ERMA (TMEM94) is a P-type ATPase transporter for Mg2+ uptake in the endoplasmic reticulum.

Intracellular Mg2+ (iMg2+) is bound with phosphometabolites, nucleic acids, and proteins in eukaryotes. Little is known about the intracellular compartmentalization and molecular details of Mg2+ transport into/from cellular organelles such as the endoplasmic reticulum (ER). We found that the ER is a major iMg2+ compartment refilled by a largely uncharacterized ER-localized protein, TMEM94. Conventional and AlphaFold2 predictions suggest that ERMA (TMEM94) is a multi-pass transmembrane protein with large cytosolic headpiece actuator, nucleotide, and phosphorylation domains, analogous to P-type ATPases. However, ERMA uniquely combines a P-type ATPase domain and a GMN motif for ERMg2+ uptake. Experiments reveal that a tyrosine residue is crucial for Mg2+ binding and activity in a mechanism conserved in both prokaryotic (mgtB and mgtA) and eukaryotic Mg2+ ATPases. Cardiac dysfunction by haploinsufficiency, abnormal Ca2+ cycling in mouse Erma+/- cardiomyocytes, and ERMA mRNA silencing in human iPSC-cardiomyocytes collectively define ERMA as an essential component of ERMg2+ uptake in eukaryotes.

Assessment of sex-specific differences in adverse events following immunization reporting in Ontario, 2012-15.

We assessed sex-specific trends within passive vaccine safety surveillance in Ontario, Canada. AEFIs reported following vaccines administered between 2012 and 2015 were included. There were 2466 AEFI reports; 66.2% were female. Annualized reporting rates were 5.9 and 3.1 per 100,000 population, for females and males respectively. The female:male reporting rate ratio (RRR) was 1.9. Sex-specific differences by age group were greatest in adults 18-64years (RRR 6.3); whereas there were no differences in children <10years. Vaccine-specific RRRs were highest for vaccines recommended for routine use in adults or high risk populations. All event categories were female-predominant. The highest event-specific RRRs were for oculorespiratory syndrome (5.1), anaesthesia/paraesthesia (4.6) and anaphylaxis (3.0). Serious AEFIs (n=113) were more evenly distributed (57.5% female, RRR 1.3) than non-serious (66.6% female, RRR 1.9). AEFI reporting among females was consistently elevated within the passive surveillance system in Ontario. Further study of the relationship between sex/gender and AEFI reporting is needed.

The role of the glutamatergic system in posttraumatic stress disorder.

Antiglutamatergic agents, such as lamotrigine, have been used successfully for the treatment of posttraumatic stress disorder (PTSD). They could be potentially acting through the stabilization of the corticotropin-releasing factor (CRF) systems. Glutamate mediates CRF release in various brain regions involved in the pathophysiology of PTSD, antiglutamatergic agents could stabilize the CRF system and, thereby, improve the symptom complex of PTSD (reexperiencing, hyperarousal, and avoidance). The role of glutamate and CRF in PTSD and other anxiety disorders are still being elucidated. However, it is clear that the glutamatergic systems play a role in the pathophysiology of PTSD.

Clinical review: evidence-based diagnosis and treatment of ADHD in children.

Attention Deficit/Hyperactivity Disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children. Diagnosis is clinical. The role of imaging, rating scales and computerized screening tests in patient evaluation is examined. Management involves the use of medication as well as patient-specific psychosocial intervention. Psychostimulants are first line agents and have been shown to be highly efficacious for treating ADHD. Mode of action and pertinent clinical issues regarding each stimulant and non-stimulant medication uses are discussed.

Framework for developing a hierarchical model of reward focusing on the nucleus accumbens.

Computational modeling using GENESIS platform has led to advances in fabricating a model to test the influence of molecular/proteomic adaptations on behavior due to reward. The nucleus accumbens is an area of the brain that processes information from other parts of the brain and is an integral element of the 'reward pathway' in the brain. A simplified model of the accumbens using one neuron is developed as part of a larger effort to study reward and chemical dependency with a focus on cocaine addiction. A preliminary model of a biologically realistic neuron was developed with inhibitory and excitatory afferents as well as intrasynapse dynamics. The neuron displayed characteristic behavior of a neuron found in the nucleus accumbens including bistability. The neuron has afferents from other neurons via dendrites which carry the inputs relating to behavioral aspects and to learning. To add behavioral aspects to the model, a methodology is developed to model contexts and their reinforcing effects on behavior, similar to cocaine addiction. Results using both the biological and behavioral modeling are encouraging for this preliminary model.

Modeling obsessive compulsive disorder.

A preliminary computational model for obsessive compulsive disorder is developed using neuro-circuitry information and systems biology principles. The model captures the salient features of the neuro-psychiatric disorder reported in the literature. Studies are on-going to model in more detail both the intra-cellular and extra-cellular features of the model, within the framework proposed.

Computational modeling of hysterical paralysis.

A preliminary computational model for hysterical paralysis is developed using neuro-circuitry information and systems biology principles. The model captures the salient features of the neuro-psychiatric disorder reported in the literature. Studies are on-going to model in more detail both the intra-cellular and extra-cellular features of the model, within the framework proposed.

Global policy: aspects of diabetes in India.

Diabetes has already been described as an epidemic, but predictions for future increases in prevalence, especially in developing countries, point to a major healthcare crisis for the future. Very little is known about the economic impact of diabetes in the developing world where predicted increases in prevalence are greatest. This paper discusses the implications of a recent study of the economic aspects of diabetes in India. The study aims were to estimate the costs of diabetes care and to assess the awareness of patients and healthcare professionals about the prevention and treatment of diabetes. The findings confirm reports from earlier studies of the high costs of treatment amongst all socio-economic patient groups resulting in a serious burden on both patients and state resources alike. Both patients and medical practitioners displayed a lack of comprehension of the need for constant disease monitoring and consistent approaches to tight glycaemic control. The long term economic implications are worrying. With the Indian diabetic population predicted to rise to >80.9 million by the year 2030, immediate health policy restructuring and investment will be needed if the best use is to be made of the scarce healthcare resources.