Transcriptional activation and nuclear targeting signals of the human androgen receptor

The androgen receptor (AR) is a signal-transducing protein required for sexual differentiation, development, and expression of the male phenotype. A series of human AR deletion mutants were created either by site-directed mutagenesis using restriction enzyme digestion, the polymerase chain reaction, or, for a series of unidirectional NH2-terminal deletions, exonuclease III digestion. Receptor mutants were expressed in monkey kidney COS cells as truncated AR proteins between 20 and 107 kDa as revealed on immunoblots, where wild type AR was a doublet of 114 and 108 kDa. Subcellular localization by immunocytochemical staining demonstrated androgen-dependent nuclear uptake of AR from a perinuclear region of the cytoplasm. A nuclear targeting signal similar in sequence and position to the glucocorticoid receptor and homologous to the SV40 large T antigen was required for androgen-induced nuclear uptake of wild type AR. AR mutants lacking the NH2-terminal and/or steroid binding domains were constitutively nuclear with reduced transcriptional activity. Transcriptional activation by wild type AR was androgen-dependent in cotransfection studies of CV1 cells using the chloramphenicol acetyltransferase reporter gene linked to the mouse mammary tumor virus promoter. Deletion mutagenesis revealed within the NH2-terminal region a domain required for full transcriptional activity and within the steroid binding domain, an inhibitory function, deletion of which yielded a constitutively active receptor. Inhibition of wild type AR by coexpression with an inactive NH2-terminal fragment suggested competition for nuclear factors required for transcriptional regulation. These studies demonstrate a concerted interplay among the domains of the AR protein in regulating gene transcription

Natural disordered sequences in the amino terminal domain of nuclear receptors: lessons from the androgen and glucocorticoid receptors

Steroid hormones are a diverse class of structurally related molecules, derived from cholesterol, that include androgens, estrogens, progesterone and corticosteroids. They represent an important group of physiologically active signalling molecules that bind intracellular receptor proteins and regulate genes involved in developmental, reproductive and metabolic processes. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains, but possess distinct N-terminal domains (NTD) of unique length and amino acids sequence. The NTD contains sequences important for gene regulation, exhibit structure plasticity and are likely to contribute to the specificity of the steroid hormone/receptor response

Importance of Magnesium Status in COVID-19

A large amount of published research points to the interesting concept (hypothesis) that magnesium (Mg) status may have relevance for the outcome of COVID-19 and that Mg could be protective during the COVID disease course. As an essential element, Mg plays basic biochemical, cellular, and physiological roles required for cardiovascular, immunological, respiratory, and neurological functions. Both low serum and dietary Mg have been associated with the severity of COVID-19 outcomes, including mortality; both are also associated with COVID-19 risk factors such as older age, obesity, type 2 diabetes, kidney disease, cardiovascular disease, hypertension, and asthma. In addition, populations with high rates of COVID-19 mortality and hospitalization tend to consume diets high in modern processed foods, which are generally low in Mg. In this review, we review the research to describe and consider the possible impact of Mg and Mg status on COVID-19 showing that (1) serum Mg between 2.19 and 2.26 mg/dL and dietary Mg intakes > 329 mg/day could be protective during the disease course and (2) inhaled Mg may improve oxygenation of hypoxic COVID-19 patients. In spite of such promise, oral Mg for COVID-19 has thus far been studied only in combination with other nutrients. Mg deficiency is involved in the occurrence and aggravation of neuropsychiatric complications of COVID-19, including memory loss, cognition, loss of taste and smell, ataxia, confusion, dizziness, and headache. Potential of zinc and/or Mg as useful for increasing drug therapy effectiveness or reducing adverse effect of anti-COVID-19 drugs is reviewed. Oral Mg trials of patients with COVID-19 are warranted

A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat.

The complete form of androgen insensitivity is an inherited X-linked syndrome in which genetic males fail to undergo masculinization in utero due to defective functioning of the androgen receptor (AR). The molecular basis of androgen insensitivity was investigated in the testicular feminized (Tfm) rat with this syndrome. AR mRNA size and amount, as well as nuclear AR protein revealed by immunocytochemistry, suggested normal expression of the AR gene in the Tfm rat. Sequence analysis of the AR coding region from Tfm and wild-type littermate male rats revealed a single transition mutation, guanine to adenine, within exon E, changing arginine 734 to glutamine within the steroid-binding domain of the AR. This arginine is highly conserved among the family of nuclear receptors and may be part of a phosphorylation recognition site. A recreated mutant AR (Arg734----Gln) expressed in COS cells had only 10-15% of the androgen-binding capacity of wild-type AR; the reduced androgen-binding capacity was similar to that of AR in tissue extracts of the Tfm rat. Stimulation of transcriptional activity by the recreated mutant AR was reduced relative to wild-type AR in cotransfection assays in CV1 cells using as reporter plasmid the mouse mammary tumor virus promoter linked to the chloramphenicol acetyltransferase gene. Thus, arginine 734 appears essential for normal AR function both in androgen binding and transcriptional activation. Absence of these functions results in androgen insensitivity and lack of male sexual development

Allosteric Modulators of Steroid Hormone Receptors : Structural Dynamics and Gene Regulation

Peer reviewedPublisher PD

Visual Analytics for Epidemiologists: Understanding the Interactions Between Age, Time, and Disease with Multi-Panel Graphs

Visual analytics, a technique aiding data analysis and decision making, is a novel tool that allows for a better understanding of the context of complex systems. Public health professionals can greatly benefit from this technique since context is integral in disease monitoring and biosurveillance. We propose a graphical tool that can reveal the distribution of an outcome by time and age simultaneously.We introduce and demonstrate multi-panel (MP) graphs applied in four different settings: U.S. national influenza-associated and salmonellosis-associated hospitalizations among the older adult population (≥65 years old), 1991-2004; confirmed salmonellosis cases reported to the Massachusetts Department of Public Health for the general population, 2004-2005; and asthma-associated hospital visits for children aged 0-18 at Milwaukee Children's Hospital of Wisconsin, 1997-2006. We illustrate trends and anomalies that otherwise would be obscured by traditional visualization techniques such as case pyramids and time-series plots.MP graphs can weave together two vital dynamics--temporality and demographics--that play important roles in the distribution and spread of diseases, making these graphs a powerful tool for public health and disease biosurveillance efforts

De Nueva España a México : El universo musical mexicano entre centenarios (1517-1917)

742 págs. Imágenes color y b/n. Partituras musicales.El fenómeno de las conmemoraciones culturales siempre ha sido un terreno abonado para la producción cultural y artística del que se han valido los Estados para ofrecer interpretaciones legitimadoras e ideologizadas de la historia, articuladas en torno a las ideas de memoria, nación y progreso. El presente volumen, resultado de una triple conmemoración (el centenario de la Revolución Mexicana y la publicación de la primera historia de la música en México de Alba Herrera –1917–, por un lado; y la llegada del militar andaluz Francisco Hernández de Córdoba a la costa de la península del Yucatán –1517–, por otro), presenta una visión retrospectiva de la historia musical mexicana a lo largo de esas cuatro centurias. Frente a la rígida división cronológica impuesta por ciertas narrativas, se ofrece así una noción inclusiva, actual e informada del universo musical mexicano en toda su multiplicidad y riqueza de matices, integrando las épocas colonial e independiente como lo que realmente son: partes constitutivas de la memoria musical, histórica, cultural y política del país, con las luces y las sombras propias de cualquier otro periodo