bluuebunny/crossref_metadata_2025 huggingface dataset:
Significance of N6-Methyladenosine RNA Methylation Regulators in Immune Infiltrates of Ovarian Cancer
Authors: Gu Jing , Bi Fangfang
Published: July 2021

N6-methyladenosine (m6A) RNA methylation regulators play an important role in the occurrence and development of tumors. Here, we aimed to identify the potential roles of m6A RNA methylation regulators in immune infiltrates of ovarian cancer. We obtained two distinct m6A patterns (m6Acluster.A and m6Acluster.B) based on the expression levels of all 21 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) database using a consensus clustering algorithm. Differential analysis of m6Acluster.A and m6Acluster.B identified 196 m6A-related genes. We further validated the m6A regulation mechanism based on the 196 m6A-related genes using another consensus clustering algorithm. Considering individual differences, principal component analysis algorithms were used to calculate an m6A score for each sample in order to quantify the m6A patterns. A low m6A score was associated with immune activation and enhanced response to immune checkpoint inhibitors, whereas a high m6A score was associated with tumor progression. Finally, we successfully verified the correlation between m6A regulators and immune microenvironment in OC using our microarray analysis data. In summary, m6A regulators play non-negligible roles in immune infiltrates of ovarian cancer. Our investigation of m6A patterns may help to guide future immunotherapy strategies for advanced ovarian cancer.
A Novel circRNA–miRNA–mRNA Hub Regulatory Network in Lung Adenocarcinoma
Authors: Zuo Haiwei , Li Xia , Zheng Xixi , Sun Qiuwen , Yang Qianqian , Xin Yong
Published: July 2021

The growing evidence suggests that circular RNAs (circRNAs) have significant associations with tumor occurrence and progression, yet the regulatory mechanism of circRNAs in lung adenocarcinoma (LUAD) remains unclear. This study clarified the potentially regulatory network and functional mechanism of circRNAs in LUAD. The expression data of circRNAs, microRNAs (miRNAs), and messenger RNAs (mRNAs) were obtained from the Gene Expression Omnibus (GEO) database. Relying on GSE101586, GSE101684, and GSE112214, we identified differentially expressed circRNAs (DEcircRNAs). Depending on GSE135918 and GSE32863, we screened out differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs), respectively. Then, a novel competing endogenous RNA (ceRNA) regulatory network related to LUAD was constructed. We also revealed biological processes and signal pathways regulated by these DEcircRNAs. Based on gene expression data and survival information of LUAD patients in The Cancer Genome Atlas (TCGA) and GEO, we implemented survival analysis to select DEmRNAs related to prognosis and build a novel circRNA–miRNA–mRNA hub regulatory network. Meanwhile, quantitative real-time PCR (qRT-PCR) was utilized to validate DEcircRNAs in the ceRNA hub regulatory network. As a result, a total of 8 DEcircRNAs, 19 DEmiRNAs, and 85 DEmRNAs were identified. The novel ceRNA regulatory network included 5 circRNAs, 8 miRNAs, and 22 mRNAs. The final ceRNA hub regulatory network contained two circRNAs, two miRNAs, and two mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that the five DEcircRNAs may affect LUAD onset and progression through Wnt signaling pathway and Hippo signaling pathway. All in all, this study revealed the regulatory network and functional mechanism of circRNA-related ceRNAs in LUAD.
Investigation of a Novel LRP6 Variant Causing Autosomal-Dominant Tooth Agenesis
Authors: Huang Yan-xia , Gao Chun-yan , Zheng Chun-yan , Chen Xu , Yan You-sheng , Sun Yong-qing , Dong Xing-yue , Yang Kai , Zhang Dong-liang
Published: July 2021

Background

The low-density lipoprotein receptor-related protein 6 (LRP6) gene is a recently defined gene that is associated with the autosomal-dominant inherited tooth agenesis (TA). In the present study, a family of four generations having TA was recruited and subjected to a series of clinical, genetic, in silico, and in vitro investigations.

Methods

After routine clinical evaluation, the proband was subjected to whole-exome sequencing (WES) to detect the diagnostic variant. Next, in silico structural and molecular dynamics (MD) analysis was conducted on the identified novel missense variant for predicting its intramolecular impact. Subsequently, an in vitro study was performed to further explore the effect of this variant on protein maturation and phosphorylation.

Results

WES identified a novel variant, designated as LRP6: c.2570G > A (p.R857H), harbored by six members of the concerned family, four of whom exhibited varied TA symptoms. The in silico analysis suggested that this novel variant could probably damage the Wnt bonding function of the LRP6 protein. The experimental study demonstrated that although this novel variant did not affect the LRP6 gene transcription, it caused a impairment in the maturation and phosphorylation of LRP6 protein, suggesting the possibility of the disruption of the Wnt signaling.

Conclusion

The present study expanded the mutation spectrum of human TA in the LRP6 gene. The findings of the present study are insightful and conducive to understanding the functional significance of specific LRP6 variants.
Evaluation of the Clinical, Biochemical, Neurological, and Genetic Presentations of Glutaric Aciduria Type 1 in Patients From China
Authors: E. Huishu , Liang Lili , Zhang Huiwen , Qiu Wenjuan , Ye Jun , Xu Feng , Gong Zhuwen , Gu Xuefan , Han Lianshu
Published: July 2021

Purpose

To characterize the phenotypic and genotypic variations associated with Glutaric aciduria type 1 (GA1) in Chinese patients.

Methods

We analyzed the clinical, neuroradiological, biochemical, and genetic information from 101 GA1 patients in mainland China.

Results

20 patients were diagnosed by newborn screening and the remaining 81 cases were identified following clinical intervention. Macrocephaly was the most common presentation, followed by movement disorders and seizures. A total of 59 patients were evaluated by brain MRI and 58 patients presented with abnormalities, with widening of the sylvian fissures being the most common symptom. The concentration of glutarylcarnitine in the blood, glutarylcarnitine/capryloylcarnitine ratio, and urine levels of glutaric acid were increased in GA1 patients and were shown to decrease following intervention. A total of 88 patient samples were available for genotyping and 74 variants within the GCDH gene, including 23 novel variants, were identified. The most common variant was c.1244-2A > C (18.4%) and there were no significant differences in the biochemical or clinical phenotypes described for patients with the four most common variants: c.1244-2A > C, c.1064G > A, c.533G > A, and c.1147C > T. Patients identified by newborn screening had better outcomes than clinical patients.

Conclusion

Our findings expand the spectrum of phenotypes and genotypes for GA1 in Chinese populations and suggest that an expanded newborn screening program using tandem mass spectrometry may facilitate the early diagnosis and treatment of this disease, improving clinical outcomes for patients in China.
From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape
Authors: Chakraborty Chiranjib , Sharma Ashish Ranjan , Bhattacharya Manojit , Lee Sang-Soo
Published: July 2021

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.
Identification and Immune Assessment of T Cell Epitopes in Five Plasmodium falciparum Blood Stage Antigens to Facilitate Vaccine Candidate Selection and Optimization
Authors: Kotraiah Vinayaka , Phares Timothy W. , Terry Frances E. , Hindocha Pooja , Silk Sarah E. , Nielsen Carolyn M. , Moise Leonard , Tucker Kenneth D. , Ashfield Rebecca , Martin William D. , De Groot Anne S. , Draper Simon J. , Gutierrez Gabriel M. , Noe Amy R.
Published: July 2021

The hurdles to effective blood stage malaria vaccine design include immune evasion tactics used by the parasite such as redundant invasion pathways and antigen variation among circulating parasite strains. While blood stage malaria vaccine development primarily focuses on eliciting optimal humoral responses capable of blocking erythrocyte invasion, clinically-testedPlasmodium falciparum(Pf) vaccines have not elicited sterile protection, in part due to the dramatically high levels of antibody needed. Recent development efforts with non-redundant, conserved blood stage antigens suggest both high antibody titer and rapid antibody binding kinetics are important efficacy factors. Based on the central role of helper CD4 T cells in development of strong, protective immune responses, we systematically analyzed the class II epitope content in five leading Pf blood stage antigens (RH5, CyRPA, RIPR, AMA1 and EBA175) usingin silico,in vitro, andex vivomethodologies. We employedin silicoT cell epitope analysis to enable identification of 67 HLA-restricted class II epitope clusters predicted to bind a panel of nine HLA-DRB1 alleles. We assessed a subset of these for HLA-DRB1 allele bindingin vitro, to verify thein silicopredictions. All clusters assessed (40 clusters represented by 46 peptides) bound at least two HLA-DR allelesin vitro. The overall epitope prediction toin vitroHLA-DRB1 allele binding accuracy was 71%. Utilizing the set of RH5 class II epitope clusters (10 clusters represented by 12 peptides), we assessed stimulation of T cells collected from HLA-matched RH5 vaccinees using an IFN-γ T cell recall assay. All clusters demonstrated positive recall responses, with the highest responses – by percentage of responders and response magnitude – associated with clusters located in the N-terminal region of RH5. Finally, a statistically significant correlation betweenin silicoepitope predictions andex vivoIFN-γ recall response was found when accounting for HLA-DR matches between the epitope predictions and donor HLA phenotypes. This is the first comprehensive analysis of class II epitope content in RH5, CyRPA, RIPR, AMA1 and EBA175 accompanied byin vitroHLA binding validation for all five proteins andex vivoT cell response confirmation for RH5.
Mucosal Vaccination Primes NK Cell-Dependent Development of CD8+ T Cells Against Pulmonary Brucella Infection
Authors: Bhagyaraj Ella , Wang Hongbin , Yang Xinghong , Hoffman Carol , Akgul Ali , Goodwin Zakia I. , Pascual David W.
Published: July 2021

Past studies with the live, double-mutant B. abortus (znBAZ) strain resulted in nearly complete protection of mice against pulmonary challenge with wild-type (wt) Brucella via a dominant CD8+ T cell response. To understand the contribution innate immune cells in priming CD8+ T cell responses, mice were nasally dosed with wt B. abortus, smooth vaccine strain 19 (S19), or znBAZ, and examined for innate immune cell activation. Flow cytometric analysis revealed that znBAZ, but not wt B. abortus nor S19 infection, induces up to a 5-fold increase in the frequency of IFN-γ-producing NK cells in mouse lungs. These NK cells express increased CXCR3 and Ki67, indicating their recruitment and proliferation subsequent to znBAZ infection. Their activation status was augmented noted by the increased NKp46 and granzyme B, but decreased NKG2A expression. Further analysis demonstrated that both lung caspase-1+ inflammatory monocytes and monocyte-derived macrophages secrete chemokines and cytokines responsible for NK cell recruitment and activation. Moreover, neutralizing IL-18, an NK cell-activating cytokine, reduced the znBAZ-induced early NK cell response. NK cell depletion also significantly impaired lung dendritic cell (DC) activation and migration to the lower respiratory lymph nodes (LRLNs). Both lung DC activation and migration to LRLNs were significantly impaired in NK cell-depleted or IFN-γ-/- mice, particularly the CD11b+ and monocytic DC subsets. Furthermore, znBAZ vaccination significantly induced CD8+ T cells, and upon in vivo NK cell depletion, CD8+ T cells were reduced 3-fold compared to isotype-treated mice. In summary, these data show that znBAZ induces lung IFN-γ+ NK cells, which plays a critical role in influencing lung DC activation, migration, and promoting protective CD8+ T cell development.
Dynamic Decrease in Eosinophil After Intravenous Thrombolysis Predicts Poor Prognosis of Acute Ischemic Stroke: A Longitudinal Study
Authors: Yang Dehao , Huang Honghao , Weng Yiyun , Ren Junli , Yang Chenguang , Wang Jianing , Gao Beibei , Zeng Tian , Hu Jingyu , Pan Wenjing , Sun Fangyue , Zhou Xinbo , Chen Guangyong
Published: July 2021

Background and Purpose

Blood eosinophil counts are thought to be associated with atherosclerosis in acute ischemic stroke (AIS) and AIS severity. We aimed to investigate 1): the temporal profile of eosinophil in AIS patients treated with recombinant tissue plasminogen activator (r-tPA); 2): The association between dynamic eosinophil and 3-month outcomes in different AIS etiologies; 3): incremental predictive ability of dynamic eosinophil adding to conventional model; and 4): the longitudinal change of neutrophil-to-lymphocyte ratio (NLR) and compared its prognostic value with eosinophils.

Methods

A total of 623 AIS patients with intravenous thrombolysis in two hospitals were included. Blood samples were obtained on admission, within 24 h after an intravenous thrombolysis and on the seventh day. A multivariate logistic regression model with restricted cubic spline was performed to explore the association between dynamic eosinophil and a 3-month poor outcome. C-statistic, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were adopted to explore the incremental predictive ability.

Results

Percent change in eosinophil counts after intravenous thrombolysis was median −25.00% (IQR −68.25%–+14.29%). Decrease in eosinophil >75% after intravenous thrombolysis was associated with 2.585 times risk for poor outcome and 13.836 times risk for death. However, the association were weak for patients outside of cardioembolic stroke. Adding eosinophil changes to a conventional model improved the discriminatory ability of poor outcome (NRI = 53.3%; IDI = 2.2%) and death (NRI = 101.0%; IDI = 6.9%).

Conclusions

Dynamic decrease in eosinophil after intravenous thrombolysis predicts a 3-month poor outcome and death in AIS patients with r-tPA treatment and improved the predictive ability of conventional model. However, this result needs to be interpreted carefully in non-cardioembolic AIS patients.
The Role and Mechanism of Pyroptosis and Potential Therapeutic Targets in Sepsis: A Review
Authors: Zheng Xiangtao , Chen Weiwei , Gong Fangchen , Chen Ying , Chen Erzhen
Published: July 2021

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Recently was been found that pyroptosis is a unique form of proinflammatory programmed death, that is different from apoptosis. A growing number of studies have investigated pyroptosis and its relationship with sepsis, including the mechanisms, role, and relevant targets of pyroptosis in sepsis. While moderate pyroptosis in sepsis can control pathogen infection, excessive pyroptosis can lead to a dysregulated host immune response and even organ dysfunction. This review provides an overview of the mechanisms and potential therapeutic targets underlying pyroptosis in sepsis identified in recent decades, looking forward to the future direction of treatment for sepsis.
Ocean Acidification Amplifies Multi-Stressor Impacts on Global Marine Invertebrate Fisheries
Authors: Tai Travis C. , Sumaila U. Rashid , Cheung William W. L.
Published: July 2021

Elevated atmospheric carbon dioxide (CO2) is causing global ocean changes and drives changes in organism physiology, life-history traits, and population dynamics of natural marine resources. However, our knowledge of the mechanisms and consequences of ocean acidification (OA) – in combination with other climatic drivers (i.e., warming, deoxygenation) – on organisms and downstream effects on marine fisheries is limited. Here, we explored how the direct effects of multiple changes in ocean conditions on organism aerobic performance scales up to spatial impacts on fisheries catch of 210 commercially exploited marine invertebrates, known to be susceptible to OA. Under the highest CO2 trajectory, we show that global fisheries catch potential declines by as much as 12% by the year 2100 relative to present, of which 3.4% was attributed to OA. Moreover, OA effects are exacerbated in regions with greater changes in pH (e.g., West Arctic basin), but are reduced in tropical areas where the effects of ocean warming and deoxygenation are more pronounced (e.g., Indo-Pacific). Our results enhance our knowledge on multi-stressor effects on marine resources and how they can be scaled from physiology to population dynamics. Furthermore, it underscores variability of responses to OA and identifies vulnerable regions and species.
Examining Scale Dependent Environmental Effects on American Lobster (Homarus americanus) Spatial Distribution in a Changing Gulf of Maine
Authors: Behan Jamie , Li Bai , Chen Yong
Published: July 2021

The Gulf of Maine (GOM) is a highly complex environment and previous studies have suggested the need to account for spatial nonstationarity in species distribution models (SDMs) for the American lobster (Homarus americanus). To explore impacts of spatial nonstationarity on species distribution, we compared models with the following three assumptions : (1) large-scale and stationary relationships between species distributions and environmental variables; (2) meso-scale models where estimated relationships differ between eastern and western GOM, and (3) finer-scale models where estimated relationships vary across eastern, central, and western regions of the GOM. The spatial scales used in these models were largely determined by the GOM coastal currents. Lobster data were sourced from the Maine-New Hampshire Inshore Bottom Trawl Survey from years 2000–2019. We considered spatial and environmental variables including latitude and longitude, bottom temperature, bottom salinity, distance from shore, and sediment grain size in the study. We forecasted distributions for the period 2028–2055 using each of these models under the Representative Concentration Pathway (RCP) 8.5 “business as usual” climate warming scenario. We found that the model with the third assumption (i.e., finest scale) performed best. This suggests that accounting for spatial nonstationarity in the GOM leads to improved distribution estimates. Large-scale models revealed a tendency to estimate global relationships that better represented a specific location within the study area, rather than estimating relationships appropriate across all spatial areas. Forecasted distributions revealed that the largest scale models tended to comparatively overestimate most season × sex × size group lobster abundances in western GOM, underestimate in the western portion of central GOM, and overestimate in the eastern portion of central GOM, with slightly less consistent and patchy trends amongst groups in eastern GOM. The differences between model estimates were greatest between the largest and finest scale models, suggesting that fine-scale models may be useful for capturing effects of unique dependencies that may operate at localized scales. We demonstrate how estimates of season-, sex-, and size- specific American lobster spatial distribution would vary based on the spatial scale assumption of nonstationarity in the GOM. This information may help develop appropriate local adaptation measures in a region that is susceptible to climate change.
Syphilis Testing as a Proxy Marker for a Subgroup of Men Who Have Sex With Men With a Central Role in HIV-1 Transmission in Guangzhou, China
Authors: Huang Liping , Wu Hao , Yan Huanchang , Liang Yuanhao , Li Qingmei , Shui Jingwei , Han Zhigang , Tang Shixing
Published: July 2021

Objectives: The objectives of this study were to distinguish the role of men who have sex with men (MSM) with or without syphilis testing in HIV-1 transmission and to provide molecular evidence of syphilis testing as a proxy marker for identifying the subgroup of MSM.

Methods: HIV-1 transmission clusters were constructed by HIV-TRACE and Cluster Picker using HIV-1 pol sequences from 729 newly diagnosed HIV-infected MSM from 2008 to 2012 in Guangzhou, China. The role of MSM in HIV-1 transmission networks was determined by a node influence measurement and centrality analysis. The association between syphilis testing and factors related to HIV-1 transmission and antiretroviral treatment (ART) were analyzed by the Cox regression model.

Results: Among HIV-infected MSM, 56.7% did not test for syphilis at the time of HIV-1 diagnosis. MSM without syphilis testing was a specific subgroup of MSM with a larger closeness centrality and clustering coefficient than the recipients of syphilis testing (P < 0.001), indicating their central position in the HIV-1 transmission networks. The median degree and radiality within HIV-1 transmission networks as well as the median K-shell scores were also greater for MSM without syphilis testing (P < 0.001), suggesting their relatively greater contribution in transmitting HIV-1 than the receipts of syphilis testing. MSM with syphilis testing usually did not disclose their occupation or were more likely to be unemployed or to take non-skilled jobs, to have a history of sexually transmitted infections (STIs), and to be AIDS patients when diagnosed with HIV-1 infection (P < 0.05). Multivariable Cox regression analysis indicated that syphilis testing per se did not promote the engagement of ART (P = 0.233) or affect the speed of CD4+ T cell count recovery after treatment (P = 0.256).

Conclusions: Our study identifies syphilis testing as a proxy marker of a specific subgroup of HIV-infected MSM who refuse syphilis testing during HIV-1 diagnosis with an important role in HIV-1 transmission. Specific prevention and intervention targeting MSM without syphilis testing during HIV-1 care are urgently needed.
USA: Ophthalmologic Evaluation and Management of Acute Stevens-Johnson Syndrome
Authors: Gregory Darren G.
Published: July 2021

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can cause significant damage to the ocular surface and eyelids. The sloughing and inflammation of the ocular mucosal epithelium during the acute phase may lead to scarring sequelae of the eyelids and ocular surface, resulting in pain and vision loss. Amniotic membrane transplantation (AMT) to the eyes and eyelids during the initial 1–2 weeks of the disease can decrease the chronic sequelae. The main development in the ophthalmologic treatment of SJS/TEN in the USA over the last 15 years has been the use of AMT on the ocular surface and eyelids during the acute phase. The evolution of AMT techniques, refinement of the evaluation of the eyes in acute SJS, and the efforts to increase the use of AMT in the USA are discussed.
Validation and Extrapolation of a Multimodal Infection Prevention and Control Intervention on Carbapenem-Resistant Klebsiella pneumoniae in an Epidemic Region: A Historical Control Quasi-Experimental Study
Authors: Dai Yunqi , Meng Tianjiao , Wang Xiaoli , Tang Bin , Wang Feng , Du Ying , Qiu Yuzhen , Liu Jialin , Tan Ruoming , Qu Hongping
Published: July 2021

Objective: To verify the effects of comprehensive infection prevention and control (IPC) interventions for the prevention of the cross-transmission of carbapenem-resistant Klebsiella pneumoniae (CRKP) within intensive care units (ICUs) in an epidemic region.

Methods: A historical control, quasi-experimental design was performed. The study was conducted between January 2017 and December 2019, following the implementation of a multimodal IPC bundle. The baseline period was established from January 2013 to June 2013, when only basic IPC measures were applied.

Results: A total of 748 patients were enrolled during the entire study. The incidence of ICU-acquired CRKP colonization/infection was 1.16 per 1,000 patient-days during the intervention period, compared with 10.19 per 1,000 patient-days during the baseline period (p = 0.002). The slope of the monthly incidence of CRKP at admission showed an increasing trend (p = 0.03). The incidence of ICU-acquired catheter-related bloodstream infections caused by CRKP decreased from 2.54 to 0.96 per 1,000 central-line-days (p = 0.08). Compliance with contact precautions and terminal room disinfection improved during the intervention period. All environmental surface culture samples acquired after terminal room disinfection were negative for CRKP.

Conclusion: Our findings suggest that in epidemic settings, multimodal IPC intervention strategies and consistent monitoring of compliance, may limit the spread of CRKP in ICUs.
Case Report: PD-1 Blockade Combined Autologous Hematopoietic Stem Cell Transplantation With Modified BEAM Regimen Containing High-Dose Cytarabine to Treat R/R Hodgkin's Lymphoma
Authors: Wang Xiaoqi , Cassady Kaniel , Zou Zhongmin , Zhang Xi , Feng Yimei
Published: July 2021

The emergence of new drugs has provided additional options in the treatment of relapsed and refractory (R/R) Hodgkin's lymphoma (HL). However, the use of autologous stem cell transplantation (ASCT) has not been completely replaced in this setting. The use of anti-programmed death-1 (PD-1) antibody bridging to ASCT and as maintenance after transplantation is a novel approach in HL treatment. In this case, we report that PD-1 monoclonal antibody (mAb) plus ASCT with modified BEAM regimen (carmustine + etoposide + cytarabine + melphalan) containing high-dose cytarabine to treat R/R HL may represent a promising regimen in this difficult-to-treat setting.
Conserved Metabolic and Evolutionary Themes in Microbial Degradation of Carbamate Pesticides
Authors: Malhotra Harshit , Kaur Sukhjeet , Phale Prashant S.
Published: July 2021

Carbamate pesticides are widely used as insecticides, nematicides, acaricides, herbicides and fungicides in the agriculture, food and public health sector. However, only a minor fraction of the applied quantity reaches the target organisms. The majority of it persists in the environment, impacting the non-target biota, leading to ecological disturbance. The toxicity of these compounds to biota is mediated through cholinergic and non-cholinergic routes, thereby making their clean-up cardinal. Microbes, specifically bacteria, have adapted to the presence of these compounds by evolving degradation pathways and thus play a major role in their removal from the biosphere. Over the past few decades, various genetic, metabolic and biochemical analyses exploring carbamate degradation in bacteria have revealed certain conserved themes in metabolic pathways like the enzymatic hydrolysis of the carbamate ester or amide linkage, funnelling of aryl carbamates into respective dihydroxy aromatic intermediates, C1 metabolism and nitrogen assimilation. Further, genomic and functional analyses have provided insights on mechanisms like horizontal gene transfer and enzyme promiscuity, which drive the evolution of degradation phenotype. Compartmentalisation of metabolic pathway enzymes serves as an additional strategy that further aids in optimising the degradation efficiency. This review highlights and discusses the conclusions drawn from various analyses over the past few decades; and provides a comprehensive view of the environmental fate, toxicity, metabolic routes, related genes and enzymes as well as evolutionary mechanisms associated with the degradation of widely employed carbamate pesticides. Additionally, various strategies like application of consortia for efficient degradation, metabolic engineering and adaptive laboratory evolution, which aid in improvising remediation efficiency and overcoming the challenges associated with in situ bioremediation are discussed.
Introduction and Characteristics of SARS-CoV-2 in North-East of Romania During the First COVID-19 Outbreak
Authors: Lobiuc Andrei , Dimian Mihai , Gheorghita Roxana , Sturdza Olga Adriana Caliman , Covasa Mihai
Published: July 2021

Romania officially declared its first Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) case on February 26, 2020. The first and largest coronavirus disease 2019 (COVID-19) outbreak in Romania was recorded in Suceava, North-East region of the country, and originated at the Suceava regional county hospital. Following sheltering-in-place measures, infection rates decreased, only to rise again after relaxation of measures. This study describes the spread of SARS-CoV-2 in Suceava and other parts of Romania and analyses the mutations and their association with clinical manifestation of the disease during the period of COVID-19 outbreak. Sixty-two samples were sequenced via high-throughput platform and screened for variants. For selected mutations, putative biological significance was assessed, and their effects on disease severity. Phylogenetic analysis was conducted on Romanian genomes (n = 112) and on sequences originating from Europe, United Kingdom, Africa, Asia, South, and North America (n = 876). The results indicated multiple introduction events for SARS-CoV-2 in Suceava, mainly from Italy, Spain, United Kingdom, and Russia although some sequences were also related to those from the Czechia, Belgium, and France. Most Suceava genomes contained mutations common to European lineages, such as A20268G, however, approximately 10% of samples were missing such mutations, indicating a possible different arrival route. While overall genome regions ORF1ab, S, and ORF7 were subject to most mutations, several recurring mutations such as A105V were identified, and these were mainly present in severe forms of the disease. Non-synonymous mutations, such as T987N (Thr987Asn in NSP3a domain), associated with changes in a protein responsible for decreasing viral tethering in human host were also present. Patients with diabetes and hypertension exhibited higher risk ratios (RR) of acquiring severe forms of the disease and these were mainly related to A105V mutation. This study identified the arrival routes of SARS-CoV-2 in Romania and revealed potential associations between the SARS-CoV-2 genomic organization circulating in the country and the clinical manifestation of COVID-19 disease.
Highly Specific and Sensitive Detection of Yersinia pestis by Portable Cas12a-UPTLFA Platform
Authors: You Yang , Zhang Pingping , Wu Gengshan , Tan Yafang , Zhao Yong , Cao Shiyang , Song Yajun , Yang Ruifu , Du Zongmin
Published: July 2021

The recent discovery of collateral cleavage activity of class-II clustered regularly interspaced short palindromic repeats–CRISPR-associated protein (CRISPR-Cas) makes CRISPR-based diagnosis a potential high-accuracy nucleic acid detection method. Colloidal gold-based lateral flow immunochromatographic assay (LFA), which has been combined with CRISPR/Cas-based nucleic detection, usually associates with drawbacks of relative high background and the subjectivity in naked-eye read-out of the results. Here, we developed a novel system composed of Cas12a-based nucleic acid detection and up-converting phosphor technology (UPT)-based LFA (UPT–LFA), termed Cas12a-UPTLFA. We further demonstrated the utility of this platform in highly sensitive and specific detection of Yersinia pestis, the causative agent of the deadly plague. Due to high infectivity and mortality, as well as the potential to be misused as bioterrorism agent, a culture-free, ultrasensitive, specific, and rapid detection method for Y. pestis has long been desired. By incorporating isothermal recombinase polymerase amplification, the Cas12a-UPTLFA we established can successfully detect genomic DNA of Y. pestis as low as 3 attomolar (aM) and exhibited high sensitivity (93.75%) and specificity (90.63%) for detection of spiked blood samples with a detection limit of 102 colony-forming unit per 100 μl of mouse blood. With a portable biosensor, Cas12a-UPTLFA assay can be operated easily by non-professional personnel. Taken together, we have developed a novel Cas12a-UPTLFA platform for rapid detection of Y. pestis with high sensitivity and specificity, which is portable, not expensive, and easy to operate as a point-of-care method. This detection system can easily be extended to detect other pathogens and holds great promise for on-site detection of emerging infectious pathogens.
Comprehensive Molecular Analyses of a Novel Mutational Signature Classification System with Regard to Prognosis, Genomic Alterations, and Immune Landscape in Glioma
Authors: Liu Zaoqu , Lu Taoyuan , Wang Libo , Liu Long , Li Lifeng , Han Xinwei
Published: July 2021

Background: Glioma is the most common malignant brain tumor with complex carcinogenic process and poor prognosis. The current molecular classification cannot fully elucidate the molecular diversity of glioma.

Methods: Using broad public datasets, we performed cluster analysis based on the mutational signatures and further investigated the multidimensional heterogeneity of the novel glioma molecular subtypes. The clinical significance and immune landscape of four clusters also investigated. The nomogram was developed using the mutational clusters and clinical characteristics.

Results: Four heterogenous clusters were identified, termed C1, C2, C3, and C4, respectively. These clusters presented distinct molecular features: C1 was characterized by signature 1, PTEN mutation, chromosome seven amplification and chromosome 10 deletion; C2 was characterized by signature 8 and FLG mutation; C3 was characterized by signature 3 and 13, ATRX and TP53 mutations, and 11p15.1, 11p15.5, and 13q14.2 deletions; and C4 was characterized by signature 16, IDH1 mutation and chromosome 1p and 19q deletions. These clusters also varied in biological functions and immune status. We underlined the potential immune escape mechanisms: abundant stromal and immunosuppressive cells infiltration and immune checkpoints (ICPs) blockade in C1; lack of immune cells, low immunogenicity and antigen presentation defect in C2 and C4; and ICPs blockade in C3. Moreover, C4 possessed a better prognosis, and C1 and C3 were more likely to benefit from immunotherapy. A nomogram with excellent performance was also developed for assessing the prognosis of patients with glioma.

Conclusion: Our results can enhance the mastery of molecular features and facilitate the precise treatment and clinical management of glioma.
Cannabinoids Regulate Sensory Processing in Early Olfactory and Visual Neural Circuits
Authors: Heinbockel Thomas , Straiker Alex
Published: July 2021

Our sensory systems such as the olfactory and visual systems are the target of neuromodulatory regulation. This neuromodulation starts at the level of sensory receptors and extends into cortical processing. A relatively new group of neuromodulators includes cannabinoids. These form a group of chemical substances that are found in the cannabis plant. Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main cannabinoids. THC acts in the brain and nervous system like the chemical substances that our body produces, the endogenous cannabinoids or endocannabinoids, also nicknamed the brain’s own cannabis. While the function of the endocannabinoid system is understood fairly well in limbic structures such as the hippocampus and the amygdala, this signaling system is less well understood in the olfactory pathway and the visual system. Here, we describe and compare endocannabinoids as signaling molecules in the early processing centers of the olfactory and visual system, the olfactory bulb, and the retina, and the relevance of the endocannabinoid system for synaptic plasticity.
Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management
Authors: Sechi Elia , Flanagan Eoin P.
Published: July 2021

Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.
Association Between Amygdala Volume and Trajectories of Neuropsychiatric Symptoms in Alzheimer's Disease and Dementia With Lewy Bodies
Authors: Jaramillo-Jimenez Alberto , Giil Lasse M. , Tovar-Rios Diego A. , Borda Miguel Germán , Ferreira Daniel , Brønnick Kolbjørn , Oppedal Ketil , Aarsland Dag
Published: July 2021

Introduction: The amygdala is implicated in psychiatric illness. Even as the amygdala undergoes significant atrophy in mild dementia, amygdala volume is underexplored as a risk factor for neuropsychiatric symptoms (NPS).

Objective: To analyze the association between baseline amygdala volume and the longitudinal trajectories of NPS and cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) over 5 years.

Methods: Eighty-nine patients with mild dementia were included (AD = 55; DLB = 34). Amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi-automatic method (Freesurfer 6.0) and normalized by intracranial volumes. The intracranial volume-normalized amygdala was used as a predictor of the Neuropsychiatric Inventory (NPI) total score, ordinal NPI item scores (0 = absence of symptoms, 1–3 = mild symptoms, ≥4 = clinically relevant symptoms), and Mini-Mental State Examination (MMSE) as measured annually over 5 years using gamma, ordinal, and linear mixed-effects models, respectively. The models were adjusted for demographic variables, diagnosis, center of sMRI acquisition, and cognitive performance. Multiple testing-corrected p-values (q-values) are reported.

Results: Larger intracranial volume-normalized amygdala was associated with less agitation/aggression (odds ratio (OR) = 0.62 [0.43, 0.90], p = 0.011, q = 0.038) and less MMSE decline per year (fixed effect = 0.70, [0.29, 1.03], p = 0.001, q = 0.010) but more depression (OR = 1.49 [1.09, 2.04], p = 0.013, q = 0.040).

Conclusions: Greater amygdala volume in mild dementia is associated with lower odds of developing agitation/aggression, but higher odds of developing depression symptoms during the 5-year study period.
Diagnostic Utility of Radiomics in Thyroid and Head and Neck Cancers
Authors: Gul Maryam , Bonjoc Kimberley-Jane C. , Gorlin David , Wong Chi Wah , Salem Amirah , La Vincent , Filippov Aleksandr , Chaudhry Abbas , Imam Muhammad H. , Chaudhry Ammar A.
Published: July 2021

Radiomics is an emerging field in radiology that utilizes advanced statistical data characterizing algorithms to evaluate medical imaging and objectively quantify characteristics of a given disease. Due to morphologic heterogeneity and genetic variation intrinsic to neoplasms, radiomics have the potential to provide a unique insight into the underlying tumor and tumor microenvironment. Radiomics has been gaining popularity due to potential applications in disease quantification, predictive modeling, treatment planning, and response assessment – paving way for the advancement of personalized medicine. However, producing a reliable radiomic model requires careful evaluation and construction to be translated into clinical practices that have varying software and/or medical equipment. We aim to review the diagnostic utility of radiomics in otorhinolaryngology, including both cancers of the head and neck as well as the thyroid.
Diagnosis and Molecular Profiles of Large Cell Neuroendocrine Carcinoma With Potential Targets for Therapy
Authors: Popper Helmut , Brcic Luka
Published: July 2021

Large cell neuroendocrine carcinoma (LCNEC) together with small cell carcinoma (SCLC) and typical and atypical carcinoids form the group of pulmonary neuroendocrine tumors. LCNEC and SCLC are high-grade carcinomas. Although both can be found outside the thoracic cavity, they are most common in the lung. LCNEC differs from SCLC by morphologic pattern, and by cytological features such as nuclear size, nucleoli, chromatin pattern, but also by genetic differences. Originally thought to represent a single entity, it became evident, that three subgroups of LCNEC can be identified at the molecular level: a SCLC-like type with loss of retinoblastoma 1 gene (RB1) and TP53 mutations; a non-small cell lung carcinoma (NSCLC)-like type with wildtype RB1, TP53 mutation, and activating mutations of the phosphoinositol-3 kinase (PI3K-CA), or loss of PTEN; and a carcinoid-like type with MEN1 gene mutation. These subtypes can be identified by immunohistochemical staining for RB1, p53, and molecular analysis for PI3K and MEN1 mutations. These subtypes might also respond differently to chemotherapy. Immuno-oncologic treatment has also been applied to LCNEC, however, in addition to the evaluation of tumor cells the stroma evaluation seems to be important. Based on personal experiences with these tumors and available references this review will try to encompass our present knowledge in this rare entity and provoke new studies for better treatment of this carcinoma.
Radiomics Analysis of Multi-Sequence MR Images For Predicting Microsatellite Instability Status Preoperatively in Rectal Cancer
Authors: Li Zongbao , Dai Hui , Liu Yunxia , Pan Feng , Yang Yanyan , Zhang Mengchao
Published: July 2021

Background

Immunotherapy, adjuvant chemotherapy, and prognosis of colorectal cancer are associated with MSI. Biopsy pathology cannot fully reflect the MSI status and heterogeneity of rectal cancer.

Purpose

To develop a radiomic-based model to preoperatively predict MSI status in rectal cancer on MRI.

Assessment

The patients were divided into two cohorts (training and testing) at a 7:3 ratio. Radiomics features, including intensity, texture, and shape, were extracted from the segmented volumes of interest based on T2-weighted and ADC imaging.

Statistical Tests

Independent sample t test, Mann-Whitney test, the chi-squared test, Receiver operating characteristic curves, calibration curves, decision curve analysis and multi-variate logistic regression analysis

Results

The radiomics models were significantly associated with MSI status. The T2-based model showed an area under the curve of 0.870 with 95% CI: 0.794–0.945 (accuracy, 0.845; specificity, 0.714; sensitivity, 0.976) in training set and 0.895 with 95% CI, 0.777–1.000 (accuracy, 0.778; specificity, 0.887; sensitivity, 0.772) in testing set. The ADC-based model had an AUC of 0.790 with 95% CI: 0.794–0.945 (accuracy, 0.774; specificity, 0.714; sensitivity, 0.976) in training set and 0.796 with 95% CI, 0.777–1.000 (accuracy, 0.778; specificity, 0.889; sensitivity, 0.772) in testing set. The combined model integrating T2 and ADC features showed an AUC of 0.908 with 95% CI: 0.845–0.971 (accuracy, 0.857; specificity, 0.762; sensitivity, 0.952) in training set and 0.926 with 95% CI: 0.813-1.000 (accuracy, 0.852; specificity, 1.000; sensitivity, 0.778) in testing set. Calibration curve showed that the combined score had a good calibration degree, and the decision curve demonstrated that the combined score was of benefit for clinical use.

Data Conclusion

Radiomics analysis of T2W and ADC images showed significant relevance in the prediction of microsatellite status, and the accuracy of combined model of ADC and T2W features was better than either alone.