In this study the effectiveness of an equine-assisted therapy (EAT) in improving adaptive and executive functioning in children with autism spectrum disorder (ASD) was examined (children attending ...EAT, n = 15, control group n = 13; inclusion criteria: IQ > 70). Therapeutic sessions consisted in structured activities involving horses and included both work on the ground and riding. Results indicate an improvement in social functioning in the group attending EAT (compared to the control group) and a milder effect on motor abilities. Improved executive functioning was also observed (i.e. reduced planning time in a problem-solving task) at the end of the EAT program. Our findings provide further support for the use of animal-assisted intervention programs as complementary intervention strategies for children with ASD.
Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for ...biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.
microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies ...including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.
This study was conducted in the Middle Branch of Bue Marino Cave (Sardinia, Italy) to reconstruct paleoecological conditions during the Holocene through microfaunal proxies in seven surface sediment ...samples and a short sediment core (BMD-2018, 18 cm), all collected in 2018 and another core sampled in 2021 (BMD-2021, 28 cm). The first attempt at dating cave sediment through luminescence was conducted on BMD-2021; the derived age was 6.04 ± 0.47 ka at 18 cm depth. Although continuous sedimentation and constant rates are not probable in the cave, this indicates that the sedimentary record dates to the early times after the Holocene flooding of the cave by the sea. Benthic foraminifera and grain size were analyzed in all surface samples and core BMD-2018, while only benthic foraminifera were studied in BMD-2021. The recent foraminiferal assemblages, studied from an ecological point of view, were applied as modern analog to reconstruct the paleoecological conditions in sediment cores. Significant changes in the sedimentary environment were excluded; the two cores showed a similar foraminiferal turnover at a similar depth, from an older assemblage with prevailing indifferent Ammonia inflata to a younger one with prevailing opportunist Eggerelloides advena. This turnover was attributed to changes in the amount and/or quality of available nutrients. Based on these results, this event is likely related to possibly attributable to the effects of climate changes that occurred in the Holocene. However, more extensive studies are necessary to better understand the effects of the climatic/environmental events in the Late-Holocene in the caves. Although it represents a first attempt at paleoenvironmental reconstruction based on sediments from a Mediterranean marine cave, this study demonstrated that benthic foraminifera are refined paleoenvironmental proxies and that the integrated approach with the luminescence dating produces reliable results for studying the effects of global changes in these environments.
Despite development of novel agents targeting oncogenic pathways, matching targeted therapies to the genetic status of individual tumors is proving to be a daunting task for clinicians. To improve ...the clinical efficacy and to reduce the toxic side effects of treatments, a deep characterization of genetic alterations in different tumors is required. The mutational profile often evidences a gain of function or hyperactivity of phosphoinositide 3-kinases (PI3Ks) in tumors. These enzymes are activated downstream tyrosine kinase receptors (RTKs) and/or G proteins coupled receptors (GPCRs) and, via AKT, are able to induce mammalian target of rapamycin (mTOR) stimulation. Here, we elucidate the impact of class I (p110α, β, γ, and δ) catalytic subunit mutations on AKT-mediated cellular processes that control crucial mechanisms in tumor development. Moreover, the interrelation of PI3K signaling with mTOR, ERK, and RAS pathways will be discussed, exploiting the potential benefits of PI3K signaling inhibitors in clinical use.
Class II PI3K Functions in Cell Biology and Disease Gulluni, Federico; De Santis, Maria Chiara; Margaria, Jean Piero ...
Trends in cell biology,
April 2019, 2019-04-00, 20190401, Volume:
29, Issue:
4
Journal Article
Peer reviewed
The phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate inositol phospholipids, thereby controlling membrane lipid composition and regulating a wide range of ...intracellular processes, including vesicular trafficking and signal transduction. Despite the vast knowledge on class I PI3Ks, recent studies are only now revealing the importance of class II PI3Ks in cell proliferation, survival, and migration. Increasing evidence suggests that the three class II PI3Ks isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) have distinct and non-overlapping cellular roles. Here, we focus on the cellular functions of class II PI3Ks in different cell systems and underline the emerging importance of these enzymes in various physiological and pathological contexts.
Class II PI3Ks synthetize two different phosphoinositides, PI(3)P and PI(3,4)P2, in distinct cellular compartments.
PI3K-C2α plays a central role in clathrin-mediated endocytosis, vesicular trafficking, and mitosis.
PI3K-C2β is activated by growth factors and is involved in cell migration and mTOR signaling repression.
PI3K-C2γ localizes on early endosomes and controls Akt2 activation and glycogen storage in the liver.
The phosphatidylinositide 3 kinases (PI3Ks) and their downstream mediators AKT and mammalian target of rapamycin (mTOR) are central regulators of glycolysis, cancer metabolism, and cancer cell ...proliferation. At the molecular level, PI3K signaling involves the generation of the second messenger lipids phosphatidylinositol 3,4,5-trisphosphate PI(3,4,5)P3 and phosphatidylinositol 3,4-bisphosphate PI(3,4)P2. There is increasing evidence that PI(3,4)P2 is not only the waste product for the removal of PI(3,4,5)P3 but can also act as a signaling molecule. The selective cellular functions for PI(3,4)P2 independent of PI(3,4,5)P3 have been recently described, including clathrin-mediated endocytosis and mTOR regulation. However, the specific spatiotemporal dynamics and signaling role of PI3K minor lipid messenger PI(3,4)P2 are not well-understood. This review aims at highlighting the biological functions of this lipid downstream of phosphoinositide kinases and phosphatases and its implication in cancer metabolism.
Directional transport of recycling cargo from early endosomes (EE) to the endocytic recycling compartment (ERC) relies on phosphatidylinositol 3-phosphate (PtdIns(3)P) hydrolysis and activation of ...the small GTPase Rab11. However, how these events are coordinated is yet unclear. By using a novel genetically-encoded FRET biosensor for Rab11, we report that generation of endosomal PtdIns(3)P by the clathrin-binding phosphoinositide 3-kinase class 2 alpha (PI3K-C2α) controls the activation of Rab11. Active Rab11, in turn, prompts the recruitment of the phosphatidylinositol 3-phosphatase myotubularin 1 (MTM1), eventually enabling the release of recycling cargo from the EE and its delivery toward the ERC. Our findings thus define that delivery of recycling cargo toward the ERC requires spatial and sequential coupling of Rab11 activity with PtdIns(3)P turnover.
The interplay between rewiring tumor metabolism and oncogenic driver mutations is only beginning to be appreciated. Metabolic deregulation has been described for decades as a bystander effect of ...genomic aberrations. However, for the biology of malignant cells, metabolic reprogramming is essential to tackle a harsh environment, including nutrient deprivation, reactive oxygen species production, and oxygen withdrawal. Besides the well-investigated glycolytic metabolism, it is emerging that several other metabolic fluxes are relevant for tumorigenesis in supporting redox balance, most notably pentose phosphate pathway, folate, and mitochondrial metabolism. The relationship between metabolic rewiring and mutant genes is still unclear and, therefore, we will discuss how metabolic needs and oncogene mutations influence each other to satisfy cancer cells' demands. Mutations in oncogenes, i.e., PI3K/AKT/mTOR, RAS pathway, and MYC, and tumor suppressors, i.e., p53 and liver kinase B1, result in metabolic flexibility and may influence response to therapy. Since metabolic rewiring is shaped by oncogenic driver mutations, understanding how specific alterations in signaling pathways affect different metabolic fluxes will be instrumental for the development of novel targeted therapies. In the era of personalized medicine, the combination of driver mutations, metabolite levels, and tissue of origins will pave the way to innovative therapeutic interventions.
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