Miracle-dz/UniFAR-FTUs huggingface dataset:
Bypassing Phase Variation of Lipooligosaccharide (LOS): Using Heptose 1 Glycan Mutants To Establish Widespread Efficacy of Gonococcal Anti-LOS Monoclonal Antibody 2C7

The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. ABSTRACT The sialylatable lacto-N-neotetraose (LNnT; Gal-GlcNAc-Gal-Glc) moiety from heptose I (HepI) of the lipooligosaccharide (LOS) of Neisseria gonorrhoeae undergoes positive selection during human infection. Lactose (Gal-Glc) from HepII, although phase variable, is commonly expressed in humans; loss of HepII lactose compromises gonococcal fitness in mice. Anti-LOS monoclonal antibody (MAb) 2C7, a promising antigonococcal immunotherapeutic that elicits complement-dependent bactericidal activity and attenuates gonococcal colonization in mice, recognizes an epitope comprised of lactoses expressed simultaneously from HepI and HepII. Glycan extensions beyond lactose on HepI modulate binding and function of MAb 2C7 in vitro. Here, four gonococcal LOS mutants, each with lactose from HepII but fixed (unable to phase-vary) LOS HepI glycans extended beyond the lactose substitution of HepI (lactose alone, Gal-lactose, LNnT, or GalNAc-LNnT), were used to define how HepI glycan extensions affect (i) mouse vaginal colonization and (ii) efficacy in vitro and in vivo of a human IgG1 chimeric derivative of MAb 2C7 (2C7-Ximab) with a complement-enhancing E-to-G Fc mutation at position 430 (2C7-Ximab-E430G). About 10-fold lower 2C7-Ximab-E430G concentrations achieved similar complement-dependent killing of three gonococcal mutants with glycan extensions beyond lactose-substituted HepI (lactose alone, LNnT, or GalNAc-LNnT) as 2C7-Ximab (unmodified Fc). The fourth mutant (Gal-lactose) resisted direct complement-dependent killing but was killed approximately 70% by 2C7-Ximab-E430G in the presence of polymorphonuclear leukocytes and complement. Only mutants with (sialylatable) LNnT from HepI colonized mice for >3 days, reiterating the importance of LNnT sialylation for infection. 2C7-Ximab-E430G significantly attenuated colonization caused by the virulent mutants.
Genomic Diversity of Common Sequence Types of Listeria monocytogenes Isolated from Ready-to-Eat Products of Animal Origin in South Africa

Listeria monocytogenes is a highly fatal foodborne causative agent that has been implicated in numerous outbreaks and related deaths of listeriosis in the world. In this study, six L. monocytogenes isolated from ready-to-eat (RTE) meat products were analysed using Whole Genome Sequencing (WGS) to identify virulence and resistance genes, prophage sequences, PCR-serogroups, and sequence types (STs). The WGS identified four different STs (ST1, ST121, ST204, and ST876) that belonged to serogroup 4b (lineage I) and 1/2a (lineage II). Core genome, and average nucleotide identity (ANI) phylogenetic analyses showed that the majority of strains from serogroup 4b (lineage I) clustered together. However, two isolates that belong to serogroup 1/2a (lineage II) grouped far from each other and the other strains. Examination of reference-guided scaffolds for the presence of prophages using the PHAge Search Tool Enhanced Release (PHASTER) software identified 24 diverse prophages, which were either intact or incomplete/questionable. The National Center for Biotechnology Information- Nucleotide Basic Local Alignment Search Tool (NCBI-BLASTn) revealed that Listeria monocytogenes strains in this study shared some known major virulence genes that are encoded in Listeria pathogenicity islands 1 and 3. In general, the resistance profiles for all the isolates were similar and encoded for multidrug, heavy metal, antibiotic, and sanitizer resistance genes. All the isolates in this study possessed genes that code for resistance to common food processing antiseptics such as Benzalkonium chloride.
Presence of B19V in Patients with Thyroid Gland Disorders

Background and Objectives: Viral infections are frequently cited as a major environmental factor implicated in thyroid gland diseases. This work aimed to estimate the presence of B19V infection in patients with thyroid gland disorders. Materials and Methods: Thyroid gland tissue and blood samples of 50 patients with autoimmune thyroid gland diseases (AITDs), 76 patients with non-autoimmune thyroid gland diseases (non-AITDs), and 35 deceased subjects whose histories did not show any autoimmune or thyroid diseases (control group) were enrolled in the study. Virus-specific IgM and IgG were detected using ELISA, and the presence and viral load of B19V in the tissue and blood were detected using PCRs. Results: B19V IgG antibodies were detected in 35/50 AITDs patients and in 51/76 non-AITDs patients, and B19V IgM antibodies were detected in 1/50 patients with AITDs and in none of the 76 patients with non-AITDs. The B19V NS sequence was found in the tissue DNA of 10/50 patients with AITDs, in 30/76 with non-AITDs, and in 1/35 control group individuals. The median B19V load in the tissue of patients with AITDs and non-AITDs was 423.00 copies/µg DNA (IQR: 22.50–756.8) and 43.00 copies/µg DNA (IQR: 11.50–826.5), respectively. The viral load in one of the 35 nPCR B19V-positive thyroid tissue samples from the deceased subjects was 13.82 copies/µg DNA. The viral load in the tissue of patients with AITDs was higher than in whole blood, which possibly indicates B19V persistency in thyrocytes (p = 0.0076). Conclusion: The fact that the genoprevalence of B19V NS was significantly higher in patients with non-AITDs compared to the control group and in the thyroid gland tissue of patients with AITDs, and that the non-AITDs viral load was higher than in tissue derived from the control group individuals, suggest the possibility that B19V infection could be involved in the development of thyroid gland diseases.
Reactive Oxygen Species‐Scavenging Scaffold with Rapamycin for Treatment of Intervertebral Disk Degeneration

The chronic inflammatory microenvironment is characterized by the elevated level of reactive oxygen species (ROS). Here, it is hypothesized that developing an ROS‐scavenging scaffold loaded with rapamycin (Rapa@Gel) may offer a new strategy for modulating the local inflammatory microenvironment to improve intervertebral disk tissue regeneration. The therapeutic scaffold consisting of ROS‐degradable hydrogel can be injected into the injured degeneration site of intervertebral disk (IVD) and can release therapeutics in a programmed manner. The ROS scavenged by scaffold reduces the inflammatory responses. It is found that when rats are treated with Rapa@Gel, this results in an increase in the percentage of M2‐like macrophages and a decrease in M1‐like macrophages in the inflammatory environment, respectively. Regeneration of IVD is achieved by Rapa@Gel local treatment, due to the increased M2 macrophages and reduced inflammation. This strategy may be extended to the treatment of many other inflammatory diseases.
Functionalized Upconversion Nanoparticles for Targeted Labelling of Bladder Cancer Cells

Bladder cancer is the ninth most common cancer worldwide. Due to a high risk of recurrence and progression of bladder cancer, every patient needs long-term surveillance, which includes regular cystoscopy, sometimes followed by a biopsy of suspicious lesions or resections of recurring tumours. This study addresses the development of novel biohybrid nanocomplexes representing upconversion nanoparticles (UCNP) coupled to antibodies for photoluminescent (PL) detection of bladder cancer cells. Carrying specific antibodies, these nanoconjugates selectively bind to urothelial carcinoma cells and make them visible by emitting visible PL upon excitation with deeply penetrating near-infrared light. UCNP were coated with a silica layer and linked to anti-Glypican-1 antibody MIL38 via silica-specific solid-binding peptide. Conjugates have been shown to specifically attach to urothelial carcinoma cells with high expression of Glypican-1. This result highlights the potential of produced conjugates and conjugation technology for further studies of their application in the tumour detection and fluorescence-guided resection.
Higher Sodium Intake Assessed by 24 Hour Urinary Sodium Excretion Is Associated with Non-Alcoholic Fatty Liver Disease: The PREVEND Cohort Study

A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by sodium excretion in two complete consecutive 24 h urine collections in 6132 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI) ≥60 and Hepatic Steatosis Index (HSI) >36 were used as proxies of suspected NAFLD. 1936 (31.6%) participants had an FLI ≥60, coinciding with the increased prevalence of type 2 diabetes (T2D), metabolic syndrome, hypertension and history of cardiovascular disease. Sodium intake was higher in participants with an FLI ≥60 (163.63 ± 61.81 mmol/24 h vs. 136.76 ± 50.90 mmol/24 h, p < 0.001), with increasing incidence in ascending quartile categories of sodium intake (p < 0.001). Multivariably, an FLI ≥60 was positively associated with a higher sodium intake when taking account for T2D, a positive cardiovascular history, hypertension, alcohol intake, smoking and medication use (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.44–1.64, p < 0.001). Additional adjustment for the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) diminished this association (OR 1.30, 95% CI 1.21–1.41, p < 0.001). HSI >36 showed similar results. Associations remained essentially unaltered after adjustment for body surface area or waist/hip ratio. In conclusion, suspected NAFLD is a feature of higher sodium intake. Insulin resistance-related processes may contribute to the association of NAFLD with sodium intake.
Crystal Structures of the 43 kDa ATPase Domain of Xanthomonas Oryzae pv. Oryzae Topoisomerase IV ParE Subunit and its Complex with Novobiocin

Topoisomerase IV, one of the best-established antibacterial targets, is an enzyme crucial for chromosome segregation and cell division by catalyzing changes in DNA topology through breaking and rejoining DNA. This enzyme functions as a heterotetramer consisting of two ParC and two ParE subunits. Aminocoumarin class inhibitors target the ParE subunit, while widely used quinolones target the ParC subunit. Here, we determined the crystal structure of the ParE 43 kDa ATPase domain from Xanthomonas oryzae pv. oryzae. Size exclusion chromatography showed that the ParE ATPase domain exists as a monomer in solution, while it dimerizes when ATP is added. Structural comparison with the structure of Escherichia coli ParE in complex with an ATP analogue showed large conformational change of the subdomains within the protein. We also determined the structure of the ParE ATPase domain in complex with novobiocin, a natural product aminocoumarin class inhibitor, revealing its binding mode and the structural change within the ATP-binding site induced by novobiocin binding. These results could provide a basis for the design of more potent topoisomerase IV inhibitors with improved antibacterial activity.
Poor Sleep Quality in Crohn's Disease Is Associated With Disease Activity and Risk for Hospitalization or Surgery.

BACKGROUND AND AIMS Poor sleep quality in Crohn's disease (CD) is associated with histologic activity and clinical relapse. We sought to characterize sleep dysfunction and determine the effect of poor sleep quality on risk for hospitalization and surgery. METHODS Clinical data were collected for CD subjects including the Pittsburgh Sleep Quality Index (PSQI) and Harvey-Bradshaw index (HBI). The PSQI score and a brief medical history were obtained for control subjects. The PSQI and HBI correlation was tested at an initial clinic visit and at follow-up. Crohn's disease subjects with and without poor sleep were compared for risk of hospitalization or surgery by Kaplan-Meier and Cox proportional hazards. RESULTS Ninety-two CD and 82 control subjects were included. Crohn's disease and control subjects shared similar baseline characteristics and PSQI (8.3 vs 7.8, P = 0.31), and 77% of the CD population had PSQI >5. Crohn's disease subjects with PSQI >5 more often had inflammatory phenotypes and reported increased benzodiazepine and psychiatric medication use. Crohn's disease subjects with PSQI >5 also reported more night awakenings due to pain and bathroom use. The PSQI correlated with HBI (r = 0.256, P = 0.014), and ΔPSQI on follow-up correlated with ΔHBI (r = 0.47, P = 0.002). Cox proportional hazards model for hospitalization or surgery showed that PSQI >8 was predictive of surgery or hospitalization (hazards ratio 5.37; 95% confidence interval, 1.39-27.54). CONCLUSION There is a high burden of poor sleep quality in CD, which is associated with risk for adverse outcomes. Sleep quality may identify CD patients at risk for complications and have prognostic value in CD.
MicroRNA-23a-3p improves traumatic brain injury through modulating the neurological apoptosis and inflammation response in mice

ABSTRACT Secondary brain damage plays an important role in Traumatic brain injury (TBI) and inhibition of this damage has benefit for TBI treatment. However, the pathogenesis of secondary brain damage remains largely unknown. Here, we tried to explore the influence of microRNAs (miRNAs) on neuron apoptosis and inflammatory response after TBI. Firstly, the miRNA expression profiles were analyzed in the cerebral cortex tissues from the TBI mice model (controlled cortical impact) using miRNA microarray. miR-23a-3p (miR-23a) attracted our attention as its suppressive effects on apoptosis and inflammation. The further results showed that miR-23a upregulation improved long-term neurological function, the neuron apoptosis, and inhibited neuroinflammation, whereas knockdown of miR-23a had an opposite result. Using etoposide-induced primary cortical neurons injury model, we found that miR-23a was decreased in this cell model and miR-23a overexpression-suppressed etoposide induced the activity of caspase 3 and the releases of inflammatory mediators in primary cortical neurons. Phosphatase and tensin homolog (PTEN), a well‑known regulator of the AKT/mTOR pathway, was found to be a direct target of miR‑23a in the primary cortical neurons. Most importantly, it was found that miR-23a overexpression reactivated the AKT/mTOR pathway in TBI mice model, as demonstrated by the upregulation of phosphorylated (p‑)AKT and p‑mTOR. Taken together, these data indicate that miR-23a may serve as a therapeutic target for the treatment of TBI.
Aberrant activation of hepatocyte growth factor/MET signaling promotes β-catenin–mediated prostatic tumorigenesis

Co-occurrence of aberrant hepatocyte growth factor (HGF)/MET proto-oncogene receptor tyrosine kinase (MET) and Wnt/β-catenin signaling pathways has been observed in advanced and metastatic prostate cancers. This co-occurrence positively correlates with prostate cancer progression and castration-resistant prostate cancer development. However, the biological consequences of these abnormalities in these disease processes remain largely unknown. Here, we investigated the aberrant activation of HGF/MET and Wnt/β-catenin cascades in prostate tumorigenesis by using a newly generated mouse model in which both murine Met transgene and stabilized β-catenin are conditionally co-expressed in prostatic epithelial cells. These compound mice displayed accelerated prostate tumor formation and invasion compared with their littermates that expressed only stabilized β-catenin. RNA-Seq and quantitative RT-PCR analyses revealed increased expression of genes associated with tumor cell proliferation, progression, and metastasis. Moreover, Wnt signaling pathways were robustly enriched in prostate tumor samples from the compound mice. ChIP-qPCR experiments revealed increased β-catenin recruitment within the regulatory regions of the Myc gene in tumor cells of the compound mice. Interestingly, the occupancy of MET on the Myc promoter also appeared in the compound mouse tumor samples, implicating a novel role of MET in β-catenin–mediated transcription. Results from implanting prostate graft tissues derived from the compound mice and controls into HGF-transgenic mice further uncovered that HGF induces prostatic oncogenic transformation and cell growth. These results indicate a role of HGF/MET in β-catenin–mediated prostate cancer cell growth and progression and implicate a molecular mechanism whereby nuclear MET promotes aberrant Wnt/β-catenin signaling–mediated prostate tumorigenesis.
Negative Control of Cell Migration by Rac1b in Highly Metastatic Pancreatic Cancer Cells Is Mediated by Sequential Induction of Nonactivated Smad3 and Biglycan

Expression of the small GTPase, Ras-related C3 botulinum toxin substrate 1B (RAC1B), a RAC1-related member of the Rho GTPase family, in tumor tissues of pancreatic ductal adenocarcinoma (PDAC) has been shown previously to correlate positively with patient survival, but the underlying mechanism(s) and the target genes involved have remained elusive. Screening of a panel of established PDAC-derived cell lines by immunoblotting indicated that both RAC1B and Mothers against decapentaplegic homolog 3 (SMAD3) were more abundantly expressed in poorly metastatic and well-differentiated lines as opposed to highly metastatic, poorly differentiated ones. Both siRNA-mediated RAC1B knockdown in the transforming growth factor (TGF)-β-sensitive PDAC-derived cell lines, Panc1 and PaCa3, or CRISPR/Cas-mediated knockout of exon 3b of RAC1 in Panc1 cells resulted in a dramatic decrease in the expression of SMAD3. Unexpectedly, the knockdown of SMAD3 reproduced the promigratory activity of a RAC1B knockdown in Panc1 and PaCa3, but not in TGF-β-resistant BxPC3 and Capan1 cells, while forced expression of SMAD3 alone was able to mimic the antimigratory effect of ectopic RAC1B overexpression in Panc1 cells. Moreover, overexpression of SMAD3 was able to rescue Panc1 cells from the RAC1B knockdown-induced increase in cell migration, while knockdown of SMAD3 prevented the RAC1B overexpression-induced decrease in cell migration. Using pharmacological and dominant-negative inhibition of SMAD3 C-terminal phosphorylation, we further show that the migration-inhibiting effect of SMAD3 is independent of its activation by TGF-β. Finally, we provide evidence that the antimigratory program of RAC1B-SMAD3 in Panc1 cells is executed through upregulation of the migration and TGF-β inhibitor, biglycan (BGN). Together, our data suggest that a RAC1B-SMAD3-BGN axis negatively controls cell migration and that SMAD3 can induce antimigratory genes, i.e., BGN independent of its role as a signal transducer for TGF-β. Therefore, targeting this novel pathway for activation is a potential therapeutic strategy in highly metastatic PDAC to interfere with invasion and metastasis.
Reliability of a multi-domain sedentary behaviour questionnaire and comparability to an overall sitting time estimate

ABSTRACT This study evaluated the test–retest reliability of a questionnaire assessing five domains of sedentary behaviour, and compared an overall indicator of sitting time with measures obtained by a multi-domain questionnaire, among adults living in Brazil. Data from two different studies carried out in Pelotas, Brazil, were used. Study A: evaluated 7-day reliability of a multi-domain sedentary behaviour questionnaire among 78 adults (≥18 years). Study B was a population-based study (n = 2,871 adults aged 20+ years) where a score of sedentary behaviour based on time spent sitting in five domains was compared with overall sitting time. Lin’s Concordance Correlation coefficients (CCC) and Bland–Altman plots were used to assess agreement between measures. The 7-day reliability of multi-domain questionnaire did not show marked differences in the median of minutes spent in each domain (Study A). For the total score, the Lin’s CCC was 0.87. When sitting time was measured by a single question, participants reported on average less sedentary time compared to the multiple-domain questionnaire (Study B). There was a slightly greater difference between measures among participants who reported higher sedentary time. Assessing sedentary behaviour in different domains would appear to be preferable to employing a general question on the total time spent sitting per day.
Full Separation or Full Integration? An Investigation of the Optimal Renewables Policy Employing Tradable Green Certificate Systems in Two Countries’ Electricity Markets

Tradable green certificate (TGC) systems are increasingly used to promote renewable energy generation and mitigate greenhouse gas emissions. In this paper, we investigate the performance of the optimal renewables policy under full separation and full integration scenarios for two countries with TGCs. Our analysis suggests that under full separation, one country’s optimal renewable quota, which maximizes its own welfare, is strategically substitutional for the other country’s in a Cournot Nash equilibrium of the monopolistic market, when cross-border pollution exists. A country tends to become the “leader” in the market by using an information advantage to gain higher welfare. Using geometric illustrations we demonstrate the possibility that a potentially fully integrated electricity market under a TGC system can improve welfare for each country, when compensation between the countries is possible. From a policy point of view, this is significant in support of the demand for a convergence of national renewable policy schemes, where countries cooperate on solving cross-border environmental problems.
Short-Term Temporal Metabolic Behavior in Halophilic Cyanobacterium Synechococcus sp. Strain PCC 7002 after Salt Shock

In response to salt stress, cyanobacteria increases the gene expression of Na+/H+ antiporter and K+ uptake system proteins and subsequently accumulate compatible solutes. However, alterations in the concentrations of metabolic intermediates functionally related to the early stage of the salt stress response have not been investigated. The halophilic cyanobacterium Synechococcus sp. PCC 7002 was subjected to salt shock with 0.5 and 1 M NaCl, then we performed metabolomics analysis by capillary electrophoresis/mass spectrometry (CE/MS) and gas chromatography/mass spectrometry (GC/MS) after cultivation for 1, 3, 10, and 24 h. Gene expression profiling using a microarray after 1 h of salt shock was also conducted. We observed suppression of the Calvin cycle and activation of glycolysis at both NaCl concentrations. However, there were several differences in the metabolic changes after salt shock following exposure to 0.5 M and 1 M NaCl: (i): the main compatible solute, glucosylglycerol, accumulated quickly at 0.5 M NaCl after 1 h but increased gradually for 10 h at 1 M NaCl; (ii) the oxidative pentose phosphate pathway and the tricarboxylic acid cycle were activated at 0.5 M NaCl; and (iii) the multi-functional compound spermidine greatly accumulated at 1 M NaCl. Our results show that Synechococcus sp. PCC 7002 acclimated to different levels of salt through a salt stress response involving the activation of different metabolic pathways.