New perspectives in B-1 B cell development and function

In contrast to the predominant population of B-2 B cells produced in the bone marrow, B-1 B cells are a minor population of B lymphocytes that are found in multiple tissues, including the pleural and peritoneal cavities in mice. Although the role of B-1 B cells as effectors of innate-like immunity is widely accepted, their developmental origin has been controversial. This review highlights recent experimental data from murine studies supporting the hypothesis that B-1 B cells belong to a developmental lineage distinct from B-2 B cells, and draws attention to recent studies that have defined new roles for the B-1a and B-1b B-cell subsets in the response to bacteria and self-antigens.     

Reassessing the role of growth hormone and sex steroids in thymic involution

The concomitant decline in growth hormone (GH) and increase in sex steroid production with age is thought to be responsible for thymic involution. If changes in the production of these hormones trigger or sustain thymic involution, that process should be accelerated in little mice, which have a genetic deficiency resulting in reduced production of thymopoietic GH, and delayed in the hypogonadal strain, which fails to produce thymocytotoxic sex steroids. The results indicated that thymic involution in both strains progressed in a manner similar to their normal littermates. That blocking sex steroid production did not delay thymic involution was surprising since castration reportedly increases thymus cellularity. Re-examination of that phenomenon revealed that, while gonadectomy results in increased thymus size, its effects are transient, and the thymus ultimately undergoes involution. Taken together, these data suggest that age-related changes in the endocrine system do not underlie thymic involution.     

The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells

BACKGROUND AND PURPOSE

Follicular lymphoma is the second most common non-Hodgkin''s lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems.

EXPERIMENTAL APPROACH

The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment.

KEY RESULTS

Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice.

CONCLUSIONS AND IMPLICATIONS

The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.     

Evaluation of the correlation of caspofungin MICs and treatment outcome in murine infections by wild type strains of Candida parapsilosis

We have evaluated the in vitro activity of caspofungin against 36 wild-type strains of Candida parapsilosis sensu stricto using 3 techniques: broth microdilution, disk diffusion, and the determination of minimal fungicidal concentration (MFC). The first 2 methods showed a good in vitro activity of caspofungin, but the MFCs were ≥2 dilutions above their corresponding MICs. In a murine model of disseminated infection, we evaluated the efficacy of caspofungin at 5 mg/kg against 8 strains of C. parapsilosis representing different degrees of in vitro susceptibility (0.12–1 μg/mL). All the isolates responded to treatment and (1→3)-β-D-glucan levels were reduced in all the cases; however, the study revealed differences among isolates, since caspofungin reduced the tissue burden of mice infected with isolates with MICs ≤0.5 μg/mL but was less effective against those with MICs of 1 μg/mL.     

Temporal dynamics of parietal activity during word-location binding

Most of human cognitive activity involves, to a greater or lesser extent, the integration of information from different modalities, a process also referred to as 'binding'. Although the neural basis of several forms of binding has been extensively investigated, the neurobiological mechanisms of the encoding phase of integration of words and their spatial location have not been previously investigated. This process is at the core of what Baddeley proposed in his revised model as episodic buffer. In the current experiment, the authors used magnetoencephalography to investigate the spatiotemporal patterns of brain activity related to encoding words, locations, and the integration of both types of information using a working memory paradigm. The spatiotemporal analysis showed a preferential activation of superior parietal lobe (SPL) during the integration of information, which was modulated by performance in the task. These findings are in agreement with proposals suggesting that SPL participates in binding processes by encoding and maintaining a detailed, complex integrated representation in working memory (WM). Considering Baddeley's episodic buffer, it appears that the same mechanisms involved in integrating information within one subsystem (i.e., visuospatial buffer) also support the integration of information between previously considered independent subsystems (i.e., verbal and visuospatial buffers).     

B-1 B cell development in the fetus and adult

Models of hematopoiesis often depict lymphocyte production as a uniform process in which a homogenous population of hematopoietic stem cells (HSCs) generates progenitors from which all types of lymphocytes are derived. However, it is increasingly evident that these schemes are too simplistic and that the lymphoid potential of HSCs and precursors arising in the embryo, fetus, neonate, and adult is remarkably distinct. We review recent findings regarding the development of B lymphocytes, and the B-1 B cell lineage in particular, as a case in point. These studies show that B-1 and B-2 B cells involved in innate and adaptive immune responses, respectively, arise in staggered waves of development from distinct progenitors. We discuss the implications of this layered model of B cell development for understanding normal and dysregulated B lymphopoiesis.     

Mutation rates at Y chromosome specific microsatellites

A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.     

Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf

Lymphoid progenitors exhibit severe growth defects during aging while myelopoiesis is relatively unperturbed. These effects are due in part to the preferential expression of p16^Ink4a and Arf in aged lymphoid progenitors. Their increased expression contributes to reduced growth and survival of lymphoid progenitors and makes them refractory to malignant transformation. Down-regulation of p16^Ink4a and Arf in aged lymphoid progenitors reverted the senescent phenotype and restored susceptibility to transformation. These data provide a molecular explanation for the preferential effects of aging on lymphopoiesis, suggest that inhibiting p16^Ink4a and Arf expression can rejuvenate B lymphopoiesis, and link aging and cancer resistance.     

Genetic differences between the standard Ames tester strains TA100 and TA98

The standard Ames tester strains of Salmonella typhimurium areseparated by many steps in their pedigree, some involving mutagentreatments, and contain independently isolated uvrB-bio-galdeletions and rfa mutations. In this work the araD531 mutationwas introduced into the Ames tester strains TA100 and TA98.The responsiveness of the resulting strains (BA15 and BA14)to a number of chemical mutagens was then assessed by monitoringthe induction of forward mutations to L-arabinose resistance(Ara test). Here we have shown that these two strains of theAmes test differ greatly in their responses to mutagens, inways that are not associated with the mutagenic specificitiesof the original his mutations. In general, the genetic backgroundof strain TA100 appears to be more sensitive to the killingeffects of chemicals than that of TA98. The greatest differenceswere found with nifurtimox (NFX) and its analogue, compound1K. The Ara test responded to the mutagenic effects of thesetwo nitrofurans when carried out in the genetic background ofstrain TA98 but not in that of TA100. A higher sensitivity tothe lethal effects of NFX and 1K together with the greater nitroreductioncapability of strain TA100 as compared with TA98 might explainthe differences. In conclusion, our results indicate that thestandard Ames S. typhimurium tester strains are not isogenicand that genetic differences at loci other than his might besignificant for mutagenicity testing. To this respect the routineuse of the isogenic set of S. typhimurium strains constructedby Popkin et al. (Mut. Res., 224, 453–464, 1989) and derivedfrom strain hisD3052 (as the standard TA98) seems advisable.