Expression of the proteoglycans versican and mel-CSPG in dysplastic nevi

Nevi with architectural disorder and cytologic atypia of melanocytes (NAD) (also called dysplastic nevi) have been controversial with regard to their relationship with melanoma risk and to their gradation in 3 degrees of atypia. Versican and the melanoma-associated proteoglycan (mel-CSPG) are 2 major proteoglycans expressed by malignant melanoma, and they have a role in the regulation of cell adhesion, migration, and differentiation. We evaluated the differences in versican and mel-CSPG expression in nevi, NAD with several degrees of atypia, and primary malignant melanoma. Immunoreactivity for versican was negative in benign melanocytic nevi, positive in NAD (ranging from weakly to intensely positive), and intensely positive in malignant melanoma. Immunostaining for mel-CSPG was negative in benign melanocytic nevi and mild to moderately positive in NAD and melanoma. Our results suggest that versican expression may be of value for distinguishing NAD from benign melanocytic nevi and for distinguishing severe NAD from mild and moderate NAD.     

The elephant in the room: talking race in medical education

The deaths of black men and women while in police custody, rising anti-immigrant sentiment and rhetoric in high-income countries, and the continued health disparities experienced by Indigenous communities globally have brought race and racism to the forefront of public discourse in recent years. In a context where academic health science centres are increasingly called to be “socially accountable,” ignoring the larger social context of race and racism is something that medical education institutions can little afford to do. However, many such institutions have largely remained silent on the issue of race and racism, both within and outside of healthcare. Most medical education continues to emphasize a primarily biological understanding of race. We argue that a different approach is needed. Highlighting the social construction of race is an essential starting point for educators and trainees to tackle racialized health disparities in our clinics and to challenge racism in our classrooms, educational and research institutions, and communities.     

State‐dependent blocking mechanism of Kv1.3 channels by the antimycobacterial drug clofazimine

Background and Purpose

K_v1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca²⁺ signalling in T cells by regulating the membrane potential and with it the driving force for Ca²⁺ influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen‐induced Ca²⁺ oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting K_v1.3 channels with high potency and selectivity.

Experimental Approach

We used patch‐clamp methodology to investigate clofazimine''s mechanism of action in K_v1.3 channels expressed in HEK293 cells.

Key Results

Clofazimine blocked K_v1.3 channels by involving two discrete mechanisms, both of which contribute to effective suppression of channels: (i) a use‐dependent open‐channel block during long depolarizations, resulting in accelerated K⁺ current inactivation and (ii) a block of closed deactivated channels after channels were opened by brief depolarizations. Both modes of block were use‐dependent and state‐dependent in that they clearly required prior channel opening. The clofazimine‐sensitive closed‐deactivated state of the channel was distinct from the resting closed state because channels at hyperpolarized voltages were not inhibited by clofazimine. Neither were channels in the C‐type inactivated state significantly affected. K_v1.3 channels carrying the H399T mutation and lacking C‐type inactivation were insensitive to clofazimine block of the closed‐deactivated state, but retained their susceptibility to open‐channel block.

Conclusions and Implications

Given the prominent role of K_v1.3 in shaping Ca²⁺ oscillations, the use‐dependent and state‐dependent block of K_v1.3 channels by clofazimine offers therapeutic potential for selective immunosuppression in the context of autoimmune diseases in which K_v1.3‐expressing T cells play a significant role.

Abbreviations

CLF

clofazimine

FDA

Food and Drug Administration

IPI

interpulse intervals

WT

wild type

     

Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker

A prerequisite to dephosphorylation at Ser–Pro or Thr–Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker.     

The Moroccan Genetic Disease Database (MGDD): a database for DNA variations related to inherited disorders and disease susceptibility

National and ethnic mutation databases provide comprehensive information about genetic variations reported in a population or an ethnic group. In this paper, we present the Moroccan Genetic Disease Database (MGDD), a catalogue of genetic data related to diseases identified in the Moroccan population. We used the PubMed, Web of Science and Google Scholar databases to identify available articles published until April 2013. The Database is designed and implemented on a three-tier model using Mysql relational database and the PHP programming language. To date, the database contains 425 mutations and 208 polymorphisms found in 301 genes and 259 diseases. Most Mendelian diseases in the Moroccan population follow autosomal recessive mode of inheritance (74.17%) and affect endocrine, nutritional and metabolic physiology. The MGDD database provides reference information for researchers, clinicians and health professionals through a user-friendly Web interface. Its content should be useful to improve researches in human molecular genetics, disease diagnoses and design of association studies. MGDD can be publicly accessed at http://mgdd.pasteur.ma.