Effects of in vivo 3-iodothyronamine administration on gene expression in adipose tissue.

Thyroid hormones (THs) control the adipose tissue development and metabolism. They regulate both adipocyte proliferation and differentiation and, as they cause weight loss by increasing the metabolic rate, may be useful for obesity treatment. However, due to their cardiotoxic effects, like tachycardia and arrhythmia, their use is limited to hypothyroid obese patients. Some TH metabolites have been recently shown to possess the same beneficial metabolic effects as THs without the same negative effects. A biogenic amine named 3-Iodothyronamine (T1AM), i.e., is an endogenous compound derived by thyroxine (T4) deiodination and decarboxylation that affects carbohydrate and lipid metabolism without undesirable side effects. T1AM exhibits cardiac effects opposite to those associated with thyroid hormones, like bradycardia in mice, and in isolated working rat heart, it produces a rapid, reversible, dose-dependent decrease in cardiac output, aortic pressure and coronary flow. These findings suggest that T1AM produces a negative inotropic and chronotropic effect. Intraperitoneal injections of T1AM also induce reduction of RQ from 0.9 to 0.7, both in mice and Djungarian hamsters. This indicates that carbohydrate utilisation is reduced in response to T1AM and energy requirements are covered by lipid utilisation. Interestingly, the complete RQ shift is reached 4.5 h after the T1AM injection and persists at least for 24 hours. Ketone bodies in the urine and the significant loss of body fat mass confirm that lipids are predominantly used to cover the energy requirements in response to T1AM administration. The molecular mechanisms by which T1AM favours lipid than glucose catabolism are not known, but changes in gene expression can be hypothesized, given the delayed and long lasting phenotypical effects of T1AM. To verify this hypothesis we analyzed by microarrays the gene expression profiles in subcutaneous adipose tissues of eight rats chronically treated with T1AM as compared with eight untreated rats. Many genes linked to lipid metabolism, adipogenesis and angiogenesis appeared affected by chronic administration of T1AM, thus explaining, at least in part, the T1AM phenotypic effects observed in rodents. Furthermore, T1AM influenced the expression of several genes relating to lipoprotein metabolism that provide new insights on T1AM mechanism of action, like, i.e., the regulation of cholesterol homeostasis

Genes and Aggressive Behavior: Epigenetic Mechanisms Underlying Individual Susceptibility to Aversive Environments

Over the last two decades, the study of the relationship between nature and nurture in shaping human behavior has encountered a renewed interest. Behavioral genetics showed that distinct polymorphisms of genes that code for proteins that control neurotransmitter metabolic and synaptic function are associated with individual vulnerability to aversive experiences, such as stressful and traumatic life events, and may result in an increased risk of developing psychopathologies associated with violence. On the other hand, recent studies indicate that experiencing aversive events modulates gene expression by introducing stable changes to DNA without modifying its sequence, a mechanism known as “epigenetics”. For example, experiencing adversities during periods of maximal sensitivity to the environment, such as prenatal life, infancy and early adolescence, may introduce lasting epigenetic marks in genes that affect maturational processes in brain, thus favoring the emergence of dysfunctional behaviors, including exaggerate aggression in adulthood. The present review discusses data from recent research, both in humans and animals, concerning the epigenetic regulation of four genes belonging to the neuroendocrine, serotonergic and oxytocinergic pathways—Nuclear receptor subfamily 3-group C-member 1 (NR3C1), oxytocin receptor (OXTR), solute carrier-family 6 member 4 (SLC6A4) and monoamine oxidase A (MAOA)—and their role in modulating vulnerability to proactive and reactive aggressive behavior. Behavioral genetics and epigenetics are shedding a new light on the fine interaction between genes and environment, by providing a novel tool to understand the molecular events that underlie aggression. Overall, the findings from these studies carry important implications not only for neuroscience, but also for social sciences, including ethics, philosophy and law

Effects on human transcriptome of mutated BRCA1 BRCT domain: A microarray study

BACKGROUND: BRCA1 (breast cancer 1, early onset) missense mutations have been detected in familial breast and ovarian cancers, but the role of these variants in cancer predisposition is often difficult to ascertain. In this work, the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT (BRCA1 C Terminus) domain, have been investigated. Both these variants were isolated from familial breast cancer patients and the study of their effect on yeast cell transcriptome has previously provided interesting clues to their possible role in the pathogenesis of breast cancer. METHODS: We compared by Human Whole Genome Microarrays the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type. Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), considering the two variants as a single mutation of BRCT domain. RESULTS: 201 differentially expressed genes were found in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes mapped in pathways deregulated in cancer, such as cell cycle progression and DNA damage response and repair. CONCLUSIONS: Our results represent the first molecular evidence of the pathogenetic role of M1775R, already proposed by functional studies, and give support to a similar role for A1789T that we first hypothesized based on the yeast cell experiments. This is in line with the very recently suggested role of BRCT domain as the main effector of BRCA1 tumor suppressor activity

Marcadores moleculares y morfológicos para la descripción de variabilidad en caña de azúcar (Saccharum officiarum) con fines de manejo y conservación de germoplasma

La caña de azúcar es uno de los cultivos industriales más importantes de regiones tropicales y subtropicales. El INTA (Argentina) administra un Banco de Germoplasma de caña de azúcar y lleva a cabo un programa de mejora. El presente trabajo fue diseñado para estimar la variabilidad fenotípica y genética entre 65 accesiones de caña de azúcar seleccionadas del INTA. Se aplicaron métodos de clasificación y ordenamiento en el análisis de datos morfológicos y de SSR. EL Análisis de Procrustes Generalizado permitió evaluar la correlación entre las relaciones establecidas a partir de ambos tipos de marcadores. Un buen ajuste entre los dendrogramas y las matrices de similitud fue soportado por un alto coeficiente de correlación cofenética (r=0,82, p<0,0001; r=0,73, p<0,0001; r=0,82, p<0,0001 para datos cuantitativos, cualitativos y moleculares respectivamente). La presencia de una estructura poblacional fue reconocida cuando se consideraron los diferentes tipos de datos. El Procrustes permitió detectar aquellas accesiones que serían responsables de la baja correlación detectada entre configuraciones individuales (73%). Tanto los marcadores morfológicos como los moleculares resultaron lo suficientemente discriminativos para diferenciar accesiones. No obstante, no fue posible correlacionar las asociaciones establecidas por los marcadores con el origen de los materiales. Las distancias fenotípicas y genéticas basadas en información morfológica y molecular será de utilidad para asistir en la conservación y organización de los materiales de la colección y elegir combinaciones parentales con propósito de mejora.Sugarcane is one of the most important industrial crops in tropical and subtropical regions. INTA (Argentina) administrates a Sugarcane Germplasm Bank and carries out a breeding program. The current study was designed to assess the phenotypic and genetic diversity among 65 sugarcane accessions selected from the INTA. Clustering and ordination methods based on quantitative and qualitative morphological traits and SSR data were applied. Generalized Procrustes Analysis allowed evaluating the correlation between relationships established with both markersA good of fit between dendrograms and similarity matrices were revealed by high cophenetic coefficients (r=0.82, p<0.0001; r=0.73, p<0.0001; r=0.82, p<0.0001 for phenotypic quantitative, phenotypic qualitative and molecular data respectively). The presence of different reliable population structure was observed when considering different data sources. Procrustes allowed finding those accessions that should have been responsible for the low correlation found between the individual configurations (73%). Both morphologic and molecular markers resulted discriminative enough to differentiate among accessions. It was not possible, however, to correlate associations of markers with the origin of materials. Phenotypic and genetic distances based on morphology and molecular information serves to assist conservation and organization of collection of materials, and the choice of parent combinations for breeding purposes.Fil: Pocovi, Mariana Inés. Universidad Nacional de Salta. Facultad de Ciencias Naturales; ArgentinaFil: Collavino, Norma Graciela. Universidad Nacional de Salta. Facultad de Ciencias Naturales; ArgentinaFil: Gutiérrez, Angela Verónica. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; ArgentinaFil: Taboada, Gisel María. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; ArgentinaFil: Castillo, Veronica. Universidad Nacional de Salta. Facultad de Ciencias Naturales; ArgentinaFil: Delgado, Romina Paola. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta; ArgentinaFil: Mariotti, Jorge. Universidad Nacional de Salta. Facultad de Ciencias Naturales; Argentin

Characterisation of gene expression profiles of yeast cells expressing BRCA1 missense variants

Germline mutations in breast cancer susceptibility gene 1 (BRCA1) confer high risk of developing breast and ovarian cancers. Even though most BRCA1 cancer-predisposing mutations produce a non-functional truncated protein, 5-10% of them cause single amino acid substitutions. This second type of mutations represents a useful tool for examining BRCA1 molecular functions. Human BRCA1 inhibits cell proliferation in transformed Saccharomyces cerevisiae cells and this effect is abolished by disease-associated mutations in the BRCT domain. Moreover, BRCA1 mutations located both inside and outside the BRCT domain may induce an increase in the homologous recombination frequency in yeast cells. Here we present a microarray analysis of gene expression induced in yeast cells transformed with five BRCA1 missense variants, in comparison with gene expression induced by wildtype BRCA1. Data analysis was performed by grouping the BRCA1 variants into three sets: Recombination (R)-set (Y179C and S1164I), Recombination and Proliferation (RP)-set(I1766S and M1775R) and Proliferation (P)-set (A1789T), according to their effects on yeast cell phenotype. We found 470, 740 and 1136 differentially expressed genes in R-, P- and RP-set, respectively. Our results point to some molecular mechanisms critical for the control of cell proliferation and of genome integrity providing support to a possible pathogenic role of the analysed mutations. They also confirm that yeast, despite the absence of a BRCA1 homologue, represents a valid model system to examine BRCA1 molecular functions, as the molecular pathways activated by BRCA1 variants are conserved in humans

Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score

AbstractIntroductionAromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs.Methods100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤−2.5 or BMD between −2.5 and −1 plus either increased risk by FRAX® or degraded microstructure by TBS.ResultsAt baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%).ConclusionsThe combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs

Genetically-Driven Enhancement of Dopaminergic Transmission Affects Moral Acceptability in Females but Not in Males: A Pilot Study

Moral behavior has been a key topic of debate for philosophy and psychology for a long time. In recent years, thanks to the development of novel methodologies in cognitive sciences, the question of how we make moral choices has expanded to the study of neurobiological correlates that subtend the mental processes involved in moral behavior. For instance, in vivo brain imaging studies have shown that distinct patterns of brain neural activity, associated with emotional response and cognitive processes, are involved in moral judgment. Moreover, while it is well-known that responses to the same moral dilemmas differ across individuals, to what extent this variability may be rooted in genetics still remains to be understood. As dopamine is a key modulator of neural processes underlying executive functions, we questioned whether genetic polymorphisms associated with decision-making and dopaminergic neurotransmission modulation would contribute to the observed variability in moral judgment. To this aim, we genotyped five genetic variants of the dopaminergic pathway [rs1800955 in the dopamine receptor D4 (DRD4) gene, DRD4 48 bp variable number of tandem repeat (VNTR), solute carrier family 6 member 3 (SLC6A3) 40 bp VNTR, rs4680 in the catechol-O-methyl transferase (COMT) gene, and rs1800497 in the ankyrin repeat and kinase domain containing 1 (ANKK1) gene] in 200 subjects, who were requested to answer 56 moral dilemmas. As these variants are all located in genes belonging to the dopaminergic pathway, they were combined in multilocus genetic profiles for the association analysis. While no individual variant showed any significant effects on moral dilemma responses, the multilocus genetic profile analysis revealed a significant gender-specific influence on human moral acceptability. Specifically, those genotype combinations that improve dopaminergic signaling selectively increased moral acceptability in females, by making their responses to moral dilemmas more similar to those provided by males. As females usually give more emotionally-based answers and engage the “emotional brain” more than males, our results, though preliminary and therefore in need of replication in independent samples, suggest that this increase in dopamine availability enhances the cognitive and reduces the emotional components of moral decision-making in females, thus favoring a more rationally-driven decision process

Long Term Assessment of Anti-SARS-CoV-2 Immunogenicity after mRNA Vaccine in Persons Living with HIV

(1) Background: Waning of neutralizing and cell-mediated immune response after the primary vaccine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/mm3. (2) Methods: Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G/Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at four time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, ≤200/mm3; ICD4, 201–500/mm3, and HCD4, &gt;500/mm3). Mixed models were used to compare mean responses over T1–T4 across CD4 groups. (3) Results: 314 PLWH on ART (LCD4 = 56; ICD4 = 120; HCD4 = 138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs. ICD4/HCD4 (p = 0.04). The BD was crucial for increasing nAbs titers above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p = 0.31). (4) Conclusions: Waning of nAbs after PVC was more important in LCD4 group. The BD managed to re-establish higher levels of nAbs against WD614G, which were retained for 5 months, but for shorter time for Omicron BA.1. The T cellular response in the LCD4 group was lower than that seen in participants with higher CD4 count, but, importantly, it remained above detectable levels over the entire study period

The feeling of anger: From brain networks to linguistic expressions.

This review of the neuroscience of anger is part of The Human Affectome Project, where we attempt to map anger and its components (i.e., physiological, cognitive, experiential) to the neuroscience literature (i.e., genetic markers, functional imaging of human brain networks) and to linguistic expressions used to describe anger feelings. Given the ubiquity of anger in both its normative and chronic states, specific language is used in humans to express states of anger. Following a review of the neuroscience literature, we explore the language that is used to convey angry feelings, as well as metaphors reflecting inner states of anger experience. We then discuss whether these linguistic expressions can be mapped on to the neural circuits during anger experience and to distinct components of anger. We also identify relationships between anger components, brain networks, and other affective research relevant to motivational states of dominance and basic needs for safety

The early expansion of anergic NKG2Apos/CD56dim/CD16neg natural killer cells represents a therapeutic target in haploidentical haematopoietic stem cell transplantation

Natural Killer cells are the first lymphocyte population to reconstitute early after non myelo-ablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The present study characterizes the transient and predominant expansion starting from the 2nd week after haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkable high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16pos natural killer cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg natural killer cells are greatly expanded in the following 7 weeks after haploidentical hematopoietic stem cell transplantation and express high levels of the activating receptors NKGD and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg natural killer cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation