Introducción. El fluconazol es el antifúngico más utilizado para la prevención y el tratamiento de infecciones causadas por el género Cryptococcus, agente etiológico de la criptococosis. La ...resistencia al fluconazol en los aislamientos de Cryptoccocus neoformans puede hacer fracasar el tratamiento y generar recaídas de la infección.Objetivo. Evaluar los perfiles de expresión de los genes AFR1, MDR1 y ERG11 en aislamientos clínicos de C. neoformans var. grubii, durante la respuesta in vitro a la inducción con fluconazol.Materiales y métodos. Se estudiaron 14 aislamientos de C. neoformans var. grubii provenientes de pacientes con HIV, de los cuales 6 eran sensibles al fluconazol y 8 presentaban sensibilidad disminuida. Los niveles de expresión de los genes ERG11, AFR1 y MDR1 se determinaron mediante PCR en tiempo real.Resultados. Los aislamientos resistentes al fluconazol mostraron sobreexpresión de los genes AFR1 y MDR1, mientras que la expresión de los fenotipos de resistencia evaluados se mantuvo homogénea en ERG11, en todos los aislamientos de C. neoformans var. grubii.Conclusiones. La sobreexpresión de los genes AFR1 y MDR1 que codifican las bombas de eflujo, contribuye a la resistencia al fluconazol en los aislamientos estudiados. Sin embargo, los patrones de resistencia que se registran en este hongo, sumado a los casos de recaídas en pacientes con HIV, no pueden atribuirse únicamente a los casos de resistencia por exposición al fármaco. Otros mecanismos podrían también estar involucrados en este fenómeno, como la resistencia emergente (resistencia mediante otros genes ERG) y la heterorresistencia, los cuales deben ser estudiados en estos aislamientos.
ABSTRACT We present a sample of accreting supermassive black holes (SMBHs) in dwarf galaxies at . We identify dwarf galaxies in the NEWFIRM Medium Band Survey with stellar masses of that have ...spectroscopic redshifts from the DEEP2 survey and lie within the region covered by deep (flux limit of ) archival Chandra X-ray data. From our sample of 605 dwarf galaxies, 10 exhibit X-ray emission consistent with that arising from active galactic nucleus (AGN) activity. If black-hole mass scales roughly with stellar mass, then we expect that these AGNs are powered by SMBHs with masses of and typical Eddington ratios of . Furthermore, we find an AGN fraction consistent with extrapolations of other searches of for and . Our AGN fraction is in good agreement with a semi-analytic model, suggesting that, as we search larger volumes, we may use comparisons between observed AGN fractions and models to understand seeding mechanisms in the early universe.
La infección crónica por el virus de la hepatitis B es un grave problema de salud pública a nivel mundial. Sus consecuencias llegan a ser mortales y el tratamiento actual no ofrece curación sino ...control de la enfermedad. Las principales limitantes para una cura son la dificultad para destruir el ADNccc del virus en el núcleo celular y la presencia de material genético viral integrado en el ADN de la célula hospedera. No obstante, hay múltiples frentes de investigación enfocados en encontrar una cura definitiva al potenciar la respuesta inmune del hospedero o al actuar directamente contra el virus y su ciclo de replicación. En este artículo se exponen los principales avances que se han realizado en este campo.
We report on deep, coordinated radio and X-ray observations of the black hole X-ray binary XTE J1118+480 in quiescence. The source was observed with the Karl G. Jansky Very Large Array for a total of ...17.5 h at 5.3 GHz, yielding a 4.8 ± 1.4 μJy radio source at a position consistent with the binary system. At a distance of 1.7 kpc, this corresponds to an integrated radio luminosity between 4 and 8 × 1025 erg s−1, depending on the spectral index. This is the lowest radio luminosity measured for any accreting black hole to date. Simultaneous observations with the Chandra X-ray Telescope detected XTE J1118+480 at 1.2 × 10−14 erg s−1 cm−2 (1–10 keV), corresponding to an Eddington ratio of ∼4 × 10−9 for a 7.5 M⊙ black hole. Combining these new measurements with data from the 2005 and 2000 outbursts available in the literature, we find evidence for a relationship of the form ℓr = α+βℓX (where ℓ denotes logarithmic luminosities), with β = 0.72 ± 0.09. XTE J1118+480 is thus the third system – together with GX339-4 and V404 Cyg – for which a tight, non-linear radio/X-ray correlation has been reported over more than 5 dex in ℓX. Confirming previous results, we find no evidence for a dependence of the correlation normalization of an individual system on orbital parameters, relativistic boosting, reported black hole spin and/or black hole mass. We then perform a clustering and linear regression analysis on what is arguably the most up-to-date collection of coordinated radio and X-ray luminosity measurements from quiescent and hard-state black hole X-ray binaries, including 24 systems. At variance with previous results, a two-cluster description is statistically preferred only for random errors ≲0.3 dex in both ℓr and ℓX, a level which we argue can be easily reached when the known spectral shape/distance uncertainties and intrinsic variability are accounted for. A linear regression analysis performed on the whole data set returns a best-fitting slope β = 0.61 ± 0.03 and intrinsic scatter σ0 = 0.31 ± 0.03 dex.
Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression ...of miRNAs that act as tumor suppressor genes, such as miR-34a.
Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo.
Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity.
Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a-based treatment strategies in MM patients.
Epigenetic mechanisms, such as alterations in histone acetylation based on histone deacetylases (HDACs) activity, have been linked not only to normal brain function but also to several brain ...disorders including epilepsy and the epileptogenic process. In WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild-depression comorbidity, we investigated the effects of two HDAC inhibitors (HDACi), namely sodium butyrate (NaB), valproic acid (VPA) and their co-administration, on the development of absence seizures and related psychiatric/neurologic comorbidities following two different experimental paradigms. Treatment effects have been evaluated by EEG recordings (EEG) and behavioural tests at different time points. Prolonged and daily VPA and NaB treatment, started before absence seizure onset (P30), significantly reduced the development of absence epilepsy showing antiepileptogenic effects. These effects were enhanced by NaB/VPA co-administration. Furthermore, early-chronic HDACi treatment improved depressive-like behaviour and cognitive performance 1 month after treatment withdrawal. WAG/Rij rats of 7 months of age showed reduced acetylated levels of histone H3 and H4, analysed by Western Blotting of homogenized brain, in comparison to WAG/Rij before seizure onset (P30). The brain histone acetylation increased significantly during treatment with NaB or VPA alone and more markedly during co-administration. We also observed decreased expression of both HDAC1 and 3 following HDACi treatment compared to control group. Our results suggest that histone modifications may have a crucial role in the development of epilepsy and early treatment with HDACi might be a possible strategy for preventing epileptogenesis also affecting behavioural comorbidities.
There is abundant evidence for the ‘video deficit’: children under 2 years old learn better in person than from video. We evaluated whether these findings applied to video chat by testing whether ...children aged 12–25 months could form relationships with and learn from on‐screen partners. We manipulated social contingency: children experienced either real‐time FaceTime conversations or pre‐recorded Videos as the partner taught novel words, actions and patterns. Children were attentive and responsive in both conditions, but only children in the FaceTime group responded to the partner in a temporally synced manner. After one week, children in the FaceTime condition (but not the Video condition) preferred and recognized their Partner, learned more novel patterns, and the oldest children learned more novel words. Results extend previous studies to demonstrate that children under 2 years show social and cognitive learning from video chat because it retains social contingency. A video of this article can be viewed at: https://youtu.be/rTXaAYd5adA
Children ages 22‐25 months learned novel words from interactive video chat, but not from pre‐recorded videos. Also, beginning at 17 months of age, children recognized someone they had previously only ‘met’ via video chat. Social contingency enables learning from video chat for children under 2 years old.
Interferon regulatory factor 4 (IRF4) is an attractive therapeutic target in multiple myeloma (MM). We here report that expression of IRF4 mRNA inversely correlates with microRNA (miR)-125b in MM ...patients. Moreover, we provide evidence that miR-125b is downregulated in TC2/3 molecular MM subgroups and in established cell lines. Importantly, constitutive expression of miR-125b-5p by lentiviral vectors or transfection with synthetic mimics impaired growth and survival of MM cells and overcame the protective role of bone marrow stromal cells in vitro. Apoptotic and autophagy-associated cell death were triggered in MM cells on miR-125b-5p ectopic expression. Importantly, we found that the anti-MM activity of miR-125b-5p was mediated via direct downregulation of IRF4 and its downstream effector BLIMP-1. Moreover, inhibition of IRF4 translated into downregulation of c-Myc, caspase-10 and cFlip, relevant IRF4-downstream effectors. Finally, in vivo intra-tumor or systemic delivery of formulated miR-125b-5p mimics against human MM xenografts in severe combined immunodeficient/non-obese diabetic mice induced significant anti-tumor activity and prolonged survival. Taken together, our findings provide evidence that miR-125b, differently from other hematologic malignancies, has tumor-suppressor activity in MM. Furthermore, our data provide proof-of-concept that synthetic miR-125b-5p mimics are promising anti-MM agents to be validated in early clinical trials.
The concept of severity in irritable bowel syndrome (IBS) is clinically recognized and operative in diagnostic decision making and treatment planning. Yet, there is no consensus on its definition, ...and there are limited data on the prevalence of severity subgroups, its medical and psychosocial determinants, and its association with other health status measures. The aims of the Rome Foundation Working Team Committee were to summarize current research, to develop a consensus of understanding on this concept, and to make recommendations for its use in research and clinical care.
In 2006, a multinational committee of clinical investigators with expertise in IBS and/or psychometric research methods undertook a systematic review of the literature relating to severity in IBS. Owing to limited data, the Foundation commissioned three clinical studies to better characterize the concept of severity in IBS, and summary information and recommendations for future research and clinical care were developed.
The main findings were: (i) severity in IBS is defined as a biopsychosocial composite of patient-reported gastrointestinal and extraintestinal symptoms, degree of disability, and illness-related perceptions and behaviors; (ii) both visceral and central nervous system physiological factors affect severity; as severity increases, the central nervous system provides a greater contribution; (iii) severity is related to and influences health-related quality of life and health behaviors and also guides diagnostic and therapeutic clinical decision making; (iv) severity can be subcategorized into clinically meaningful subgroups as mild (∼40%), moderate (∼35%), and severe (∼25%), and this provides a working model for use in future research and clinical care.
Future work is required to understand more precisely the factors contributing to severity and to develop a valid patient-reported instrument to measure severity in IBS.
Immune checkpoint inhibitors (ICIs) have demonstrated significant overall survival (OS) benefit in lung adenocarcinoma (LUAD). Nevertheless, a remarkable interpatient heterogeneity characterizes ...immunotherapy efficacy, regardless of programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB). KEAP1 mutations are associated with shorter survival in LUAD patients receiving chemotherapy. We hypothesized that the pattern of KEAP1 co-mutations and mutual exclusivity may identify LUAD patients unresponsive to immunotherapy.
KEAP1 mutational co-occurrences and somatic interactions were studied in the whole MSKCC LUAD dataset. The impact of coexisting alterations on survival outcomes in ICI-treated LUAD patients was verified in the randomized phase II/III POPLAR/OAK trials (blood-based sequencing, bNGS cohort, N = 253). Three tissue-based sequencing studies (Rome, MSKCC and DFCI) were used for independent validation (tNGS cohort, N = 289). Immunogenomic features were analyzed using The Cancer Genome Atlas (TCGA) LUAD study.
On the basis of KEAP1 mutational co-occurrences, we identified four genes potentially associated with reduced efficacy of immunotherapy (KEAP1, PBRM1, SMARCA4 and STK11). Independent of the nature of co-occurring alterations, tumors with coexisting mutations (CoMut) had inferior survival as compared with single-mutant (SM) and wild-type (WT) tumors (bNGS cohort: CoMut versus SM log-rank P = 0.048, CoMut versus WT log-rank P < 0.001; tNGS cohort: CoMut versus SM log-rank P = 0.037, CoMut versus WT log-rank P = 0.006). The CoMut subset harbored higher TMB than the WT disease and the adverse significance of coexisting alterations was maintained in LUAD with high TMB. Significant immunogenomic differences were observed between the CoMut and WT groups in terms of core immune signatures, T-cell receptor repertoire, T helper cell signatures and immunomodulatory genes.
This study indicates that coexisting alterations in a limited set of genes characterize a subset of LUAD unresponsive to immunotherapy and with high TMB. An immune-cold microenvironment may account for the clinical course of the disease.
•Coexisting alterations in KEAP1, PBRM1, SMARCA4 and STK11 define a subset of lung adenocarcinoma unresponsive to immunotherapy.•Tumors harboring co-mutations had inferior survival outcomes compared with both single-mutant and wild-type tumors.•Tumors with co-occurring alterations are misclassified as immunoresponsive by tumor mutational burden.•An immunologically cold phenotype characterizes lung adenocarcinoma with coexisting mutations.
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