bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic and clinical phenotypic analysis of carney complex with external auditory canal myxoma
Authors: Wan Wei , Zeng Liang , Jiang Hongqun , Xia Yunyan , Xiong Yuanping
Published: August 2022

Background: Mutations in PRKAR1A gene can lead to Carney complex (CNC), and most CNC patients develop cardiac and cutaneous myxomas. In particular, cardiac myxomas are a common cause of mortality in CNC patients. Cutaneous myxomas of the external ear are extremely rare, and do not have any specific clinical features

Methods: In this retrospective study, we analyzed the clinical and genetic data of the proband and his family and fifty whole blood control samples selected from the molecular genetic database of our hospital. Whole exome DNA sequencing analysis was used to detect the mutation in the peripheral blood samples.

Results: The results of the clinical analysis showed the presence of spotty skin pigmentation and external auditory canal myxoma in the proband as well as in his sister and mother. Whole-exome DNA sequencing showed a novel heterozygous mutation in the PRKAR1A gene i.e., c.824_825delAG (p.Gln275Leufs*2), in the proband and his sister and mother.

Conclusion: In conclusion, the family members had the same autosomal dominant PRKAR1A mutation. DNA sequencing revealed a novel c.824_825delAG in exon 9 of PRKAR1A. This pathogenic mutation has not been reported previously, and may be related to the occurrence of external auditory canal myxomas and spotty pigmentation. This study broadens the genotypic spectrum of PRKAR1A mutations in CNC.
Neuromuscular junction dysfunctions due to immune checkpoint inhibitors therapy: An analysis of FAERS data in the past 15 years
Authors: Zhang Ping , Lao Donghui , Chen Haoyan , Zhao Bin , Du Qiong , Zhai Qing , Ye Xuan , Yu Bo
Published: August 2022

Introduction

The adverse effects of neuromuscular junction dysfunctions caused by immune checkpoint inhibitor (ICI) drugs have not been thoroughly assessed in the clinics.

Objective

To assess the neuromuscular junction dysfunctions in cancer patients with adverse events caused by ICI therapy by searching the Food and Drug Administration Adverse Event Reporting System (FAERS) database.

Methods

The FAERS data from January 2004 to December 2020 were collected to analyze the association between neuromuscular connection dysfunction and ICI use. Disproportionate analysis and Bayesian analysis were used to quantify the association between the neuromuscular junction dysfunctions and ICIs. The onset time and outcome of neuromuscular junction dysfunctions in different ICI regimens were also compared.

Results

Out of 88,617 adverse event reports, 557 neuromuscular junction dysfunction reports (0.63%) were analyzed. Marketed ICI drugs, including ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab, avelumab, as well as their combinations, showed positive associations with four detection methods. Most of the adverse event reports were associated with the use of nivolumab (53.32%) and pembrolizumab (31.96%). However, nivolumab-related neuromuscular junction dysfunctions were similar with pembrolizumab (33.33% vs 33.14%, p > 0.05). The onset time of neuromuscular junction dysfunctions showed no significant difference among different ICIs (p > 0.05).

Conclusions

Analysis of FAERS data identified that over 30% (32.85%) of reports of neuromuscular junction dysfunctions resulted in death. Ongoing monitoring, risk evaluations, and further comparative studies of ICIs should be considered.
Cyclic di-AMP as endogenous adjuvant enhanced BCG-induced trained immunity and protection against Mycobacterium tuberculosis in mice
Authors: Ning Huanhuan , Kang Jian , Lu Yanzhi , Liang Xuan , Zhou Jie , Ren Rui , Zhou Shan , Zhao Yong , Xie Yanling , Bai Lu , Zhang Linna , Kang Yali , Gao Xiaojing , Xu Mingze , Ma Yanling , Zhang Fanglin , Bai Yinlan
Published: August 2022

Bacillus Calmette-Guérin (BCG) is a licensed prophylactic vaccine against tuberculosis (TB). Current TB vaccine efforts focus on improving BCG effects through recombination or genetic attenuation and/or boost with different vaccines. Recent years, it was revealed that BCG could elicit non-specific heterogeneous protection against other pathogens such as viruses through a process termed trained immunity. Previously, we constructed a recombinant BCG (rBCG-DisA) with elevated c-di-AMP as endogenous adjuvant by overexpressing di-adenylate cyclase of Mycobacterium tuberculosis DisA, and found that rBCG-DisA induced enhanced immune responses by subcutaneous route in mice after M. tuberculosis infection. In this study, splenocytes from rBCG-DisA immunized mice by intravenous route (i.v) elicited greater proinflammatory cytokine responses to homologous and heterologous re-stimulations than BCG. After M. tuberculosis infection, rBCG-DisA immunized mice showed hallmark responses of trained immunity including potent proinflammatory cytokine responses, enhanced epigenetic changes, altered lncRNA expressions and metabolic rewiring in bone marrow cells and other tissues. Moreover, rBCG-DisA immunization induced higher levels of antibodies and T cells responses in the lung and spleen of mice after M. tuberculosis infection. It was found that rBCG-DisA resided longer than BCG in the lung of M. tuberculosis infected mice implying prolonged duration of vaccine efficacy. Then, we found that rBCG-DisA boosting could prolong survival of BCG-primed mice over 90 weeks against M. tuberculosis infection. Our findings provided in vivo experimental evidence that rBCG-DisA with c-di-AMP as endogenous adjuvant induced enhanced trained immunity and adaptive immunity. What’s more, rBCG-DisA showed promising potential in prime-boost strategy against M. tuberculosis infection in adults.
Krill biomass estimation: Sampling and measurement variability
Authors: Bairstow Fiona , Gastauer Sven , Wotherspoon Simon , Brown C. Tom A. , Kawaguchi So , Edwards Tom , Cox Martin J.
Published: August 2022

Krill are the subject of growing commercial fisheries and therefore fisheries management is necessary to ensure long-term sustainability. Krill catch limits, set by Commission for the Conservation of Antarctic Marine Living Resources, are based on absolute krill biomass, estimated from acoustic-trawl surveys. In this work, we develop a method for determining an error budget for acoustic-trawl surveys of krill which includes sampling and measurement variability. We use our error budget method to examine the sensitivity of biomass estimates to parameters in acoustic target strength (TS) models, length frequency distribution and length to wetmass relationships derived from net data. We determined that the average coefficient of variation (CV) of estimated biomass was 17.7% and the average CV due from scaling acoustic observations to biomass density was 5.3%. We found that a large proportion of the variability of biomass estimates is due to the krill orientation distribution, a parameter in the TS model. Orientation distributions with narrow standard deviations were found to emphasise the results of nulls in the TS to length relationship, which has to potential to lead to biologically implausible results.
Insights into adaptive divergence of Japanese mantis shrimp Oratosquilla oratoria inferred from comparative analysis of full-length transcriptomes
Authors: Cheng Jiao , Zhang Liwen , Hui Min , Li Yuan , Sha Zhongli
Published: August 2022

The heterogeneous seascapes in the northwestern Pacific (NWP) can be important selective forces driving adaptive divergence of marine coastal species distributed along the gradients. Here, we tested this hypothesis in Japanese mantis shrimp (Oratosquilla oratoria) with a wide distribution in the NWP and a significant north-south population structure. To this end, the full-length (FL) transcriptomes of northern and southern O. oratoria were firstly sequenced using PacBio single molecule real-time sequencing technology. Based on the FL transcriptome data, we captured large-scale FL transcripts of O. oratoria and predicted the FL transcriptome structure, including coding region, transcription factor and long noncoding RNA. To reveal the divergence between northern and southern O. oratoria, we identified 2,182 pairs of orthologous genes and inferred their sequence divergences. The average differences in coding, 5’ untranslated and 3’ untranslated region were 1.44%, 2.79% and 1.46%, respectively, providing additional support to previous proposition that northern and southern O. oratoria are two species. We provided further evolutionary context to our analysis by identifying positive selected genes (PSGs) between northern and southern O. oratoria. In total, 98 orthologs were found evolving under positive selection and involved several environmentally responsive genes associated with stress response, immunity and cytoskeletal organization, etc. Furthermore, we found PSGs also diverged in gene expression response of northern and southern O. oratoria to heat stress. These findings not only highlight the importance of genetic variation in these genes in adapting to environmental changes in O. oratoria, but also suggest that natural selection may act on the plasticity of gene expression to facilitate O. oratoria adaptation to environmental gradients. Overall, our work contributes to understanding how marine coastal species has evolved to adapt to heterogeneous seascapes in the NWP.
Role of DNA methylation in ecophysiological responses to salinity in natural populations of Phragmites australis from coastal and inland habitats
Authors: Song Huijia , Guo Xiao , Liu Lele , Xu Zhenwei , Wang Ning , Liu Xiao , Du Ning , Guo Weihua
Published: August 2022

There are different environmental pressures in coastal and inland wetlands resulting in phenotypic variation among plant populations, which might be related to epigenetic modifications. Phragmites australis is a widespread plant in coastal and inland wetlands, and the phenotype of the population is selected by salinity, but the reasons for the population differences in salt tolerance and phenotype are unclear. We investigated coastal and inland P. australis populations grown under two salinities and two manipulated DNA methylation levels in common gardens. The plants were sprayed with 5-azacytidine (DNA demethylation agent) regularly, and the physiological and morphological traits of reeds were measured. Plant height, density, and basal stem of reeds from different sources were significantly different and correlated with soil conductivity of sampling sites (P < 0.05). Salinity significantly decreased the biomass (37.04%, P < 0.05) and plant height (24.68%, P < 0.05) of inland reeds but had no significant effect on coastal populations (13.48%). P. australis responds to salt stress through phenotypic plasticity, and inland wetland populations exhibit local adaptation to freshwater. Increased salt tolerance in inland populations following DNA demethylation, particularly biomass, plant height, and basal stems (increased 23.62%; 13.08%; 5.35%, respectively), could provide more opportunities in adverse environments. This study will provide important insights into the highly adaptive mechanisms of the large non-model plant.
Behavior of floating stone columns reinforced with geogrid encasement in model tests
Authors: Gu Meixiang , Mo Haizhao , Qiu Jianlin , Yuan Jie , Xia Quan
Published: August 2022

The bearing capacity and deformation characteristics of floating stone columns were complicated and are not thoroughly understood. In the present study, a series of experimental model tests of floating stone columns under vertical plate loading was performed. This study investigated the influence of geogrid encasement on the behavior of floating stone columns and provided valuable insight into the load-displacement behavior, bulging deformation, load transfer mechanism, and the radial stress of the geogrid encasement. The test results show that the bearing capacity of the floating stone column was significantly improved due to the geogrid encasement. The column with longer encasement showed higher stiffness at large settlements. The bulging deformation pattern of the column changed with different encasement lengths. More vertical pressure transferred from the top of the column to the bottom of the column due to the existence of the geogrid encasement. The fully encased stone columns developed high radial stress and achieved effective confinement of the column. The bearing capacities of the floating-encased stone columns with different encasement lengths were controlled by bulging deformation instead of penetration failure, which gave confidence that the floating-encased stone columns were an effective method for field construction in extensive soft soils.
Concurrent Use of Oral Anticoagulants and Sulfonylureas in Individuals With Type 2 Diabetes and Risk of Hypoglycemia: A UK Population-Based Cohort Study
Authors: Alwafi Hassan , Wong Ian C. K. , Naser Abdallah Y. , Banerjee Amitava , Mongkhon Pajaree , Whittlesea Cate , Alsharif Alaa , Wei Li
Published: August 2022

Objective

To investigate the association of concurrent use of oral anticoagulants (OACs) and sulfonylureas and the risk of hypoglycemia in individuals with type 2 diabetes mellitus (T2DM).

Research Design and Methods

A retrospective cohort study was conducted between 2001 and 2017 using electronic primary healthcare data from the IQVIA Medical Research Data (IMRD) that incorporates data supplied by The Health Improvement Network (THIN), a propriety database of Cegedim SA. Individuals with T2DM who received OAC prescription and sulfonylureas were included. We compared the risk of hypoglycemia with sulfonylureas and OACs using propensity score matching and Cox regression.

Results

109,040 individuals using warfarin and sulfonylureas and 77,296 using direct oral anticoagulants (DOACs) and sulfonylureas were identified and included. There were 285 hypoglycemia events in the warfarin with sulfonylureas group (incidence rate = 17.8 per 1,000 person-years), while in the sulfonylureas only, 304 hypoglycemia events were observed (incidence rate = 14.4 per 1,000 person-years). There were 14 hypoglycemic events in the DOACs with sulfonylureas group (incidence rates = 14.8 per 1,000 person-years), while in the sulfonylureas alone group, 60 hypoglycemia events were observed (incidence rate =23.7 per 1,000 person-years). Concurrent use of warfarin and sulfonylureas was associated with increased risk of hypoglycemia compared with sulfonylureas alone (HR 1.38; 95% CI 1.10–1.75). However, we found no evidence of an association between concurrent use of DOACs and sulfonylureas and risk of hypoglycemia (HR 0.54; 95% CI, 0.27–1.10) when compared with sulfonylureas only.

Conclusions

We provide real-world evidence of possible drug-drug interactions between warfarin and sulfonylureas. The decision to prescribe warfarin with coexistent sulfonylureas to individuals with T2DM should be carefully evaluated in the context of other risk factors of hypoglycemia, and availability of alternative medications.
Risk factors and management of biliary stones after living donor liver transplant and its effect on graft outcome
Authors: Dabbous Hany , Elsayed Ashraf , Salah Manar , Montasser Iman , Atef Mohamed , Elmetenini Mahmoud
Published: August 2022

Background

Bile stones are associated with numerous complications in liver transplant recipients. Endoscopic retrograde cholangiopancreatography (ERCP) has been proven to be safe and highly effective in dealing with most post-transplant biliary complications.

Objective

The objective of this study was to identify the possible risk factors for bile stone formation on top of biliary stricture, the effects of stones on graft outcomes, and their management.

Methods

This case–control study included 83 patients who underwent living donor liver transplant (LDLT) and suffered from postoperative biliary stricture with or without stones. Patients were divided into two groups. Group 1 (n = 55) included patients with biliary strictures with no stones and group 2 (n = 28) included patients who developed stones on top of biliary strictures. Data about the recipient and donor characteristics, surgical technique, blood lipid profile, immunosuppressive drugs, post-transplant complications, and interventions were collected from the medical records.

Results

The frequency of hepatitis C virus (HCV) was significantly higher in group 2 compared to group 1 (71.4% vs. 47.3%, p = 0.036). The body mass index (BMI) of the donors was significantly higher in group 2 than in group 1 (25.17 ± 2.53 vs. 23.68 ± 2.63, p = 0.015). Episodes of acute rejection were significantly higher in group 2 than in group 1 (21.4% vs. 5.5%, p = 0.027). The ERCP was sufficient in most of the cases (89.2%) to ensure biliary drainage. The identified independent risk factors for biliary stones included HCV, biliary drain, donor's BMI, and serum cholesterol level.

Conclusion

Positive HCV, biliary drain insertion, donor's BMI, and serum cholesterol level were independent risk factors for developing bile stones on top of biliary strictures. Biliary stones were associated with high episodes of acute graft rejection, and they could be successfully managed by the ERCP modality.
Intervention to severe lower trachea obstruction supported by extracorporeal membrane oxygenation in a human immunodeficiency virus patient: A case report and literature review
Authors: Zhang Xiaolin , Pan Lei , Wang Lei , Li Li Q. , Zhang Peng , Tang Hai C. , Wu Qing G. , Li Feng
Published: August 2022

Here we reported a case, male, 33 years old, diagnosed with human immunodeficiency virus (HIV) infection 5 months ago, but he didn’t take antiretroviral drugs regularly. He was admitted to intensive care unit emergently due to hypoxemia, hypercapnia, and hypotension. CT showed severe lower trachea obstruction caused by soft tissue. After rapid bedside assessment, the patient was considered to need endotracheal operation, but he couldn‘t tolerate intubation and mechanical ventilation. Extracorporeal membrane oxygenation (ECMO) was used. Hemodynamics improved significantly along with rehydration and low-dose vasoactive drugs. Subsequently, the patient underwent rigid bronchoscopy, airway tumor resection and Y-type silicone stent implantation. Postoperatively protective endotracheal intubation and mechanical ventilation was followed. ECMO was weaned off after the operation, and endotracheal cannula was removed 6 h later. The pathological examination of excisional tissue showed lung squamous cell carcinoma. Finally, the patient was discharged safely and went to local hospital for further treatment. From this case, we conclude that ECMO could play a key role for those who need endotracheal surgery while cannot endure conventional intubation and mechanical ventilation.
Development of a loop-mediated isothermal amplification assay for the rapid detection of Russula subnigricans and Russula japonica
Authors: Long Pan , Jiang Zijuan , He Zhengmi , Chen Zuohong
Published: August 2022

Russula subnigricans is the only deadly species in the genus Russula with a mortality rate of more than 50%, and Russula japonica is the most common poisonous species, making rapid species identification in mushroom poisoning incidents extremely important. The main objective of this study was to develop a rapid, specific, sensitive, and simple loop-mediated isothermal amplification (LAMP) assay for the detection of R. subnigricans and R. japonica. Two sets of species-specific LAMP primers targeting internal transcribed spacer (ITS) regions were designed to identify R. subnigricans and R. japonica. The results demonstrated that while LAMP could specifically detect R. subnigricans and R. japonica, the polymerase chain reaction (PCR) could not distinguish R. subnigricans from Russula nigricans. In addition, the results demonstrated that, compared to electrophoresis-LAMP and real-time quantitative LAMP (RT-qLAMP), the detection sensitivity of HNB-LAMP (a mixture of LAMP with hydroxy naphthol blue (HNB) dye) for R. subnigricans could reach 0.5 pg/μl and was 100-fold higher than that of PCR. The LAMP reaction could be completed in 45 min, which is much faster than the conventional PCR. In the future, LAMP can be used a quick, specific, and sensitive detection tool in various fields.
Intermittent fasting positively modulates human gut microbial diversity and ameliorates blood lipid profile
Authors: Khan Muhammad Nadeem , Khan Sidra Irshad , Rana Madeeha Ilyas , Ayyaz Arshad , Khan Muhammad Yousaf , Imran Muhammad
Published: August 2022

Aim

The aim was to evaluate the impact of intermittent fasting (IF) on human body mass index (BMI) and serum lipid profile thorough constructive rectification of gut microbiota.

Methods and results

Fourteen healthy women and thirty-one men were included in the study. Their blood and fecal samples were collected before and at the end of the study. Blood parameters, anthropometric values, and gut microbiology were noted to investigate the impact of intermittent fasting (IF) on human gut microbiota and physiology. Our data revealed that IF reduces the body weight and improves blood lipid profile, such as increasing high-density lipoprotein (HDL) and decreasing total cholesterol, triglycerides, and low- and very low-density lipoprotein levels. IF also decreases culturable aerobic bacterial count and increased fungal count. It was also found that the gut metagenome is altered considerably after IF. The human fecal bacterial diversity exhibited significant changes in decreased overall bacterial population, increased bacterial diversity (alpha diversity), and promoted evenness within the bacterial population at the species level. Anti-inflammatory bacteria Lactobacillus and Bifidobacterium were favorably increased, while pathogenic bacteria were decreased.

Conclusion

Collectively, these results indicated that IF could improve lipid profile and body weight in humans, and the potential mechanisms might be via regulating gut microbiota.

Significance and impact of the study

We demonstrated for the first time that IF improved body weight and blood lipid profile, indicating that IF could mitigate gut microbiota in humans.
Composition and diversity of gut microbiota in diabetic retinopathy
Authors: Bai Jianhao , Wan Zhongqi , Zhang Yuanyuan , Wang Tianyu , Xue Yawen , Peng Qing
Published: August 2022

Objective

Diabetic retinopathy (DR) is one of the most common complications of type 2 diabetes mellitus. The current study investigates the composition, structure, and function of gut microbiota in DR patients and explores the correlation between gut microbiota and clinical characteristics of DR.

Methods

A total of 50 stool samples were collected from 50 participants, including 25 DR patients and 25 healthy controls (HCs). 16S ribosomal RNA gene sequencing was used to analyze the gut microbial composition in these two groups. DNA was extracted from the fecal samples using the MiSeq platform.

Results

The microbial structure and composition of DR patients were different from that of HCs. The microbial richness of gut microbiota in DR was higher than that of normal individuals. The alterations of microbiome of DR patients were associated with disrupted Firmicutes, Bacteroidetes, Synergistota, and Desulfobacterota phyla. In addition, increased levels of Bacteroides, Megamonas, Ruminococcus_torques_group, Lachnoclostridium, and Alistipes, and decreased levels of Blautia, Eubacterium_ hallii_group, Collinsella, Dorea, Romboutsia, Anaerostipes, and Fusicatenibacter genera were observed in the DR groups. Additionally, a stochastic forest model was developed to identify a set of biomarkers with seven bacterial genera that can differentiate patients with DR from those HC. The microbial communities exhibited varied functions in these two groups because of the alterations of the above-mentioned bacterial genera.

Conclusion

The altered composition and function of gut microbiota in DR patients indicated that gut microbiome could be used as non-invasive biomarkers, improve clinical diagnostic methods, and identify putative therapeutic targets for DR.
Nanoparticles in association with antimicrobial peptides (NanoAMPs) as a promising combination for agriculture development
Authors: Maximiano Mariana Rocha , Rios Thuanny Borba , Campos Marcelo Lattarulo , Prado Guilherme Souza , Dias Simoni Campos , Franco Octávio Luiz
Published: August 2022

Antimicrobial peptides are small molecules, up to 10 kDa, present in all kingdoms of life, including in plants. Several studies report that these molecules have a broad spectrum of activity, including antibacterial, antifungal, antiviral, and insecticidal activity. Thus, they can be employed in agriculture as alternative tools for phytopathogen and pest control. However, the application of peptides in agriculture can present challenges, such as loss of activity due to degradation of these molecules, off-target effects, and others. In this context, nanotechnology can offer versatile structures, including metallic nanoparticles, liposomes, polymeric nanoparticles, nanofibers, and others, which might act both in protection and in release of AMPs. Several polymers and biomaterials can be employed for the development of nanostructures, such as inorganic metals, natural or synthetic lipids, synthetic and hybrid polymers, and others. This review addresses the versatility of NanoAMPs (Nanoparticles in association with antimicrobial peptides), and their potential applications in agribusiness, as an alternative for the control of phytopathogens in crops.
Oncogenic fusion of BCAR4 activates EGFR signaling and is sensitive to dual inhibition of EGFR/HER2
Authors: Bae Kieun , Kim Jin Hee , Lee Ja Young , Kong Sun-Young , Kim Yun-Hee , Kim Sunshin , Yoon Kyong-Ah
Published: August 2022

We previously reported CD63-BCAR4 fusion as a novel oncogene that significantly enhanced cell migration and metastasis in lung cancer. To identify effective inhibitors of metastatic activity induced by BCAR4 fusion, we screened a drug library of 381 FDA-approved compounds. The effect of drugs on cell migration was evaluated by monitoring wound healing. Drugs that decreased the cellular mobility of fusion-overexpressing cells compared with that of control cells were selected as candidates. Library screening revealed that erlotinib, canertinib, and lapatinib demonstrated inhibitory effects on cell migration. Activation of the EGFR signaling pathway was detected after ectopic expression of CD63-BCAR4 in normal bronchial epithelial cells, as observed by the increased phosphorylation of tyrosine residues in the EGFR protein. We also confirmed increased levels of the phosphorylated EGFR protein in resected tumors from mice injected with CD63-BCAR4 overexpressing cells. Tyrosine kinase inhibitors (TKIs) of the EGFR family significantly inhibit the migration of BCAR4 fusion-overexpressing cells and induce apoptosis at high concentrations. Among the EGFR family TKIs, canertinib, a dual EGFR/HER2 inhibitor, showed the best inhibitory effect on the migration and viability of BCAR4 fusion-overexpressing cells. We examined the effect of canertinib in vivo using a mouse xenograft model. Oral administration of canertinib to xenografted mice reduced tumor growth induced by the CD63-BCAR4 fusion gene. In addition, canertinib treatment restored E-cadherin expression and reduced the expression of epithelial–mesenchymal transition regulatory factors such as Slug and Snail. Taken together, these results suggest that EGFR/HER2 inhibitors are potential therapeutic options for BCAR4 fusion-harboring lung cancer patients, even in the absence of EGFR mutations.
The SARS-CoV-2 envelope protein disrupts barrier function in an in vitro human blood-brain barrier model
Authors: Ju Jiahang , Su Yuwen , Zhou You , Wei Hui , Xu Qi
Published: August 2022

Patients with coronavirus disease 2019 (COVID-19) have been frequently reported to exhibit neurological manifestations and disruption of the blood-brain barrier (BBB). Among the risk factors for BBB breakdown, the loss of endothelial cells and pericytes has caused widespread concern. Recent studies have revealed that severe acute respiratory syndrome coronavirus 2 envelope (S2E) protein caused cell death. We tested the hypothesis that the S2E protein alone could induce BBB dysfunction. The S2E protein bound to human BBB-related cells and inhibited cell viability in a dose- and time-dependent manner. Importantly, the S2E protein disrupted barrier function in an in vitro BBB model composed of HCMEC/D3 (brain endothelial cell line), HBVP (brain vascular pericyte), and U87MG (astrocyte cell line) cells and suppressed the expression of major genes involved in maintaining endothelial permeability and function. In addition, the S2E protein crossed the HCMEC/D3 monolayer. The S2E protein triggered inflammatory responses in HCMEC/D3 and U87MG cells. Taken together, these results show for the first time that the S2E protein has a negative impact on the BBB. Therapies targeting the S2E protein could protect against and treat central nervous system manifestations in COVID-19 patients.
Medial septum: relevance for social memory
Authors: Griguoli Marilena , Pimpinella Domenico
Published: August 2022

Animal species are named social when they develop the capability of complex behaviors based on interactions with conspecifics that include communication, aggression, mating and parental behavior, crucial for well-being and survival. The underpinning of such complex behaviors is social memory, namely the capacity to discriminate between familiar and novel individuals. The Medial Septum (MS), a region localized in the basal forebrain, is part of the brain network involved in social memory formation. MS receives several cortical and subcortical synaptic and neuromodulatory inputs that make it an important hub in processing social information relevant for social memory. Particular attention is paid to synaptic inputs that control both the MS and the CA2 region of the hippocampus, one of the major MS output, that has been causally linked to social memory. In this review article, we will provide an overview of local and long range connectivity that allows MS to integrate and process social information. Furthermore, we will summarize previous strategies used to determine how MS controls social memory in different animal species. Finally, we will discuss the impact of an altered MS signaling on social memory in animal models and patients affected by neurodevelopmental and neurodegenerative disorders, including autism and Alzheimer’s Disease.
Mechanisms of ginsenosides exert neuroprotective effects on spinal cord injury: A promising traditional Chinese medicine
Authors: Qi Le , Zhang Jun , Wang Jinghong , An Junyan , Xue Wu , Liu Qinyi , Zhang Yan
Published: August 2022

Spinal cord injury (SCI) is a devastating disorder of the central nervous system (CNS). It is mainly caused by trauma and reduces the quality of life of the affected individual. Ginsenosides are safe and effective traditional Chinese medicines (TCMs), and their efficacy against SCI is being increasingly researched in many countries, especially in China and Korea. This systematic review evaluated the neuroprotective effects of ginsenosides in SCI and elucidated their properties.

Methods

All experimental information and summaries used in this review were acquired from peer-reviewed articles in the relevant fields. The PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure databases were searched for relevant articles. Information on the manual classification and selection of ginsenosides that protect against SCI is included in this review.

Results

A literature survey yielded studies reporting several properties of ginsenosides, including anti-inflammation, anti-apoptosis, anti-oxidative stress, and inhibition of glial scar formation.

Conclusion

In this review, we discuss the mechanisms of action of different ginsenosides that exert neuroprotective effects in SCI. These results suggest that after further verification in the future, ginsenosides may be used as adjunctive therapy to promote neurological recovery.
Cannabis use is associated with sexually dimorphic changes in executive control of visuospatial decision-making
Authors: Banks Parker J. , Bennett Patrick J. , Sekuler Allison B. , Gruber Aaron J.
Published: August 2022

When the outcome of a choice is less favorable than expected, humans and animals typically shift to an alternate choice option on subsequent trials. Several lines of evidence indicate that this “lose-shift” responding is an innate sensorimotor response strategy that is normally suppressed by executive function. Therefore, the lose-shift response provides a covert gauge of cognitive control over choice mechanisms. We report here that the spatial position, rather than visual features, of choice targets drives the lose-shift effect. Furthermore, the ability to inhibit lose-shift responding to gain reward is different among male and female habitual cannabis users. Increased self-reported cannabis use was concordant with suppressed response flexibility and an increased tendency to lose-shift in women, which reduced performance in a choice task in which random responding is the optimal strategy. On the other hand, increased cannabis use in men was concordant with reduced reliance on spatial cues during decision-making, and had no impact on the number of correct responses. These data (63,600 trials from 106 participants) provide strong evidence that spatial-motor processing is an important component of economic decision-making, and that its governance by executive systems is different in men and women who use cannabis frequently.
Genetic association between circulating selenium level and the risk of schizophrenia in the European population: A two-sample Mendelian randomization study
Authors: Deng Ming-Gang , Cui Han-Tao , Nie Jia-Qi , Liang Yuehui , Chai Chen
Published: August 2022

Background

The association between circulating the selenium level and the risk of schizophrenia remains unclear.

Objective

To determine the relationship between the circulating selenium level and the risk of schizophrenia, using the Mendelian Randomization method in the European population.

Methods

Single nucleotide polymorphisms (SNPs) associated with the circulating selenium level were identified at p < 5 × 10−8. The inverse variance weighted (IVW) method was used as the principal MR analysis, and MR Egger, weighted median, and MR PRESSO were used to determine the accuracy of IVW results. The Cochran's Q-test and Leave-One-Out sensitivity analysis were performed to evaluate the heterogeneity and stability of genetic variants on schizophrenia.

Results

The circulating selenium level was associated with decreased risk of schizophrenia by the IVW method (OR: 0.906, 95% CI:0.867–0.947). MR Egger, weighted median, and MR PRESSO methods got similar results. No heterogeneity was detected by the Cochran's Q-test, and no single SNP was driving the overall effect by leave-one-out analysis.

Conclusion

Our study provides support for the genetic relationship between the circulating selenium level and schizophrenia; the decreased circulating selenium level was associated with an elevated risk of schizophrenia.
Genoprotective activity of the Pleurotus eryngii mushrooms following their in vitro and in vivo fermentation by fecal microbiota
Authors: Boulaka Athina , Mantellou Panagiota , Stanc Gabriela-Monica , Souka Efthymia , Valavanis Christoς , Saxami Georgia , Mitsou Evdokia , Koutrotsios Georgios , Zervakis Georgios I. , Kyriacou Adamantini , Pletsa Vasiliki , Georgiadis Panagiotis
Published: August 2022

Pleurotus eryngii mushrooms are commercially cultivated and widely consumed due to their organoleptic properties, and the low caloric and high nutritional value. In addition, they contain various biologically active and health-promoting compounds; very recently, their genoprotective effect in Caco-2 cells after their fermentation by the human fecal microbiota was also documented. In the current study, the effect of P. eryngii pre- and post-fermentation supernatants in micronuclei formation was evaluated in human lymphocytes. In addition, the genoprotective properties of increasing concentrations of aqueous extracts from P. eryngii mushrooms (150, 300, 600 mg/kg) against the cyclophosphamide-induced DNA damage were studied in young and elderly female and male mice in bone marrow and whole blood cells. The ability of the highest dose (600 mg/kg) to regulate the main cellular signaling pathways was also evaluated in gut and liver tissues of female animals by quantifying the mRNA expression of NrF2, Nfkβ, DNMT1, and IL-22 genes. P. eryngii post-fermentation, but not pre-fermentation, supernatants were able to protect human lymphocytes from the mitomycin C-induced DNA damage in a dose-dependent manner. Similarly, genoprotection was also observed in bone marrow cells of mice treated by gavage with P. eryngii extract. The effect was observed in all the experimental groups of mice (young and elderly, male and female) and was more potent in young female mice. Overexpression of all genes examined was observed in both tissues, mainly among the elderly animals. In conclusion, P. eryngii mushrooms were shown to maintain genome integrity through protecting cells from genotoxic insults. These beneficial effects can be attributed to their antioxidant and immunomodulatory properties, as well as their ability to regulate the cell’s epigenetic mechanisms and maintain cell homeostasis.
Evaluation of circulating tumor DNA as a prognostic biomarker for metastatic pancreatic adenocarcinoma
Authors: Guan Shasha , Deng Guochao , Sun Jingjie , Han Quanli , Lv Yao , Xue Tianhui , Ding Lijuan , Yang Tongxin , Qian Niansong , Dai Guanghai
Published: August 2022

Purpose

Pancreatic cancer is an aggressive solid tumor with a severe prognosis. Although tumor biomarkers are often used to identify advanced pancreatic cancer, this is not accurate, and the currently used biomarkers are not indicative of prognosis. The present study evaluated circulating tumor DNA (ctDNA) as a biomarker for prognosis prediction and disease monitoring in metastatic pancreatic adenocarcinoma (PAC).

Methods

From 2017 to 2018, 40 patients with metastatic PAC were enrolled, and tumor tissue and blood samples were collected from 40 and 35 patients, respectively. CtDNA was sequenced by next-generation sequencing (NGS) with a 425-gene capture panel. The association of clinical characteristics, laboratory indicators, and dynamic ctDNA with patient outcomes was analyzed.

Results

Mutations in KRAS (87.5%, N = 35) and TP53 (77.5%, N = 31) were most common in 40 tumor tissue. Patients’ ECOG score, CA19-9, CEA, neutrophil-lymphocyte ratio (NLR), platelet- lymphocyte ratio (PLR) levels and mutations in ≥ 3 driver genes were strongly correlated with patients’ overall survival (OS). Patients’ gender, ECOG score, CA19-9, and CEA levels were associated with progression-free survival (PFS) (P<0.05). In 35 blood samples, univariate analysis showed a significant association between ECOG score, CA19-9, KRAS or CDKN2A mutation in ctDNA and OS and between CA19-9, CDKN2A or SMAD4 mutation in ctDNA and PFS. Cox hazard proportion model showed that patients’ CDKN2A mutation in ctDNA (HR=16.1, 95% CI=4.4-59.1, P<0.001), ECOG score (HR=6.2, 95% CI=2.4-15.7, P<0.001) and tumor location (HR=0.4, 95% CI=0.1-0.9, P=0.027) were significantly associated with OS. Patients’ CDKN2A mutation in ctDNA (HR=6.8, 95% CI=2.3-19.9, P=0.001), SMAD4 mutation in ctDNA (HR=3.0, 95% CI=1.1-7.9, P=0.031) and metastatic organ (HR=0.4, 95% CI=0.2-1.0, P=0.046) were significantly associated with PFS. Longitudinal changes in gene mutation allelic frequency (MAF) value were evaluated in 24 patients. Detection of progression disease (PD) by ctDNA was 0.9 months earlier than by radiological imaging (mean PFS: 4.6m vs 5.5m, P=0.004, paired t-test).

Conclusions

The ctDNA has the potential as a specific survival predictive marker for metastatic PAC patients. Longitudinal ctDNA tracking could potentially help identify disease progression and be a valuable complement for routine clinical markers and imaging.
Phelan–McDermid Syndrome in Pediatric Patients With Novel Mutations: Genetic and Phenotypic Analyses
Authors: Chen Liang , Yao Zhi-ye , Wu Xiangtao , He Shao-ru , Liu Yu-mei , Wang Xue-yan , Cao De-zhi , Yang Xing-kun , Zhao Jian-bo , Ren Zi , Li Hong , Pei Zheng , Ding Hong-ke , Feng Zhi-chun
Published: August 2022

Background

PhelanrMcDermid syndrome (PMS) is an uncommon autosomal dominant inherited developmental disorder. The main characteristics are hypotonia, intellectual disability, autism spectrum disorder, autism-like behaviors and tiny facial deformities. Most cases are caused by the deletion of the 22q13 genomic region, including the deletion of SHANK3.

Methods

Genetic and phenotype evaluations of ten Chinese pediatric patients were performed. The clinical phenotypes and genetic testing results were collected statistically. We analyzed the deletion of the 22q13 genomic region and small mutations in SHANK3 (GRCh37/hg19) and performed parental genotype verification to determine whether it was related to the parents or was a novel mutation.

Results

The age of the patients diagnosed with PMS ranged from 0 to 12 years old. Nine of the pediatric patients experienced Intellectual Disability, language motion development delay and hypotonia as prominent clinical features. One subject had autism, two subjects had abnormal electroencephalogram discharge and one subject was aborted after fetal diagnosis. Three patients had a SHANK3 mutation or deletion. All but the aborted fetuses had intellectual disability. Among the ten patients, a deletion in the 22q13 region occurred in seven patients, with the smallest being 60.6 kb and the largest being >5.5 Mb. Three patients had heterozygous mutations in the SHANK3 gene.

Conclusion

All ten patients had novel mutations, and three of these were missense or frameshift mutations. For the first time reported, it is predicted that the amino acid termination code may appear before protein synthesis. The novel mutations we discovered provide a reference for clinical research and the diagnosis of PMS.
Expression of TRPM6 and TRPM7 in the preterm piglet heart
Authors: Forbes Elizabeth M. , Bakrania Bhavisha A. , Steane Sarah E. , Moritz Karen M. , Lingwood Barbara E. , Eiby Yvonne A.
Published: August 2022

Preterm infants are at increased risk of death and disability, and cardiovascular instability after birth is a contributing factor. Immaturity of calcium handling in the preterm heart may limit myocardial contractility and cardiac output. Two transmembrane cation channels, TRPM6 and TRPM7, may regulate intracellular cardiac calcium in the neonatal period. The aim of this study was to determine TRPM6 and TRPM7 mRNA expression in piglet hearts in late gestation, and the effects of sex, maternal glucocorticoids, and the transition to extrauterine life. Left and right ventricular tissue was collected at a range of gestational ages from cesarean delivered piglets at birth and at 6 h old. Additional groups included piglets exposed to maternal glucocorticoid treatment and spontaneously born term piglets at 12–24 h old. TRPM6 and TRPM7 mRNA expression was measured using RT-qPCR. Males had significantly lower TRPM7 expression in the left ventricle across all gestational ages compared to females. At term, both ventricles had higher TRPM7 expression at 6 h old than at birth. In preterm piglets, TRPM7 expression only increased postnatally in the right ventricle following maternal glucocorticoid exposure. At 12–24 h old, TRPM7 expression in both ventricles was lower than levels in 6 h old term Caesar piglets (113 days). Male preterm piglets may have immature myocardial Ca2+ handling and this could contribute to their poorer outcomes. Increased TRPM7 expression is the mature response to birth that is missing in preterm neonates. TRPM7 could serve as a novel target to improve cardiac function in preterm neonates.
The process of transition from pediatric to adult healthcare services for nephrological patients: Recommendations vs. reality—A single center experience
Authors: Scarponi Dorella , Cangini Gabriella , Pasini Andrea , La Scola Claudio , Mencarelli Francesca , Bertulli Cristina , Amabile Domenico , Busutti Marco , La Manna Gaetano , Pession Andrea
Published: August 2022

Transitional care is an essential step for patients with kidney disease, and it is supported by policy documents in the United Kingdom and United States. We have previously described the heterogeneous situation currently found in Europe regarding certain aspects of transitional care: the written transition plan, the educational program, the timing of transfer to adult services, the presence of a coordinator and a dedicated off-site transition clinic. In line with the transition protocol “RISE to transition,” the objective of this paper is to describe the experience of the Bologna center in defining a protocol for the management of chronic kidney disease and the difficulties encountered in implementing it. We apply this model to various chronic diseases along the process of transfer to adult services. It begins when the patient is 14 years old and is complete by the time they reach 18. The family is continuously involved and all the patients in transitional care receive continuous medical care and psychological support. We identified a series of tests designed to measure various criteria: medical condition, psychological state, quality of life, and degree of patient satisfaction, which are repeated at set intervals during the transition process. The organization of the service provided an adequate setting for taking charge of the patients in the long term. The transition program implemented by the adult and pediatric nephrology services of the Bologna center has lowered the risk of discontinuity of care and greatly improved the patients’ awareness of responsibility for their own healthy lifestyle choices.
Case report: Intrapulmonary tidal volumes in a preterm infant with chest wall rigidity
Authors: Gaertner Vincent D. , Restin Tanja , Bassler Dirk , Fauchère Jean-Claude , Rüegger Christoph M.
Published: August 2022

Background

Chest wall rigidity is a known side effect of fentanyl use, which is why fentanyl is usually combined with a muscle relaxant such as mivacurium. Verifying endotracheal intubation is difficult in case of a rigid chest wall.

Case presentation

We present the case of a preterm infant (29 completed weeks gestation, birth weight 1,150 g) with a prolonged chest wall rigidity after fentanyl administration for intubation despite adequate doses of mivacurium. This resulted in a pronounced desaturation without any effect on heart rate. Clinically, the infant showed no chest wall movement despite intubation and common tools to verify intubation (including end-tidal carbon dioxide measurement and auscultation) were inconclusive. However, using electrical impedance tomography (EIT), we were able to demonstrate minimal tidal volumes at lung level and thereby, EIT was able to accurately show correct placement of the endotracheal tube.

Conclusions

This case may increase vigilance for fentanyl-induced chest wall rigidity in the neonatal population even when simultaneously administering mivacurium. Higher airway pressures exceeding 30 mmHg and the use of μ-receptor antagonists such as naloxone should be considered to reverse opioid-induced chest wall rigidity. Most importantly, our data may imply a relevant clinical benefit of using EIT during neonatal intubation as it may accurately show correct endotracheal tube placement.