Mitochondria are involved in multiple aspects of neurodevelopmental processes and play a major role in the pathogenetic mechanisms leading to neuro-degenerative diseases. Fragile-X-related disorders ...(FXDs) are genetic conditions that occur due to the dynamic expansion of CGG repeats of the
gene encoding for the RNA-binding protein FMRP, particularly expressed in the brain. This gene expansion can lead to premutation (PM, 56-200 CGGs), full mutation (FM, >200 CGGs), or unmethylated FM (UFM), resulting in neurodegeneration, neurodevelopmental disorders, or no apparent intellectual disability, respectively. To investigate the mitochondrial mechanisms that are involved in the FXD patients, we analyzed mitochondrial morphology and bioenergetics in fibroblasts derived from patients. Donut-shaped mitochondrial morphology and excessive synthesis of critical mitochondrial proteins were detected in FM, PM, and UFM cells. Analysis of mitochondrial oxidative phosphorylation in situ reveals lower respiration in PM fibroblasts. Importantly, mitochondrial permeability transition-dependent apoptosis is sensitized to reactive oxygen species in FM, PM, and UFM models. This study elucidated the mitochondrial mechanisms that are involved in the FXD phenotypes, and indicated altered mitochondrial function and morphology. Importantly, a sensitization to permeability transition and apoptosis was revealed in FXD cells. Overall, our data suggest that mitochondria are novel drug targets to relieve the FXD symptoms.
A AuNP-modified screen-printed carbon electrode (AuNP/SPCE) for monitoring important biomolecules, such as dopamine (DA) and riboflavin (RF), having a high potential for personalized medicine and for ...continuous monitoring of human health is here proposed. AuNPs were synthesized using the extract of Rhanterium suaveolens as a reducing medium and were characterized by UV–vis spectroscopy, dynamic light scattering (DLS), and scanning and transmission electron microscopy (SEM and TEM). The synthesized AuNPs appear spherical and present a bimodal size distribution with a maximum centered at around 30–50 nm. Cyclic voltammetry (CV) experiments demonstrated that the modified AuNP/SPCE sensor exhibits superior electrochemical performances to the bare SPCE. Low limits of detection (LODs) of 0.2 and 0.07 μM at S/N = 3 and sensitivities of 550.4 and 2399 μA mM–1 cm–2 were registered for DA and RF detection, respectively. Results demonstrate the promising electrochemical characteristics of the synthesized AuNPs and developed AuNP/SPCE electrochemical sensor for the determination of these important biomolecules.
Fragile X syndrome (FXS) results from the loss of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates a variety of cytoplasmic mRNAs. FMRP regulates mRNA ...translation and may be important in mRNA localization to dendrites. We report a third cytoplasmic regulatory function for FMRP: control of mRNA stability. In mice, we found that FMRP binds, in vivo, the mRNA encoding PSD-95, a key molecule that regulates neuronal synaptic signaling and learning. This interaction occurs through the 3' untranslated region of the PSD-95 (also known as Dlg4) mRNA, increasing message stability. Moreover, stabilization is further increased by mGluR activation. Although we also found that the PSD-95 mRNA is synaptically localized in vivo, localization occurs independently of FMRP. Through our functional analysis of this FMRP target we provide evidence that dysregulation of mRNA stability may contribute to the cognitive impairments in individuals with FXS.
The oral-facial-digital syndromes (OFDS) result from the pleiotropic effect of a morphogenetic impairment affecting almost invariably the mouth, face and digits. Other organ systems can be involved, ...defining specific types of OFDS. To date, 13 types have been distinguished based on characteristic clinical manifestations. An updated list of these types is provided and recent molecular data are discussed.
Fragile X syndrome (FXS) is a very frequent cause of inherited intellectual disability (ID) and autism. Most FXS patients have an expansion over 200 repeats of (CGG)
sequence ("full mutation" (FM)) ...located in the 5'UTR of the FMR1 gene, resulting in local DNA methylation (methylated "full mutation" (MFM)) and epigenetic silencing. The absence of the FMRP protein is responsible for the clinical phenotype of FXS. FM arises from a smaller maternal allele with 56-200 CGG repeats ("premutation" (PM)) during maternal meiosis. Carriers of PM alleles, which are typically unmethylated, can manifest other clinical features (primary ovarian insufficiency (POI) or FXS-associated tremor-ataxia syndrome (FXTAS)), known as fragile X-related disorders. In FXS families, rare males who have inherited an unmethylated "full mutation" (UFM) have been described. These individuals produce enough FMRP to allow normal intellectual functioning. Here we report the rare case of three sisters with a completely methylated PM of around 140 CGGs and detail their neuropsychological function. X inactivation analysis confirmed that the three sisters have a random inactivation of the X chromosome, suggesting that the PM allele is always methylated also when residing on the active X. We propose that in exceptional cases, just as the FM may be unmethylated, also a PM allele may be fully methylated. To our knowledge, females with a methylated PM allele and a mild impairment have reported only once. The study of these atypical individuals demonstrates that the size of the CGG expansion is not as tightly coupled to methylation as previously thought.
Small cell lung cancer (SCLC) is a highly aggressive malignancy that accounts for about 14% of all lung cancers. Platinum-based chemotherapy has been the only available treatment for a long time, ...until the introduction of immune checkpoint inhibitors (ICIs) recently changed first-line standard of care and shed light on the pivotal role of the immune system. Despite improved survival in a subset of patients, a lot of them still do not benefit from first-line chemo-immunotherapy, and several studies are investigating whether different combination strategies (with both systemic and local treatments, such as radiotherapy) may improve patient outcomes. Moreover, research of biomarkers that may be used to predict patients’ outcomes is ongoing. In addition to ICIs, immunotherapy offers other different strategies, including naked monoclonal antibodies targeting tumor associated antigens, conjugated antibody, bispecific antibodies and cellular therapies. In this review, we summarize the main evidence available about the use of immunotherapy in SCLC, the rationale behind combination strategies and the studies that are currently ongoing in this setting, in order to give the reader a clear and complete view of this rapidly expanding topic.
Gender is associated with several features of psychotic disorders, including age of illness onset, symptomatology, a higher prevalence of history of childhood sexual abuse (CSA) and needs for care. ...Childhood sexual abuse is associated with adverse mental health consequences but as there is a gender difference in stress reactivity, there may be a differential impact of CSA on psychopathology, age of psychosis onset and needs for care in First Episode Psychosis (FEP) patients. We hypothesized that a history of abuse would be associated with lowering of age of onset, increased symptomatology and more unmet needs in women but not men. A total of 444 FEP patients have been recruited within the context of the GET UP trial. Symptomatology has been assessed using the PANSS scale, needs for care with the CAN scale and childhood abuse with the CECA-Q scale. Childhood sexual abuse was more frequent among female patients 22.6% in women vs 11.6% in men (OR = 0.45, p < 0.01), whereas there was no gender difference in the prevalence of childhood physical abuse (29.0% in women vs 31.7% in men). Childhood abuse was associated with higher levels of negative symptoms in both men and women, with a reduced age of onset in women only and little increase in needs for care in both men and women. Our results seem to suggest that childhood sexual abuse in female FEP patients may be linked to a more severe form of psychosis whose presentation is characterized by earlier age of onset and higher levels of negative symptoms and we can also speculate that gender-specific protective factors in women, but not in men, may be outweighed by the consequences of childhood abuse.
Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which ...are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.
Fragile X-related disorders are due to a dynamic mutation of the CGG repeat at the 5′ UTR of the
FMR1
gene, coding for the RNA-binding protein FMRP. As the CGG sequence expands from premutation (PM, ...56-200 CGGs) to full mutation (> 200 CGGs), FMRP synthesis decreases until it is practically abolished in fragile X syndrome (FXS) patients, mainly due to
FMR1
methylation. Cells from rare individuals with no intellectual disability and carriers of an unmethylated full mutation (UFM) produce slightly elevated levels of
FMR1
-mRNA and relatively low levels of FMRP, like in PM carriers. With the aim of clarifying how UFM cells differ from CTRL and FXS cells, a comparative proteomic approach was undertaken, from which emerged an overexpression of SOD2 in UFM cells, also confirmed in PM but not in FXS. The
SOD2
-mRNA bound to FMRP in UFM more than in the other cell types. The high SOD2 levels in UFM and PM cells correlated with lower levels of superoxide and reactive oxygen species (ROS), and with morphological anomalies and depolarization of the mitochondrial membrane detected through confocal microscopy. The same effect was observed in CTRL and FXS after treatment with MC2791, causing SOD2 overexpression. These mitochondrial phenotypes reverted after knock-down with siRNA against
SOD2
-mRNA and
FMR1
-mRNA in UFM and PM. Overall, these data suggest that in PM and UFM carriers, which have high levels of
FMR1
transcription and may develop FXTAS, SOD2 overexpression helps to maintain low levels of both superoxide and ROS with signs of mitochondrial degradation.
The development of fast and reliable gas sensors is a pressing and growing problem for environmental monitoring due to the presence of pollutants in the atmosphere. Among all gases, particular ...attention is devoted to NO, which can cause serious health problems. WO3 nanorods represent promising candidates for this purpose due to their high electrical stability and low cost of production. Here, the hydrothermal synthesis of WO3 nanorods is reported, in addition to the realization of a chemo-resistive NO sensor. NO-sensing tests were performed at different temperatures (250–400 °C) and under different gas concentrations (250–2500 ppm), and NO response and recovery curves were also modeled by using the Langmuir adsorption theory by highlighting the NO-sensing mechanism of the WO3 nanorods. An interaction occurred at the surface between NO and the adsorbed oxygen ions, thus clarifying the NO-reducing behavior. The fast response and recovery times open the route for the development of fast NO sensors based on WO3.
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