bluuebunny/crossref_metadata_2025 huggingface dataset:
Dampened Inflammatory Signalling and Myeloid-Derived Suppressor-Like Cell Accumulation Reduces Circulating Monocytic HLA-DR Density and May Associate With Malignancy Risk in Long-Term Renal Transplant Recipients
Authors: Bottomley Matthew J. , Harden Paul N. , Wood Kathryn J. , Hester Joanna , Issa Fadi
Published: July 2022

Background

Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.

Methods

A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.

Results

Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.

Conclusions

Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.
Commonalities of Mycobacterium tuberculosis Transcriptomes in Response to Defined Persisting Macrophage Stresses
Authors: Vilchèze Catherine , Yan Bo , Casey Rosalyn , Hingley-Wilson Suzie , Ettwiller Laurence , Jacobs William R.
Published: July 2022

As the goal of a bacterium is to become bacteria, evolution has imposed continued selections for gene expression. The intracellular pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis, has adopted a fine-tuned response to survive its host’s methods to aggressively eradicate invaders. The development of microarrays and later RNA sequencing has led to a better understanding of biological processes controlling the relationship between host and pathogens. In this study, RNA-seq was performed to detail the transcriptomes of M. tuberculosis grown in various conditions related to stresses endured by M. tuberculosis during host infection and to delineate a general stress response incurring during persisting macrophage stresses. M. tuberculosis was subjected to long-term growth, nutrient starvation, hypoxic and acidic environments. The commonalities between these stresses point to M. tuberculosis maneuvering to exploit propionate metabolism for lipid synthesis or to withstand propionate toxicity whilst in the intracellular environment. While nearly all stresses led to a general shutdown of most biological processes, up-regulation of pathways involved in the synthesis of amino acids, cofactors, and lipids were observed only in hypoxic M. tuberculosis. This data reveals genes and gene cohorts that are specifically or exclusively induced during all of these persisting stresses. Such knowledge could be used to design novel drug targets or to define possible M. tuberculosis vulnerabilities for vaccine development. Furthermore, the disruption of specific functions from this gene set will enhance our understanding of the evolutionary forces that have caused the tubercle bacillus to be a highly successful pathogen.
Increased Tumor Intrinsic Growth Potential and Decreased Immune Function Orchestrate the Progression of Lung Adenocarcinoma
Authors: Zhao Yue , Shang Jun , Gao Jian , Han Han , Gao Zhendong , Yan Yueren , Zheng Qiang , Ye Ting , Fu Fangqiu , Deng Chaoqiang , Ma Zelin , Zhang Yang , Zheng Difan , Zheng Shanbo , Li Yuan , Cao Zhiwei , Shi Leming , Chen Haiquan
Published: July 2022

Background

The overall 5-year survival of lung cancer was reported to be only ~15%, with lung adenocarcinoma (LUAD) as the main pathological subtype. Before developing into invasive stages, LUAD undergoes pre-invasive stages of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), where surgical resection gives an excellent 5-year survival rate. Given the dramatic decline of prognosis from pre-invasive to invasive stages, a deeper understanding of key molecular changes driving the progression of LUAD is highly needed.

Methods

In this study, we performed whole-exome sequencing and RNA sequencing on surgically resected 24 AIS, 74 MIA, 99 LUAD specimens, and their adjacent paired normal tissues. Survival data were obtained by follow-up after surgery. Key molecular events were found by comparing the gene expression profiles of tumors with different stages. Finally, to measure the level of imbalance between tumor intrinsic growth potential and immune microenvironment, a tumor progressive (TP) index was developed to predict tumor progression and patients’ survival outcome and validated by external datasets.

Results

As tumors progressed to more invasive stages, they acquired higher growth potential, mutational frequency of tumor suppressor genes, somatic copy number alterations, and tumor mutation burden, along with suppressed immune function. To better predict tumor progression and patients’ outcome, TP index were built to measure the imbalance between tumor intrinsic growth potential and immune microenvironment. Patients with a higher TP index had significantly worse recurrence-free survival [Hazard ratio (HR), 10.47; 95% CI, 3.21–34.14; p < 0.0001] and overall survival (OS) [Hazard ratio (HR), 4.83e8; 95% CI, 0–Inf; p = 0.0013]. We used The Cancer Genome Atlas (TCGA)-LUAD dataset for validation and found that patients with a higher TP index had significantly worse OS (HR, 1.10; 95% CI, 0.83–1.45; p = 0.048), demonstrating the prognostic value of the TP index for patients with LUAD.

Conclusions

The imbalance of tumor intrinsic growth potential and immune function orchestrate the progression of LUAD, which can be measured by TP index. Our study provided new insights into predicting survival of patients with LUAD and new target discovery for LUAD through assessing the imbalance between tumor intrinsic growth potential and immune function.
Dietary Supplementation of Chitosan Oligosaccharide–Clostridium butyricum Synbiotic Relieved Early-Weaned Stress by Improving Intestinal Health on Pigeon Squabs (Columba livia)
Authors: Wen Jiashu , Zhao Wenyan , Li Jiankui , Hu Caihong , Zou Xiaoting , Dong Xinyang
Published: July 2022

According to a previous study, we had found that early weaning causes harm to growth performance, intestinal morphology, activity of digestive enzymes, and antioxidant status in pigeon squabs (Columba livia). Chitosan oligosaccharides (COS) and Clostridium butyricum have been reported to have great potential to improve the growth performance and intestinal health of early-weaned animals. Therefore, the aim of this study is to explore whether dietary supplementation with COS-C. butyricum synbiotic could relieve early-weaned stress by evaluating its effects on growth performance and intestinal health in pigeon squabs. A total of 160 squabs (weaned at 7 days of age) were randomly divided into 5 groups: the control group, fed with artificial crop milk; the COS supplementation group, fed with artificial crop milk + 150 mg/kg COS; and three synbiotic supplementation groups, fed with artificial crop milk + 150 mg/kg COS + 200, 300, and 400 mg/kg C. butyricum. The results showed that a diet supplemented with COS-C. butyricum synbiotic benefitted the growth performance of early-weaned squabs; even so the differences were not significant among the five groups (p > 0.05). In addition, dietary supplementation of 150 mg/kg COS + 300~400 mg/kg C. butyricum significantly improved the intestinal morphology (especially villus surface area and the ratio of villus height to crypt depth), the activity of digestive enzymes (lipase, trypsin, and leucine aminopeptidase) in duodenum contents, and the production of total short-chain fatty acids and acetic acid in ileum content (p < 0.05). Additionally, dietary supplementation of 150 mg/kg COS + 400 mg/kg C. butyricum benefitted gut health by improving the antioxidant capacity (glutathione peroxidase and total antioxidant capacity) and cytokine status (IL-4 and IL-10) (p < 0.05), as well as by improving the intestinal microbiota diversity. In conclusion, our results revealed that dietary supplementation with synbiotic (150 mg/kg COS + 300~400 mg/kg C. butyricum) could relieve early-weaned stress by maintaining intestinal health in pigeon squabs.
Ultrasound-Targeted Microbubble Destruction: Modulation in the Tumor Microenvironment and Application in Tumor Immunotherapy
Authors: Han Ye , Sun Jiawei , Wei Hong , Hao Jiarong , Liu Weiyao , Wang Xiaolei
Published: July 2022

Tumor immunotherapy has shown strong therapeutic potential for stimulating or reconstructing the immune system to control and kill tumor cells. It is a promising and effective anti-cancer treatment besides surgery, radiotherapy and chemotherapy. Presently, some immunotherapy methods have been approved for clinical application, and numerous others have demonstrated promising in vitro results and have entered clinical trial stages. Although immunotherapy has exhibited encouraging results in various cancer types, however, a large proportion of patients are limited from these benefits due to specific characteristics of the tumor microenvironment such as hypoxia, tumor vascular malformation and immune escape, and current limitations of immunotherapy such as off-target toxicity, insufficient drug penetration and accumulation and immune cell dysfunction. Ultrasound-target microbubble destruction (UTMD) treatment can help reduce immunotherapy-related adverse events. Using the ultrasonic cavitation effect of microstreaming, microjets and free radicals, UTMD can cause a series of changes in vascular endothelial cells, such as enhancing endothelial cells’ permeability, increasing intracellular calcium levels, regulating gene expression, and stimulating nitric oxide synthase activities. These effects have been shown to promote drug penetration, enhance blood perfusion, increase drug delivery and induce tumor cell death. UTMD, in combination with immunotherapy, has been used to treat melanoma, non-small cell lung cancer, bladder cancer, and ovarian cancer. In this review, we summarized the effects of UTMD on tumor angiogenesis and immune microenvironment, and discussed the application and progress of UTMD in tumor immunotherapy.
Recent Advances on Synthesis and Potential Applications of Carbon Quantum Dots
Authors: Magesh Vasanth , Sundramoorthy Ashok K. , Ganapathy Dhanraj
Published: July 2022

Fluorescent carbon nanoparticles also termed as carbon quantum dots (CQDs) have attracted so much interest when compared to the traditional semiconductor quantum dots due to their applications in chemical sensing, biomedical imaging, nanotechnology, photovoltaics, light-emitting diodes (LEDs), and electrochemistry. Along with their optical features, CQDs have desired properties such as less toxicity, environmentally friendly nature, inexpensive, and simple preparation processes. In addition, CQDs can have their physical and chemical properties controlled by surface passivation and functionalization. This article provides an account of CQDs because of their distinct characteristics and considerable capacity in diverse applications. The article is categorized into various sections that highlight various synthesis methodologies of CQDs with their advantages/disadvantages and their potential applications in sensors, bio-imaging, drug delivery, solar cells, and supercapacitors. The different applications of CQDs can be demonstrated by controlled synthesis methods. We have also discussed gas sensing applications of CQDs briefly and provided a brief overview of osmotic power generation using CQDs for energy applications.
Histopathology of Psoriatic Arthritis Synovium—A Narrative Review
Authors: Tenazinha Catarina , Barros Rita , Fonseca João Eurico , Vieira-Sousa Elsa
Published: July 2022

Psoriatic arthritis (PsA) is a phenotypically heterogeneous chronic inflammatory disease associated to type I major histocompatibility complex alleles whose complex pathogenesis is still not completely understood. The psoriatic synovium shares general features of chronic inflammation with rheumatoid arthritis (RA) and other arthritis, such as hyperplasia of the intimal lining layer, sublining influx of inflammatory cells and neoangiogenesis, but recognizing disease-specific histopathologic findings may help in diagnosis and definition of therapeutic targets. Available literature reports conflicting data regarding the extension of lining hyperplasia, that does not allow depiction from RA. Sublining inflammatory cells consist of T and B cells and macrophages, plasma cells, mast cells and follicular dendritic cells, with a higher amount of overall T, mast cell and IL-17 producing CD8+ T lymphocytes and lower proportion of plasma cells when compared to the rheumatoid synovium. The amount of synovium IL17+ CD8+ T cells correlates positively to measures of disease activity. Lymphoid follicles with characteristics of germinal centers have been identified, similar to the ones described in RA. Neoangiogenesis is more prominent in PsA but can also be an outstanding feature in some RA samples, and different molecules involved in the process appear to have different influence in each disease. IL-17 and IL-22 expression in the synovium does not allow depiction between diseases. Among other cytokines and molecules likely implicated in disease physiopathology, only IL-35 is demonstrated to be reduced in PsA when compared to RA.
Prenatal Diagnosis of Pulmonary Atresia With Ventricular Septal Defect and an Aberrant Ductus Arteriosus in a Dextrocardia by Two- and Three-Dimensional Echocardiography: A Case Report
Authors: Liang Lulu , Wang Yu , Zhang Ying
Published: July 2022

Introduction

Prenatal diagnosis of pulmonary atresia is difficult in relative, especially when the pulmonary artery is slim and hypoplastic in development. It is of great importance to search for the blood supply to the pulmonary artery in those fetuses while it challenges most screening sonographers, even fetal echocardiography specialists. We herein report a rare case of pulmonary atresia with ventricular septal defect, complicated with an aberrant ductus arteriosus which provides the blood supply to the pulmonary artery. Besides, the case was also accompanied by cardiac malposition, dextrocardia with situs solitus. The echocardiographic characteristics and autopsy findings are also presented to approach the skill of fetal diagnosis.

Case presentation

A 30-year-old primigravida woman was referred to our center at gestational age of (24 ± 3) weeks for further fetal cardiac examination for suspected fetal cardiac anomalies. Fetal echocardiography revealed dextrocardia, situs solitus of the atria, an L-ventricular loop, a ventricular septal defect, an enlarged coronary sinus, and pulmonary atresia by transverse scanning. The ductus arteriosus was not present at the three-vessel trachea view with the retrograde flow showing in the pulmonary artery trunk, which suggested the possibility of an aberrant ductus arteriosus. Sagittal and coronal scanning was attempted to find that the pulmonary artery connected with the innominate artery via the aberrant ductus arteriosus. Three-dimensional echocardiography with spatio-temporal image correlation and high-definition flow imaging technique was performed to obtain the three-dimensional rendered image, which clearly showed the malformation in space. The pregnancy was terminated and the gross findings confirmed the prenatal diagnosis.

Conclusion

A detailed evaluation of fetal cardiac anatomy and hemodynamics is crucial for the detection of an aberrant ductus arteriosus, which plays an important role in the diagnosis of pulmonary atresia with ventricular septal defect. Sagittal and coronal scanning is useful to find the course of this aberrant ductus arteriosus. The three-dimensional echocardiography with spatio-temporal image correlation technique could provide additional spatial information to show great arteries in detail, which can serve as a supplement to traditional two-dimensional modality and benefit examiners to make an accurate diagnosis.
Validation Study of Airgo, an Innovative Device to Screen Sleep Respiratory Disorders
Authors: Braghiroli Alberto , Kuller David , Godio Massimo , Rossato Fabio , Sacco Carlo , Morrone Elisa
Published: July 2022

Background

Obstructive sleep apnea affects a consistent percentage of the population, and only a minority of patients have been diagnosed and treated because of a discrepancy between resources available for diagnosis and the epidemiology of a disorder possibly affecting nearly one billion people in the world.

Aim

We conducted a study to compare a standard home respiratory monitoring system (Nox T3) with a novel device (Airgo™) consisting of an elastic band and a small recorder, light, comfortable for the patient, and low-cost complete with automatic analysis of the data that produces a screening report indicating the type and severity of sleep respiratory disorder.

Patients and Results

We examined 120 patients, reduced to 118 for technical problems. The mean (SD) age of the patients is 55.7 ± 13 years, their BMI is 27.8 ± 4.3 kg/m2, and their AHI is 22 ± 22 events/h. Patients belong to all the different severity rates of OSA, with a percentage of them classified as free of respiratory disorders. The Airgo™ showed excellent agreement with the results of the gold standard, reporting high levels of sensitivity, specificity, positive and negative predicted value, and accuracy.

Conclusion

Airgo™ is a reliable tool to screen patients with suspected sleep respiratory disorders, well tolerated by the patient based on totally automatic analysis and reporting system, leading to more efficient use of doctor’s and clinician’s time and resources and extending the opportunity to diagnose more possible candidates for treatment.
Next-Generation Metagenome Sequencing Shows Superior Diagnostic Performance in Acid-Fast Staining Sputum Smear-Negative Pulmonary Tuberculosis and Non-tuberculous Mycobacterial Pulmonary Disease
Authors: Xu Peng , Yang Ke , Yang Lei , Wang Zhongli , Jin Fang , Wang Yubao , Feng Jing
Published: July 2022

In this study, we explored the clinical value of next-generation metagenome sequencing (mNGS) using bronchoalveolar lavage fluid (BALF) samples from patients with acid-fast staining (AFS) sputum smear-negative pulmonary tuberculosis (PTB) and non-tuberculous mycobacterial pulmonary disease (NTM-PD). Data corresponding to hospitalized patients with pulmonary infection admitted to the hospital between July 2018 and July 2021, who were finally diagnosed with AFS sputum smear-negative PTB and NTM-PD, were retrospectively analyzed. Bronchoscopy data as well as mNGS, Xpert, AFS (BALF analysis), and T-SPOT (blood) data, were extracted from medical records. Thereafter, the diagnostic performances of these methods with respect to PTB and NTM-PD were compared. Seventy-one patients with PTB and 23 with NTM-PD were included in the study. The sensitivities of mNGS, Xpert, T-SPOT, and AFS for the diagnosis of PTB were 94.4% (67/71), 85.9% (61/71), 64.8% (46/71), and 28.2% (20/71), respectively, and the diagnostic sensitivity of mNGS combined with Xpert was the highest (97.2%, 67/71). The specificity of Xpert was 100%, while those of AFS and T-SPOT were 73.9% (17/23) and 91.3% (21/23), respectively. Further, the 23 patients with NTM-PD could be identified using mNGS, and in the population with immunosuppression, the sensitivities of mNGS, Xpert, T-SPOT, and AFS were 93.5% (29/31), 80.6% (25/31), 48.4% (15/31), and 32.3% (10/31), respectively, and the diagnostic sensitivity of mNGS combined with Xpert was the highest (100%, 31/31). The specificities of Xpert and T-SPOT in this regard were both 100%, while that of AFS was 40% (2/5). Furthermore, using mNGS, all the NTM samples could be identified. Thus, the analysis of BALF samples using mNGS has a high accuracy in the differential diagnosis of MTB and NTM. Further, mNGS combined with Xpert can improve the detection of MTB, especially in AFS sputum smear-negative samples from patients with compromised immune states or poor responses to empirical antibiotics.
The Role of SilX in Bacteriocin Production of Streptococcus anginosus
Authors: Vogel Verena , Fuchs Miki , Jachmann Marie , Bitzer Alina , Mauerer Stefanie , Münch Jan , Spellerberg Barbara
Published: July 2022

Streptococcus anginosus produces the novel antimicrobial peptide Angicin, which inhibits Gram positive microorganisms and is classified as a group IId bacteriocin. Production of Angicin is regulated by the quorum sensing system Sil (Streptococcus invasion locus), which is located adjacent to the bacteriocin gene cluster. Within this genetic region a typical CAAX protease is encoded, which was designated SilX. Nelfinavir, a HIV protease inhibitor, led to a concentration dependent reduction in antimicrobial activity, presumably through the inhibition of SilX. Concentrations exceeding 25 μM Nelfinavir caused a complete abolishment of bacteriocin activity against Listeria monocytogenes. These results are supported by the observation, that a SilX deletion mutant of S. anginosus strain BSU 1211 no longer inhibits the growth of L. monocytogenes. Antimicrobial activity could be restored by addition of synthetically synthesized mature SilCR, implying that SilX may be involved in the export and processing of the signal peptide SilCR. Some CAAX proteases have been reported to provide immunity against bacteriocins. However, in a radial diffusion assay the deletion mutant S. anginosus BSU 1211ΔSilX showed no sensitivity toward Angicin arguing against a role of SilX in the immunity of S. anginosus. The putative processing of the signal peptide SilCR indicates a novel function of the CAAX protease SilX, in the context of S. anginosus bacteriocin production.
Characterization of Pseudomonas aeruginosa Bacteriophage L5 Which Requires Type IV Pili for Infection
Authors: Yang Lan , Zhang Tingting , Li Linlin , Zheng Chao , Tan Demeng , Wu Nannan , Wang Mingyang , Zhu Tongyu
Published: July 2022

Pseudomonas aeruginosa is a common opportunistic human pathogen. With the emergence of multidrug-resistant (MDR) clinical infection of P. aeruginosa, phage therapy has received renewed attention in treating P. aeruginosa infections. Moreover, a detailed understanding of the host receptor of lytic phage is crucial for selecting proper phages for therapy. Here, we describe the characterization of the P. aeruginosa bacteriophage L5 with a double-stranded DNA genome of 42,925 bp. The genomic characteristics indicate that L5 is a lytic bacteriophage belonging to the subfamily Autographivirinae. In addition, the phage receptors for L5 were also identified as type IV pili, because the mutation of pilZ, which is involved in pili synthesis, resists phage infection, while the complementation of pilZ restored its phage sensitivity. This research reveals that L5 is a potential phage therapy candidate for the treatment of P. aeruginosa infection.
Molecular Epidemiology of New Delhi Metallo-β-Lactamase-Producing Escherichia coli in Food-Producing Animals in China
Authors: Kuang Xu , Zhang Yan , Liu Juan , Yang Run-Shi , Qiu Zhi-Ying , Sun Jian , Liao Xiao-Ping , Liu Ya-Hong , Yu Yang
Published: July 2022

We conducted a molecular surveillance study for carbapenem-resistant Enterobacteriaceae (CRE) colonization in food-producing animals in China that included primarily swine and poultry for three consecutive years. A total of 2,771 samples from food-producing animals and their surrounding environments were collected from different regions in China from 2015 to 2017. Enrichment cultures supplemented with meropenem were used to isolate carbapenem non-susceptible isolates and these were subsequently identified by MALDI-TOF MS. Resistance phenotypes and genotypes were confirmed using antimicrobial susceptibility testing and molecular biological techniques. Genomic characteristics of the carbapenemase-producing isolates were investigated using whole genome sequencing (WGS) and bioinformatic analysis. In total, 88 NDM-positive Enterobacteriaceae were identified from 2,771 samples and 96.6% were Escherichia coli. The New Delhi metallo-β-lactamase (NDM)-positive E. coli displayed a diversity of sequence types (ST), and ST48 and ST165 were the most prevalent. Three variants of blaNDM (blaNDM-1, blaNDM-4, and blaNDM-5) were detected and WGS indicated that blaNDM-5 predominated and was carried primarily on IncX3 plasmids. All these isolates were also multiply-drug resistant. These results revealed that food-producing animals in China are an important reservoir for NDM-positive E. coli and pose a potential threat to public health.
In vivo Delivery Tools for Clustered Regularly Interspaced Short Palindromic Repeat/Associated Protein 9-Mediated Inhibition of Hepatitis B Virus Infection: An Update
Authors: Kayesh Mohammad Enamul Hoque , Hashem Md Abul , Kohara Michinori , Tsukiyama-Kohara Kyoko
Published: July 2022

Chronic hepatitis B virus (HBV) infection remains a major global health problem despite the availability of an effective prophylactic HBV vaccine. Current antiviral therapies are unable to fully cure chronic hepatitis B (CHB) because of the persistent nature of covalently closed circular DNA (cccDNA), a replicative template for HBV, which necessitates the development of alternative therapeutic approaches. The CRISPR/Cas system, a newly emerging genome editing tool, holds great promise for genome editing and gene therapy. Several in vitro and/or in vivo studies have demonstrated the effectiveness of HBV-specific clustered regularly interspaced short palindromic repeat (CRISPR)/associated protein 9 (CRISPR/Cas9) systems in cleaving HBV DNA and cccDNA. Although recent advances in CRISPR/Cas technology enhance its prospects for clinical application against HBV infection, in vivo delivery of the CRISPR/Cas9 system at targets sites remains a major challenge that needs to be resolved before its clinical application in gene therapy for CHB. In the present review, we discuss CRISPR/Cas9 delivery tools for targeting HBV infection, with a focus on the development of adeno-associated virus vectors and lipid nanoparticle (LNP)-based CRISPR/Cas ribonucleoprotein (RNP) delivery to treat CHB. In addition, we discuss the importance of delivery tools in the enhancement of the antiviral efficacy of CRISPR/Cas9 against HBV infection.
Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene
Authors: Singh Natalia N. , O'Leary Collin A. , Eich Taylor , Moss Walter N. , Singh Ravindra N.
Published: July 2022

Humans contain two nearly identical copies of Survival Motor Neuron genes, SMN1 and SMN2. Deletion or mutation of SMN1 causes spinal muscular atrophy (SMA), one of the leading genetic diseases associated with infant mortality. SMN2 is unable to compensate for the loss of SMN1 due to predominant exon 7 skipping, leading to the production of a truncated protein. Antisense oligonucleotide and small molecule-based strategies aimed at the restoration of SMN2 exon 7 inclusion are approved therapies of SMA. Many cis-elements and transacting factors have been implicated in regulation of SMN exon 7 splicing. Also, several structural elements, including those formed by a long-distance interaction, have been implicated in the modulation of SMN exon 7 splicing. Several of these structures have been confirmed by enzymatic and chemical structure-probing methods. Additional structures formed by inter-intronic interactions have been predicted by computational algorithms. SMN genes generate a vast repertoire of circular RNAs through inter-intronic secondary structures formed by inverted Alu repeats present in large number in SMN genes. Here, we review the structural context of the exonic and intronic cis-elements that promote or prevent exon 7 recognition. We discuss how structural rearrangements triggered by single nucleotide substitutions could bring drastic changes in SMN2 exon 7 splicing. We also propose potential mechanisms by which inter-intronic structures might impact the splicing outcomes.
The Role of Microglia in Alzheimer’s Disease From the Perspective of Immune Inflammation and Iron Metabolism
Authors: Long Hui-Zhi , Zhou Zi-Wei , Cheng Yan , Luo Hong-Yu , Li Feng-Jiao , Xu Shuo-Guo , Gao Li-Chen
Published: July 2022

Alzheimer’s disease (AD), the most common type of senile dementia, includes the complex pathogenesis of abnormal deposition of amyloid beta-protein (Aβ), phosphorylated tau (p-tau) and neuroimmune inflammatory. The neurodegenerative process of AD triggers microglial activation, and the overactivation of microglia produces a large number of neuroimmune inflammatory factors. Microglia dysfunction can lead to disturbances in iron metabolism and enhance iron-induced neuronal degeneration in AD, while elevated iron levels in brain areas affect microglia phenotype and function. In this manuscript, we firstly discuss the role of microglia in AD and then introduce the role of microglia in the immune-inflammatory pathology of AD. Their role in AD iron homeostasis is emphasized. Recent studies on microglia and ferroptosis in AD are also reviewed. It will help readers better understand the role of microglia in iron metabolism in AD, and provides a basis for better regulation of iron metabolism disorders in AD and the discovery of new potential therapeutic targets for AD.
Effects of Glucocorticoids on Postoperative Neurocognitive Disorders in Adult Patients: A Systematic Review and Meta-Analysis
Authors: Xie Xiaoyu , Gao Rui , Chen Hai , Zhang Xueying , Cai Xingwei , Zhang Changteng , Liu Changliang , Zhu Tao , Chen Chan
Published: July 2022

Background

Postoperative neurocognitive disorders (PNDs) is common among surgical patients, however, the effect of glucocorticoids for preventing PNDs is not clear. This review aims to evaluate the effect of glucocorticoids on the incidence of PNDs in adult patients undergoing surgery.

Methods

The databases of PubMed/Medline, Embase, the Cochrane Library, and Web of science were searched for all available randomized controlled trials (RCTs) from inception to April 30, 2022. RCTs comparing the effect of glucocorticoids with placebo on the incidence of PNDs in adult surgical patients (≥18 years old) were eligible. Subgroup analyses and meta-regressions were performed to evaluate sources of clinical heterogeneity. The level of certainty for main outcomes were assessed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

Results

Eleven trials with a total of 10,703 patients were identified. Compared with the control group, glucocorticoids did not reduce the incidence of PNDs (RR: 0.84, 95% CI: 0.67 to 1.06, P = 0.13, GRADE = moderate). Secondary analyses for primary outcome did not change the result. In addition, the length of ICU stay was decreased in glucocorticoids group (RR: −13.58, 95% CI: −26.37 to −0.80, P = 0.04, GRADE = low). However, there were no significant differences between groups with regards to the incidence of postoperative infection (RR: 0.94, 95% CI: 0.84 to 1.06, P = 0.30, GRADE = moderate), blood glucose level (RR: 1.05, 95% CI: −0.09 to 2.19, P = 0.07, GRADE = low), duration of mechanical ventilation (RR: −2.44, 95% CI: −5.47 to 0.59, P = 0.14, GRADE = low), length of hospital stay (RR: −0.09, 95% CI: −0.27 to 0.09, P = 0.33, GRADE = moderate) and 30-day mortality (RR: 0.86, 95% CI: 0.70 to 1.06, P = 0.16, GRADE = moderate).

Conclusions

This meta-analysis suggests that perioperative administration of glucocorticoids may not reduce the incidence of PNDs after surgery. The effect of glucocorticoids on decreased length of ICU stay needs further researches. Future high-quality trials using acknowledged criteria and validated diagnostic tools are needed to determine the influence of glucocorticoids on long-term PNDs.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022302262, identifier: CRD42022302262.
An Augmented Neural Network for Sentiment Analysis Using Grammar
Authors: Zhang Baohua , Zhang Huaping , Shang Jianyun , Cai Jiahao
Published: July 2022

Understanding human sentiment from their expressions is very important in human-robot interaction. But deep learning models are hard to represent grammatical changes for natural language processing (NLP), especially for sentimental analysis, which influence the robot's judgment of sentiment. This paper proposed a novel sentimental analysis model named MoLeSy, which is an augmentation of neural networks incorporating morphological, lexical, and syntactic knowledge. This model is constructed from three concurrently processed classical neural networks, in which output vectors are concatenated and reduced with a single dense neural network layer. The models used in the three grammatical channels are convolutional neural networks (CNNs), long short-term memory (LSTM) networks, and fully connected dense neural networks. The corresponding output in the three channels is morphological, lexical, and syntactic results, respectively. Experiments are conducted on four different sentimental analysis corpuses, namely, hotel, NLPCC2014, Douban movie reviews dataset, and Weibo. MoLeSy can achieve the best performance over previous state-of-art models. It indicated that morphological, lexical, and syntactic grammar can augment the neural networks for sentimental analysis.
Efficacy and Safety of Vagus Nerve Stimulation on Upper Limb Motor Recovery After Stroke. A Systematic Review and Meta-Analysis
Authors: Ramos-Castaneda Jorge A. , Barreto-Cortes Carlos Federico , Losada-Floriano Diego , Sanabria-Barrera Sandra Milena , Silva-Sieger Federico A. , Garcia Ronald G.
Published: July 2022

Background

Upper limb motor impairment is one of the main complications of stroke, affecting quality of life both for the patient and their family. The aim of this systematic review was to summarize the scientific evidence on the safety and efficacy of Vagus Nerve Stimulation (VNS) on upper limb motor recovery after stroke.

Methods

A systematic review and meta-analysis of studies that have evaluated the efficacy or safety of VNS in stroke patients was performed. The primary outcome was upper limb motor recovery. A search of articles published on MEDLINE, CENTRAL, EBSCO and LILACS up to December 2021 was performed, and a meta-analysis was developed to calculate the overall effects.

Results

Eight studies evaluating VNS effects on motor function in stroke patients were included, of which 4 used implanted and 4 transcutaneous VNS. It was demonstrated that VNS, together with physical rehabilitation, increased upper limb motor function on average 7.06 points (95%CI 4.96; 9.16) as assessed by the Fugl-Meyer scale. Likewise, this improvement was significantly greater when compared to a control intervention (mean difference 2.48, 95%CI 0.98; 3.98). No deaths or serious adverse events related to the intervention were reported. The most frequent adverse events were dysphonia, dysphagia, nausea, skin redness, dysgeusia and pain related to device implantation.

Conclusion

VNS, together with physical rehabilitation, improves upper limb motor function in stroke patients. Additionally, VNS is a safe intervention.
Chemistry of Protein-Phenolic Interactions Toward the Microbiota and Microbial Infections
Authors: Yilmaz Hilal , Gultekin Subasi Busra , Celebioglu Hasan Ufuk , Ozdal Tugba , Capanoglu Esra
Published: July 2022

Along with health concerns, interest in plants as food and bioactive phytochemical sources has been increased in the last few decades. Phytochemicals as secondary plant metabolites have been the subject of many studies in different fields. Breakthrough for research interest on this topic is re-juvenilized with rising relevance in this global pandemics' era. The recent COVID-19 pandemic attracted the attention of people to viral infections and molecular mechanisms behind these infections. Thus, the core of the present review is the interaction of plant phytochemicals with proteins as these interactions can affect the functions of co-existing proteins, especially focusing on microbial proteins. To the best of our knowledge, there is no work covering the protein-phenolic interactions based on their effects on microbiota and microbial infections. The present review collects and defines the recent data, representing the interactions of phenolic compounds -primarily flavonoids and phenolic acids- with various proteins and explores how these molecular-level interactions account for the human health directly and/or indirectly, such as increased antioxidant properties and antimicrobial capabilities. Furthermore, it provides an insight about the further biological activities of interacted protein-phenolic structure from an antiviral activity perspective. The research on the protein-phenolic interaction mechanisms is of great value for guiding how to take advantage of synergistic effects of proteins and polyphenolics for future medical and nutritive approaches and related technologies.
Determining Methyl-Esterification Patterns in Plant-Derived Homogalacturonan Pectins
Authors: Yu Yang , Cui Liangnan , Liu Xianbin , Wang Yuwen , Song Chenchen , Pak UnHak , Mayo Kevin H. , Sun Lin , Zhou Yifa
Published: July 2022

Homogalacturonan (HG)-type pectins are nutrient components in plants and are widely used in the food industry. The methyl-esterification pattern is a crucial structural parameter used to assess HG pectins in terms of their nutraceutical activity. To better understand the methyl-esterification pattern of natural HG pectins from different plants, we purified twenty HG pectin-rich fractions from twelve plants and classified them by their monosaccharide composition, Fourier transform-infrared spectroscopy (FT-IR) signatures, and NMR analysis. FT-IR shows that these HG pectins are all minimally esterified, with the degree of methyl-esterification (DM) being 5 to 40%. To examine their methyl-esterification pattern by enzymatic fingerprinting, we hydrolyzed the HG pectins using endo-polygalacturonase. Hydrolyzed oligomers were derivatized with 2-aminobenzamide and subjected to liquid chromatography-fluorescence-tandem mass spectrometry (HILIC-FLR-MSn). Twenty-one types of mono-/oligo-galacturonides having DP values of 1–10 were found to contain nonesterified monomers, dimers, and trimers, as well as oligomers with 1 to 6 methyl-ester groups. In these oligo-galacturonides, MSn analysis demonstrated that the number of methyl-ester groups in the continuous sequence was 2 to 5. Mono- and di-esterified oligomers had higher percentages in total methyl-esterified groups, suggesting that these are a random methyl-esterification pattern in these HG pectins. Our study analyzes the characteristics of the methyl-esterification pattern in naturally occurring plant-derived HG pectins and findings that will be useful for further studying HG structure-function relationships.
The Effect of Leucine Supplementation on Sarcopenia-Related Measures in Older Adults: A Systematic Review and Meta-Analysis of 17 Randomized Controlled Trials
Authors: Guo Yufei , Fu Xiaoya , Hu Qingjing , Chen Lihua , Zuo Hui
Published: July 2022

Background

The role of leucine in sarcopenia prevention remains unclear. We aimed to summarize the published data from randomized controlled trials (RCTs) to estimate the effect of leucine supplementation on sarcopenia-related measures in older adults.

Methods

A systematic literature search was performed using the electronic databases PubMed, Embase, and Web of Science with restriction to randomized controlled trials design from January 1, 2009 to March 19, 2022. Sarcopenia-related measures included handgrip strength, total lean mass, gait speed, leg press, 6-min walk test, short-physical performance battery, timed up-and-go test and 30-s chair-stand test. Fixed- and random-effects meta-analysis models were used to generate pooled weighted mean differences (WMDs) and 95% CIs. Heterogeneity was examined in subgroup and sensitivity analyses. Publication bias assessments were performed.

Results

A total of 17 RCTs enrolling 1418 subjects were identified. Leucine-isolated supplementation showed no effect on total lean mass (WMD = 0.03 kg, 95% CI: –0.51, 0.57, P = 0.917), handgrip strength (WMD = 1.23 kg, 95% CI: –0.58, 3.03, P = 0.183) and leg press (WMD = –1.35 kg, 95% CI: –7.46, 4.77, P = 0.666). However, leucine-combined supplementation including vitamin D showed a significant improvement in handgrip strength (WMD = 2.17 kg, 95% CI: 0.24, 4.10, P = 0.027) and gait speed (WMD = 0.03 m/s, 95% CI: 0.01, 0.05, P = 0.008).

Conclusion

Leucine-isolated supplementation did not improve muscle mass and strength in elderly. However, leucine-combined supplementation including vitamin D exhibited a significant benefit for muscle strength and performance including handgrip strength and gait speed in older adults. A combination of nutritional supplements would be a viable option for improving sarcopenia.
Surgical Options for Resectable Lung Adenosquamous Carcinoma: A Propensity Score-Matched Analysis
Authors: Zhu Shuncang , Ge Tao , Xiong Yicheng , Zhang Jing , Zhu Di , Sun Liangdong , Song Nan , Zhang Peng
Published: July 2022

Background

Surgery is the primary treatment option for Lung adenosquamous carcinoma (ASC) patients. However, no study compares the benefits of lobectomy and sublobar resection in ASC patients.

Methods

A total of 1379 patients in the Surveillance, epidemiology, and End Results (SEER) database and 466 patients in Shanghai Pulmonary Hospital (SPH) were enrolled. Survival benefits were evaluated after possible confounders were eliminated by propensity score matching (PSM).

Results

After 1:3 PSM, 463 SEER database patients and 244 SPH patients were enrolled. Lobectomy was associated with better overall survival (OS) and disease-free survival (DFS) than sublobar resection for ASC patients (5-year OS of SEER: 46.9% vs. 33.3%, P =0.017; 5-year OS of SPH: 35.0% vs. 16.4%, P =0.002; 5-year DFS of SPH: 29.5% vs. 14.8%, P =0.002). Similar results were observed in stage I patients. Univariate and multivariate Cox regression analyses showed that sublobar resection was an adverse prognostic factor independently (SEER: HR: 1.40, 95%CI: 1.08-1.81, P =0.012; SPH: HR: 1.73, 95%CI: 1.11-2.70, P =0.015). Subgroup analysis showed that all of the ASC patient subtypes tended to benefit more from lobectomy than sublobar resection.

Conclusions

Lobectomy remains the primary option for ASC patients compared to sublobar resection, including stage I.
Childhood Cancer Survival, 2006-2012 Cohorts of Mexican Institute of Social Security Beneficiaries at the Central-South Region of Mexico
Authors: Castro-Ríos Angélica , Martínez-Valverde Silvia
Published: July 2022

Introduction

In Mexico, the main institution of social security is the “Instituto Mexicano del Seguro Social” (IMSS), with more than 60 million enrolled individuals. This study of childhood cancer survival is the first based on complete cohorts of incident cases for the population IMSS- affiliated in the central-south region, which represents 27% of all children IMSS affiliated.

Methods

It is an observational cohort study from 2006 to 2012 to estimate the 5-year observed survival of the minors under 18 years old, identified in the Central-South Region Registry of Children with Cancer. The survival of cases was carried out through the active and passive search. Survival rates were estimated by the Kaplan–Meier (KM) method, the analysis of equality of survival functions was evaluated for some clinical variables.

Results

The study included 2,357 minors; the 5-year observed survival was 56.1% with a time of survival median of 3.4 years, and the overall loss of follow-up was 18.4%. The 5-year survival in cases with a diagnosis of leukemia was 53.5%, while for solid tumors, it was 57.9%. The median time of death was 1 year. The types of cancer with a survival greater than 70% were group V-retinoblastoma (87.2%), IIa-Hodgkin’s lymphoma (86.8%), Xc- gonadal tumors (83.3%), Iid-miscellaneous lymphomas (80%), IVa-nephroblastoma (79.5%), and IIc-Burkitt’s lymphoma (75.4%). Meanwhile, the lowest survival rates were in group VIII-bone tumors (32.3%), III-CNS (central nervous system; 44.1%), and IX-soft tissues (46.8%).

Conclusions

Survival results in the 2006–2012 cohorts show a significant gap in relation to the goal of 60% proposed by the World Health Organization for 2030.
A Transfer Learning Framework for Deep Learning-Based CT-to-Perfusion Mapping on Lung Cancer Patients
Authors: Ren Ge , Li Bing , Lam Sai-kit , Xiao Haonan , Huang Yu-Hua , Cheung Andy Lai-yin , Lu Yufei , Mao Ronghu , Ge Hong , Kong Feng-Ming (Spring) , Ho Wai-yin , Cai Jing
Published: July 2022

Purpose

Deep learning model has shown the feasibility of providing spatial lung perfusion information based on CT images. However, the performance of this method on lung cancer patients is yet to be investigated. This study aims to develop a transfer learning framework to evaluate the deep learning based CT-to-perfusion mapping method specifically on lung cancer patients.

Methods

SPECT/CT perfusion scans of 33 lung cancer patients and 137 non-cancer patients were retrospectively collected from two hospitals. To adapt the deep learning model on lung cancer patients, a transfer learning framework was developed to utilize the features learned from the non-cancer patients. These images were processed to extract features from three-dimensional CT images and synthesize the corresponding CT-based perfusion images. A pre-trained model was first developed using a dataset of patients with lung diseases other than lung cancer, and subsequently fine-tuned specifically on lung cancer patients under three-fold cross-validation. A multi-level evaluation was performed between the CT-based perfusion images and ground-truth SPECT perfusion images in aspects of voxel-wise correlation using Spearman’s correlation coefficient (R), function-wise similarity using Dice Similarity Coefficient (DSC), and lobe-wise agreement using mean perfusion value for each lobe of the lungs.

Results

The fine-tuned model yielded a high voxel-wise correlation (0.8142 ± 0.0669) and outperformed the pre-trained model by approximately 8%. Evaluation of function-wise similarity indicated an average DSC value of 0.8112 ± 0.0484 (range: 0.6460-0.8984) for high-functional lungs and 0.8137 ± 0.0414 (range: 0.6743-0.8902) for low-functional lungs. Among the 33 lung cancer patients, high DSC values of greater than 0.7 were achieved for high functional volumes in 32 patients and low functional volumes in all patients. The correlations of the mean perfusion value on the left upper lobe, left lower lobe, right upper lobe, right middle lobe, and right lower lobe were 0.7314, 0.7134, 0.5108, 0.4765, and 0.7618, respectively.

Conclusion

For lung cancer patients, the CT-based perfusion images synthesized by the transfer learning framework indicated a strong voxel-wise correlation and function-wise similarity with the SPECT perfusion images. This suggests the great potential of the deep learning method in providing regional-based functional information for functional lung avoidance radiation therapy.