is an important opportunistic pathogen that commonly causes nosocomial infections and contributes to substantial morbidity and mortality. We sought to investigate the antibiotic resistance profile, ...pathogenic potential and the clonal relationships between
(
= 25) isolated from patients and sources at a tertiary care hospital's intensive care units (ICUs) in the northern region of Brazil. Most of
isolates (
= 21, 84%) were classified as multidrug resistant (MDR) with high-level resistance to β-lactams, aminoglycosides, quinolones, tigecycline, and colistin. All the 25 isolates presented extended-spectrum beta-lactamase-producing (ESBL), including carbapenemase producers, and carried the
(100%),
(100%),
variants (
= 24, 96%),
group (
= 21, 84%) and
group (
= 18, 72%) genes. The K2 serotype was found in 4% (
= 1) of the isolates, and the K1 was not detected. The virulence-associated genes found among the 25 isolates were
D (
= 24, 96%),
H-1 (
= 22, 88%),
B (100%),
A (
= 10, 40%),
S (
= 15, 60%). The genes related with efflux pumps and outer membrane porins found were
(100%),
C (
= 24, 96%),
K (
= 22, 88%),
K35 (
= 15, 60%), and
K36 (
= 7, 28%). ERIC-PCR was employed to determine the clonal relationship between the different isolated strains. The obtained ERIC-PCR patterns revealed that the similarity between isolates was above 70%. To determine the sequence types (STs) a multilocus sequence typing (MLST) assay was used. The results indicated the presence of high-risk international clones among the isolates. In our study, the wide variety of MDR
harboring β-lactams and virulence genes strongly suggest a necessity for the implementation of effective strategies to prevent and control the spread of antibiotic resistant infections.
Paclitaxel is an antineoplastic agent widely used to treat several solid tumor types. The primary mechanism of action of paclitaxel is based on microtubule stabilization inducing cell-cycle arrest. ...Here, we use several tumor models to show that paclitaxel not only induces tumor cell-cycle arrest, but also promotes antitumor immunity.
, paclitaxel reprogrammed M2-polarized macrophages to the M1-like phenotype in a TLR4-dependent manner, similarly to LPS. Paclitaxel also modulated the tumor-associated macrophage (TAM) profile in mouse models of breast and melanoma tumors; gene expression analysis showed that paclitaxel altered the M2-like signature of TAMs toward an M1-like profile. In mice selectively lacking TLR4 on myeloid cells, for example, macrophages (LysM-Cre
/TLR4
), the antitumor effect of paclitaxel was attenuated. Gene expression analysis of tumor samples from patients with ovarian cancer before and after treatment with paclitaxel detected an enrichment of genes linked to the M1 macrophage activation profile (IFNγ-stimulated macrophages). These findings indicate that paclitaxel skews TAMs toward an immunocompetent profile via TLR4, which might contribute to the antitumor effect of paclitaxel and provide a rationale for new combination regimens comprising paclitaxel and immunotherapies as an anticancer treatment.
This study provides new evidence that the antitumor effect of paclitaxel occurs in part via reactivation of the immune response against cancer, guiding tumor-associated macrophages toward the M1-like antitumor phenotype.
http://cancerres.aacrjournals.org/content/canres/78/20/5891/F1.large.jpg
.
Luminescent metal–organic frameworks (LMOFs) are promising materials for lighting and sensing applications. Herein, exposure of the highly luminescent Zn2(bpdc)2(bpee) MOF (H2bpdc = ...4,4′-biphenyldicarboxylic acid and bpee = 1,2-bipyridylethene) to subppm amine contents turns on a new absorption band unambiguously ascribed to free bpee molecules concomitant with the gradual appearance of a new photoluminescence band at shorter wavelengths. These findings combined with Fourier-transform infrared spectra, powder X-ray diffraction and thermogravimetric analysis of exposed LMOF powders confirm that bpee ligands are exchanged by amines and released inside the LMOF, triggering absorption and luminescence features which can be exploited for highly sensitive amine recognition. This principle was demonstrated in mixed matrix membranes (MMMs) prepared by a simple solvent-free method consisting of mixing Zn2(bpdc)2(bpee) with dimethylvinyl-terminated dimethylsiloxane and dimethylhydrogen siloxane. This method enabled the production of free-standing, permeable, and highly transparent MMMs which showed enormous potential and sensitivity to the detection of amines in gas phase and aqueous medium.
COVID-19 is characterized by severe acute lung injury, which is associated with neutrophil infiltration and the release of neutrophil extracellular traps (NETs). COVID-19 treatment options are ...scarce. Previous work has shown an increase in NETs release in the lung and plasma of COVID-19 patients suggesting that drugs that prevent NETs formation or release could be potential therapeutic approaches for COVID-19 treatment.
Here, we report the efficacy of NET-degrading DNase I treatment in a murine model of COVID-19. SARS-CoV-2-infected K18-hACE2 mice were performed for clinical sickness scores and lung pathology. Moreover, the levels of NETs were assessed and lung injuries were by histopathology and TUNEL assay. Finally, the injury in the heart and kidney was assessed by histopathology and biochemical-specific markers.
DNase I decreased detectable levels of NETs, improved clinical disease, and reduced lung, heart, and kidney injuries in SARS-CoV-2-infected K18-hACE2 mice. Furthermore, our findings indicate a potentially deleterious role for NETs lung tissue in vivo and lung epithelial (A549) cells in vitro, which might explain part of the pathophysiology of severe COVID-19. This deleterious effect was diminished by the treatment with DNase I.
Together, our results support the role of NETs in COVID-19 immunopathology and highlight NETs disruption pharmacological approaches as a potential strategy to ameliorate COVID-19 clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Deficits in decoding rewarding (and aversive) signals are present in several neuropsychiatric conditions such as depression and addiction, emphasising the importance of studying the underlying neural ...circuits in detail. One of the key regions of the reward circuit is the nucleus accumbens (NAc). The classical view on the field postulates that NAc dopamine receptor D1-expressing medium spiny neurons (D1-MSNs) convey reward signals, while dopamine receptor D2-expressing MSNs (D2-MSNs) encode aversion. Here, we show that both MSN subpopulations can drive reward and aversion, depending on their neuronal stimulation pattern. Brief D1- or D2-MSN optogenetic stimulation elicited positive reinforcement and enhanced cocaine conditioning. Conversely, prolonged activation induced aversion, and in the case of D2-MSNs, decreased cocaine conditioning. Brief stimulation was associated with increased ventral tegmenta area (VTA) dopaminergic tone either directly (for D1-MSNs) or indirectly via ventral pallidum (VP) (for D1- and D2-MSNs). Importantly, prolonged stimulation of either MSN subpopulation induced remarkably distinct electrophysiological effects in these target regions. We further show that blocking κ-opioid receptors in the VTA (but not in VP) abolishes the behavioral effects induced by D1-MSN prolonged stimulation. In turn, blocking δ-opioid receptors in the VP (but not in VTA) blocks the behavioral effects elicited by D2-MSN prolonged stimulation. Our findings demonstrate that D1- and D2-MSNs can bidirectionally control reward and aversion, explaining the existence of controversial studies in the field, and highlights that the proposed striatal functional opposition needs to be reconsidered.
The lesser spot-nosed monkey (
Cercopithecus petaurista
) is a widely distributed West African guenon, which is generally considered less vulnerable to local extinctions than many sympatric primate ...species. Guinea-Bissau harbours the westernmost populations of the species, which is thought to be very rare or even extinct on the mainland, but to have putative populations on some islands of the Bijagós Archipelago. However, due to a lack of regional studies, baseline information on these insular populations is missing. We collected baseline data on the anthropogenic activities that possibly threaten the long-term conservation of this primate by using non-systematic ethnographic methodologies. The species was reported to be decreasing in number or rare by locals on two of the islands, and we identified two main conservation threats to it: generalised habitat loss/degradation, and hunting. While subsistence hunting has been recorded before in these areas, we report, to the best of our knowledge for the first time for these islands, the presence of a semi-organised commercial wild meat trade. The carcasses of western lesser spot-nosed monkeys were observed being stored and shipped from seaports to be sold at urban hubs (Bissau and Bubaque Island). The effect of commercial trade on the species could be severe, considering the small, naturally occurring, carrying capacities typical of insular ecosystems. The results of this study highlight the importance of understanding the leading social drivers of wild meat hunting of lesser spot-nosed monkeys on the Bijagós Archipelago, and the need to conduct baseline research on these insular populations, for which qualitative and quantitative methods could be combined.
Abstract
Objective
To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population.
Methods
In this retrospective cross-sectional study, clinicopathological ...features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo.
Results
Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs).
Conclusion
This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.
A multistage treatment system, at a scale close to the industrial, was designed for the treatment of a mature raw landfill leachate, including: a) an activated sludge biological oxidation (ASBO), ...under aerobic and anoxic conditions; b) a solar photo-Fenton process, enhancing the bio-treated leachate biodegradability, with and without sludge removal after acidification; and c) a final polishing step, with further ASBO.
The raw leachate was characterized by a high concentration of humic substances (HS) (1211 mg CHS/L), representing 39% of the dissolved organic carbon (DOC) content, and a high nitrogen content, mainly in the form of ammonium nitrogen (>3.8 g NH4+–N/L).
In the first biological oxidation step, a 95% removal of total nitrogen and a 39% mineralization in terms of DOC were achieved, remaining only the recalcitrant fraction, mainly attributed to HS (57% of DOC). Under aerobic conditions, the highest nitrification rate obtained was 8.2 mg NH4+–N/h/g of volatile suspended solids (VSS), and under anoxic conditions, the maximum denitrification rate obtained was 5.8 mg (NO2−–N + NO3−–N)/h/g VSS, with a C/N consumption ratio of 2.4 mg CH3OH/mg (NO2−–N + NO3−–N).
The precipitation of humic acids (37% of HS) after acidification of the bio-treated leachate corresponds to a 96% DOC abatement. The amount of UV energy and H2O2 consumption during the photo-Fenton reaction was 30% higher in the experiment without sludge removal and, consequently, the reaction velocity was 30% lower. The phototreatment process led to the depletion of HS >80%, of low-molecular-weight carboxylate anions >70% and other organic micropollutants, thus resulting in a total biodegradability increase of >70%.
The second biological oxidation allowed to obtain a final treated leachate in compliance with legal discharge limits regarding water bodies (with the exception of sulfate ions), considering the experiment without sludge.
Finally, the high efficiency of the overall treatment process was further reinforced by the total removal percentages attained for the identified organic trace contaminants (>90%).
Display omitted
•Multistage treatment system for stabilized raw leachate from sanitary landfill.•Integration of biological/chemical/biological oxidations processes.•Nitrogen removal using biological nitrification and denitrification reactions.•The photo-oxidation led to the depletion of HS and other organic micropollutants.•Organic trace contaminants identification and evolution profile follow-up.
Multicomponent Reactions (MCRs) with o‐Quinone Methides Martins, Maria Tereza M.; Dias, Flaviana Rodrigues F.; Moraes, Raphael Silva M. ...
Chemical record,
March 2022, 2022-Mar, 2022-03-00, 20220301, Letnik:
22, Številka:
3
Journal Article
Recenzirano
This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho‐quinone methide intermediates (o‐QM) generated in the reaction medium. Examples of ...applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron‐rich dienophiles in inverse‐electron demand hetero‐Diels‐Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.
This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho‐quinone methide intermediates (o‐QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described.
A series of pyridyl analogues of rosamines was prepared by employing two methodologies: (i) the conventional‐heating condensation of a pyridinecarboxaldehyde with 3‐(diethylamino)phenol in propionic ...acid, and (ii) the novel ohmic‐heating assisted condensation under “on water” conditions, followed by oxidation. The 4‐pyridyl substituted rosamine was further converted into the N‐methylpyridinium derivative through N‐alkylation using methyl iodide. The influence of the position and cationization of the nitrogen atom of the pyridyl ring in the physicochemical properties of fluorophores was investigated by 1H, 13C, 15N NMR spectral analysis, UV/Vis and fluorescence spectroscopy, single‐crystal X‐ray diffraction (4‐pyridyl and N‐methylpyridinium derivatives) and thermal‐behavior analysis. Curiously, for ethanolic solutions of 4‐pyridyl and N‐methylpyridinium derivatives an extinction of color and fluorescence over time was observed. This phenomenon was further studied and the data revealed that it is the result of nucleophilic addition of ethoxide ion to the central 9‐position of the xanthene. The kinetics of the process is slower for the 4‐pyridyl rosamine, which emphasizes the importance of the charge in the N‐methylpyridinium analogue in the reactivity of the molecule towards a nucleophile agent. This phenomenon is reversible, meaning that the compounds can be rapidly recovered by decreasing the pH, opening new avenues in the sensing applications of this class of rosamines.
Pyridyl and N‐methylpyridinium analogues of rosamines: The ohmic‐heating approach to synthesize triarylmethane derivatives, followed by oxidative cyclization, is presented. The influence of the position and cationization of the nitrogen atom in the pyridyl ring was evaluated by photophysical and thermal behavior analysis. In addition, the quenching behavior of the highly reactive N‐methylpyridinium rosamine in ethanol is reported for the first time.
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