Miracle-dz/UniFAR-FTUs huggingface dataset:
An Ultrahigh-Affinity Complement C4b-Specific Nanobody Inhibits In Vivo Assembly of the Classical Pathway Proconvertase

Key Points hC4Nb8 is a potent cross-reactive inhibitor of CP and LP proconvertase formation. hC4Nb8 binds to a neoepitope exposed upon C4 activation and C4b generation. hC4Nb8 inhibits the CP of complement in vivo. The classical and lectin pathways of the complement system are important for the elimination of pathogens and apoptotic cells and stimulation of the adaptive immune system. Upon activation of these pathways, complement component C4 is proteolytically cleaved, and the major product C4b is deposited on the activator, enabling assembly of a C3 convertase and downstream alternative pathway amplification. Although excessive activation of the lectin and classical pathways contributes to multiple autoimmune and inflammatory diseases and overexpression of a C4 isoform has recently been linked to schizophrenia, a C4 inhibitor and structural characterization of the convertase formed by C4b is lacking. In this study, we present the nanobody hC4Nb8 that binds with picomolar affinity to human C4b and potently inhibits in vitro complement C3 deposition through the classical and lectin pathways in human serum and in mouse serum. The crystal structure of the C4b:hC4Nb8 complex and a three-dimensional reconstruction of the C4bC2 proconvertase obtained by electron microscopy together rationalize how hC4Nb8 prevents proconvertase assembly through recognition of a neoepitope exposed in C4b and reveals a unique C2 conformation compared with the alternative pathway proconvertase. On human induced pluripotent stem cell–derived neurons, the nanobody prevents C3 deposition through the classical pathway. Furthermore, hC4Nb8 inhibits the classical pathway-mediated immune complex delivery to follicular dendritic cells in vivo. The hC4Nb8 represents a novel ultrahigh-affinity inhibitor of the classical and lectin pathways of the complement cascade under both in vitro and in vivo conditions.
Price-Denomination Effect: Choosing to Pay With Denominations That Are the Same as the Product Prices

Building on past research on judgment anchoring, we investigate the effect of price information on consumers’ choice of denomination when making a purchase. Across seven experiments, including two in the field (N = 4,020), we find that people tend to purchase with denominations that are the same as the product prices. They use larger denominations for higher priced products that are priced at the value of the denomination held, and smaller denominations for lower priced products that are priced at the value of the smaller denomination held. The effect is not explained by storage or purchase convenience. We propose the “price-denomination effect” is driven by consumers anchoring on product price and then choosing the denomination that matches the anchor. The effect replicates across participants from different continents (United States, Europe, and Africa) and samples (online panelists, and actual consumers), as well as prices in different currencies (United States $, €, and Nigerian Naira). We further demonstrate that people’s preference for denominations also affects the choice of the form of payment used: cash versus card. Consumers are more likely to use cash (vs. card) when product price is exactly the same as a denomination held. We conclude with a discussion of theoretical and practical implications.
Iturin A Extracted From Bacillus subtilis WL-2 Affects Phytophthora infestans via Cell Structure Disruption, Oxidative Stress, and Energy Supply Dysfunction

Potato late blight, caused by Phytophthora infestans (Mont.) de Bary, represents a great food security threat worldwide and is difficult to control. Recently, Bacillus spp. have been considered biocontrol agents to control many plant diseases. Here, Bacillus subtilis WL-2 was selected as a potent strain against P. infestans mycelium growth, and its functional metabolite was identified as Iturin A via electrospray ionization mass spectrometry (ESI-MS). Analyses using scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed that Iturin A caused cell membrane disruption and an irregular internal cell structure. In addition, Iturin A triggered oxidative stress reactions similarly to reactive oxygen species (ROS) in P. infestans cells and caused mitochondrial damage, including mitochondrial membrane potential (MMP), mitochondrial respiratory chain complex activity (MRCCA), and ATP production decline. These results highlight that the cell structure disruption, oxidative stress, and energy supply dysfunction induced by Iturin A play an important role in inhibiting P. infestans. Additionally, B. subtilis WL-2 and Iturin A have great potential for inhibiting P. infestans mycelium growth and controlling potato late blight in the future.
Emerging Trends in Biological Treatment of Wastewater From Unconventional Oil and Gas Extraction

Unconventional oil and gas exploration generates an enormous quantity of wastewater, commonly referred to as flowback and produced water (FPW). Limited freshwater resources and stringent disposal regulations have provided impetus for FPW reuse. Organic and inorganic compounds released from the shale/brine formation, microbial activity, and residual chemicals added during hydraulic fracturing bestow a unique as well as temporally varying chemical composition to this wastewater. Studies indicate that many of the compounds found in FPW are amenable to biological degradation, indicating biological treatment may be a viable option for FPW processing and reuse. This review discusses commonly characterized contaminants and current knowledge on their biodegradability, including the enzymes and organisms involved. Further, a perspective on recent novel hybrid biological treatments and application of knowledge gained from omics studies in improving these treatments is explored.
Structural and Proteomic Studies of the Aureococcus anophagefferens Virus Demonstrate a Global Distribution of Virus-Encoded Carbohydrate Processing

Viruses modulate the function(s) of environmentally relevant microbial populations, yet considerations of the metabolic capabilities of individual virus particles themselves are rare. We used shotgun proteomics to quantitatively identify 43 virus-encoded proteins packaged within purified Aureococcus anophagefferens Virus (AaV) particles, normalizing data to the per-virion level using a 9.5-Å-resolution molecular reconstruction of the 1900-Å (AaV) particle that we generated with cryogenic electron microscopy. This packaged proteome was used to determine similarities and differences between members of different giant virus families. We noted that proteins involved in sugar degradation and binding (e.g., carbohydrate lyases) were unique to AaV among characterized giant viruses. To determine the extent to which this virally encoded metabolic capability was ecologically relevant, we examined the TARA Oceans dataset and identified genes and transcripts of viral origin. Our analyses demonstrated that putative giant virus carbohydrate lyases represented up to 17% of the marine pool for this function. In total, our observations suggest that the AaV particle has potential prepackaged metabolic capabilities and that these may be found in other giant viruses that are widespread and abundant in global oceans.
Identification of Potential Biomarkers for CAD Using Integrated Expression and Methylation Data

DNA methylation plays an essential role in the pathogenesis of coronary artery disease (CAD) through regulating mRNA expressions. This study aimed to identify hub genes regulated by DNA methylation as biomarkers of CAD. Gene expression and methylation datasets of peripheral blood leukocytes (PBLs) of CAD were downloaded from the Gene Expression Omnibus (GEO) database. Subsequently, multiple computational approaches were performed to analyze the regulatory networks and to recognize hub genes. Finally, top hub genes were verified in a case-control study, based on their differential expressions and methylation levels between CAD cases and controls. In total, 535 differentially expressed-methylated genes (DEMGs) were identified and partitioned into 4 subgroups. TSS200 and 5′UTR were confirmed as high enrichment areas of differentially methylated CpGs sites (DMCs). The function of DEMGs is enriched in processes of histone H3-K27 methylation, regulation of post-transcription and DNA-directed RNA polymerase activity. Pathway enrichment showed DEMGs participated in the VEGF signaling pathway, adipocytokine signaling pathway, and PI3K-Akt signaling pathway. Besides, expressions of hub genes fibronectin 1 (FN1), phosphatase (PTEN), and tensin homolog and RNA polymerase III subunit A (POLR3A) were discordantly expressed between CAD patients and controls and related with DNA methylation levels. In conclusion, our study identified the potential biomarkers of PBLs for CAD, in which FN1, PTEN, and POLR3A were confirmed.
Supplementation of Diet With Different n-3/n-6 PUFA Ratios Ameliorates Autistic Behavior, Reduces Serotonin, and Improves Intestinal Barrier Impairments in a Valproic Acid Rat Model of Autism

The implication of different dietary n-3/n-6 polyunsaturated fatty acids (PUFAs) ratios has been investigated in some neurodevelopmental disorders (including autism and depression). However, the mechanisms underlying the effects of different PUFAs ratios on the autism are still poorly understood. In the present study, a valproic acid (VPA) rat model of autism was used to study the effects of diet with different n-3/n-6 PUFA ratios on the autism, and the underlying mechanisms explored. Our results showed that rats with prenatal administration of VPA took less response time to sniff three odorants in the olfactory habituation/dishabituation tests, had lower frequency of pinning and following patterns, and had decreased hippocampal 5-hydroxytryptamine (5-HT), increased serum 5-HT and downregulated expression of tight junction protein (occludin and claudin-1) in the colon. However, supplementation of n-3/n-6 PUFAs (1:5) in the VPA treated rats ameliorated the autistic behaviors, increased hippocampal 5-HT and tight junction expression in the colon, and decreased serum 5-HT. In conclusion, dietary supplementation of n-3/n-6 PUFAs (1:5) significantly improves VPA-induced autism-like behaviors in rats, which may be, at least partially, related to the increased hippocampal 5-HT. Furthermore, this diet can increase the expression of tight junction proteins to improve intestinal barrier impairment.
Genome-Wide Association Study of Smoking Behavior Traits in a Chinese Han Population

Tobacco use is one of the leading causes of preventable disease worldwide. Genetic studies have elucidated numerous smoking-associated risk loci in American and European populations. However, genetic determinants for cigarette smoking in Chinese populations are under investigated. In this study, a whole-genome sequencing (WGS)-based genome-wide association study (GWAS) was performed in a Chinese Han population comprising 620 smokers and 564 nonsmokers. Thirteen single-nucleotide polymorphisms (SNPs) of the raftlin lipid linker 1 (RFTN1) gene achieved genome-wide significance levels (P < 5 x 10−8) for smoking initiation. The rs139753473 from RFTN1 and six other suggestively significant loci from CUB and sushi multiple domains 1 (CSMD1) gene were also associated with cigarettes per day (CPD) in an independent Chinese sample consisting of 1,329 subjects (805 smokers and 524 nonsmokers). When treating males separately, associations between smoking initiation and PCAT5/ANKRD30A, two genes involved in cancer development, were identified and replicated. Within RFTN1, two haplotypes (i.e., C-A-C-G and A-G-T-C) formed by rs796812630-rs796584733-rs796349027-rs879511366 and three haplotypes (i.e., T-T-C-C-C, T-T-A-T-T, and C-A-A-T-T) formed by rs879401109-rs879453873-rs75180423-rs541378415-rs796757175 were strongly associated with smoking initiation. In addition, we also revealed two haplotypes (i.e., C-A-G-G and T-C-T-T derived from rs4875371-rs4875372-rs17070935-rs11991366) in the CSMD1 gene showing a significant association with smoking initiation. Further bioinformatics functional assessment suggested that RFTN1 may participate in smoking behavior through modulating immune responses or interactions with the glucocorticoid receptor alpha and the androgen receptor. Together, our results may help understand the mechanisms underlying smoking behavior in the Chinese Han population.
Genetic Diversity, Pedigree Relationships, and A Haplotype-Based DNA Fingerprinting System of Red Bayberry Cultivars

High throughput sequencing was used to reveal the distribution of whole-genome variations in cultivated Morella rubra (Sieb. et Zucc.). A total of 3,151,123 SNPs, 371,757 small indels, and 15,904 SVs were detected in 52 accessions. Verification by Sanger sequencing demonstrated that the positive rate of the SNPs was approximately 97.3%. Search for more genetic variations was expanded to 141 red bayberry accessions, most of which were cultivars, by sequencing 19 selected genomic segments (SEG1-19). The results showed that each segment harbored, on average, 7.8 alleles (haplotypes), a haplotype diversity of 0.42, and a polymorphic information content (PIC) of 0.40. Seventy-two different genotypes were identified from the 141 accessions, and statistical analysis showed that the accessions with duplicated genotypes were either somatic mutants or simply synonyms. Core set selection results showed that a minimum of 34 genotypes could already have covered all the alleles on the segments. A DNA fingerprinting system was developed for red bayberry, which used the diversity information of only 8 DNA segments yet still achieved a very high efficiency without losing robustness. No large clade was robustly supported by hierarchical clustering, and well-supported small clusters mainly included close relatives. These results should lead to an improved understanding of the genetic diversity of red bayberry and be valuable for future molecular breeding and variety protection.
Association of Antibiotics Administration Timing With Mortality in Children With Sepsis in a Tertiary Care Hospital of a Developing Country

Objective: To investigate the association between antibiotics administration timing with morbidity and mortality in children with severe sepsis and septic shock, presenting to a tertiary care center in a developing country. Methods: This is a retrospective study of children aged 14 years or younger diagnosed with severe sepsis or septic shock at a free-standing tertiary children's hospital in Saudi Arabia between April 2015 and February 2018. We investigated the association between antibiotic administration timing and pediatric intensive care unit (PICU) mortality, PICU length of stay (LOS), hospital LOS, and ventilation-free days after adjusting for confounders. Results: Among the 189 admissions, 77 patients were admitted with septic shock and 112 with severe sepsis. Overall, the mortality rate was 16.9%. The overall median time from sepsis recognition to antibiotic administration was 105 min (IQR: 65–185.5 min); for septic shock patients, it was 85 min (IQR: 55–148 min), and for severe sepsis, 130 min (IQR: 75.5–199 min). Delayed antibiotic administration (> 3 h) was associated with 3.85 times higher PICU mortality (95% confidence intervals 1.032–14.374) in children with septic shock than in children who receive antibiotics within 3 h, after controlling for severity of illness, age, comorbidities, and volume resuscitation. However, delayed antibiotics administration was not significantly associated with higher PICU mortality in children diagnosed with severe sepsis. Conclusions: Delayed antibiotics administration in children with septic shock admitted to a free-standing children's hospital in a developing country was associated with PICU mortality.
The LysR-Type Transcriptional Regulator YeeY Plays Important Roles in the Regulatory of Furazolidone Resistance in Aeromonas hydrophila

Aeromonas hydrophila is an aquatic pathogen of freshwater fish. The emergence of widespread antimicrobial-resistance strains of this pathogen has caused increasing rates of fish infections. Our previous research reported that A. hydrophila yeeY, a LysR-type transcriptional regulator (LTTR), negatively regulated furazolidone (FZ) resistance. Although, it’s intrinsic regulatory mechanism is still unclear. In this study, a data-independent acquisition (DIA) quantitative proteomics method was used to compare the differentially expressed proteins (DEPs) between the ΔyeeY and wild-type strain under FZ treatment. When compared to the control, a total of 594 DEPs were identified in ΔyeeY. Among which, 293 and 301 proteins were substantially increased and decreased in abundance, respectively. Bioinformatics analysis showed that several biological pathways such as the secretion system and protein transport were mainly involved in FZ resistance. Subsequently, the antibiotics susceptibility assays of several gene deletion strains identified from the proteomics results showed that YeeY may regulate some important genes such as cysD, AHA_2766, AHA_3195, and AHA_4275, which affects the FZ resistance in A. hydrophila. Furthermore, 34 antimicrobial resistance genes (ARGs) from the bacterial drug resistance gene database (CARD) were found to be directly or indirectly regulated by YeeY. A subsequent assay of several ARGs mutants showed that ΔAHA_3222 increased the susceptibility of A. hydrophila to FZ, while ΔcysN and ΔAHA_3753 decreased the susceptibility rate. Finally, the chromatin immunoprecipitation (ChIP) PCR and an electrophoretic mobility shift assay (EMSA) have revealed that the genes such as AHA_3222 and AHA_4275 were directly and transcriptionally regulated by YeeY. Taken together, our findings demonstrated that YeeY may participate in antimicrobial resistance of A. hydrophila to FZ, which provides a new target for the development of novel antimicrobial agents in the future.
Monitoring Anti-tuberculosis Treatment Response Using Analysis of Whole Blood Mycobacterium tuberculosis Specific T Cell Activation and Functional Markers

Background Blood-based biomarkers have been proposed as an alternative to current sputum-based treatment monitoring methods in active tuberculosis (ATB). The aim of this study was to validate previously described phenotypic, activation, and cytokine markers of treatment response in a West African cohort. Methods Whole blood immune responses to Mycobacterium tuberculosis ESAT-6/CFP-10 (EC) and purified protein derivative (PPD) were measured in twenty adults at baseline and after 2 months of standard TB treatment. Patients were classified as fast or slow responders based on a negative or positive sputum culture result at 2 months, respectively. Cellular expression of activation markers (CD38, HLA-DR), memory markers (CD27), and functional intracellular cytokine and proliferation (IFN-γ, Ki-67, TNF-α) markers were measured using multi-color flow cytometry. Results There was a significant increase in the proportion of CD4+CD27+ cells expressing CD38 and HLA-DR following EC stimulation at 2 months compared to baseline (p = 0.0328 and p = 0.0400, respectively). Following PPD stimulation, slow treatment responders had a significantly higher proportion of CD8+CD27–IFN-γ+ (p = 0.0105) and CD4+CD27+HLA-DR+CD38+ (p = 0.0077) T cells than fast responders at baseline. Receiver operating curve analysis of these subsets resulted in 80% sensitivity and 70 and 100% specificity, respectively (AUC of 0.82, p = 0.0156 and 0.84, p = 0.0102). Conclusion Our pilot data show reductions in expression of T cell activation markers were seen with treatment, but this was not associated with fast or slow sputum conversion at 2 months. However, baseline proportions of activated T cell subsets are potentially predictive of the subsequent speed of response to treatment.
Effect of tree density on competition between Leucaena leucocephala and Chloris gayana using a Nelder Wheel trial. I. Aboveground interactions

Abstract. Silvopastoral systems with the tree legume leucaena (Leucaena leucocephala (Lam.) de Wit) and grass pastures are widely used for ruminant feeding in subtropical and tropical regions. Different densities and planting configurations of leucaena will influence relative yields of both species because of intra- and interspecific competition. With the aim to describe the effects of competition between leucaena and Rhodes grass (Chloris gayana Kunth), a Nelder Wheel trial with 10 different leucaena tree densities (100–80 000 trees ha–1) growing with and without Rhodes grass was established in a subtropical environment at Gatton, south-east Queensland, in November 2013. From 2014 to 2016, the biomass of leucaena (six harvests) and Rhodes grass (seven harvests) was measured by using allometric equations and the BOTANAL sampling procedure over 742 and 721 days, respectively. No complementary or facilitative aboveground interactions were observed between the leucaena and Rhodes grass components of the pasture system. Increasing leucaena tree density resulted in greater aboveground intra- and interspecific competition. Average maximum individual tree yield (38.9 kg DM tree–1 year–1) was reached at 100 trees ha–1 without grass competition and was reduced by 60% with grass competition. Rhodes grass biomass yield was negatively affected by shading from the leucaena canopy, with negligible grass yield at tree densities ≥8618 trees ha–1. Therefore, there was effectively no grass competition on individual tree yield at higher leucaena densities. Accordingly, edible leucaena biomass per unit area was positively related to log10 leucaena density (R2 = 0.99) regardless of grass competition, reaching 21.7 t DM ha–1 year–1 (2014–15) and 27 t DM ha–1 year–1 (2015–16) at the highest leucaena density of 80 000 trees ha–1. By contrast, the yield of Rhodes grass was linearly and inversely correlated with log10 tree density (R2 = 0.99). Practical implications for the design and management of commercial leucaena–grass pastures are discussed.