Mechanism and regulation of natural cytotoxicity. Minireview on cancer research

Natural killer (NK) cells comprise a heterogeneous population of effector cells functionally and phenotypically distinct from B cells and mature antigen-sensitive T cells, with the capacity to spontaneously lyse target cells of widely different tissue provenance in a genetically unrestricted fashion. As such they have been widely implicated in immunosurveillance against neoplastic and virus-infected cells, as well as in the homeostasis of haematopoietic differentiation and regulation of immune function. In common with cytotoxic T cells, the lytic mechanism may be resolved into several discrete stages. Target cell recognition appears to involve several chemical entities, while susceptibility is also influenced by a multiplicity of factors operative at post-recognition stages of the lytic process. NK activity is subject to both positive and negative regulation. The potentiating effects of interferons and interleukin-2, products of activated T cells, indicate a possible pathway by which adaptive immune responses may augment natural cytotoxicity under local physiological conditions. Negative regulation is mediated by certain prostaglandins and a variety of cell types including macrophages, granulocytes and thymocytes as well as subsets of peripheral blood lymphocytes.     

Pyridoxal isonicotinoyl hydrazone and analogues

Summary The ultraviolet-visible absorption spectra of the orally effective iron chelator, pyridoxal isonicotinoyl hydrazone (PIH), and three analogues, pyridoxal benzoyl hydrazone (PBH), pyridoxalp-methoxybenzoyl hydrazone (PpMBH) and pyridoxalm-fluorobenzoyl hydrazone (PmFBH) have been measured in aqueous solution with various concentrations of added acid or alkali. Assignment of absorption bands to various molecular species in equilibrium in aqueous solution is made by reference to their acid ionisation constants. All four hydrazones were stable at physiologial pH, but hydrolysed in strongly acidic and basic solutions, resulting in the liberation of pyridoxal and the acid hydrazide. In acidic solutions this resulted in a dramatic decrease in the intensity of absorption at wavelengths of 225 nm and above 300 nm, allowing a quantitative estimate of the degree of acid-catalysed hydrolysis of the ligands. These results indicate that for oral administration the chelator should be administered with calcium carbonate or provided with an enteric coating to minimise acid-catalysed hydrolysis in the stomach. At high pH, base-catalysed hydrolysis occurred, resulting in a decrease in the absorption at a wavelength of 387 run.     

Production of enterochelin by Escherichia coli 0111

The major neutral iron-transporting compound produced by Escherichia coli 0111/K58/H2 has been isolated from iron-deficient cultures of the organism and compared with the corresponding compound, enterochelin, produced by E. coli K12. The product contained serine and 2,3-dihydroxybenzoic acid and formed a complex with Fe³⁺. Since the PMR spectra of the products from the two strains were identical, it was concluded that E. coli 0111 also secreted enterochelin under iron-deficient conditions. although it was not possible to establish the optical configuration of the serine residues in the molecule, the CD spectra of the metal free and Fe³⁺, complexes were found to be of the same sign and magnitude. The spectra show that metal binding results in considerable conformational changes in the enterochelin molecule. The biological properties of the two compounds appear to be identical as judged by their ability to abolish the bacteriostatic effect of serum on E. coli 0111.     

Diversity of the Lactic Acid Bacterium and Yeast Microbiota in the Switch from Firm- to Liquid-Sourdough Fermentation

Four traditional type I sourdoughs were comparatively propagated (28 days) under firm (dough yield, 160) and liquid (dough yield, 280) conditions to mimic the alternative technology options frequently used for making baked goods. After 28 days of propagation, liquid sourdoughs had the lowest pH and total titratable acidity (TTA), the lowest concentrations of lactic and acetic acids and free amino acids, and the most stable density of presumptive lactic acid bacteria. The cell density of yeasts was the highest in liquid sourdoughs. Liquid sourdoughs showed simplified microbial diversity and harbored a low number of strains, which were persistent. Lactobacillus plantarum dominated firm sourdoughs over time. Leuconostoc lactis and Lactobacillus brevis dominated only some firm sourdoughs, and Lactobacillus sanfranciscensis persisted for some time only in some firm sourdoughs. Leuconostoc citreum persisted in all firm and liquid sourdoughs, and it was the only species detected in liquid sourdoughs at all times; it was flanked by Leuconostoc mesenteroides in some sourdoughs. Saccharomyces cerevisiae, Candida humilis, Saccharomyces servazzii, Saccharomyces bayanus-Kazachstania sp., and Torulaspora delbrueckii were variously identified in firm and liquid sourdoughs. A total of 197 volatile components were identified through purge and trap–/solid-phase microextraction–gas chromatography-mass spectrometry (PT–/SPME–GC-MS). Aldehydes, several alcohols, and some esters were at the highest levels in liquid sourdoughs. Firm sourdoughs mainly contained ethyl acetate, acetic acid, some sulfur compounds, and terpenes. The use of liquid fermentation would change the main microbial and biochemical features of traditional baked goods, which have been manufactured under firm conditions for a long time.     

Sacrifice as Social Capital among Israeli Conscientious Objectors

This article considers counterhegemonic sacrifices as a means of social intervention, and in doing so explores the social efficacy of non-ritual sacrifice in the modern era. Ethnographically, this article examines the way Israeli conscientious objectors succeed in having their refusal of military service and the social costs they incur understood as sacrifices by the Israeli public. Ex-soldiers accumulate social capital in light of public perception that they have ‘paid the price’ for their beliefs. Other ethnographic contexts that further elucidate the ability of socially abject to use sacrifice to counterhegemonic effect are presented. I claim that the recognition of sacrifice depends on an intersubjective combination of sacrificial intention and community recognition. This article suggests that the meaning of sacrifice is determined by how sacrifice is used and understood in social context, and as such breaks ranks with literatures on sacrifice concerned with the intrinsic coherence of ritual sacrifice.     

Stringent response processes suppress DNA damage sensitivity caused by deficiency in full‐length translation initiation factor 2 or PriA helicase

When Escherichia coli grows in the presence of DNA‐damaging agents such as methyl methanesulphonate (MMS), absence of the full‐length form of Translation Initiation Factor 2 (IF2‐1) or deficiency in helicase activity of replication restart protein PriA leads to a considerable loss of viability. MMS sensitivity of these mutants was contingent on the stringent response alarmone (p)ppGpp being at low levels. While zero levels (ppGpp⁰) greatly aggravated sensitivity, high levels promoted resistance. Moreover, M+ mutations, which suppress amino acid auxotrophy of ppGpp⁰ strains and which have been found to map to RNA polymerase subunits, largely restored resistance to IF2‐1‐ and PriA helicase‐deficient mutants. The truncated forms IF2‐2/3 played a key part in inducing especially severe negative effects in ppGpp⁰ cells when restart function priB was knocked out, causing loss of viability and severe cell filamentation, indicative of SOS induction. Even a strain with the wild‐type infB allele exhibited significant filamentation and MMS sensitivity in this background whereas mutations that prevent expression of IF2‐2/3 essentially eliminated filamentation and largely restored MMS resistance. The results suggest different influences of IF2‐1 and IF2‐2/3 on the replication restart system depending on (p)ppGpp levels, each having the capacity to maximize survival under differing growth conditions.     

Reproductive Success and Body Size in the Cricket Gryllus firmus

Male body size influences mate choice and sexual selection in many animal species. Here we investigate the role of male body size in the reproductive success of the field cricket Gryllus firmus. This species hybridizes with a close smaller relative, G. pennsylvanicus, and it is thought that this size difference may affect reproductive isolation between these species. We paired large and small G. firmus males with a single G. firmus female and genotyped the resulting offspring. Overall, larger males sired a greater proportion of offspring and in a majority of the crosses the larger male sired all of the offspring. For crosses in which both males sired offspring, there was no difference in the proportion of offspring sired by small and large males. Intrasexual competition, female choice, and differences in ejaculates between males could all influence the patterns we observe. We discuss the implications of our findings within the context of reproductive isolation between G. firmus and G. pennsylvanicus.     

Mutations in CSPP1, Encoding a Core Centrosomal Protein,Cause a Range of Ciliopathy Phenotypes in Humans

Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies.     

Significant sex difference in the association between C‐reactive protein concentration and anthropometry among 13‐ to 19‐year olds,but not 6‐ to 12‐year olds in Nepal

Life history theory predicts a trade‐off between immunostimulation and growth. Using a cross‐sectional study design, this study aims to test the hypothesis that C‐reactive protein (CRP) is negatively associated with height‐for‐age z‐scores (HAZ scores) and BMI‐for‐age z‐scores (BAZ scores) among 6‐ to 19‐year olds (N = 426) residing in five Nepalese communities. Dried blood spot (DBS) samples were collected and assayed for CRP using an in‐house enzyme immunoassay (EIA). Sex‐ and age‐group‐specific CRP quartiles were used to examine its association with growth in linear mixed‐effects (LME) models. A significant difference was found in the proportion of elevated CRP (>2 mg/L, equivalent to ～3.2 mg/L serum CRP) between 13‐ and 19‐year‐old boys (12%) and girls (4%). Concentrations of CRP were positively associated with HAZ score among adolescent (13–19 years) boys, which may indicate that individuals with greater energy resources have better growth and a better response to infections, thus eliminating the expected trade‐off between body maintenance (immunostimulation) and growth. Adolescent boys with low BAZ and HAZ scores had low CRP values, suggesting that those who do not have enough energy for growth cannot increase their CRP level even when infected with pathogens. Among adolescent girls a positive association was observed between CRP and BAZ scores suggesting the possible effects of chronic low‐grade inflammation due to body fat rather than infection. The association between CRP and growth was less evident among children (6–12 years) compared with adolescents, indicating that the elevated energy requirement needed for the adolescent growth spurt and puberty may play some role. Am J Phys Anthropol 154:42–51, 2014. © 2014 Wiley Periodicals, Inc.