Elucidation of the gating of the GIRK channel using a spectroscopic approach

The traditional view of G protein-coupled receptor (GPCR)-mediated signalling puts the players in this signalling cascade, namely the GPCR, the G protein and its effector, as individual components in space, where the signalling specificity is obtained mainly by the interaction of the GPCR and the Gα subunits of the G protein. A question is then raised as to how fidelity in receptor signalling is achieved, given that many systems use the same components of the G protein signalling machinery. One possible mechanism for obtaining the specific flow of the downstream signals, from the activated G protein to its specific effector target, in a timely manner, is compartmentalization, a spatial arrangement of the complex in a rather restricted space. Here we review our recent findings related to these issues, using the G protein-coupled potassium channel (GIRK) as a model effector and fluorescence-based approaches to reveal how the signalling complex is arranged and how the G protein exerts its action to activate the GIRK channel in intact cells.     

Peripheral B cell receptor editing may promote the production of high-affinity autoantibodies in CD22-deficient mice

CD22-deficient mice are characterized by B cell hyperactivity and autoimmunity. We have constructed knock-in CD22-/- mice, expressing an anti-DNA heavy (H) chain (D42), alone or combined with Vkappa1-Jkappa1 or Vkappa8-Jkappa5 light (L) chains. The Ig-targeted mice produced a lupus-like serology that was age- and sex-dependent. High-affinity IgG autoantibodies were largely dependent on the selection of B cells with a particular H/L combination, in which a non-transgenic, endogenous L chain was assembled by secondary rearrangements through the mechanism of receptor editing. Moreover, we present evidence that these secondary rearrangements are very prominent in splenic peripheral B cells. Since CD22 is primarily expressed on the surface of peripheral B cells, we propose a model for the development of a lupus-like autoimmune disease by a combination of peripheral receptor editing and abnormal B cell activation.     

“Balint Group” Meetings for Oncology Residents as a Tool to Improve Therapeutic Communication Skills and Reduce Burnout Level

Medical training, particularly residency, may pose many challenges and may lead to burnout. Oncology training may be more stressful, given the prolonged exposure to death and dying. Balint group is an intervention method common in medical training, aimed at improving communication skills and strengthening doctor–patient relationships. We arranged for our oncology residents, guided by a senior oncologist and a clinical psychologist, to meet monthly for a discussion of personal cases from the residents’ experiences. At the beginning of the year, higher measures in two burnout parameters were found in junior residents compared to senior residents. At the end of the year, the gap in Maslach Burnout Inventory scores between junior and senior residents had decreased, while burnout level decreased slightly during the year in junior residents. It was felt that participation in a Balint group could improve communication abilities of residents and contribute to their feelings of self-accomplishment as doctors.     

More Than Words: The Role of Multiword Sequences in Language Learning and Use

The ability to convey our thoughts using an infinite number of linguistic expressions is one of the hallmarks of human language. Understanding the nature of the psychological mechanisms and representations that give rise to this unique productivity is a fundamental goal for the cognitive sciences. A long-standing hypothesis is that single words and rules form the basic building blocks of linguistic productivity, with multiword sequences being treated as units only in peripheral cases such as idioms. The new millennium, however, has seen a shift toward construing multiword linguistic units not as linguistic rarities, but as important building blocks for language acquisition and processing. This shift—which originated within theoretical approaches that emphasize language learning and use—has far-reaching implications for theories of language representation, processing, and acquisition. Incorporating multiword units as integral building blocks blurs the distinction between grammar and lexicon; calls for models of production and comprehension that can accommodate and give rise to the effect of multiword information on processing; and highlights the importance of such units to learning. In this special topic, we bring together cutting-edge work on multiword sequences in theoretical linguistics, first-language acquisition, psycholinguistics, computational modeling, and second-language learning to present a comprehensive overview of the prominence and importance of such units in language, their possible role in explaining differences between first- and second-language learning, and the challenges the combined findings pose for theories of language.     

Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice

Thrombin-activated Factor XIII (FXIIIa), a plasma transglutaminase, stabilizes fibrin clots by crosslinking fibrin chains. FXIIIa was previously shown by us to exhibit proangiogenic activity associated with downregulation of thrombospondin-1, phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2), and upregulation of c-Jun. In the current study, we evaluated the proangiogenic effect of FXIIIa in two murine models: a neonatal heterotopic cardiac allograft model in normal mice, and a Matrigel plug model in FXIII-deficient mice. In the neonatal cardiac allograft model, the number of new vessels as well as graft viability (contractile performance) was significantly higher in FXIIIa-injected animals than in controls. A significant increase in the level of c-Jun mRNA and a significant decrease in the level of TSP-1 mRNA were observed in heart allografts treated with FXIIIa. A marked decrease in TSP-1 protein expression was observed within the endothelial cells of hearts treated with FXIIIa. In the Matrigel plug model, FXIII-deficient mice showed a significantly decreased number of new vessels compared to that of the control mice, and the number of vessels almost reached normal levels following addition of FXIIIa. The results of this study provide substantial in vivo evidence for the proangiogenic activity of FXIIIa.     

Update on management of connective tissue panniculitides

In connective tissue diseases, panniculitis can be the sole manifestation or can occur along with the underlying disease process. The best described forms of connective tissue panniculitis are lupus erythematosus panniculitis and lupus profundus, panniculitis associated with dermatomyositis, and morphea- and scleroderma-associated panniculitis. These processes cause significant morbidity, such as deep atrophic scars, cosmetic disfigurement, and psychiatric sequelae. Because the inflammation is located in the subcutaneous adipose layer, topical therapies may not penetrate enough to be effective, and systemic agents are required. Despite the large number of reported cases and therapies, recommendations for treatment are based largely on case series and expert opinion due to a lack of controlled therapeutic trials. All treatments are off-label in the United States. The lack of validated clinical outcome measures makes systematic and controlled studies difficult. Nonetheless, further investigation into the most effective therapies for these conditions is needed.     

Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation. H. Toledano and Y. Goldberg contributed equally to the paper.