bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Five Different Criteria for Diagnosis of Subclinical Hypothyroidism in a Large-Scale Chinese Population
Authors: Zheng Yan-song , Dong Sheng-yong , Gong Yan , Wang Jia-hong , Wang Fei , Zeng Qiang
Published: February 2022

Background

Several different criteria for subclinical hypothyroidism (SCH) have been used in the literature, but the performance of these criteria was unknown.

Objective

This retrospective study was to evaluate the diagnostic criteria for SCH.

Methods

Eligible participants were based on centration of thyroglobulin antibodies (TG-Ab), thyroid peroxidase antibodies (TPO-Ab), and five thyroid-related hormones including total thyroxine (TT4), total triiodothyronine (TT3), free thyroxine (FT4), free triiodothyronine (FT3), and thyroid-stimulating hormone (TSH). Euthyroid individuals were identified via specific criteria. Five different SCH diagnostic criteria were compared based on the distributions of those indicators. An appropriate TSH cut-off value was reconsidered.

Results

The study included 145,015 participants. The number of SCH cases diagnosed using criterion 5 was significantly different compared to the cases diagnosed using criteria 1-4 (P<0.05) and had the highest positive proportions of TG-Ab and TPO-Ab. Analysis of 60,515 subjects with normal other thyroid hormones revealed a median TSH concentration of 2.04 mIU/L, and the P2.5–P97.5 CI was 0.48-7.03 mIU/L. When the threshold for TSH elevation was elevated from ≥4.5 mIU/L to ≥6.50 mIU/L, the number of diagnosed SCH cases decreased from 7.30% to 2.09% and the proportions of positive TG-Ab and TPO-Ab increased from 23.69% and 24.07% to 33.75% and 35.06%, respectively (P<0.01).

Conclusions

Combination of an elevated TSH and normal TT3, TT4, FT3, and FT4 concentrations is a must for the diagnosis of SCH. A new TSH threshold should be identified for better patient monitoring and management, according to the real-world characteristics of TSH distribution in Chinese population.
Genetic Analysis of TB Susceptibility Variants in Ghana Reveals Candidate Protective Loci in SORBS2 and SCL11A1 Genes
Authors: Asante-Poku Adwoa , Morgan Portia , Osei-Wusu Stephen , Aboagye Samuel Yaw , Asare Prince , Otchere Isaac Darko , Adadey Samuel Mawuli , Mnika Khuthala , Esoh Kevin , Mawuta Kenneth Hayibor , Arthur Nelly , Forson Audrey , Mazandu Gaston Kuzamunu , Wonkam Ambroise , Yeboah-Manu Dorothy
Published: February 2022

Despite advancements made toward diagnostics, tuberculosis caused by Mycobacterium africanum (Maf) and Mycobacterium tuberculosis sensu stricto (Mtbss) remains a major public health issue. Human host factors are key players in tuberculosis (TB) outcomes and treatment. Research is required to probe the interplay between host and bacterial genomes. Here, we explored the association between selected human/host genomic variants and TB disease in Ghana. Paired host genotype datum and infecting bacterial isolate information were analyzed for associations using a multinomial logistic regression. Mycobacterium tuberculosis complex (MTBC) isolates were obtained from 191 TB patients and genotyped into different phylogenetic lineages by standard methods. Two hundred and thirty-five (235) nondisease participants were used as healthy controls. A selection of 29 SNPs from TB disease-associated genes with high frequency among African populations was assayed using a TaqMan® SNP Genotyping Assay and iPLEX Gold Sequenom Mass Genotyping Array. Using 26 high-quality SNPs across 326 case-control samples in an association analysis, we found a protective variant, rs955263, in the SORBS2 gene against both Maf and Mtb infections (PBH = 0.05; OR = 0.33; 95% CI = 0.32–0.34). A relatively uncommon variant, rs17235409 in the SLC11A1 gene was observed with an even stronger protective effect against Mtb infection (MAF = 0.06; PBH = 0.04; OR = 0.05; 95% CI = 0.04–0.05). These findings suggest SLC11A1 and SORBS2 as a potential protective gene of substantial interest for TB, which is an important pathogen in West Africa, and highlight the need for in-depth host-pathogen studies in West Africa.
The Follow-Up of Chinese Patients in cblC Type Methylmalonic Acidemia Identified Through Expanded Newborn Screening
Authors: Ling Shiying , Wu Shengnan , Shuai Ruixue , Yu Yue , Qiu Wenjuan , Wei Haiyan , Yang Chiju , Xu Peng , Zou Hui , Feng Jizhen , Niu Tingting , Hu Haili , Zhang Huiwen , Liang Lili , Lu Deyun , Gong Zhuwen , Zhan Xia , Ji Wenjun , Gu Xuefan , Han Lianshu
Published: February 2022

Objective: The cblC type of combined methylmalonic acidemia and homocystinuria, an inherited disorder with variable phenotypes, is included in newborn screening (NBS) programs at multiple newborn screening centers in China. The present study aimed to investigate the long-term clinical benefits of screening individual.

Methods: A national, retrospective multi-center study of infants with confirmed cblC defect identified by NBS between 2004 and 2020 was conducted. We collected a large cohort of 538 patients and investigated their clinical data in detail, including disease onset, biochemical metabolites, and gene variation, and explored different factors on the prognosis.

Results: The long-term outcomes of all patients were evaluated, representing 44.6% for poor outcomes. In our comparison of patients with already occurring clinical signs before treatment to asymptomatic ones, the incidence of intellectual impairment, movement disorders, ocular complications, hydrocephalus, and death were significantly different (p < 0.01). The presence of disease onset [Odd ratio (OR) 12.39, 95% CI 5.15–29.81; p = 0.000], variants of c.609G>A (OR 2.55, 95% CI 1.49–4.35; p = 0.001), and c.567dupT (OR 2.28, 95% CI 1.03–5.05; p = 0.042) were independently associated with poor outcomes, especially for neurodevelopmental deterioration.

Conclusion: NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have protective effects on the prognosis of infants with cblC defect.
Establishment and Validation of a Ferroptosis-Related Long Non-Coding RNA Signature for Predicting the Prognosis of Stomach Adenocarcinoma
Authors: Zhang Shuqiong , Zheng Naisheng , Chen Xiaocui , Du Kun , Yang Junyao , Shen Lisong
Published: February 2022

Background: Ferroptosis is a form of regulated cell death that follows cell membrane damage and mostly depends on iron-mediated oxidative. Long non-coding RNAs (LncRNAs) are associated with the development of a variety of tumors. Till date, LncRNAs have been reported to intervene in ferroptosis. Therefore, we intended to provide a prognostic ferroptosis-related-lncRNA signature in stomach adenocarcinoma (STAD).

Methods: We downloaded ferroptosis-related genes from the FerrDb database and RNA sequencing data and clinicopathological characteristics from The Cancer Genome Atlas. Gene differential expression analysis was performed using the “limma” package. We used Cox regression analysis to determine the ferroptosis-related lncRNAs signature with the lowest AIC value. The Kaplan–Meier curve, ROC curve, and nomogram were used to evaluate the prognostic value of the risk score. Gene set enrichment analysis (GSEA) was used to explore the biologic functions of the three ferroptosis-related lncRNAs. LINC01615 expression in gastric cancer cell lines and tissues was measured by real-time PCR. A nuclear-cytoplasmic fractionation assay was used to analyze the subcellular localization for LINC01615. Furthermore, we used bioinformatics to predict potential target microRNAs (miRNAs) of LINC01615 and their target ferroptosis-related mRNAs.

Results: Three ferroptosis-related-lncRNA signatures (AP000695.2, AL365181.3, and LINC01615) were identified, and then Kaplan–Meier, Cox regression analyses, and ROC curve confirmed that the ferroptosis-related-lncRNA model could predict the prognosis of STAD. The GSEA indicated that the three ferroptosis-related lncRNAs might be related to the extracellular matrix and cellular activities. LINC01615 is highly expressed in gastric cancer cell lines and tissues. A nuclear-cytoplasmic fractionation assay confirmed that in gastric cancer cell lines, most LINC01615 was enriched in the cytoplasm. Bioinformatics further predicts four potential target miRNAs of LINC01615 and then figured out 26 target ferroptosis-related mRNAs.

Conclusion: We established a three-ferroptosis-related-lncRNA model (AP000695.2, AL365181.3, and LINC01615) that can predict the prognosis of STAD patients. We also expected to provide a promising target for LINC01615 for research in the future, which was highly expressed in gastric cancer and cell lines and acted as a ceRNA to get involved in ferroptosis.
The Human Being as a Creator of (in) Human Life: The Example of Mary Shelley’s Frankenstein; or, the Modern Prometheus
Authors: Rédei Anna C.
Published: February 2022

Humans have an inquiring mind. Throughout history, one may find documentation that shows on human curiosity, and our drive to stretch boundaries to satisfy it. Thus, this is not something that characterizes our time in any particular way. Sources, for instance, from the 13th century can serve as good examples that support such an assumption. Mary Shelley’s novel from the 19th century, “Frankenstein; or, the modern Prometheus,” might perhaps be the most known commentary to that boundary stretching, which continues in a slightly new form in the ongoing debate and the popular culture within the scientific community. Shelley’s narrative about the scientist Frankenstein and his Creature has continued to interest the audience. Through adaptations to film, the story has reached many new generations of cinema goers. However, new interpretations have altered some aspects the original message. Shelley’s conception of the monstrous was more complex than today when parts of the narrative have been downplayed and others have been upscaled.
Chemokines in Type 1 Diabetes Mellitus
Authors: Pan Xiongfeng , Kaminga Atipatsa C. , Kinra Sanjay , Wen Shi Wu , Liu Hongying , Tan Xinrui , Liu Aizhong
Published: February 2022

Background

Previous studies suggested that chemokines may play an important role in the formation and mediation of immune microenvironments of patients affected by Type 1 Diabetes Mellitus (T1DM). The aim of this study was to summarise available evidence on the associations of different chemokines with T1DM.

Methods

Following PRISMA guidelines, we systematically searched in PubMed, Web of Science, Embase and Cochrane Library databases for studies on the associations of different chemokines with T1DM. The effect size of the associations were the standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs) of the chemokines concentrations, calculated as group differences between the T1DM patients and the controls. These were summarized using network meta-analysis, which was also used to rank the chemokines by surface under cumulative ranking curve (SUCRA) probabilities.

Results

A total of 32 original studies on the association of different chemokines with T1DM were identified. Fifteen different chemokine nodes were compared between 15,683 T1DM patients and 15,128 controls, and 6 different chemokine receptor nodes were compared between 463 T1DM patients and 460 controls. Circulating samples (blood, serum, and plasma) showed that concentrations of CCL5 and CXCL1 were significantly higher in the T1DM patients than in the controls (SMD of 3.13 and 1.50, respectively). On the other hand, no significant difference in chemokine receptors between T1DM and controls was observed. SUCRA probabilities showed that circulating CCL5 had the highest rank in T1DM among all the chemokines investigated.

Conclusion

The results suggest that circulating CCL5 and CXCL1 may be promising novel biomarkers of T1DM. Future research should attempt to replicate these findings in longitudinal studies and explore potential mechanisms underlying this association.
Phosphatidylcholine-Derived Lipid Mediators: The Crosstalk Between Cancer Cells and Immune Cells
Authors: Saito Renata de Freitas , Andrade Luciana Nogueira de Sousa , Bustos Silvina Odete , Chammas Roger
Published: February 2022

To become resistant, cancer cells need to activate and maintain molecular defense mechanisms that depend on an energy trade-off between resistance and essential functions. Metabolic reprogramming has been shown to fuel cell growth and contribute to cancer drug resistance. Recently, changes in lipid metabolism have emerged as an important driver of resistance to anticancer agents. In this review, we highlight the role of choline metabolism with a focus on the phosphatidylcholine cycle in the regulation of resistance to therapy. We analyze the contribution of phosphatidylcholine and its metabolites to intracellular processes of cancer cells, both as the major cell membrane constituents and source of energy. We further extended our discussion about the role of phosphatidylcholine-derived lipid mediators in cellular communication between cancer and immune cells within the tumor microenvironment, as well as their pivotal role in the immune regulation of therapeutic failure. Changes in phosphatidylcholine metabolism are part of an adaptive program activated in response to stress conditions that contribute to cancer therapy resistance and open therapeutic opportunities for treating drug-resistant cancers.
Rhinovirus-Induced Cytokine Alterations With Potential Implications in Asthma Exacerbations: A Systematic Review and Meta-Analysis
Authors: Liew Kong Yen , Koh Sue Kie , Hooi Suet Li , Ng Matthew Kah Lup , Chee Hui-Yee , Harith Hanis Hazeera , Israf Daud Ahmad , Tham Chau Ling
Published: February 2022

Background

Rhinovirus (RV) infections are a major cause of asthma exacerbations. Unlike other respiratory viruses, RV causes minimal cytotoxic effects on airway epithelial cells and cytokines play a critical role in its pathogenesis. However, previous findings on RV-induced cytokine responses were largely inconsistent. Thus, this study sought to identify the cytokine/chemokine profiles induced by RV infection and their correlations with airway inflammatory responses and/or respiratory symptoms using systematic review, and to determine whether a quantitative difference exists in cytokine levels between asthmatic and healthy individuals via meta-analysis.

Methods

Relevant articles were obtained from PubMed, Scopus, and ScienceDirect databases. Studies that compared RV-induced cytokine responses between asthmatic and healthy individuals were included in the systematic review, and their findings were categorized based on the study designs, which were ex vivo primary bronchial epithelial cells (PBECs), ex vivo peripheral blood mononuclear cells (PBMCs), and human experimental studies. Data on cytokine levels were also extracted and analyzed using Review Manager 5.4.

Results

Thirty-four articles were included in the systematic review, with 18 of these further subjected to meta-analysis. Several studies reported the correlations between the levels of cytokines, such as IL-8, IL-4, IL-5, and IL-13, and respiratory symptoms. Evidence suggests that IL-25 and IL-33 may be the cytokines that promote type 2 inflammation in asthmatics after RV infection. Besides that, a meta-analysis revealed that PBECs from children with atopic asthma produced significantly lower levels of IFN-β [Effect size (ES): -0.84, p = 0.030] and IFN-λ (ES: -1.00, p = 0.002), and PBECs from adult atopic asthmatics produced significantly lower levels of IFN-β (ES: -0.68, p = 0.009), compared to healthy subjects after RV infection. A trend towards a deficient production of IFN-γ (ES: -0.56, p = 0.060) in PBMCs from adult atopic asthmatics was observed. In lower airways, asthmatics also had significantly lower baseline IL-15 (ES: -0.69, p = 0.020) levels.

Conclusion

Overall, RV-induced asthma exacerbations are potentially caused by an imbalance between Th1 and Th2 cytokines, which may be contributed by defective innate immune responses at cellular levels. Exogenous IFNs delivery may be beneficial as a prophylactic approach for RV-induced asthma exacerbations.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=184119, identifier CRD42020184119.
KIR in Allogeneic Hematopoietic Stem Cell Transplantation: Need for a Unified Paradigm for Donor Selection
Authors: Dhuyser Adèle , Aarnink Alice , Pérès Michaël , Jayaraman Jyothi , Nemat-Gorgani Neda , Rubio Marie Thérèse , Trowsdale John , Traherne James
Published: February 2022

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a lifesaving therapy for hematological malignancies. For years, a fully matched HLA donor was a requisite for the procedure. However, new immunosuppressive strategies have enabled the recruitment of viable alternative donors, particularly haploidentical donors. Over 95% of patients have at least two potential haploidentical donors available to them. To identify the best haploidentical donor, the assessment of new immunogenetic criteria could help. To this end, the clinical benefit of KIR genotyping in aHSCT has been widely studied but remains contentious. This review aims to evaluate the importance of KIR-driven NK cell alloreactivity in the context of aHSCT and explain potential reasons for the discrepancies in the literature. Here, through a non-systematic review, we highlight how the studies in this field and their respective predictive models or scoring strategies could be conceptually opposed, explaining why the role of NK cells remains unclear in aHCST outcomes. We evaluate the limitations of each published prediction model and describe how every scoring strategy to date only partly delivers the requirements for optimally effective NK cells in aHSCT. Finally, we propose approaches toward finding the optimal use of KIR genotyping in aHSCT for a unified criterion for donor selection.
The COVID-19/Tuberculosis Syndemic and Potential Antibody Therapy for TB Based on the Lessons Learnt From the Pandemic
Authors: Dass Sylvia Annabel , Balakrishnan Venugopal , Arifin Norsyahida , Lim Crystale Siew Ying , Nordin Fazlina , Tye Gee Jun
Published: February 2022

2020 will be marked in history for the dreadful implications of the COVID-19 pandemic that shook the world globally. The pandemic has reshaped the normality of life and affected mankind in the aspects of mental and physical health, financial, economy, growth, and development. The focus shift to COVID-19 has indirectly impacted an existing air-borne disease, Tuberculosis. In addition to the decrease in TB diagnosis, the emergence of the TB/COVID-19 syndemic and its serious implications (possible reactivation of latent TB post-COVID-19, aggravation of an existing active TB condition, or escalation of the severity of a COVID-19 during TB-COVID-19 coinfection), serve as primary reasons to equally prioritize TB. On a different note, the valuable lessons learnt for the COVID-19 pandemic provide useful knowledge for enhancing TB diagnostics and therapeutics. In this review, the crucial need to focus on TB amid the COVID-19 pandemic has been discussed. Besides, a general comparison between COVID-19 and TB in the aspects of pathogenesis, diagnostics, symptoms, and treatment options with importance given to antibody therapy were presented. Lastly, the lessons learnt from the COVID-19 pandemic and how it is applicable to enhance the antibody-based immunotherapy for TB have been presented.
Oral Administration of Bacillus toyonensis Strain SAU-20 Improves Insulin Resistance and Ameliorates Hepatic Steatosis in Type 2 Diabetic Mice
Authors: Ren Zhihua , Okyere Samuel Kumi , Xie Lei , Wen Juan , Wang Jiayi , Chen Zhengli , Ni Xueqin , Deng Junliang , Hu Yanchun
Published: February 2022

In this study, the ameliorative effects of Bacillus toyonensis-SAU-20 (B. toyo SAU-20), a new probiotic strain isolated and identified by our laboratory from Ageratina adenophora, on the development of insulin resistance and hepatic steatosis in type 2 diabetic (T2DM) mice was investigated. Thirty Specific-pathogen free Kunming (SPFKM) mice were randomly allocated to three groups: control, high fat diet/streptozotocin (HFD/STZ), and HFD/STZ+B. toyo SAU-20 groups with oral administration of B. toyo SAU-20 for 35 days. Biochemistry parameters, glucose tolerance, and insulin resistance were measured in the blood whereas histological analysis, inflammatory cytokines and lipogenic genes in the liver tissues. The results showed that, the levels of serum glucose, lipid profile, mRNA expression of lipogenic related genes and pro-inflammatory cytokines were significantly increased in T2DM mice. However, after B. toyo SAU-20 administration, the elevation of these parameters was significantly suppressed (P<0.05). In addition, the feeding of B. toyo SAU-20 significantly improved the morphological changes of the liver with significant alleviation of dyslipidemia, oxidative stress status and inflammation (P<0.05) indicating the ameliorating effect of B. toyo SAU-20 in hepatic steatosis in T2DM. Therefore, we concluded that, B. toyo SAU-20 alleviated insulin resistance and hepatic steatosis by improving the lipid profiles, antioxidant status and downregulating lipogenic genes as well as pro-inflammation cytokines expression.
Cannabidiol and Terpene Formulation Reducing SARS-CoV-2 Infectivity Tackling a Therapeutic Strategy
Authors: Santos Susana , Barata Pedro , Charmier Adilia , Lehmann Inês , Rodrigues Suzilaine , Melosini Matteo M. , Pais Patrick J. , Sousa André P. , Teixeira Catarina , Santos Inês , Rocha Ana Catarina , Baylina Pilar , Fernandes Ruben
Published: February 2022

In late 2019, COVID-19 emerged in Wuhan, China. Currently, it is an ongoing global health threat stressing the need for therapeutic compounds. Linking the virus life cycle and its interaction with cell receptors and internal cellular machinery is key to developing therapies based on the control of infectivity and inflammation. In this framework, we evaluate the combination of cannabidiol (CBD), as an anti-inflammatory molecule, and terpenes, by their anti-microbiological properties, in reducing SARS-CoV-2 infectivity. Our group settled six formulations combining CBD and terpenes purified from Cannabis sativa L, Origanum vulgare, and Thymus mastichina. The formulations were analyzed by HPLC and GC-MS and evaluated for virucide and antiviral potential by in vitro studies in alveolar basal epithelial, colon, kidney, and keratinocyte human cell lines.

Conclusions and Impact

We demonstrate the virucide effectiveness of CBD and terpene-based formulations. F2TC reduces the infectivity by 17%, 24%, and 99% for CaCo-2, HaCat, and A549, respectively, and F1TC by 43%, 37%, and 29% for Hek293T, HaCaT, and Caco-2, respectively. To the best of our knowledge, this is the first approach that tackles the combination of CBD with a specific group of terpenes against SARS-CoV-2 in different cell lines. The differential effectiveness of formulations according to the cell line can be relevant to understanding the pattern of virus infectivity and the host inflammation response, and lead to new therapeutic strategies.
COVID-19 and Chagas Disease in Buenos Aires, Argentina
Authors: Fernandez Marisa Liliana , Benchetrit Andres , Astudillo Osvaldo German , Garay Alejandra M. , De Vedia Lautaro , Garcia Bournissen Facundo , Lloveras Susana Cristina , Orduna Tomas Agustín , Gonzalez Gustavo Daniel
Published: February 2022

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2. COVID-19 leads, in most patients, to mild-to-moderate symptoms, but some develop severe disease and succumbed to death. People with medical conditions have a higher risk of death than those without them. Chagas disease (CD) can cause cardiac diseases in approximately one-third of affected people. The aim of this study is to find out if there is any clinical association between Chagas disease and COVID-19 severity. This is a cohort study of 29 patients who were hospitalized with COVID-19 and had a diagnosis of chronic Trypanosoma cruzi infection. This coinfected cohort was matched by sex, age, presence of comorbidities, and requirement of hospitalization on intensive care unit (ICU) at admission with a control cohort of patients hospitalized due to COVID-19 without CD in a 3:1 ratio (n = 87). The clinical outcomes evaluated were as follows: days of hospitalization, death, and requirement of ICU and mechanical respiratory assistance (MV). The study protocol was approved by the Institutional Ethics in Research Committee. The Chagas disease/COVID-19 coinfected cohort had a median age of 55 years old (49.0, 66.0); 17 (59%) were male. All patients survived the acute COVID-19. Three of them were admitted to the ICU, and two required MV. Twenty-two (75.8%) required supplemental oxygen. There were no statistical differences in any laboratory parameters between the groups except for lactic acid dehydrogenase, which showed higher levels in the coinfected cohort, with a median of 573 U/L (interquartile range: 486.00, 771.00) vs. 476 U/L (346.00, 641.00) in the control group (p = 0.007). There were no differences in clinical outcomes between both groups. On the cohort with Chagas disease, there were zero deaths, three (10.3%) were admitted in the ICU, and two (6.9%) required MV, while for the control group there were six deaths (6.6%), 13 required ICU (14.9%), and 11 required MV (12.6%), without a statistically significant difference. This small series of coinfected Chagas disease and COVID-19 does not suggest differences in clinical evolution compared to non-Chagas patients. This data is similar to a Brazilian cohort. More data of this population with and without cardiomyopathy is needed to optimize the follow-up and recommendation for the population affected by this neglected tropical disease about COVID-19.
Coinfection With SARS-CoV-2 and Dengue Virus: A Case Report Highlighting Diagnostic Challenges
Authors: Hariadi Prasetyo , Lokida Dewi , Menur Naysilla Adhella , Lukman Nurhayati , Kosasih Herman , Mardian Yan , Andru Gestana , Pertiwi Inggar , Sugiyono Retna I. , Pradana Antonius A. , Salim Gustiani , Butar-butar Deni P. , Lau Chuen-Yen , Karyana Muhammad
Published: February 2022

Background

Since its emergence in China, SARS-CoV-2 has infected more than 240 million people worldwide, including in regions where dengue virus (DENV) is hyperendemic such as Latin America and Southeast Asia, including Indonesia. Diagnosis of COVID-19 in dengue endemic regions as well as DENV and SARS-CoV-2 co-infection can be challenging.

Case Presentation

We describe a 68-year-old woman with diabetes mellitus type II who was admitted to the Tangerang District Hospital on 14 April 2020. She lived in a neighborhood where a few people were contracting dengue fever. She presented with five days of fever, malaise, anorexia, nausea, myalgia, and arthralgia. Hematology revealed anemia, thrombocytopenia, normal leukocyte count, increased neutrophil proportion, and decreased lymphocyte proportion and absolute lymphocytes. Her chest X-ray showed right pericardial infiltrates. Although dengue was clinically suspected, she was also tested for SARS-CoV-2 infection as she met screening criteria. After being confirmed SARS-CoV-2 positive by RT-PCR, she was treated with ceftriaxone, paracetamol, azithromycin, oseltamivir, and chloroquine. She was clinically improved four days later and discharged from the hospital on 25 April 2020 after SARS-CoV-2 RT-PCR was negative on two consecutive samples. Dengue was diagnosed retrospectively based on sero-conversion of dengue IgM and a very high dengue IgG index (ELISA, Focus Diagnostics®, Cypress, CA, USA), and sero-conversion of dengue IgM and positive IgG (Rapid test, PanBio ®Dengue duo cassette, Inverness Medical Innovations, QLD, AU), which was equivalent to high Hemagglutination Inhibition (HI) antibody titer (≥1280) found in secondary dengue infection.

Conclusion

The overlapping clinical presentations of COVID-19 and dengue; limited diagnostic capacity of laboratories in resource constrained settings; and complexities of interpreting results make identification of COVID-19 in the dengue endemic setting challenging. Clinicians in endemic areas must be aware of diagnostic challenges and maintain a high index of suspicion for COVID-19 coinfection with DENV and other tropical pathogens.
The Distribution of K. pneumoniae in Different Specimen Sources and Its Antibiotic Resistance Trends in Sichuan, China From 2017 to 2020
Authors: Zhang Jie , Li Dan , Huang Xiangning , Long Shanshan , Yu Hua
Published: February 2022

Objective

We aim to analyze the distribution of Klebsiella pneumoniae in different specimen sources and its antibiotic resistance trends from the Antimicrobial Resistant Investigation Network of Sichuan Province (ARINSP) between 2017 and 2020.

Methods

According to the monitoring scheme, each participating hospital identified the bacteria and performed antimicrobial susceptibility tests using approved procedures. The data of non-repetitive isolates collected from outpatients and inpatients were submitted to ARINSP. The WHONET 5.6 software was used to analyze the results according to the Clinical and Laboratory Standards Institute (CLSI).

Results

Between 2017 and 2020, 833,408 non-repetitive clinical isolates of bacteria were isolated in total. The bacterial strains isolated from sputum and broncho-alveolar lavage accounted for 48.7, 56.4, 49.2, and 43.7% from 2017 to 2020 respectively, among all sources. The number of Klebsiella pneumoniae isolates from sputum and broncho-alveolar lavage increased from 18,809 in 2018, 19,742 in 2019, to 19,376 in 2020, playing a predominant role among all specimens. Meropenem-resistant K. pneumoniae occurrences (5.7% in 2017, 7.3% in 2018, 8.0% in 2019, and 7.5% in 2020) remained highest among carbapenems, and increased slightly over time. The resistance rate to tigecycline remained lowest, and declined from 2.4% in 2017, to 0.4% in 2018, and from 0.7% in 2019, to 0.6% in 2020.

Conclusion

The overall resistance rates of Klebsiella pneumoniae to carbapenems increased in Sichuan Province, giving a significant challenge to control K. pneumoniae related infections. Tigecycline has retained activity to against K. pneumoniae. Ongoing surveillance is essential. It can help for implementing intervention programs to reduce the occurrence of antimicrobial resistance and to provide with a rational use of antimicrobials.
Synergistic Inhibition of Plantaricin E/F and Lactic Acid Against Aeromonas hydrophila LPL-1 Reveals the Novel Potential of Class IIb Bacteriocin
Authors: Wang Yang , Wei Yunlu , Shang Nan , Li Pinglan
Published: February 2022

Plantaricin E/F (PlnEF) is a pair of two-component class IIb bacteriocin produced by lactic acid bacteria. PlnEF commonly displays potent antimicrobial activity against certain Gram-positive organisms. In this study, we investigated the synergistic activity of PlnEF combined with lactic acid against Gram-negative food and aquaculture potential pathogen Aeromonas hydrophila LPL-1, which is naturally resistant to PlnEF. We applied SDS-PAGE, wavelength-scanning, laser confocal microscopy, flow cytometer, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and two-dimensional electrophoresis to investigate their synergistic inhibitory activities. The results showed that L-lactic acid drove the release of LPS from A. hydrophila, making it possible for PlnEF to contact the inner cell membrane of A. hydrophila. Besides, co-treatment of lactic acid and PlnEF caused severe morphological and intracellular changes of A. hydrophila, including blebs on the cell surface, abnormal cell elongation, inner membrane disruption, pore-forming through the outer and inner membrane, coagulation of the cytoplasm, and structural transformation of DNA. Protein profile analysis revealed that combined treatment of lactic acid and PlnEF inhibited the energy metabolism, protein synthesis, protein folding, and DNA replication in A. hydrophila. These findings proved that PlnEF combined with lactic acid was efficient against A. hydrophila and shed light on bacteriocin’s potential and a new inhibition mechanism against A. hydrophila.

Importance

Bacteriocins and their producing strains are increasingly used to substitute artificial preservatives and antibiotics in the food and aquaculture industries. However, the bacteriocins produced by lactic acid bacteria are efficient to mainly Gram-positive bacteria. Our paper had demonstrated the antimicrobial activity of class IIb bacteriocin against potential Gram-negative pathogen, A. hydrophila LPL-1, when combined with lactic acid. The results could refresh our knowledge about the potential of class IIb bacteriocins produced by lactic acid bacteria.
The Non-phosphorylating Glyceraldehyde-3-Phosphate Dehydrogenase GapN Is a Potential New Drug Target in Streptococcus pyogenes
Authors: Eisenberg Philip , Albert Leon , Teuffel Jonathan , Zitzow Eric , Michaelis Claudia , Jarick Jane , Sehlke Clemens , Große Lisa , Bader Nicole , Nunes-Alves Ariane , Kreikemeyer Bernd , Schindelin Hermann , Wade Rebecca C. , Fiedler Tomas
Published: February 2022

The strict human pathogen Streptococcus pyogenes causes infections of varying severity, ranging from self-limiting suppurative infections to life-threatening diseases like necrotizing fasciitis or streptococcal toxic shock syndrome. Here, we show that the non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase GapN is an essential enzyme for S. pyogenes. GapN converts glyceraldehyde 3-phosphate into 3-phosphoglycerate coupled to the reduction of NADP to NADPH. The knock-down of gapN by antisense peptide nucleic acids (asPNA) significantly reduces viable bacterial counts of S. pyogenes laboratory and macrolide-resistant clinical strains in vitro. As S. pyogenes lacks the oxidative part of the pentose phosphate pathway, GapN appears to be the major NADPH source for the bacterium. Accordingly, other streptococci that carry a complete pentose phosphate pathway are not prone to asPNA-based gapN knock-down. Determination of the crystal structure of the S. pyogenes GapN apo-enzyme revealed an unusual cis-peptide in proximity to the catalytic binding site. Furthermore, using a structural modeling approach, we correctly predicted competitive inhibition of S. pyogenes GapN by erythrose 4-phosphate, indicating that our structural model can be used for in silico screening of specific GapN inhibitors. In conclusion, the data provided here reveal that GapN is a potential target for antimicrobial substances that selectively kill S. pyogenes and other streptococci that lack the oxidative part of the pentose phosphate pathway.
Combination Effect of Engineered Endolysin EC340 With Antibiotics
Authors: Hong Hye-Won , Kim Young Deuk , Jang Jaeyeon , Kim Min Soo , Song Miryoung , Myung Heejoon
Published: February 2022

Bacteriophage lysins, also known as endolysins or murein hydrolases, are hydrolytic enzymes produced by bacteriophages during the final stage of the lytic cycle to enable cleavage through the host’s cell wall, thus allowing the phages to burst out of their host bacteria after multiplication inside them. When applied externally to Gram-negative bacteria as recombinant proteins, lysins cannot easily reach the cell wall due to the presence of an outer membrane (OM). In this study, endolysin EC340 obtained from phage PBEC131 infecting Escherichia coli was engineered for improved OM permeability and increased activity against Gram-negative bacteria. The engineered endolysin, LNT113, was tested for potential synergistic effects with standard-of-care antibiotics. A synergistic effect was demonstrated with colistin, while an additive effect was seen with meropenem, tigecycline, chloramphenicol, azithromycin, and ciprofloxacin. Neither ceftazidime nor kanamycin showed any synergy or additive effects with the LNT113 endolysin. Moreover, synergy and additive effects could not be generalized by antibiotic class, OM traverse mechanism, molecular weight, or the bactericidal nature of each antibiotic tested.
Emerging Roles of Cyclophilin A in Regulating Viral Cloaking
Authors: Mamatis John E. , Pellizzari-Delano Isabella E. , Gallardo-Flores Carla E. , Colpitts Che C.
Published: February 2022

Cellular cyclophilins (Cyps) such as cyclophilin A (CypA) have emerged as key players at the virus-host interface. As host factors required for the replication of many unrelated viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and coronaviruses (CoVs), Cyps are attractive targets for antiviral therapy. However, a clear understanding of how these viruses exploit Cyps to promote their replication has yet to be elucidated. Recent findings suggest that CypA contributes to cloaking of viral replication intermediates, an evasion strategy that prevents detection of viral nucleic acid by innate immune sensors. Furthermore, Cyps are emerging to have roles in regulation of cellular antiviral signaling pathways. Recruitment of Cyps by viral proteins may interfere with their ability to regulate these signaling factors. Consistent with disruption of viral cloaking and innate immune evasion, treatment with Cyp inhibitors such as cyclosporine A (CsA) restores antiviral innate immunity and induces expression of a subset of antiviral genes that restrict viral infection, which may help to explain the broad antiviral spectrum of CsA. In this review, we provide an overview of the roles of CypA in viral cloaking and evasion of innate immunity, focusing on the underlying mechanisms and new perspectives for antiviral therapies.
Case Report: Transformation of Visual Snow Syndrome From Episodic to Chronic Associated With Acute Cerebellar Infarct
Authors: Puledda Francesca , Villar-Martínez María Dolores , Goadsby Peter J.
Published: February 2022

Visual snow syndrome is a novel neurological condition characterized by a panfield visual disturbance associated with several additional symptoms. Although it is usually a continuous and primary disorder, cases of intermittent visual snow have been described in the literature, as well as rare secondary forms. This report is the first description of a case of intermittent visual snow syndrome, which transformed into a persistent form following a posterior circulation stroke due to vertebral artery dissection. At 1 and 2 years after experiencing the acute cerebellar infarct, the patient's only neurological sequalae was visual snow. This case provides a description of how visual snow syndrome may be caused by an underlying brain disorder, and highlights the importance of the cerebellum in the pathophysiology of this relatively unknown condition. It further shows evidence of how existing predispositions might be relevant to the development of visual snow, in certain subjects and following specific circumstances.
Transient Anomalous Diffusion MRI in Excised Mouse Spinal Cord: Comparison Among Different Diffusion Metrics and Validation With Histology
Authors: Caporale Alessandra , Bonomo Giovanni Battista , Tani Raffaelli Giulio , Tata Ada Maria , Avallone Bice , Wehrli Felix Werner , Capuani Silvia
Published: February 2022

Neural tissue is a hierarchical multiscale system with intracellular and extracellular diffusion compartments at different length scales. The normal diffusion of bulk water in tissues is not able to detect the specific features of a complex system, providing nonlocal, diffusion measurement averaged on a 10-20 μm length scale. Being able to probe tissues with sub-micrometric diffusion length and quantify new local parameters, transient anomalous diffusion (tAD) would dramatically increase the diagnostic potential of diffusion MRI (DMRI) in detecting collective and sub-micro architectural changes of human tissues due to pathological damage. In DMRI, the use of tAD parameters quantified using specific DMRI acquisition protocols and their interpretation has often aroused skepticism. Although the derived formulas may accurately fit experimental diffusion-weighted data, the relationships between the postulated dynamical feature and the underlying geometrical structure remains elusive, or at most only suggestive. This work aimed to elucidate and validate the image contrast and information that can be obtained using the tAD model in white matter (WM) through a direct comparison between different diffusion metrics and histology. Towards this goal, we compared tAD metrics extracted from pure subdiffusion (α-imaging) and super-pseudodiffusion (γ-imaging) in excised mouse spinal cord WM, together with T2 and T2* relaxometry, conventional (normal diffusion-based) diffusion tensor imaging (DTI) and q-space imaging (QSI), with morphologic measures obtained by optical microscopy, to determine which structural and topological characteristics of myelinated axons influenced tAD contrast. Axon diameter (AxDiam), the standard deviation of diameters (SDax.diam), axonal density (AxDens) and effective local density (ELD) were extracted from optical images in several WM tracts. Among all the diffusion parameters obtained at 9.4 T, γ-metrics confirmed a strong dependence on magnetic in-homogeneities quantified by R2* = 1/T2* and showed the strongest associations with AxDiam and ELD. On the other hand, α-metrics showed strong associations with SDax.diamand was significantly related to AxDens, suggesting its ability to quantify local heterogeneity degree in neural tissue. These results elucidate the biophysical mechanism underpinning tAD parameters and show the clinical potential of tAD-imaging, considering that both physiologic and pathologic neurodegeneration translate into alterations of WM morphometry and topology.
Dynamics of Neuromuscular Transmission Reproduced by Calcium-Dependent and Reversible Serial Transitions in the Vesicle Fusion Complex
Authors: Martínez-Valencia Alejandro , Ramírez-Santiago Guillermo , De-Miguel Francisco F.
Published: February 2022

Neuromuscular transmission, from spontaneous release to facilitation and depression, was accurately reproduced by a mechanistic kinetic model of sequential maturation transitions in the molecular fusion complex. The model incorporates three predictions. First, calcium-dependent forward transitions take vesicles from docked to preprimed to primed states, followed by fusion. Second, prepriming and priming are reversible. Third, fusion and recycling are unidirectional. The model was fed with experimental data from previous studies, whereas the backward (β) and recycling (ρ) rate constant values were fitted. Classical experiments were successfully reproduced with four transition states in the model when every forward (α) rate constant had the same value, and both backward rate constants were 50–100 times larger. Such disproportion originated an abruptly decreasing gradient of resting vesicles from docked to primed states. By contrast, a three-state version of the model failed to reproduce the dynamics of transmission by using the same set of parameters. Simulations predict the following: (1) Spontaneous release reflects primed to fusion spontaneous transitions. (2) Calcium elevations synchronize the series of forward transitions that lead to fusion. (3) Facilitation reflects a transient increase of priming following the calcium-dependent maturation transitions. (4) The calcium sensors that produce facilitation are those that evoke the transitions form docked to primed states. (5) Backward transitions and recycling restore the resting state. (6) Depression reflects backward transitions and slow recycling after intense release. Altogether, our results predict that fusion is produced by one calcium sensor, whereas the modulation of the number of vesicles that fuse depends on the calcium sensors that promote the early transition states. Such finely tuned kinetics offers a mechanism for collective non-linear transitional adaptations of a homogeneous vesicle pool to the ever-changing pattern of electrical activity in the neuromuscular junction.
Correlative Live-Cell and Super-Resolution Imaging to Link Presynaptic Molecular Organisation With Function
Authors: Jackson Rachel E. , Compans Benjamin , Burrone Juan
Published: February 2022

Information transfer at synapses occurs when vesicles fuse with the plasma membrane to release neurotransmitters, which then bind to receptors at the postsynaptic membrane. The process of neurotransmitter release varies dramatically between different synapses, but little is known about how this heterogeneity emerges. The development of super-resolution microscopy has revealed that synaptic proteins are precisely organised within and between the two parts of the synapse and that this precise spatiotemporal organisation fine-tunes neurotransmission. However, it remains unclear if variability in release probability could be attributed to the nanoscale organisation of one or several proteins of the release machinery. To begin to address this question, we have developed a pipeline for correlative functional and super-resolution microscopy, taking advantage of recent technological advancements enabling multicolour imaging. Here we demonstrate the combination of live imaging of SypHy-RGECO, a unique dual reporter that simultaneously measures presynaptic calcium influx and neurotransmitter release, with post hoc immunolabelling and multicolour single molecule localisation microscopy, to investigate the structure-function relationship at individual presynaptic boutons.
Strawberry Proteome Responses to Controlled Hot and Cold Stress Partly Mimic Post-harvest Storage Temperature Effects on Fruit Quality
Authors: Lv Jinhua , Zheng Ting , Song Zenglu , Pervaiz Tariq , Dong Tianyu , Zhang Yanyi , Jia Haifeng , Fang Jinggui
Published: February 2022

To determine the effect of different temperature on strawberry after harvest, physiological indicator analysis and proteomics analysis were conducted on ripened strawberry (“Sweet Charlie”) fruit stored at 4, 23, and 37°C for 10 or 20 days. Results showed that 4°C maintained a better visual quality of strawberry, and the weight loss and firmness remained stable within 3 days. Low temperature negatively affected anthocyanin but positively affected soluble sugars. Though anthocyanin content was higher with increasing temperature, anthocyanin synthesis related proteins were downregulated. Higher indole-acetic acid (IAA) content in seeds and lower abscisic acid (ABA) content were found in berry at 4°C. Antioxidant related proteins were upregulated during storage, showing a significant up-regulation of peroxidase (POD) at 4°C, and ascorbate-glutathione (AsA-GSH) cycle related proteins and heat shock proteins (HSPs) at 37°C. In addition, overexpressed sugar phosphate/phosphate translocator, 1-aminocyclopropane-1-carboxylate oxidase, and aquaporin PIP2-2 had a positive effect in response to low temperature stress for containing higher protopectin content and POD activity.