Intense Research Scrutiny Research Articles

Deciphering Depression: Epigenetic Mechanisms and Treatment Strategies.

Depression, a significant mental health disorder, is under intense research scrutiny to uncover its molecular foundations. Epigenetics, which focuses on controlling gene expression without altering DNA sequences, offers promising avenues for innovative treatment. This review explores the pivotal role of epigenetics in depression, emphasizing two key aspects: (I) identifying epigenetic targets for new antidepressants and (II) using personalized medicine based on distinct epigenetic profiles, highlighting potential epigenetic focal points such as DNA methylation, histone structure alterations, and non-coding RNA molecules such as miRNAs. Variations in DNA methylation in individuals with depression provide opportunities to target genes that are associated with neuroplasticity and synaptic activity. Aberrant histone acetylation may indicate that antidepressant strategies involve enzyme modifications. Modulating miRNA levels can reshape depression-linked gene expression. The second section discusses personalized medicine based on epigenetic profiles. Analyzing these patterns could identify biomarkers associated with treatment response and susceptibility to depression, facilitating tailored treatments and proactive mental health care. Addressing ethical concerns regarding epigenetic information, such as privacy and stigmatization, is crucial in understanding the biological basis of depression. Therefore, researchers must consider these issues when examining the role of epigenetics in mental health disorders. The importance of epigenetics in depression is a critical aspect of modern medical research. These findings hold great potential for novel antidepressant medications and personalized treatments, which would significantly improve patient outcomes, and transform psychiatry. As research progresses, it is expected to uncover more complex aspects of epigenetic processes associated with depression, enhance our comprehension, and increase the effectiveness of therapies.

Secure Software Development Awareness: A Case Study of Undergraduate Developers

As ubiquitous computing becomes an increasingly inherent component of everyday life due to the rapid growth of communication technologies and globalization, threats against information systems have taken a more latent yet lethal dimension. This emergent digital security challenge has correspondingly motivated a proactive change in the software engineering process in recent decades. This change has inspired more intense research scrutiny on security as a crucial component of any software system. Moreover, in today’s virtual world of hyperconnectivity, the most significant vulnerabilities in modern information systems security are software centred. Nevertheless, research shows that software developers often lack the required knowledge and skills in secure software systems development (SSD). Such knowledge ensures that all the resultant software components of each development lifecycle are correctly implemented rather than merely following the SSD lifecycle. Also, the knowledge engenders software security consciousness as a professional attitude amongst developers. Therefore, investigating students’ awareness of SSD principles can generate insight into evolving the undergraduate software development curriculum – a path to building future career developers. The study used a voluntary online survey to recruit a sample of 76 undergraduate developers and employed a descriptive approach to data analysis. Among other findings, the study revealed that participants' perception of the threat of software vulnerability impacts their attitude towards security on online and mobile platforms. And that though over 90% of the undergraduate developers took software vulnerability threats either “serious” or “extremely serious”, this disposition did not reflect the depth of their knowledge and experience in SSD.

SECURE SOFTWARE DEVELOPMENT AWARENESS: A CASE STUDY OF UNDERGRADUATE DEVELOPERS

As ubiquitous computing becomes an increasingly inherent component of everyday life due to the rapid growth of communication technologies and globalization, threats against information systems have taken a more latent yet lethal dimension. This emergent digital security challenge has correspondingly motivated a proactive change in the software engineering process in recent decades. This change has inspired more intense research scrutiny on security as a crucial component of any software system. Moreover, in today’s virtual world of hyperconnectivity, the most significant vulnerabilities in modern information systems security are software centred. Nevertheless, research shows that software developers often lack the required knowledge and skills in secure software systems development (SSD). Such knowledge ensures that all the resultant software components of each development lifecycle are correctly implemented rather than merely following the SSD lifecycle. Also, the knowledge engenders software security consciousness as a professional attitude amongst developers. Therefore, investigating students’ awareness of SSD principles can generate insight into evolving the undergraduate software development curriculum – a path to building future career developers. The study used a voluntary online survey to recruit a sample of 76 undergraduate developers and employed a descriptive approach to data analysis. Among other findings, the study revealed that participants’ perception of the threat of software vulnerability impacts their attitude towards security on online and mobile platforms. And that though over 90% of the undergraduate developers took software vulnerability threats either “serious” or “extremely serious”, this disposition did not reflect the depth of their knowledge and experience in SSD.

Earth’s volatile accretion as told by Cd, Bi, Sb and Tl core–mantle distribution

The timing and origin of volatile elements accretion on Earth has been and continues to be key questions, despite intense research scrutiny. Two end-member scenarios are usually proposed in which (1) volatile elements were delivered during the main phases of Earth’s accretion and underwent subsequent core–mantle differentiation, or (2) Earth accreted from largely dry and volatile-depleted material, with late addition of volatile-rich material after differentiation. Studying the behaviour of elements that are both volatile and siderophile in a metal–silicate equilibrium can help discriminate between those two scenarios by deconvolving the effect of siderophile processes such as the Earth’s differentiation from the effect of volatile processes. We report high-pressure and high-temperature metal–silicate equilibrium experiments that are used to trace the behaviour of four moderately siderophile and volatile elements: Cd, Bi, Sb and Tl. Experiments were performed in piston cylinder and multianvil presses between 2 and 20 GPa, from 1700 to 2600 K, in order to study the partitioning behaviour of these elements, including the relative influence of pressure, temperature, oxygen fugacity (fO2), and composition. Our results indicate that Cd, Bi, Sb and Tl partitioning coefficients are largely controlled by changes in temperature, pressure, fO2 and the S content of the metal phase. The pressure effect on Tl and Bi partitioning is measured for the first time and improves significantly the knowledge of Bi and Tl behaviour during core formation. Core formation modelling was used to reconcile the experimental data with observed abundances for different accretion scenarios. Homogeneous accretion with full core–mantle equilibration induces a massive segregation of Bi, Sb and Tl in the core, preventing reproduction of observed present-day mantle abundances. We find that a scenario in which the volatile elements are accreted in the last 10–20 % of the Earth’s accretion is the most suitable accretion process that is able to explain the abundances of Cd, Bi, Sb and Tl in Earth’s mantle. Partial core–mantle equilibration is necessary to reproduce Bi and Tl abundances. Our partitioning data also suggests that a 0.5 % chondritic late veneer may account for the Bi abundance measured in the bulk silicate Earth. These observations corroborate a growing wealth of evidence in support of this schematic heterogeneous accretion pathway.

Immune cell-mediated inflammation and the early improvements in glucose metabolism after gastric banding surgery

The contribution of immune cells to the inflammasome that characterises type 2 diabetes mellitus and obesity is under intense research scrutiny. We hypothesised that early changes in glucose metabolism following gastric banding surgery may relate to systemic inflammation, particularly cell-mediated immunity. Obese participants (BMI 43.4 ± 4.9 kg/m(2), n = 15) with diabetes or impaired glucose tolerance (IGT) underwent laparoscopic adjustable gastric banding surgery. Measurements taken before, and at 2 and 12 weeks after surgery included: fasting glucose, glucose levels 2 h after a 75 g oral load, glucose incremental AUC, oral glucose insulin sensitivity index (OGIS), circulating immune cell numbers and activation, and adipokine levels. Subcutaneous and visceral adipose tissue were collected at surgery, and macrophage number and activation measured. There were significant reductions in fasting and 2 h glucose, as well as improved OGIS at 2 and 12 weeks. At 12 weeks, 80% of the diabetic participants reverted to normal glucose tolerance or IGT, and all IGT participants had normalised glucose tolerance. The 12 week fall in fasting glucose was significantly related to baseline lymphocyte and T lymphocyte numbers, and to granulocyte activation, but also to the magnitude of the 12 week reduction in lymphocyte and T lymphocyte numbers and TNF-α levels. In a model that explained 75% of the variance in the change in fasting glucose, the 12 week change in T lymphocytes was independently associated with the 12 week fall in fasting glucose. Rapid improvements in glucose metabolism after gastric banding surgery are related to reductions in circulating pro-inflammatory immune cells, specifically T lymphocytes. The contribution of immune cell-mediated inflammation to glucose homeostasis in type 2 diabetes and its improvement after bariatric surgery require further investigation.

The Formamidopyrimidines: Purine Lesions Formed in Competition With 8-Oxopurines From Oxidative Stress

DNA is constantly exposed to agents that induce structural damage, from sources both internal and external to an organism. Endogenous species, such as oxidizing chemicals, and exogenous agents, such as ultraviolet rays in sunlight, together produce more than 70 distinct chemical modifications of native nucleotides. Of these, about 15 of the lesions have been detected in cellular DNA. This kind of structural DNA damage can be cytotoxic, carcinogenic, or both and is being linked to an increasingly lengthy list of diseases. The formamidopyrimidine (Fapy) lesions are a family of DNA lesions that result after purines undergo oxidative stress. The Fapy lesions are produced in yields comparable to the 8-oxopurines, which, owing in part to a perception of mutagenicity in some quarters, have been subjected to intense research scrutiny. But despite the comparable abundance of the formamidopyrimidines and the 8-oxopurines, until recently very little was known about the effects of Fapy lesions on biochemical processes involving DNA or on the structure and stability of the genomic material. In this Account, we discuss the detection of Fapy lesions in DNA and the mechanism proposed for their formation. We also describe methods for the chemical synthesis of oligonucleotides containing Fapy·dA or Fapy·dG and the outcomes of chemical and biochemical studies utilizing these compounds. These experiments reveal that the formamidopyrimidines decrease the fidelity of polymerases and are substrates for DNA repair enzymes. The mutation frequency of Fapy·dG in mammals is even greater than that of 8-oxodGuo (8-oxo-7,8-dihydro-2'-deoxyguanosine, one of the 8-oxopurines), suggesting that this lesion could be a useful biomarker and biologically significant. Despite clear similarities, the formamidopyrimidines have lived in the shadow of the corresponding 8-oxopurine lesions. But the recent development of methods for synthesizing oligonucleotides containing Fapy·dA or Fapy·dG has accelerated research on these lesions, revealing that the formamidopyrimidines are repaired as efficiently and, in some cases, more rapidly than the 8-oxopurines. Fapy·dG appears to be a lesion of biochemical consequence, and further study of its mutagenicity, repair, and interactions with DNA structure will better define the cellular details involving this important product of DNA stress.

Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Mitogen-activated protein kinase (MAPK) cascades are key signaling pathways involved in the regulation of normal cell proliferation, survival and differentiation. Aberrant regulation of MAPK cascades contribute to cancer and other human diseases. In particular, the extracellular signal-regulated kinase (ERK) MAPK pathway has been the subject of intense research scrutiny leading to the development of pharmacologic inhibitors for the treatment of cancer. ERK is a downstream component of an evolutionarily conserved signaling module that is activated by the Raf serine/threonine kinases. Raf activates the MAPK/ERK kinase (MEK)1/2 dual-specificity protein kinases, which then activate ERK1/2. The mutational activation of Raf in human cancers supports the important role of this pathway in human oncogenesis. Additionally, the Raf-MEK-ERK pathway is a key downstream effector of the Ras small GTPase, the most frequently mutated oncogene in human cancers. Finally, Ras is a key downstream effector of the epidermal growth factor receptor (EGFR), which is mutationally activated and/or overexpressed in a wide variety of human cancers. ERK activation also promotes upregulated expression of EGFR ligands, promoting an autocrine growth loop critical for tumor growth. Thus, the EGFR-Ras-Raf-MEK-ERK signaling network has been the subject of intense research and pharmaceutical scrutiny to identify novel target-based approaches for cancer treatment. In this review, we summarize the current status of the different approaches and targets that are under evaluation and development for the therapeutic intervention of this key signaling pathway in human disease.

Homeobox genes in the genetic control of eye development.

Vertebrate eye formation is a complex process which involves early specification of the prospective eye territory, induction events, patterning along the polarity axes and regional specification, to bring about the proper morphogenetic movements, cell proliferation, cell differentiation and neural connections allowing visual function. The molecular machinery underlying such complex developmental events is presently under an intense research scrutiny and many associated genetic factors have been isolated and characterized. These studies produced striking knowledge in the field, especially with respect to uncovering the role of key genes and their possible evolutionary conservation. Presently, a major task is to define the complex interactions connecting the multiplicity of molecular players that regulate eye development. We recently identified two homeobox genes, Xrx1 and Xvax2, and studied their function by using the Xenopus embryo as a developmental model system. Xrx1 and Xvax2 control key aspects of eye development. In particular, Xrx1 appears to play a role in the early specification of anterior neural regions fated to give rise to retina and forebrain structures, and in promoting cell proliferation within these territories. On the other hand, Xvax2 is involved in regulating the eye proximo-distal and/or dorsoventral polarity, and the morphogenetic movements taking place during formation of the optic stalk and cup. Here we review the experimental results addressing the roles of Xrx1 and Xvax2 and their vertebrate orthologues, and discuss their relationship with other molecules also playing a related function in eye development.

EPIDEMIOLOGY OF ISLET CELL ANTIBODIES

In spite of the potential assay problems, a relatively clear general picture concerning islet cell antibodies has emerged. They are undoubtedly the most potent indicator of risk for insulin-dependent diabetes, at least among high-risk persons (that is, first-degree relatives of insulin-dependent diabetics). Islet cell antibodies have been the focus of intense research scrutiny over the last decade, yet their etiologic role remains unclear. In patients with insulin-dependent diabetes, there is no striking relation at onset between islet cell antibodies and determinants such as age and HLA type. Certain characteristics, however, may be related to islet cell autoimmunity in a more complex way. There appears to be some racial difference in onset-related islet cell antibody prevalence and other autoimmunity. The observation that autoimmune abnormalities are more frequent among women and among diabetics leads to the question of whether there is an interaction of sex and autoimmune diabetes. There may be a group of early-onset patients, distinguished by persistent islet cell antibodies or coexistent autoimmune phenomena, who are predominantly female. At present, there is only limited evidence for this in the literature: Bottazzo et al. found that juvenile diabetics with persistent islet cell antibodies were more often female. Female diabetics have been shown to have an increased prevalence of thyroid autoantibodies compared with male diabetics. Several observations of differences based on sex have emerged from recent studies of insulin-dependent diabetes: 1) the HLA-DR4 antigen is more frequent among female diabetic patients; 2) male HLA-identical siblings of diabetics have a lowered insulin response to glucose administered intravenously; 3) in areas of low insulin-dependent diabetes incidence, the patterns of onset by age differ markedly between the sexes. These sex-specific differences may help to clarify the relation between islet cell autoimmunity and sex. Among nondiabetic persons, those having the highest genetic "risk" for disease appear to have an increased prevalence of islet cell antibodies. There is also some indication that HLA-DR3 may be associated with islet cell autoimmunity. Other related diseases, notably gestational diabetes, non-insulin-dependent diabetes, and certain autoimmune endocrinopathies, are associated with an increased prevalence of islet cell antibodies. An increase in islet cell antibody prevalence occurs in certain viral infections, particularly mumps and congenital rubella. Islet cell antibodies have been noted in the sera of subjects many years before the onset of insulin-dependent diabetes, as well as in normoglycemic relatives.