Function and regulation of the polysaccharide utilization locus, don, in the gut symbiont bacteroides fragilis

Bacteroides fragilis is the most common anaerobe isolated from clinical infections and in this report we demonstrate a novel feature of the species that is critical to their success as an opportunistic pathogen. Among the Bacteroides spp. in the gut, B. fragilis has a unique ability to efficiently harvest complex N-linked glycans from the glycoproteins common to serum and serous fluid. This activity is mediated by a Sus-like outer membrane protein complex designated as Don. Using the abundant serum glycoprotein transferrin as a model it was shown that B. fragilis alone can rapidly and efficiently deglycosylate this protein in vitro and that transferrin glycans can provide the sole source of carbon and energy for growth in defined media. We then showed that transferrin deglycosylation occurs in vivo when B. fragilis is propagated in the rat tissue cage model of extraintestinal growth and that this ability provides a competitive advantage in vivo over strains lacking the don locus. Thus, Don functionally is an extraintestinal growth factor that may contribute to B. fragilis opportunistic infection. The regulation of don expression is controlled by two independent pathways. The first one was shown to be a typical ECF sigma/anti-sigma factor switch, commonly found in Sus-like Polysaccharide Utilization Loci (PULs), which responds to the presence of specific substrate. In the ECF sigma factor deletion mutant, [delta]donA, expression of the don PUL was completely abolished in the presence of substrate glycans, while the cognate anti-sigma deletion strain, [delta]donB, expressed the don genes even in the absence of substrate glycans. The donA overexpressing strain highly expressed the don PUL regardless of the substrate glycan presence. The second regulatory pathway is involved with a cis-encoded antisense sRNA which is associated within the don locus, DonS. DonS was shown to negatively regulate don expression. In contrast, expression of the don genes was induced two- to six-fold in the donS silencing mutant and highly repressed in the donS overexpressing strain. Notably, this sRNA controlled regulatory pathway is not commonly found associated with B. fragilis PULs. Only 14 of more than 50 PULs in B. fragilis possess DonS-like sRNAs, but at the present time their roles in commensal colonization and opportunistic infections is not understood.Ph.D

Neurotoxicity and Underlying Mechanisms of Endogenous Neurotoxins

Endogenous and exogenous neurotoxins are important factors leading to neurodegenerative diseases. In the 1980s, the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) contributes to Parkinson’s disease (PD) symptoms led to new research investigations on neurotoxins. An abnormal metabolism of endogenous substances, such as condensation of bioamines with endogenous aldehydes, dopamine (DA) oxidation, and kynurenine pathway, can produce endogenous neurotoxins. Neurotoxins may damage the nervous system by inhibiting mitochondrial activity, increasing oxidative stress, increasing neuroinflammation, and up-regulating proteins related to cell death. This paper reviews the biological synthesis of various known endogenous neurotoxins and their toxic mechanisms

Risk management on joint product development with power asymmetry between supplier and manufacturer

Risk management is a critical issue in complex product development, especially when suppliers are integrated. The power asymmetry between the supplier and manufacturer may largely influence the development process and affect the occurrence and interaction of risks, and it should be systematically examined. In this paper, we establish a structural model to study the impact of power asymmetry on risk occurrence in the joint product development (JPD). Empirical data collected from engineers in airspace industries show that path coefficients of the risk structural model are significantly different between the manufacturer-advantaged situation and the supplier-advantaged situation. The results indicate that power asymmetry has significant effects on risk occurrence and interaction. Furthermore, we provide managerial insights into customized risk-reduction measures from the perspective of the discovered relationship difference

Function and regulation of the polysaccharide utilization locus, don, in the gut symbiont bacteroides fragilis

Bacteroides fragilis is the most common anaerobe isolated from clinical infections and in this report we demonstrate a novel feature of the species that is critical to their success as an opportunistic pathogen. Among the Bacteroides spp. in the gut, B. fragilis has a unique ability to efficiently harvest complex N-linked glycans from the glycoproteins common to serum and serous fluid. This activity is mediated by a Sus-like outer membrane protein complex designated as Don. Using the abundant serum glycoprotein transferrin as a model it was shown that B. fragilis alone can rapidly and efficiently deglycosylate this protein in vitro and that transferrin glycans can provide the sole source of carbon and energy for growth in defined media. We then showed that transferrin deglycosylation occurs in vivo when B. fragilis is propagated in the rat tissue cage model of extraintestinal growth and that this ability provides a competitive advantage in vivo over strains lacking the don locus. Thus, Don functionally is an extraintestinal growth factor that may contribute to B. fragilis opportunistic infection. The regulation of don expression is controlled by two independent pathways. The first one was shown to be a typical ECF sigma/anti-sigma factor switch, commonly found in Sus-like Polysaccharide Utilization Loci (PULs), which responds to the presence of specific substrate. In the ECF sigma factor deletion mutant, [delta]donA, expression of the don PUL was completely abolished in the presence of substrate glycans, while the cognate anti-sigma deletion strain, [delta]donB, expressed the don genes even in the absence of substrate glycans. The donA overexpressing strain highly expressed the don PUL regardless of the substrate glycan presence. The second regulatory pathway is involved with a cis-encoded antisense sRNA which is associated within the don locus, DonS. DonS was shown to negatively regulate don expression. In contrast, expression of the don genes was induced two- to six-fold in the donS silencing mutant and highly repressed in the donS overexpressing strain. Notably, this sRNA controlled regulatory pathway is not commonly found associated with B. fragilis PULs. Only 14 of more than 50 PULs in B. fragilis possess DonS-like sRNAs, but at the present time their roles in commensal colonization and opportunistic infections is not understood

Neurotoxicity and Underlying Mechanisms of Endogenous Neurotoxins

Endogenous and exogenous neurotoxins are important factors leading to neurodegenerative diseases. In the 1980s, the discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) contributes to Parkinson’s disease (PD) symptoms led to new research investigations on neurotoxins. An abnormal metabolism of endogenous substances, such as condensation of bioamines with endogenous aldehydes, dopamine (DA) oxidation, and kynurenine pathway, can produce endogenous neurotoxins. Neurotoxins may damage the nervous system by inhibiting mitochondrial activity, increasing oxidative stress, increasing neuroinflammation, and up-regulating proteins related to cell death. This paper reviews the biological synthesis of various known endogenous neurotoxins and their toxic mechanisms

Pregnancy‐related knowledge in women with epilepsy in childbearing age: A pilot questionnaire survey from China

Abstract Purpose We aim to understand the knowledge of and attitudes toward pregnancy issues among women with epilepsy (WWE) and their caregivers and analyze the answers from the questionnaire to expose topics that require educational activities; thus, WWE experiences pregnancy better. Methods WWE at their childbearing age and/or their caregivers who entered the Fourth Affiliated Hospital of Zhejiang University for treatment of their condition were invited to fill out a questionnaire between March 1 and November 31, 2022. Results A combined total of 205 WWE and 142 caregivers completed the questionnaires. Among the surveyed WWE, a majority (63.74%) reported experiencing at least one miscarriage or induced abortion. However, a significant proportion (84.62%) of these WWE were still able to successfully give birth to at least one child. Furthermore, the offspring of these WWE showed no significant differences compared to the offspring of women without epilepsy, as reported by 93.51% of the participants. The participants’ knowledge regarding the impact of epilepsy on pregnancy was found to be comparable, with average scores of 7.74 and 7.84, respectively. The participants exhibited a limited comprehension of antiseizure medications (ASMs)‐related knowledge, specifically pertaining to ASMs adjustment during pregnancy (17.56% vs. 16.90%) and offspring outcomes (30.24% vs. 26.06%). Statistical analysis revealed significant correlations between the overall score and education level (p < .001), as well as epilepsy duration (p = .008). Regarding the source of knowledge, participants acknowledged primarily relying on neurologists, who remained their preferred choice for consultation. Conclusion In our study, the understanding of pregnancy‐related knowledge did not differ from WWE and their caregivers, both are far from satisfactory in certain areas. It is urgent for WWE and their caregivers to improve their pregnancy‐related knowledge of epilepsy. As their primary access is from knowledgeable health care professionals like neurologists, well‐trained neurologists in epilepsy management during pregnancy are in need

Cationic Palladium(II) Complexes of Phosphine–Sulfonamide Ligands: Synthesis, Characterization, and Catalytic Ethylene Oligomerization

A series of cationic palladium­(II) complexes bearing phosphine–sulfonamide ligands, [(P,O)­PdMe­(lutidine)]­[SbF₆], were synthesized and used for catalytic ethylene oligomerization. The molecular structure of the complex {[<i>N</i>,<i>N</i>-dicyclohexyl-2-(diphenylphosphanyl)­benzenesulfonamide]­PdMe­(lutidine)}­[SbF₆] shows that the phosphorus atom and the oxygen atom coordinate to the palladium center. The ethylene oligomerization behavior is greatly influenced by the phosphino substituents, while the substituents on sulfonamide show only minimal effects. Complexes containing the diphenylphosphanyl group are highly selective for ethylene dimerization, affording 1-butene exclusively with moderate activity. The bulkier bis­(2-methoxyphenyl)­phosphanyl group leads to higher activity and gives α-olefins containing mainly 1-butene and 1-hexene, with a 1-hexene content of up to 35%. The palladium complexes bearing alkyl phosphino substituents give 1-butene and 1-hexene as the major products; a small amount of 2-butene (<5%) was observed, suggesting the occurrence of chain walking. The addition of B­(C₆F₅)₃ greatly enhances the catalytic activity. Experimental results suggest that the increase in activity is likely due to the abstraction of lutidine, not from the coordination of B­(C₆F₅)₃ to the sulfonamide oxygen atom

Evaluation of Heterocyclic Carboxamides as Potential Efflux Pump Inhibitors in Pseudomonas aeruginosa

The ability to rescue the activity of antimicrobials that are no longer effective against bacterial pathogens such as Pseudomonas aeruginosa is an attractive strategy to combat antimicrobial drug resistance. Herein, novel efflux pump inhibitors (EPIs) demonstrating strong potentiation in combination with levofloxacin against wild-type P. aeruginosa ATCC 27853 are presented. A structure activity relationship of aryl substituted heterocyclic carboxamides containing a pentane diamine side chain is described. Out of several classes of fused heterocyclic carboxamides, aryl indole carboxamide compound 6j (TXA01182) at 6.25 &micro;g/mL showed 8-fold potentiation of levofloxacin. TXA01182 was found to have equally synergistic activities with other antimicrobial classes (monobactam, fluoroquinolones, sulfonamide and tetracyclines) against P. aeruginosa. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA01182. TXA01182 was determined to lower the frequency of resistance (FoR) of the partner antimicrobials and enhance the killing kinetics of levofloxacin. Furthermore, TXA01182 demonstrated a synergistic effect with levofloxacin against several multidrug resistant P. aeruginosa clinical isolates

Evaluation of a Conformationally Constrained Indole Carboxamide as a Potential Efflux Pump Inhibitor in Pseudomonas&nbsp;aeruginosa

Efflux pumps in Gram-negative bacteria such as Pseudomonas aeruginosa provide intrinsic antimicrobial resistance by facilitating the extrusion of a wide range of antimicrobials. Approaches for combating efflux-mediated multidrug resistance involve, in part, developing indirect antimicrobial agents capable of inhibiting efflux, thus rescuing the activity of antimicrobials previously rendered inactive by efflux. Herein, TXA09155 is presented as a novel efflux pump inhibitor (EPI) formed by conformationally constraining our previously reported EPI TXA01182. TXA09155 demonstrates strong potentiation in combination with multiple antibiotics with efflux liabilities against wild-type and multidrug-resistant (MDR) P.&nbsp;aeruginosa. At 6.25 &micro;g/mL, TXA09155, showed &ge;8-fold potentiation of levofloxacin, moxifloxacin, doxycycline, minocycline, cefpirome, chloramphenicol, and cotrimoxazole. Several biophysical and genetic studies rule out membrane disruption and support efflux inhibition as the mechanism of action (MOA) of TXA09155. TXA09155 was determined to lower the frequency of resistance (FoR) to levofloxacin and enhance the killing kinetics of moxifloxacin. Most importantly, TXA09155 outperformed the levofloxacin-potentiation activity of EPIs TXA01182 and MC-04,124 against a CDC/FDA panel of MDR clinical isolates of P. aeruginosa. TXA09155 possesses favorable physiochemical and ADME properties that warrant its optimization and further development