Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain

Ever since the discovery of thyroid hormone deficiency as the primary cause of cretinism in the second half of the 19th century, the crucial role of thyroid hormone (TH) signaling in embryonic brain development has been established. However, the biological understanding of TH function in brain formation is far from complete, despite advances in treating thyroid function deficiency disorders. The pleiotropic nature of TH action makes it difficult to identify and study discrete roles of TH in various aspect of embryogenesis, including neurogenesis and brain maturation. These challenges notwithstanding, enormous progress has been achieved in understanding TH production and its regulation, their conversions and routes of entry into the developing mammalian brain. The endocrine environment has to adjust when an embryo ceases to rely solely on maternal source of hormones as its own thyroid gland develops and starts to produce endogenous TH. A number of mechanisms are in place to secure the proper delivery and action of TH with placenta, blood-brain interface, and choroid plexus as barriers of entry that need to selectively transport and modify these hormones thus controlling their active levels. Additionally, target cells also possess mechanisms to import, modify and bind TH to further fine-tune their action. A complex picture of a tightly regulated network of transport proteins, modifying enzymes, and receptors has emerged from the past studies. TH have been implicated in multiple processes related to brain formation in mammals—neuronal progenitor proliferation, neuronal migration, functional maturation, and survival—with their exact roles changing over developmental time. Given the plethora of effects thyroid hormones exert on various cell types at different developmental periods, the precise spatiotemporal regulation of their action is of crucial importance. In this review we summarize the current knowledge about TH delivery, conversions, and function in the developing mammalian brain. We also discuss their potential role in vertebrate brain evolution and offer future directions for research aimed at elucidating TH signaling in nervous system development

Drosophila CPEB Orb2A Mediates Memory Independent of Its RNA-Binding Domain

SummaryLong-term memory and synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. The CPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. The precise mechanism by which these molecules regulate memory formation is however poorly understood. We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene in order to investigate its role in long-term memory formation. We show that the Orb2A and Orb2B isoforms, while both essential, have distinct functions in memory formation. These two isoforms have common glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2B the latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both its glutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB to regulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventional manner to form stable Orb2 complexes that are essential for memory to persist

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

La chimica dei nanocomposti e la loro applicazione al restauro dei manoscritti

Cellulose-based artifacts are susceptible to fast degradation due to the presence of detrimental components and to the action of environmental pollutants. As a result, the acidity of pristine material increases, promoting the acid-catalysed depolymerisation of cellulose that alters the mechanical properties of paper. In this paper, the use of innovative dispersions of alkaline earth metal hydroxide nanoparticles will be discussed as a method of counteracting the degradation of paper. The application of the most recent formulations of nanoparticles dispersions for the deacidification of artworks will be highlighted. Finally, the usage of innovative gel formulations for the cleaning of cellulose-based artworks will be discussed

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Abstract: Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10−8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04–1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76–0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02–1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96–1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development

Análisis de la migración marítima : entre los derechos humanos y el derecho del mar

La Especialización en Derecho del Mar de la Universidad del Rosario, tiene por objeto de estudio las costas y océanos que se ubican en nuestro país, que históricamente han sido invisibles en la política pública y en el desarrollo normativo en Colombia. Internacionalmente se ha logrado un importante desarrollo, siendo paradigma, la Convención de las Naciones Unidas sobre el Derecho del Mar de 1982, la cual estuvo precedida por difíciles y prolongados procesos de concertación entre los Estados con intereses contrapuestos en los usos verticales y horizontales de los océanos

Shame, Masculinity and Desire of Belonging in the Novels of Hanif Kureishi, Philip Roth and Hubert Klimko-Dobrzaniecki, 1997-2007

This thesis provides a comparative study of male shame in Hanif Kureishi’s Intimacy (1998), Philip Roth’s Everyman (2006) and Portnoy’s Complaint (1969), and finally Hubert Klimko- Dobrzaniecki’s Raz. Dwa. Trzy (2007). As this reading of the novels reveals, shame in the male characters results from a failure to measure up to the hegemonic ideal of masculinity promoted in their respective cultures. This study shows that shame is an emotion, which conditions masculinity protecting the powerful hierarchies that exist between different masculinities and between men and women. This reading of shame as applied to masculinity in Polish, British and American contexts aims to expose those hierarchies demonstrating the liberating potential of shame, which can queer traditional masculinity allowing new forms of masculinity to emerge. The analysis of male shame illuminates further the clash between male gender, constructed primarily as a symbol of power, and shame considered as a disempowering and emasculating emotion. The writers selected for this analysis hold a status of the cultural other: Kureishi as British- Pakistani, Roth as Jewish-American and Klimko-Dobrzaniecki as bom in Silesia, a borderline region between Poland, Germany and the Czech Republic. The writers’ status and personal experience is mirrored in their male protagonists’ sexuality, ethnic and class belonging. Significantly, in their texts, the writers represent diasporic masculinity which clashes with the hegemonic ideal promoted by their respective cultures. Drawing on David Gilmore’s concept of ‘achieved manhood’, Elspeth Probyn’s notion of ‘belonging’ and Raewyn Connell’s concept of ‘masculinity crisis’ this study explains why shame occurs as a result of the male protagonists’ failure to secure their place within the realm of the hegemonic masculinity. The interdisciplinary approach taken in this study draws heavily on a post-colonial conceptual framework mainly due to the status of shame as both an individual and social emotion; it can be used as a means of social control as well as being a private feeling. This methodological approach facilitates the literary analysis of shame, embodied for instance in the images of the penis as expressing or failing to express virility and potency in the characters, as well as investigation of narrative expressions of shame examined through different concepts linked to the emotion, namely, gaze in Kureishi’s Intimacy, hardness and softness in Roth’s novels Everyman and Portnoy’s Complaint, and dirt and disgust in Raz. Dwa. Trzy by Hubet Klimko-Dobrzaniecki

Clinical characteristics and long-term outcomes of MINOCA accompanied by active cancer. A retrospective insight into a cardio-oncology center registry

BACKGROUND: Clinical characteristics and long-term outcomes of patients with myocardial infarction with non-obstructive coronary arteries (MINOCA) and cancer are insufficiently elucidated. OBJECTIVES: We sought to characterize these patients hospitalized in a tertiary cardio-oncology center and to find the potential determinants affecting their long-term mortality. METHODS: MINOCA was diagnosed in 72 of the 1,011 patients with consecutive myocardial infarction who underwent coronary angiography. Mortality rates and their determinants were analyzed within a median follow-up of 69.2 (37.8–79.9) months. RESULTS: Active cancer was identified in 21 (29.2%) of patients with MINOCA and in 113 (12.0%) patients with myocardial infarction and obstructive coronary artery disease (MI-CAD) (p < 0.001). MINOCA patients with cancer were characterized by a higher incidence of anemia (47.6 vs. 21.6%, p = 0.03) and more frequently Takotsubo syndrome (19.1 vs. 2.0%, p = 0.01) than in non-cancer MINOCA. The troponin T/hemoglobin ratio was higher in both cancer MINOCA and MI-CAD groups when compared with their respective non-cancer patients (both p < 0.05). The age and sex-standardized mortality rates were significantly higher in cancer MINOCA (26.7%/year) when compared with non-cancer MINOCA (2.3%/year, p = 0.002) and in cancer MI-CAD (25.0%/year) vs. non-cancer MI-CAD (3.7%/year, p < 0.001). Active cancer (HR 3.12, 95% CI 2.41–4.04) was independently associated with higher long-term mortality, while higher hemoglobin levels (HR 0.93, 95% CI 0.88–0.99, per g/dl) and a MINOCA diagnosis (HR 0.69, 95% CI 0.47–0.97) improved long-term survival. CONCLUSION: Patients with MINOCA were comorbid with cancer more frequently than MI-CAD. In turn, an active malignancy was associated with an unfavorable long-term survival both in MI-CAD population and in patients with MINOCA

Generation of interspecies mouse-rat chimeric embryos by embryonic stem (ES) cell microinjection

Summary: Interspecies chimerism is a useful tool to study interactions between cells of different genetic makeup in order to elucidate the mechanisms underlying non-cell-autonomous processes, including evolutionary events. However, generating interspecies chimeras with high efficiency and chimerism level remains challenging. Here, we describe a protocol for generating chimeras between mouse and rat. Donor embryonic stem cells of one species are microinjected into early embryos of the other species (recipient), which are implanted into host foster mothers of the recipient species.For complete details on the use and execution of this protocol, please refer to Stepien et al. (2020)