bluuebunny/crossref_metadata_2025 huggingface dataset:
Taxonomic and Functional Dysregulation in Salivary Microbiomes During Oral Carcinogenesis
Authors: Chen Jiung-Wen , Wu Jer-Horng , Chiang Wei-Fan , Chen Yuh-Ling , Wu Wei-Sheng , Wu Li-Wha
Published: September 2021

Exploring microbial community compositions in humans with healthy versus diseased states is crucial to understand the microbe-host interplay associated with the disease progression. Although the relationship between oral cancer and microbiome was previously established, it remained controversial, and yet the ecological characteristics and their responses to oral carcinogenesis have not been well studied. Here, using the bacterial 16S rRNA gene amplicon sequencing along with the in silico function analysis by PICRUSt2 (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States 2), we systematically characterized the compositions and the ecological drivers of saliva microbiome in the cohorts of orally healthy, non-recurrent oral verrucous hyperplasia (a pre-cancer lesion), and oral verrucous hyperplasia–associated oral cancer at taxonomic and function levels, and compared them with the re-analysis of publicly available datasets. Diversity analyses showed that microbiome dysbiosis in saliva was significantly linked to oral health status. As oral health deteriorated, the number of core species declined, and metabolic pathways predicted by PICRUSt2 were dysregulated. Partitioned beta-diversity revealed an extremely high species turnover but low function turnover. Functional beta-diversity in saliva microbiome shifted from turnover to nestedness during oral carcinogenesis, which was not observed at taxonomic levels. Correspondingly, the quantitative analysis of stochasticity ratios showed that drivers of microbial composition and functional gene content of saliva microbiomes were primarily governed by the stochastic processes, yet the driver of functional gene content shifted toward deterministic processes as oral cancer developed. Re-analysis of publicly accessible datasets supported not only the distinctive family taxa of Veillonellaceae and Actinomycetaceae present in normal cohorts but also that Flavobacteriaceae and Peptostreptococcaceae as well as the dysregulated metabolic pathways of nucleotides, amino acids, fatty acids, and cell structure were related to oral cancer. Using predicted functional profiles to elucidate the correlations to the oral health status shows superior performance than using taxonomic data among different studies. These findings advance our understanding of the oral ecosystem in relation to oral carcinogenesis and provide a new direction to the development of microbiome-based tools to study the interplay of the oral microbiome, metabolites, and host health.
Clinical and Bacterial Characteristics of Klebsiella pneumoniae Affecting 30-Day Mortality in Patients With Bloodstream Infection
Authors: Wu Xingbing , Shi Qingyi , Shen Shimo , Huang Chen , Wu Hongcheng
Published: September 2021

Background

There is a paucity of studies using clinical characteristics and whole-genome sequencing together to fully identify the risk factors of patients with Klebsiella pneumoniae (KP) bloodstream infection (BSI).

Methods

We retrospectively analyzed the clinical and microbiological characteristics of patients with KP BSI. Isolates were processed using Illumina NGS, and relevant bioinformatics analysis was conducted (multi-locus sequence typing, serotype, phylogenetic reconstruction, detection of antibiotic resistance, and virulence genes). A logistic regression model was used to evaluate the risk factors of hosts and causative KP isolates associated with 30-day mortality in patients infected with KP BSI.

Results

Of the 79 eligible patients, the 30-day mortality rate of patients with KP BSI was 30.4%. Multivariate analysis showed that host-associated factors (increased APACHE II score and septic shock) were strongly associated with increased 30-day mortality. For the pathogenic factors, carriage of iutA (OR, 1.46; 95% CI, 1.11–1.81, p = 0.002) or Kvar_1549 (OR, 1.31; 95% CI, 1.02–1.69, p = 0.043) was an independent risk factor, especially when accompanied by a multidrug-resistant phenotype. In addition, ST11-K64 hypervirulent carbapenem-resistant KP co-harbored acquired blaKPC-2 together with iutA (76.5%, 13/17) and Kvar_1549 (100%, 17/17) genes. Comparative genomic analysis showed that they were clustered together based on a phylogenetic tree, and more virulence genes were observed in the group of ST11-K64 strains compared with ST11-non-K64. The patients infected with ST11-K64 strains were associated with relatively high mortality (47.2%, 7/17).

Conclusion

The carriage of iutA and Kvar_1549 was seen to be an independent mortality risk factor in patients with KP BSI. The identification of hypervirulent and carbapenem-resistant KP strains associated with high mortality should prompt surveillance.
Lichen Polyphenolic Compounds for the Eradication of Candida albicans Biofilms
Authors: Girardot Marion , Millot Marion , Hamion Guillaume , Billard Jeanne-Louise , Juin Camille , Ntoutoume G M A Ndong , Sol Vincent , Mambu Lengo , Imbert Christine
Published: September 2021

Lichens, due to their symbiotic nature (association between fungi and algae), constitute a chemical factory of original compounds. Polyphenolic compounds (depsides and depsidones) are the main constituents of lichens and are exclusively biosynthesized by these organisms. A panel of 11 polyphenols was evaluated for their anti-biofilm activity against Candida albicans biofilms on the maturation phase (anti-maturation) (MMIC50) as well as on preformed 24-h-old biofilm (anti-biofilm) (MBIC50) using the XTT assay. Minimum inhibitory concentrations of compounds (MICs) against C. albicans planktonic yeast were also determined using a broth microdilution method. While none of the tested compounds were active against planktonic cells (IC50 > 100 µg/ml), three depsides slowed the biofilm maturation (MMIC50 ≤12.5 µg/ml after 48 h of contact with Candida cells). Evernic acid was able to both slow the maturation and reduce the already formed biofilms with MBIC50 ≤12.5 µg/ml after 48 h of contact with the biofilm. This compound shows a weak toxicity against HeLa cells (22%) at the minimal active concentration and no hemolytic activity at 100 µg/ml. Microscopic observations of evernic acid and optimization of its solubility were performed to further study this compound. This work confirmed the anti-biofilm potential of depsides, especially evernic acid, and allows to establish the structure–activity relationships to better explain the anti-biofilm potential of these compounds.
Gilbert’s Syndrome and the Gut Microbiota – Insights From the Case-Control BILIHEALTH Study
Authors: Zöhrer Patrick A. , Hana Claudia A. , Seyed Khoei Nazlisadat , Mölzer Christine , Hörmann-Wallner Marlies , Tosevska Anela , Doberer Daniel , Marculescu Rodrig , Bulmer Andrew C. , Herbold Craig W. , Berry David , Wagner Karl-Heinz
Published: September 2021

The heme catabolite bilirubin has anti-inflammatory, anti-oxidative and anti-mutagenic effects and its relation to colorectal cancer (CRC) risk is currently under evaluation. Although the main metabolic steps of bilirubin metabolism, including the formation of stercobilin and urobilin, take place in the human gastrointestinal tract, potential interactions with the human gut microbiota are unexplored. This study investigated, whether gut microbiota composition is altered in Gilbert’s Syndrome (GS), a mild form of chronically elevated serum unconjugated bilirubin (UCB) compared to matched controls. Potential differences in the incidence of CRC-associated bacterial species in GS were also assessed. To this end, a secondary investigation of the BILIHEALTH study was performed, assessing 45 adults with elevated UCB levels (GS) against 45 age- and sex-matched controls (C). Fecal microbiota analysis was performed using 16S rRNA gene sequencing. No association between mildly increased UCB and the composition of the gut microbiota in this healthy cohort was found. The alpha and beta diversity did not differ between C and GS and both groups showed a typical representation of the known dominant phyla. Furthermore, no difference in abundance of Firmicutes and Proteobacteria, which have been associated with the mucosa of CRC patients were observed between the groups. A sequence related to the Christensenella minuta strain YIT 12065 was identified with a weak association value of 0.521 as an indicator species in the GS group. This strain has been previously associated with a lower body mass index, which is typical for the GS phenotype. Overall, sex was the only driver for an identifiable difference in the study groups, as demonstrated by a greater bacterial diversity in women. After adjusting for confounding factors and multiple testing, we can conclude that the GS phenotype does not affect the composition of the human gut microbiota in this generally healthy study group.
Environmental Geopolitics of Climate Engineering Proposals in the IPCC 5th Assessment Report
Authors: O'Lear Shannon , Hane Madisen K. , Neal Abigail P. , Stallings Lauren Louise M. , Wadood Sierra , Park Jimin
Published: September 2021

Environmental geopolitics offers an analytical approach that considers how environmental themes are brought into the service of geopolitical agendas. Of particular concern are claims about environment-related security and risk and the justification of actions (or inactions) proposed to deal with those claims. Environmental geopolitical analysis focuses on geographical knowledge and how that knowledge is generated and applied to stabilize specific understandings of the world. Climate engineering is a realm in which certain kinds of geographical knowledge, in the form of scientific interpretations of environmental interactions, are utilized to support a selective agenda that, despite claims about benefiting people and environments on a global scale, may be shown to reinforce uneven relationships of power as well as patterns of injustice. This paper focuses on how the IPCC AR5 discusses and portrays climate engineering. This particular conversation is significant, since the IPCC is widely recognized as reflecting current, international science and understanding of climate change processes and possible responses. We demonstrate an initial, environmental geopolitical analysis of this portrayal and discussion around climate engineering proposals by observing how the role and meaning of environmental features is limited, how human agency and impact in these scenarios is selective, and how insufficient attention is paid to spatial dimensions and impacts of these proposals. This paper contributes to a larger conversation about why it matters how we engage in discussion about climate impacts and issues; a central argument is that it is vital that we consider these proposed plans in terms of what they aim to secure, for whom, how and where.
Fostering Environmental Health Literacy in Contaminated Sites: National and Local Experience in Italy From a Public Health and Equity Perspective
Authors: Marsili Daniela , Pasetto Roberto , Iavarone Ivano , Fazzo Lucia , Zona Amerigo , Comba Pietro
Published: September 2021

The present article deals with environmental health literacy (EHL) in contaminated sites. The Italian national epidemiological surveillance system of population resident in contaminated sites, including vulnerable subgroups, and the local epidemiological studies and communication initiatives implemented in specific sites are considered. The Italian experience in contaminated sites corroborates the importance of EHL as a key component of community capacity to participate in mitigating environmental health risks. Effective access to evidence-based information on environmental health risk is the basis for improving awareness of local institutional and social actors. The proactive involvement of stakeholders in preventive actions and the adoption of shared practices reflect the progressive increase of their EHL. Bidirectional communication relying on participative approaches, collaborative nationallocal initiatives, and dialogue with the communities is an effective tool for increasing EHL at each site. This enhances the community capacity to use the acquired knowledge in promoting prevention actions. Consideration of socioeconomic fragilities and vulnerable groups in well-designed EHL practices contributes to prevent adverse health effects induced by specific environmental exposures and to promote environmental justice at local level.
Cardioprotective Effect of Stem-Leaf Saponins From Panax notoginseng on Mice With Sleep Deprivation by Inhibiting Abnormal Autophagy Through PI3K/Akt/mTOR Pathway
Authors: Cao Yin , Li Qinglin , Yang Yingbo , Ke Zunji , Chen Shengqi , Li Mingrui , Fan Wenjing , Wu Hui , Yuan Jinfeng , Wang Zhengtao , Wu Xiaojun
Published: September 2021

Sleep deprivation (SD) may lead to serious myocardial injury in cardiovascular diseases. Saponins extracted from the roots of Panax notoginseng, a traditional Chinese medicine beneficial to blood circulation and hemostasis, are the main bioactive components exerting cardiovascular protection in the treatment of heart disorders, such as arrhythmia, ischemia and reperfusion injury, and cardiac hypertrophy. This study aimed to explore the protective effect of stem-leaf saponins from Panax notoginseng (SLSP) on myocardial injury in SD mice. SD was induced by a modified multi-platform method. Cardiac morphological changes were assessed by hematoxylin and eosin (H&E) staining. Heart rate and ejection fraction were detected by specific instruments. Serum levels of atrial natriuretic peptide (ANP) and lactate dehydrogenase (LDH) were measured with biochemical kits. Transmission electron microscopy (TEM), immunofluorescent, and Western blotting analysis were used to observe the process and pathway of autophagy and apoptosis in heart tissue of SD mice. In vitro, rat H9c2 cells pretreated with rapamycin and the effect of SLSP were explored by acridine orange staining, transient transfection, flow cytometry, and Western blotting analysis. SLSP prevented myocardial injury, such as morphological damage, accumulation of autophagosomes in heart tissue, abnormal high heart rate, serum ANP, and serum LDH induced by SD. In addition, it reversed the expressions of proteins involved in the autophagy and apoptosis and activated PI3K/Akt/mTOR signaling pathway that is disturbed by SD. On H9c2 cells induced by rapamycin, SLSP could markedly resume the abnormal autophagy and apoptosis. Collectively, SLSP attenuated excessive autophagy and apoptosis in myocardial cells in heart tissue induced by SD, which might be acted through activating PI3K/Akt/mTOR signaling pathway.
Correlation Between Thyroid Nodules and Metabolic Syndrome: A Systematic Review and Meta-Analysis
Authors: Zhang Chenyu , Gao Xiaotong , Han Yutong , Teng Weiping , Shan Zhongyan
Published: September 2021

Objective

Thyroid nodules (TNs) are a common thyroid disorder that can be caused by many factors. Several studies have investigated the relationship between TNs and metabolic syndrome (MetS), but the role of sex and age remains controversial. The purpose of this paper was to analyze published data from all relevant studies to reliably estimate the relationship between TNs and MetS.

Methods

Thirteen articles were included in this study; articles were identified by searching for publications until July 2021 in PubMed, EMBASE, the Cochrane Library and the Web of Science. The outcomes are presented as the summary odds ratio (OR) and 95% confidence interval (CI) and the pooled prevalence and 95% CI.

Results

The TNs prevalence was significantly higher in MetS patients than in controls (OR 1.88, 95% CI 1.42-2.50, P < 0.0001) and was independent of sex (male: OR 1.53, 95% CI 1.20-1.94, P = 0.0006; female: OR 1.90, 95% CI 1.54-2.33, P < 0.00001; combined: OR 2.06, 95% CI 1.31-3.25, P = 0.002) and age (< 40 years old: OR 1.62, 95% CI 1.39-1.89, P < 0.0001; 40~50 years old: OR 2.14, 95% CI 1.49-3.08, P < 0.0001;50~60 years old: OR 1.50, 95% CI 1.08-2.07, P = 0. 01; 60 years old: OR 1.70, 95% CI 1.36-2.14, P < 0.00001); the pooled TNs prevalence in MetS patients was 45% (95% CI 36-54%). However, it has not yet been considered that MetS is related to TNs in people with iodine deficiency (OR 3.14, 95% CI 0.92-10.73, P = 0.07).

Conclusion

The meta-analysis results showed a strong correlation between TNs and MetS. Both male and female patients with MetS had an increased TNs prevalence. In addition, the prevalence was independent of age. However, MetS is not considered to be associated with TNs in iodine-deficient populations.
Clinical Effects of Microwave Ablation in the Treatment of Low-Risk Papillary Thyroid Microcarcinomas and Related Histopathological Changes
Authors: Lu Chenya , Li Xingjia , Chu Xiaoqiu , Li Ruiping , Li Jie , Wang Jianhua , Wang Yalin , Xu Yang , Chen Guofang , Xu Shuhang , Liu Chao
Published: September 2021

Objective

This study aimed to evaluate the feasibility and efficacy of ultrasound-guided percutaneous microwave ablation (MWA) in the treatment of low-risk papillary thyroid microcarcinoma (PTMC), and to observe the histopathological changes after MWA.

Methods

MWA was performed under ultrasound guidance for 73 unifocal PTMC patients without clinically cervical or distant metastasis. The target ablation zone exceeded the tumor edge (judged by contrast-enhanced US) to avoid marginal residue and recurrence. Ultrasound evaluation was performed at 1 day, 1, 3, 6, 12 and 24 months after treatment, and thyroid function evaluation at the first 6 months. Repeated fine needle aspiration cytology or core needle biopsy pathology was performed at 3 or 6 months after MWA to evaluate residual tumors. Any adverse event associated with MWA was evaluated.

Results

The follow-up after MWA lasted 6 (6, 12) months. Tumor volume decreased significantly from 0.06 mm3 (0.04, 0.11 mm3) to 0.03 mm3 (0.00, 0.06 mm3) at 12 months after MWA (P< 0.001), with a median volume reduction ratio of 80.28% (-7.43, 100%) and 16 cases (21.92%) presenting complete remission. The largest diameter, volume and ablation energy were found to be different in patients with and without complete remission 12 months after MWA. On histopathological examinations, no atypical or malignant follicular cells were identified after thermal ablation. The most common pathological characteristics were fibroblastic proliferation (34/39, 87.18%) and chronic inflammation (32/39, 82.05%), followed by infarction (21/39, 53.85%). Five patients were transferred to thyroidectomy and 4 of them were confirmed with local recurrence and/or lymph node metastasis. Serum thyrotropin decreased transiently after MWA (P< 0.01) but normalized thereafter. No serious and permanent complications were reported.

Conclusions

MWA is a safe and effective treatment for low-risk PTMC. Fibroblastic proliferation and chronic inflammation are the most common pathological changes after MWA of PTMC.
Assessing Antibiotics Biodegradation and Effects at Sub-inhibitory Concentrations by Quantitative Microbial Community Deconvolution
Authors: Özel Duygan Birge D. , Gaille Caroline , Fenner Kathrin , van der Meer Jan R.
Published: September 2021

Antibiotics in the environment cause widespread concern as a result of their potent inhibitory action on microbial growth and their role in potentially creating selective conditions for proliferation of antibiotic resistant bacteria. Comprising a carbon skeleton, antibiotics should be amenable to microbial biodegradation, but this is still largely uncharted territory because of their simultaneous strong toxicity. In this study, we estimated potential antibiotics degradation by and effects on mixed microbial communities at concentrations sufficiently high to allow sensitive detection of biomass growth, but simultaneously, low enough to mitigate their toxic action. We used three different mixed inoculum sources freshly derived from freshwater, activated sludge or soil, and tested a series of 15 antibiotics from different classes at 1 mg C-carbon l−1 dosage. Consistent community growth was observed for freshwater and activated sludge with ampicillin, erythromycin and chloramphenicol, and with sulfomethoxazole for activated sludge, which was accompanied by parent compound disappearance. Community growth could be attributed to a few subclasses of recognized cell types by using supervised machine-learning-based classifiers. Most other tested antibiotics resulted in inhibition of community growth on background assimilable organic carbon, concomitant with altered composition of the resulting communities. We conclude that growth-linked biodegradation of antibiotics at low concentrations may be present among typical environmental microbiota, but for a selected subset only, whereas for the majority of antibiotics negative effects prevail without any sign of productive growth.
Historical Forest Management Practices Influence Tree-Ring Based Climate Reconstructions
Authors: Skiadaresis Georgios , Muigg Bernhard , Tegel Willy
Published: September 2021

Tree-ring widths (TRW) of historical and archeological wood provide crucial proxies, frequently used for high-resolution multi-millennial paleoclimate reconstructions. Former growing conditions of the utilized trees, however, are largely unknown. Potential influences of historical forest management practices on climatic information, derived from TRW variability need to be considered but have not been assessed so far. Here, we examined the suitability of TRW series from traditionally managed oak forests (Quercus spp.) for climate reconstructions. We compared the climate signal in TRW chronologies of trees originating from high forests and coppice-with-standards (CWS) forests, a silvicultural management practice widely used in Europe for most of the common era. We expected a less distinct climate control in CWS due to management-induced growth patterns, yet an improved climate-growth relationship with TRW data from conventionally managed high forests. CWS tree rings showed considerably weaker correlations with hydroclimatic variables than non-CWS trees. The greatest potential for hydroclimate reconstructions was found for a large dataset containing both CWS and non-CWS trees, randomly collected from lumber yards, resembling the randomness in sources of historical material. Our results imply that growth patterns induced by management interventions can dampen climate signals in TRW chronologies. However, their impact can be minimized in well replicated, randomly sampled regional chronologies.
A Seven-Gene Signature to Predict Prognosis of Patients With Hepatocellular Carcinoma
Authors: Wang Junli , Zhang Qi , Shi Fukang , Yadav Dipesh Kumar , Hong Zhengtao , Wang Jianing , Liang Tingbo , Bai Xueli
Published: September 2021

Purpose: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant diseases worldwide and has a poor prognosis. Gene-based prognostic models have been reported to predict the overall survival of patients with HCC. Unfortunately, most of the genes used in earlier prognostic models lack prospective validation and, thus, cannot be used in clinical practice.

Methods: Candidate genes were selected from GEPIA (Gene Expression Profiling Interactive Analysis), and their associations with patients’ survival were confirmed by RT-PCR using cDNA tissue microarrays established from patients with HCC after radical resection. A multivariate Cox proportion model was used to calculate the coefficient of corresponding gene. The expression of seven genes of interest (MKI67, AR, PLG, DNASE1L3, PTTG1, PPP1R1A, and TTR) with two reference genes was defined to calculate a risk score which determined groups of different risks.

Results: Our risk scoring efficiently classified patients (n = 129) with HCC into a low-, intermediate-, and high-risk group. The three groups showed meaningful distinction of 3-year overall survival rate, i.e., 88.9, 74.5, and 20.6% for the low-, intermediate-, and high-risk group, respectively. The prognostic prediction model of risk scores was subsequently verified using an independent prospective cohort (n = 77) and showed high accuracy.

Conclusion: Our seven-gene signature model performed excellent long-term prediction power and provided crucially guiding therapy for patients who are not a candidate for surgery.
The Role of m6A Ribonucleic Acid Modification in the Occurrence of Atherosclerosis
Authors: Fu Jie , Cui Xinghui , Zhang Xiaoyun , Cheng Min , Li Xiaoxia , Guo Zhiliang , Cui Xiaodong
Published: September 2021

The N6-methyladenosine (m6A) modification is the most abundant epitranscriptomic modification in eukaryotic messenger RNA (mRNA). The m6A modification process is jointly regulated by various enzymes and proteins, such as methyltransferases, demethylases and related m6A-binding proteins. The process is dynamic and reversible, and it plays an essential role in mRNA metabolism and various biological activities. Recently, an increasing number of researchers have confirmed that the onset and development of many diseases are closely associated with the molecular biological mechanism of m6A RNA methylation. This study focuses on the relationship between m6A RNA modification and atherosclerosis (AS). It thoroughly summarizes the mechanisms and processes of m6A RNA modification in AS-related cells and the relationships between m6A RNA modification and AS risk factors, and it provides a reference for exploring new targets for the early diagnosis and treatment of AS.
Multiomics Analysis Reveals the Prognostic Non-tumor Cell Landscape in Glioblastoma Niches
Authors: Xiao Zixuan , Zhang Wei , Li Guanzhang , Li Wendong , Li Lin , Sun Ting , He Yufei , Liu Guang , Wang Lu , Han Xiaohan , Wen Hao , Liu Yong , Chen Yifan , Wang Haoyu , Li Jing , Fan Yubo , Zhang Jing
Published: September 2021

A comprehensive characterization of non-tumor cells in the niches of primary glioblastoma is not fully established yet. This study aims to present an overview of non-malignant cells in the complex microenvironment of glioblastoma with detailed characterizations of their prognostic effects. We curate 540 gene signatures covering a total of 64 non-tumor cell types. Cell type-specific expression patterns are interrogated by normalized enrichment score across four large gene expression profiling cohorts of glioblastoma with a total number of 967 cases. The glioblastoma multiforms (GBMs) in each cohort are hierarchically clustered into negative or positive immune response classes with significantly different overall survival. Our results show that astrocytes, macrophages, monocytes, NKTs, and MSC are risk factors, while CD8 T cells, CD8 naive T cells, and plasma cells are protective factors. Moreover, we find that the immune system and organogenesis are uniformly enriched in negative immune response clusters, in contrast to the enrichment of nervous system in positive immune response clusters. Mesenchymal differentiation is also observed in the negative immune response clusters. High enrichment status of macrophages in negative immune response clusters is independently validated by analyzing scRNA-seq data from eight high-grade gliomas, revealing that negative immune response samples comprised 46.63 to 55.12% of macrophages, whereas positive immune response samples comprised only 1.70 to 8.12%, with IHC staining of samples from six short-term and six long-term survivors of GBMs confirming the results.
Association of Antibody-Dependent Neutrophil Phagocytosis With Distinct Antibody Glycosylation Profiles Following Typhoid Vaccination
Authors: Johnson Mari , Stockdale Lisa , de Haan Noortje , Wuhrer Manfred , Nouta Jan , Koeleman Carolien A. M. , Clarke Jenny , Marinou Spyridoula , Shakya Mila , Colin-Jones Rachel , Theiss-Nyland Katherine , Voysey Merryn , Jin Celina , Pant Dikshya , Jones Elizabeth , Kelly Sarah , Dongol Sabina , Karkey Abhilasha , Shrestha Shrijana , Basnyat Buddha , Hill Jennifer , Pollard Andrew J.
Published: September 2021

Typhoid Vi-conjugate vaccines (Vi-TCV) have been developed to control typhoid fever in children in endemic regions. Previously, in a human challenge model of typhoid, Vi-TCV was administered prior to deliberate ingestion of Salmonella Typhi by healthy adult volunteers in the UK. Vi-specific antibody-dependent neutrophil phagocytosis (ADNP) was associated with protection against enteric fever in this model, but it is not known if ADNP is induced by vaccination of children. We measured ADNP in a cohort of Nepalese children receiving a Vi-TCV in a field study to investigate whether functional antibody responses were also present in children in an endemic setting. Furthermore, we investigated relationships between the functional antibody measures and other properties of the antibody response, including Vi-IgG and IgA titres, and Fc region glycosylation. Antibody-dependent neutrophil phagocytosis significantly increased in children aged 9 months to 15 years between the day of vaccination and 28 days following administration of Vi-TCV (D28). The magnitude of ADNP was also comparable with the levels of ADNP induced by plasma from vaccinated UK adults. Neither IgG nor IgA antibody titres significantly correlated with ADNP scores at D28; however, increased vaccine-induced ADNP was associated with decreased levels of IgG1 sialylation. These data suggest that vaccination with Vi-TCV produces functional antibody responses in children, which associate with specific glycosylation patterns of the Fc region.
A Possible Role of Allatostatin C in Inhibiting Ecdysone Biosynthesis Revealed in the Mud Crab Scylla paramamosain
Authors: Liu An , Shi Wenyuan , Lin Dongdong , Ye Haihui
Published: September 2021

C-type allatostatins (C-type ASTs) are a family of structurally related neuropeptides found in a wide range of insects and crustaceans. To date, the C-type allatostatin receptor in crustaceans has not been deorphaned, and little is known about its physiological functions. In this study, we aimed to functionally define a C-type ASTs receptor in the mud crab, Scylla paramamosian. We showed that C-type ASTs receptor can be activated by ScypaAST-C peptide in a dose-independent manner and by ScypaAST-CCC peptide in a dose-dependent manner with an IC50 value of 6.683 nM. Subsequently, in vivo and in vitro experiments were performed to investigate the potential roles of ScypaAST-C and ScypaAST-CCC peptides in the regulation of ecdysone (20E) and methyl farnesoate (MF) biosynthesis. The results indicated that ScypaAST-C inhibited biosynthesis of 20E in the Y-organ, whereas ScypaAST-CCC had no effect on the production of 20E. In addition, qRT-PCR showed that both ScypaAST-C and ScypaAST-CCC significantly decreased the level of expression of the MF biosynthetic enzyme gene in the mandibular organ, suggesting that the two neuropeptides have a negative effect on the MF biosynthesis in mandibular organs. In conclusion, this study provided new insight into the physiological roles of AST-C in inhibiting ecdysone biosynthesis. Furthermore, it was revealed that AST-C family peptides might inhibit MF biosynthesis in crustaceans.
Sharing With Patients the Uncertainties Regarding the Management of Dyspepsia
Authors: Benbassat Jochanan
Published: September 2021

Background: The management of patients with dyspepsia is uncertain. Some authors advocate endoscopy for all; others restrict endoscopy only to patients at high risk of gastric cancer, namely to those above an age threshold, or with a family history, dysphagia, loss of weight, anemia, or a childhood in Asian countries. Still others recommend various combinations between test-and-treat for Helicobacter pylori, anti-secretory treatment, and/or endoscopy.

Objective: To highlight the uncertainties in the choice between the various strategies and argue that these uncertainties should be shared with the patient.

Method: An overview of reported life expectancy, patient satisfaction, gastric cancer detection rates, symptom relief, and cost effectiveness of the management strategies for dyspepsia.

Main Findings: There are no randomized controlled trials of the effect of screening by endoscopy on mortality of patients with gastric cancer. Lower grades of evidence suggest that early diagnosis reduces this mortality. Analyses, which assume a survival benefit of early diagnosis, indicate that mass screening in countries of high incidence gastric cancer (> 10 cases per 100,000) and targeted screening of high-risk persons in countries of low-intermediate incidence (<10 cases per 100,000) is cost-effective at a willingness to pay of $20,000–50,000 per QALY. Prompt endoscopy appears to be best for patient satisfaction and gastric cancer detection, and test-and-treat for H pylori—for symptom relief and avoiding endoscopies.

Conclusions: The gain in life expectancy is the main source of uncertainty in the choice between management strategies. This choice should be shared with the patients after explaining uncertainties and eliciting their preferences.
Chinese Medicine Formula Huashibaidu Granule Early Treatment for Mild COVID-19 Patients: An Unblinded, Cluster-Randomized Clinical Trial
Authors: Zhao Chen , Li Li , Yang Wei , Lv Wenliang , Wang Jian , Guo Jing , Dong Yu , Shi Nannan , Lu Cheng , Li Zhiqiang , Shi Zhan , Chen Renbo , Huo Ruili , Che Qianzi , Tian Yaxin , Xiang Xinghua , Wang Jian , Zhou Junhui , Bian Yongjun , Chen Suping , Chen Yang , Chen Yingying , Cong Xiaodong , Dong Guoju , Hu Lijie , Jiang Jianxin , Leng Luxing , Li Bin , Li Dongxu , Li Hao , Li Jing , Qi Wensheng , Miao Qing , Shi Huaxin , Shi Jiaheng , Wang Bing , Wang Gang , Wang Wei , Xian Yongyue , Xie Xiaolei , Xu Chunyan , Xu Ming , Yan Bei , Yang Jinliang , Zhang Li , Zhou Zhenqi , Zhu Haoning , Xiong Yibai , Liu Bin , Huang Luqi
Published: September 2021

Background: Previous research suggested that Chinese Medicine (CM) Formula Huashibaidu granule might shorten the disease course in coronavirus disease 2019 (COVID-19) patients. This research aimed to investigate the early treatment effect of Huashibaidu granule in well-managed patients with mild COVID-19.

Methods: An unblinded cluster-randomized clinical trial was conducted at the Dongxihu FangCang hospital. Two cabins were randomly allocated to a CM or control group, with 204 mild COVID-19 participants in each cabin. All participants received conventional treatment over a 7 day period, while the ones in CM group were additionally given Huashibaidu granule 10 g twice daily. Participants were followed up to their clinical endpoint. The primary outcome was worsening symptoms before the clinical endpoint. The secondary outcomes were cure and discharge before the clinical endpoint and alleviation of composite symptoms after the 7 days of treatment.

Results: All 408 participants were followed up to their clinical endpoint and included in statistical analysis. Baseline characteristics were comparable between the two groups (P > 0.05). The number of worsening patients in the CM group was 5 (2.5%), and that in the control group was 16 (7.8%) with a significant difference between groups (P = 0.014). Eight foreseeable mild adverse events occurred without statistical difference between groups (P = 0.151).

Conclusion: Seven days of early treatment with Huashibaidu granule reduced the likelihood of worsening symptoms in patients with mild COVID-19. Our study supports Huashibaidu granule as an active option for early treatment of mild COVID-19 in similar well-managed medical environments.

Clinical Trial Registration:www.chictr.org.cn/showproj.aspx?proj=49408, identifier: ChiCTR2000029763.
The Concentration of Large Extracellular Vesicles Differentiates Early Septic Shock From Infection
Authors: Monnamorn Latthawan , Seree-aphinan Chutima , Molika Piyatida , Vichitkunakorn Polathep , Pattanapanyasat Kovit , Khwannimit Bodin , Navakanitworakul Raphatphorn
Published: September 2021

Septic shock represents a subset of sepsis with severe physiological aberrations and a higher mortality rate than sepsis alone. Currently, the laboratory tools which can be used to identify the state of septic shock are limited. In pre-clinical studies, extracellular vesicles (EVs), especially large EVs (lEVs), have been demonstrated a role as functional inflammatory mediators of sepsis. However, its longitudinal trend during the disease course has not been explored. In this study, the quantities and subtypes of plasma-derived lEVs were longitudinally compared between patients with septic shock (n= 21) and non-sepsis infection (n= 9), who presented within 48 h of their symptom onset. Blood specimens were collected for seven consecutive days after hospital admission. lEVs quantification and subtyping were performed using an imaging flow cytometer. The experiments revealed a higher lEVs concentration in septic shock patients than infected patients at the onset of the disease. In septic shock patients, lEVs concentration decreased over time as opposed to infected patients whose lEVs concentration is relatively static throughout the study period. The major contributors of lEVs in both septic shock and infected patients were of non-leukocyte origins; platelets, erythrocytes, and endothelial cells released approximately 40, 25, and 15% of lEVs, respectively. Among lEVs of leukocyte origins, neutrophils produced the highest number of EVs. Nevertheless, the proportion of each subtype of lEVs among the given amount of lEVs produced was similar between septic shock and infected patients. These findings raise the possibility of employing lEVs enumeration as a septic shock identifying tool, although larger studies with a more diverse group of participants are warranted to extrapolate the findings to a general population.
Improving Fungal Cultivability for Natural Products Discovery
Authors: Rämä Teppo , Quandt C. Alisha
Published: September 2021

The pool of fungal secondary metabolites can be extended by activating silent gene clusters of cultured strains or by using sensitive biological assays that detect metabolites missed by analytical methods. Alternatively, or in parallel with the first approach, one can increase the diversity of existing culture collections to improve the access to new natural products. This review focuses on the latter approach of screening previously uncultured fungi for chemodiversity. Both strategies have been practiced since the early days of fungal biodiscovery, yet relatively little has been done to overcome the challenge of cultivability of as-yet-uncultivated fungi. Whereas earlier cultivability studies using media formulations and biological assays to scrutinize fungal growth and associated factors were actively conducted, the application of modern omics methods remains limited to test how to culture the fungal dark matter and recalcitrant groups of described fungi. This review discusses the development of techniques to increase the cultivability of filamentous fungi that include culture media formulations and the utilization of known chemical growth factors,in situculturing and current synthetic biology approaches that build upon knowledge from sequenced genomes. We list more than 100 growth factors, i.e., molecules, biological or physical factors that have been demonstrated to induce spore germination as well as tens of inducers of mycelial growth. We review culturing conditions that can be successfully manipulated for growth of fungi and visit recent information from omics methods to discuss the metabolic basis of cultivability. Earlier work has demonstrated the power of co-culturing fungi with their host, other microorganisms or their exudates to increase their cultivability. Co-culturing of two or more organisms is also a strategy used today for increasing cultivability. However, fungi possess an increased risk for cross-contaminations between isolates in existingin situor microfluidics culturing devices. Technological improvements for culturing fungi are discussed in the review. We emphasize that improving the cultivability of fungi remains a relevant strategy in drug discovery and underline the importance of ecological and taxonomic knowledge in culture-dependent drug discovery. Combining traditional and omics techniques such as single cell or metagenome sequencing opens up a new era in the study of growth factors of hundreds of thousands of fungal species with high drug discovery potential.
Harness Organoid Models for Virological Studies in Animals: A Cross-Species Perspective
Authors: Sang Yongming , Miller Laura C. , Nelli Rahul K. , Giménez-Lirola Luis Gabriel
Published: September 2021

Animal models and cell culture in vitro are primarily used in virus and antiviral immune research. Whereas the limitation of these models to recapitulate the viral pathogenesis in humans has been made well aware, it is imperative to introduce more efficient systems to validate emerging viruses in both domestic and wild animals. Organoids ascribe to representative miniatures of organs (i.e., mini-organs), which are derived from three-dimensional culture of stem cells under respective differential conditions mimicking endogenous organogenetic niches. Organoids have broadened virological studies in the human context, particularly in recent uses for COVID19 research. This review examines the status and potential for cross-species applied organotypic culture in validating emerging animal, particularly zoonotic, viruses in domestic and wild animals.
Growth Coordination Between Butyrate-Oxidizing Syntrophs and Hydrogenotrophic Methanogens
Authors: Cong Shuqi , Xu Yiqin , Lu Yahai
Published: September 2021

Syntrophy is a thermodynamically required mutualistic cooperation between fatty acid-oxidizing bacteria and methanogens that plays the important role in organic decomposition and methanogenesis in anoxic environments. In this study, three experiments were conducted to evaluate the cell-to-cell interaction in a thermophilic coculture consisting of Syntrophothermus lipocalidus and Methanocella conradii and a mesophilic coculture consisting of Syntrophomonas wolfei and Methanococcus maripaludis. First, syntrophs and methanogens were inoculated at different initial cell ratios to evaluate the growth synchronization. The quantitative PCR analysis revealed that the organism with a lower relative abundance at the beginning always grew faster, and the cell ratio converged over time to relative constant values in both the thermophilic and mesophilic cocultures. Next, intermittent ultrasound and constant shaking treatments were used to evaluate the influence of physical disturbance on microbial aggregation in the mesophilic coculture. The fluorescence in situ hybridization and scanning electron microscopy revealed that the tendency of syntrophic aggregation was not affected by the physical disturbances, although the activity was slightly depressed. Syntrophomonas dominated in the initial microbial aggregates, which, however, did not grow until Methanococcus was attached and increased to a significant extent, indicating the local growth synchronization during the formation and maturation of syntrophic aggregates. Last, microfluidic experiments revealed that whether or not Syntrophomonas or Methanococcus was loaded first, the second organism preferred moving to the place where the first organism was located, suggesting the cell-to-cell attraction between Syntrophomonas and Methanococcus. Collectively, our study demonstrated the growth synchronization and cell-to-cell attraction between the butyrate-oxidizing bacteria and methanogens for optimizing the syntrophic cooperation.
Clinical Trials for Gene Therapy in Lysosomal Diseases With CNS Involvement
Authors: Sevin Caroline , Deiva Kumaran
Published: September 2021

There are over 70 known lysosomal storage disorders (LSDs), most caused by mutations in genes encoding lysosomal hydrolases. Central nervous system involvement is a hallmark of the majority of LSDs and, if present, generally determines the prognosis of the disease. Nonetheless, brain disease is currently poorly targeted by available therapies, including systemic enzyme replacement therapy, mostly (but not only) due to the presence of the blood–brain barrier that restricts the access of orally or parenterally administered large molecules into the brain. Thus, one of the greatest and most exciting challenges over coming years will be to succeed in developing effective therapies for the treatment of central nervous system manifestations in LSDs. Over recent years, gene therapy (GT) has emerged as a promising therapeutic strategy for a variety of inherited neurodegenerative diseases. In LSDs, the ability of genetically corrected cells to cross-correct adjacent lysosomal enzyme-deficient cells in the brain after gene transfer might enhance the diffusion of the recombinant enzyme, making this group of diseases a strong candidate for such an approach. Both in vivo (using the administration of recombinant adeno-associated viral vectors) and ex vivo (auto-transplantation of lentiviral vector-modified hematopoietic stem cells-HSCs) strategies are feasible. Promising results have been obtained in an ever-increasing number of preclinical studies in rodents and large animal models of LSDs, and these give great hope of GT successfully correcting neurological defects, once translated to clinical practice. We are now at the stage of treating patients, and various clinical trials are underway, to assess the safety and efficacy of in vivo and ex vivo GT in several neuropathic LSDs. In this review, we summarize different approaches being developed and review the current clinical trials related to neuropathic LSDs, their results (if any), and their limitations. We will also discuss the pitfalls and the remaining challenges.
Doublecortin-Expressing Neurons in Chinese Tree Shrew Forebrain Exhibit Mixed Rodent and Primate-Like Topographic Characteristics
Authors: Ai Jia-Qi , Luo Rongcan , Tu Tian , Yang Chen , Jiang Juan , Zhang Bo , Bi Rui , Tu Ewen , Yao Yong-Gang , Yan Xiao-Xin
Published: September 2021

Doublecortin (DCX) is transiently expressed in new-born neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) related to adult neurogenesis in the olfactory bulb (OB) and hippocampal formation. DCX immunoreactive (DCX+) immature neurons also occur in the cerebral cortex primarily over layer II and the amygdala around the paralaminar nucleus (PLN) in various mammals, with interspecies differences pointing to phylogenic variation. The tree shrews (Tupaia belangeri) are phylogenetically closer to primates than to rodents. Little is known about DCX+ neurons in the brain of this species. In the present study, we characterized DCX immunoreactivity (IR) in the forebrain of Chinese tree shrews aged from 2 months- to 6 years-old (n = 18). DCX+ cells were present in the OB, SVZ, SGZ, the piriform cortex over layer II, and the amygdala around the PLN. The numerical densities of DCX+ neurons were reduced in all above neuroanatomical regions with age, particularly dramatic in the DG in the 5–6 years-old animals. Thus, DCX+ neurons are present in the two established neurogenic sites (SVZ and SGZ) in the Chinese tree shrew as seen in other mammals. DCX+ cortical neurons in this animal exhibit a topographic pattern comparable to that in mice and rats, while these immature neurons are also present in the amygdala, concentrating around the PLN as seen in primates and some nonprimate mammals.