Copper(I)-organophosphine complexes of bis(3,5-dimethylpyrazol-1-yl)dithioacetate ligand

Copper(I) complexes have been synthesized from the reaction of CuCl, monodentate tertiary phosphines PR₃ (PR₃ = P(C₆H₅)₃; P(C₆H₅)₂(4-C₆H₄COOH); P(C₆H₅)₂(2-C₆H₄COOH); PTA, 1,3,5-triaza-7-phosphaadamantane; P(CH₂OH)₃, tris(hydroxymethyl)phosphine) and lithium bis(3,5-dimethylpyrazolyl)dithioacetate, Li[LCS₂]. Mono-nuclear complexes of the type [LCS₂]Cu[PR₃] have been obtained and characterized by elemental analyses, FT-IR, ESI-MS and multinuclear (¹H, ¹³C and ³¹P) NMR spectral data; in these complexes the ligand behaves as a κ³-N,N,S scorpionate system. One exception to this stoichiometry was observed in the complex [LCS₂]Cu[P(CH₂OH)₃]₂, where two phosphine co-ligands are coordinated to the copper(I) centre. The solid-state X-ray crystal structure of [LCS₂]Cu[P(C₆H₅)₃] has been determined. The [LCS₂]Cu[P(C₆H₅)₃] complex has a pseudo tetrahedral copper site where the bis(3,5-dimethylpyrazolyl)dithioacetate ligand acts as a κ³-N,N,S donor.     

IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia

Cytokine Receptor-Like Factor 2 (CRLF2) overexpression occurs in 5-15% of B-cell precursor acute lymphoblastic leukaemia (B-ALL). In ∼50% of these cases, the mechanisms underlying this dysregulation are unknown. IKAROS Family Zinc Finger 1 (IKZF1) is a possible candidate to play a role in this dysregulation since it binds to the CRLF2 promoter region and suppresses its expression. We hypothesised that IKZF1 loss of function, caused by deletions or its short isoforms expression, could be associated with CRLF2 overexpression in B-ALL. A total of 131 paediatric and adult patients and 7 B-ALL cell lines were analysed to investigate the presence of IKZF1 deletions and its splicing isoforms expression levels, the presence of CRLF2 rearrangements or mutations, CRLF2 expression and JAK2 mutations. Overall survival analyses were performed according to the CRLF2 and IKZF1 subgroups. Our analyses showed that 25.2% of patients exhibited CRLF2 overexpression (CRLF2-high). CRLF2-high was associated with the presence of IKZF1 deletions (IKZF1del, p = 0.001), particularly with those resulting in dominant-negative isoforms (p = 0.006). Moreover, CRLF2 expression was higher in paediatric samples with high loads of the short isoform IK4 (p = 0.011). It was also associated with the occurrence of the IKZF1 plus subgroup (p = 0.004). Furthermore, patients with CRLF2-high/IKZF1del had a poorer prognosis in the RELLA05 protocol (p = 0.067, 36.1 months, 95%CI 0.0-85.9) and adult cohort (p = 0.094, 29.7 months, 95%CI 11.8–47.5). In this study, we show that IKZF1 status is associated with CRLF2-high and dismal outcomes in B-ALL patients regardless of age.     

Mucuna pruriens (Velvet bean) Rescues Motor,Olfactory, Mitochondrial and Synaptic Impairment in PINK1B9 Drosophila melanogaster Genetic Model of Parkinson’s Disease

The fruit fly Drosophila melanogaster (Dm) mutant for PTEN-induced putative kinase 1 (PINK1^B9) gene is a powerful tool to investigate physiopathology of Parkinson''s disease (PD). Using PINK1^B9 mutant Dm we sought to explore the effects of Mucuna pruriens methanolic extract (Mpe), a L-Dopa-containing herbal remedy of PD. The effects of Mpe on PINK1^B9 mutants, supplied with standard diet to larvae and adults, were assayed on 3–6 (I), 10–15 (II) and 20–25 (III) days old flies. Mpe 0.1% significantly extended lifespan of PINK1^B9 and fully rescued olfactory response to 1-hexanol and improved climbing behavior of PINK1^B9 of all ages; in contrast, L-Dopa (0.01%, percentage at which it is present in Mpe 0.1%) ameliorated climbing of only PINK1^B9 flies of age step II. Transmission electron microscopy analysis of antennal lobes and thoracic ganglia of PINK1^B9 revealed that Mpe restored to wild type (WT) levels both T-bars and damaged mitochondria. Western blot analysis of whole brain showed that Mpe, but not L-Dopa on its own, restored bruchpilot (BRP) and tyrosine hydroxylase (TH) expression to age-matched WT control levels. These results highlight multiple sites of action of Mpe, suggesting that its effects cannot only depend upon its L-Dopa content and support the clinical observation of Mpe as an effective medication with intrinsic ability of delaying the onset of chronic L-Dopa-induced long-term motor complications. Overall, this study strengthens the relevance of using PINK1^B9 Dm as a translational model to study the properties of Mucuna pruriens for PD treatment.     

The immunoglobulin superfamily of neuronal cell adhesion molecules: Lessons from animal models and correlation with human disease

Neuronal cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) play a crucial role in the formation of neural circuits at different levels: cell migration, axonal and dendritic targeting as well as synapse formation. Furthermore, in perinatal and adult life, neuronal IgCAMs are required for the formation and maintenance of specialized axonal membrane domains, synaptic plasticity and neurogenesis. Mutations in the corresponding human genes have been correlated to several human neuronal disorders. Perturbing neuronal IgCAMs in animal models provides powerful means to understand the molecular and cellular basis of such human disorders. In this review, we concentrate on the NCAM, L1 and contactin subfamilies of neuronal IgCAMs summarizing recent functional studies from model systems and highlighting their links to disease pathogenesis.     

Inhibitory effects of glycosaminoglycans on basal and stimulated transforming growth factor-β1 expression in mesangial cells: biochemical and structural considerations

A number of glycosaminoglycan (GAG) species related to heparin, dermatan sulfate (DeS) and chondroitin sulfate were tested for their ability to interfere with the physiological expression and/or pathological overexpression of the TGF-β1 gene. The influence of the molecular weight, molecular weight distribution, degree of sulfation and location of the sulfate groups was examined in an attempt to unveil fine relationships between structure and activity. The nature of the polysaccharide plays a major part, heparins proving able to inhibit both basal and stimulated TGF-β1 gene expression, DeSs being essentially inactive and chondroitin sulfates only inhibiting stimulated TGF-β1 gene expression. Within this frame, the particular physical and chemical properties of some GAGs appear to further modulate TGF-β1 gene response. Judging from our investigation, chondroitin sulfates seem the most promising for potential pharmacological applications in disorders characterized by fibrogenic TGF-β1 overexpression.     

Development and First Phase Evaluation of a Maternity Leave Educational Tool for Pregnant,Working Women in California

Background

Despite the provision of maternity leave offered to mothers, many American women fail to take leave.

Methods

We developed an evidence-based maternity leave educational tool for working women in California using participatory design. We tested its short-term efficacy with a randomized controlled trial of pregnant English-speakers (n=155).

Results

Among intervention participants exposed to the tool, 65% reported that they learned something new; 38% were motivated to seek more information; and 49% said it helped them plan their maternity leave. Among participants who delivered at ≥ 37 weeks gestation and said the tool helped them plan their leave, 89% took more than one week of prenatal leave, a significantly higher proportion than among controls who did not receive the tool (64%, p=0.049). Other findings favored trial participants, but were not statistically significant in this small sample. More intervention participants took some prenatal leave (80%) vs. controls (74%, p=0.44). Among participants who had returned to work when surveyed (n=50), mean postnatal leave uptake was on average 1 week longer for intervention participants vs. controls (13.3 vs. 12.2 weeks, p=0.54).

Conclusions

The first-phase evaluation of this tool shows that it successfully informed women about maternity leave options, clarified complex regulations, encouraged women to seek further information and helped plan maternity leave. Compared to controls, trial participants who used the tool to plan their leave were far more likely to take prenatal leave close to term. Future evaluation of the tool when mediated by a health provider or employer is warranted.