Geometrically centered region: A “wet” model of protein binding hot spots not excluding water molecules

A protein interface can be as “wet” as a protein surface in terms of the number of immobilized water molecules. This important water information has not been explicitly taken by computational methods to model and identify protein binding hot spots, overlooking the water role in forming interface hydrogen bonds and in filing cavities. Hot spot residues are usually clustered at the core of the protein binding interfaces. However, traditional machine learning methods often identify the hot spot residues individually, breaking the cooperativity of the energetic contribution. Our idea in this work is to explore the role of immobilized water and meanwhile to capture two essential properties of hot spots: the compactness in contact and the far distance from bulk solvent. Our model is named geometrically centered region (GCR). The detection of GCRs is based on novel tripartite graphs, and atom burial levels which are a concept more intuitive than SASA. Applying to a data set containing 355 mutations, we achieved an F measure of 0.6414 when ΔΔG ≥ 1.0 kcal/mol was used to define hot spots. This performance is better than Robetta, a benchmark method in the field. We found that all but only one of the GCRs contain water to a certain degree, and most of the outstanding hot spot residues have water‐mediated contacts. If the water is excluded, the burial level values are poorly related to the ΔΔG, and the model loses its performance remarkably. We also presented a definition for the O‐ring of a GCR as the set of immediate neighbors of the residues in the GCR. Comparative analysis between the O‐rings and GCRs reveals that the newly defined O‐ring is indeed energetically less important than the GCR hot spot, confirming a long‐standing hypothesis. Proteins 2010. © 2010 Wiley‐Liss, Inc.     

“Prolonged grief disorder” and “persistent complex bereavement disorder”, but not “complicated grief”, are one and the same diagnostic entity: an analysis of data from the Yale Bereavement Study

There exists a general consensus that prolonged grief disorder (PGD), or some variant of PGD, represents a distinct mental disorder worthy of diagnosis and treatment. Nevertheless, confusion remains over whether different names and proposed symptom criteria for this disorder identify the same or different diagnostic entities. This study aimed to determine whether PGD, complicated grief (CG), and persistent complex bereavement disorder (PCBD) as described by the DSM‐5 are substantively or merely semantically different diagnostic entities. Data were derived from the Yale Bereavement Study, a longitudinal community‐based study of bereaved individuals funded by the US National Institute of Mental Health, designed explicitly to evaluate diagnostic criteria for disordered grief. The results suggested that the difference between PGD and PCBD is only semantic. The level of agreement between the original PGD test, a new version of the PGD test proposed for ICD‐11 and the PCBD test was high (pairwise kappa coefficients = 0.80‐0.84). Their estimates of rate of disorder in this community sample were similarly low (～10%). Their levels of diagnostic specificity were comparably high (95.0‐98.3%). Their predictive validity was comparable. In contrast, the test for CG had only moderate agreement with those for PGD and PCBD; its estimate of rate of disorder was three‐fold higher (～30%); its diagnostic specificity was poorer, and it had no predictive validity. We conclude that PGD, PCBD and proposed ICD‐11, but not CG, symptom‐diagnostic tests identify a single diagnostic entity. Ultimately, brief symptom‐diagnostic tests, such as the one proposed here for ICD‐11, may have the greatest clinical utility.     

What are genes “for” or where are traits “from”? What is the question?

For at least a century it has been known that multiple factors play a role in the development of complex traits, and yet the notion that there are genes “for” such traits, which traces back to Mendel, is still widespread. In this paper, we illustrate how the Mendelian model has tacitly encouraged the idea that we can explain complexity by reducing it to enumerable genes. By this approach many genes associated with simple as well as complex traits have been identified. But the genetic architecture of biological traits, or how they are made, remains largely unknown. In essence, this reflects the tension between reductionism as the current “modus operandi” of science, and the emerging knowledge of the nature of complex traits. Recent interest in systems biology as a unifying approach indicates a reawakened acceptance of the complexity of complex traits, though the temptation is to replace “gene for” thinking by comparably reductionistic “network for” concepts. Both approaches implicitly mix concepts of variants and invariants in genetics. Even the basic question is unclear: what does one need to know to “understand” the genetic basis of complex traits? New operational ideas about how to deal with biological complexity are needed.     

“Right” or “wrong”? insights into the ecology of sidedness in european flounder,Platichthys flesus

Sidedness polymorphism in flatfish has been linked to ecological selection between morphs. However, the alternate hypothesis that morphological differences between right‐ and left‐sided forms may be due to errors during development, as a consequence of disturbed homeostasis, which still remains largely unexplored. Here, we examined the case of Platichthys flesus (flounder), a polymorphic flatfish exhibiting large and clinal variation in the frequency of the left‐sided morph, which is the reversed condition in this generally right‐sided species. An integrated approach consisting of the analyses of shape variation, stomach contents, and skeletal anomalies was used. Morphological differences were observed between morphs, which are in agreement with previous findings in a congeneric species (Platichthys stellatus). In parallel, significant differences in feeding choices were detected, suggesting a coherent association between subtle morphological differences between morphs and their use of trophic resources. Skeletal anomalies and meristic counts did not corroborate the hypothesis that morphometric divergence in reversed individuals may be caused or reinforced by developmental instability. J. Morphol. 2012. © 2011 Wiley Periodicals, Inc.     

Autophagy and ionizing radiation in tumors: The “survive or not survive” dilemma

Autophagy is a so‐called “self‐eating” system responsible for degrading long‐lived proteins and cytoplasmic organelles, whose products are recycled to maintain cellular homeostasis. This ability makes autophagy a good candidate for a survival mechanism in response to several stresses, including the tumor cell transformation. In particular, recent studies suggested that autophagy functions as a pro‐death mechanism within different tumor contexts. It is, however, widely reported that autophagy represents both a survival mechanism or contributes directly to cell death fate. This interplay of the autophagy functions has been observed in many types of cancers and, in some cases, autophagy has been demonstrated to both promote and inhibit antitumor drug resistance. From a therapeutical point of view, the effects of the modulation of the tumor cell autophagic status, in response to ionizing radiations, are presently of particular relevance in oncology. Accordingly, this review also provides a perspective view on future works for exploring the modulation of autophagic indices in tumor cells as a novel molecular‐based adjuvant strategy, in order to improve radiotherapy and chemotherapy effects in cancer patients. J. Cell. Physiol. 228: 1–8, 2013. © 2012 Wiley Periodicals, Inc.     

Isolated deficiency of immunocytochemically detected somatostatin in Snell dwarf, but not in “little,” mice

Immunocytochemical staining of the neuropeptide somatostatin was evaluated in the brains of two growth hormone-deficient mouse mutants, Snell dwarf (dw/dw), and “little” (lit/lit). In Snell dwarf mice, in which GH is undetectable, an isolated somatostatin deficiency was observed in hypothalamic median eminence and in anterior periventricular hypothalamic neurons which are afferent to median eminence, compared to somatostatin staining in normal mice of the same strain (DW/?). Somatostatin staining in all other CNS areas in dwarfs was identical to that in normal mice. In contrast, in little mice, which exhibit 5–10% of normal GH levels, somatostatin expression was comparable between mutants and normal mice (LIT/?) in all CNS areas, including median eminence-afferent neurons in anterior periventricular hypothalamus. The results suggest that expression of somatostatin in hypophysiotropic CNS is dependent upon minimal pituitary GH secretion.     

Genesis and structure of the so-called “balbiani body” or “yolk nucleus” in the oocyte of dugesia dorotocephala (turbellaria,tricladida)

Oogenesis of the fresh-water triclad Dugesia dorotocephala has been studied by electron microscopical methods, with particular regard to the genesis and composition of the so-called “Balbiani body.” Its origin is clearly recognizable in young oocytes where the few mitochondria present seem to gather at the level of the perinuclear ooplasm. Here they surround dense masses of finely granular, fibrillar material probably coming from the nucleus. During the previtelloge ic period, mitochondria rapidly increase in number while the dense masses progressively dissolve. In the vitellogenic oocytes the Balbiani body shows its final configuration: it appears as a large area (up to 15-20 pm in diameter) consisting of innumerable densely packed mitochondria, some smooth vesicles and free ribosomes. This aggregate of cytoplasmic organelles remains unmodified in the mature oocytes. The function of the “Balbiani body” of D. dorotocephala is as yet unclear; it can only be asserted that it is not correlated with yolk production in which the endoplasmic reticulum and the Golgi complex are involved.     

Manganese and copper promote the binding of dopamine to “serotonin binding proteins” in bovine frontal cortex

The authors previously reported that Fe²⁺ is capable of increasing the binding of dopamine and of serotonin to “serotonin binding proteins” which are present in soluble extracts from calf brain. In this study, it is shown that Mn²⁺ and Cu²⁺ are also capable of increasing the binding, but for dopamine only. As for Fe²⁺, Mn²⁺ and Cu²⁺ are likely to promote the binding by virtue of their ability to enhance the oxidation of dopamine into dopamine-O-quinone, a derivative which is known to undergo covalent association with sulfhydryl groups of proteins. Data such as the irreversible nature of the majority of the binding, the inhibitory action of reducing agents (sodium ascorbate) and of reagents which contain, or modify sulfhydryl groups (reduced glutathione) are compatible with such a mechanism. The three metal ions are also capable of inactivating part of the binding sites on SBP directly; this effect is more pronounced for Cu²⁺ than for Fe²⁺ and it is only weak for Mn²⁺. The Fe²⁺-mediated binding of dopamine is inhibited by the superoxide dismutase enzyme, and it was therefore suggested that Fe²⁺ enhances the oxidation of dopamine by virtue of its ability to produce superoxide radicals out of dissolved molecular oxygen. Such a mechanism does not appear to take place in the case of Mn²⁺ and Cu²⁺. Instead, it is likely that Cu²⁺ and dopamine form a complex which is highly susceptible towards oxidation by dissolved molecular oxygen. Mn²⁺, on the other hand, can easily be oxidized into Mn³⁺, which is capable to oxidize dopamine by itself. Chronic manganese intoxication (from exposure to manganese) and Wilson's disease (related to inadequate elimination of copper) go along with neurological symptoms which are very similar to those encountered in Parkinson's disease. Our data indicate that manganese and copper ions accelerate the oxidation of catecholamines to produce toxic quinones. These quinones could, at least in part, account for the degeneration of dopamininergic neurons in such pathologies.     

Testosterone increases acetylcholine receptor number in the “levator ani” muscle of the rat

The “levator ani” muscle of male rats provides a neuromuscular system in which both the muscle and its motoneurons have high levels of androgen receptors. Two weeks of castration caused a 48% loss of acetylcholine receptors in this muscle. One week of testosterone propionate injections initiated one week after castration increased receptor number by 27% over untreated castrate levels. These changes paralleled changes in muscle protein content. In contrast, castration and testosterone treatments of castrates had no effect on total, Triton X-100-extractable acetylcholinesterase activity. This system may provide a useful model of synaptic plasticity.     

Mutations within a human IgG2 antibody form distinct and homogeneous disulfide isomers but do not affect Fc gamma receptor or C1q binding

Human IgG2 antibodies may exist in at least three distinct structural isomers due to disulfide shuffling within the upper hinge region. Antibody interactions with Fc gamma receptors and the complement component C1q contribute to immune effector functions. These interactions could be impacted by the accessibility and structure of the hinge region. To examine the role structural isomers may have on effector functions, a series of cysteine to serine mutations were made on a human IgG2 backbone. We observed structural homogeneity with these mutants and mapped the locations of their disulfide bonds. Importantly, there was no observed difference in binding to any of the Fc gamma receptors or C1q between the mutants and the wild‐type IgG2. However, differences were seen in the apparent binding affinity of these antibodies that were dependent on the selection of the secondary detection antibody used.     

Suicide is not the inevitable outcome of “perpetual” selfing in tetrahymenines collected from natural habitats

A significant fraction of the Tetrahymena clones isolated from natural habitats self (mating occurs within a clone). Early attempts to study such clones failed because stable subclones were rarely, if ever, observed, and isolated pairs all died. Isozyme analysis revealed that these wild selfers were a diverse group; some were very similar to T. australis, a species with synclonal mating type determination and to T. elliotti, shown recently to have a karyonidal mating type system. One originally stable clone of T. australis included some selfing clones after a few years in our laboratory. Other clones manifested unique zymograms. Subclones isolated from 18 selfer strains were heterogeneous. All subclones of several selfers mated massively at each transfer through 100 fissions. Selfing among subclones of other selfers was highly variable or not observed. Although 77% of the pairs isolated died, and 9% of the pair cultures selfed, 15 selfers yielded some viable nonselfing “immature” progeny. Additional immature progeny were obtained by isolating pairs from macronuclear retention synclones. Although some “immature” progeny eventually selfed, most remained stable. Giemsa staining revealed macronuclear anlagen in nearly all mating pairs and some anomalies. Crosses among the F1 progeny clones of the T. elliotti selfers yield viability data comparable to those from crosses among normal strains. Perhaps perpetual selfing is a mechanism of getting rid of deleterious combinations of genes and uncovering better combinations in homozygous state by playing genetic roulette. © 1992 Wiley-Liss, Inc.     

Genomic insights into the adaptation and evolution of the nautilus,an ancient but evolving “living fossil”

The nautilus, commonly known as a “living fossil,” is endangered and may be at risk of extinction. The lack of genomic information hinders a thorough understanding of its biology and evolution, which can shed light on the conservation of this endangered species. Here, we report the first high-quality chromosome-level genome assembly of Nautilus pompilius. The assembled genome size comprised 785.15 Mb. Comparative genomic analyses indicated that transposable elements (TEs) and large-scale genome reorganizations may have driven lineage-specific evolution in the cephalopods. Remarkably, evolving conserved genes and recent TE insertion activities were identified in N. pompilius, and we speculate that these findings reflect the strong adaptability and long-term survival of the nautilus. We also identified gene families that are potentially responsible for specific adaptation and evolution events. Our study provides unprecedented insights into the specialized biology and evolution of N. pompilius, and the results serve as an important resource for future conservation genomics of the nautilus and closely related species.