[Pharmacological interventions for intellectual disability and autism]. / Intervenciones farmacológicas en discapacidad intelectual y autismo.

No medication has been proven effective in treating core characteristics of intellectual disability or autism. Psychotropic medications are frequently used to target psychiatric symptoms in children, adolescents and adults with developmental conditions, despite the little evidence for their efficacy. This article aimed to summarize current evidence on efficacy of pharmacological interventions for the most frequent symptoms and disorders associated to autism and to intellectual disability. And also, novel molecules being studied for core symptoms of these conditions. Electronic databases were searched and supplemented with a hand search. Data were described narratively prioritizing meta-analysis and randomized controlled trials but considering also open label trials and preliminary studies. The main conclusions were that only few drugs showed efficacy for reducing psychiatric symptoms associated to these developmental conditions, mainly risperidone and aripiprazole to treat irritability and methylphenidate and atomoxetine for hyperactivity and attention deficit. Evidence is inconclusive regarding the effectiveness of other drug groups. Novel therapeutic agents showed mixed results and quality of evidence is low; some of these agents aim at biologically targeted pharmacotherapy, which may lead to successful individualized treatment options in the future. To this day, clinicians should use pharmacotherapy with caution, carefully weighing risks and benefits, and as a part of a comprehensive personalized approach.

The Homeodomain Iroquois Proteins Control Cell Cycle Progression and Regulate the Size of Developmental Fields.

During development, proper differentiation and final organ size rely on the control of territorial specification and cell proliferation. Although many regulators of these processes have been identified, how both are coordinated remains largely unknown. The homeodomain Iroquois/Irx proteins play a key, evolutionarily conserved, role in territorial specification. Here we show that in the imaginal discs, reduced function of Iroquois genes promotes cell proliferation by accelerating the G1 to S transition. Conversely, their increased expression causes cell-cycle arrest, down-regulating the activity of the Cyclin E/Cdk2 complex. We demonstrate that physical interaction of the Iroquois protein Caupolican with Cyclin E-containing protein complexes, through its IRO box and Cyclin-binding domains, underlies its activity in cell-cycle control. Thus, Drosophila Iroquois proteins are able to regulate cell-autonomously the growth of the territories they specify. Moreover, our results provide a molecular mechanism for a role of Iroquois/Irx genes as tumour suppressors.

Drosophila araucan and caupolican integrate intrinsic and signalling inputs for the acquisition by muscle progenitors of the lateral transverse fate.

A central issue of myogenesis is the acquisition of identity by individual muscles. In Drosophila, at the time muscle progenitors are singled out, they already express unique combinations of muscle identity genes. This muscle code results from the integration of positional and temporal signalling inputs. Here we identify, by means of loss-of-function and ectopic expression approaches, the Iroquois Complex homeobox genes araucan and caupolican as novel muscle identity genes that confer lateral transverse muscle identity. The acquisition of this fate requires that Araucan/Caupolican repress other muscle identity genes such as slouch and vestigial. In addition, we show that Caupolican-dependent slouch expression depends on the activation state of the Ras/Mitogen Activated Protein Kinase cascade. This provides a comprehensive insight into the way Iroquois genes integrate in muscle progenitors, signalling inputs that modulate gene expression and protein activity.

Where I am from matters: factors influencing behavioral and emotional changes in autistic individuals during COVID-19 in Latin America.

Background: The COVID-19 pandemic brought an increased incidence of disease and mortality in the world at large, making it a particularly salient and stressful life event. For those individuals residing in Latin America, the pandemic was met with fragmented healthcare systems, economic downturn, and sociopolitical crisis which puts autistic individuals at risk for more detrimental outcomes. Behavioral and emotional challenges experienced by autistic individuals at the beginning of the pandemic could later develop into more severe symptomatology as the pandemic progresses. The present study aimed to explore changes in dysregulated (overt and internalizing) behaviors and preoccupation with getting sick during the COVID-19 pandemic among autistic children in 7 Latin American countries. Method: Sample consisted of 1,743 caregivers, residing in: Argentina (n = 677, 38.8%) Brazil (n = 156, 9%), Chile (n = 251, 14.4%), Dominican Republic (n = 171, 9.8%), Mexico (n = 126, 7.2%), Uruguay (n = 259, 14.9%) and Venezuela (n = 103, 5.9%). The majority of caregivers who completed the questionnaire were mothers (85.1%), and most had a male autistic child (81.6%). A series of independent sample t-tests were conducted to assess country differences in dysregulated behaviors and preoccupation with getting sick. Linear regressions were conducted to identify which demographic characteristics and micro-level contextual factors predicted dysregulated overt behaviors and psychological changes. Results: Contextual factors, such as country of residence, were related to preoccupation with getting sick and dysregulated behavior. Particularly, residing in Mexico and Brazil were related to changes in preoccupation with getting sick and mental health concerns. Coexistence predicted dysregulated internalizing behaviors, while being older significantly predicted preoccupation with getting sick. Increased screen time only predicted anxiety. Conclusion: Our findings highlight differences and predictions of behavioral challenges and psychological changes based on certain contextual factors and individual characteristics while experiencing severe life stressors such as a worldwide pandemic. This knowledge could help inform policies and decrees aimed at protecting those most vulnerable due to their increased difficulty adapting to change.

Threat induces cardiac and metabolic changes that negatively impact survival in flies.

Adjusting to a dynamic environment involves fast changes in the body's internal state, characterized by coordinated alterations in brain activity and physiological and motor responses. Threat-induced defensive states are a classic case of coordinated adjustment of bodily responses, cardiac regulation being one of the best characterized examples in vertebrates. A great deal is known regarding the neural basis of invertebrate defensive behaviors, mainly in Drosophila melanogaster. However, whether physiological changes accompany these remains unknown. Here, we set out to describe the internal bodily state of fruit flies upon an inescapable threat and found cardiac acceleration during running and deceleration during freezing. In addition, we found that freezing leads to increased cardiac pumping from the abdomen toward the head-thorax, suggesting mobilization of energy resources. Concordantly, threat-triggered freezing reduces sugar levels in the hemolymph and renders flies less resistant to starvation. The cardiac responses observed during freezing were absent during spontaneous immobility, underscoring the active nature of freezing response. Finally, we show that baseline cardiac activity predicts the amount of freezing upon threat. This work reveals a remarkable similarity with the cardiac responses of vertebrates, suggesting an evolutionarily convergent defensive state in flies. Our findings are at odds with the widespread view that cardiac deceleration while freezing has first evolved in vertebrates and that it is energy sparing. Investigating the physiological changes coupled to defensive behaviors in the fruit fly has revealed that freezing is costly yet accompanied by cardiac deceleration and points to heart activity as a key modulator of defensive behaviors.

Covid-19 y autismo: impacto en las personas con autismo y sus familias en Uruguay / Covid-19 and autism: impact on people with autism and their families in Uruguay

La pandemia de covid-19 y las medidas asociadas determinaron cambios profundos en los individuos con trastorno del espectro autista (TEA) y sus familias. Se busca explorar estos efectos a nivel de las emociones y comportamientos en esta población en Uruguay. Dentro de un estudio multicéntrico de ocho países de Latinoamérica, se utilizó la submuestra de Uruguay para analizar los cambios de los comportamientos exhibidos por los individuos con TEA sobre la base de género y edad. Entre los 269 cuidadores que completaron una encuesta anónima, el 43,9 % reportó mayores problemas de convivencia y el 75,4 % reportó retrocesos. El empeoramiento de los comportamientos externalizados fue mayor en el sexo masculino y de los internalizados, en los adolescentes de 13 a 18 años. Estos resultados deberían considerarse a la hora de tomar medidas que comprometen la continuidad educativa, apoyos terapéuticos y de asistencia a las familias con personas con TEA en Uruguay.

COVID-19 pandemic and its associated measures, determined pro-found changes in individuals with autism spectrum disorder (ASD) and their families. Authors explore consequences regarding emotions and behaviors in this population in Uruguay. Within a multicentric study of eight Latin American countries, changes in behaviors in individuals with ASD based on gender and age were analyzed in the Uruguayan sub-sample. Among the 269 caregivers who completed an anonymous survey, 43.9% reported greater problems in daily life and 75.4% reported setbacks. The worsening of externalizing behaviors was greater in males. The internalizing ones were higher in adolescents aged 13 to 18 years. These results should be considered when taking measures that compromise educational continuity, therapeutic supports and assistance to families with people with ASD in Uruguay.

Expanding the Iroquois genes repertoire: a non-transcriptional function in cell cycle progression.

Drosophila Iroquois (Iro) proteins are components of the TALE homeodomain family of transcriptional regulators. They play key roles in territorial specification and pattern formation. A recent study has disclosed a novel developmental function of the Iro proteins. In the eye and wing imaginal discs, they can regulate the size of the territories that they specify. They do so by cell-autonomously controlling cell cycle progression. Indeed, Iro proteins down-regulate the activity of the CyclinE/Cdk2 complex by a transcription-independent mechanism. This novel function is executed mainly through 2 evolutionarily conserved domains of the Iro proteins: the Cyclin Binding Domain and the IRO-box, which mediate their binding to CyclinE-containing protein complexes. Here we discuss the functional implications of the control of the cell cycle by Iro proteins for development and oncogenesis.

The Drosophila RNA-binding protein ELAV is required for commissural axon midline crossing via control of commissureless mRNA expression in neurons.

Drosophila ELAV is the founding member of an evolutionarily conserved family of RNA-binding proteins considered as key inducers of neuronal differentiation. Although several ELAV-specific targets have been identified, little is known about the role of elav during neural development. Here, we report a detailed characterization of the elav mutant commissural phenotype. The reduced number of commissures in elav mutant embryos is not due to loss or misspecification of neural cells but results from defects in commissural axon projections across the midline. We establish a causal relationship between the elav mutant commissural phenotype and a reduction in the expression of commissureless, a key component of the Robo/Slit growth cone repulsive signalling pathway. In the nerve cord of elav mutant embryos, comm mRNA expression is strongly reduced in neurons, but not in midline glial cells. Furthermore, specific expression of an elav transgene in posterior neurons of each segment of an elav mutant nerve cord restores comm mRNA expression in these cells, as well as the formation of posterior commissures. Finally, forced expression of comm in specific commissural neuron subsets rescues the midline crossing defects of these neurons in elav mutant embryos, further indicating that elav acts cell autonomously on comm expression.