bluuebunny/crossref_metadata_2025 huggingface dataset:
The Antimicrobial Resistance Crisis: An Inadvertent, Unfortunate but Nevertheless Informative Experiment in Evolutionary Biology
Authors: Michael Carolyn A. , Gillings Michael R. , Blaskovich Mark A. T. , Franks Ashley E.
Published: July 2021

The global rise of antimicrobial resistance (AMR) phenotypes is an exemplar for rapid evolutionary response. Resistance arises as a consequence of humanity’s widespread and largely indiscriminate use of antimicrobial compounds. However, some features of this crisis remain perplexing. The remarkably widespread and rapid rise of diverse, novel and effective resistance phenotypes is in stark contrast to the apparent paucity of antimicrobial producers in the global microbiota. From the viewpoint of evolutionary theory, it should be possible to use selection coefficients to examine these phenomena. In this work we introduce an elaboration on the selection coefficient s termed selective efficiency, considering the genetic, metabolic, ecological and evolutionary impacts that accompany selective phenotypes. We then demonstrate the utility of the selective efficiency concept using AMR and antimicrobial production phenotypes as ‘worked examples’ of the concept. In accomplishing this objective, we also put forward cogent hypotheses to explain currently puzzling aspects of the AMR crisis. Finally, we extend the selective efficiency concept into a consideration of the ongoing management of the AMR crisis.
Tracking the Origin and Early Evolution of Reptiles
Authors: Marchetti Lorenzo , Voigt Sebastian , Buchwitz Michael , MacDougall Mark J. , Lucas Spencer G. , Fillmore David L. , Stimson Matthew R. , King Olivia A. , Calder John H. , Fröbisch Jörg
Published: July 2021

The origin of Reptilia and the biostratigraphic and palaeobiogeographic distribution of its early representatives are still poorly understood. An independent source of information may come from the extensive Carboniferous footprint record of reptiles, which is arguably richer and more complete than the skeletal record. Nevertheless, previous studies often failed to provide useful information because they were based on poorly preserved material and/or characters non-exclusive of reptile tracks. In fact, a large part of the supposed early reptile tracks can be assigned to the anamniote ichnotaxon Hylopus hardingi. Here, we revise the ichnotaxon Hylopus hardingi based on anatomy-consistent material, attribute it to anamniote reptiliomorphs, and distinguish it from Notalacerta missouriensis, the earliest ichnotaxon that can be attributed to reptiles, and the somewhat younger Varanopus microdactylus (attributed to parareptiles, such as bolosaurians) and Dromopus lacertoides (attributed to araeoscelid reptiles and non-varanodontine varanopids). These attributions are based on correlating morphofunctional features of tracks and skeletons. Multivariate analysis of trackway parameters indicates that the late Bashkirian Notalacerta missouriensis and Hylopus hardingi differ markedly in their trackway patterns from Late Mississippian Hylopus hardingi and Late Pennsylvanian reptile tracks, which appear to share a derived amniote-like type of gait. While the first occurrence/appearance of reptile tracks in the tetrapod footprint record during the late Bashkirian corresponds to the first occurrence/appearance of reptiles in the skeletal record, footprints significantly enlarge the paleobiogeographic distribution of the group, suggesting an earlier radiation of reptiles during the Bashkirian throughout North America and possibly North Africa. Dromopus appeared in the Kasimovian together with the diapsid group Araeoscelidia, but footprints from Western-European occurrences enlarge the paleobiogeographic distribution of diapsids and varanopids. Varanopus and bolosaurian parareptiles appear in the Gzhelian of North America. Older parareptiles are, however, known from the late Moscovian. In all, the footprint record of early reptiles supplements the skeletal record, suggesting possible future lines of research.
Natural Regeneration After Gold Mining in the Peruvian Amazon: Implications for Restoration of Tropical Forests
Authors: Chambi-Legoas Roger , Ortega Rodriguez Daigard Ricardo , Figueiredo Francisco de Marques de , Peña Valdeiglesias Joel , Zevallos Pollito Percy Amílcar , Marcelo-Peña Jose Luis , Rother Débora Cristina
Published: July 2021

Context:Gold mining is the most destructive activity in the natural forests of the Madre de Dios region in the southeastern Peruvian Amazon. Understanding the natural regeneration process of these degraded areas is necessary to develop forest restoration projects in such conditions.

Aims:We aimed to evaluate forest recovery and identify the successional and structure patterns of vegetation governing natural regeneration over time.

Methods:Structure, composition, richness, diversity, and successional status were evaluated in abandoned artisanal gold mine areas in Madre de Dios, southeastern Peru. Vegetation data were recorded in 61 plots of 250 m2established in five sites varying from 1 to 19 years of abandonment. Vegetation in abandoned areas was compared with six undisturbed forests evaluated in previous inventories.

Results:In the mining lands, tree density and basal area recovered quickly, while species richness and composition were slow. Forest recovery is an initial stage of transition from pioneer to early secondary species until at least 19 years after abandonment. The most abundant and frequent species were the fast-growing speciesOchroma pyramidaleandCecropia engleriana.These species could be considered potential candidates to promote restoration plans. Pioneer species represented 63% of the number of species in plots of 1–4 years, 57% in plots of 5–7 years, and 50% in plots of 8–19 years. Early and late secondary species represented 34 and 16%, respectively, of the number of species in plots of 8–19 years. Abandoned mining and reference plots present less than 5% of species in common.

Conclusion:Our results highlight a slow natural regeneration process in areas for up to 19 years after gold mining. Species from different successional statuses were identified as potential candidates for recovering vegetation in such areas. Our findings may have important implications for further research focusing on the ecological restoration in tropical forests severely degraded by gold mining.
Construction and Comprehensive Prognostic Analysis of a lncRNA–miRNA–mRNA Regulatory Network and Tumor Immune Cell Infiltration in Colorectal Cancer
Authors: Guo Xiong , Liang Xiaolong , Wang Yujun , Cheng Anqi , Qin Chuan , Zhang Han , Wang Ziwei
Published: July 2021

Colorectal cancer (CRC) is a malignant tumor with high morbidity and mortality worldwide. Recent studies have shown that long noncoding RNAs (lncRNAs) play an important role in almost all human tumors, including CRC. Competitive endogenous RNA (ceRNA) regulatory networks have become hot topics in cancer research. Tumor-infiltrating immune cells (TICs) have also been reported to be closely related to the survival and prognosis of CRC patients. In this study, we used the lncRNA–miRNA–mRNA regulatory network combined with tumor immune cell infiltration to predict the survival and prognosis of 598 CRC patients. First, we downloaded the lncRNA, mRNA, and miRNA transcriptome data of CRC patients from The Cancer Genome Atlas (TCGA) database and identified differentially expressed genes through “limma” package of R software. The ceRNA regulatory network was established by using the “GDCRNATools” R package. Then, univariate Cox analysis and least absolute shrinkage and selection operator analysis were performed to identify the optimal prognostic network nodes, including SRPX, UST, H19, SNHG7, hsa-miR-29b-3p, and TTYH3. Next, we analyzed the differences in 22 types of TICs between 58 normal subjects and 206 CRC patients and included memory CD4 T cells, dendritic cells and neutrophils in the construction of a prognostic model. Finally, we identified the relationship between the ceRNA prognostic model and the infiltrating immune cell prognostic model. In conclusion, we constructed two prognostic models that provide insights on the prognosis and treatment strategy of CRC.
Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease
Authors: Liu Zhuohang , Li Hang , Pan Shuyi
Published: July 2021

Background

As the most common neurodegenerative disease, Alzheimer’s disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.

Methods

The gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.

Results

There was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.

Conclusion

A model based on immune cell infiltration might be used to forecast AD patients’ diagnosis, and it provided a new perspective for AD treatment targets.
Verification of the Role of ADAMTS13 in the Cardiovascular Disease Using Two-Sample Mendelian Randomization
Authors: Ye Zixiang , Zheng Jingang
Published: July 2021

Objective

ADAMTS13 plays a crucial role in several diseases. Many observational studies have reported the relationship between ADAMTS13 and some cardiovascular diseases but have drawn different conclusions, likely attributed to confounding factors lacking adjustment. Identifying the role of ADAMTS13 in cardiovascular diseases is pivotal for prevention as well as early intervention in patients with latent cardiovascular diseases. This study aims to estimate whether the level and activity of ADAMTS13 are causally associated with common cardiovascular diseases.

Methods

We applied a two-sample Mendelian randomization approach incorporating genome-wide association summary statistics to verify the causal association between ADAMTS13 level, as well as activity and cardiovascular diseases.

Results

Lower ADAMTS13 activity was causally associated with the increased risks for coronary heart diseases (b = −0.0041, se = 0.0019, p < 0.05) as well as myocardial infarction (b = −0.0048, se = 0.0022, p < 0.05). Standard inverse-variance weighted Mendelian randomization results suggested no genetic support for a causal association between ADAMTS13 level and cardiovascular diseases including coronary heart disease, myocardial infarction, atrial fibrillation, heart failure, and venous thromboembolism (p > 0.05).

Conclusion

The causal effect of lower ADAMTS13 activity on the increased odds of having cardiovascular diseases was coronary heart disease and myocardial infarction.
Prediction of Alternative Drug-Induced Liver Injury Classifications Using Molecular Descriptors, Gene Expression Perturbation, and Toxicology Reports
Authors: Lesiński Wojciech , Mnich Krzysztof , Rudnicki Witold R.
Published: July 2021

Motivation: Drug-induced liver injury (DILI) is one of the primary problems in drug development. Early prediction of DILI, based on the chemical properties of substances and experiments performed on cell lines, would bring a significant reduction in the cost of clinical trials and faster development of drugs. The current study aims to build predictive models of risk of DILI for chemical compounds using multiple sources of information.

Methods: Using several supervised machine learning algorithms, we built predictive models for several alternative splits of compounds between DILI and non-DILI classes. To this end, we used chemical properties of the given compounds, their effects on gene expression levels in six human cell lines treated with them, as well as their toxicological profiles. First, we identified the most informative variables in all data sets. Then, these variables were used to build machine learning models. Finally, composite models were built with the Super Learner approach. All modeling was performed using multiple repeats of cross-validation for unbiased and precise estimates of performance.

Results: With one exception, gene expression profiles of human cell lines were non-informative and resulted in random models. Toxicological reports were not useful for prediction of DILI. The best results were obtained for models discerning between harmless compounds and those for which any level of DILI was observed (AUC = 0.75). These models were built with Random Forest algorithm that used molecular descriptors.
Report of the Largest Chinese Cohort With SLC19A3 Gene Defect and Literature Review
Authors: Wang Jiaping , Wang Junling , Han Xiaodi , Liu Zhimei , Ma Yanli , Chen Guohong , Zhang Haoya , Sun Dan , Xu Ruifeng , Liu Yi , Zhang Yuqin , Wen Yongxin , Bao Xinhua , Chen Qian , Fang Fang
Published: July 2021

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.
Case Report: Identification of Maternal Low-Level Mosaicism in the Dystrophin Gene by Droplet Digital Polymerase Chain Reaction
Authors: Jin Pengzhen , Gao Xiaoyang , Wang Miaomiao , Qian Yeqing , Yang Jingjin , Yang Yanmei , Xu Yuqing , Xu Yanfei , Dong Minyue
Published: July 2021

Germline mosaicism should be suspected when the same de novo mutations are identified in a second pregnancy with asymptomatic parents. Our study aims to find a feasible approach to reveal the existence of germline mosaicism. Multiplex Ligation-dependent Probe Amplification was performed on a Duchenne muscular dystrophy affected pedigree to detect deletion mutations. Then gap-polymerase chain reaction was performed to amplify the breakpoints junction sequence. Droplet digital polymerase chain reaction was utilized to identify the mutation frequencies in healthy parents. The same deletion in the exon 51 of the dystrophin gene, which was 50,035 bp in size, was detected in the proband and the fetus but not in their parents. Droplet digital polymerase chain reaction analysis of peripheral blood samples revealed mutant alleles of 3.53% in maternal blood cells. We here report a case of maternal low-level mosaicism confirmed by droplet digital polymerase chain reaction in peripheral blood samples, which reveals the existence of germline mosaicism. Gap-polymerase chain reaction combined with droplet digital polymerase chain reaction provide insights into the detection of germline mosaicism.
Folate Deficiency Triggers the Abnormal Segregation of a Region With Large Cluster of CG-Rich Trinucleotide Repeats on Human Chromosome 2
Authors: Garribba Lorenza , Vogel Ivan , Lerdrup Mads , Gonçalves Dinis Marisa M. , Ren Liqun , Liu Ying
Published: July 2021

Folate deficiency is associated with a broad range of human disorders, including anemia, fetal neural tube defects, age-associated dementia and several types of cancer. It is well established that a subgroup of rare fragile sites (RFSs) containing expanded CGG trinucleotide repeat (TNR) sequences display instability when cells are deprived of folate. However, given that folate sensitive RFSs exist in a very small percentage of the population, they are unlikely to be the cause of the widespread health problems associated with folate deficiency. We hypothesized that folate deficiency could specifically affect DNA replication at regions containing CG-rich repeat sequences. For this, we identified a region on human chromosome 2 (Chr2) comprising more than 300 CG-rich TNRs (termed “FOLD1”) by examining the human genome database. Via the analysis of chromosome shape and segregation in mitosis, we demonstrate that, when human cells are cultured under folate stress conditions, Chr2 is prone to display a “kink” or “bending” at FOLD1 in metaphase and nondisjunction in anaphase. Furthermore, long-term folate deprivation causes Chr2 aneuploidy. Our results provide new evidence on the abnormalities folate deficiency could cause in human cells. This could facilitate future studies on the deleterious health conditions associated with folate deficiency.
SNP-Based Genotyping Provides Insight Into the West Asian Origin of Russian Local Goats
Authors: Deniskova Tatiana E. , Dotsev Arsen V. , Selionova Marina I. , Reyer Henry , Sölkner Johann , Fornara Margaret S. , Aybazov Ali-Magomed M. , Wimmers Klaus , Brem Gottfried , Zinovieva Natalia A.
Published: July 2021

Specific local environmental and sociocultural conditions have led to the creation of various goat populations in Russia. National goat diversity includes breeds that have been selected for down and mohair production traits as well as versatile local breeds for which pastoralism is the main management system. Effective preservation and breeding programs for local goat breeds are missing due to the lack of DNA-based data. In this work, we analyzed the genetic diversity and population structure of Russian local goats, including Altai Mountain, Altai White Downy, Dagestan Downy, Dagestan Local, Karachaev, Orenburg, and Soviet Mohair goats, which were genotyped with the Illumina Goat SNP50 BeadChip. In addition, we addressed genetic relationships between local and global goat populations obtained from the AdaptMap project. Russian goats showed a high level of genetic diversity. Although a decrease in historical effective population sizes was revealed, the recent effective population sizes estimated for three generations ago were larger than 100 in all studied populations. The mean runs of homozygosity (ROH) lengths ranged from 79.42 to 183.94 Mb, and the average ROH number varied from 18 to 41. Short ROH segments (<2 Mb) were predominant in all breeds, while the longest ROH class (>16 Mb) was the least frequent. Principal component analysis, Neighbor-Net graph, and Admixture clustering revealed several patterns in Russian local goats. First, a separation of the Karachaev breed from other populations was observed. Moreover, genetic connections between the Orenburg and Altai Mountain breeds were suggested and the Dagestan breeds were found to be admixed with the Soviet Mohair breed. Neighbor-Net analysis and clustering of local and global breeds demonstrated the close genetic relations between Russian local and Turkish breeds that probably resulted from past admixture events through postdomestication routes. Our findings contribute to the understanding of the genetic relationships of goats originating in West Asia and Eurasia and may be used to design breeding programs for local goats to ensure their effective conservation and proper management.
The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients
Authors: Ding Ying , Yu Xiaojuan , Wu Lihua , Tan Ying , Qu Zhen , Yu Feng
Published: July 2021

Objectives

This study aimed to determine the prevalence and localization of complement factor C4d in renal biopsies from patients with lupus nephritis (LN), as well as its associations with the disease’s clinico-pathological features. The correlation between arteriolar C4d deposition and renal microvascular lesions (RVLs) was further analyzed.

Methods

A total of 325 biopsy-proven LN patients were enrolled, and their clinico-pathological data were collected. C4d staining of renal biopsies was performed by immunohistochemistry. The associations between C4d deposition and the clinico-pathological features were further analyzed.

Results

C4d deposition was present in most (98.8%) renal specimens in our cohort. These deposits were localized in the glomeruli (98.2%), tubular basement membrane (TBM) (43.7%), arterioles (31.4%), and peritubular capillary (33.8%). Patients with TBM C4d staining had higher disease activity (measured with the Systemic Lupus Erythematous Disease Activity Index) and higher National Institutes of Health pathological activity and chronicity indices (all P < 0.01). Patients with arteriolar C4d deposition were more likely to develop RVLs (91.2%) compared to those with no arteriolar C4d deposition (78.0%; P = 0.004), especially with two or more types of RVLs (P < 0.001). During the mean follow-up of 55.8 months, arteriolar C4d was related to worse renal outcomes [hazard ration (HR): 2.074, 95% confidence interval (CI) 1.056–4.075, P = 0.034]. Multivariate Cox hazard analysis showed that co-deposition of arteriolar C4d and C3c was an independent risk factor (HR: 3.681, 95% CI 1.519–8.921, P = 0.004) for predicting renal outcomes.

Conclusions

C4d deposition was common in renal tissues from LN patients. TBM C4d deposition was related to the disease activity, and arteriolar C4d deposition was associated with RVLs and worse renal outcomes.
Identification of Two Novel Candidate Genetic Variants Associated With the Responsiveness to Influenza Vaccination
Authors: Wen Simin , Wei Hejiang , Liao Qijun , Li Mao , Zhong Shuyi , Cheng Yanhui , Huang Weijuan , Wang Dayan , Shu Yuelong
Published: July 2021

Background

Annual vaccination is the most effective prevention of influenza infection. Up to now, a series of studies have demonstrated the role of genetic variants in regulating the antibody response to influenza vaccine. However, among the Chinese population, the relationship between genetic factors and the responsiveness to influenza vaccination has not been clarified through genome-wide association study (GWAS).

Method

A total of 1,968 healthy volunteers of Chinese descent were recruited and 1,582 of them were available for the subsequent two-stage analysis. In the discovery stage, according to our inclusion criteria, 123 of 1,582 subjects were selected as group 1 and received whole-genome sequencing to identify potential variants and genes. In the verification stage, 29 candidate variants identified by GWAS were selected for further validation in 481 subjects in group 2. Besides, we also analyzed nine variants from previously published reports in our study.

Results

Multivariate logistic regression analysis showed that compared with the TT genotype of ZBTB46 rs2281929, the TC + CC genotype was associated with a lower risk of low responsiveness to influenza vaccination adjusted for gender and age (Group 2: P = 7.75E-05, OR = 0.466, 95%CI = 0.319–0.680; Combined group: P = 1.18E-06, OR = 0.423, 95%CI = 0.299–0.599). In the combined group, IQGAP2 rs2455230 GC + CC genotype was correlated with a lower risk of low responsiveness to influenza vaccination compared with the GG genotype (P = 8.90E-04, OR = 0.535, 95%CI = 0.370–0.774), but the difference was not statistically significant in group 2 (P = 0.008). The antibody fold rises of subjects with ZBTB46 rs2281929 TT genotype against H1N1, H3N2,and B were all significantly lower than that of subjects with TC + CC genotype (P < 0.001). Compared with IQGAP2 rs2455230 GC + CC carriers, GG carriers had lower antibody fold rises to H1N1 (P = 0.001) and B (P = 0.032). The GG genotype of rs2455230 tended to be correlated with lower antibody fold rises (P = 0.096) against H3N2, but the difference was not statistically significant. No correlation was found between nine SNPs from previously published reports and the serological response to influenza vaccine in our study.

Conclusion

Our study identified two novel candidate missense variants, ZBTB46 rs2281929 and IQGAP2 rs2455230, were associated with the immune response to influenza vaccination among the Chinese population. Identifying these variants will provide more evidence for future research and improve the individualized influenza vaccination program.
Low Innate Immunity and Lagged Adaptive Immune Response in the Re-Tested Viral RNA Positivity of a COVID-19 Patient
Authors: Lai Changchun , Liu Xinglong , Yan Qihong , Lv Hualiang , Zhou Lei , Hu Longbo , Cai Yong , Wang Guoqiang , Chen Yufeng , Chai Renjie , Liu Zhenwei , Xu Yuhua , Huang Wendong , Xiao Fei , Hu Linhui , Li Yaocai , Huang Jianhong , Zhou Qiang , Li Luqian , Peng Tao , Zhang Haiye , Zhang Zhenhui , Chen Ling , Chen Chunbo , Ji Tianxing
Published: July 2021

Recent studies have highlighted observations regarding re-tested positivity (RP) of SARS-CoV-2 RNA in discharged COVID-19 patients, however, the immune mechanisms underlying SARS-CoV-2 RNA RP in immunocompetent patients remain elusive. Herein, we describe the case of an immunocompetent COVID-19 patient with moderate symptoms who was twice re-tested as positive for SARS-CoV-2 RNA, and the period between first and third viral RNA positivity was 95 days, longer than previously reported (18–25 days). The chest computed tomography findings, plasma anti-SARS-CoV-2 antibody, neutralizing antibodies (NAbs) titer, and whole blood transcriptic characteristics in the viral RNA RP patient and other COVID-19 patients were analyzed. During the SARS-CoV-2 RNA RP period, new lung lesions were observed. The COVID-19 patient with viral RNA RP had delayed seroconversion of anti-spike/receptor-binding domain (RBD) IgA antibody and NAbs and were accompanied with disappearance of the lung lesions. Further experimental data validated that NAbs titer was significantly associated with anti-RBD IgA and IgG, and anti-spike IgG. The RP patient had lower interferon-, T cells- and B cell-related genes expression than non-RP patients with mild-to-moderate symptoms, and displayed lower cytokines and chemokines gene expression than severe patients. Interestingly, the RP patient had low expression of antigen presentation-related genes and low B cell counts which might have contributed to the delayed anti-RBD specific antibody and low CD8+ cell response. Collectively, delayed antigen presentation-related gene expression was found related to delayed adaptive immune response and contributed to the SARS-CoV-2 RNA RP in this described immunocompetent patient.
FoxO3 Modulates LPS-Activated Hepatic Inflammation in Turbot (Scophthalmus maximus L.)
Authors: Pan Mingzhu , Liu Jiahuan , Huang Dong , Guo Yanlin , Luo Kai , Yang Mengxi , Gao Weihua , Xu Qiaoqing , Zhang Wenbing , Mai Kangsen
Published: July 2021

In mammals, forkhead box O3 (foxo3) plays important roles in liver immune system. The foxo3 can regulate cell cycle, DNA repair, hypoxia, apoptosis and so on. However, as such an important transcription factor, few studies on foxo3 in fish have been reported. The present study characterized the foxo3 in turbot (Scophthalmus maximus L.). Lipopolysaccharide (LPS) incubated in vitro (hepatocytes) and injected in vivo (turbot liver) were used to construct inflammatory models. The foxo3 was interfered and overexpressed to investigate its functions in liver inflammation. The open reading frame (ORF) of foxo3 was 1998 bp (base pair), encoding 665 amino acids. Sequence analysis showed that foxo3 of turbot was highly homologous to other fishes. Tissue distribution analysis revealed that the highest expression of foxo3 was in muscle. Immunofluorescence result showed that foxo3 was expressed in cytoplasm and nucleus. Knockdown of foxo3 significantly increased mRNA levels of tumor necrosis factor-α (tnf-α), interleukin-1β (il-1β), interleukin-6 (il-6), myeloid-differentiation factor 88 (myd88), cd83, toll-like receptor 2 (tlr-2) and protein level of c-Jun N-terminal kinase (JNK) in sifoxo3 + LPS (siRNA of foxo3+ LPS) group compared with NC + LPS (negative control + LPS) group in turbot hepatocytes. Overexpressed foxo3 significantly decreased mRNA levels of tnf-α, il-6, nuclear transcription factor-kappa B (nf-κb), cd83, tlr-2 and the protein level of JNK in vitro. In vivo analysis, foxo3 knockdown significantly increased levels of GOT in serum after LPS injection compared with NC+LPS group. Overexpressed foxo3 significantly decreased levels of GPT and GOT in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in vivo. Foxo3 knockdown significantly increased mRNA levels of tnf-α, il-1β, il-6, nf-κb, myd88 and protein level of JNK in vivo in sifoxo3+LPS group compared with NC+LPS group in turbot liver. Overexpressed foxo3 significantly decreased mRNA levels of il-1β, il-6, myd88, cd83, jnk and protein level of JNK in pcDNA3.1-foxo3+LPS group compared with pcDNA3.1+LPS group in turbot liver. The results indicated that foxo3 might modulate LPS-activated hepatic inflammation in turbot by decreasing the proinflammatory cytokines, the levels of GOT and GPT as well as activating JNK/caspase-3 and tlr-2/myd88/nf-κb pathways. Taken together, these findings indicated that FoxO3 may play important roles in liver immune responses to LPS in turbot and the research of FoxO3 in liver immunity enriches the studies on immune regulation, and provides theoretical basis and molecular targets for solving liver inflammation and liver injury in fish.
Antibody Conjugates for Targeted Therapy Against HIV-1 as an Emerging Tool for HIV-1 Cure
Authors: Umotoy Jeffrey C. , de Taeye Steven W.
Published: July 2021

Although advances in antiretroviral therapy (ART) have significantly improved the life expectancy of people living with HIV-1 (PLWH) by suppressing HIV-1 replication, a cure for HIV/AIDS remains elusive. Recent findings of the emergence of drug resistance against various ART have resulted in an increased number of treatment failures, thus the development of novel strategies for HIV-1 cure is of immediate need. Antibody-based therapy is a well-established tool in the treatment of various diseases and the engineering of new antibody derivatives is expanding the realms of its application. An antibody-based carrier of anti-HIV-1 molecules, or antibody conjugates (ACs), could address the limitations of current HIV-1 ART by decreasing possible off-target effects, reduce toxicity, increasing the therapeutic index, and lowering production costs. Broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency against HIV-1 are currently being explored to prevent or treat HIV-1 infection in the clinic. Moreover, bNAbs can be engineered to deliver cytotoxic or immune regulating molecules as ACs, further increasing its therapeutic potential for HIV-1 cure. ACs are currently an important component of anticancer treatment with several FDA-approved constructs, however, to date, no ACs are approved to treat viral infections. This review aims to outline the development of AC for HIV-1 cure, examine the variety of carriers and payloads used, and discuss the potential of ACs in the current HIV-1 cure landscape.
Post-Transcriptional Regulation of Immune Responses and Inflammatory Diseases by RNA-Binding ZFP36 Family Proteins
Authors: Makita Sohei , Takatori Hiroaki , Nakajima Hiroshi
Published: July 2021

Post-transcriptional regulation is involved in the regulation of many inflammatory genes. Zinc finger protein 36 (ZFP36) family proteins are RNA-binding proteins involved in messenger RNA (mRNA) metabolism pathways. The ZFP36 family is composed of ZFP36 (also known as tristetraprolin, TTP), ZFP36L1, ZFP36L2, and ZFP36L3 (only in rodents). The ZFP36 family proteins contain two tandemly repeated CCCH-type zinc-finger motifs, bind to adenine uridine-rich elements in the 3’-untranslated regions (3’ UTR) of specific mRNA, and lead to target mRNA decay. Although the ZFP36 family members are structurally similar, they are known to play distinct functions and regulate different target mRNAs, probably due to their cell-type-specific expression patterns. For instance, ZFP36 has been well-known to function as an anti-inflammatory modulator in murine models of systemic inflammatory diseases by down-regulating the production of various pro-inflammatory cytokines, including TNF-α. Meanwhile, ZFP36L1 is required for the maintenance of the marginal-zone B cell compartment. Recently, we found that ZFP36L2 reduces the expression of Ikzf2 (encoding HELIOS) and suppresses regulatory T cell function. This review summarizes the current understanding of the post-transcriptional regulation of immunological responses and inflammatory diseases by RNA-binding ZFP36 family proteins.
Resuspension, Redistribution, and Deposition of Oil-Residues to Offshore Depocenters After the Deepwater Horizon Oil Spill
Authors: Diercks Arne R. , Romero Isabel C. , Larson Rebekka A. , Schwing Patrick , Harris Austin , Bosman Samantha , Chanton Jeffrey P. , Brooks Gregg
Published: July 2021

The focus of this study was to determine the long-term fate of oil-residues from the 2010 Deepwater Horizon (DwH) oil spill due to remobilization, transport, and re-distribution of oil residue contaminated sediments to down-slope depocenters following initial deposition on the seafloor. We characterized hydrocarbon residues, bulk sediment organic matter, ease of resuspension, sedimentology, and accumulation rates to define distribution patterns in a 14,300 km2 area southeast of the DwH wellhead (1,500 to 2,600 m water depth). Oil-residues from the DwH were detected at low concentrations in 62% of the studied sites at specific sediment layers, denoting episodic deposition of oil-residues during 2010–2014 and 2015–2018 periods. DwH oil residues exhibited a spatial distribution pattern that did not correspond with the distribution of the surface oil slick, subsurface plume or original seafloor spatial expression. Three different regions were apparent in the overall study area and distinguished by the episodic nature of sediment accumulation, the ease of sediment resuspension, the timing of oil-residue deposition, carbon content and isotopic composition and foram fracturing extent. These data indicate that resuspension and down-slope redistribution of oil-residues occurred in the years following the DwH event and must be considered in determining the fate of the spilled oil deposited on the seafloor.
Scoping Science-Policy Arenas for Regional Ocean Governance in the Wider Caribbean Region
Authors: Mahon Robin , Fanning Lucia
Published: July 2021

This paper explores the diversity of relationships that exist between science and policy and which underpin the uptake of science in oceans policy-making in the Wider Caribbean Region (WCR). We refer to these complex relationships, influenced by organizational culture and environments, as science-policy arenas. The paper examines the types of decisions that require science input, where the decision-making responsibility lies, who the science providers are, and how science gets translated into advice for a suite of 20 regional Intergovernmental Organizations (IGOs). The picture that emerges is one of a diverse suite of well-structured and active science-policy processes, albeit with several deficiencies. These processes appear to be somewhat separated from a broad diversity of potential science inputs. The gap appears largely due to lack of accessibility and interest in both directions (providers <-> consumers), with IGOs apparently preferring to use a relatively small subset of available expertise. At the same time, there is a small number of boundary-spanners, many of which are newly emerging, that carry out a diversity of functions in seeking to address the gap. Based on our scoping assessment, there is an urgent need for actors to understand the networks of interactions and actively develop them for science-policy interfaces to be effective and efficient. This presents a major challenge for the region where most countries are small and have little if any science capacity. Innovative mechanisms that focus more on processes for accessing science than on assembling inventories of available information are needed. A managed information hub that can be used to build teams of scientists and advisors to address policy questions may be effective for the WCR given its institutional complexity. More broadly, recognition of the potential value of boundary spanning activities in getting science into policy is needed. Capacity for these should be built and boundary spanning organizations encouraged, formalized and mainstreamed.
The Use of Remote Monitoring Technologies: A Review of Recent Regulatory Scientific Advices, Qualification Opinions, and Qualification Advices Issued by the European Medicines Agency
Authors: Dekker Marieke J. H. J. , Stolk Pieter , Pasmooij Anna M. G.
Published: July 2021

Aims: Recently, the use of novel remote monitoring technologies (RMTs) in trials has gained much interest. To facilitate regulatory learning, we evaluated qualification opinions (QOs) and advices (QAs) and scientific advices (SAs) of the Committee for Medicinal Products for Human Use (CHMP) to gain insight in the types of devices that are intended to be used in clinical trials for supporting/submitting application for obtaining marketing authorization (registration trials) and the main recommendations of the CHMP.

Methods: QOs, QAs, and SAs of the CHMP that assessed RMTs between 2013 and 2019 were eligible for our study. The following information was extracted from the documents: year of advice/opinion, device and endpoints used, type of endpoint (primary, secondary, exploratory, or safety), and main recommendations of the CHMP.

Results: In total two QOs, four QAs, and 59 SAs were included in our study (total of SAs between 2013 and 2019 = 4,054). In the SAs, accelerometers to measure activity and/or sleep parameters (n = 31) were the most frequently used devices, followed by mobile applications (n = 6) and glucose monitoring devices (n = 6). Usually, these measures were proposed as secondary or exploratory endpoints (n = 32). The main recommendations of the CHMP were related to relevance of the (novel) outcome measure; validation; precision, accuracy, sensitivity, and specificity; compliance; sampling interval; and data handling and privacy.

Conclusions: Although there was a trend toward an increased use over time, the use of RMTs in registration trials is still relatively rare. In the absence of formal European regulatory guidance on mHealth technologies, insight in the main recommendations of the CHMP may stimulate the use of novel RMTs in a regulatory context.
Understanding Biofilm Formation in Ecotoxicological Assays With Natural and Anthropogenic Particulates
Authors: Gorokhova Elena , Motiei Asa , El-Shehawy Rehab
Published: July 2021

Fossil-made polymers harbor unique bacterial assemblages, and concerns have been raised that ingested microplastic may affect the consumer gut microbiota and spread pathogens in animal populations. We hypothesized that in an ecotoxicity assay with a mixture of polystyrene (PS) and clay: (1) microbiome of the test animals inoculates the system with bacteria; (2) relative contribution of PS and the total amount of suspended solids (SS) select for specific bacterial communities; and (3) particle aggregation is affected by biofilm community composition, with concomitant effects on the animal survival. Mixtures of PS and clay at different concentrations of SS (10, 100, and 1000 mg/L) with a varying microplastics contribution (%PS; 0–80%) were incubated with Daphnia magna, whose microbiome served as an inoculum for the biofilms during the exposure. After 4-days of exposure, we examined the biofilm communities by 16S rRNA gene sequencing, particle size distribution, and animal survival. The biofilm communities were significantly different from the Daphnia microbiota used to inoculate the system, with an overrepresentation of predatory, rare, and potentially pathogenic taxa in the biofilms. The biofilm diversity was stimulated by %PS and decreased by predatory bacteria. Particle aggregate size and the biofilm composition were the primary drivers of animal survival, with small particles and predatory bacteria associated with a higher death rate. Thus, in effect studies with solid waste materials, ecological interactions in the biofilm can affect particle aggregation and support potentially harmful microorganisms with concomitant effects on the test animals.
New Insights on the Early Interaction Between Typhoid and Non-typhoid Salmonella Serovars and the Host Cells
Authors: Schultz Bárbara M. , Melo-Gonzalez Felipe , Salazar Geraldyne A. , Porto Bárbara N. , Riedel Claudia A. , Kalergis Alexis M. , Bueno Susan M.
Published: July 2021

Salmonella enterica is a common source of food and water-borne infections, causing a wide range of clinical ailments in both human and animal hosts. Immunity to Salmonella involves an interplay between different immune responses, which are rapidly initiated to control bacterial burden. However, Salmonella has developed several strategies to evade and modulate the host immune responses. In this sense, the main knowledge about the pathogenicity of this bacterium has been obtained by the study of mouse models with non-typhoidal serovars. However, this knowledge is not representative of all the pathologies caused by non-typhoidal serovars in the human. Here we review the most important features of typhoidal and non-typhoidal serovars and the diseases they cause in the human host, describing the virulence mechanisms used by these pathogens that have been identified in different models of infection.
Fungal Community Composition and Diversity Vary With Soil Horizons in a Subtropical Forest
Authors: Luo Xia , Liu Kezhong , Shen Yuyu , Yao Guojing , Yang Wenguang , Mortimer Peter E. , Gui Heng
Published: July 2021

Soil fungal communities, which drive many ecosystem processes, vary across soil horizons. However, how fungal communities are influenced by soil horizon layers remains largely unstudied. In this study, soil samples were collected from the organic horizon (O horizon) and mineral matter horizon (M horizon) in two sites of Dabie Mountain, China, and the effects of the two horizons on the soil fungal community composition were assessed based on Illumina MiSeq sequencing. Our results showed that soil fungal community composition varied with soil horizons, and soil fungal species richness and diversity in the O horizon were significantly higher than that in the M horizon. Total organic carbon (TOC), total organic nitrogen (TON), alkali-hydrolyzable nitrogen (AHN), available potassium (AK), and available phosphorus (AP) significantly influenced fungal community composition, abundance, and diversity across the two horizons (P < 0.05). Furthermore, precipitation was found to have a significant effect on fungal community composition. Our results demonstrate changes in fungal communities across soil horizons and highlight the importance of soil organic matter on fungal communities and diversity.
Bacterial Community Spacing Is Mainly Shaped by Unique Species in the Subalpine Natural Lakes of China
Authors: Liu Jinxian , Su Jiahe , Zhang Meiting , Luo Zhengming , Li Xiaoqi , Chai Baofeng
Published: July 2021

Bacterial communities have been described as early indicators of both regional and global climatic change and play a critical role in the global biogeochemical cycle. Exploring the mechanisms that determine the diversity patterns of bacterial communities and how they share different habitats along environmental gradients are, therefore, a central theme in microbial ecology research. We characterized the diversity patterns of bacterial communities in Pipahai Lake (PPH), Mayinghai Lake (MYH), and Gonghai Lake (GH), three subalpine natural lakes in Ningwu County, Shanxi, China, and analyzed the distribution of their shared and unique taxa (indicator species). Results showed that the species composition and structure of bacterial communities were significantly different among the three lakes. Both the structure of the entire bacterial community and the unique taxa were significantly influenced by the carbon content (TOC and IC) and space distance; however, the structure of the shared taxa was affected by conductivity (EC), pH, and salinity. The structure of the entire bacterial community and unique taxa were mainly affected by the same factors, suggesting that unique taxa may be important in maintaining the spatial distribution diversity of bacterial communities in subalpine natural freshwater lakes. Our results provide new insights into the diversity maintenance patterns of the bacterial communities in subalpine lakes, and suggest dispersal limitation on bacterial communities between adjacent lakes, even in a small local area. We revealed the importance of unique taxa in maintaining bacterial community structure, and our results are important in understanding how bacterial communities in subalpine lakes respond to environmental change in local habitats.