The antiviral activity of alcoholic extracts of several species belonging to the Asteraceae, Labiatae, Plantaginaceae, Schizaceae, Umbelliferae, Usneaceae and Verbenaceae families has been studied. ...The tests were carried out in Vero celís-pseudorabies virus strain RC/79 (herpes suis virus) system. Eight plant extracts (Achyrocline satureioides, Ambrossia tenuifolia, Baccharis articulata, Eupatorium buniifolium, Mynthostachys verticillata, Plantago brasiliensis, Plantago mayor L and Verbascum thapsus) were able to inhibit at least 2 log, the viral infectivity.
Pitt-Hopkins Syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Children with PTHS typically present with gastrointestinal disorders and early severe ...chronic constipation is frequently found (75%). Here we describe the case of a PTHS male 10-year-old patient with chronic constipation in whom Osteopathic Manipulative Treatment (OMT) resulted in improved bowel functions, as assessed by the diary, the QPGS-Form A Section C questionnaire, and the Paediatric Bristol Stool Form Scale. The authors suggested that OMT may be a valid tool to improve the defecation frequency and reduce enema administration in PTHS patients.
The goal of this work is to improve automatic speech recognition (ASR) performance in very noisy and reverberant environments. The solution is based on extracting sub-band spectral variance ...normalization based features, which are capable of estimating the relative strengths of speech and noise components both in presence and absence of speech. The advanced ETSI-2 frontend, RASTA-PLP, MFCC alone and in combination with spectral subtraction are tested for comparison purposes. Speech recognition evaluations are performed on the noisy standard AURORA-2 and meeting recorder digit (MRD) subset of AURORA-5 databases, which represent additive noise and reverberant acoustic conditions. The results reveal that the proposed method is robust and reliable for both low SNR and reverberant scenarios, and provide considerable improvements with respect to the traditional feature extraction techniques.
Modeling Parkinson's disease (PD) using advanced experimental in vitro models is a powerful tool to study disease mechanisms and to elucidate unexplored aspects of this neurodegenerative disorder. ...Here, we demonstrate that three-dimensional (3D) differentiation of expandable midbrain floor plate neural progenitor cells (mfNPCs) leads to organoids that resemble key features of the human midbrain. These organoids are composed of midbrain dopaminergic neurons (mDANs), which produce and secrete dopamine. Midbrain-specific organoids derived from PD patients carrying the
G2019S mutation recapitulate disease-relevant phenotypes. Automated high-content image analysis shows a decrease in the number and complexity of mDANs in
G2019S compared to control organoids. The floor plate marker FOXA2, required for mDAN generation, increases in PD patient-derived midbrain organoids, suggesting a neurodevelopmental defect in mDANs expressing
G2019S. Thus, we provide a robust method to reproducibly generate 3D human midbrain organoids containing mDANs to investigate PD-relevant patho-mechanisms.
Monoclonal antibodies (mAbs) against the extracellular domain of the epidermal growth factor receptor (EGFR) have been introduced for the treatment of metastatic colorectal cancer (mCRC). We have ...reported recently that increased copy number of the EGFR can predict response to anti-EGFR mAbs and that patients might be selected for treatment based on EGFR copy number. Here, we show that mutations activating the RAS/RAF signaling pathway are also predictive and prognostic indicators in mCRC patients, being inversely correlated with response to anti-EGFR mAbs. In cellular models of CRCs, activation of the RAS signaling pathway by introduction of an activated K-RAS allele (Gly(12)Val) impairs the therapeutic effect of anti-EGFR mAbs. In cancer cells carrying constitutively active RAS, the pharmacologic inhibition of the mitogen-activated protein kinase (MAPK) signaling cascade improves anti-EGFR treatment based on mAbs. These results have implications for the identification of patients who are likely to respond to anti-EGFR treatment. They also provide the rationale for combination therapies, targeted simultaneously to the EGFR and RAS/RAF/MAPK signaling pathways in CRC patients.
EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS ...mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification.
Human immunodeficiency virus (HIV) infection affects the lesbian, gay, bisexual, transvestite, and transsexual (LGBT) population. We aimed to identify the indidual vulnerability profile of the LGBT ...population ling with H/acquired immunodeficiency syndrome (AIDS) and correlate it with the treatment situation.
This cross-sectional study included 510 LGBT people living with HIV (PLHIV)/AIDS who attended the Complex of Chronic Communicable Diseases of the municipality of São José do Rio Preto, São Paulo, Brazil, between 2008 and 2015.
There was a predominance of indiduals who were white (70.2%), male (98.4%), single (87.1%), aged 25-44 years (70.0%), educated up to high school (47.7%), economically acte (91.2%), under treatment (80.8%), having CD4 > 350 cells/mm3 (77.1%), and having undetectable viral load (53.3%). HIV transmission was mainly sexual (97.0%) and most people used drugs (76.5%). There was a weak correlation between the variables 'in treatment' and acte occupation (r = 0.148, p = 0.001), single marital status (r = 0.128, p = 0.004), white race/colour (r = 0.117, p = 0.008), high school education (r = 0.111, p = 0.012), sexual transmission (r = 0.222, p = 0.000), drug use (r = 0.087, p = 0.049), and CD4 > 350 cells/mm3 (r = 0.118, p = 0.008); and strong correlation between the variables 'in treatment' and undetectable viral load (r = -0.937, p = 0.113).
The characteristics of the indidual vulnerability of LGBT people involve, among other aspects, issues of gender and social exclusion, a situation that is part of the daily life of PLHIV/AIDS in many scenarios and territories. This can be alleviated with a network of social and health support and effecte and efficient, protecte, attitudinal, and behavioural public policies.
Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation
. The present study was designed to ...assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)
. RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
There is growing evidence about the ability of cyclic adenosine monophosphate (cAMP) signaling and nonselective phosphodiesterase (PDE) inhibitors on mitigate muscle atrophy. PDE4 accounts for the ...major cAMP hydrolyzing activity in skeletal muscles, therefore advances are necessary about the consequences of treatment with PDE4 inhibitors on protein breakdown in atrophied muscles. We postulated that rolipram (selective PDE4 inhibitor) may activate cAMP downstream effectors, inhibiting proteolytic systems in skeletal muscles of diabetic rats.
Streptozotocin-induced diabetic rats were treated with 2 mg/kg rolipram for 3 days. Changes in the levels of components belonging to the proteolytic machineries in soleus and extensor digitorum longus (EDL) muscles were investigated, as well as cAMP effectors.
Treatment of diabetic rats with rolipram decreased the levels of atrogin-1 and MuRF-1 in soleus and EDL, and reduced the activities of calpains and caspase-3; these findings partially explains the low ubiquitin conjugates levels and the decreased proteasome activity. The inhibition of muscle proteolysis may be occurring due to phosphorylation and inhibition of forkhead box O (FoxO) factors, probably as a consequence of the increased cAMP levels, followed by the activation of PKA and Akt effectors. Akt activation may be associated with the increased levels of exchange protein directly activated by cAMP (EPAC). As a result, rolipram treatment spared muscle mass in diabetic rats.
The antiproteolytic responses associated with PDE4 inhibition may be helpful to motivate future investigations about the repositioning of PDE4 inhibitors for the treatment of muscle wasting conditions.
•PDE4 inhibition decreased the atrogenes levels in muscles of diabetic rats.•PDE4 inhibition reduced the activities of proteasome, calpain and caspase-3.•PDE4 inhibition increased cAMP levels, activating PKA and EPAC in muscles.•PDE4 inhibition increased Akt activation and inhibited FoxO1/3 factors in muscles.•PDE4 inhibition decreased the loss of skeletal muscle mass in diabetic rats.
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