Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells

The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4(+) T cells. Here we explore the effector functions of HIV-1-specific CD4(+) T cells. We demonstrate HIV-1 p24-specific CD4(+)-T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4(+)-T-cell clone and CD4(+) T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4(+) T cells and the target cells. While the antiviral effector activity of CD8(+) T cells has been well documented, these results strongly suggest that HIV-1-specific CD4(+) T cells are capable of directly contributing to antiviral immunity.     

Novel nuclear signaling pathway mediates activation of fibroblast growth factor-2 gene by type 1 and type 2 angiotensin II receptors

In bovine adrenal medullary cells synergistically acting type 1 and type 2 angiotensin II (AII) receptors activate the fibroblast growth factor-2 (FGF-2) gene through a unique AII-responsive promoter element. Both the type 1 and type 2 AII receptors and the downstream cyclic adenosine 1',3'-monophosphate- and protein kinase C-dependent signaling pathways activate the FGF-2 promoter through a novel signal-transducing mechanism. This mechanism, which we have named integrative nuclear FGF receptor-1 signaling, involves the nuclear translocation of FGF receptor-1 and its subsequent transactivation of the AII-responsive element in the FGF-2 promoter.     

Muscle phenotype remains unaltered after limb autotomy and unloading

Loss of chelipeds in crustaceans results in severe atrophy of the major muscle responsible for lifting the limb, the anterior levator. We decided to test if this loss of mechanical load altered muscle phenotype as measured by SDS-PAGE analysis of levator total protein and actomyosin fractions. Levator muscles of adult crayfish, Procambarus clarkii, with either functional regenerate limbs or lack of limb buds (papilla stage) were compared with those from normal contralateral limbs and those from pristine animals. We find that there is no difference in protein profiles among the three conditions. However, the total protein profile for the dually excited levator muscle is unique compared to those of fast or slow muscles of the abdomen (L and SEL, respectively), which receive only phasic or tonic excitatory innervation. The levator myosin heavy chain profile is similar to that of slow phenotype muscles such as the SEL and opener. We conclude that load does not influence levator phenotype. This is likely due either to the intact innervation and continued activation of the levator during atrophy or to the maintenance of passive tension on the muscle. J. Exp. Zool. 289:10-22, 2001.     

Perspective: Research Activity of Enteropancreatic and Brain/Central Nervous System Hormones Across Invertebrates and Vertebrates

During the past two decades there have been rapid advances inour knowledge of the structure and function of the protein hormonesin the brain and gastroenteropancreatic system (GEP). Many publishedarticles have highlighted the superfamily of hormonal peptides,specifically, the mechanisms and control of peptide synthesisin neural and non-neural tissues, and gene structure. Here wepresent an analysis of the annual trends, between 1980 and 1997,of research emphasis on six protein/peptide hormones, as reflectedby their individual frequency of publication per year. Althoughthis symposium is focused on the GEP hormones, we provide hereina perspective on the level of research activity of the hormonesinsulin, glucagon, cholecystokinin, insulin-like growth factor-Iand -II, neuropeptide Y and somatostatin in the brain/gut systemsthroughout the vertebrates and invertebrates. Many publicationsdeal with the evolution of these peptides and their superfamilies,yet as noted in this review, there are relatively few referencesto these peptides in invertebrates and non-mammalian species.Typically in invertebrates, the number of citations is low andmostly focused on three phyla, the arthropods, mollusks andhelminths. Generally, in the vertebrates the smallest numberof citations is in the cyclostomes and elasmobranchs. Becausemost groups of invertebrates and vertebrates have received scantattention, phylogenetic comparisons are limited. Evolutionaryinformation concerning important groups of animals, such ashelminths, mollusks, protochordates and cyclostomes, is essentialto establish the phylogenetic histories of the hormonal peptides.The challenge to comparative endocrinologists is to examinespecies in key evolutionary positions in order to gain an understandingof the diversity and function of the hormones and to determinethe molecular features that form clues to their phyletic interrelationshipsand progression.     

Small RNA Derived from the Virulence Modulating Region of the Potato spindle tuber viroid Silences callose synthase Genes of Tomato Plants

The tomato (Solanum lycopersicum) callose synthase genes CalS11-like and CalS12-like encode proteins that are essential for the formation of callose, a major component of pollen mother cell walls; these enzymes also function in callose formation during pathogen infection. This article describes the targeting of these callose synthase mRNAs by a small RNA derived from the virulence modulating region of two Potato spindle tuber viroid variants. More specifically, viroid infection of tomato plants resulted in the suppression of the target mRNAs up to 1.5-fold, depending on the viroid variant used and the gene targeted. The targeting of these mRNAs by RNA silencing was validated by artificial microRNA experiments in a transient expression system and by RNA ligase-mediated rapid amplification of cDNA ends. Viroid mutants incapable of targeting callose synthase mRNAs failed to induce typical infection phenotypes, whereas a chimeric viroid obtained by swapping the virulence modulating regions of a mild and a severe variant of Potato spindle tuber viroid greatly affected the accumulation of viroids and the severity of disease symptoms. These data provide evidence of the silencing of multiple genes by a single small RNA derived from a viroid.     

Human Identity and the Evolution of Societies

Human societies are examined as distinct and coherent groups. This trait is most parsimoniously considered a deeply rooted part of our ancestry rather than a recent cultural invention. Our species is the only vertebrate with society memberships of significantly more than 200. We accomplish this by using society-specific labels to identify members, in what I call an anonymous society. I propose that the human brain has evolved to permit not only the close relationships described by the social brain hypothesis, but also, at little mental cost, the anonymous societies within which such alliances are built. The human compulsion to discover or invent labels to “mark” group memberships may originally have been expressed in hominins as vocally learned greetings only slightly different in function from chimpanzee pant hoots (now known to be society-specific). The weight of evidence suggests that at some point, conceivably early in the hominin line, the distinct groups composed of several bands that were typical of our ancestors came to be distinguished by their members on the basis of multiple labels that were socially acquired in this way, the earliest of which would leave no trace in the archaeological record. Often overlooked as research subjects, these sizable fission-fusion communities, in recent egalitarian hunter-gatherers sometimes 2,000 strong, should consistently be accorded the status of societies, in the same sense that this word is used to describe tribes, chiefdoms, and other cultures arising later in our history. The capacity of hunter-gatherer societies to grow sufficiently populous that not all members necessarily recognize one another would make the transition to larger agricultural societies straightforward. Humans differ from chimpanzees in that societal labels are essential to the maintenance of societies and the processes giving birth to new ones. I propose that anonymous societies of all kinds can expand only so far as their labels can remain sufficiently stable.     

BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages

BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long-standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2.     

MicroRNA expression profiling identifies activated B cell status in chronic lymphocytic leukemia cells

Chronic lymphocytic leukemia (CLL) is thought to be a disease of resting lymphocytes. However, recent data suggest that CLL cells may more closely resemble activated B cells. Using microRNA (miRNA) expression profiling of highly-enriched CLL cells from 38 patients and 9 untransformed B cells from normal donors before acute CpG activation and 5 matched B cells after acute CpG activation, we demonstrate an activated B cell status for CLL. Gene set enrichment analysis (GSEA) identified statistically-significant similarities in miRNA expression between activated B cells and CLL cells including upregulation of miR-34a, miR-155, and miR-342-3p and downregulation of miR-103, miR-181a and miR-181b. Additionally, decreased levels of two CLL signature miRNAs miR-29c and miR-223 are associated with ZAP70(+) and IgV(H) unmutated status and with shorter time to first therapy. These data indicate an activated B cell status for CLL cells and suggest that the direction of change of individual miRNAs may predict clinical course in CLL.     

Sexual dimorphism in relative sacral breadth among catarrhine primates

As the sacrum contributes to the size and shape of the birth canal, the sexually dimorphic sacrum of humans is frequently interpreted within obstetric contexts. However, while the human sacrum has been extensively studied, comparatively little is known about sacral morphology in nonhuman primates. Thus, it remains unclear whether sacral sexual dimorphism exists in other primates, and whether potential dimorphism is primarily related to obstetrics or other factors such as body size dimorphism. In this study, sacra of Homo sapiens, Hylobates lar, Nasalis larvatus, Gorilla gorilla, Pongo pygmaeus, Pan troglodytes, and Pan paniscus were evaluated for sexual dimorphism in relative sacral breadth (i.e., the ratio of overall sacral breadth to first sacral vertebral body breadth). Homo sapiens, H. lar, N. larvatus, and G. gorilla exhibit dimorphism in this ratio. Of these, the first three species have large cephalopelvic proportions, whereas G. gorilla has small cephalopelvic proportions. P. pygmaeus, P. troglodytes, and P. paniscus, which all have small cephalopelvic proportions, were not dimorphic for relative sacral breadth. We argue that among species with large cephalopelvic proportions, wide sacral alae in females facilitate birth by increasing the pelvic inlet's transverse diameter. However, given the small cephalopelvic proportions among gorillas, an obstetric basis for dimorphism in relative sacral breadth appears unlikely. This raises the possibility that sacral dimorphism in gorillas is attributable to selection for relatively narrow sacra in males rather than relatively broad sacra in females. Accordingly, these results have implications for interpreting pelvic dimorphism among fossil primates, including hominins. Am J Phys Anthropol 152:435–446, 2013. © 2013 Wiley Periodicals, Inc.