Monitoring the presence of commensal and pathogenic respiratory microorganisms is of critical global importance. However, community-based surveillance is difficult because nasopharyngeal swabs are ...uncomfortable and painful for a wide age range of participants. We designed a methodology for minimally invasive self-sampling at home and assessed its use for longitudinal monitoring of the oral, nasal and hand microbiota of adults and children within families. Healthy families with two adults and up to three children, living in and near Liverpool, United Kingdom, self-collected saliva, nasal lining fluid using synthetic absorptive matrices and hand swabs at home every two weeks for six months. Questionnaires were used to collect demographic and epidemiological data and assess feasibility and acceptability. Participants were invited to take part in an exit interview. Thirty-three families completed the study. Sampling using our approach was acceptable to 25/33 (76%) families, as sampling was fast (76%), easy (76%) and painless (60%). Saliva and hand sampling was acceptable to all participants of any age, whereas nasal sampling was accepted mostly by adults and children older than 5 years. Multi-niche self-sampling at home can be used by adults and children for longitudinal surveillance of respiratory microorganisms, providing key data for design of future studies.
Aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of aliphatic aldehydes, including acetaldehyde. About 45% of Han Chinese (East Asians), accounting for 8% of humans, carry a single point ...mutation in ALDH2*2 (E504K) that leads to accumulation of toxic reactive aldehydes.
Sequencing of a small Mexican cohort and a search in the ExAC genomic database for additional ALDH2 variants common in various ethnic groups was set to identify missense variants. These were evaluated in vitro, and in cultured cells expressing these new and common variants.
In a cohort of Hispanic donors, we identified 2 novel mutations in ALDH2. Using the ExAC genomic database, we found these identified variants and at least three other ALDH2 variants with a single point mutation among Latino, African, South Asian, and Finnish ethnic groups, at a frequency of >5/1000. Although located in different parts of the ALDH2 molecule, these common ALDH2 mutants exhibited a significant reduction in activity compared with the wild type enzyme in vitro and in 3T3 cells overexpressing each of the variants, and a greater ethanol-induced toxicity. As Alda-1, previously identified activator, did not activate some of the new mutant ALDH2 enzymes, we continued the screen and identified Alda-64, which is effective in correcting the loss of activity in most of these new and common ALDH2 variants.
Since ~80% of the world population consumes ethanol and since acetaldehyde accumulation contributes to a variety of diseases, the identification of additional inactivating variants of ALDH2 in different ethnic groups may help develop new ‘precision medicine’ for carriers of these inactive ALDH2.
Vulvovaginal candidiasis (VVC) affects approximately 30–50% of women at least once during their lifetime, causing uncomfortable symptoms and limitations in their daily quality of life. Antifungal ...therapy is not very effective, does not prevent recurrencies and usually causes side effects. Therefore, alternative therapies are urgently needed. The goal of this work was to investigate the potential benefits of using mannan oligosaccharides (MOS) extracts together with a
Lactobacillus
sp. pool, composed by the most significant species present in the vaginal environment, to prevent infections by
Candida albicans.
Microbial growth of isolated strains of the main vaginal lactobacilli and
Candida
strains was assessed in the presence of MOS, to screen their impact upon growth. A pool of the lactobacilli was then tested against
C. albicans
in competition and prophylaxis studies; bacterial and yeast cell numbers were quantified in specific time points, and the above-mentioned studies were assessed in simulated vaginal fluid (SVF). Finally, adhesion to vaginal epithelial cells (HeLa) was also evaluated, once again resorting to simultaneous exposure (competition) or prophylaxis assays, aiming to measure the effect of MOS presence in pathogen adherence. Results demonstrated that MOS extracts have potential to prevent vaginal candidiasis in synergy with vaginal lactobacilli, with improved results than those obtained when using lactobacilli alone.
Key points
Potential benefits of MOS extracts with vaginal lactobacilli to prevent C. albicans infections.
MOS impacts on growth of vaginal lactobacilli pool and C. albicans in SVF.
MOS extracts in synergy with L. crispatus inhibit C. albicans adhesion in HeLa cells.
Graphical Abstract
We present new data and the first rigorous analysis of latitudinal and thermal gradients of diversity, density and biomass of marine herbivorous fishes and review proposed explanatory mechanisms. ...Consistently, negative relationships between latitude, and positive relationships between sea surface temperature (SST), and relative richness and relative abundance of herbivorous fishes were found worldwide. Significant differences in the strength of gradients of richness and abundance with latitude and SST between tropical and extratropical zones were found consistently across ocean basins. Standardized sampling along the western Atlantic also showed negative relationships between latitude and total density and biomass. The trends, however, are driven by different components of the fish assemblages (i.e., scarids in the Caribbean and acanthurids in Brazil). Patterns of abundance along thermal gradients, generally associated with extensive latitudinal gradients, also were found at the local scale. Feeding rate of the ocean surgeonfish Acanthurus bahianus decreases with temperature more rapidly than the mean metabolic rate of teleost fishes. This relationship suggests a temperature-related physiological constraint. From the new standardized and comparative data presented and the review of the explanatory hypotheses, we conclude that temperature-related feeding and digestive processes are most likely involved in the distribution patterns of herbivorous fishes.PUBLICATION ABSTRACT
Herein, we report the synthesis and characterization, through elemental analysis, electronic spectroscopy, electrochemistry, potentiometric titration, electron paramagnetic resonance, and ...magnetochemistry, of two dinuclear copper(II) complexes, using the unsymmetrical ligands N′,N′,N-tris(2-pyridylmethyl)-N-(2-hydroxy-3,5-di-tert-butylbenzyl)-1,3-propanediamin-2-ol (L1) and N′,N′-bis(2-pyridylmethyl)-N,N-(2-hydroxybenzyl)(2-hydroxy-3,5-di-tert-butylbenzyl)-1,3-propanediamin-2-ol (L2). The structures of the complexes Cu2(L1)(μ-OAc)(ClO4)2·(CH3)2CHOH (1) and Cu2(L2)(μ-OAc)(ClO4)·H2O·(CH3)2CHOH (2) were determined by X-ray crystallography. The complex Cu2(L3)(μ-OAc)2+ 3; L3 = N-(2-hydroxybenzyl)-N′,N′,N-tris(2-pyridylmethyl)-1,3-propanediamin-2-ol was included in this study for comparison purposes only (Neves et al. Inorg. Chim. Acta 2005, 358, 1807–1822). Magnetic data show that the CuII centers in 1 and 2 are antiferromagnetically coupled and that the difference in the exchange coupling J found for these complexes (J = −4.3 cm–1 for 1 and J = −40.0 cm–1 for 2) is a function of the Cu–O–Cu bridging angle. In addition, 1 and 2 were tested as catalysts in the oxidation of the model substrate 3,5-di-tert-butylcatechol and can be considered as functional models for catechol oxidase. Because these complexes possess labile sites in their structures and in solution they have a potential nucleophile constituted by a terminal CuII-bound hydroxo group, their activity toward hydrolysis of the model substrate 2,4-bis(dinitrophenyl)phosphate and DNA was also investigated. Double electrophilic activation of the phosphodiester by monodentate coordination to the CuII center that contains the phenol group with tert-butyl substituents and hydrogen bonding of the protonated phenol with the phosphate O atom are proposed to increase the hydrolase activity (K ass. and k cat.) of 1 and 2 in comparison with that found for complex 3. In fact, complexes 1 and 2 show both oxidoreductase and hydrolase/nuclease activities and can thus be regarded as man-made models for studying catalytic promiscuity.
In the last decade, several access cavity designs involveing minimal removal of tooth tissue have been described for gaining entry to pulp chambers during root canal treatment. The premise behind ...this concept assumes that maximum preservation of as much of the pulp chamber roof as possible during access preparation would maintain the fracture resistance of teeth following root canal treatment. However, the smaller the access cavity, the more difficult it may be to visualize and debride the pulp chamber as well as locate, shape, clean and fill the canals. At the same time, a small access cavity may increase the risk of iatrogenic complications as a result of poor visibility, which may have an impact on treatment outcome. This study aimed to critically analyse the literature on minimal access cavity preparations, propose new nomenclature based on self‐explanatory abbreviations and highlight the areas in which more research is required. The search was conducted without restrictions using specifics terms and descriptors in four databases. A complementary screening of the references within the selected studies, as well as a manual search in the highest impact journals in endodontics, namely International Endodontic Journal and Journal of Endodontics, was also performed. The initial search retrieved 1831 publications. The titles and s of these papers were reviewed, and the full text of 94 studies was assessed. Finally, a total of 28 studies were identified as evaluating the influence of minimally invasive access cavity designs on the fracture resistance of teeth and on the different stages of root canal treatment (orifice location, canal shaping, canal cleaning, canal filling and retreatment). Overall, the studies had major methodological drawbacks and reported inadequate and/or inconclusive results on the utility of minimally invasive access preparations. Furthermore, they offered limited scientific evidence to support the use of minimally invasive access cavities to improve the outcome of root canal treatment and retreatment; they also provided little evidence that they preserved the fracture resistance of root filled teeth to a greater extent than traditional access cavity preparations. It was concluded that at present, there is a lack of supporting evidence for the introduction of minimally invasive access cavity preparation into routine clinical practice and/or training of undergraduate and postgraduate students.
Mitochondrial dysfunction is a common feature of aging, neurodegeneration, and metabolic diseases. Hence, mitotherapeutics may be valuable disease modifiers for a large number of conditions. In this ...study, we have set up a large-scale screening platform for mitochondrial-based modulators with promising therapeutic potential.
Using differentiated human neuroblastoma cells, we screened 1200 FDA-approved compounds and identified 61 molecules that significantly increased cellular ATP without any cytotoxic effect. Following dose response curve-dependent selection, we identified the flavonoid luteolin as a primary hit. Further validation in neuronal models indicated that luteolin increased mitochondrial respiration in primary neurons, despite not affecting mitochondrial mass, structure, or mitochondria-derived reactive oxygen species. However, we found that luteolin increased contacts between mitochondria and endoplasmic reticulum (ER), contributing to increased mitochondrial calcium (Ca
) and Ca
-dependent pyruvate dehydrogenase activity. This signaling pathway likely contributed to the observed effect of luteolin on enhanced mitochondrial complexes I and II activities. Importantly, we observed that increased mitochondrial functions were dependent on the activity of ER Ca
-releasing channels inositol 1,4,5-trisphosphate receptors (IP
Rs) both in neurons and in isolated synaptosomes. Additionally, luteolin treatment improved mitochondrial and locomotory activities in primary neurons and Caenorhabditis elegans expressing an expanded polyglutamine tract of the huntingtin protein.
We provide a new screening platform for drug discovery validated in vitro and ex vivo. In addition, we describe a novel mechanism through which luteolin modulates mitochondrial activity in neuronal models with potential therapeutic validity for treatment of a variety of human diseases.
High-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are ...mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100-300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.
Aims
To investigate the effects of the lectin from Punica granatum sarcotesta (PgTeL) on growth, viability, cell structure, biofilm formation and chitinase activity of Listeria monocytogenes. In ...addition, the effect of PgTeL on the adhesion and invasion of human cells (HeLa) was determined.
Methods and Results
PgTeL showed bacteriostatic and bactericidal effects on the strains L. monocytogenes N53‐1 and EGD‐e, causing morphometric alterations, cell aggregation, strong deformation and cell disruption. PgTeL inhibited biofilm formation by EGD‐e and N53‐1 and also interfered with the adhesion and invasion processes of EGD‐e and N53‐1 in HeLa cells. Finally, the chitinase activity of L. monocytogenes EGD‐e was reduced in the presence of PgTeL, which can be involved in the inhibition of adhesion process.
Conclusion
PgTeL is an antibacterial agent against L. monocytogenes, inhibiting growth and promoting cell death, as well as impairing biofilm formation and bacterial adhesion and invasion into human cells.
Significance and Impact of the Study
The results stimulate future investigations on the potential of PgTeL for protection of contamination in food products.
The lectin PgTeL is an antibacterial agent against Listeria monocytogenes, inhibiting growth and promoting cell death, as well as impairing biofilm formation and bacterial adhesion and invasion into human cells.
To develop and validate the content of a free web-based software (desktop and mobile applications) for the self-management of and customised foot-ankle exercises for people with diabetes and diabetic ...neuropathy.
The development of the programme was based on gamification principles and addressed three main areas: foot care recommendations; self-assessment of feet according to the main complications of diabetic neuropathy; and customised foot-ankle exercises to strengthen muscles, increase the range of motion and improve functionality. The content was validated using the Delphi methodology and a quantitative approach in two rounds with diabetes specialists (n = 9) and users with diabetes (n = 20). A 70% approval rate was considered sufficient in the second round for final validation purposes. The data analysis was conducted using descriptive statistics, absolute and relative frequencies and the content-validity index (CVI).
Among specialists, the CVI was 0.812 after the first round, and final approval was 100% after the second round. Among users, the CVI was 0.902 in the first round, and the final approval was 97%.
This free access web software was developed based on the high agreement rating between specialists and users and has the potential to prevent complications arising from diabetic polyneuropathy. It allows for self-monitoring and promotes personalised exercises, following a preventive model that can be applied in primary and secondary care services as a complementary treatment for chronic complications. However, further steps to validate the software in a larger population are recommended.
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