pandemic variants. Mutation analysis shows SNPs, stop codon mutation gain, and deletion/insertion mutations, with distinct patterns of mutations governed by Nextclade or WHO variant. Finally, we observed a large number of highly correlated mutations, and some negatively correlated mutations, and identified a general inclination toward mutations that lead to enhanced thermodynamic stability of the spike protein. Overall, this study contributes genetic and phylogenetic data, as well as provides insights into SARS-CoV-2 viral evolution that may eventually help in the prediction of evolving mutations for better vaccine development and drug targets.
Classification of Parkinson's disease stages with a two-stage deep neural network
Authors: Pedrero-Sánchez José Francisco , Belda-Lois Juan Manuel , Serra-Añó Pilar , Mollà-Casanova Sara , López-Pascual Juan
Published: June 2023

Introduction

Parkinson's disease is one of the most prevalent neurodegenerative diseases. In the most advanced stages, PD produces motor dysfunction that impairs basic activities of daily living such as balance, gait, sitting, or standing. Early identification allows healthcare personnel to intervene more effectively in rehabilitation. Understanding the altered aspects and impact on the progression of the disease is important for improving the quality of life. This study proposes a two-stage neural network model for the classifying the initial stages of PD using data recorded with smartphone sensors during a modified Timed Up & Go test.

Methods

The proposed model consists on two stages: in the first stage, a semantic segmentation of the raw sensor signals classifies the activities included in the test and obtains biomechanical variables that are considered clinically relevant parameters for functional assessment. The second stage is a neural network with three input branches: one with the biomechanical variables, one with the spectrogram image of the sensor signals, and the third with the raw sensor signals.

Results

This stage employs convolutional layers and long short-term memory. The results show a mean accuracy of 99.64% for the stratified k-fold training/validation process and 100% success rate of participants in the test phase.

Discussion

The proposed model is capable of identifying the three initial stages of Parkinson's disease using a 2-min functional test. The test easy instrumentation requirements and short duration make it feasible for use feasible in the clinical context.
The correlation between changes in gray matter microstructure and cerebral blood flow in Alzheimer’s disease
Authors: Niu Xiaoxi , Guo Ying , Chang Zhongyu , Li Tongtong , Chen Yuanyuan , Zhang Xianchang , Ni Hongyan
Published: June 2023

Objective

To investigate the relationship between changes in cerebral blood flow (CBF) and gray matter (GM) microstructure in Alzheimer’s disease (AD) and mild cognitive impairment (MCI).

Methods

A recruited cohort of 23 AD patients, 40 MCI patients, and 37 normal controls (NCs) underwent diffusional kurtosis imaging (DKI) for microstructure evaluation and pseudo-continuous arterial spin labeling (pCASL) for CBF assessment. We investigated the differences in diffusion- and perfusion-related parameters across the three groups, including CBF, mean diffusivity (MD), mean kurtosis (MK), and fractional anisotropy (FA). These quantitative parameters were compared using volume-based analyses for the deep GM and surface-based analyses for the cortical GM. The correlation between CBF, diffusion parameters, and cognitive scores was assessed using Spearman coefficients, respectively. The diagnostic performance of different parameters was investigated with k-nearest neighbor (KNN) analysis, using fivefold cross-validation to generate the mean accuracy (mAcc), mean precision (mPre), and mean area under the curve (mAuc).

Results

In the cortical GM, CBF reduction primarily occurred in the parietal and temporal lobes. Microstructural abnormalities were predominantly noted in the parietal, temporal, and frontal lobes. In the deep GM, more regions showed DKI and CBF parametric changes at the MCI stage. MD showed most of the significant abnormalities among all the DKI metrics. The MD, FA, MK, and CBF values of many GM regions were significantly correlated with cognitive scores. In the whole sample, the MD, FA, and MK were associated with CBF in most evaluated regions, with lower CBF values associated with higher MD, lower FA, or lower MK values in the left occipital lobe, left frontal lobe, and right parietal lobe. CBF values performed best (mAuc = 0.876) for distinguishing the MCI from the NC group. Last, MD values performed best (mAuc = 0.939) for distinguishing the AD from the NC group.

Conclusion

Gray matter microstructure and CBF are closely related in AD. Increased MD, decreased FA, and MK are accompanied by decreased blood perfusion throughout the AD course. Furthermore, CBF values are valuable for the predictive diagnosis of MCI and AD. GM microstructural changes are promising as novel neuroimaging biomarkers of AD.
Neurometabolic and structural alterations of medial septum and hippocampal CA1 in a model of post-operative sleep fragmentation in aged mice: a study combining 1H-MRS and DTI
Authors: Li Yun , Zhao Lina , Zhang Kai , Shen Mengxi , Li Yize , Yu Yang , Yu Jiafeng , Feng Jingyu , Xie Keliang , Yu Yonghao
Published: June 2023

Post-operative sleep disturbance is a common feature of elderly surgical patients, and sleep fragmentation (SF) is closely related to post-operative cognitive dysfunction (POCD). SF is characterized by sleep interruption, increased number of awakenings and sleep structure destruction, similar to obstructive sleep apnea (OSA). Research shows that sleep interruption can change neurotransmitter metabolism and structural connectivity in sleep and cognitive brain regions, of which the medial septum and hippocampal CA1 are key brain regions connecting sleep and cognitive processes. Proton magnetic resonance spectroscopy (1H-MRS) is a non-invasive method for the evaluation of neurometabolic abnormalities. Diffusion tensor imaging (DTI) realizes the observation of structural integrity and connectivity of brain regions of interest in vivo. However, it is unclear whether post-operative SF induces harmful changes in neurotransmitters and structures of the key brain regions and their contribution to POCD. In this study, we evaluated the effects of post-operative SF on neurotransmitter metabolism and structural integrity of medial septum and hippocampal CA1 in aged C57BL/6J male mice. The animals received a 24-h SF procedure after isoflurane anesthesia and right carotid artery exposure surgery. 1H-MRS results showed after post-operative SF, the glutamate (Glu)/creatine (Cr) and glutamate + glutamine (Glx)/Cr ratios increased in the medial septum and hippocampal CA1, while the NAA/Cr ratio decreased in the hippocampal CA1. DTI results showed post-operative SF decreased the fractional anisotropy (FA) of white matter fibers in the hippocampal CA1, while the medial septum was not affected. Moreover, post-operative SF aggravated subsequent Y-maze and novel object recognition performances accompanied by abnormal enhancement of glutamatergic metabolism signal. This study suggests that 24-h SF induces hyperglutamate metabolism level and microstructural connectivity damage in sleep and cognitive brain regions in aged mice, which may be involved in the pathophysiological process of POCD.
A brain CT-based approach for predicting and analyzing stroke-associated pneumonia from intracerebral hemorrhage
Authors: Yang Guangtong , Xu Min , Chen Wei , Qiao Xu , Shi Hongfeng , Hu Yongmei
Published: June 2023

Introduction

Stroke-associated pneumonia (SAP) is a common complication of stroke that can increase the mortality rate of patients and the burden on their families. In contrast to prior clinical scoring models that rely on baseline data, we propose constructing models based on brain CT scans due to their accessibility and clinical universality.

Methods

Our study aims to explore the mechanism behind the distribution and lesion areas of intracerebral hemorrhage (ICH) in relation to pneumonia, we utilized an MRI atlas that could present brain structures and a registration method in our program to extract features that may represent this relationship. We developed three machine learning models to predict the occurrence of SAP using these features. Ten-fold cross-validation was applied to evaluate the performance of models. Additionally, we constructed a probability map through statistical analysis that could display which brain regions are more frequently impacted by hematoma in patients with SAP based on four types of pneumonia.

Results

Our study included a cohort of 244 patients, and we extracted 35 features that captured the invasion of ICH to different brain regions for model development. We evaluated the performance of three machine learning models, namely, logistic regression, support vector machine, and random forest, in predicting SAP, and the AUCs for these models ranged from 0.77 to 0.82. The probability map revealed that the distribution of ICH varied between the left and right brain hemispheres in patients with moderate and severe SAP, and we identified several brain structures, including the left-choroid-plexus, right-choroid-plexus, right-hippocampus, and left-hippocampus, that were more closely related to SAP based on feature selection. Additionally, we observed that some statistical indicators of ICH volume, such as mean and maximum values, were proportional to the severity of SAP.

Discussion

Our findings suggest that our method is effective in classifying the development of pneumonia based on brain CT scans. Furthermore, we identified distinct characteristics, such as volume and distribution, of ICH in four different types of SAP.
A smart devices based secondary prevention program for cerebrovascular disease patients
Authors: Motolese Francesco , Capone Fioravante , Magliozzi Alessandro , Vico Carlo , Iaccarino Gianmarco , Falato Emma , Pilato Fabio , Di Lazzaro Vincenzo
Published: June 2023

Background

Commercially available health devices are gaining momentum and represent a great opportunity for monitoring patients for prolonged periods. This study aimed at testing the feasibility of a smart device-based secondary prevention program in a cohort of patients with cryptogenic stroke.

Methods

In this proof-of-principle study, patients with non-disabling ischemic stroke and transient ischemic attacks (TIA) in the subacute phase were provided with a smartwatch and smart devices to monitor several parameters – i.e., oxygen saturation, blood pressure, steps a day, heart rate and heart rate variability - for a 4-week period (watch group). This group was compared with a standard-of-care group. Our primary endpoint was the compliance with the use of smart devices that was evaluated as the number of measures performed during the observation period.

Results

In total, 161 patients were recruited, 87 in the WATCH group and 74 in the control group. In the WATCH group, more than 90% of patients recorded the ECG at least once a day. In total, 5,335 ECGs were recorded during the study. The median blood pressure value was 132/78 mmHg and the median oxygen saturation value was 97%. From a clinical standpoint, although not statistically significant, nine atrial fibrillation episodes (10.3%) in the WATCH group vs. 3 (4%) in the control group were detected.

Conclusion

Our study suggests that prevention programs for cerebrovascular disease may benefit from the implementation of new technologies.