Effect of hypercaloric and isocaloric diets different in fatty acid content on the endo cannabinoid system in pregnant dams and their offspring.

Lipid molecules are the building blocks of all cell membranes and provide essential secondary metabolites. The central nervous system is enriched in polyunsaturated fatty acids (PUFAs): arachidonic acid (AA) and docosahexaenoic acid (DHA). During brain development, PUFAs play a critical role in determining neuronal structure, particularly axonal outgrowth. In mammals, AA and DHA cannot be synthesized de novo and must be obtained largely from dietary sources. Moreover, during pregnancy and lactation, fetuses and infants rely on PUFAs from their mothers through the placenta and breast milk, respectively. Thus, the maternal diet needs to contain an appropriate omega-3/omega-6 PUFAs ratio to help child development. Based on these premises, we investigated the consequences of maternal malnutrition, defined as a shifted dietary ratio of omega-3 or omega-6 PUFAs on the brain of the offspring. In particular, we modeled human relevance by manipulating both the content and time of daily diets, with a keen focus on endocannabinoid (eCB) system given the critical roles of this AA-derived neuromodulator system during pre- and postnatal brain development. In the first approach of this project we fed female mice with hypercaloric diets, rich in omega-3 or in omega-6 PUFA, for two (short-term diet) or nine weeks (long-term diet) before mating and during gestation. We found that, levels of endocannabinoids (AEA, 2-AG) and AEA-like mediators (PEA, OEA) did not change with short-term diet in pregnant dams. Moreover, only omega-3 diet induced a significant increase of 2-AG levels, after long-term protocol. In embryos, we found that the short-term exposure of two weeks of omega-3 and omega-6 diet feeding is already sufficient to allow alteration of endocannabinoid system, especially FAAH and CB1R. In fact, in female embryos, we found down-regulation of CB1R and increase of FAAH after treatment with both diets. Interestingly, both enzyme and receptor levels are normalized after high-fat diet administration for a long period, where AEA levels were found decreased. By contrast, in males the alterations found in CB1R after the shorter protocol persist also after the prolongation of the treatment. In line with this, these data suggest a relationship among AEA, CB1R and FAAH, and an important link between PUFAs and endocannabinoid system. The second approach of this project was based on the administration of isocaloric diets, different in omega-3 levels but not in omega-6 PUFAs throughout gestation and until adulthood. We discovered that during gestation, not only the increase but also the decrease of omega-3 levels markedly affected the eCB system in the hippocampus of embryos. Furthermore, our in vivo results strongly suggest that omega-3 diets enriched and deficient affect the principal presynaptic marker in embryonic hippocampus but not in adult, where maternal malnutrition leads to long-term behavioral alterations in adult rats characterized by the presence of recognition memory deficits. As a whole, the second approach of this study supports our hypothesis about a relationship between PUFAs and the endocannabinoid system and provides further evidence on the importance of omega-3 PUFA on hippocampal development and functioning. All together, our results suggest that changes in dietary omega-3/omega-6 PUFAs ratio during gestation affect the endocannabinoid system in the brain of the offspring and the major effects of diets are present at the beginning of the treatment (i.e during gestation). Moreover, these data suggest that not only lipids but also fat can have a role in these changes

Landlord Duties To Combat Tenant-on-Tenant Discrimination under the Fair Housing Act

Congress passed the Fair Housing Act (“FHA”) during the Civil Rights movement, seeking to dispel discriminatory practices in the United States housing market. Relevant here, the FHA makes it unlawful to discriminate against protected class members in the “terms, conditions, or privileges of...rental of a dwelling, or in the provision of services or facilities in connection therewith....” Additionally, under the FHA, it is unlawful to “...interfere with any person in the exercise or enjoyment of...any right granted or protected...in this title.” Whether the FHA can be construed to make it unlawful for a property owner to acquiesce in tenant-on-tenant discriminatory harassment without facing potential liability under §§ 3604 and 3617 was addressed by the seventh circuit in Wetzel and second circuit in Francis.This post was originally published on the Cardozo Journal of Equal Rights and Social Justice website on November 28, 2022. The original post can be accessed via the Archived Link button above

Effect of hypercaloric and isocaloric diets different in fatty acid content on the endo cannabinoid system in pregnant dams and their offspring.

Lipid molecules are the building blocks of all cell membranes and provide essential secondary metabolites. The central nervous system is enriched in polyunsaturated fatty acids (PUFAs): arachidonic acid (AA) and docosahexaenoic acid (DHA). During brain development, PUFAs play a critical role in determining neuronal structure, particularly axonal outgrowth. In mammals, AA and DHA cannot be synthesized de novo and must be obtained largely from dietary sources. Moreover, during pregnancy and lactation, fetuses and infants rely on PUFAs from their mothers through the placenta and breast milk, respectively. Thus, the maternal diet needs to contain an appropriate omega-3/omega-6 PUFAs ratio to help child development. Based on these premises, we investigated the consequences of maternal malnutrition, defined as a shifted dietary ratio of omega-3 or omega-6 PUFAs on the brain of the offspring. In particular, we modeled human relevance by manipulating both the content and time of daily diets, with a keen focus on endocannabinoid (eCB) system given the critical roles of this AA-derived neuromodulator system during pre- and postnatal brain development. In the first approach of this project we fed female mice with hypercaloric diets, rich in omega-3 or in omega-6 PUFA, for two (short-term diet) or nine weeks (long-term diet) before mating and during gestation. We found that, levels of endocannabinoids (AEA, 2-AG) and AEA-like mediators (PEA, OEA) did not change with short-term diet in pregnant dams. Moreover, only omega-3 diet induced a significant increase of 2-AG levels, after long-term protocol. In embryos, we found that the short-term exposure of two weeks of omega-3 and omega-6 diet feeding is already sufficient to allow alteration of endocannabinoid system, especially FAAH and CB1R. In fact, in female embryos, we found down-regulation of CB1R and increase of FAAH after treatment with both diets. Interestingly, both enzyme and receptor levels are normalized after high-fat diet administration for a long period, where AEA levels were found decreased. By contrast, in males the alterations found in CB1R after the shorter protocol persist also after the prolongation of the treatment. In line with this, these data suggest a relationship among AEA, CB1R and FAAH, and an important link between PUFAs and endocannabinoid system. The second approach of this project was based on the administration of isocaloric diets, different in omega-3 levels but not in omega-6 PUFAs throughout gestation and until adulthood. We discovered that during gestation, not only the increase but also the decrease of omega-3 levels markedly affected the eCB system in the hippocampus of embryos. Furthermore, our in vivo results strongly suggest that omega-3 diets enriched and deficient affect the principal presynaptic marker in embryonic hippocampus but not in adult, where maternal malnutrition leads to long-term behavioral alterations in adult rats characterized by the presence of recognition memory deficits. As a whole, the second approach of this study supports our hypothesis about a relationship between PUFAs and the endocannabinoid system and provides further evidence on the importance of omega-3 PUFA on hippocampal development and functioning. All together, our results suggest that changes in dietary omega-3/omega-6 PUFAs ratio during gestation affect the endocannabinoid system in the brain of the offspring and the major effects of diets are present at the beginning of the treatment (i.e during gestation). Moreover, these data suggest that not only lipids but also fat can have a role in these changes

Effect of hypercaloric and isocaloric diets different in fatty acid content on the endo cannabinoid system in pregnant dams and their offspring.

Lipid molecules are the building blocks of all cell membranes and provide essential secondary metabolites. The central nervous system is enriched in polyunsaturated fatty acids (PUFAs): arachidonic acid (AA) and docosahexaenoic acid (DHA). During brain development, PUFAs play a critical role in determining neuronal structure, particularly axonal outgrowth. In mammals, AA and DHA cannot be synthesized de novo and must be obtained largely from dietary sources. Moreover, during pregnancy and lactation, fetuses and infants rely on PUFAs from their mothers through the placenta and breast milk, respectively. Thus, the maternal diet needs to contain an appropriate omega-3/omega-6 PUFAs ratio to help child development. Based on these premises, we investigated the consequences of maternal malnutrition, defined as a shifted dietary ratio of omega-3 or omega-6 PUFAs on the brain of the offspring. In particular, we modeled human relevance by manipulating both the content and time of daily diets, with a keen focus on endocannabinoid (eCB) system given the critical roles of this AA-derived neuromodulator system during pre- and postnatal brain development. In the first approach of this project we fed female mice with hypercaloric diets, rich in omega-3 or in omega-6 PUFA, for two (short-term diet) or nine weeks (long-term diet) before mating and during gestation. We found that, levels of endocannabinoids (AEA, 2-AG) and AEA-like mediators (PEA, OEA) did not change with short-term diet in pregnant dams. Moreover, only omega-3 diet induced a significant increase of 2-AG levels, after long-term protocol. In embryos, we found that the short-term exposure of two weeks of omega-3 and omega-6 diet feeding is already sufficient to allow alteration of endocannabinoid system, especially FAAH and CB1R. In fact, in female embryos, we found down-regulation of CB1R and increase of FAAH after treatment with both diets. Interestingly, both enzyme and receptor levels are normalized after high-fat diet administration for a long period, where AEA levels were found decreased. By contrast, in males the alterations found in CB1R after the shorter protocol persist also after the prolongation of the treatment. In line with this, these data suggest a relationship among AEA, CB1R and FAAH, and an important link between PUFAs and endocannabinoid system. The second approach of this project was based on the administration of isocaloric diets, different in omega-3 levels but not in omega-6 PUFAs throughout gestation and until adulthood. We discovered that during gestation, not only the increase but also the decrease of omega-3 levels markedly affected the eCB system in the hippocampus of embryos. Furthermore, our in vivo results strongly suggest that omega-3 diets enriched and deficient affect the principal presynaptic marker in embryonic hippocampus but not in adult, where maternal malnutrition leads to long-term behavioral alterations in adult rats characterized by the presence of recognition memory deficits. As a whole, the second approach of this study supports our hypothesis about a relationship between PUFAs and the endocannabinoid system and provides further evidence on the importance of omega-3 PUFA on hippocampal development and functioning. All together, our results suggest that changes in dietary omega-3/omega-6 PUFAs ratio during gestation affect the endocannabinoid system in the brain of the offspring and the major effects of diets are present at the beginning of the treatment (i.e during gestation). Moreover, these data suggest that not only lipids but also fat can have a role in these changes

Una dimensión afectiva del Ipsum Esse Subsistens

The text addresses the importance of the profile of the university graduate from a philosophical perspective, especially influenced by Thomistic metaphysics. It is proposed that understanding the profile of the graduate implies understanding both the point of arrival and the point of departure, that is, both the final objective and the initial reality of the students. Two fundamental causes that influence reality stand out: the formal cause (the essence or substantial form of things) and the final cause (the end or purpose towards which things tend). These causes determine the being of what is caused and are intrinsically related. The text explores how these philosophical perspectives affect human nature and its pursuit of perfection. The natural dimension of appetite is addressed, where it is explained that each thing tends towards its own good according to its substantial form. The natural inclination of beings towards their perfection and how this inclination guides their actions and desires is discussed. Furthermore, the entity dimension of appetite is examined, focusing on the concept of end. It is held that each being seeks its perfection and moves towards its ultimate goal, which is its own realization and completeness. Finally, the theological-natural perspective of being is explored, where it is argued that the radical love of beings towards their own being reflects their dependence and connection with God as the absolute principle of being. In summary, the text reflects on how the understanding of the profile of the university graduate is rooted in deep philosophical concepts about the nature, purpose and search for perfection in the human being.El texto aborda la importancia del perfil del egresado universitario desde una perspectiva filosófica, especialmente influenciada por la metafísica tomista. Se plantea que entender el perfil del egresado implica comprender tanto el punto de llegada como el punto de partida, es decir, tanto el objetivo final como la realidad inicial de los estudiantes. Se destacan dos causas fundamentales que influyen en la realidad: la causa formal (la esencia o forma sustancial de las cosas) y la causa final (el fin o propósito hacia el cual tienden las cosas). Estas causas determinan el ser de lo causado y están intrínsecamente relacionadas. El texto explora cómo estas perspectivas filosóficas afectan la naturaleza humana y su búsqueda de la perfección. Se aborda la dimensión natural del apetito, donde se explica que cada cosa tiende hacia su propio bien de acuerdo con su forma sustancial. Se discute la inclinación natural de los seres hacia su perfección y cómo esta inclinación guía sus acciones y deseos. Además, se examina la dimensión entitativa del apetito, centrándose en el concepto de fin. Se sostiene que cada ser busca su perfección y se mueve hacia su fin último, que es su propia realización y completitud. Finalmente, se explora la perspectiva teológico-natural del ser, donde se argumenta que el amor radical de los seres hacia su propio ser refleja su dependencia y conexión con Dios como el principio absoluto de ser. En resumen, el texto reflexiona sobre cómo la comprensión del perfil del egresado universitario está arraigada en conceptos filosóficos profundos sobre la naturaleza, el propósito y la búsqueda de la perfección en el ser humano

GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts

Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disorder caused by loss-of-function mutations in SLC2A10, which encodes facilitative glucose transporter 10 (GLUT10). The role of GLUT10 in ATS pathogenesis remains an enigma, and the transported metabolite(s), i.e. glucose and/or dehydroascorbic acid, have not been clearly elucidated. To discern the molecular mechanisms underlying the ATS aetiology, we performed gene expression profiling and biochemical studies on skin fibroblasts. Transcriptome analyses revealed the dysregulation of several genes involved in TGFβ signalling and extracellular matrix (ECM) homeostasis as well as the perturbation of specific pathways that control both the cell energy balance and the oxidative stress response. Biochemical and functional studies showed a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1. ATS fibroblasts also showed activation of a non-canonical TGFβ signalling due to TGFBRI disorganization, the upregulation of TGFBRII and connective tissue growth factor, and the activation of the αvβ3 integrin transduction pathway, which involves p125FAK, p60Src and p38 MAPK. Stable GLUT10 expression in patients' fibroblasts normalized redox homeostasis and PPARγ activity, rescued canonical TGFβ signalling and induced partial ECM re-organization. These data add new insights into the ATS dysregulated biological pathways and definition of the pathomechanisms involved in this disorder

Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers-Danlos syndrome: A retrospective cross-sectional study from an Italian reference center

The most common conditions with symptomatic joint hypermobility are hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). Diagnosing these overlapping connective tissue disorders remains challenging due to the lack of established causes and reliable diagnostic tests. hEDS is diagnosed applying the 2017 diagnostic criteria, and patients with symptomatic joint hypermobility but not fulfilling these criteria are labeled as HSD, which is not officially recognized by all healthcare systems. The 2017 criteria were introduced to improve diagnostic specificity but have faced criticism for being too stringent and failing to adequately capture the multisystemic involvement of hEDS. Herein, we retrospectively evaluated 327 patients from 213 families with a prior diagnosis of hypermobility type EDS or joint hypermobility syndrome based on Villefranche and Brighton criteria, to assess the effectiveness of the 2017 criteria in distinguishing between hEDS and HSD and document the frequencies of extra-articular manifestations. Based on our findings, we propose that the 2017 criteria should be made less stringent to include a greater number of patients who are currently encompassed within the HSD category. This will lead to improved diagnostic accuracy and enhanced patient care by properly capturing the diverse range of symptoms and manifestations present within the hEDS/HSD spectrum

Expanding the clinical and mutational spectrum of B4GALT7-spondylodysplastic Ehlers-Danlos syndrome

Spondylodysplastic EDS (spEDS) is a rare connective tissue disorder that groups the phenotypes caused by biallelic B4GALT7, B3GALT6, and SLC39A13 mutations. In the 2017 EDS nosology, minimal criteria (general and gene-specific) for a clinical suspicion of spEDS have been proposed, but molecular analysis is required to reach a definite diagnosis. The majority of spEDS patients presented with short stature, skin hyperextensibility, facial dysmorphisms, peculiar radiological findings, muscle hypotonia and joint laxity and/or its complications. To date only 7 patients with β4GALT7-deficiency (spEDS-B4GALT7) have been described and their clinical data suggested that, in addition to short stature and muscle hypotonia, radioulnar synostosis, hypermetropia, and delayed cognitive development might be a hallmark of this specific type of spEDS. Additional 22 patients affected with an overlapping phenotype, i.e., Larsen of Reunion Island syndrome, all carrying a homozygous B4GALT7 mutation, are also recognized. Herein, we report on a 30-year-old Moroccan woman who fitted the minimal criteria to suspect spEDS, but lacked radioulnar synostosis and intellectual disability and presented with neurosensorial hearing loss and limb edema of lymphatic origin. Sanger sequencing of B4GALT7 was performed since the evaluation of the spEDS gene-specific minor criteria suggested this specific subtype. Mutational screening revealed the homozygous c.829G>T, p.Glu277* pathogenetic variant leading to aberrant splicing. Our findings expand both the clinical and mutational spectrum of this ultrarare connective tissue disorder. The comparison of the patient's features with those of the other spEDS and Larsen of Reunion Island syndrome patients reported up to now offers future perspectives for spEDS nosology and clinical research in this field