L-mimosine is a compound found in Leucaena leucocephala, that is used as animal feed due to its high protein content, but it can also cause intoxication. Due to its low solubility in organic and ...aqueous solvents, its administration in laboratory animals is difficult, especially in delicate periods such as pregnancy. Thus, to circumvent such problems, this study proposes a stress-free form of oral administration with gelatin tablets with flavoring (meat broth) for 14 consecutive days of the gestational period (GD06 to GD20). For that, 17 pregnant Wistar rats divided into 3 groups were used: control (CO; n = 5) not treated; gelatin (GEL; n = 6), which received a gelatin tablet with flavoring; and gelatin with flavoring added 140 mg/kg of L-mimosine (GM; n = 6). All animals received feed and water ad libitum. The parameters analyzed were body weight gain, water and feed consumption, serum biochemistry, blood count and reproductive indices. Among these, only the real and total weight gains of dams showed statistically significant differences, with a decrease in the group GM. Thus, we could observe that flavored gelatin was an efficient and effective administration method to insoluble compounds and long-term administration to pregnant rats, with quick adaptation and without refusal by the animals. In addition, we could observe a direct effect of L-mimosine on the animals' weight gain; however, the dose administered was not sufficient to confer maternal and fetal toxicity.
•Oral alternative method of insoluble toxin included into flavored gelatin in rats.•L-mimosine extracted from L. leucochephala was administered to pregnant rats.•L-mimosine incorporated into gelatin was well accepted by the animals.•The methodology used to administer insoluble compounds was efficient.
Objectives
To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data.
Methods
After the first Candida auris‐colonised patient was ...diagnosed in a COVID‐19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis.
Results
Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30‐day attributable mortality of 33.3%.
Conclusions
Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.
Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF). The mechanism of the ...formation of the aggregates in the nucleus remains uncertain. The present study demonstrated that the DNA-binding domain of p53 (p53C) underwent phase separation (PS) on the pathway to aggregation under various conditions. p53C phase separated in the presence of the crowding agent polyethylene glycol (PEG). Similarly, mutant p53C (M237I and R249S) underwent PS; however, the process evolved to a solid-like phase transition faster than that in the case of wild-type p53C. The data obtained by microscopy of live cells indicated that transfection of mutant full-length p53 into the cells tended to result in PS and phase transition (PT) in the nuclear compartments, which are likely the cause of the GoF effects. Fluorescence recovery after photobleaching (FRAP) experiments revealed liquid characteristics of the condensates in the nucleus. Mutant p53 tended to undergo gel- and solid-like phase transitions in the nucleus and in nuclear bodies demonstrated by slow and incomplete recovery of fluorescence after photobleaching. Polyanions, such as heparin and RNA, were able to modulate PS and PT
in vitro
. Heparin apparently stabilized the condensates in a gel-like state, and RNA apparently induced a solid-like state of the protein even in the absence of PEG. Conditions that destabilize p53C into a molten globule conformation also produced liquid droplets in the absence of crowding. The disordered transactivation domain (TAD) modulated both phase separation and amyloid aggregation. In summary, our data provide mechanistic insight into the formation of p53 condensates and conditions that may result in the formation of aggregated structures, such as mutant amyloid oligomers, in cancer. The pathway of mutant p53 from liquid droplets to gel-like and solid-like (amyloid) species may be a suitable target for anticancer therapy.
Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF).
To provide species distribution and antifungal susceptibility profiles of 358 Trichosporon clinical isolates collected from 24 tertiary-care hospitals.
Species identification was performed by ...sequencing the IGS1 region of rDNA. Antifungal susceptibility testing for amphotericin B, fluconazole, voriconazole and posaconazole followed the Clinical and Laboratory Standards Institute reference method. Tentative epidemiologic cutoff values (97.5% ECVs) of antifungals for Trichosporon asahii were also calculated.
Isolates were cultured mostly from urine (155/358, 43.3%) and blood (82/358, 23%) samples. Trichosporon asahii was the most common species (273/358, 76.3%), followed by T. inkin (35/358, 9.7%). Isolation of non–T. asahii species increased substantially over the last 11 years 11/77 (14.2%) from 1997 to 2007 vs. 74/281, (26.3%) from 2008 to 2018, p0.03. Antifungal susceptibility testing showed high amphotericin B minimum inhibitory concentrations against Trichosporon isolates, with higher values for T. faecale. The ECV for amphotericin B and T. asahii was set at 4 μg/mL. Among the triazole derivatives, fluconazole was the least active drug. The ECVs for fluconazole and posaconazole against T. asahii were set at 8 and 0.5 μg/mL, respectively. Voriconazole showed the strongest in vitro activity against the Trichosporon isolates; its ECV for T. asahii was set at 0.25 μg/mL after 48 hours' incubation.
Trichosporon species diversity has increased over the years in human samples, and antifungal susceptibility profiles were species specific. Trichosporon asahii antifungal ECVs were proposed, which may be helpful to guide antifungal therapy.
Abstract Objective HIV-1 infection is accompanied by severe metabolic and immune dysfunction. The aim of this study was to evaluate the role of metabolic syndrome (MetS) and antiretroviral therapy ...(ART) utilization on the adiponectin levels and oxidative stress in patients infected with HIV-1. Methods We allocated 285 patients into four groups: group 1: patients without MetS who were not using ART; group 2: patients without MetS using ART; group 3: patients with MetS who were not using ART; and group 4: patients with MetS using ART. Biochemical, immunologic, and oxidative stress parameters were measured. Results Group 4 exhibited higher lipoperoxides when compared with group 1 ( P < 0.0001) and higher advanced oxidation protein products (AOPP) compared with group 2 or group 1 ( P < 0.0001). Group 3 also presented higher AOPP than group 2 ( P < 0.05). Group 4 showed lower adiponectin levels compared with groups 1 or 2 ( P < 0.0001). Similarly, group 3 presented lower adiponectin levels compared with group 2 ( P < 0.05) or group 1 ( P < 0.0001). Multivariate analysis showed that both an increase in AOPP and a decrease in total radical-trapping antioxidant parameter/uric acid were independently associated with MetS in HIV-1 patients. Regarding immunologic markers of HIV-1 disease progression and viral replication, group 4 exhibited significantly higher CD45+ , CD3+ , and CD4+ T cells count compared with group 2 ( P < 0.01). Conclusion HIV-1–infected patients with MetS exhibited hypoadiponectinemia and increased oxidative stress, and these findings were not influenced by ART use. The findings of the present study allow the suggestion that MetS and inflammation might be mainly responsible for the aforementioned features. More studies are needed to verify whether drugs or food, which yield increased adiponectinemia and decreased oxidative stress, could reduce cardiovascular risk in HIV-infected patients.
Central nervous system (CNS) infection by
Histoplasma capsulatum
is a rare disease in immunocompromised individuals in endemic areas. About one quarter of cases result from hematogenous ...dissemination. A 23-year-old upholsterer with chronic occipital headache had developed intracranial hypertension and dizziness, incoordination with ataxic gait, and acute confusion 5 months prior to admission. Laboratory examinations and chest roentgenogram were normal. Postcontrast T1-weighted MRI of the brain revealed a multiple ring-enhancing cerebellar, brain stem and parietal lobe lesions, and meningeal contrast enhancement. Cerebrospinal fluid culture was positive for
H. capsulatum
species complex, which was confirmed by phylogenetic analysis. Thirteen years after the diagnosis and treatment, there was no
H. capsulatum
recurrence; sequels related to complications due to the ventriculoperitoneal shunt. This case shows a primary neurological presentation of cerebral histoplasmosis, without meningitis or disseminated disease in nonimmune-compromised patient. The authors propose a categorization of the diagnosis of CNS histoplasmosis. Routine diagnostics of sibling species within the
H. capsulatum
complex proved to be difficult.
Soybean (
Glycine max
L.) is an important legume that greatly benefits from inoculation with nitrogen-fixing bacteria. In a previous study, five efficient nitrogen-fixing bacterial strains, isolated ...from nodules of soybean inoculated with soil from semi-arid region, Northeast Brazil, were identified as a new group within the genus
Bradyrhizobium
. The taxonomic status of these strains was evaluated in this study. The phylogenetic analysis of the 16S rRNA gene showed the high similarity of the five strains to
Bradyrhizobium brasilense
UFLA03-321
T
(100%),
B
.
pachyrhizi
PAC48
T
(100%),
B. ripae
WR4
T
(100%),
B
.
elkanii
USDA 76
T
(99.91%), and
B. macuxiense
BR 10303
T
(99.91%). However, multilocus sequence analysis of the housekeeping genes
atpD
,
dnaK
,
gyrB
,
recA,
and
rpoB
, average nucleotide identity, and digital DNA–DNA hybridization analyses supported the classification of the group as
B. brasilense.
Some phenotypic characteristics allowed differentiating the five strains and the type strain of
B. brasilense
from the two neighboring species (
B. pachyrhizi
PAC48
T
and
B. elkanii
USDA 76
T
). The
nodC
and
nifH
genes’ analyses showed that these strains belong to symbiovar sojae, together with
B. elkanii
(USDA 76
T
) and
B. ferriligni
(CCBAU 51502
T
). The present results support the classification of these five strains as
Bradyrhizobium brasilense
(symbiovar sojae).
ATM inhibitors, such as 7, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of ...7 result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of 64 (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo4,5-cquinolin-2-one core. 64 has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. 64 has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents.
The role of vitamin D in the pathophysiology of human immunodeficiency virus type 1 (HIV-1) infection is still unclear.
To evaluate the associations between vitamin D and immunological, virological, ...and oxidative stress biomarkers in individuals with human immunodeficiency virus type 1 (HIV-1) infection.
The serum levels of 25 hydroxyvitamin D 25(OH)D were determined in 314 HIV-1- infected individuals and 127 controls and the values ≥30 ng/mL defined a vitamin D sufficient (VDS) status, and <30 ng/mL defined the presence of hypovitaminosis D (HD). Oxidative stress was evaluated with plasma levels of lipid hydroperoxides, advanced oxidation protein products (AOPP), carbonyl protein, nitric oxide metabolites (NOx), total radical-trapping antioxidant parameter (TRAP), and sulfhydryl groups of proteins. Plasma HIV-1 viral load and CD4+/CD8+ T cells were quantified.
The 25(OH)D levels and vitamin D status did not differ between HIV-1-infected individuals and controls. Hydroperoxides and AOPP were higher (p<0.0001 and p=0.002, respectively), whereas TRAP, carbonyl protein, and NOx were lower in HIV-1-infected individuals than controls (p<0.0001). HIV-1-infected individuals with HD showed higher hydroperoxide levels than those with a VDS status (p=0.012) and controls (p=0.022), independent of ethnicity and antiretroviral therapy. A positive correlation between 25(OH)D ≥30 ng/mL and viral load was observed when expressed as the number of copies/mL (r=0.178, p=0.039), as well as log10 copies/mL (r=0.183, p=0.033).
These results suggest the bimodal influence of vitamin D in the modulation of immune response in HIV-1 infection, considering its differential susceptibility to modulation of the various immune targets and pathways.
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