The cause of schizophrenia is unknown, but it has a significant genetic component. Pharmacologic studies, studies of gene expression in man, and studies of mouse mutants suggest involvement of glutamate and dopamine neurotransmitter systems. However, so far, strong association has not been found between schizophrenia and variants of the genes encoding components of these systems. Here, we report the results of a genomewide scan of schizophrenia families in Iceland; these results support previous work, done in five populations, showing that schizophrenia maps to chromosome 8p. Extensive fine-mapping of the 8p locus and haplotype-association analysis, supplemented by a transmission/disequilibrium test, identifies neuregulin 1 (NRG1) as a candidate gene for schizophrenia. NRG1 is expressed at central nervous system synapses and has a clear role in the expression and activation of neurotransmitter receptors, including glutamate receptors. Mutant mice heterozygous for either NRG1 or its receptor, ErbB4, show a behavioral phenotype that overlaps with mouse models for schizophrenia. Furthermore, NRG1 hypomorphs have fewer functional NMDA receptors than wild-type mice. We also demonstrate that the behavioral phenotypes of the NRG1 hypomorphs are partially reversible with clozapine, an atypical antipsychotic drug used to treat schizophrenia.

Human axillary odor is known to be formed upon the action of Corynebacteria sp. on odorless axilla secretions. The known axilla odor determinant 3-methyl-2-hexenoic acid was identified in hydrolyzed axilla secretions along with a chemically related compound, 3-hydroxy-3-methylhexanoic acid. The natural precursors of both these acids were purified from non-hydrolyzed axilla secretions. From liquid chromatography/ mass spectrometry analysis, it appeared that the acids are covalently linked to a glutamine residue in fresh axilla secretions, and the corresponding conjugates were synthesized for confirmation. Bacterial isolates obtained from the human axilla and belonging to the Corynebacteria were found to release the acids from these odorless precursors in vitro. A Zn 2؉ -dependent aminoacylase mediating this cleavage was purified from Corynebacterium striatum Ax20, and the corresponding gene agaA was cloned and heterologously expressed in Escherichia coli. The enzyme is highly specific for the glutamine residue but has a low specificity for the acyl part of the substrate. agaA is closely related to many genes coding for enzymes involved in the cleavage of N-terminal acyl and aryl substituents from amino acids. This is the first report of the structure elucidation of precursors for human body odorants and the isolation of the bacterial enzyme involved in their cleavage.The axilla region of humans contains a dense arrangement of apocrine, eccrine, and sebaceous glands, and it is an everyday experience, that volatile substances emanating from these areas make a key contribution to human body odor. Although this odor is perceived by today's society as mainly unpleasant, several studies indicate that it may contain chemical signals that affect the menstrual cycle (1) or that may be involved in a major histocompatibility complex allele-dependent mate selection (2). These studies point to an important role of body odors in the evolutionary history of man.Sweat as it is secreted by axillary glands is odorless. Since the pioneering work of Shelley et al. (3), it is known that (a) the typical strong axilla odor can only be released from apocrine secretions, and (b) that the action of skin bacteria is needed to generate the odoriferous compounds from non-smelling molecules present in these secretions. Indeed, the axilla is a skin region supporting a dense bacterial population, which is dominated by the two genera Staphylococcus and Corynebacteria (4, 5). Most individuals carry a flora that is dominated by either one of these two genera, and a strong correlation was found between a high population of Corynebacteria and a strong axillary odor formation (4, 6). As a practical consequence of these findings, halogenated antibacterials and aluminum preparations for reducing the bacterial population have become the main active ingredient of commercial deodorants for the last 40 years. The scientific conclusion from this early work was that axilla secretions contain non-odoriferous precursors that must be transformed by bacterial en...

This report is concerned with the structural characterization and genetic regulation of new bacterial groES and groEL chaperonin genes, and presents two novelties. The first is the discovery that the nitrogen fixing soybean root nodule bacterium, Bradyrhizobium japonicum, unlike all other prokaryotes investigated so far, possesses a multigene family consisting of five very similar, though not identical, groESL‐like genes. The second novelty relates to the finding that these five homologues are expressed to different degrees and, in particular, that one family member (namely groESL3) is induced by a mechanism that does not involve the well‐known heat shock response. By contrast, the groESL3 genes are co‐regulated together with symbiotic nitrogen fixation genes, in that they are activated by the nitrogen fixation regulatory protein NifA at low oxygen conditions and transcribed from a −24/−12 promoter by the sigma 54 RNA polymerase. Two other members of the groESL gene family are apparently expressed constitutively at different levels, and yet another one is strongly induced by high temperature. As an attractive hypothesis it follows that B. japonicum may modulate its cellular contents of GroES‐ and GroEL‐like chaperonins in response to specific environmental conditions and physiological needs.

Epidemiologic studies have yielded controversial information regarding an association between antenatal steroid administration and elevations in arterial blood pressure (BP). The aim of the study was to determine whether antenatal administration of a clinically relevant dose of steroids at a time when fetal nephrogenesis is at its highest results in abnormal kidney development and adult hypertension. Pregnant sheep were treated with either vehicle or betamethasone. Maternal injections were given 24 h apart at 80 d of gestational age (dGA; 0.55 of gestation). Animals were studied either as fetuses or as immature adults. Fetuses were delivered by cesarean section at 135 dGA. Adults were studied at 6 mo of age. Betamethasone administration did not induce premature labor or intrauterine growth restriction. In the betamethasone-exposed group, we found at 135 dGA a 25.5% decrease in the number of glomeruli with no differences in fetal kidney weight. In adults, mean, systolic, and diastolic arterial BPs were significantly higher, whereas there were no significant differences in heart rate over the same study period. The major finding of this study is that a single course of antenatal steroids alters renal development and is associated with elevations in arterial BP in lambs at 6 mo of age. We conclude that antenatal glucocorticoid administration under the National Institutes of Health consensus guidelines may alter human fetal renal development. (Pediatr Res 58: 510-515, 2005) Abbreviations AT, angiotensin receptor BP, blood pressure dGA, days of gestational age PAH, para aminohippuric acid RAS, renin-angiotensin systemThe pioneering work of Liggins and Howie (1) resulted in antenatal steroid treatment's becoming standard of care for enhancing fetal lung maturation in pregnancies that are threatened by premature labor between 24 and 34 wk of gestation. Following the National Institutes of Health consensus conference recommendation (2), the use of corticosteroid therapy in the United States has increased from Ͻ15% of individuals who threatened to deliver prematurely in 1990 to Ͼ75% now (3). However, the growing use of glucocorticoids in the perinatal period has become an issue of extreme concern because of the potential for untoward effects found only with long-term outcome studies (3,4). A recent epidemiologic study shows an association between antenatal glucocorticoid administration and elevations in systolic and diastolic blood pressure (BP) at 14 y of age (5). Studies in animals have also associated administration of glucocorticoids during pregnancy with hypertension in the adult offspring (6 -10). However, in these studies, either the dose of glucocorticoids or the developmental stage at which the fetus was exposed does not parallel the clinical use.Fetal exposure to excess glucocorticoids of maternal origin seems to play a central role in the development of hypertension after fetal undernutrition. Maternal adrenalectomy (11) and inhibition of adrenal function with metyrapone (12) negate the effect of protein restr...

Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T-and NK-cell-based cancer immunotherapies.

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