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Sleep disorders are highly prevalent in children with Autism Spectrum Disorder (ASD), profoundly impacting their neurodevelopment and daily functioning. Alterations in sleep architecture and regulatory mechanisms contribute to difficulties with sleep onset, maintenance, and overall sleep quality. Sensory processing differences, commonly observed in ASD, may further exacerbate these disturbances by affecting arousal regulation and environmental responsiveness during sleep. Given the fundamental role of sleep in brain maturation, its disruption negatively impacts synaptic plasticity and neurological development, particularly during critical periods. These sleep-related alterations can influence cognitive and behavioral outcomes and may serve as early indicators of ASD, highlighting their potential value in early diagnosis and intervention. Understanding the neurobiological mechanisms linking sleep and ASD is essential for developing targeted therapeutic strategies. Ongoing research increasingly focuses on pharmacological, nutraceutical, and behavioral interventions aimed at mitigating sleep disorders and their cascading effects on neurodevelopment. Optimizing these therapeutic approaches through a multidisciplinary lens is crucial for enhancing clinical outcomes and improving overall quality of life in children with ASD.

Parasites of the phylum Apicomplexa include many important human and veterinary pathogens such as Plasmodium (malaria), Toxoplasma (a leading opportunistic infection associated with AIDS and congenital neurological birth defects), and Eimeria (an economically significant disease of poultry and cattle) 1 , 2 , 3 , 4 . Recent studies have identified an unusual organelle in these parasites 5 , 6 , 7 : a plastid that appears to have been acquired by secondary endosymbiosis of a green alga 7 . Here we show that replication of the apicomplexan plastid (apicoplast) genome in Toxoplasma gondii tachyzoites can be specifically inhibited using ciprofloxacin, and that this inhibition blocks parasite replication. Moreover, parasite death occurs with peculiar kinetics that are identical to those observed after exposure to clindamycin and macrolide antibiotics 8 , 9 , which have been proposed to target protein synthesis in the apicoplast 9 , 10 . Conversely, clindamycin (and functionally related compounds) immediately inhibits plastid replication upon drug application—the earliest effect so far described for these antibiotics. Our results directly link apicoplast function with parasite survival, validating this intriguing organelle as an effective target for parasiticidal drug design.

The chronic inflammation of Crohn's disease is caused, at least in part, by repression of TGF-β1 signaling, which is caused by high levels of SMAD7. This trial shows that mongersen, an antisense inhibitor of SMAD7 mRNA, induces disease remission in some persons. Crohn’s disease is a chronic inflammatory illness that primarily affects the terminal ileum and right colon. Crohn’s disease–related inflammation is segmental and transmural, leading to various degrees of tissue damage. 1 At disease onset, most patients have inflammatory lesions, which become predominantly strictures or penetrating lesions over time. 2 , 3 Mucosal healing can be promoted with the use of immunosuppressive drugs and anti–tumor necrosis factor α (TNF- α ) antibodies; however, more than one third of patients do not have a response to these therapies. The efficacy of these drugs may also diminish over time, and they can increase a patient’s risk . . .

Previous studies indicated that a few risk variants for autoimmune diseases are subject to pathogen-driven selection. Nonetheless, the proportion of risk loci that has been targeted by pathogens and the type of infectious agent(s) that exerted the strongest pressure remain to be evaluated. We assessed whether different pathogens exerted a pressure on known Crohn's disease (CD) risk variants and demonstrate that these single-nucleotide polymorphisms (SNPs) are preferential targets of protozoa-driven selection (P = 0.008). In particular, 19% of SNPs associated with CD have been subject to protozoa-driven selective pressure. Analysis of P values from genome-wide association studies (GWASs) and meta-analyses indicated that protozoan-selected SNPs display significantly stronger association with CD compared with nonselected variants. This same behavior was not observed for GWASs of other autoimmune diseases. Thus, we integrated selection signatures and meta-analysis results to prioritize five genic SNPs for replication in an Italian cohort. Three SNPs were significantly associated with CD risk, and combination with meta-analysis results yielded P values < 4 × 10−6. The bona fide risk alleles are located in ARHGEF2, an interactor of NOD2, NSF, a gene involved in autophagy, and HEBP1, encoding a possible mediator of inflammation. Pathway analysis indicated that ARHGEF2 and NSF participate in a molecular network, which also contains VAMP3 (previously associated to CD) and is centered around miR-31 (known to be disregulated in CD). Thus, we show that protozoa-driven selective pressure had a major role in shaping predisposition to CD. We next used this information for the identification of three bona fide novel susceptibility loci.

Memory retention and transfer in organisms happen at either the neural or genetic level. In humans, addictive behavior is known to pass from parents to offspring. In flatworm planaria (Dugesia tigrina), memory transfer has been claimed to be horizontal, i.e., through cannibalism. Our study is a preliminary step to understand the mechanisms underlying the transfer of addictive behavior to offspring. Since the neural and neurochemical responses of planaria share similarities with humans, it is possible to induce addictions and get predictable behavioral responses. Addiction can be induced in planaria, and decapitation will reveal if the addictive memories are solely stored in the brain. The primary objective was to test the hypothesis that addictive memory is also retained in the brainless posterior region of planaria. The surface preference of the planaria was first determined between smooth and rough surfaces. Through Pavlovian conditioning, the preferred surface was paired with water and the unpreferred surface with sucrose. After the planaria were trained and addicted, their surface preference shifted as a conditioned place preference (CPP) was established. When decapitated, the regenerated segment from the anterior part containing the brain retained the addiction, thus maintaining a shift in the surface preference. Importantly, we observed that the posterior part preserved this CPP as well, suggesting that memory retention is not attributed exclusively to the brain but might also occur at the genetic level. As a secondary objective, the effects of neurotransmitter blocking agents in preventing addiction were studied by administering a D1 dopamine antagonist to planaria, which could provide pointers to treat addictions in humans.

A multivariate insight into the in vitro antitumour screen database of the NCI by means of the SIMCA package allows to propose hypotheses on the mechanism of action of novel anticancer compounds. As an example, the application of multivariate analysis to the NCI standard database provided clues to the classification of drugs whose mechanism is either unknown or controversial. Moreover, the influence of intrinsic biochemical cell line properties (molecular targets) on the sensitivity to drug treatment could be evaluated simultaneously for classes of compounds which act by the same mechanism. Interestingly, the present approach can also provide a correlation between the molecular targets and the therapeutical fingerprint of novel active compounds thus suggesting specific biochemical studies for the investigation of new mechanisms of drug action and resistance. The statistical approach reported here represents a valuable tool for handling theenormous data sets deriving from recent genome-wide investigations of gene expression in the NCI cell lines.

Lincosamide and macrolide antibiotics are effective chemotherapeutic agents against Toxoplasma gondii and other protozoan parasites, both in vitro and in vivo. These agents are well-known inhibitors of transpeptidation in prokaryotes, but fail to inhibit cytoplasmic protein synthesis or impair mitochondrial function in Toxoplasma. Their mechanism of action in Toxoplasma has therefore been unclear. The research described in this thesis was undertaken to characterize the in vitro effect of clindamycin on T. gondii replication. High concentrations of clindamycin have no immediate effect on parasite replication, but growth rates are reduced after parasites lyse out of the infected cell where they are treated and establish a new parasitophorous vacuole within the next host cell. This 'delayed death' phenotype is also exhibited by the structurally unrelated antibiotics azithromycin and chloramphenicol. Toxoplasma is not a prokaryotic organism but sequence analysis of ribosomal genes from its 35 kb episomal genome suggested that this may be the functional target for clindamycin. This mysterious genome is associated with an endosymbiotic organelle of unknown function--the apicomplexan plastid, or apicoplast. It has not been possible to directly test the apicoplast as a target for clindamycin. While the apicoplast genome is transcribed, it has not been possible to demonstrate synthesis of plastid proteins. Furthermore, no transpeptidation-domain mutations have been identified on the plastid genome in any clindamycin-resistant parasites. To test whether the apicoplast is an essential organelle, the prokaryotic gyrase inhibitor ciprofloxacin was employed to block replication of the circular plastid genome. Quantitative analysis of plastid vs. nuclear DNA in ciprofloxacin-treated parasites revealed a selective reduction in genome copy. Ciprofloxacin also displays the 'delayed death' phenotype--demonstrating a link between this peculiar effect and the plastid. Moreover, clindamycin, azithromycin and chloramphenicol treatment cause a decline in apicoplast DNA within the first host cell, providing the earliest manifestation of treatment yet observed. These data directly link apicoplast function with parasite survival, validating this organelle as an effective target for parasiticidal drug design.

We describe a case of diffuse plane normolipemic xanthomatosis (DPNX) associated with Takayasu's disease and hyperhomocysteinemia. This report of an association of Takayasu's disease with hyperhomocysteinemia and DPNX is the only such report in literature. This report corroborates the study by Marcoval et al on 8 patients in 1988 where they highlighted that in every case of DPNX a possible concomitant condition should be always suspected and found out.