In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination

Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants. We have therefore taken an approach to adjuvant discovery that uses in silico modeling and structure-based drug-design. As proof-of-principle we chose to target the interaction of the chemokines CCL22 and CCL17 with their receptor CCR4. CCR4 was posited as an adjuvant target based on its expression on CD4(+)CD25(+) regulatory T cells (Tregs), which negatively regulate immune responses induced by dendritic cells (DC), whereas CCL17 and CCL22 are chemotactic agents produced by DC, which are crucial in promoting contact between DC and CCR4(+) T cells. Molecules identified by virtual screening and molecular docking as CCR4 antagonists were able to block CCL22- and CCL17-mediated recruitment of human Tregs and Th2 cells. Furthermore, CCR4 antagonists enhanced DC-mediated human CD4(+) T cell proliferation in an in vitro immune response model and amplified cellular and humoral immune responses in vivo in experimental models when injected in combination with either Modified Vaccinia Ankara expressing Ag85A from Mycobacterium tuberculosis (MVA85A) or recombinant hepatitis B virus surface antigen (rHBsAg) vaccines. The significant adjuvant activity observed provides good evidence supporting our hypothesis that CCR4 is a viable target for rational adjuvant design.

Watermark-only security attack on DM-QIM watermarking:vulnerability to guided key guessing

This paper addresses the security of a specific class of common watermarking methods based on Dither modulation-quantisation index modulation (DM-QIM) and focusing on watermark-only attacks (WOA). The vulnerabilities of and probable attacks on lattice structure based watermark embedding methods have been presented in the literature. DM-QIM is one of the best known lattice structure based watermarking techniques. In this paper, the authors discuss a watermark-only attack scenario (the attacker has access to a single watermarked content only). In the literature it is an assumption that DM-QIM methods are secure to WOA. However, the authors show that the DM-QIM based embedding method is vulnerable against a guided key guessing attack by exploiting subtle statistical regularities in the feature space embeddings for time series and images. Using a distribution-free algorithm, this paper presents an analysis of the attack and numerical results for multiple examples of image and time series data.

Watermark-only security attack on DM-QIM watermarking:vulnerability to guided key guessing

This paper addresses the security of a specific class of common watermarking methods based on Dither modulation-quantisation index modulation (DM-QIM) and focusing on watermark-only attacks (WOA). The vulnerabilities of and probable attacks on lattice structure based watermark embedding methods have been presented in the literature. DM-QIM is one of the best known lattice structure based watermarking techniques. In this paper, the authors discuss a watermark-only attack scenario (the attacker has access to a single watermarked content only). In the literature it is an assumption that DM-QIM methods are secure to WOA. However, the authors show that the DM-QIM based embedding method is vulnerable against a guided key guessing attack by exploiting subtle statistical regularities in the feature space embeddings for time series and images. Using a distribution-free algorithm, this paper presents an analysis of the attack and numerical results for multiple examples of image and time series data.

Contradictory reasoning network:an EEG and FMRI study

Contradiction is a cornerstone of human rationality, essential for everyday life and communication. We investigated electroencephalographic (EEG) and functional magnetic resonance imaging (fMRI) in separate recording sessions during contradictory judgments, using a logical structure based on categorical propositions of the Aristotelian Square of Opposition (ASoO). The use of ASoO propositions, while controlling for potential linguistic or semantic confounds, enabled us to observe the spatial temporal unfolding of this contradictory reasoning. The processing started with the inversion of the logical operators corresponding to right middle frontal gyrus (rMFG-BA11) activation, followed by identification of contradictory statement associated with in the right inferior frontal gyrus (rIFG-BA47) activation. Right medial frontal gyrus (rMeFG, BA10) and anterior cingulate cortex (ACC, BA32) contributed to the later stages of process. We observed a correlation between the delayed latency of rBA11 response and the reaction time delay during inductive vs. deductive reasoning. This supports the notion that rBA11 is crucial for manipulating the logical operators. Slower processing time and stronger brain responses for inductive logic suggested that examples are easier to process than general principles and are more likely to simplify communication. © 2014 Porcaro et al.

Implementação em FPGA de módulo de efeito de reverberação

Reverberation is caused by the reflection of the sound in adjacent surfaces close to the sound source during its propagation to the listener. The impulsive response of an environment represents its reverberation characteristics. Being dependent on the environment, reverberation takes to the listener characteristics of the space where the sound is originated and its absence does not commonly sounds like “natural”. When recording sounds, it is not always possible to have the desirable characteristics of reverberation of an environment, therefore methods for artificial reverberation have been developed, always seeking a more efficient implementations and more faithful to the real environments. This work presents an implementation in FPGAs (Field Programmable Gate Arrays ) of a classic digital reverberation audio structure, based on a proposal of Manfred Schroeder, using sets of all-pass and comb filters. The developed system exploits the use of reconfigurable hardware as a platform development and implementation of digital audio effects, focusing on the modularity and reuse characteristics

Ecologia de comunidades e comportamento reprodutivo de anfíbios anuros em savana amazônica

The Amazon savannas occur as isolated patches throughout extensive areas of forest in the states of Amapá, Amazonas, Pará, and Roraima. There is a considerable variation in the composition of anuran assemblages in the localities and phytophysiognomies of Amazon savannas and given the absence of studies on reproductive behavior, a systematic and geographically wide sampling has been carried out in the Amapá savanna, located in the Eastern Amazon. The study was conducted in a savanna area in the state of Amapá to examine the composition, ecology, and reproductive behavior of anuran amphibians. We carried out 24 field trips in each phytophysiognomy (gramineous-woody savana, gramineous-herbaceous-woody savana, park savana, and arboreal savanna); for analysis of reproductive behavior observations were made during the period January to December 2013, lasting four consecutive days. Samples were collected by active and acoustic search along 20 plots of 100x50 meters. Twenty-one anuran species were recorded, of which four are new records for the state of Amapá: Dendropsophus walfordi, Scinax fuscomarginatus, Pseudopaludicola boliviana e Elachistocleis helianneae. The KruskalWallis ANOVA revealed significant differences between richness and species diversity in the phytophysiognomies (p < 0.05). The Bray-Curtis similarity coefficient divided the phytophysiognomies into three groups: arboreal savana, gramineous-woody savanna and gramineous-herbaceous-woody savanna, and park savanna. According to the non-metric multidimensional scaling, the structure of the anuran community resulted in a separation into three phytophysiognomies, with significant differences in the structure of communities (ANOSIM, R = 0.823; p < 0.001). In the study of community ecology, the results obtained for spatial, temporal, and trophic niche breadth suggest that the assemblage of anurans of the Amapá savanna is not composed of predominantly generalist species. Also, the presence of other specialist anurans may explain the processes of speciation associated with the isolation of habitats, resulting in heterogeneity and spatial discontinuity in the phytophysiognomies with open formations. The null model analysis revealed that the community is structured based on temporal and trophic niche, indicating a significant influence of contemporary ecological factors on the assemblage. The absence of structure based on spatial niche might be explained by the spatial segregation in the distribution and occupation of anurans in the different phytophysiognomies of the Amapá savanna. Regarding the reproductive behavior of anurans, 11 species were classified as having a long breeding season, intrinsically associated with the rainy season and the reproductive mode of most species that lay egg clutches in lentic water bodies. Six reproductive modes were recorded and parental care was observed in Leptodactylus macrosternum and L. podicipinus, whose reproductive mode is characterized by foam nests. Regarding behavioral reproductive strategies, calling males were observed in all species of anurans, satellite males were recorded only for D. walfordi, Hypsiboas multifasciatus, S. nebulosus and S. fuscomarginatus; active search for females was observed for Phyllomedusa hypochondrialis and L. fuscus, and male displacement was recorded only for Rhinella major and R. margaritifera. Of the reproductive behaviors observed, throat and vocal sac display is associated with courtship and territorial behavior exhibited by males. In addition to courtship behavior, visual signals associated with courtship strategies were recorded for the anurans of the Amapá savanna.

Occurrence and Function of Hoogsteen Base Pairs in Nucleic Acids

Nucleic acids (DNA and RNA) play essential roles in the central dogma of biology for the storage and transfer of genetic information. The unique chemical and conformational structures of nucleic acids – the double helix composed of complementary Watson-Crick base pairs, provide the structural basis to carry out their biological functions. DNA double helix can dynamically accommodate Watson-Crick and Hoogsteen base-pairing, in which the purine base is flipped by ~180° degrees to adopt syn rather than anti conformation as in Watson-Crick base pairs. There is growing evidence that Hoogsteen base pairs play important roles in DNA replication, recognition, damage or mispair accommodation and repair. Here, we constructed a database for existing Hoogsteen base pairs in DNA duplexes by a structure-based survey from the Protein Data Bank, and structural analyses based on the resulted Hoogsteen structures revealed that Hoogsteen base pairs occur in a wide variety of biological contexts and can induce DNA kinking towards the major groove. As there were documented difficulties in modeling Hoogsteen or Watson-Crick by crystallography, we collaborated with the Richardsons’ lab and identified potential Hoogsteen base pairs that were mis-modeled as Watson-Crick base pairs which suggested that Hoogsteen can be more prevalent than it was thought to be. We developed solution NMR method combined with the site-specific isotope labeling to characterize the formation of, or conformational exchange with Hoogsteen base pairs in large DNA-protein complexes under solution conditions, in the absence of the crystal packing force. We showed that there are enhanced chemical exchange, potentially between Watson-Crick and Hoogsteen, at a sharp kink site in the complex formed by DNA and the Integration Host Factor protein. In stark contrast to B-form DNA, we found that Hoogsteen base pairs are strongly disfavored in A-form RNA duplex. Chemical modifications N1-methyl adenosine and N1-methyl guanosine that block Watson-Crick base-pairing, can be absorbed as Hoogsteen base pairs in DNA, but rather potently destabilized A-form RNA and caused helix melting. The intrinsic instability of Hoogsteen base pairs in A-form RNA endows the N1-methylation as a functioning post-transcriptional modification that was known to facilitate RNA folding, translation and potentially play roles in the epitranscriptome. On the other hand, the dynamic property of DNA that can accommodate Hoogsteen base pairs could be critical to maintaining the genome stability.

Loess as a Collapsible Soil: Some Basic Particle Packing

Loess is the most important collapsible soil; possibly the only engineering soil in which real collapse occurs. A real collapse involves a diminution in volume - it would be an open metastable packing being reduced to a more closely packed, more stable structure. Metastability is at the heart of the collapsible soils problem. To envisage and to model the collapse process in a metastable medium, knowledge is required about the nature and shape of the particles, the types of packings they assume (real and ideal), and the nature of the collapse process - a packing transition upon a change to the effective stress in a media of double porosity. Particle packing science has made little progress in geoscience discipline - since the initial packing paradigms set by Graton and Fraser (1935) - nevertheless is relatively well-established in the soft matter physics discipline. The collapse process can be represented by mathematical modelling of packing – including the Monte Carlo simulations - but relating representation to process remains difficult. This paper revisits the problem of sudden packing transition from a micro-physico-mechanical viewpoint (i.e. collapse imetan terms of structure-based effective stress). This cross-disciplinary approach helps in generalization on collapsible soils to be made that suggests loess is the only truly collapsible soil, because it is only loess which is so totally influenced by the packing essence of the formation process.

Ground Plane Slot Structures for Isolation of Cosited Microstrip Antennas

Ground plane slot structures have been shown to reduce coupling between cosited antennas. Although some such structures have already been reported, no analytical model exists to describe their behavior and there are no design guidelines. In this work, the behavior of reported ground plane structures is used as a clue to obtain generalizable information about such structures' behavior. The structures' scalability and excitation behavior is investigated. Next a circuit model is derived that describes the interaction of microstrip patch antennas with a ground plane slot structure based on mutual admittances between the ground plane slots and the effective slots at the antennas' radiating edges. The circuit model leads to design guidelines for the ground plane slot structure and an approximate relationship between mutual admittances which must be satisfied in order to isolate the antennas. Finally, we present a novel ground plane slot structure that mitigates some of the disadvantages of earlier designs.

High diversity of skin-associated bacterial communities of marine fishes is promoted by their high variability among body parts, individuals and species

Animal-associated microbiotas form complex communities, which are suspected to play crucial functions for their host fitness. However, the biodiversity of these communities, including their differences between host species and individuals, has been scarcely studied, especially in case of skin-associated communities. In addition, the intraindividual variability (i.e. between body parts) has never been assessed to date. The objective of this study was to characterize skin bacterial communities of two teleostean fish species, namely the European seabass (Dicentrarchus labrax) and gilthead seabream (Sparus aurata), using a high-throughput DNA sequencing method. In order to focus on intrinsic factors of host-associated bacterial community variability, individuals of the two species were raised in controlled conditions. Bacterial diversity was assessed using a set of four complementary indices, describing the taxonomic and phylogenetic facets of biodiversity and their respective composition (based on presence/absence data) and structure (based on species relative abundances) components. Variability of bacterial diversity was quantified at the interspecific, interindividual and intraindividual scales. We demonstrated that fish surfaces host highly diverse bacterial communities, whose composition was very different from that of surrounding bacterioplankton. This high total biodiversity of skin-associated communities was supported by the important variability, between host species, individuals and the different body parts (dorsal, anal, pectoral and caudal fins).

English syllable confusion and imitation in Korean bilingual and monolingual children and adults

In the present study, Korean-English bilingual (KEB) and Korean monolingual (KM) children, between the ages of 8 and 13 years, and KEB adults, ages 18 and older, were examined with one speech perception task, called the Nonsense Syllable Confusion Matrix (NSCM) task (Allen, 2005), and two production tasks, called the Nonsense Syllable Imitation Task (NSIT) and the Nonword Repetition Task (NRT; Dollaghan & Campbell, 1998). The present study examined (a) which English sounds on the NSCM task were identified less well, presumably due to interference from Korean phonology, in bilinguals learning English as a second language (L2) and in monolinguals learning English as a foreign language (FL); (b) which English phonemes on the NSIT were more challenging for bilinguals and monolinguals to produce; (c) whether perception on the NSCM task is related to production on the NSIT, or phonological awareness, as measured by the NRT; and (d) whether perception and production differ in three age-language status groups (i.e., KEB children, KEB adults, and KM children) and in three proficiency subgroups of KEB children (i.e., English-dominant, ED; balanced, BAL; and Korean-dominant, KD). In order to determine English proficiency in each group, language samples were extensively and rigorously analyzed, using software, called Systematic Analysis of Language Transcripts (SALT). Length of samples in complete and intelligible utterances, number of different and total words (NDW and NTW, respectively), speech rate in words per minute (WPM), and number of grammatical errors, mazes, and abandoned utterances were measured and compared among the three initial groups and the three proficiency subgroups. Results of the language sample analysis (LSA) showed significant group differences only between the KEBs and the KM children, but not between the KEB children and adults. Nonetheless, compared to normative means (from a sample length- and age-matched database provided by SALT), the KEB adult group and the KD subgroup produced English at significantly slower speech rates than expected for monolingual, English-speaking counterparts. Two existing models of bilingual speech perception and production—the Speech Learning Model or SLM (Flege, 1987, 1992) and the Perceptual Assimilation Model or PAM (Best, McRoberts, & Sithole, 1988; Best, McRoberts, & Goodell, 2001)—were considered to see if they could account for the perceptual and production patterns evident in the present study. The selected English sounds for stimuli in the NSCM task and the NSIT were 10 consonants, /p, b, k, g, f, θ, s, z, ʧ, ʤ/, and 3 vowels /I, ɛ, æ/, which were used to create 30 nonsense syllables in a consonant-vowel structure. Based on phonetic or phonemic differences between the two languages, English sounds were categorized either as familiar sounds—namely, English sounds that are similar, but not identical, to L1 Korean, including /p, k, s, ʧ, ɛ/—or unfamiliar sounds—namely, English sounds that are new to L1, including /b, g, f, θ, z, ʤ, I, æ/. The results of the NSCM task showed that (a) consonants were perceived correctly more often than vowels, (b) familiar sounds were perceived correctly more often than unfamiliar ones, and (c) familiar consonants were perceived correctly more often than unfamiliar ones across the three age-language status groups and across the three proficiency subgroups; and (d) the KEB children perceived correctly more often than the KEB adults, the KEB children and adults perceived correctly more often than the KM children, and the ED and BAL subgroups perceived correctly more often than the KD subgroup. The results of the NSIT showed (a) consonants were produced more accurately than vowels, and (b) familiar sounds were produced more accurately than unfamiliar ones, across the three age-language status groups. Also, (c) familiar consonants were produced more accurately than unfamiliar ones in the KEB and KM child groups, and (d) unfamiliar vowels were produced more accurately than a familiar one in the KEB child group, but the reverse was true in the KEB adult and KM child groups. The KEB children produced sounds correctly significantly more often than the KM children and the KEB adults, though the percent correct differences were smaller than for perception. Production differences were not found among the three proficiency subgroups. Perception on the NSCM task was compared to production on the NSIT and NRT. Weak positive correlations were found between perception and production (NSIT) for unfamiliar consonants and sounds, whereas a weak negative correlation was found for unfamiliar vowels. Several correlations were significant for perceptual performance on the NSCM task and overall production performance on the NRT: for unfamiliar consonants, unfamiliar vowels, unfamiliar sounds, consonants, vowels, and overall performance on the NSCM task. Nonetheless, no significant correlation was found between production on the NSIT and NRT. Evidently these are two very different production tasks, where immediate imitation of single syllables on the NSIT results in high performance for all groups. Findings of the present study suggest that (a) perception and production of L2 consonants differ from those of vowels; (b) perception and production of L2 sounds involve an interaction of sound type and familiarity; (c) a weak relation exists between perception and production performance for unfamiliar sounds; and (d) L2 experience generally predicts perceptual and production performance. The present study yields several conclusions. The first is that familiarity of sounds is an important influence on L2 learning, as claimed by both SLM and PAM. In the present study, familiar sounds were perceived and produced correctly more often than unfamiliar ones in most cases, in keeping with PAM, though experienced L2 learners (i.e., the KEB children) produced unfamiliar vowels better than familiar ones, in keeping with SLM. Nonetheless, the second conclusion is that neither SLM nor PAM consistently and thoroughly explains the results of the present study. This is because both theories assume that the influence of L1 on the perception of L2 consonants and vowels works in the same way as for production of them. The third and fourth conclusions are two proposed arguments: that perception and production of consonants are different than for vowels, and that sound type interacts with familiarity and L2 experience. These two arguments can best explain the current findings. These findings may help us to develop educational curricula for bilingual individuals listening to and articulating English. Further, the extensive analysis of spontaneous speech in the present study should contribute to the specification of parameters for normal language development and function in Korean-English bilingual children and adults.

The development of planar high-K/III-V p-channel MOSFETs for post-silicon CMOS

Conventional Si complementary-metal-oxide-semiconductor (CMOS) scaling is fast approaching its limits. The extension of the logic device roadmap for future enhancements in transistor performance requires non-Si materials and new device architectures. III-V materials, due to their superior electron transport properties, are well poised to replace Si as the channel material beyond the 10nm technology node to mitigate the performance loss of Si transistors from further reductions in supply voltage to minimise power dissipation in logic circuits. However several key challenges, including a high quality dielectric/III-V gate stack, a low-resistance source/drain (S/D) technology, heterointegration onto a Si platform and a viable III-V p-metal-oxide-semiconductor field-effect-transistor (MOSFET), need to be addressed before III-Vs can be employed in CMOS. This Thesis specifically addressed the development and demonstration of planar III-V p-MOSFETs, to complement the n-MOSFET, thereby enabling an all III-V CMOS technology to be realised. This work explored the application of InGaAs and InGaSb material systems as the channel, in conjunction with Al2O3/metal gate stacks, for p-MOSFET development based on the buried-channel flatband device architecture. The body of work undertaken comprised material development, process module development and integration into a robust fabrication flow for the demonstration of p-channel devices. The parameter space in the design of the device layer structure, based around the III-V channel/barrier material options of In_x≥0.53Ga_1-xAs/In_0.52Al_0.48As and In_x≥0.1Ga_1-xSb/AlSb, was systematically examined to improve hole channel transport. A mobility of 433 cm²/Vs, the highest room temperature hole mobility of any InGaAs quantum-well channel reported to date, was obtained for the In_0.85Ga_0.15As (2.1% strain) structure. S/D ohmic contacts were developed based on thermally annealed Au/Zn/Au metallisation and validated using transmission line model test structures. The effects of metallisation thickness, diffusion barriers and de-oxidation conditions were examined. Contacts to InGaSb-channel structures were found to be sensitive to de-oxidation conditions. A fabrication process, based on a lithographically-aligned double ohmic patterning approach, was realised for deep submicron gate-to-source/drain gap (L_side) scaling to minimise the access resistance, thereby mitigating the effects of parasitic S/D series resistance on transistor performance. The developed process yielded gaps as small as 20nm. For high-k integration on GaSb, ex-situ ammonium sulphide ((NH₄)₂S) treatments, in the range 1%-22%, for 10min at 295K were systematically explored for improving the electrical properties of the Al₂O₃/GaSb interface. Electrical and physical characterisation indicated the 1% treatment to be most effective with interface trap densities in the range of 4 - 10×10¹²cm^-2eV^-1 in the lower half of the bandgap. An extended study, comprising additional immersion times at each sulphide concentration, was further undertaken to determine the surface roughness and the etching nature of the treatments on GaSb. A number of p-MOSFETs based on III-V-channels with the most promising hole transport and integration of the developed process modules were successfully demonstrated in this work. Although the non-inverted InGaAs-channel devices showed good current modulation and switch-off characteristics, several aspects of performance were non-ideal; depletion-mode operation, modest drive current (I_d,sat=1.14mA/mm), double peaked transconductance (g_m=1.06mS/mm), high subthreshold swing (SS=301mV/dec) and high on-resistance (R_on=845kΩ.μm). Despite demonstrating substantial improvement in the on-state metrics of I_d,sat (11×), g_m (5.5×) and R_on (5.6×), inverted devices did not switch-off. Scaling gate-to-source/drain gap (L_side) from 1μm down to 70nm improved I_d,sat (72.4mA/mm) by a factor of 3.6 and gm (25.8mS/mm) by a factor of 4.1 in inverted InGaAs-channel devices. Well-controlled current modulation and good saturation behaviour was observed for InGaSb-channel devices. In the on-state In_0.3Ga_0.7Sb-channel (I_d,sat=49.4mA/mm, g_m=12.3mS/mm, R_on=31.7kΩ.μm) and In_0.4Ga_0.6Sb-channel (I_d,sat=38mA/mm, g_m=11.9mS/mm, R_on=73.5kΩ.μm) devices outperformed the InGaAs-channel devices. However the devices could not be switched off. These findings indicate that III-V p-MOSFETs based on InGaSb as opposed to InGaAs channels are more suited as the p-channel option for post-Si CMOS.

Photovoltaic power forecast modeling with artificial neural networks

Dissertação de Mestrado, Engenharia Eletrónica e Telecomunicações, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2016

Knowledge, perceptions and attitudes on the sexuality of nursing students and teachers

Introduction: The personal attitudes regarding specific aspects of sexuality are of interest to practices of personal concern, as they are to practices inserted in professional roles. General attitudes towards sexuality and sexual health were evaluated. Objectives: To describe the perceptions and attitudes of students and nursing teachers about sexuality. Methods: We used a mixed methods design with a sequential strategy: QUAN→qual of descriptive and explanatory type. 646 students and teachers participated. The Sexual Attitudes Scale (EAS) of Hendrick & Hendrick (Alferes, 1999) and Attitude Scale Address Sexual and Reproductive Health (EAFSSR) of Nemčić et al (Abreu, 2008) were used. Results: There are significant differences in the level of knowledge about sexuality depending on the sample (χ2KW (2)=18.271; p=.000): students of 1st year have lower levels. The profile of the four dimensions of EAS per sample is identical in all 3 samples, having responsibility the highest average value. In subscales EAFSSR per sample and sex there are significant diferences (p<.05) for all samples and uniform pattern was noted: females have higher median values, indicating that they have more favorable attitudes towards sexual health. Conclusions: Sexual attitudes reveal a multidimensional structure based in the female identity, that shows responsibility towards family planning and sexual education, as well as towards individual self-care regarding the body and sexual and reproductive health. An attitudinal profile by gender emerges, accentuating the polarity between male and female. The importance of the training process in nursing following the personal and social development of students is corroborated.

Design and synthesis of E3 ligase RNF5 inhibitors as innovative strategy to trigger mutant CFTR rescue in Cystic Fibrosis

In Cystic Fibrosis (CF) the deletion of phenylalanine 508 (F508del) in the CFTR anion channel is associated to misfolding and defective gating of the mutant protein. Among the known proteins involved in CFTR processing, one of the most promising drug target is the ubiquitin ligase RNF5, which normally promotes F508del-CFTR degradation. In this context, a small molecule RNF5 inhibitor is expected to chemically mimic a condition of RNF5 silencing, thus preventing mutant CFTR degradation and causing its stabilization and plasma membrane trafficking. Hence, by exploiting a virtual screening (VS) campaign, the hit compound inh-2 was discovered as the first-in-class inhibitor of RNF5. Evaluation of inh-2 efficacy on CFTR rescue showed that it efficiently decreases ubiquitination of mutant CFTR and increases chloride current in human primary bronchial epithelia. Based on the promising biological results obtained with inh-2, this thesis reports the structure-based design of potential RNF5 inhibitors having improved potency and efficacy. The optimization of general synthetic strategies gave access to a library of analogues of the 1,2,4-thiadiazol-5-ylidene inh-2 for SAR investigation. The new analogues were tested for their corrector activity in CFBE41o- cells by using the microfluorimetric HS-YFP assay as a primary screen. Then, the effect of putative RNF5 inhibitors on proliferation, apoptosis and the formation of autophagic vacuoles was evaluated. Some of the new analogs significantly increased the basal level of autophagy, reproducing RNF5 silencing effect in cell. Among them, one compound also displayed a greater rescue of the F508del-CFTR trafficking defect than inh-2. Our preliminary results suggest that the 1,2,4-thiadiazolylidene could be a suitable scaffold for the discovery of potential RNF5 inhibitors able to rescue mutant CFTRs. Biological tests are still ongoing to acquire in-depth knowledge about the mechanism of action and therapeutic relevance of this unprecedented pharmacological strategy.