Publications by authors named "Valentina Riva"

55 Publications

Impact of Early Rhythmic Training on Language Acquisition and Electrophysiological Functioning Underlying Auditory Processing: Feasibility and Preliminary Findings in Typically Developing Infants.

Brain Sci 2021 Nov 21;11(11). Epub 2021 Nov 21.

Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842 Lecco, Italy.

Previous evidence has shown that early auditory processing impacts later linguistic development, and targeted training implemented at early ages can enhance auditory processing skills, with better expected language development outcomes. This study focuses on typically developing infants and aims to test the feasibility and preliminary efficacy of music training based on active synchronization with complex musical rhythms on the linguistic outcomes and electrophysiological functioning underlying auditory processing. Fifteen infants participated in the training (RTr+) and were compared with two groups of infants not attending any structured activities during the same time frame (RTr-, N = 14). At pre- and post-training, expressive and receptive language skills were assessed using standardized tests, and auditory processing skills were characterized through an electrophysiological non-speech multi-feature paradigm. Results reveal that RTr+ infants showed significantly broader improvement in both expressive and receptive pre-language skills. Moreover, at post-training, they presented an electrophysiological pattern characterized by shorter latency of two peaks (N2* and P2), reflecting a neural change detection process: these shifts in latency go beyond those seen due to maturation alone. These results provide preliminary evidence on the efficacy of our training in improving early linguistic competences, and in modifying the neural underpinnings of auditory processing in infants.
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http://dx.doi.org/10.3390/brainsci11111546DOI Listing
November 2021

A Pilot Study Evaluating the Effects of Early Intervention for Italian Siblings of Children with Autism Spectrum Disorder.

Brain Sci 2021 Oct 21;11(11). Epub 2021 Oct 21.

Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842 Lecco, Italy.

Autism spectrum disorder (ASD) is a high-cost/high-burden problem. Early intervention may prevent development of the disorder, improving child outcomes and reducing long-term consequences. However, few studies have investigated the role of early intervention in children younger than two years. This study aims to examine the effect of early intervention in 18-month-old high-risk siblings of children with ASD (HR-ASD) with clinical signs of autism. The intervention is based on the principles of Applied Behavior Analysis and focuses on the development of early precursors to social and communicative competence (joint attention and imitation behaviors). After controlling for baseline differences, two comparison HR-ASD groups were included: 15 HR-ASD toddlers receiving behavioral intervention for 3 h per week for 5 months (INT+) and 15 HR-ASD toddlers who were only clinically monitored from age 18 months (INT-). Changes in social communication, restricted/repetitive behaviors, and language were assessed using standardized measures at pre- (T0) and post-intervention (T1). From T0 to T1, the INT+ group showed significant improvements in communication, social interaction, and language compared to INT- group. There was no effect on restricted/repetitive behaviors. Our findings highlighted the importance of early detection/intervention in autism and supported a positive impact of targeted interventions to improve outcomes in at-risk children.
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http://dx.doi.org/10.3390/brainsci11111381DOI Listing
October 2021

The (a)typical burden of COVID-19 pandemic scenario in Autism Spectrum Disorder.

Sci Rep 2021 11 22;11(1):22655. Epub 2021 Nov 22.

Theoretical and Cognitive Neuroscience Unit-Child Psychopathology Department, Scientific Institute, IRCCS E. Medea, Bosisio Parini, Italy.

Psychological and mental health consequences of large-scale anti-contagion policies are assuming strong relevance in the COVID-19 pandemic. We proposed a specific focus on a large sample of children with Autism Spectrum Disorder (ASD), developing an ad hoc instrument to investigate changes occurred in specific (sub-)domains during a period of national lockdown (Italy). Our questionnaire, named AutiStress, is both context-specific (being set in the COVID-19 pandemic scenario) and condition-specific (being structured taking into account the autistic functioning peculiarities in the paediatric age). An age- and gender-matched group of neurotypical (TD) controls was also provided. As expected, the severe lockdown policies had a general negative impact both on ASD and TD children, reflecting the obvious burden of the pandemic situation. However, our findings also indicate that children with ASD experienced more positive changes than TD ones. Noteworthy, we report a thought-provoking double dissociation in the context-specific predictor (i.e., accessibility to private outdoor spaces), indicating that it impacts differently on the two groups. Focusing on the ASD group, results suggest a condition-specific impact of the COVID-19 pandemic on core autistic (sub-)domains. Taken together, our data call for a multi-layered, context- and condition-specific analysis of the pandemic burden beyond any oversimplification.
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http://dx.doi.org/10.1038/s41598-021-01907-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608876PMC
November 2021

Targeting DDX3X Helicase Activity with BA103 Shows Promising Therapeutic Effects in Preclinical Glioblastoma Models.

Cancers (Basel) 2021 Nov 7;13(21). Epub 2021 Nov 7.

Department of Biotechnology, Chemistry & Pharmacy, University of Siena, I-53100 Siena, Italy.

DDX3X is an ATP-dependent RNA helicase that has recently attracted interest for its involvement in viral replication and oncogenic progression. Starting from hit compounds previously identified by our group, we have designed and synthesized a new series of DDX3X inhibitors that effectively blocked its helicase activity. These new compounds were able to inhibit the proliferation of cell lines from different cancer types, also in DDX3X low-expressing cancer cell lines. According to the absorption, distribution, metabolism, elimination properties, and antitumoral activity, compound BA103 was chosen to be further investigated in glioblastoma models. BA103 determined a significant reduction in the proliferation and migration of U87 and U251 cells, downregulating the oncogenic protein β-catenin. An in vivo evaluation demonstrated that BA103 was able to reach the brain and reduce the tumor growth in xenograft and orthotopic models without evident side effects. This study represents the first demonstration that DDX3X-targeted small molecules are feasible and promising drugs also in glioblastoma.
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http://dx.doi.org/10.3390/cancers13215569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582824PMC
November 2021

Bacterial Inoculants Mitigating Water Scarcity in Tomato: The Importance of Long-Term Experiments.

Front Microbiol 2021 15;12:675552. Epub 2021 Jun 15.

Department of Food, Environmental, and Nutritional Sciences, Università degli Studi di Milano, Milan, Italy.

Global population growth and climate change raise a challenge to agriculture, which, combined with the issues concerning the use of chemical fertilizers, have generated increasing attention in the use of plant-associated bacteria as a sustainable strategy in agri-food systems. The objective of this study is to evaluate the ability of five bacterial strains, previously isolated from the rhizosphere or endosphere of plants adapted to harsh environmental conditions, to act as potential plant biofertilizers in different conditions of water availability. The strain biosafety for a deliberate environmental release was investigated through a literature survey and antibiotic resistance testing. The selected strains were first characterized for their plant growth-promoting (PGP) and rhizocompetence-related traits through assays and then on short-term experiments on tomato plants. A long-term greenhouse experiment was further conducted to monitor the PGP effect of the bacteria during the entire life cycle of tomato plants subjected to full irrigation or to severe water deficit conditions, aiming to assess their actual effect on plant productivity, which is the ultimate target of the agricultural sector. Some of the strains showed a potential in improving water use efficiency and mitigating plant water stress. Under severe irrigation deficit, four of the tested strains, M1, RP-26, SR7-77, and 2-50, significantly increased the number of productive plants in comparison to non-bacterized control ones. Two of them, RP-26 and 2-50, demonstrated also, under full irrigation, to significantly improve the water productivity in comparison with non-bacterized plants. Despite all the strains showed promising PGP potential in short-term assays, the positive effect of the bacterial inoculants on plant physiology and fruit yield was observed in some cases but never corroborated by statistical significance. These results highlight the importance of performing long-term experiments to define the real PGP ability of a bacterial inoculant to positively impact plant production.
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http://dx.doi.org/10.3389/fmicb.2021.675552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239394PMC
June 2021

Detection without further processing or processing without automatic detection? Differential ERP responses to lexical-semantic processing in toddlers at high clinical risk for autism and language disorder.

Cortex 2021 08 27;141:465-481. Epub 2021 May 27.

Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.

Delays in early expressive vocabulary can reflect a specific delay in language acquisition or more general impairments in social communication. The neural mechanisms underlying the (dis)ability to establish the first lexical-semantic representations remain relatively unknown. Here, we investigate the electrophysiological underpinnings of these mechanisms during the critical phase of lexical acquisition in two groups of 19-month-old toddlers at risk for neurodevelopmental disorders, i.e., children characterized by low expressive vocabulary (late talkers, N = 18) and children with early signs of Autism Spectrum Disorder (ASD, N = 18) as compared to typically developing children (N = 28), with the aim to identify similarities and specificities in lexical-semantic processing between these groups. ERPs elicited by words (either congruous or incongruous with the previous picture context) and pseudo-words are investigated within a picture-word matching paradigm. In order to further interpret ERP responses, we look at longitudinal intra-group associations with language and socio-communications skills at age 24 months. As expected, we found differences between the groups that might underlie specificities, but also similarities. On the one side, late talkers differed from the other two groups in the early component (phonological-lexical priming effect) reflecting detection of the correspondence between the heard word and the lexical representation pre-activated by the picture. On the other side, children with early symptoms of ASD differed from the other two groups in the late component (late positive component) reflecting the effortful semantic re-analysis following a violation. The functional interpretation of the two components is corroborated by significant correlations suggesting that the early component is associated with later socio-communication skills, whereas the late component is associated with linguistic skills. Results point in the direction of differential impaired mechanisms in the two populations, i.e., impaired automatic detection of incongruencies in late talkers vs. absence of high-level re-analysis of such incongruencies in children with early signs of ASD.
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http://dx.doi.org/10.1016/j.cortex.2021.04.020DOI Listing
August 2021

Epidemiology of neuronal surface antibody-mediated autoimmune encephalitis and antibody-based diagnostics.

J Neuroimmunol 2021 08 1;357:577598. Epub 2021 May 1.

Department of Neurology, Ospedale Santa Chiara, Trento, Italy.

Epidemiologic data on neuronal surface antibody (NSAb)-associated autoimmune encephalitides (NSAE) are scarce and heterogeneous. We review our 13-year-long biobank-data collection and provide the incidence of NSAE in two Italian provinces (approx. Population of 1,400,000) over a 5-year period (July 2013-June 2018). NSAbs were diagnosed in 75 out of 1179 tested patients (6.4%). The most common NSAbs were anti-LGI1 (30 cases), followed by NMDAR (24). Eleven cases of NSAE were diagnosed in Treviso and Trento provinces with an estimated incidence of 1.54 per 1,000,000 population (LGI1-encephalitis 0.84; C.I. 0.38-1.88). LGI1-E is the most frequent NSAE among adults.
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http://dx.doi.org/10.1016/j.jneuroim.2021.577598DOI Listing
August 2021

Effects of COVID-19 Lockdown on the Emotional and Behavioral Profiles of Preschool Italian Children with and without Familial Risk for Neurodevelopmental Disorders.

Brain Sci 2021 Apr 9;11(4). Epub 2021 Apr 9.

Child Psychopathology Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, 23842 Lecco, Italy.

The effects of COVID-19 containment measures on the emotional and behavioral development of preschoolers are not clear. We investigated them within an ongoing longitudinal project including typically developing children (TD) and children at high familial risk for neurodevelopmental disorders (HR-NDD) who were potentially more vulnerable. The study included ninety children aged 2-6 years (TD = 48; HR-NDD = 42). Before the emergency phase (T0), all children received a clinical assessment, including the parent questionnaire Child Behavior Checklist for Ages 1.5-5 (CBCL 1.5-5). The same questionnaire was filled out again during the emergency (T1), together with an ad-hoc questionnaire investigating environmental factors characterizing the specific period. Changes in the CBCL profiles between T0 and T1 were evaluated. Overall, irrespective of familial risk, the average T-scores on specific CBCL scales at T1 were higher than at T0. Associations emerged between delta scores reflecting worsening scores on specific CBCL scales and clinical and environmental factors. Our results confirmed the negative impact of the lockdown on preschool children's emotional/behavioral profiles, and highlight the need for strategic approaches in the age range of 2-6 years, especially for more susceptible children owing to environmental factors and pre-existing emotional problems.
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http://dx.doi.org/10.3390/brainsci11040477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070543PMC
April 2021

Early developmental trajectories of expressive vocabulary and gesture production in a longitudinal cohort of Italian infants at high-risk for Autism Spectrum Disorder.

Autism Res 2021 07 1;14(7):1421-1433. Epub 2021 Mar 1.

Research Coordination and Support Service, Istituto Superiore di Sanità, Rome, Italy.

Delays in language are a hallmark feature of Autism Spectrum Disorder (ASD). However, little is known about the predictive role of language developmental trajectories on ASD. The present study aimed at identifying early different language developmental profiles of infants at high familial risk for ASD (HR-ASD) and testing their predictive role on ASD symptoms at 2 years. The role of gestures on socio-communicative skills has also been explored. Trajectories of expressive vocabulary were investigated in 137 HR-ASD infants at 12, 18, and, 24 months of age. Parents were requested to complete the Italian version of the MacArthur-Bates Communicative Development Inventory and ASD symptoms were measured by ADOS-2. Latent class growth analysis defined four trajectories: above average language development group (above-average LD, 18.2%), normal language development group (NLD, 38.7%), late-onset language development group (late-onset LD, 11.7%), and a group of children with stable language delay (SLD, 31.4%). Results showed that the SLD group obtained higher communicative difficulties and restricted/repetitive behavior compared to the other groups. Examining early increase of produced gestures in the different language classes, we found fewer produced gestures between 12 and 18 months in the SLD group compared to the late-onset LD group. The results identified clusters of HR infants who follow similar estimated trajectories based on individual differences in language development. These patterns of early language acquisition, together with produced gestures, may be predictive of later ASD symptoms and useful for planning prompt intervention. LAY SUMMARY: Language/gesture deficits are hallmark features of Autism Spectrum Disorder (ASD), but the predictive role of communicative trajectories on ASD remains unclear. In a longitudinal Italian sample of infants at high familial risk for ASD (HR-ASD), we tested if language trajectories and their link with gestures can predict ASD symptoms. We found four trajectories and HR infants with a stable language delay (SLD) trajectory showed more ASD symptoms later on. SLD infants produced fewer gestures compared to late-onset language development group that show more typical communicative skills.
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http://dx.doi.org/10.1002/aur.2493DOI Listing
July 2021

Dysfunctions in Infants' Statistical Learning are Related to Parental Autistic Traits.

J Autism Dev Disord 2021 Dec 13;51(12):4621-4631. Epub 2021 Feb 13.

Department of Psychology, Università degli Studi di Milano-Bicocca, Piazza Ateneo Nuovo, 1 (U6), 20126, Milano, Italy.

Statistical learning refers to the ability to extract the statistical relations embedded in a sequence, and it plays a crucial role in the development of communicative and social skills that are impacted in the Autism Spectrum Disorder (ASD). Here, we investigated the relationship between infants' SL ability and autistic traits in their parents. Using a visual habituation task, we tested infant offspring of adults (non-diagnosed) who show high (HAT infants) versus low (LAT infants) autistic traits. Results demonstrated that LAT infants learned the statistical structure embedded in a visual sequence, while HAT infants failed. Moreover, infants' SL ability was related to autistic traits in their parents, further suggesting that early dysfunctions in SL might contribute to variabilities in ASD symptoms.
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http://dx.doi.org/10.1007/s10803-021-04894-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8531064PMC
December 2021

The Mediation Role of Dynamic Multisensory Processing Using Molecular Genetic Data in Dyslexia.

Brain Sci 2020 Dec 16;10(12). Epub 2020 Dec 16.

Developmental Cognitive Neuroscience Lab, Department of General Psychology, University of Padua, 35131 Padua, Italy.

Although substantial heritability has been reported and candidate genes have been identified, we are far from understanding the etiopathogenetic pathways underlying developmental dyslexia (DD). Reading-related endophenotypes (EPs) have been established. Until now it was unknown whether they mediated the pathway from gene to reading (dis)ability. Thus, in a sample of 223 siblings from nuclear families with DD and 79 unrelated typical readers, we tested four EPs (i.e., rapid auditory processing, rapid automatized naming, multisensory nonspatial attention and visual motion processing) and 20 markers spanning five DD-candidate genes (i.e., , , , and ) using a multiple-predictor/multiple-mediator framework. Our results show that rapid auditory and visual motion processing are mediators in the pathway from -rs9853895 to reading. Specifically, the T/T genotype group predicts impairments in rapid auditory and visual motion processing which, in turn, predict poorer reading skills. Our results suggest that is related to reading via multisensory temporal processing. These findings support the use of EPs as an effective approach to disentangling the complex pathways between candidate genes and behavior.
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http://dx.doi.org/10.3390/brainsci10120993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765588PMC
December 2020

Novel alternative ribonucleotide excision repair pathways in human cells by DDX3X and specialized DNA polymerases.

Nucleic Acids Res 2020 11;48(20):11551-11565

Institute of Molecular Genetics IGM-CNR 'Luigi Luca Cavalli-Sforza', via Abbiategrasso 207, I-27100 Pavia, Italy.

Removal of ribonucleotides (rNMPs) incorporated into the genome by the ribonucleotide excision repair (RER) is essential to avoid genetic instability. In eukaryotes, the RNaseH2 is the only known enzyme able to incise 5' of the rNMP, starting the RER process, which is subsequently carried out by replicative DNA polymerases (Pols) δ or ϵ, together with Flap endonuclease 1 (Fen-1) and DNA ligase 1. Here, we show that the DEAD-box RNA helicase DDX3X has RNaseH2-like activity and can support fully reconstituted in vitro RER reactions, not only with Pol δ but also with the repair Pols β and λ. Silencing of DDX3X causes accumulation of rNMPs in the cellular genome. These results support the existence of alternative RER pathways conferring high flexibility to human cells in responding to the threat posed by rNMPs incorporation.
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http://dx.doi.org/10.1093/nar/gkaa948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672437PMC
November 2020

An Environmental Strain Is Naturally Competent to Acquire Exogenous DNA.

Front Microbiol 2020 3;11:574301. Epub 2020 Sep 3.

Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Milan, Italy.

The diffusion of antibiotic resistance determinants in different environments, e.g., soil and water, has become a public concern for global health and food safety and many efforts are currently devoted to clarify this complex ecological and evolutionary issue. Horizontal gene transfer (HGT) has an important role in the spread of antibiotic resistance genes (ARGs). However, among the different HGT mechanisms, the capacity of environmental bacteria to acquire naked exogenous DNA by natural competence is still poorly investigated. This study aimed to characterize the ability of the environmental strain ED1, isolated from the crustacean sp., to acquire exogenous DNA by natural competence. Transformation experiments were carried out varying different parameters, i.e., cell growth phase, amount of exogenous DNA and exposition to artificial lake water (ALW) and treated wastewater to mimic environmental-like conditions that may be encountered in the agri-food system. Results were compared with those showed by the laboratory strain DH5α. Our experimental data, supported by genomic sequencing, showed that, when exposed to pure water, ED1 strain was able to acquire exogenous DNA with frequencies (10-10) statistically higher than the ones observed for DH5α strain (10). Interestingly, higher values were retrieved for ED1 than DH5α strains exposed to ALW (10 vs. 10, respectively) or treated wastewater (10 vs. 10, respectively). We tested, therefore, ED1 strain ability to colonize the rhizosphere of lettuce, a model plant representative of raw-consumed vegetables of high economic importance in the ready-to-eat food industry. Results showed that ED1 strain was able to efficiently colonize lettuce rhizosphere, revealing a stable colonization for 14 days-long period. In conclusion, ED1 strain ability to acquire exogenous DNA in environmental-like conditions by natural competence, combined with its ability to efficiently and stably colonize plant rhizosphere, poses the attention to food and human safety showing a possible route of diffusion of antibiotic resistance in the agri-food system, sustaining the "One Health" warnings related to the antibiotic spread.
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http://dx.doi.org/10.3389/fmicb.2020.574301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494812PMC
September 2020

Novel Insights into the Biochemical Mechanism of CK1ε and its Functional Interplay with DDX3X.

Int J Mol Sci 2020 Sep 3;21(17). Epub 2020 Sep 3.

Institute of Molecular Genetics IGM-CNR "Luigi Luca Cavalli-Sforza", via Abbiategrasso 207, 27100 Pavia, Italy.

Casein Kinase 1 epsilon (CK1ε) is a member of the serine (Ser)/threonine (Thr) CK1 family, known to have crucial roles in several biological scenarios and, ever more frequently, in pathological contexts, such as cancer. Recently, the human DEAD-box RNA helicase 3 X-linked (DDX3X), involved in cancer proliferation and viral infections, has been identified as one of CK1ε substrates and its positive regulator in the Wnt/β-catenin network. However, the way by which these two proteins influence each other has not been fully clarified. In order to further investigate their interplay, we defined the kinetic parameters of CK1ε towards its substrates: ATP, casein, Dvl2 and DDX3X. CK1ε affinity for ATP depends on the nature of the substrate: increasing of casein concentrations led to an increase of Km, while increasing DDX3X reduced it. In literature, DDX3X is described to act as an allosteric activator of CK1ε. However, when we performed kinase reactions combining DDX3X and casein, we did not find a positive effect of DDX3X on casein phosphorylation by CK1ε, while both substrates were phosphorylated in a competitive manner. Moreover, CK1ε positively stimulates DDX3X ATPase activity. Our data provide a more detailed kinetic characterization on the functional interplay of these two proteins.
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http://dx.doi.org/10.3390/ijms21176449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503845PMC
September 2020

Unique Domain for a Unique Target: Selective Inhibitors of Host Cell DDX3X to Fight Emerging Viruses.

J Med Chem 2020 09 18;63(17):9876-9887. Epub 2020 Aug 18.

Istituto di Genetica Molecolare IGM-CNR "Luigi Luca Cavalli-Sforza", Via Abbiategrasso 207, I-27100 Pavia, Italy.

Emerging viruses like dengue, West Nile, chikungunya, and Zika can cause widespread viral epidemics. Developing novel drugs or vaccines against specific targets for each virus is a difficult task. As obligate parasites, all viruses exploit common cellular pathways, providing the possibility to develop broad-spectrum antiviral agents targeting host factors. The human DEAD-box RNA helicase DDX3X is an essential cofactor for viral replication but dispensable for cell viability. Herein, we exploited the presence of a unique structural motif of DDX3X not shared by other cellular enzymes to develop a theoretical model to aid in the design of a novel class of highly selective inhibitors acting against such specific targets, thus limiting off-targeting effects. High-throughput virtual screening led us to identify hit compound , endowed with promising antienzymatic activity. To improve its aqueous solubility, and its two enantiomers were synthesized and converted into their corresponding acetate salts (compounds , , and ). mutagenesis and biochemical and cellular assays further confirmed that the developed molecules were selective for DDX3X and were able to suppress replication of West Nile and dengue viruses in infected cells in the micromolar range while showing no toxicity for uninfected cells. These results provide proof of principle for a novel strategy in developing highly selective and broad-spectrum antiviral molecules active against emerging and dangerous viral pathogens. This study paves the way for the development of larger focused libraries targeting such domain to expand SAR studies and fully characterize their mode of interaction.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01039DOI Listing
September 2020

Unveiling the Microbiota Diversity of the Xerophyte Argania spinosa L. Skeels Root System and Residuesphere.

Microb Ecol 2020 Nov 25;80(4):822-836. Epub 2020 Jun 25.

Department of Food Environmental and Nutritional Sciences, Università degli Studi di Milano, 20133, Milan, Italy.

The microbiota associated to xerophyte is a "black box" that might include microbes involved in plant adaptation to the extreme conditions that characterize their habitat, like water shortage. In this work, we studied the bacterial communities inhabiting the root system of Argania spinosa L. Skeels, a tree of high economic value and ecological relevance in Northern Africa. Illumina 16S rRNA gene sequencing and cultivation techniques were applied to unravel the bacterial microbiota's structure in environmental niches associated to argan plants (i.e., root endosphere, rhizosphere, root-surrounding soil), not associated to the plant (i.e., bulk soil), and indirectly influenced by the plant being partially composed by its leafy residue and the associated microbes (i.e., residuesphere). Illumina dataset indicated that the root system portions of A. spinosa hosted different bacterial communities according to their degree of association with the plant, enriching for taxa typical of the plant microbiome. Similar alpha- and beta-diversity trends were observed for the total microbiota and its cultivable fraction, which included 371 isolates. In particular, the residuesphere was the niche with the highest bacterial diversity. The Plant Growth Promotion (PGP) potential of 219 isolates was investigated in vitro, assessing several traits related to biofertilization and biocontrol, besides the production of exopolysaccharides. Most of the multivalent isolates showing the higher PGP score were identified in the residuesphere, suggesting it as a habitat that favor their proliferation. We hypothesized that these bacteria can contribute, in partnership with the argan root system, to the litter effect played by this tree in its native arid lands.
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http://dx.doi.org/10.1007/s00248-020-01543-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550381PMC
November 2020

DDX3X inhibitors, an effective way to overcome HIV-1 resistance targeting host proteins.

Eur J Med Chem 2020 Aug 7;200:112319. Epub 2020 May 7.

Istituto di Genetica Molecolare "Luigi Luca Cavalli - Sforza", IGM-CNR, Via Abbiategrasso 207, I-27100, Pavia, Italy. Electronic address:

The huge resources that had gone into Human Immunodeficiency virus (HIV) research led to the development of potent antivirals able to suppress viral load in the majority of treated patients, thus dramatically increasing the life expectancy of people living with HIV. However, life-long treatments could result in the emergence of drug-resistant viruses that can progressively reduce the number of therapeutic options, facilitating the progression of the disease. In this scenario, we previously demonstrated that inhibitors of the human DDX3X helicase can represent an innovative approach for the simultaneous treatment of HIV and other viral infections such as Hepatitis c virus (HCV). We reported herein 6b, a novel DDX3X inhibitor that thanks to its distinct target of action is effective against HIV-1 strains resistant to currently approved drugs. Its improved in vitro ADME properties allowed us to perform preliminary in vivo studies in mice, which highlighted optimal biocompatibility and an improved bioavailability. These results represent a significant advancement in the development of DDX3X inhibitors as a novel class of broad spectrum and safe anti-HIV-1 drugs.
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http://dx.doi.org/10.1016/j.ejmech.2020.112319DOI Listing
August 2020

Exploring the Implication of DDX3X in DENV Infection: Discovery of the First-in-Class DDX3X Fluorescent Inhibitor.

ACS Med Chem Lett 2020 May 9;11(5):956-962. Epub 2020 Apr 9.

Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, via Aldo Moro 2, 53100 Siena, Italy.

In the absence of effective drugs or vaccines for the treatment of the five Dengue Virus serotypes, the search for novel antiviral drugs is of primary importance for the scientific community. In this context, drug repurposing represents the most used strategy; however, the study of host targets is now attracting attention since it allows identification of broad-spectrum drugs endowed with high genetic barrier. In the last ten years our research group identified several small molecules DDX3X inhibitors and proved their efficacy against different viruses including novel emerging ones. Herein, starting from a screening of our compounds, we designed and synthesized novel derivatives with potent activity and high selectivity. Finally, we synthesized a fluorescent inhibitor that allowed us to study DDX3X cellular localization during DENV infection . Immunofluorescence analysis showed that our inhibitor colocalized with DDX3X, promoting the reduction of infected cells and recovering the number of viable cells.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236276PMC
May 2020

EEG Effective Source Projections Are More Bilaterally Symmetric in Infants Than in Adults.

Front Hum Neurosci 2020 12;14:82. Epub 2020 Mar 12.

Swartz Center for Computational Neuroscience, Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United States.

Although anatomical brain hemispheric asymmetries have been clearly documented in the infant brain, findings concerning functional hemispheric specialization have been inconsistent. The present report aims to assess whether bilaterally symmetric synchronous activity between the two hemispheres is a characteristic of the infant brain. To asses cortical bilateral synchronicity, we used decomposition by independent component analysis (ICA) of high-density electroencephalographic (EEG) data collected in an auditory passive oddball paradigm. Decompositions of concatenated EEG data epochs from each of 34 typically developing 6-month-old infants and from 18 healthy young adults participating in the same passive auditory oddball protocol were compared to characterize differences in functional brain organization between early life and adulthood. Our results show that infant EEG decompositions comprised a larger number of independent component (IC) effective source processes compatible with a cortical origin and having bilaterally near-symmetric scalp projections (13.8% of the infant data ICs presented a bilateral pattern vs. 4.3% of the adult data ICs). These IC projections could be modeled as the sum of potentials volume-conducted to the scalp from synchronous locally coherent field activities in corresponding left and right cortical source areas. To conclude, in this paradigm, source-resolved infant brain EEG exhibited more bilateral synchronicity than EEG produced by the adult brain, supporting the hypothesis that more strongly unilateral and likely more functionally specialized unihemispheric cortical field activities are concomitants of brain maturation.
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http://dx.doi.org/10.3389/fnhum.2020.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080990PMC
March 2020

Infants' Learning of Rule-Based Visual Sequences Predicts Language Outcome at 2 Years.

Front Psychol 2020 25;11:281. Epub 2020 Feb 25.

Department of Psychology, University of Milano-Bicocca, Milan, Italy.

The ability to learn and generalize abstract rules from sensory input - i.e., Rule Learning (RL) - is seen as pivotal to language development, and specifically to the acquisition of the grammatical structure of language. Although many studies have shown that RL in infancy is operating across different perceptual domains, including vision, no studies have directly investigated the link between infants' visual RL and later language acquisition. Here, we conducted a longitudinal study to investigate whether 7-month-olds' ability to detect visual structural regularities predicts linguistic outcome at 2 years of age. At 7 months, infants were tested for their ability to extract and generalize ABB and ABA structures from sequences of visual shapes, and at 24 months their lexical and grammatical skills were assessed using the MacArthur-Bates CDI. Regression analyses showed that infants' visual RL abilities selectively predicted early grammatical abilities, but not lexical abilities. These results may provide the first evidence that RL mechanisms are involved in language acquisition, and suggest that RL abilities may act as an early neurocognitive marker for language impairments.
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http://dx.doi.org/10.3389/fpsyg.2020.00281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052175PMC
February 2020

Paternal-but Not Maternal-Autistic Traits Predict Frontal EEG Alpha Asymmetry in Infants with Later Symptoms of Autism.

Brain Sci 2019 Nov 26;9(12). Epub 2019 Nov 26.

Child Psychopathology Unit, Scientific Institute IRCCS E. Medea, Bosisio Parini, 23842 Lecco, Italy.

Previous research found that the parental autism phenotype is associated with child autism spectrum disorder (ASD), even if the pathway between autistic traits in parents and child ASD is still largely unknown. Several studies investigated frontal asymmetry in alpha oscillation (FAA) as an early marker for ASD. However, no study has examined the mediational effect of FAA between parental autistic traits and child ASD symptoms in the general population. We carried out a prospective study of 103 typically developing infants and measured FAA as a mediator between both maternal and paternal autistic traits and child ASD traits. We recorded infant baseline electroencephalogram (EEG) at 6 months of age. Child ASD symptoms were measured at age 24 months by the Child Behavior Checklist 1½-5 Pervasive Developmental Problems Scale, and parental autistic traits were scored by the Autism spectrum Quotient questionnaire. The mediation model showed that paternal vs. maternal autistic traits are associated with greater left FAA which, in turn, is associated with more child ASD traits with a significant indirect effect only in female infants vs. male infants. Our findings show a potential cascade of effects whereby paternal autistic traits drive EEG markers contributing to ASD risk.
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http://dx.doi.org/10.3390/brainsci9120342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956226PMC
November 2019

Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X.

Molecules 2019 Nov 4;24(21). Epub 2019 Nov 4.

Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100 Siena, Italy.

The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development.
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http://dx.doi.org/10.3390/molecules24213988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864647PMC
November 2019

Microbial assisted phytodepuration for water reclamation: Environmental benefits and threats.

Chemosphere 2020 Feb 12;241:124843. Epub 2019 Sep 12.

Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, 20133, Milano, Italy. Electronic address:

Climate changes push for water reuse as a priority to counteract water scarcity and minimize water footprint especially in agriculture, one of the highest water consuming human activities. Phytodepuration is indicated as a promising technology for water reclamation, also in the light of its economic and ecological sustainability, and the use of specific bacterial inocula for microbial assisted phytodepuration has been proposed as a further advance for its implementation. Here we provided an overview on the selection and use of plant growth promoting bacteria in Constructed Wetland (CW) systems, showing their advantages in terms of plant growth support and pollutant degradation abilities. Moreover, CWs are also proposed for the removal of emerging organic pollutants like antibiotics from urban wastewaters. We focused on this issue, still debated in the literature, revealing the necessity to deepen the knowledge on the antibiotic resistance spread into the environment in relation to treated wastewater release and reuse. In addition, given the presence in the plant system of microhabitats (e.g. rhizosphere) that are hot spot for Horizontal Gene Transfer, we highlighted the importance of gene exchange to understand if these events can promote the diffusion of antibiotic resistance genes and antibiotic resistant bacteria, possibly entering in the food production chain when treated wastewater is used for irrigation. Ideally, this new knowledge will lead to improve the design of phytodepuration systems to maximize the quality and safety of the treated effluents in compliance with the 'One Health' concept.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124843DOI Listing
February 2020

Oscillatory gamma activity mediates the pathway from socioeconomic status to language acquisition in infancy.

Infant Behav Dev 2019 11 8;57:101384. Epub 2019 Oct 8.

Scientific Institute, IRCCS E. Medea, Child Psychopathology Unit, Bosisio Parini, Lecco, Italy.

Background: The predictable path to child language acquisition is largely constrained by both brain maturation and environmental experience. The synchronized activity of large numbers of neurons gives rise to macroscopic brain oscillations on an electroencephalogram (EEG). It has been found that neural oscillations at rest in the gamma frequency band (25-45 Hz) are associated with development of different cognitive systems, including language. Although the etiology of language is explained by genetically driven brain maturation factors, environment plays a significant role. Specifically, candidate pathways from environment to language development include sociodemographic factors, primarily socioeconomic status (SES) which is likely to exert its effects on language development through other factors, such as parenting style. Despite these assumptions, no studies have so far examined the interrelation between brain maturation factors such as gamma frequency oscillatory activity, environmental factors such as SES, and language acquisition.

Aim And Method: In a longitudinal study of 84 Italian typically developing infants, we measured the power of oscillatory gamma activity as mediator between SES and language acquisition. Baseline EEG and information about SES were collected when infants were aged 6 months. Children were followed-up longitudinally to measure expressive vocabulary and Mean Length of Utterance (MLU) at 24 months.

Results: The mediation model showed that SES is associated with gamma power which, in turn, is associated with expressive language at age 24 months. A higher SES predicted an increase in left central gamma power which, in turn, predicted better language scores.

Conclusions: These results confirm the predictive role of gamma activity oscillatory activity on later language acquisition, suggesting a specific role for these oscillatory mechanisms in language development milestones such as vocabulary development and early word combination. Furthermore, they suggest that SES differences in brain activity may be apparent at early stages of life and affect later language skills. If replicated, our findings could contribute to identifying highest-risk children and may prompt cost-effective preventive/treatment strategies.
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http://dx.doi.org/10.1016/j.infbeh.2019.101384DOI Listing
November 2019

Root Bacteria Recruited by in Constructed Wetlands Have the Potential to Enhance Azo-Dye Phytodepuration.

Microorganisms 2019 Sep 24;7(10). Epub 2019 Sep 24.

Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, 20133 Milano, Italy.

The microbiome associated with plants used in phytodepuration systems can boost plant growth and services, especially in ecosystems dealing with recalcitrant compounds, hardly removed via traditional wastewater (WW) treatments, such as azo-dyes used in textile industry. In this context, we aimed to study the cultivable microbiome selected by plants in a Constructed Wetland (CW) in Morocco, in order to obtain candidate inoculants for the phytodepuration of azo-dye contaminated WW. A collection of 152 rhizospheric and endophytic bacteria was established. The strains were phylogenetically identified and characterized for traits of interest in the phytodepuration context. All strains showed Plant Growth Promotion potential in vitro and 67% of them significantly improved the growth of a model plant in vivo compared to the non bacterized control plants. Moreover, most of the isolates were able to grow in presence of several model micropollutants typically found in WW, indicating their potential use in phytodepuration of a wide spectrum of effluents. The six most promising strains of the collection were tested in CW microcosms alone or as consortium: the consortium and two single inocula demonstrated to significantly increase the removal of the model azo-dye Reactive Black 5 compared to the non bacterized controls.
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http://dx.doi.org/10.3390/microorganisms7100384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843347PMC
September 2019

Postnatal maternal symptoms of depression and child emotion dysregulation: The mediation role of infant EEG alpha asymmetry.

Infant Behav Dev 2019 11 21;57:101321. Epub 2019 May 21.

Child Psychopathology Unit, Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco, Italy. Electronic address:

In a community-based sample of 104 infants and their mothers, we hypothesized a pathway from postnatal maternal symptoms of depression to child emotion dysregulation, and tested at 6 months of age the mediation role of alpha asymmetry at frontal and parietal sites. We recorded infant resting-state EEG at 6 months of age. Child emotion dysregulation was measured at 24 months by the Child Behavior Checklist Dysregulation Profile derived from the CBCL 1½-5. Maternal depression symptoms were scored 6 months after the delivery by the Anxious/Depressed scale of the Adult Self-Report. We used structural equation modeling to test the mediation model from maternal depression symptoms to child emotion dysregulation mediated by frontal and parietal alpha asymmetry. The mediation model provided an excellent fit to the data [χ2(3) = 3.088, p = .378; RMSEA = .017, CFI = .1.00; SRMR = 0.040] and explained 23.3% of the variance in child emotion dysregulation. The indirect path via parietal alpha asymmetry was significant (β = .065; SE = .033; 95% CI = .001-.139; p = .048), i.e. greater levels of maternal depression symptoms predicted left parietal alpha asymmetry, which predicted higher levels of child emotion dysregulation. The direct effect, i.e. the pathway linking maternal depression symptoms and child emotion dysregulation above and beyond the indirect effects, was also significant. We found evidence for a partial mediation role of left parietal alpha asymmetry in a longitudinal pathway from postnatal maternal symptoms of depression to child emotion dysregulation, providing support for left parietal asymmetry as an index of biological vulnerability to emotion dysregulation in the first years of life.
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http://dx.doi.org/10.1016/j.infbeh.2019.04.003DOI Listing
November 2019

Ratio Aβ1-42:p-Tau: a Possible Diagnostic Tool in Differentiating Dementias.

Clin Lab 2019 05;65(5)

Background: Patients with Alzheimer's disease (AD) present a typical biochemical profile of biomarkers: low concentration of β amyloid 1-42 (Aβ1-42), high concentration of total Tau (t-Tau) and phosphorylated Tau at threonine 181 (p-Tau). Several neurodegenerative diseases may overlap with AD, both in regards to clinical symptoms and neuropathology. Many data suggest that Alzheimer's disease (AD) pathophysiology can be identified using biomarkers. It has been hypothesized that subjects with dementia due to AD showed low levels of Aβ1-42 combined with the highest levels of total Tau and phosphorylated Tau; moreover, it has been hypothesized that the ratio Aβ1-42:p-Tau further help in discriminating Alzheimer's disease from other diagnoses. The aim of this work is to verify this hypothesis in our cohort of patients and to investigate if the same ratio could be a sensitive index able to discriminate MCI due to neurodegenerative factors (MCId) from MCI due to vascular factors (MCIv).

Methods: Two hundred sixty-two patients meeting the NIA-AA and NINDS-AIREN criteria were diagnosed as follow: AD in 120 patients [mean age 71.6 (42 - 87)], FTD in 23 patients [mean age 67.3 (46 - 78)], LBD in 17 patients [mean age 73.2 (58 - 83)], VAD in 9 patients [mean age 71.2 (60 - 81)]. According to the criteria proposed by Petersen RC, 24 patients had the diagnosis of MCId [mean age 71.8 (59 - 81)], 38 MCIv [mean age 69.3 (55-82). The comparison between the ratio of Aβ1-42/p-Tau among the six groups was done using t-test for independent samples. A p-value < 0.05 was considered to represent statistical significance. The ROC (Receiver Operating Characteristic) curve analysis was made using R-studio software.

Results: The ratio Aβ1-42:p-Tau was significantly lower in AD and MCId with respect to all the other groups and the difference was also statistically significant between MCId and MCIv.

Conclusions: Aβ1-42:p-Tau ratio has potential for being implemented in the clinical routine for differential diagnosis between AD and other dementias and to distinguish underling pathology such as neurodegenerative or vascular disease.
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http://dx.doi.org/10.7754/Clin.Lab.2018.181019DOI Listing
May 2019

Reduced left-lateralized pattern of event-related EEG oscillations in infants at familial risk for language and learning impairment.

Neuroimage Clin 2019 12;22:101778. Epub 2019 Mar 12.

Center for Molecular and Behavioral Neuroscience, Rutgers University-Newark, USA.

The ability to rapidly discriminate successive auditory stimuli within tens-of-milliseconds is crucial for speech and language development, particularly in the first year of life. This skill, called Rapid Auditory Processing (RAP), is altered in infants at familial risk for language and learning impairment (LLI) and is a robust predictor of later language outcomes. In the present study, we investigate the neural substrates of RAP, i.e., the underlying neural oscillatory patterns, in a group of Italian 6-month-old infants at risk for LLI (FH+, n = 24), compared to control infants with no known family history of LLI (FH-, n = 32). Brain responses to rapid changes in fundamental frequency and duration were recorded via high-density electroencephalogram during a non-speech double oddball paradigm. Sources of event-related potential generators were localized to right and left auditory regions in both FH+ and FH- groups. Time-frequency analyses showed variations in both theta (Ɵ) and gamma (ɣ) ranges across groups. Our results showed that overall RAP stimuli elicited a more left-lateralized pattern of oscillations in FH- infants, whereas FH+ infants demonstrated a more right-lateralized pattern, in both the theta and gamma frequency bands. Interestingly, FH+ infants showed reduced early left gamma power (starting at 50 ms after stimulus onset) during deviant discrimination. Perturbed oscillatory dynamics may well constitute a candidate neural mechanism to explain group differences in RAP. Additional group differences in source location suggest that anatomical variations may underlie differences in oscillatory activity. Regarding the predictive value of early oscillatory measures, we found that the amplitude of the source response and the magnitude of oscillatory power and phase synchrony were predictive of expressive vocabulary at 20 months of age. These results further our understanding of the interplay among neural mechanisms that support typical and atypical rapid auditory processing in infancy.
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http://dx.doi.org/10.1016/j.nicl.2019.101778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428938PMC
January 2020

From the magic bullet to the magic target: exploiting the diverse roles of DDX3X in viral infections and tumorigenesis.

Future Med Chem 2019 06 28;11(11):1357-1381. Epub 2019 Feb 28.

Department of DNA Enzymology & Molecular Virology, Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy.

DDX3X is an ATPase/RNA helicase of the DEAD-box family and one of the most multifaceted helicases known up to date, acting in RNA metabolism, cell cycle control, apoptosis, stress response and innate immunity. Depending on the virus or the viral cycle stage, DDX3X can act either in a proviral fashion or as an antiviral factor. Similarly, in different cancer types, it can act either as an oncogene or a tumor-suppressor gene. Accumulating evidence indicated that DDX3X can be considered a promising target for anticancer and antiviral chemotherapy, but also that its exploitation requires a deeper understanding of the molecular mechanisms underlying its dual role in cancer and viral infections. In this Review, we will summarize the known roles of DDX3X in different tumor types and viral infections, and the different inhibitors available, illustrating the possible advantages and potential caveats of their use as anticancer and antiviral drugs.
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http://dx.doi.org/10.4155/fmc-2018-0451DOI Listing
June 2019

DDX3X Helicase Inhibitors as a New Strategy To Fight the West Nile Virus Infection.

J Med Chem 2019 03 21;62(5):2333-2347. Epub 2019 Feb 21.

Dipartimento Biotecnologie, Chimica e Farmacia , Università degli Studi di Siena , Via A. De Gasperi 2 , I-53100 Siena , Italy.

Increased frequency of arbovirus outbreaks in the last 10 years represents an important emergence for global health. Climate warming, extensive urbanization of tropical regions, and human migration flows facilitate the expansion of anthropophilic mosquitos and the emerging or re-emerging of new viral infections. Only recently the human adenosinetriphosphatase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against infectious diseases. Herein, starting from our previous studies, a new family of DDX3X inhibitors was designed, synthesized, validated on the target enzyme, and evaluated against the West Nile virus (WNV) infection. Time of addition experiments after virus infection indicated that the compounds exerted their antiviral activities after the entry process, likely at the protein translation step of WNV replication. Finally, the most interesting compounds were then analyzed for their in vitro pharmacokinetic parameters, revealing favorable absorption, distribution, metabolism, and excretion values. The good safety profile together with a good activity against WNV for which no treatments are currently available, make this new class of molecules a good starting point for further in vivo studies.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01403DOI Listing
March 2019
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