Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

Functional interplay between p63 and p53 controls RUNX1 function in the transition from proliferation to differentiation in human keratinocytes

The interfollicular epidermis is continuously renewed, thanks to a regulated balance between proliferation and differentiation. The ΔNp63 transcription factor has a key role in the control of this process. It has been shown that ΔNp63 directly regulates Runt-related transcription factor 1 (RUNX1) transcription factor expression in mouse keratinocytes. The present study showed for the first time that RUNX1 is expressed in normal human interfollicular epidermis and that its expression is tightly regulated during the transition from proliferation to differentiation. It demonstrated that ΔNp63 directly binds two different RUNX1 regulatory DNA sequences and modulates RUNX1 expression differentially in proliferative or differentiated human keratinocytes. It also showed that the regulation of RUNX1 expression by ΔNp63 is dependent on p53 and that this coregulation relies on differential binding and activation of RUNX1 regulatory sequences by ΔNp63 and p53. We also found that RUNX1 inhibits keratinocyte proliferation and activates directly the expression of KRT1, a critical actor in early keratinocyte differentiation. Finally, we described that RUNX1 expression, similar to ΔNp63 and p53, was strongly expressed and downregulated in basal cell carcinomas and squamous cell carcinomas respectively. Taken together, these data shed light on the importance of tight control of the functional interplay between ΔNp63 and p53 in regulating RUNX1 transcription factor expression for proper regulation of interfollicular epidermal homeostasis

Biocatalytic Synthesis of Polymers of Precisely Defined Structures

The fabrication of functional nanoscale devices requires the construction of complex architectures at length scales characteristic of atoms and molecules. Currently microlithography and micro-machining of macroscopic objects are the preferred methods for construction of small devices, but these methods are limited to the micron scale. An intriguing approach to nanoscale fabrication involves the association of individual molecular components into the desired architectures by supramolecular assembly. This process requires the precise specification of intermolecular interactions, which in turn requires precise control of molecular structure

Structural and functional insights into asymmetric enzymatic dehydration of alkenols

The asymmetric dehydration of alcohols is an important process for the direct synthesis of alkenes. We report the structure and substrate specificity of the bifunctional linalool dehydratase isomerase (LinD) from the bacterium Castellaniella defragrans that catalyzes in nature the hydration of β-myrcene to linalool and the subsequent isomerization to geraniol. Enzymatic kinetic resolutions of truncated and elongated aromatic and aliphatic tertiary alcohols (C5-C15) that contain a specific signature motif demonstrate the broad substrate specificity of LinD. The three-dimensional structure of LinD from Castellaniella defragrans revealed a pentamer with active sites at the protomer interfaces. Furthermore, the structure of LinD in complex with the product geraniol provides initial mechanistic insights into this bifunctional enzyme. Site-directed mutagenesis confirmed active site amino acid residues essential for its dehydration and isomerization activity. These structural and mechanistic insights facilitate the development of hydrating catalysts, enriching the toolbox for novel bond-forming biocatalysis

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.

CAPRISA, 2014.Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development

Consensus definition of a low disease activity state in systemic lupus erythematosus

Free Paper Oral Sessions FP01: Systemic Lupus Erythematosus and Infection in Rheumatic DiseaseBackground: In systemic lupus erythematosus (SLE), organ damage, morbidity and mortality are the result of acute or sustained disease activity. The diversity of clinical features of active SLE makes quantification of disease activity problematic. The definition of a low disease activity state in rheumatoid arthritis has resulted in it being widely applied in research and clinical practice, but in SLE there is currently no such definition and thus no related outcome data. In contrast, clinicians often intuitively recognize a state of low SLE disease activity, wherein patient Os disease activity is low and treatment burden acceptable. No empirical definition of a low disease activity state in SLE has been described. Objectives: To define a lupus low disease activity state (LLDAS), for subsequent validation using prospective cohort data. Methods: Firstly, we defined LLDAS conceptually as follows: A state which, if sustained, is associated with a low likelihood of adverse outcome, considering both disease activity and medication safety. Next, a panel of experts from Hong Kong, China, Philippines, Thailand, Singapore, Indonesia and Australia individually generated items for potential inclusion in a definition of LLDAS. These items were scored on a 5-point scale, then reduced using the Delphi method. Six experts participated in the first round of Delphi, and items with a mean score >3 were retained. Eleven experts then participated in a consensus meeting using the nominal group technique and in a second round of Delphi, in which items with a mean score >4 were retained. Results: Fifty-six unique items were initially generated. These fell into two domains: (i) descriptions of disease activity, and (ii) descriptions of medication use. Following two rounds of Delphi, unanimous agreement on the preliminary definition of LLDAS was reached. The final list of five items defining LLDAS comprised: 1 SLEDAI-2K ≤ 4, with no SLEDAI activity in major organ systems (renal, CNS, cardiopulmonary, vasculitis, hemolytic anemia, fever) and no gastrointestinal activity; 2 No new features of lupus disease activity compared to the previous assessment; 3 SELENA-SLEDAI physician global assessment (PGA, scale 0–3) ≤ 1; 4 Current prednisolone (or equivalent) dose ≤7.5 mg daily; and 5 Well-tolerated standard maintenance doses of immunosuppressive drugs and/or approved biologic agents, excluding investigational drugs Conclusions: We have generated a definition of LLDAS. The definition of LLDAS will be validated in a large prospective multicentre Asian-Pacific lupus cohort, using outcomes including organ damage and death, and refined in response to subsequent findings. Once validated, LLDAS may serve alone, or in combination with variables such as patient reported outcomes, as a treatment target in SLE clinical practice, research, and clinical trials.Link_to_subscribed_fulltex