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Structure, function and evolution of microbial adenylyl and guanylyl cyclases.

Cells respond to signals of both environmental and biological origin. Responses are often receptor mediated and result in the synthesis of so-called second messengers that then provide a link between extracellular signals and downstream events, including changes in gene expression. Cyclic nucleotides (cAMP and cGMP) are among the most widely studied of this class of molecule. Research on their function and mode of action has been a paradigm for signal transduction systems and has shaped our understanding of this important area of biology. Cyclic nucleotides have diverse regulatory roles in both unicellular and multicellular organisms, highlighting the utility and success of this system of molecular communication. This review will examine the structural diversity of microbial adenylyl and guanylyl cyclases, the enzymes that synthesize cAMP and cGMP respectively. We will address the relationship of structure to biological function and speculate on the complex origin of these crucial regulatory molecules. A review is timely because the explosion of data from the various genome projects is providing new and exciting insights into protein function and evolution.

Adenylyl Cyclases↗

Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking.

The effective onset of adaptive immune responses requires that naïve antigen-specific lymphocytes, being inherently rare throughout the body, rapidly encounter foreign antigens. This problem has been elegantly solved in evolution by inventing secondary lymphoid tissues as intersections in the migratory pathway of antigen-presenting dendritic cells and antigen-specific lymphocytes. Chemokines play a central role in guiding cell movements in the course of immune responses and in lymphoid system homeostasis. In particular, the chemokine receptors CCR7 and CXCR5 are key molecules for the entry of lymphocytes and dendritic cells into secondary lymphoid organs and their homing to T-cell and B-cell zones therein. CCR7 and CXCR5 are differentially expressed on the cell surface of lymphocytes and dendritic cells depending on the stage of cellular differentiation and activation, thus allowing these cells to change their homing capacity and prospective traffic routes.

Adaptation, Physiological↗

Longitudinal dynamics of gene expression and metabolomics in an aging population cohort.

Multiomic profiling provides a comprehensive physiological overview at the molecular level, but understanding of its spatiotemporal dynamics remains limited in human populations. We profiled longitudinal whole-blood gene expression and metabolite levels in 335 females over 8 years. Levels of 5061 genes and 181 metabolites changed over time, with individual trajectories often diverging from population-level trends. Longitudinally variable genes showed cell type specificity and enrichment for aging-relevant pathways, including cardiometabolic and neurodegenerative disorders. Longitudinal trajectories were further shaped by genetics, circadian rhythm, seasonality, and environmental pollutant exposures. Integrative analyses revealed extensive static and time-variable cross-omic connectivity. Longitudinal profiling offers insight into the temporal evolution of age-related conditions at the molecular level, and understanding individual variation within these longitudinal patterns will be essential for future precision medicine approaches.

Female↗

Shaping up adaptive immunity: the impact of CCR7 and CXCR5 on lymphocyte trafficking.

The effective onset of adaptive immune responses requires that naïve antigen-specific lymphocytes, being inherently rare throughout the body, rapidly encounter foreign antigens. This problem has been elegantly solved in evolution by inventing secondary lymphoid tissues as intersections in the migratory pathway of antigen-presenting dendritic cells and antigen-specific lymphocytes. Chemokines play a central role in guiding cell movements in the course of immune responses and in lymphoid system homeostasis. In particular, the chemokine receptors CCR7 and CXCR5 are key molecules for the entry of lymphocytes and dendritic cells into secondary lymphoid organs and their homing to T-cell and B-cell zones therein. CCR7 and CXCR5 are differentially expressed on the cell surface of lymphocytes and dendritic cells depending of the stage of cellular differentiation and activation, thus allowing these cells to change their homing capacity and prospective traffic routes.

B-Lymphocytes↗

Comparison of vegetative anatomy of Piperales. II. Leaf.

Many characters of leaf (hair, hypodermal cells, palisade layers, intercellular space, distinction between spongy and palisade parenchyma, "palisade ratio", distribution of collenchyma and sclerenchyma, presence or absence of starch grains, calcium oxalate crystals, number, shape and arrangement of bundles of petiole) are useful distinguishing characters. Reduction of palisade layers seems to be the trend of evolution in Piper and Peperomia.

Plants↗

Plant profilins rescue the aberrant phenotype of profilin-deficient Dictyostelium cells.

To characterize the function of plant profilins in vivo, we expressed two pollen specific Zea mays (maize) profilin isoforms in profilin-minus Dictyostelium discoideum mutants. In maize, profilins exist as a multigene family containing 4 or more members which are highly similar to each other but substantially less similar to profilins from animals and lower eukaryotes. Previously we have shown that D. discoideum profilin-minus cells have an aberrant phenotype due to defects in cell shape, cytokinesis, and development. These defects could be rescued by introducing the pollen-specific profilins 1 or 2 from maize using a newly constructed expression vector. Expression of the heterologous profilins in Dictyostelium clones was assayed by affinity purification of the pollen profilins with poly-proline agarose and by immunoblotting with a polyclonal antiserum raised against maize pollen profilin. In contrast to the profilin-minus mutants, Dictyostelium cells expressing plant profilins showed normal cell shape, contained less F-actin, and were able to form fruiting bodies. These data provide genetic evidence that maize pollen profilins, even though they are specific for a distinct developmental stage, share functional properties with profilin from a lower eukaryote and apparently act as G-actin-sequestering proteins in this system.

Animals↗

Population differentiation within and among Asian elephant (Elephas maximus) populations in southern India.

Southern India, one of the last strongholds of the endangered Asian elephant (Elephas maximus), harbours about one-fifth of the global population. We present here the first population genetic study of free-ranging Asian elephants, examining within- and among-population differentiation by analysing mitochondrial DNA (mtDNA) and nuclear microsatellite DNA differentiation across the Nilgiris-Eastern Ghats, Anamalai, and Periyar elephant reserves of southern India. Low mtDNA diversity and 'normal' microsatellite diversity were observed. Surprisingly, the Nilgiri population, which is the world's single largest Asian elephant population, had only one mtDNA haplotype and lower microsatellite diversity than the two other smaller populations examined. There was almost no mtDNA or microsatellite differentiation among localities within the Nilgiris, an area of about 15,000 km2. This suggests extensive gene flow in the past, which is compatible with the home ranges of several hundred square kilometres of elephants in southern India. Conversely, the Nilgiri population is genetically distinct at both mitochondrial and microsatellite markers from the two more southerly populations, Anamalai and Periyar, which in turn are not genetically differentiated from each other. The more southerly populations are separated from the Nilgiris by only a 40-km-wide stretch across a gap in the Western Ghats mountain range. These results variably indicate the importance of population bottlenecks, social organization, and biogeographic barriers in shaping the distribution of genetic variation among Asian elephant populations in southern India.

Animals↗

Control of filamentous fungal cell shape by septins and formins.

Studies in various model systems have identified two protein families that are crucial for shaping cell morphology: the septins and the formins. Both families are conserved in most eukaryotes, but the functions and regulation of individual homologues can vary depending on their precise cellular context. The rich array of cell geometries found in different filamentous fungal species provides a powerful experimental canvas for studying the evolution and regulation of septins and formins. Here, I assimilate what is known about the function of these protein families in filamentous fungi and propose that further studies in these organisms could answer some open mechanistic questions that pertain in general to eukaryotic cells.

Cell Cycle Proteins↗

Lamins: building blocks or regulators of gene expression?

Intermediate filament (IF) proteins are the building blocks of cytoskeletal filaments, the main function of which is to maintain cell shape and integrity. The lamins are thought to be the evolutionary progenitors of IF proteins and they have profound influences on both nuclear structure and function. These influences require the lamins to have dynamic properties and dual identities--as building blocks and transcriptional regulators. Which one of these identities underlies a myriad of genetic diseases is a topic of intense debate.

Animals↗

A model of the early evolution of soma-to-germline feedback.

The V-genes of the immunoglobulin locus in vertebrates code for a part of the heavy and light chain variable regions of antibodies and are extremely variable. Steele (1979) has developed a theory that explains the evolution of adaptive immune response by a soma-to-germline flow of cDNAs derived from somatically mutated V-genes. Here we model the early evolution of soma-to-germline feedback in a population living in a changing viral environment in terms of the dynamics of an initially rare genetic modifier that controls transfer of V-genes to germ cells' DNA. It is shown that a modifier invades the population and creates a great variety of V-genes if the environment follows stepwise temporal changes, i.e. a soma-to-germline feedback machinery evolves in a population if newly derived V-alleles still play a role in protecting the population against foreign antigens in some following generations. The distribution of the age of V-genes evolves to a bell-shaped curve the width and the maximum of which depend mainly on selection strength. Two phases of modifier evolution are distinguished. In the first phase, the dynamics are slow while the number of different V-genes is small. In the second phase, when a sufficiently large number of different V-genes is created, the modifier increases faster in frequency. Linkage of V-genes and the modifier enhances the rate of evolution.

Animals↗

Contributions of the Mac-1 glycoprotein family to adherence-dependent granulocyte functions: structure-function assessments employing subunit-specific monoclonal antibodies.

MAb directed at the alpha-subunits of Mac-1 (alpha M), LFA-1 (alpha L), p150,95 (alpha X), or their common beta-subunit were used to characterize the contributions of the Mac-1 glycoprotein family to granulocyte adherence reactions. Inhibitory effects of these MAb in incubation experiments with normal granulocytes indicated distinct adhesive contributions of each subunit. Significantly greater adherence, and inhibition of adherence by anti alpha M, alpha X, and beta MAb, was observed under chemotactic conditions designed to "up-regulate" the surface expression of the alpha M beta and alpha X beta complexes. Adherence to protein-coated glass and binding of albumin-coated latex beads were significantly inhibited by anti-beta greater than anti-alpha M (OKM-10, M1/70, LM2/1.6 and OKM-1) greater than anti-alpha X greater than anti-alpha L MAb, but no effects of anti-HLA, AB, or anti-CR-1 MAb were evident. A similar rank order of inhibition was observed in granulocyte aggregation assays in response to C5a, PMA, or f-Met-Leu-Phe. Significant inhibition of directed migration by anti-beta or anti-alpha M (OKM-1 or OKM-10) MAb was observed in subagarose but not Boyden chemotaxis assays; inhibition was dependent on a continuous cell exposure to anti-Mac-1 alpha or beta during the assay, suggesting that a continuum of new Mac-1 expression is required for directed translocation. Phagocytosis of Oil-Red-O paraffin or zymosan selectively opsonized with C3-derived ligands was significantly inhibited by anti-alpha M MAb (OKM-10 greater than LM2/1.6 greater than M1/70 greater than OKM-1) or by combinations of anti-alpha M + anti-CR-1 MAb, but only minimal inhibitory effects of anti-beta MAb and no effects of anti-alpha L or anti-alpha X MAb were seen. Similarly, complement-dependent phagocytosis-associated lactoferrin release, ingestion, and intracellular killing of Staphylococcus aureus 502A, and binding of iC3b-opsonized SRBC, were significantly inhibited by anti-alpha M (OKM-10, M1/70) or combinations of anti-alpha M + anti-CR-1 MAb, but not by anti-beta, alpha L, or alpha X MAb. Notably, none of the anti-Mac-1 MAb demonstrated inhibitory effects in assays of adherence-independent functions including shape change, specific f-Met-Leu-3H-Phe binding, O-2 generation, chemiluminescence evolution, or lactoferrin release in response to PMA.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Salmonellosis: host immune responses and bacterial virulence determinants.

The lifestyle of bacterial pathogens requires them to establish infection in the face of host immunity. Upon entering a potential host, a variety of interactions are initiated, the outcome of which depends upon a myriad of attributes of each of the participants. In this review we discuss the interactions that occur between pathogenic Salmonella species and the host immune systems, but when appropriate to broaden perspective, we have provided a general overview of the interactions between bacterial pathogens and animal hosts. Pathogenic Salmonella species possess an array of invasion genes that produce proteins secreted by a specialized type III secretion apparatus. These proteins are used by the bacteria to penetrate the intestinal mucosa by invading and destroying specialized epithelial M cells of the Peyer's patches. This maneuver deposits the bacteria directly within the confines of the reticuloendothelial system. The host responds to these actions with nonspecific phagocytic cells and an inflammatory response as well as by activating specific cellular and humoral immune responses. Salmonella responds to this show of force directly. It appears that the bacteria invade and establish a niche within the very cells that have been sent to destroy them. Efforts are underway to characterize the factors that allow these intracellular bacteria to customize intracellular vacuoles for their own purposes. It is the constant play between these interactions that determines the outcome of the host infection, and clearly they will also shape the evolution of new survival strategies for both the bacterium and the host.

Animals↗

Solitary bronchioloalveolar adenoma of the lung.

A case of an unusual pulmonary neoplasia, called bronchioloalveolar adenoma of the lung, is reported. The neoplasm presented as a solitary peripheral lesion of the left lung on computed tomography. Examination of the tumor revealed a focal proliferating lesion consisting of cuboidal or peg-shaped epithelial cells with slight nuclear atypia. Immunohistochemical study with anti-carcinoembryonic antigen antibody, anti-surfactant apoprotein antibody, and anti-Clara cell antibody suggested that this neoplasia has the characteristics of a type II pneumocyte. It is likely that more of these small peripheral lesions, which have potential for evolution to carcinoma, will now be encountered due to the introduction of helical CT of the chest.

Adenoma↗

Histological and immunological features of primary Kaposi's sarcoma: evaluation before and after chemotherapy.

Forty-one patients with primary Kaposi's sarcoma (KS) have been evaluated clinically, histologically and immunologically at the time of diagnosis. There was no correlation between histological and immunological features. Moreover, the disease did not appear to be related to particular HLA phenotypes. The T4/T8 ratio was augmented. Leu 7+ cells were also significantly increased. The last 15 patients who received chemotherapy were recently reevaluated after treatment and an increase in B lymphocytes was observed. We also observed that spindle-shaped cells (SSC), which appear later in the histopathological course of the disease, disappear first during chemotherapy, concomitantly with the increase in B cells. We conclude that the course of the disease appears to be controlled by the host's immune response, though there is no clear correlation between histological and immunological evolution. Several immunological features differentiating it from AIDS associated KS have been found.

Aged↗

Asynchronous transitions from high-risk hepatoblastoma to carcinoma.

BACKGROUND & AIMS: Most pediatric hepatocellular tumors are classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features. These hepatoblastomas with carcinoma features (HBCs) include cases provisionally designated as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. It is unclear whether HBCs comprise hybrid cells with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. We characterized the biology, etiology, cellular composition, and evolutionary dynamics of HBCs. METHODS: We performed multi-omics profiling - including single-nucleus RNA sequencing, single-nucleus DNA sequencing, and multi-region longitudinal bulk RNA and DNA sequencing - to characterize HBC composition, evolution, and treatment response. Two-thirds of our samples were post-chemotherapy resections. RESULTS: HBCs comprise heterogeneous mixtures of HB-like, HBC-like, and HCC-like molecular cell types. Outcomes in HBC are significantly worse than in HB, and HBC cells are more chemoresistant than HB cells, with resistance shaped by their cell identity, genetic alterations, and embryonic differentiation stage. HBC cells originate from HB cells that were arrested at early hepatic stem cell development stages because of aberrant WNT signaling activation. Inhibition of WNT signaling promoted differentiation and enhanced sensitivity to chemotherapy. Furthermore, each analyzed HBC reflected a dynamic process of multiple HB-to-HBC and HBC-to-HCC transitions, underscoring their evolutionary complexity. A limitation of our study is our inability to pinpoint the role of chemotherapy-induced genome modifications. CONCLUSIONS: Multi-omics profiling of HBCs revealed key insights into their biology and composition, demonstrating that they originate from HB precursors at early hepatic stem cell development stages and that their differentiation arrest depends on sustained aberrant WNT signaling activity. IMPACT AND IMPLICATIONS: Hepatoblastomas with carcinoma features (HBCs) represent a poorly understood subset of pediatric liver tumors with mixed characteristics of hepatoblastoma (HB) and hepatocellular carcinoma (HCC). Using multi-omics profiling, we show that HBCs comprise heterogeneous mixtures of HB-like, intermediate HBC-like, and HCC-like cell populations that arise from HB precursors arrested at early hepatic stem cell developmental stages due to aberrant WNT signaling. This differentiation arrest contributes to chemoresistance and poorer clinical outcomes compared with HB. Importantly, pharmacologic inhibition of WNT signaling promoted differentiation and increased chemotherapy sensitivity, suggesting a potential therapeutic strategy. These findings refine the biological classification of HBCs and highlight differentiation-based treatment approaches for this aggressive tumor subtype.

Multiomics↗

Biological gas channels for NH3 and CO2: evidence that Rh (Rhesus) proteins are CO2 channels.

Physiological evidence from our laboratory indicates that Amt/Mep proteins are gas channels for NH3, the first biological gas channels to be described. This view has now been confirmed by structural evidence and is displacing the previous belief that Amt/Mep proteins were active transporters for the NH4+ ion. Still disputed is the physiological substrate for Rh proteins, the only known homologues of Amt/Mep proteins. Many think they are mammalian ammonium (NH4+ or NH3) transporters. Following Monod's famous dictum, "Anything found to be true of E. coli must also be true of elephants" [Perspect. Biol. Med. 47(1) (2004) 47], we explored the substrate for Rh proteins in the unicellular green alga Chlamydomonas reinhardtii. C. reinhardtii is one of the simplest organisms to have Rh proteins and it also has Amt proteins. Physiological studies in this microbe indicate that the substrate for Rh proteins is CO2 and confirm that the substrate for Amt proteins is NH3. Both are readily hydrated gases. Knowing that transport of CO2 is the ancestral function of Rh proteins supports the inference from hematological research that a newly evolving role of the human Rh30 proteins, RhCcEe and RhD, is to help maintain the flexible, flattened shape of the red cell.

Algal Proteins↗

The cytogenetic basis for classifying ependymomas.

The phylogeny of ependymal cells and astrocytes can be traced to a single primitive progenitor the ependymoglia or the tanycyte, respectively. Ependymoglia cells have ependymal perikarya having astrocyte-like processes that terminate subpially in primitive glial footplates. Such cells prevail in primitive nervous systems, but they also persist regionally in the mature mammalian brain. Their fine structure has been studied in many species. An electronmicroscopic study of 8 ependymomas reveals that the neoplastic cells possess features characteristic of primitive ependymoglia; in particular they possess cell processes filled with glial filaments, terminating submesenchymally in a primitive, piston-shaped footplate. The perivascular pseudorosettes of ependymomas are the equivalents of these cell poles. The dominant phenomenon of ependymoma structure appears to be a reversion of cellular organization to the stage of primitive ependymoglia cells. On reviewing 43 ependymomas and 71 astrocytomas 11 neoplasms were found having a tissue structure reminiscent of the evolution of piloid astrocytes from ependymoglia or tanycytes, respectively. These features correspond to transitional stages seen in normal primitive brains. Tumors of this type may be characterized as a tanycytic variant of ependymomas. They appear to be relatively common in the spinal cord and present a source of confusion with piloid astrocytomas.

Adolescent↗

Mapping receptive fields in primary visual cortex.

Nearly 40 years ago, in the pages of this journal, Hubel and Wiesel provided the first description of receptive fields in the primary visual cortex of higher mammals. They defined two classes of cortical cells, "simple" and "complex", based on neural responses to simple visual stimuli. The notion of a hierarchy of receptive fields, where increasingly intricate receptive fields are constructed from more elementary ones, was introduced. Since those early days we have witnessed the birth of quantitative methods to map receptive fields and mathematical descriptions of simple and complex cell function. Insights gained from these models, along with new theoretical concepts, are refining our understanding of receptive field structure and the underlying cortical circuitry. Here, I provide a brief historical account of the evolution of receptive field mapping in visual cortex along with the associated conceptual advancements, and speculate on the shape novel theories of the cortex may take as a result these measurements.

Animals↗