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Per definition, rare diseases affect only a small number of subjects within a given population. Taken together however, they represent a considerable medical burden, which remains poorly addressed in terms of treatment. Compared to other diseases, obstacles to the development of therapies for rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Recently, advances in high-throughput and high-content screening (HTS and HCS) have been fostered by the development of specific routines that use robot- and computer-assisted technologies to automatize tasks, allowing screening of a large number of compounds in a short period of time, using experimental model of diseases. These approaches are particularly relevant for drug repositioning in rare disease, which restricts the search to compounds that have already been tested in humans, thereby reducing the need for extensive preclinical tests. In the future, these same tools, combined with computational modeling and artificial neural network analyses, may also be used to predict individual clinical responses to drugs in a personalized medicine approach.

Nephropathic cystinosis is a rare genetic disorder characterized by cystine accumulation in lysosomes that causes early renal dysfunction and progressive chronic kidney disease. Although several metabolic pathways, including oxidative stress and inflammation, have been implicated in the progression of renal parenchyma damage, the precise mechanisms driving its progression are not fully understood. Recent studies suggest that epigenetic modifications, particularly DNA methylation (DNAm), play a critical role in the development of chronic kidney disease. We hypothesized that epigenetic dysregulation may contribute to the progression of kidney disease in cystinosis. To investigate this, we conducted genome-wide DNAm analyses on kidneys harvested from 6-month-old wild type (WT) and mice, a well-established model of cystinosis. Our analysis revealed extensive DNAm alterations in cystinotic kidneys, characterized by a significant hypermethylation profile. Interestingly, the majority of differentially methylated CpG sites were located within gene bodies and to a lesser extent in promoter and enhancer regions. Methylation changes were primarily found in genes and pathways crucial for kidney function, particularly those related to the physiology of the proximal tubules. Importantly, DNAm changes correlated with changes in gene expression, as validated by qPCR analyses of key genes. Furthermore, treatment of human proximal tubular epithelial cells with the demethylating agent decitabine resulted in the upregulation of critical transporter genes, suggesting a potential therapeutic approach. These findings underscore the role of epigenetic regulation in the progression of kidney damage in cystinosis and suggest that DNAm could serve as a promising target for novel therapeutic strategies.

In this paper we derive from first principles the expected body sizes of the parasite communities that can coexist in a mammal of given body size. We use a mixture of mathematical models and known allometric relationships to examine whether host and parasite life histories constrain the diversity of parasite species that can coexist in the population of any host species. The model consists of one differential equation for each parasite species and a single density-dependent nonlinear equation for the affected host under the assumption of exploitation competition. We derive threshold conditions for the coexistence and competitive exclusion of parasite species using invasion criteria and stability analysis of the resulting equilibria. These results are then used to evaluate the range of parasites species that can invade and establish in a target host and identify the ‘optimal’ size of a parasite species for a host of a given body size; ‘optimal’ is defined as the body size of a parasite species that cannot be outcompeted by any other parasite species. The expected distributions of parasites body sizes in hosts of different sizes are then compared with those observed in empirical studies. Our analysis predicts the relative abundance of parasites of different size that establish in the host and suggests that increasing the ratio of parasite body size to host body size above a minimum threshold increases the persistence of the parasite population.

This work illustrates potential adverse effects linked with the expression of proteinase inhibitor (PI) in plants used as a strategy to enhance pest resistance. Tobacco (Nicotiana tabacum L. cv Xanthi) and Arabidopsis [Heynh.] ecotype Wassilewskija transgenic plants expressing the mustard trypsin PI 2 (MTI-2) at different level were obtained. First-instar larvae of the Egyptian cotton worm (Spodoptera littoralis Boisd.) were fed on detached leaves of these plants. The high level of MTI-2 expression in leaves had deleterious effects on larvae, causing mortality and decreasing mean larval weight, and was correlated with a decrease in the leaf surface eaten. However, larvae fed leaves from plants expressing MTI-2 at the low expression level did not show increased mortality, but a net gain in weight and a faster development compared with control larvae. The low MTI-2 expression level also resulted in increased leaf damage. These observations are correlated with the differential expression of digestive proteinases in the larval gut; overexpression of existing proteinases on low-MTI-2-expression level plants and induction of new proteinases on high-MTI-2-expression level plants. These results emphasize the critical need for the development of a PI-based defense strategy for plants obtaining the appropriate PI-expression level relative to the pest's sensitivity threshold to that PI

The intensity and frequency of climate-driven disturbances are increasing in coastal marine ecosystems. Understanding the factors that enhance or inhibit ecosystem resilience to climatic disturbance is essential. We surveyed 97 experts in six major coastal biogenic ecosystem types to identify “bright spots” of resilience in the face of climate change. We also evaluated literature that was recommended by the experts that addresses the responses of habitat-forming species to climatic disturbance. Resilience was commonly reported in the expert surveys (80% of experts). Resilience was observed in all ecosystem types and at multiple locations worldwide. The experts and literature cited remaining biogenic habitat, recruitment/connectivity, physical setting, and management of local-scale stressors as most important for resilience. These findings suggest that coastal ecosystems may still hold great potential to persist in the face of climate change and that local- to regional-scale management can help buffer global climatic impacts.

The term 'uterine STUMP' (smooth-muscle tumors of uncertain malignant potential) is currently used to define a heterogeneous group of uterine tumors distinct from leiomyomas and leiomyosarcomas. This rare entity is often characterized by a slow growth and protracted patient survival when compared to leiomyosarcomas but few data are available about its clinical management and outcome. In this review, we summarize the current state of knowledge about uterine STUMP, with a particular focus on cases of recurrence.

Long term outcome in childhood autism spectrum disorders (ASD) was evaluated by studying quality of life (QoL) in young adulthood in comparison to the outcome of other child psychiatric disorders. In this follow-up study, objective and subjective QoL of 169 high-functioning (IQ>70) adults with ASD (19 to 30years) was contrasted with QoL data of age matched adults diagnosed with attention deficit/hyperactivity disorder (N=85), disruptive behaviour disorders (N=83), and affective disorders (N=85) during childhood. The mean follow-up period of the ASD patients was 13.9years. Objective QoL included marital status, living arrangements, level of education, employment, and usage of mental health care. Subjective QoL included satisfaction concerning living arrangements, work or education, physical condition, partner relationship, social relationships, state of mind, and future perspective. QoL was more compromised in adults diagnosed with ASD in childhood than in adults with other psychiatric disorders in childhood. A relatively large proportion of the adults with ASD were single, few lived with a partner or a family and many of them were institutionalized. Adults with ASD had lower educational levels, relatively few had paid employment and many were social security recipients, as compared to the other psychiatric patients. In case the adults with ASD used medication, 47% used anti-psychotics. Regarding the subjective QoL, the adults with ASD were less satisfied about their work or education, partner relationship, and future perspective than the other groups. Even when highly educated adults with ASD were compared to highly educated adults diagnosed with other childhood disorders, the QoL appeared to be more disadvantageous in adults with ASD. Many studies have shown that QoL is threatened in psychiatric patients, but findings of this study indicate that young high-functioning adults diagnosed with ASD in childhood are at relatively high risk for poor QoL compared to other childhood psychiatric disorders.

The purpose of this study was to examine several behavioral problems in school-aged hearing-impaired children with hearing aids or cochlear implants, compared to normally hearing children. Additionally, we wanted to investigate which sociodemographic, linguistic, and medical factors contributed to the level of behavioral problems, to pinpoint where targeted interventions can take place. This large, retrospective study included a sample of 261 school-aged children (mean age = 11.8 years, SD = 1.6), that consisted of three age- and gender-matched subgroups: 75 with hearing aids, 57 with cochlear implants, and 129 normally hearing controls. Self- and parent-reports concerning reactive and proactive aggression, delinquency, and symptoms of psychopathy, attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder were used. In addition, several language and intelligence tests were administered. Hearing-impaired children showed significantly more proactive aggression, symptoms of psychopathy, attention deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder than their normally hearing peers. More behavioral problems were associated with special schools for the deaf, sign (-supported) language, hearing aids (in contrast to cochlear implants), higher age, male gender, lower socioeconomic status, lower intelligence, and delayed language development. Hearing-impaired children face multiple problems regarding their behavior. The outcomes implicate that professionals should be aware of the higher risk of developing behavioral problems, in order to screen, detect, and treat in time. Furthermore, the associated risk and protective factors emphasize that clinicians must always consider the heterogeneity of the group of hearing-impaired children, in order to help and support the individual patient.

Aim To explore the patterns of connectivity between marine protected areas (MPAs) and neighbouring non-protected areas and the scale at which the benefits of MPAs are expected using the white sea bream as model species. Location Marine protected area of Torre Guaceto (TGMPA, Italy) in the south Adriatic Sea. Methods A multidisciplinary approach was used combining (1) a genetic survey using 12 highly informative microsatellite loci of samples collected within the MPA and in several locations up to 100 km from the MPA; and (2) larval trajectories using Lagrangian simulations based on an oceanographical model of the region that includes specific data on early life-history traits. Both genetic and simulation studies were temporarily replicated during two consecutive years. Results The overall genetic homogeneity observed indicates that the TGMPA is not isolated and that there is genetic connectivity among locations across a scale of at least ~200 km. A high degree of connectivity between the TGMPA and neighbouring areas is in agreement with Lagrangian simulations, which indicate that white sea bream larvae can be transported over large distances up to about 300 km. Trajectories released from the TGMPA showed that on average, 12.75% of the larvae remains within the TGMPA, while the rest travel south towards non-protected areas. Main conclusions Our findings highlight the potential benefits of effectively enforced MPAs for neighbouring or relatively distant non-protected fishing areas and the potential connection with other MPAs at regional scale. Combining genetics and modelling can provide a general framework to investigate the role of connectivity in MPA design that can be easily extended to other species and geographical areas.