bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a new malaria susceptibility locus (Char4) in recombinant congenic strains of mice
Authors: Fortin Anny , Cardon Lon R. , Tam Mifong , Skamene Emil , Stevenson Mary M. , Gros Philippe
Published: July 2002

The genetic component of susceptibility to malaria is complex, both in humans and in the mouse model of infection. Two murine loci on chromosomes 8 (Pchr/Char2) and 9 (Char1) have previously been mapped in F2crosses, and play an important role in regulating blood parasitemia and survival to infection withPlasmodium chabaudi. These loci explain only part of the interstrain phenotypic variance, and their penetrance and expressivity vary in different inbred strains. Novel loci regulating response toP. chabaudiinfection were investigated by using an alternative strategy based on a newly derived set of AcB/BcA recombinant congenic strains bred from malaria-susceptible A/J (A) and resistant C57BL/6J (B6). One of the AcB strains, AcB55, is shown to be highly resistant to infection despite 83% susceptible A genomic composition, including susceptibility alleles atChar1andPchr/Char2. Early onset of parasite clearance in AcB55 is associated with lower peak parasitemia and absence of mortality. Linkage analysis in an informative (AcB55 × A)F2population, using peak parasitemia as a quantitative trait, located a new B6-derived resistance locus on chromosome 3 (lod score = 6.57) that we designateChar4. A second, suggestive linkage on chromosome 10 (lod score = 2.53) shows additive effect withChar4on peak parasitemia.Char4maps to a small congenic B6 fragment in AcB55 that should facilitate the search for candidate genes. Our findings provide an entry point for parallel association studies in humans between the syntenic 4q21–4q25 region and susceptibility to disease in endemic areas of malaria.
A note on Kalman Filter
Authors: Rao C. R.
Published: July 2002

The Kalman Filter commonly employed by control engineers and other physical scientists has been successfully used in such diverse areas as the processing of signals in aerospace tracking and underwater sonar, and statistical quality control. More recently, it has been used in some nonengineering applications such as short-term forecasting, time series, survival analysis, and so on. In all of these situations, we have a set of equations governing the true state of a system and another set connecting the observations made at any given time on the system with its true state. The problem is that of predicting the true state of the system at any given time point based on available observations. The solution proposed in the vast literature of the subject depends on the assumptions made on the initial state of the system. In this paper, a method that is independent of the initial state is proposed. This is useful when thea prioriinformation on the initial state is not available. The method is also applicable when some observations are missing.
RALF, a 5-kDa ubiquitous polypeptide in plants, arrests root growth and development
Authors: Pearce Gregory , Moura Daniel S. , Stratmann Johannes , Ryan Clarence A.
Published: July 2002

A 5-kDa polypeptide was isolated from tobacco leaves that induced a rapid alkalinization of the culture medium of tobacco suspension-cultured cells and a concomitant activation of an intracellular mitogen-activated protein kinase. An N-terminal sequence was obtained, and a cDNA coding for the 49-aa polypeptide was isolated from a tobacco cDNA library. The cDNA encoded a preproprotein of 115 amino acids that contained the polypeptide at its C terminus. A search among known expressed sequence tags revealed that genes encoding
R
apid
AL
kalinization
F
actor (RALF) preproproteins were present in various tissues and organs from 16 species of plants representing 9 families. A tomato homolog of the polypeptide was synthesized and, when supplied to germinating tomato and
Arabidopsis
seeds, it caused an arrest of root growth and development. Although its specific role in growth has not been established, the polypeptide joins the ranks of the increasing number of polypeptide hormones that are known to regulate plant stress, growth, and development.
Regulation of T cell activation, anxiety, and male aggression by RGS2
Authors: Oliveira-dos-Santos Antonio J. , Matsumoto Goichi , Snow Bryan E. , Bai Donglin , Houston Frank P. , Whishaw Ian Q. , Mariathasan Sanjeev , Sasaki Takehiko , Wakeham Andrew , Ohashi Pamela S. , Roder John C. , Barnes Carol A. , Siderovski David P. , Penninger Josef M.
Published: July 2002

Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Gα protein subunitsin vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family memberrgs2was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2in vivo, we generatedrgs2-deficient mice. We show that targeted mutation ofrgs2in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunityin vivo. Interestingly,rgs2−/−mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.
Phase coupling and synchrony in the spatiotemporal dynamics of muskrat and mink populations across Canada
Authors: Haydon D. T. , Stenseth N. C. , Boyce M. S. , Greenwood P. E.
Published: July 2002

Population ecologists have traditionally focused on the patterns and causes of population variation in the temporal domain for which a substantial body of practical analytic techniques have been developed. More recently, numerous studies have documented how populations may fluctuate synchronously over large spatial areas; analyses of such spatially extended time-series have started to provide additional clues regarding the causes of these population fluctuations and explanations for their synchronous occurrence. Here, we report on the development of a phase-based method for identifying coupling between temporally coincident but spatially distributed cyclic time-series, which we apply to the numbers of muskrat and mink recorded at 81 locations across Canada. The analysis reveals remarkable parallel clines in the strength of coupling between proximate populations of both species—declining from west to east—together with a corresponding increase in observed synchrony between these populations the further east they are located.
A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell
Authors: Rich Thomas C. , Fagan Kent A. , Tse Tonia E. , Schaack Jerome , Cooper Dermot M. F. , Karpen Jeffrey W.
Published: July 2002

cAMP, the classical second messenger, regulates many diverse cellular functions. The primary effector of cAMP signals, protein kinase A, differentially phosphorylates hundreds of cellular targets. Little is known, however, about the spatial and temporal nature of cAMP signals and their information content. Thus, it is largely unclear how cAMP, in response to different stimuli, orchestrates such a wide variety of cellular responses. Previously, we presented evidence that cAMP is produced in subcellular compartments near the plasma membrane, and that diffusion of cAMP from these compartments to the bulk cytosol is hindered. Here we report that a uniform extracellular stimulus initiates distinct cAMP signals within different cellular compartments. By using cyclic nucleotide-gated ion channels engineered as cAMP biosensors, we found that prostaglandin E
1
stimulation of human embryonic kidney cells caused a transient increase in cAMP concentration near the membrane. Interestingly, in the same time frame, the total cellular cAMP rose to a steady level. The decline in cAMP levels near the membrane was prevented by pretreatment with phosphodiesterase inhibitors. These data demonstrate that spatially and temporally distinct cAMP signals can coexist within simple cells.
The SOCS box of suppressor of cytokine signaling-1 is important for inhibition of cytokine action
in
vivo
Authors: Zhang Jian-Guo , Metcalf Donald , Rakar Steven , Asimakis Maria , Greenhalgh Christopher J. , Willson Tracy A. , Starr Robyn , Nicholson Sandra E. , Carter Wendy , Alexander Warren S. , Hilton Douglas J. , Nicola Nicos A.
Published: July 2002

Suppressor of Cytokine Signaling-1 (SOCS-1) is an essential physiological inhibitor of IFN-γ signaling. Mice lacking this gene die in the early postnatal period from a disease characterized by hyperresponsiveness to endogenous IFN-γ. The SOCS box is a C-terminal domain shared with over 30 other proteins that links SOCS proteins to an E3 ubiquitin ligase activity and the proteasome, but whether it contributes to inhibition of cytokine signaling is currently disputed. We have deleted only the SOCS box of the SOCS-1 gene in mice and show that such mice have an increased responsiveness to IFN-γ and slowly develop a fatal inflammatory disease. These results demonstrate that deletion of the SOCS box leads to a partial loss of function of SOCS-1.
Postnatal human dental pulp stem cells (DPSCs)
in vitro
and
in
vivo
Authors: Gronthos S. , Mankani M. , Brahim J. , Robey P. Gehron , Shi S.
Published: July 2002

Dentinal repair in the postnatal organism occurs through the
activity of specialized cells, odontoblasts, that are thought to be
maintained by an as yet undefined precursor population associated with
pulp tissue. In this study, we isolated a clonogenic, rapidly
proliferative population of cells from adult human dental pulp. These
DPSCs were then compared with human bone marrow stromal cells (BMSCs),
known precursors of osteoblasts. Although they share a similar
immunophenotype
in vitro
, functional studies showed that
DPSCs produced only sporadic, but densely calcified nodules, and did
not form adipocytes, whereas BMSCs routinely calcified throughout the
adherent cell layer with clusters of lipid-laden adipocytes. When DPSCs
were transplanted into immunocompromised mice, they generated a
dentin-like structure lined with human odontoblast-like cells that
surrounded a pulp-like interstitial tissue. In contrast, BMSCs formed
lamellar bone containing osteocytes and surface-lining osteoblasts,
surrounding a fibrous vascular tissue with active hematopoiesis and
adipocytes. This study isolates postnatal human DPSCs that have the
ability to form a dentin/pulp-like complex.
The role of prefrontal cortex and posterior parietal cortex in task switching
Authors: Sohn Myeong-Ho , Ursu Stefan , Anderson John R. , Stenger V. Andrew , Carter Cameron S.
Published: July 2002

Human ability to switch from one cognitive task to another involves
both endogenous preparation without an external stimulus
and exogenous adjustment in response to the external stimulus. In an
event-related functional MRI study, participants performed pairs of two
tasks that are either the same (task repetition) or different (task
switch) from each other. On half of the trials, foreknowledge about
task repetition or task switch was available. On the other half, it was
not. Endogenous preparation seems to involve lateral
prefrontal cortex (BA 46/45) and posterior parietal cortex (BA 40).
During preparation, higher activation increases in inferior lateral
prefrontal cortex and superior posterior parietal cortex were
associated with foreknowledge than with no foreknowledge. Exogenous
adjustment seems to involve superior prefrontal cortex (BA 8) and
posterior parietal cortex (BA 39/40) in general. During a task switch
with no foreknowledge, activations in these areas were relatively
higher than during a task repetition with no foreknowledge. These
results suggest that endogenous preparation and exogenous
adjustment for a task switch may be independent processes involving
different brain areas.
Dissociation in human prefrontal cortex of affective influences on working memory-related activity
Authors: Perlstein William M. , Elbert Thomas , Stenger V. Andrew
Published: July 2002

Although neural activity associated with emotion is becoming better understood, the influence of affective parameters on brain activity reflecting cognitive functioning in humans remains poorly characterized. We examined affective influences on working memory (WM) and tested the hypotheses that (i) dorsolateral prefrontal cortex (DLPFC) activity reflecting WM is influenced by the emotion-evoking qualities of task-relevant stimuli, but only when brought “on-line” by task demands, and (ii) DLPFC and orbitofrontal cortex (OFC) activities are inversely related as a function of emotional valence. Participants performed two tasks while event-related functional MRI measured brain activity; one task required active maintenance of stimulus representations in WM, and the other task required target detection responses with no demand for WM. Stimuli were standardized emotional (pleasant and unpleasant) and neutral pictures. Emotional stimuli differentially influenced DPFC and OFC activity during WM; DLPFC was influenced by emotional valence, enhanced by pleasant and reduced by unpleasant, compared to neutral stimuli, only when task conditions required WM. OFC was valence-sensitive during both tasks, greater to arousing than neutral stimuli when WM demand was low and in inverse relationship to DLPFC with high WM demand. Further, DLPFC and OFC activities are inversely related with respect to emotional valence during the WM task. The results are consistent with the hypothesis that the intrinsic valence of task-relevant stimuli maintained in WM modulates DLPFC activity but only when the DLPFC is required for task demands. Findings suggest a conceptualization of DLPFC and its involvement in WM that takes into account a role for affective parameters.
Global structure and mechanical properties of a 10-bp nucleosome positioning motif
Authors: Roychoudhury M. , Sitlani A. , Lapham J. , Crothers D. M.
Published: July 2002

The method of DNA cyclization kinetics reveals special properties
of the TATAAACGCC sequence motif found in DNA sequences that have high
affinity for core histones. Replacement of 30 bp of generic DNA by
three 10-bp repeats of the motif in small cyclization constructs
increases cyclization rates by two orders of magnitude. We document a
13° bend in the motif and characterize the direction of curvature.
The bending force constant is smaller by nearly 2-fold and there is a
35% decrease in the twist modulus, relative to generic DNA. These
features are the likely source of the high affinity for bending around
core histones to form nucleosomes. Our results establish a protocol for
determination of the ensemble-averaged global solution structure and
mechanical properties of any ≈10-bp DNA sequence element of interest,
providing information complementary to that from NMR and
crystallographic structural studies.
The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors
Authors: Ozinsky Adrian , Underhill David M. , Fontenot Jason D. , Hajjar Adeline M. , Smith Kelly D. , Wilson Christopher B. , Schroeder Lea , Aderem Alan
Published: July 2002

Toll-like receptors (TLRs) have been shown to participate in the recognition of pathogens by the innate immune system, but it is not clear how a restricted family of receptors has the capacity to recognize the wide spectrum of TLR stimuli known to exist. We report here that two members of the TLR family, TLR2 and TLR6, together coordinate macrophage activation by Gram-positive bacteria and the yeast cell-wall particle, zymosan. TLR6 and TLR2 both are recruited to the macrophage phagosome, where they recognize peptidoglycan, a Gram-positive pathogen component. By contrast, TLR2 recognizes another component, bacterial lipopeptide, without TLR6. The requirement for TLR cooperation is supported by the finding that TLR2 needs a partner to activate tumor necrosis factor-α production in macrophages. Dimerization of the cytoplasmic domain of TLR2 does not induce tumor necrosis factor-α production in macrophages, whereas similar dimerization of the TLR4 cytoplasmic domain does. We show that the cytoplasmic domain of TLR2 can form functional pairs with TLR6 or TLR1, and this interaction leads to cytokine induction. Thus, the cytoplasmic tails of TLRs are not functionally equivalent, with certain TLRs requiring assembly into heteromeric complexes, whereas others are active as homomeric complexes. Finally, we show that TLR6, TLR2, and TLR1 are recruited to macrophage phagosomes that contain IgG-coated erythrocytes that do not display microbial components. The data suggest that TLRs sample the contents of the phagosome independent of the nature of the contents, and can establish a combinatorial repertoire to discriminate among the large number of pathogen-associated molecular patterns found in nature.
Structural characterization of the human respiratory syncytial virus fusion protein core
Authors: Zhao Xun , Singh Mona , Malashkevich Vladimir N. , Kim Peter S.
Published: July 2002

Human respiratory syncytial virus (HRSV) is a major cause of a
number of severe respiratory diseases, including bronchiolitis and
pneumonia, in infants and young children. The HRSV F protein, a
glycoprotein essential for viral entry, is a primary target for vaccine
and drug development. Two heptad-repeat regions within the HRSV F
sequence were predicted by the computer program
learncoil-vmf
. These regions are thought to form
trimer-of-hairpins–like structures, similar to those found in the
fusion proteins of several enveloped viruses. The hairpin structure
likely brings the viral and cellular membranes into close apposition,
thereby facilitating membrane fusion and subsequent viral entry. Here,
we show that peptides, denoted HR-N and HR-C, corresponding to the
heptad-repeat regions from the N-terminal and C-terminal segments of
the HRSV F protein, respectively, form a stable α-helical trimer of
heterodimers. The HRSV N/C complex was crystallized and its x-ray
structure was determined at 2.3-Å resolution. As anticipated, the
complex is a six-helix bundle in which the HR-N peptides form a
three-stranded, central coiled coil, and the HR-C peptides pack in an
antiparallel manner into hydrophobic grooves on the coiled-coil
surface. There is remarkable structural similarity between the HRSV
N/C complex and the fusion protein core of other viruses, including
HIV-1 gp41. In addition, earlier work has shown that HRSV HR-C
peptides, like the HIV-1 gp41 C peptides, inhibit viral infection.
Thus, drug discovery and vaccine development strategies aimed at
inhibiting viral entry by blocking hairpin formation may be applied to
the inhibition of HRSV.
Vip3A, a novel Bacillus thuringiensis vegetative insecticidal protein with a wide spectrum of activities against lepidopteran insects.
Authors: Estruch J J , Warren G W , Mullins M A , Nye G J , Craig J A , Koziel M G
Published: July 2002

A novel vegetative insecticidal gene, vip3A(a), whose gene product shows activity against lepidopteran insect larvae including black cutworm (Agrotis ipsilon), fall armyworm (Spodoptera frugiperda), beet armyworm (Spodoptera exigua), tobacco budworm (Heliothis virescens), and corn earworm (Helicoverpa zea) has been isolated from Bacillus thuringiensis strain AB88. VIP3-insecticidal gene homologues have been detected in approximately 15% of Bacillus strains analyzed. The sequence of the vip3A(b) gene, a homologue of vip3A(a) isolated from B. thuringiensis strain AB424 is also reported. Vip3A(a) and (b) proteins confer upon Escherichia coli insecticidal activity against the lepidopteran insect larvae mentioned above. The sequence of the gene predicts a 791-amino acid (88.5 kDa) protein that contains no homology with known proteins. Vip3A insecticidal proteins are secreted without N-terminal processing. Unlike the B. thuringiensis 5-endotoxins, whose expression is restricted to sporulation, Vip3A insecticidal proteins are expressed in the vegetative stage of growth starting at mid-log phase as well as during sporulation. Vip3A represents a novel class of proteins insecticidal to lepidopteran insect larvae.
Cholesterol starvation induces differentiation of the intestinal parasite Giardia lamblia.
Authors: Luján H D , Mowatt M R , Byrd L G , Nash T E
Published: July 2002

Giardia lamblia, like most human intestinal parasitic protozoa, sustains fundamental morphological and biochemical changes to survive outside the small intestine of its mammalian host by differentiating into an infective cyst. However, the stimulus that triggers this differentiation remains totally undefined. In this work, we demonstrate the induction of cyst formation in vitro when trophozoites are starved for cholesterol. Expression of cyst wall proteins was detected within encystation-specific secretory vesicles 90 min after the cells were placed in lipoprotein-deficient TYI-S-33 medium. Four cloned lines derived from two independent Giardia isolates were tested, and all formed cysts similarly. Addition of cholesterol, low density or very low density lipoproteins to the lipoprotein-deficient culture medium, inhibited the expression of cyst wall proteins, the generation of encystation-specific vesicles, and cyst wall biogenesis. In contrast, high density lipoproteins, phospholipids, bile salts, or fatty acids had little or no effect. These results indicate that cholesterol starvation is necessary and sufficient for the stimulation of Giardia encystation in vitro and, likely, in the intestine of mammalian hosts.
Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.
Authors: Ragsdale D S , McPhee J C , Scheuer T , Catterall W A
Published: July 2002

Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage- and frequency-dependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel alpha subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ia and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2- to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.
Phosphate transporters from the higher plant Arabidopsis thaliana.
Authors: Muchhal U S , Pardo J M , Raghothama K G
Published: July 2002

Two cDNAs (AtPT1 and AtPT2) encoding plant phosphate transporters have been isolated from a library prepared with mRNA extracted from phosphate-starved Arabidopsis thaliana roots, The encoded polypeptides are 78% identical to each other and show high degree of amino acid sequence similarity with high-affinity phosphate transporters of Saccharomyces cerevisiae, Neurospora crassa, and the mycorrhizal fungus Glomus versiforme. The AtPT1 and AtPT2 polypeptides are integral membrane proteins predicted to contain 12 membrane-spanning domains separated into two groups of six by a large charged hydrophilic region. Upon expression, both AtPT1 and AtPT2 were able to complement the pho84 mutant phenotype of yeast strain NS219 lacking the high-affinity phosphate transport activity. AtPT1 and AtPT2 are representatives of two distinct, small gene families in A. thaliana. The transcripts of both genes are expressed in roots and are not detectable in leaves. The steady-state level of their mRNAs increases in response to phosphate starvation.
Multilocus DNA fingerprinting reveals high rate of heritable genetic mutation in herring gulls nesting in an industrialized urban site.
Authors: Yauk C L , Quinn J S
Published: July 2002

Genotoxins, such as polycyclic aromatic compounds, are ubiquitous in urban and industrial environments. Our understanding of the role that these chemicals play in generating DNA sequence mutations is predominantly derived from laboratory studies with specific genotoxins or extracts of contaminants from environmental media. Most assays are not indicative of the germinal effects of exposure in situ to complex mixtures of common environmental mutagens. Using multilocus DNA fingerprinting, we found the mutation rate in herring gulls inhabiting a heavily industrialized urban harbor (Hamilton Harbour, Ontario) to be more than twice as high as three rural sites: Kent Island, Bay of Fundy; Chantry Island, Lake Huron; and Presqu'ile Provincial Park in Lake Ontario. Overall we found a mutation rate of 0.017 +/- 0.004 per offspring band in Hamilton, 0.006 +/- 0.002 at Kent Island, 0.002 +/- 0.002 from Chantry Island, and 0.004 +/- 0.002 from Presqu'ile Provincial Park. The mutation rate from the rural sites (pooled) was significantly lower than the rate observed in Hamilton Harbour (Fisher's exact test, two-tailed; P = 0.0006). These minisatellite DNA mutations may be important biomarkers for heritable genetic changes resulting from in situ exposure to environmental genotoxins in a free-living vertebrate species.
Mutants in the Exo I motif of Escherichia coli dnaQ: defective proofreading and inviability due to error catastrophe.
Authors: Fijalkowska I J , Schaaper R M
Published: July 2002

The Escherichia coli dnaQ gene encodes the proofreading 3' exonuclease (epsilon subunit) of DNA polymerase III holoenzyme and is a critical determinant of chromosomal replication fidelity. We constructed by site-specific mutagenesis a mutant, dnaQ926, by changing two conserved amino acid residues (Asp-12-->Ala and Glu-14-->Ala) in the Exo I motif, which, by analogy to other proofreading exonucleases, is essential for the catalytic activity. When residing on a plasmid, dnaQ926 confers a strong, dominant mutator phenotype, suggesting that the protein, although deficient in exonuclease activity, still binds to the polymerase subunit (alpha subunit or dnaE gene product). When dnaQ926 was transferred to the chromosome, replacing the wild-type gene, the cells became inviable. However, viable dnaQ926 strains could be obtained if they contained one of the dnaE alleles previously characterized in our laboratory as antimutator alleles or if it carried a multicopy plasmid containing the E. coli mutL+ gene. These results suggest that loss of proofreading exonuclease activity in dnaQ926 is lethal due to excessive error rates (error catastrophe). Error catastrophe results from both the loss of proofreading and the subsequent saturation of DNA mismatch repair. The probability of lethality by excessive mutation is supported by calculations estimating the number of inactivating mutations in essential genes per chromosome replication.
Heterogeneities in the transmission of infectious agents: Implications for the design of control programs
Authors: Woolhouse M. E. J. , Dye C. , Etard J.-F. , Smith T. , Charlwood J. D. , Garnett G. P. , Hagan P. , Hii J. L. K. , Ndhlovu P. D. , Quinnell R. J. , Watts C. H. , Chandiwana S. K. , Anderson R. M.
Published: July 2002

From an analysis of the distributions of measures of transmission rates among hosts, we identify an empirical relationship suggesting that, typically, 20% of the host population contributes at least 80% of the net transmission potential, as measured by the basic reproduction number,R0. This is an example of a statistical pattern known as the 20/80 rule. The rule applies to a variety of disease systems, including vector-borne parasites and sexually transmitted pathogens. The rule implies that control programs targeted at the “core” 20% group are potentially highly effective and, conversely, that programs that fail to reach all of this group will be much less effective than expected in reducing levels of infection in the population as a whole.
Differences between males and females in rates of serotonin synthesis in human brain
Authors: Nishizawa S. , Benkelfat C. , Young S. N. , Leyton M. , Mzengeza S. , de Montigny C. , Blier P. , Diksic M.
Published: July 2002

Rates of serotonin synthesis were measured in the human brain using positron emission tomography. The sensitivity of the method is indicated by the fact that measurements are possible even after a substantial lowering of synthesis induced by acute tryptophan depletion. Unlike serotonin levels in human brain, which vary greatly in different brain areas, rates of synthesis of the indolamine are rather uniform throughout the brain. The mean rate of synthesis in normal males was found to be 52% higher than in normal females; this marked difference may be a factor relevant to the lower incidence of major unipolar depression in males.
Evolution of plastid generps2in a lineage of hemiparasitic and holoparasitic plants: Many losses of photosynthesis and complex patterns of rate variation
Authors: dePamphilis Claude W. , Young Nelson D. , Wolfe Andrea D.
Published: July 2002

The plastid genomes of some nonphotosynthetic parasitic plants have experienced an extreme reduction in gene content and an increase in evolutionary rate of remaining genes. Nothing is known of the dynamics of these events or whether either is a direct outcome of the loss of photosynthesis. The parasitic Scrophulariaceae and Orobanchaceae, representing a continuum of heterotrophic ability ranging from photosynthetic hemiparasites to nonphotosynthetic holoparasites, are used to investigate these issues. We present a phylogenetic hypothesis for parasitic Scrophulariaceae and Orobanchaceae based on sequences of the plastid generps2, encoding the S2 subunit of the plastid ribosome. Parasitic Scrophulariaceae and Orobanchaceae form a monophyletic group in which parasitism can be inferred to have evolved once. Holoparasitism has evolved independently at least five times, with certain holoparasitic lineages representing single species, genera, and collections of nonphotosynthetic genera. Evolutionary loss of the photosynthetic generbcLis limited to a subset of holoparasitic lineages, with several holoparasites retaining a full lengthrbcLsequence. In contrast, the translational generps2is retained in all plants investigated but has experienced rate accelerations in several hemi- as well as holoparasitic lineages, suggesting that there may be substantial molecular evolutionary changes to the plastid genome of parasites before the loss of photosynthesis. Independent patterns of synonymous and nonsynonymous rate acceleration inrps2point to distinct mechanisms underlying rate variation in different lineages. Parasitic Scrophulariaceae (including the traditional Orobanchaceae) provide a rich platform for the investigation of molecular evolutionary process, gene function, and the evolution of parasitism.
HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway
Authors: Gallay Philippe , Hope Thomas , Chin Daniel , Trono Didier
Published: July 2002

The karyophilic properties of the HIV-1 nucleoprotein complex facilitate infection of nondividing cells such as macrophages and quiescent T lymphocytes, and allow the
in vivo
delivery of transgenes by HIV-derived retroviral vectors into terminally differentiated cells such as neurons. Although the viral matrix (MA) and Vpr proteins have previously been shown to play important roles in this process, we demonstrate here that integrase, the enzyme responsible for mediating the integration of the viral genome in the host cell chromosome, can suffice to connect the HIV-1 preintegration complex with the cell nuclear import machinery. This novel function of integrase reflects the recognition of an atypical bipartite nuclear localization signal by the importin/karyopherin pathway.
Interleukin 9: A candidate gene for asthma
Authors: Nicolaides Nicholas C. , Holroyd Kenneth J. , Ewart Susan L. , Eleff Scott M. , Kiser Matthew B. , Dragwa Carl R. , Sullivan Christine D. , Grasso Luigi , Zhang Liu-Yi , Messler Carol J. , Zhou Tingyi , Kleeberger Steven R. , Buetow Kenneth H. , Levitt Roy C.
Published: July 2002

Asthma is a complex heritable inflammatory disorder of the airways associated with clinical signs of atopy and bronchial hyperresponsiveness. Recent studies localized a major gene for asthma to chromosome 5q31-q33 in humans. Thus, this segment of the genome represents a candidate region for genes that determine susceptibility to bronchial hyperresponsiveness and atopy in animal models. Homologs of candidate genes on human chromosome 5q31-q33 are found in four regions in the mouse genome, two on chromosome 18, and one each on chromosomes 11 and 13. We assessed bronchial responsiveness as a quantitative trait in mice and found it linked to chromosome 13. Interleukin 9 (IL-9) is located in the linked region and was analyzed as a gene candidate. The expression of IL-9 was markedly reduced in bronchial hyporesponsive mice, and the level of expression was determined by sequences within the qualitative trait locus (QTL). These data suggest a role for IL-9 in the complex pathogenesis of bronchial hyperresponsiveness as a risk factor for asthma.
Geometries of knowledge
Authors: Grenander Ulf
Published: July 2002

It is argued that knowledge representations formalized through pattern theoretic structures are geometric in nature in the following sense. The configurations and resulting patterns appearing in such representations exhibit invariances with respect to the similarity groups and are characterized topologically through their connection types. Starting with a special pattern from microbiology, it is shown how the basic pattern theoretic concepts are introduced in general and what their function is in representing knowledge. Variance/invariance of the patterns is discussed in geometric language. The measures on the configuration spaces are implemented by difference/differential equations which are used as a basis for computer algorithms.
Initiation of liver growth by tumor necrosis factor: Deficient liver regeneration in mice lacking type I tumor necrosis factor receptor
Authors: Yamada Yasuhiro , Kirillova Irina , Peschon Jacques J. , Fausto Nelson
Published: July 2002

The mechanisms that initiate liver regeneration after resection of
liver tissue are not known. To determine whether cytokines are involved
in the initiation of liver growth, we studied the regeneration of the
liver after partial hepatectomy (PH) in mice lacking type I tumor
necrosis factor receptor (TNFR-I). DNA synthesis after PH was severely
impaired in these animals, and the expected increases in the binding of
the NF-κB and STAT3 transcription factors shortly after PH failed to
occur. Binding of AP-1 after PH was decreased in TNFR-I knockout mice
compared with animals with the intact receptor whereas C/EBP binding
was not modified. Injection of interleukin 6 in TNFR-I-deficient
animals 30 min before PH corrected the defect in DNA synthesis and
restored STAT3 and AP-1 binding to normal levels but had no effect on
NF-κB binding in the regenerating liver. The results indicate that
TNF, signaling through the TNFR-I, can initiate liver regeneration and
acts by activating an interleukin 6-dependent pathway that involves the
STAT3 transcription factor.
The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage
Authors: Brown Kevin D. , Ziv Yael , Sadanandan Sunanda N. , Chessa Luciana , Collins Francis S. , Shiloh Yosef , Tagle Danilo A.
Published: July 2002

The product of the ataxia-telangiectasia gene (
ATM
) was identified by using an antiserum developed to a peptide corresponding to the deduced amino acid sequence. The ATM protein is a single, high-molecular weight protein predominantly confined to the nucleus of human fibroblasts, but is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes. ATM protein levels and localization remain constant throughout all stages of the cell cycle. Truncated ATM protein was not detected in lymphoblasts from ataxia-telangiectasia patients homozygous for mutations leading to premature protein termination. Exposure of normal human cells to γ-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 levels over the same time interval. These findings are consistent with a role for the ATM protein in ensuring the fidelity of DNA repair and cell cycle regulation following genome damage.
Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development
Authors: Liu Xin , Wu Hong , Byrne Michael , Krane Stephen , Jaenisch Rudolf
Published: July 2002

Type III collagen is a fibrillar forming collagen comprising three α1(III) chains and is expressed in early embryos and throughout embryogenesis. In the adult, type III collagen is a major component of the extracellular matrix in a variety of internal organs and skin. Mutations in the COL3A1 gene have been implicated as a cause of type IV Ehlers–Danlos syndrome, a disease leading to aortic rupture in early adult life. To directly study the role of Col3a1 in development and disease, we have inactivated the Col3a1 gene in embryonic stem cells by homologous recombination. The mutated allele was transmitted through the mouse germ line and homozygous mutant animals were derived from heterozygous intercrosses. About 10% of the homozygous mutant animals survived to adulthood but have a much shorter life span compared with wild-type mice. The major cause of death of mutant mice was rupture of the major blood vessels, similar to patients with type IV Ehlers–Danlos syndrome. Ultrastructural analysis of tissues from mutant mice revealed that type III collagen is essential for normal collagen I fibrillogenesis in the cardiovascular system and other organs.
Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH
2
-terminal kinase activation, and defects in AP-1 transcriptional activity
Authors: Yang Di , Tournier Cathy , Wysk Mark , Lu Hong-Tao , Xu Jie , Davis Roger J. , Flavell Richard A.
Published: July 2002

MKK4 is a member of the mitogen-activated protein kinase kinase group of dual specificity protein kinases that functions as an activator of the c-Jun NH
2
-terminal kinase (JNK)
in vitro
. To examine the function of MKK4
in vivo
, we investigated the effect of targeted disruption of the MKK4 gene. Crosses of heterozygous MKK4 (+/−) mice demonstrated that homozygous knockout (−/−) animals die before embryonic day 14, indicating that the MKK4 gene is required for viability. The role of MKK4 in JNK activation was examined by investigation of cultured MKK4 (+/+) and MKK4 (−/−) cells. Disruption of the MKK4 gene blocked JNK activation caused by: (
i
) the mitogen-activated protein kinase kinase kinase MEKK1, and (
ii
) treatment with anisomycin or heat shock. In contrast, JNK activation caused by other forms of environmental stress (UV-C radiation and osmotic shock) was partially inhibited in MKK4 (−/−) cells. Regulated AP-1 transcriptional activity, a target of the JNK signal transduction pathway, was also selectively blocked in MKK4 (−/−) cells. Complementation studies demonstrated that the defective AP-1 transcriptional activity was restored by transfection of MKK4 (−/−) cells with an MKK4 expression vector. These data establish that MKK4 is a JNK activator
in vivo
and demonstrate that MKK4 is an essential component of the JNK signal transduction pathway.
Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs
Authors: Moore Kateri A. , Pytowski Bronislaw , Witte Larry , Hicklin Daniel , Lemischka Ihor R.
Published: July 2002

Primitive hematopoietic stem cells are closely associated with discretein vivomicroenvironments. These “niches” are thought to provide the molecular signals that mediate stem cell differentiation and self-renewal. We have dissected the fetal liver microenvironment into distinct cellular components by establishing an extensive panel of stromal cell lines. One particular cell line maintains repopulating stem cells for prolongedin vitroculture periods. A subtraction cloning strategy has yielded a cDNA that encodes a cell surface glycoprotein with a restricted pattern of expression among stromal cell lines. This molecule, previously identified as delta-like/preadipocyte factor-1, contains epidermal growth factor-like repeats that are related to those in the notch/delta/serrate family of proteins. We have investigated the potential role of this molecule in hematopoietic stem/progenitor cell regulation. We show that the delta-like protein displays activity on purified stem cells by promoting the formation of “cobblestone areas” of proliferation. These cobblestone areas contain both primitive high-proliferative potential progenitors andin vivorepopulating stem cells.
Galaxy formation
Authors: Peebles P. J. E.
Published: July 2002

It is argued that within the standard Big Bang cosmological model
the bulk of the mass of the luminous parts of the large galaxies likely
had been assembled by redshift
z
∼ 10. Galaxy
assembly this early would be difficult to fit in the widely discussed
adiabatic cold dark matter model for structure formation, but it could
agree with an isocurvature version in which the cold dark matter is the
remnant of a massive scalar field frozen (or squeezed) from quantum
fluctuations during inflation. The squeezed field fluctuations would be
Gaussian with zero mean, and the distribution of the field mass
therefore would be the square of a random Gaussian process. This offers
a possibly interesting new direction for the numerical exploration of
models for cosmic structure formation.
The effect of recombinant recoverin on the photoresponse of truncated rod photoreceptors
Authors: Erickson Martha A. , Lagnado Leon , Zozulya Sergey , Neubert Thomas A. , Stryer Lubert , Baylor Denis A.
Published: July 2002

Recoverin is a heterogeneously acylated calcium-binding protein thought to regulate visual transduction. Its effect on the photoresponse was investigated by dialyzing the recombinant protein into truncated salamander rod outer segments. At high Ca
2+
(Ca), myristoylated recoverin (Ca-recoverin) prolonged the recovery phase of the bright flash response but had less effect on the dim flash response. The prolongation of recovery had an apparent
K
d
for Ca of 13 μM and a Hill coefficient of 2. The prolongation was shown to be mediated by inhibition of rhodopsin deactivation. After a sudden imposed drop in Ca concentration, the effect of recoverin switched off with little lag. The myristoyl (C14:0) modification of recoverin increased its activity 12-fold, and the C12:0 or C14:2 acyl group gave similar effects. These experiments support the notion that recoverin mediates Ca-dependent inhibition of rhodopsin phosphorylation and thereby controls light-triggered phosphodiesterase activity, particularly at high light levels.
Temporal dynamics of verbal object comprehension
Authors: Hart John , Crone Nathan E. , Lesser Ronald P. , Sieracki Jeffrey , Miglioretti Diana L. , Hall Charles , Sherman David , Gordon Barry
Published: July 2002

Knowledge of the stage composition and the temporal dynamics of human cognitive operations is critical for building theories of higher mental activity. This information has been difficult to acquire, even with different combinations of techniques such as refined behavioral testing, electrical recording/interference, and metabolic imaging studies. Verbal object comprehension was studied herein in a single individual, by using three tasks (object naming, auditory word comprehension, and visual word comprehension), two languages (English and Farsi), and four techniques (stimulus manipulation, direct cortical electrical interference, electrocorticography, and a variation of the technique of direct cortical electrical interference to produce time-delimited effects, called timeslicing), in a subject in whom indwelling subdural electrode arrays had been placed for clinical purposes. Electrical interference at a pair of electrodes on the left lateral occipitotemporal gyrus interfered with naming in both languages and with comprehension in the language tested (English). The naming and comprehension deficit resulted from interference with processing of verbal object meaning. Electrocorticography indices of cortical activation at this site during naming started 250–300 msec after visual stimulus presentation. By using the timeslicing technique, which varies the onset of electrical interference relative to the behavioral task, we found that completion of processing for verbal object meaning varied from 450 to 750 msec after current onset. This variability was found to be a function of the subject’s familiarity with the objects.
NEEDLY
, a
Pinus radiata
ortholog of
FLORICAULA/LEAFY
genes, expressed in both reproductive and vegetative meristems
Authors: Mouradov Aidyn , Glassick Tina , Hamdorf Britt , Murphy Lawrence , Fowler Beth , Marla Soma , Teasdale Robert D.
Published: July 2002

The
LEAFY/FLORICAULA
genes from
Arabidopsis
and
Antirrhinum
are necessary for normal flower development and play a key role in diverse angiosperm species. A homologue of these flower meristem-identity genes,
NEEDLY
(
NLY
), has been identified in
Pinus radiata
. Although the NLY protein shares extensive sequence similarity with its angiosperm counterparts, it is lacking the proline-rich and acidic motifs thought to function as transcriptional activation domains.
NLY
already is expressed during vegetative development at least 5 years before the transition to the reproductive phase. Expression of
NLY
in transgenic
Arabidopsis
promotes floral fate, demonstrating that, despite its sequence divergence,
NLY
encodes a functional ortholog of the
FLORICAULA/LEAFY
genes of angiosperms. Expression of the
LFY∷NLY
transgene can largely complement the defects in flower development caused by a severe
lfy
allele.