Neuropsychiatric disease (NPD) clustering in families with Autism Spectrum Disorder (ASD): genetic, epigenetic and environmental issues

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, epilepsy, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and further clinical presentation. Both miRNA and lncRNA are functional RNA molecules that are transcribed from DNA but not translated into proteins, instead they act as powerful regulators of gene expression. While miRNA are small noncoding RNAs with 22-25 nucleotides in length that act at the post-transcriptional level of gene expression, the lncRNA are bigger molecules (>200 nucleotides in length) that are capped, spliced, and polyadenylated, similar to messenger RNA. Although few lncRNA were well characterized until date, there is a great evidence that they are implicated in several levels of gene expression (transcription/post-transcription/post-translation, organization of protein complexes, cell– cell signaling as well as recombination) as shown in figure 1.

Contribution of plant phytochemicals to organic homeostasis: focus on the aging process and opportunistic infections

Aging process is conceived as a normal stage during human life cycle, but it is also considered a hot topic among scientists and medical community. Alarming rates of premature aging and oxidative stress-related diseases have increasingly affect human individuals. Stress, pollution and exposition to chemical substances are considered the main triggering factors for those conditions; in addition, they also suppress the immune system and, therefore, improve organic vulnerability and occurrence of opportunistic infections [I]. Apart from the associated morbidity and mortality, the increasing rates of antimicrobial resistance improve the severity of the clinical conditions [2]. Botanical preparations possess a multitude of bioactive properties, namely acting as antimicrobials, antioxidants, and homeostasis modulators. Thus, upcoming alternatives, mainly based in plant phytochemicals, are necessary to improve the wellbeing as also life expectancy of individuals. The present study aims to evaluate and to compare both antioxidant and antimicrobial properties of plant extracts rich in phenolic compounds. Among the tested plants, Glycyrrhiza glabra L. (licorice) evidenced the most pronounced free radicals scavenging and antimicrobial effects, followed by Salvia officina/is L. (sage), Thymus vulgaris L. (thyme) and Origanum vulgare L. (oregano). Eucalyptus globulus Labill. (blue gum) and Juglans regia L. (walnut) also showed a high effect, while Pterospartum tridentatum (L.) Willk. (carqueja) and Rubus ulmifolius Schott (elm leaf blackberry) displayed moderate effects, and lastly, Tabebuia impetigirwsa (Mart. ex DC) Standley (pau d'arco), Foeniculum vulgare Miller (fennel), Rosa canina L. (rose hips) and Matricaria recutita L. (chamomile) gave only slight effects. In general, the most pronounced bioactivities were observed in the plant preparations (infusion>decoction>hydromethanolic extract) with higher levels of phenolic compounds (both flavonoids and phenolic acids). The observed synergisms between the phenolic compounds present in the extracts highlight the use of phytochemicals as future health promoters. However, further studies are necessary to understand the effective mode of action of individual phenolic constituents as also the existence of polyvalence relationships between them.

Porównawcza analiza strukturalno-funkcjonalna in silico białek STAT i IRF, w celu identyfikacji związków chemicznych, działających jako specyficzne inhibitory funkcjonalne

Wydział Biologii: Instytut Biologii Molekularnej i Biotechnologii

Holistic Design In High-Speed Optical Interconnects

Integrated circuit scaling has enabled a huge growth in processing capability, which necessitates a corresponding increase in inter-chip communication bandwidth. As bandwidth requirements for chip-to-chip interconnection scale, deficiencies of electrical channels become more apparent. Optical links present a viable alternative due to their low frequency-dependent loss and higher bandwidth density in the form of wavelength division multiplexing. As integrated photonics and bonding technologies are maturing, commercialization of hybrid-integrated optical links are becoming a reality. Increasing silicon integration leads to better performance in optical links but necessitates a corresponding co-design strategy in both electronics and photonics. In this light, holistic design of high-speed optical links with an in-depth understanding of photonics and state-of-the-art electronics brings their performance to unprecedented levels. This thesis presents developments in high-speed optical links by co-designing and co-integrating the primary elements of an optical link: receiver, transmitter, and clocking.

In the first part of this thesis a 3D-integrated CMOS/Silicon-photonic receiver will be presented. The electronic chip features a novel design that employs a low-bandwidth TIA front-end, double-sampling and equalization through dynamic offset modulation. Measured results show -14.9dBm of sensitivity and energy efficiency of 170fJ/b at 25Gb/s. The same receiver front-end is also used to implement source-synchronous 4-channel WDM-based parallel optical receiver. Quadrature ILO-based clocking is employed for synchronization and a novel frequency-tracking method that exploits the dynamics of IL in a quadrature ring oscillator to increase the effective locking range. An adaptive body-biasing circuit is designed to maintain the per-bit-energy consumption constant across wide data-rates. The prototype measurements indicate a record-low power consumption of 153fJ/b at 32Gb/s. The receiver sensitivity is measured to be -8.8dBm at 32Gb/s.

Next, on the optical transmitter side, three new techniques will be presented. First one is a differential ring modulator that breaks the optical bandwidth/quality factor trade-off known to limit the speed of high-Q ring modulators. This structure maintains a constant energy in the ring to avoid pattern-dependent power droop. As a first proof of concept, a prototype has been fabricated and measured up to 10Gb/s. The second technique is thermal stabilization of micro-ring resonator modulators through direct measurement of temperature using a monolithic PTAT temperature sensor. The measured temperature is used in a feedback loop to adjust the thermal tuner of the ring. A prototype is fabricated and a closed-loop feedback system is demonstrated to operate at 20Gb/s in the presence of temperature fluctuations. The third technique is a switched-capacitor based pre-emphasis technique designed to extend the inherently low bandwidth of carrier injection micro-ring modulators. A measured prototype of the optical transmitter achieves energy efficiency of 342fJ/bit at 10Gb/s and the wavelength stabilization circuit based on the monolithic PTAT sensor consumes 0.29mW.

Lastly, a first-order frequency synthesizer that is suitable for high-speed on-chip clock generation will be discussed. The proposed design features an architecture combining an LC quadrature VCO, two sample-and-holds, a PI, digital coarse-tuning, and rotational frequency detection for fine-tuning. In addition to an electrical reference clock, as an extra feature, the prototype chip is capable of receiving a low jitter optical reference clock generated by a high-repetition-rate mode-locked laser. The output clock at 8GHz has an integrated RMS jitter of 490fs, peak-to-peak periodic jitter of 2.06ps, and total RMS jitter of 680fs. The reference spurs are measured to be –64.3dB below the carrier frequency. At 8GHz the system consumes 2.49mW from a 1V supply.

Phytochemical mediated-modulation of the expression and transporter function of breast cancer resistance protein at the blood-brain barrier:an in-vitro study

Clinical translation of BCRP inhibitors have failed due to neurotoxicity and novel approaches are required to identify suitable modulators of BCRP to enhance CNS drug delivery. In this study we examine 18 compounds, primarily phytochemicals, as potential novel modulators of AhR-mediated regulation of BCRP expression and function in immortalised and primary porcine brain microvascular endothelial cells as a mechanism to enhance CNS drug delivery. The majority of modulators possessed a cellular viability IC50 > 100 µM in both cell systems. BCRP activity, when exposed to modulators for 1 hour, was diminished for most modulators through significant increases in H33342 accumulation at < 10 µM with 2,6,4-trimethoflavone increasing H33342 intracellular accumulation by 3.7–6.6 fold over 1–100 µM. Western blotting and qPCR identified two inducers of BCRP (quercetin and naringin) and two down-regulators (17-β-estradiol and curcumin) with associated changes in BCRP efflux transport function further confirmed in both cell lines. siRNA downregulation of AhR resulted in a 1.75 ± 0.08 fold change in BCRP expression, confirming the role of AhR in the regulation of BCRP. These findings establish the regulatory role AhR of in controlling BCRP expression at the BBB and confirm quercetin, naringin, 17-β-estradiol, and curcumin as novel inducers and down-regulators of BCRP gene, protein expression and functional transporter activity and hence potential novel target sites and candidates for enhancing CNS drug delivery.

Staphylococcus aureus CC398: host adaptation and emergence of methicillin resistance in livestock

UNLABELLED Since its discovery in the early 2000s, methicillin-resistant Staphylococcus aureus (MRSA) clonal complex 398 (CC398) has become a rapidly emerging cause of human infections, most often associated with livestock exposure. We applied whole-genome sequence typing to characterize a diverse collection of CC398 isolates (n = 89), including MRSA and methicillin-susceptible S. aureus (MSSA) from animals and humans spanning 19 countries and four continents. We identified 4,238 single nucleotide polymorphisms (SNPs) among the 89 core genomes. Minimal homoplasy (consistency index = 0.9591) was detected among parsimony-informative SNPs, allowing for the generation of a highly accurate phylogenetic reconstruction of the CC398 clonal lineage. Phylogenetic analyses revealed that MSSA from humans formed the most ancestral clades. The most derived lineages were composed predominantly of livestock-associated MRSA possessing three different staphylococcal cassette chromosome mec element (SCCmec) types (IV, V, and VII-like) including nine subtypes. The human-associated isolates from the basal clades carried phages encoding human innate immune modulators that were largely missing among the livestock-associated isolates. Our results strongly suggest that livestock-associated MRSA CC398 originated in humans as MSSA. The lineage appears to have undergone a rapid radiation in conjunction with the jump from humans to livestock, where it subsequently acquired tetracycline and methicillin resistance. Further analyses are required to estimate the number of independent genetic events leading to the methicillin-resistant sublineages, but the diversity of SCCmec subtypes is suggestive of strong and diverse antimicrobial selection associated with food animal production. IMPORTANCE Modern food animal production is characterized by densely concentrated animals and routine antibiotic use, which may facilitate the emergence of novel antibiotic-resistant zoonotic pathogens. Our findings strongly support the idea that livestock-associated MRSA CC398 originated as MSSA in humans. The jump of CC398 from humans to livestock was accompanied by the loss of phage-carried human virulence genes, which likely attenuated its zoonotic potential, but it was also accompanied by the acquisition of tetracycline and methicillin resistance. Our findings exemplify a bidirectional zoonotic exchange and underscore the potential public health risks of widespread antibiotic use in food animal production.

The epigenome as a therapeutic target for Parkinson's disease

Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients. There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. This article first discusses the present evidence implicating global, and dopaminergic neuron-specific, alterations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Landscape structure shapes carnivore-mediated seed dispersal kernels

Context Seed dispersal is recognized as having profound effects on the distribution, dynamics and structure of plant populations and communities. However, knowledge of how landscape structure shapes carnivore-mediated seed dispersal patterns is still scarce, thereby limiting our understanding of large-scale plant population processes. Objectives We aim to determine how the amount and spatial configuration of forest cover impacted the relative abundance of carnivorous mammals, and how these effects cascaded through the seed dispersal kernels they generated. Methods Camera traps activated by animal movement were used for carnivore sampling. Colour-coded seed mimics embedded in common figs were used to know the exact origin of the dispersed seed mimics later found in carnivore scats. We applied this procedure in two sites differing in landscape structure. Results We did not find between-site differences in the relative abundance of the principal carnivore species contributing to seed dispersal patterns, Martes foina. Mean dispersal distance and the probability of long dispersal events were higher in the site with spatially continuous and abundant forest cover, compared to the site with spatially aggregated and scarcer forest cover. Seed deposition closely matched the spatial patterning of forest cover in both study sites, suggesting behaviour-based mechanisms underpinning seed dispersal patterns generated by individual frugivore species. Conclusions Our results provide the first empirical evidence of the impact of landscape structure on carnivore-mediated seed dispersal kernels. They also indicate that seed dispersal kernels generated strongly depend on the effect that landscape structure exerts on carnivore populations, particularly on habitat-use preferences.