Structural rearrangements as a recurrent pathogenic mechanism for SETBP1 haploinsufficiency.

Chromosomal structural rearrangements consist of anomalies in genomic architecture that may or may not be associated with genetic material gain and loss. Evaluating the precise breakpoint is crucial from a diagnostic point of view, highlighting possible gene disruption and addressing to appropriate genotype-phenotype association. Structural rearrangements can either occur randomly within the genome or present with a recurrence, mainly due to peculiar genomic features of the surrounding regions. We report about three non-related individuals, harboring chromosomal structural rearrangements interrupting SETBP1, leading to gene haploinsufficiency. Two out of them resulted negative to Chromosomal Microarray Analysis (CMA), being the rearrangement balanced at a microarray resolution. The third one, presenting with a complex three-chromosome rearrangement, had been previously diagnosed with SETBP1 haploinsufficiency due to a partial gene deletion at one of the chromosomal breakpoints. We thoroughly characterized the rearrangements by means of Optical Genome Mapping (OGM) and Whole Genome Sequencing (WGS), providing details about the involved sequences and the underlying mechanisms. We propose structural variants as a recurrent event in SETBP1 haploinsufficiency, which may be overlooked by laboratory routine genomic analyses (CMA and Whole Exome Sequencing) or only partially determined when associated with genomic losses at breakpoints. We finally introduce a possible role of SETBP1 in a Noonan-like phenotype.

Bloodstream infections in haematological cancer patients colonized by multidrug-resistant bacteria.

Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram-negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram-negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization.

Identification of compounds from Palicourea rigida leaves with topical anti-inflammatory potential using experimental models.

Palicourea rigida Kunth is traditionally used for the treatment of skin diseases, kidney pains and ovarian inflammation. Based on these traditional uses, this study evaluated the topical anti-inflammatory activity of the ethanol extract from P. rigida leaves (EEPR) and identified bioactive compounds. Ear edema was induced in Swiss mice by the topical application of Croton oil, arachidonic acid, phenol and capsaicin. Histopathological analysis and myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities were determined. EEPR was characterized by UHPLC-UV-MS HPLC and the isolated compound was identified through 1H and 13C nuclear magnetic resonance and mass fragmentation. Interaction profiles between quercetin 3-O-ß-D-glucoside and cyclooxygenase-1 and -2 were established by molecular docking. EEPR significantly inhibited ear edema induced by Croton oil (p < 0.001), arachidonic acid (p < 0.01), phenol (p < 0.001) and capsaicin (p < 0.01 or p < 0.001). Histopathological analysis showed a reduction of edema, inflammatory cell infiltration and vasodilation. Additionally, the myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities were decreased (p < 0.001). From spectroscopic data, quercetin 3-O-ß-D-glucoside was the identified compound. This compound can to interact with cyclooxygenase-1 and -2 through van der Waals interactions and dipole-dipole and hydrogen bonding's, demonstrating inhibition of these enzymes. The results indicate that EEPR is a source of active compounds with topical anti-inflammatory activity, justifying the traditional use of P. rigida and showing that this species has a therapeutic potential to treat skin inflammatory processes.

Bioactivities of the ethanol extract from Ageratum fastigiatum branches: antioxidant, antinociceptive and anti-inflammatory.

The present study was designed to investigate the antioxidant, antinociceptive and anti-inflammatory activities of the ethanol extract from Ageratum fastigiatum branches. Phytochemical screening and total phenol and flavonoid contents were determined. The antioxidant activity was assessed by 2,2-diphenyl-1-pycrilhydrazin (DPPH) and iron reducing power methods. The antinociceptive effect was evaluated using the acetic acid-induced writhing, formalin, hot plate and tail immersion assays; while the carrageenan-induced paw edema and pleurisy tests were performed to examine the anti-inflammatory activity against acute inflammation. The extract revealed the presence of flavonoids, tannins, coumarins, terpenes, sterols and saponins. Expressive levels of total phenols and flavonoids and a promising antioxidant effect were quantified. At the doses of 50, 100 and 200 mg/kg, the extract inhibited the writhing, reduced both phases of paw licking time and increased the reaction time on the hot plate. In the tail immersion test, the extract (50, 100 and 200 mg/kg) caused a significant inhibition of pain. In these doses, the paw edema, exudate volume and leucocyte mobilization were significantly reduced. These results suggest that A. fastigiatum can be an active source of substances with antioxidant, antinociceptive and anti-inflammatory activities, adding scientific support to the appropriate use in the Brazilian folk medicine.

Evidence of Bioactive Compounds from Vernonia polyanthes Leaves with Topical Anti-Inflammatory Potential.

Vernonia polyanthes Less. (Asteraceae), popularly known as "assa-peixe", is a plant species used in Brazilian traditional medicine for the treatment of cutaneous damage, cicatrization, inflammation, and rheumatism. Based on these ethnopharmacological findings, the current study evaluated the topical anti-inflammatory effects of the hexane (HEVP) and ethyl acetate (EAEVP) extracts from V. polyanthes leaves in experimental models of skin inflammation. Chemical characterization was carried out by HPLC-UV/DAD analysis. Anti-inflammatory activity was evaluated using Croton oil-, arachidonic acid (AA)-, phenol-, ethyl phenylpropiolate (EPP)-, and capsaicin-induced ear edema models in mice. Histopathological evaluation and measurements of myeloperoxidase (MPO) and N-acetyl-ß-d-glucosaminidase (NAG) enzymes were also performed. Rutin, luteolin, and apigenin were identified in EAEVP. Topically applied HEVP and EAEVP significantly (p < 0.05, p < 0.01 or p < 0.001) reduced edema induced by five different irritants at the doses tested (0.1, 0.5 and 1.0 mg/ear). Histopathological analysis revealed a reduction of edema, inflammatory cell infiltration, and vasodilation. In addition, the enzymes activity (MPO and NAG) in the ear tissues was reduced by the topical treatment of HEVP and EAEVP (p < 0.05, p < 0.01 or p < 0.001). The results suggest that V. polyanthes leaves are effective against cutaneous damage, which support its traditional use and open up new possibilities for the treatment of skin disorders.

Protective effects of Baccharis dracunculifolia leaves extract against carbon tetrachloride- and acetaminophen-induced hepatotoxicity in experimental animals.

In this work we investigated the in vivo protective effects of Baccharis dracunculifolia leaves extract (BdE) against carbon tetrachloride (CCl4)- and acetaminophen (APAP)-induced hepatotoxicity. Total phenolic content, total flavonoid content, antioxidant DPPH radical scavenging activity, and HPLC analysis were performed. Our results showed that pretreatment with BdE significantly reduced the damage caused by CCl4 and APAP on the serum markers of hepatic injury, AST, ALT, and ALP. Results were confirmed by histopathological analysis. Phytochemical analysis, performed by HPLC, showed that BdE was rich in p-coumaric acid derivatives, caffeoylquinic acids and flavonoids. BdE also showed DPPH antioxidant activity (EC50 of 15.75±0.43 µg/mL), and high total phenolic (142.90±0.77 mg GAE/g) and flavonoid (51.47±0.60 mg RE/g) contents. This study indicated that B. dracunculifolia leaves extract has relevant in vivo hepatoprotective properties.

Magnetic hysteresis mechanism in Lu0.9Sr0.1Cr0.5Fe0.5O3studied by Monte Carlo simulations.

In this work we report magnetic properties of the orthorhombic perovskite Lu0.9Sr0.1Cr0.5Fe0.5O3synthesized by a wet chemical method. As in LuCr0.5Fe0.5O3the compound with Sr shows the magnetization reversal phenomenon, but the magnetic order and the compensation temperature occur at higher temperatures. Interestingly, in M vs H curves a hysteresis loop is observed when Cr4+and Cr3+ions coexist as a consequence of the aliovalent substitution of Lu3+by Sr2+in the B sites of the perovskite. To explain this behavior, we performed numerical simulations with a magnetic model for Lu1-xSrxCr0.5Fe0.5O3perovskites withx= 0 andx= 0.1. We found that the ferromagnetic coupling of Fe3+and Cr4+through superexchange interactions (according the empiric Goodenough-Kanamori-Anderson rules) increases the magnetization at high fields and that the presence of ferromagnetic clusters explains the hysteretic behavior found in simulations.

Chemical composition and biological activities of essential oils of Eremanthus erythropappus (DC) McLeisch (Asteraceae).

The chemical composition of the essential oils obtained by hydrodistillation of different parts of Eremanthus erythropappus, including leaves, branches and inflorescences, was investigated by Gas Chromatography and Gas Chromatography/Mass Spectrometry. The antimicrobial activity of the oils was assessed by the disc diffusion and microdilution methods, while the antioxidant activity was evaluated by DPPH and reducing power tests. The main compounds found in the essential oils derived from the inflorescences and leaves were ß-caryophyllene, germacrene-D, α-copaene and ß-pinene. α-Bisabolol was the major component in the branches. The oils were active against Staphylococcus aureus, Streptococcus pyogenes and fungi, but not Escherichia coli and Pseudomonas aeruginosa. The MIC values ranged from 0.01 to 0.50 mg/mL. Using the DPPH test, the IC50 values ranged from 38.77 ± 0.76 to 102.24 ± 1.96 µg/mL, while the reducing power test produced IC50 values between 109.85 ± 1.68 and 169.53 ± 0.64 µg/mL. The results revealed that the E. erythropappus oils are new promising potential sources of antimicrobial and antioxidant compounds with good future practical applications for human health.

Magnetization reversal study of Ni4-xZnxNb2O9compounds using Monte Carlo simulations.

The magnetization reversal (MR) of the layered Ni4-xZnxNb2O9ferrimagnetic compounds, withx=0,0.25,0.50and 0.75, is studied in this work using Monte Carlo (MC) simulations and mean field (MF) calculations. First, we analyze the parent compound to set the parameters of our simulations; testing together MC simulations, MF calculations, and MR experiments reported by Bollettaet al(2022J. Appl. Phys.132153901). Then using two different approaches we fit the MR curves of the series of compounds finding a quite good agreement between MC simulations and the experiments. According to these results, Zn substitutions change the relative contribution to the magnetization of the different layers. Here we present two possible hypotheses to explain this effect; one involving a heterogeneous distribution of Zn2+among the layers, and the other related to distortions of the NiO6octahedra.

Chemical composition and biological activities of the essential oils from Duguetia lanceolata St. Hil. barks.

Essential oils of Duguetia lanceolata barks, obtained at 2 (T2) and 4 h (T4), were identified by gas chromatography and gas chromatography/mass spectrometry. ß-elemene (12.7 and 14.9%), caryophyllene oxide (12.4 and 10.7%) and ß-selinene (8.4 and 10.4%) were the most abundant components in T2 and T4, respectively. The essential oils inhibited the growth of Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Candida albicans. The essential oils were cytotoxic against brine shrimp. The extraction time influenced the chemical composition and biological activities of essential oils obtained from the barks of D. lanceolata.

Solidagenone from Solidago chilensis Meyen inhibits skin inflammation in experimental models.

Solidagenone (SOL) is a labdane-type diterpenoid found in Solidago chilensis, a plant traditionally used to treat skin diseases, kidney pain and ovarian inflammation. In this study, the topical anti-inflammatory activity of SOL was evaluated using in vivo and in silico assays. Croton oil-, arachidonic acid (AA)- and phenol-induced ear oedema mouse models were applied in the in vivo studies. Myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAG) activities and tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and nitric oxide (NO) levels were determined, as well as histopathological analyses were conducted. Interaction profiles between SOL and cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), glucocorticoid receptor, estradiol-17-ß-dehydrogenase and prostaglandin-E(2)-9-reductase were established using molecular docking. SOL significantly inhibited croton oil-, AA- and phenol-induced ear oedema (P < .001) at doses of 0.1, 0.5 and 1.0 mg/ear. The MPO and NAG activities and TNF-α, IL-6 and NO levels were decreased (P < .001). The histopathological data revealed that inflammatory parameters (oedema thickness, leucocyte infiltration and vasodilatation) were reduced by treatment with SOL at doses of 0.1, 0.5 and 1.0 mg/ear. The docking study showed that SOL interacts with COX-1 and prostaglandin-E(2)-9-reductase through hydrogen bonding, inhibiting these enzymes. These results indicate that SOL may be a promising compound for the treatment of cutaneous inflammatory disorders and has potential as a topical anti-inflammatory agent.

In vivo manipulation of Vgamma9Vdelta2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients.

The potent anti-tumour activities of gammadelta T cells have prompted the development of protocols in which gammadelta-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vgamma9Vdelta2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vgamma9Vdelta2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vgamma9Vdelta2 T cell numbers emerged, as seven patients who failed to sustain Vgamma9Vdelta2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vgamma9Vdelta2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vgamma9Vdelta2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatment-refractory patients with advanced breast cancer.

Clinical predictors of Dimethyl Fumarate response in multiple sclerosis: a real life multicentre study.

BACKGROUND: Dimethyl-fumarate (DMF) was effective and safe in relapsing-remitting multiple sclerosis (MS) in randomized clinical trials. We aimed to evaluate the efficacy and safety of DMF and factors related to drug response in real-life setting. METHODS: We analysed prospectively collected demographic and clinical data for patients treated with DMF in six multiple sclerosis (MS) centers from 2015 to 2017 in Campania region, Italy. We performed univariate and multivariate analyses to assess relationships between baseline parameters and DMF efficacy outcomes, Annualized Relapse Rate (ARR), Expanded Disability Status Scale (EDSS) progression and No Evidence of Disease Activity (NEDA-3) status. RESULTS: we analyzed data of 456 patients (67% female subjects, mean age 40 ± 12 years, mean disease duration 9 ± 9 years, mean treatment duration 18 ± 11 months, median EDSS 2.5, 0-8). Proportion of Naïve versus pretreated with other DMTs patients was 149/307 (32.7%), with 122 patients switching to DMF for disease activity (26.7%) and 185 for safety and tolerability issues (40.6%). During treatment with DMF, the annualized relapse rate was reduced by 75% respect to the pre-treatment ARR [incidence-rate-ratio (IRR) = 0.25, p < 0.001, CI 0.18-0.33]. Factors influencing ARR rate while on DMF were relapsing remitting (RR) MS course (IRR = 2.0, p = <0.001, CI 1.51-2.73) and previous DMTs status: de-escalating from second-line therapies was associated to higher risk of relapsing (IRR = 1.8, p < 0.001, CI 1.39-2.31). At multivariable Cox proportional hazard model, only age of onset was related with rate or relapses, with younger age being protective (HR 0.96, p = 0,02). EDSS remained stable in 88% of patients. Disease duration was associated with higher rate of NEDA-3 failure, that was instead maintained in 65% of patients at 24 months. 109 patients (22%) discontinued therapy after a mean of 1.1 ±+ 0.7 years. Reasons for DMF discontinuation over time were lack of efficacy (50%), safety issues (30%), tolerability (7%), poor compliance (7%), and pregnancy (4%). Higher pre-treatment EDSS was associated with DMF discontinuation (p = 0.009). Only 33 patients dropped out due to safety reasons (7%), the most frequent safety issues driving to drop out being lymphopenia, liver/pancreatic enzymes increase, gatrointestinal severe tolerability issues. We recorded 95 cases (24%) of lymphopenia: 60 grade I (13%), 31 grade II (7%) and 4 grade III (1%). CONCLUSIONS: We confirm that DMF shows a good efficacy in both naïve patients and patients switching from other first-line DMTs, especially in patients with early onset of disease. Higher baseline EDSS was a risk factor for discontinuing DMF therapy, while shorter disease duration was protective for both EDSS progression and NEDA-3 status maintenance.

Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation.

Gene regulation is a complex process. Numerous factors appear to be required for the accurate temporal and spatial regulation of each gene. Often these factors are assembled into multiprotein complexes, contributing to specific gene regulation events. Understanding how all these factors are organized in the chromosome and how their function is regulated in vivo is a challenging task. One of the most useful techniques for studying this level of gene regulation is the in vivo fixation by formaldehyde crosslinking of proteins to proteins and proteins to DNA, followed by immunoprecipitation of the fixed material.

Universal and nonuniversal neural dynamics on small world connectomes: A finite-size scaling analysis.

Evidence of critical dynamics has been found recently in both experiments and models of large-scale brain dynamics. The understanding of the nature and features of such a critical regime is hampered by the relatively small size of the available connectome, which prevents, among other things, the determination of its associated universality class. To circumvent that, here we study a neural model defined on a class of small-world networks that share some topological features with the human connectome. We find that varying the topological parameters can give rise to a scale-invariant behavior either belonging to the mean-field percolation universality class or having nonuniversal critical exponents. In addition, we find certain regions of the topological parameter space where the system presents a discontinuous, i.e., noncritical, dynamical phase transition into a percolated state. Overall, these results shed light on the interplay of dynamical and topological roots of the complex brain dynamics.