Differential patterns of multisensory interactions in core and belt areas of human auditory cortex

The auditory cortex is anatomically segregated into a central core and a peripheral belt region, which exhibit differences in preference to bandpassed noise and in temporal patterns of response to acoustic stimuli. While it has been shown that visual stimuli can modify response magnitude in auditory cortex, little is known about differential patterns of multisensory interactions in core and belt. Here, we used functional magnetic resonance imaging and examined the influence of a short visual stimulus presented prior to acoustic stimulation on the spatial pattern of blood oxygen level-dependent signal response in auditory cortex. Consistent with crossmodal inhibition, the light produced a suppression of signal response in a cortical region corresponding to the core. In the surrounding areas corresponding to the belt regions, however, we found an inverse modulation with an increasing signal in centrifugal direction. Our data suggest that crossmodal effects are differentially modulated according to the hierarchical core-belt organization of auditory cortex.

Analysis of gene order data supports vertical inheritance of the leukotoxin operon and genome rearrangements in the 5' flanking region in genus Mannheimia

BACKGROUND: The Mannheimia subclades belong to the same bacterial genus, but have taken divergent paths toward their distinct lifestyles. For example, M. haemolytica + M. glucosida are potential pathogens of the respiratory tract in the mammalian suborder Ruminantia, whereas M. ruminalis, the supposed sister group, lives as a commensal in the ovine rumen. We have tested the hypothesis that vertical inheritance of the leukotoxin (lktCABD) operon has occurred from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades by exploring gene order data. RESULTS: We examined the gene order in the 5' flanking region of the leukotoxin operon and found that the 5' flanking gene strings, hslVU-lapB-artJ-lktC and xylAB-lktC, are peculiar to M. haemolytica + M. glucosida and M. granulomatis, respectively, whereas the gene string hslVU-lapB-lktC is present in M. ruminalis, the supposed sister group of M. haemolytica + M. glucosida, and in the most ancient subclade M. varigena. In M. granulomatis, we found remnants of the gene string hslVU-lapB-lktC in the xylB-lktC intergenic region. CONCLUSION: These observations indicate that the gene string hslVU-lapB-lktC is more ancient than the hslVU-lapB-artJ-lktC and xylAB-lktC gene strings. The presence of (remnants of) the ancient gene string hslVU-lapB-lktC among any subclades within genus Mannheimia supports that it has been vertically inherited from the last common ancestor of genus Mannheimia to any ancestor of the diverging subclades, thus reaffirming the hypothesis of vertical inheritance of the leukotoxin operon. The presence of individual 5' flanking regions in M. haemolytica + M. glucosida and M. granulomatis reflects later genome rearrangements within each subclade. The evolution of the novel 5' flanking region in M. haemolytica + M. glucosida resulted in transcriptional coupling between the divergently arranged artJ and lkt promoters. We propose that the chimeric promoter have led to high level expression of the leukotoxin operon which could explain the increased potential of certain M. haemolytica + M. glucosida strains to cause a particular type of infection.

Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity

Reduced activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) plays a role in essential hypertension and the sensitivity of blood pressure to dietary salt. Nonconservative mutations in the coding region are extremely rare and do not explain the variable 11beta-HSD2 activity. We focused therefore on the 5'-regulatory region and identified and characterized the first promoter polymorphisms. Transfections of variants G-209A and G-126A into SW620 cells reduced promoter activity and affinity for activators nuclear factor 1 (NF1) and Sp1. Chromatin immunoprecipitation revealed Sp1, NF1, and glucocorticoid receptor (GR) binding to the HSD11B2 promoter. Dexamethasone induced expression of mRNA and activity of HSD11B2. GR and/or NF1 overexpression increased endogenous HSD11B2 mRNA and activity. GR complexes cooperated with NF1 to activate HSD11B2, an effect diminished in the presence of the G-209A variant. When compared to salt-resistant subjects (96), salt-sensitive volunteers (54) more frequently had the G-209A variant, higher occurrence of alleles A4/A7 of polymorphic microsatellite marker, and higher urinary ratios of cortisol to cortisone metabolites. First, we conclude that the mechanism of glucocorticoid-induced HSD11B2 expression is mainly mediated by cooperation between GR and NF1 on the HSD11B2 promoter and, second, that the newly identified promoter variants reduce activity and cooperation of cognate transcription factors, resulting in diminished HSD11B2 transcription, an effect favoring salt sensitivity.

The Southern Hemisphere at glacial terminations: insights from the Dome C ice core

The many different proxy records from the European Project for Ice Coring in Antarctica (EPICA) Dome C ice core allow for the first time a comparison of nine glacial terminations in great detail. Despite the fact that all terminations cover the transition from a glacial maximum into an interglacial, there are large differences between single terminations. For some terminations, Antarctic temperature increased only moderately, while for others, the amplitude of change at the termination was much larger. For the different terminations, the rate of change in temperature is more similar than the magnitude or duration of change. These temperature changes were accompanied by vast changes in dust and sea salt deposition all over Antarctica. Here we investigate the phasing between a South American dust proxy (non-sea-salt calcium flux, nssCa2+), a sea ice proxy (sea salt sodium flux, ssNa+) and a proxy for Antarctic temperature (deuterium, δD). In particular, we look into whether a similar sequence of events applies to all terminations, despite their different characteristics. All proxies are derived from the EPICA Dome C ice core, resulting in a relative dating uncertainty between the proxies of less than 20 years. At the start of the terminations, the temperature (δD) increase and dust (nssCa2+ flux) decrease start synchronously. The sea ice proxy (ssNa+ flux), however, only changes once the temperature has reached a particular threshold, approximately 5°C below present day temperatures (corresponding to a δD value of −420‰). This reflects to a large extent the limited sensitivity of the sea ice proxy during very cold periods with large sea ice extent. At terminations where this threshold is not reached (TVI, TVIII), ssNa+ flux shows no changes. Above this threshold, the sea ice proxy is closely coupled to the Antarctic temperature, and interglacial levels are reached at the same time for both ssNa+ and δD. On the other hand, once another threshold at approximately 2°C below present day temperature is passed (corresponding to a δD value of −402‰), nssCa2+ flux has reached interglacial levels and does not change any more, despite further warming. This threshold behaviour most likely results from a combination of changes to the threshold friction velocity for dust entrainment and to the distribution of surface wind speeds in the dust source region.

Climatic and environmental changes during the Weichselian Lateglacial Interstadial in the Weerterbos region, the Netherlands

Lake sediment records from the Weerterbos region, in the southern Netherlands, were studied to reconstruct summer temperature and environmental changes during the Weichselian Lateglacial Interstadial. A sediment core obtained from a small lacustrine basin was analysed for multiple proxies, including lithological changes, oxygen isotopes of bulk carbonates, pollen and chironomids. It was found that the oxygen isotope record differed strongly from the other proxies. Based on a comparison with three additional lake sediment records from the same region, it emerged that the oxygen isotope records were strongly affected by local environmental conditions, impeding the distinction of a regional palaeoclimate signal. The chironomid-inferred July air temperature reconstruction produced inferred interstadial temperatures ranging between ∼15° and 18°C, largely consistent with previously published results from the northern part of the Netherlands. A temporary regressive phase in the pollen record, which can be tentatively correlated with the Older Dryas, preceded the expansion of birch woodland. Despite differences between the four pollen records from the Weerterbos region, a comparable regressive vegetation phase that was possibly the result of a shift to drier conditions could be discerned in all of the profiles. In addition, a temporary temperature decline of ∼1.5°C was inferred from the chironomid record during this regressive phase. The multi-proxy approach used here enabled a direct comparison of inferred changes in temperature, vegetation and environmental conditions at an individual site, while the multi-site approach provided insight into the factors influencing the pollen and isotope records from these small-scale depressions.

High-resolution mineral dust and sea ice proxy records from the Talos Dome ice core

In this study we report on new non-sea salt calcium (nssCa2+, mineral dust proxy) and sea salt sodium (ssNa+, sea ice proxy) records along the East Antarctic Talos Dome deep ice core in centennial resolution reaching back 150 thousand years (ka) before present. During glacial conditions nssCa2+ fluxes in Talos Dome are strongly related to temperature as has been observed before in other deep Antarctic ice core records, and has been associated with synchronous changes in the main source region (southern South America) during climate variations in the last glacial. However, during warmer climate conditions Talos Dome mineral dust input is clearly elevated compared to other records mainly due to the contribution of additional local dust sources in the Ross Sea area. Based on a simple transport model, we compare nssCa2+ fluxes of different East Antarctic ice cores. From this multi-site comparison we conclude that changes in transport efficiency or atmospheric lifetime of dust particles do have a minor effect compared to source strength changes on the large-scale concentration changes observed in Antarctic ice cores during climate variations of the past 150 ka. Our transport model applied on ice core data is further validated by climate model data. The availability of multiple East Antarctic nssCa2+ records also allows for a revision of a former estimate on the atmospheric CO2 sensitivity to reduced dust induced iron fertilisation in the Southern Ocean during the transition from the Last Glacial Maximum to the Holocene (T1). While a former estimate based on the EPICA Dome C (EDC) record only suggested 20 ppm, we find that reduced dust induced iron fertilisation in the Southern Ocean may be responsible for up to 40 ppm of the total atmospheric CO2 increase during T1. During the last interglacial, ssNa+ levels of EDC and EPICA Dronning Maud Land (EDML) are only half of the Holocene levels, in line with higher temperatures during that period, indicating much reduced sea ice extent in the Atlantic as well as the Indian Ocean sector of the Southern Ocean. In contrast, Holocene ssNa+ flux in Talos Dome is about the same as during the last interglacial, indicating that there was similar ice cover present in the Ross Sea area during MIS 5.5 as during the Holocene.

Analysis of a human placental lactogen gene promoter

Human placental lactogen (hPL) and human growth hormone (hGH) comprise a multigene family that share $>$90% nucleic acid sequence homology including 500 bp of 5$\sp\prime$ flanking sequence. Despite these similarities, hGH is produced in the anterior pituitary while hPL is expressed in the placenta. For most genes studied to date, regulation of expression occurs by alterations at the level of transcriptional initiation. Nuclear proteins bind specific DNA sequences in the promoter to regulate gene expression. In this study, the hPL$\sb3$ promoter was analyzed for DNA sequences that contribute to its expression. The interaction between the hPL$\sb3$ promoter and nuclear proteins was examined using nuclear extracts from placental and non-placental cells.^ To identify regulatory elements in the promoter of the hPL$\sb3$ gene, 5$\sp\prime$ deletion mutants were constructed by cleaving 1200 bp of upstream sequence with various restriction enzymes. These DNA fragments were ligated 5$\sp\prime$ to a promoterless bacterial gene chloramphenicol acetyltransferase (CAT) and transfected into JEG-3 cells, a human placental choriocarcinoma cell line. The level of CAT activity reflects the ability of the promoter mutants to activate transcription. Deletion of the sequence between $-$142 bp and $-$129 bp, relative to the start of transcription, resulted in an 8-fold decrease in CAT activity. Nuclear proteins from JEG-3, HeLa, and HepG2 (human liver cells), formed specific binding complexes with this region of the hPL$\sb3$ promoter, as shown by gel mobility shift assay. The $-$142 bp to $-$129 bp region contains a sequence similar to that of a variant binding site for the transcription factor Sp1. Sp1-like proteins were identified by DNA binding assay, in the nuclear extracts of the three cell lines. A series of G nucleotides in the hPL$\sb3$ promoter regulatory region were identified by methylation interference assay to interact with the DNA-binding proteins and the pattern obtained is similar to that for other Sp1 binding sites that have been studied. This suggests that hPL$\sb3$ may be transcriptionally regulated by Sp1 or a Sp1-like transacting factor. ^

Functional characterization of transcription factor USF

USF, Upstream Stimulatory Factor, is a family of ubiquitous transcription factors that contain highly conserved basic helix-loop-helix leucine zipper DNA binding domains and recognize the core DNA sequence CACGTG. In human and mouse, two members of the USF family, USF1 and USF2, encoded by two different genes, contribute to the USF activity. In order to gain insights into the mechanisms by which USFs function as transcriptional activators, different approaches were used to map the domains of USF2 responsible for nuclear localization and transcriptional activation. Two stretches of amino acids, one in the basic region of the DNA binding domain, the other in a highly conserved N-terminal region, were found to direct nuclear localization independently of one another. Two distinct activation domains were also identified. The first one, located in the conserved N-terminal region that overlaps the C-terminal nuclear localization signal, functioned only in the presence of an initiator element in the promoter of the reporter. The second, in a nonconserved region, activated transcription in the absence of an initiator element or when fused to a heterologous DNA binding domain. These results suggest that USF2 functions in different promoter contexts by selectively utilizing different activation domains.^ The deletion analysis of USF2 also identified two dominant negative mutants of USF, one lacking the activation domain, the other lacking the basic domain. The latter proved useful for testing the direct involvement of USFs in the transcriptional activation mediated by the viral protein IE62.^ To investigate the biological function of USFs, foci and colony formation assays were used to study the growth regulation by USFs. It was found that USFs had a strong antagonistic effect on cellular transformation mediated by the bHLH/LZ protein Myc. This effect required the DNA binding activity of either USF 1 or USF2. Moreover, USF2, but not USF1 or other mutants of USFs, was also found to have strong inhibitory effect on the cellular transformation by E1a and on the growth of HeLa cells. These results demonstrate that USFs could potentially regulate growth through two mechanisms, one by antagonizing the function of Myc in cellular transformation, the other by mediating a more general growth inhibitory effect. ^

Human TNF receptor p75/80 gene structure and promoter characterization

Tumor necrosis factor receptor p75/80 ((TNF-R p75/80) is a 75 kDa type 1 transmembrane protein expressed predominately on cells of hematopoietic lineage. TNF-R p75/80 belongs to the TNF receptor superfamily characterized by cysteine-rich extracellular regions composed of three to six disulfide-linked domains. In the present report, we have characterized, for the first time, the complete gene structure for human TNF-R p75/80 which spans approximately 43 kbp. The gene consists of 10 exons (ranging from 34 bp to 2.5 kbp) and 9 introns (343 bp to 19 kbp). Consensus elements for transcription factors involved in T cell development and activation were noted in the 5$\sp\prime$ flanking region including TCF-1, Ikaros, AP-1, CK-2, IL-6RE, ISRE, GAS, NF-$\kappa$B and SP1, as well as an unusually high GC content and CpG frequency that appears characteristic of some TNF-R family members. The unusual (GATA)$\sb{\rm n}$ and (GAA)(GGA) repeats found within intron 1 may prove useful for further genome analysis within the 1p36 chromosomal locus. The human TNF-R p75/80 gene structure will permit further assessment of its involvement in normal hematopoietic cell development and function, autoimmune disease, and non-random translocations in hematopoietic malignancies. The region 1.8 kb 5$\sp\prime$ of the ATG was able to drive luciferase expression when transfected into cell lines expressing TNF-R p75/80. Further characterization of the 5$\sp\prime$-regulatory region will aid in determining factors and signal transduction pathways involved in regulating TNF-R p75/80 expression. ^

The role of the amino terminus of Bacillus subtilis sigmaK in transcription initiation

The sigma (σ) subunit of eubacterial RNA polymerase (RNAP) is required for specific recognition of promoter DNA sequences and transcription initiation. Regulation of bacterial gene expression can be achieved by modulating a factor activity. The Bacillus subtilis sporulation a σ factor, σ K, controls gene expression of the late sporulation regulon. σ K is synthesized as an inactive precursor protein, pro-σ K, with a 20 amino acid pro sequence. Proteolytic processing of the pro sequence produces the active form, σK, which is able to bind to the core subunits of RNAP to direct gene expression. Thus, the pro sequence renders σK inactive in vivo. After processing, the amino terminus of σK consists of region 1.2, which is conserved among various σ factors. To understand the role of the amino terminus of σK, namely the pro sequence and region 1.2, mutagenesis of both regions was pursued. NH 2-terminal truncations of pro-σK were constructed to address how the pro sequence silences σK activity. The work described here shows that the pro sequence inhibits the ability of σ K to associate with the core subunits and that a deletion of only six amino acids of the pro sequence is sufficient to activate pro-σ K for DNA binding and transcription initiation to levels similar to σ K. Additionally, site directed mutagenesis was used to obtain single amino acid substitutions in region 1.2 to address the role of region 1.2 in σ K transcriptional activity. Two mutations were isolated, converting a lysine (K) to an alanine (A) at position three, and an asparagine (N) to a tyrosine (Y) at position five, both of which alter the efficiency of transcription initiation by RNAP containing the mutant σKs. Surprisingly, σ KK3A increased transcript production when compared to wild type. This increase is due to improvement in DNA affinity and increased stability of RNAP-DNA promoter open complexes. σKN5Y showed a decrease in transcription activity that is related to defects in the ability of RNAP to make the transition from the closed to open RNAP-DNA complex. Results of both the pro sequence and region 1.2 analyses indicate that the amino terminus of σK is important for transcription activity and this work adds to the increasing body of evidence that the amino termini of many σ factors modulate transcription initiation by RNAP. ^

Seasonal Deuterium Excess in a Tien Shan Ice Core: Influence of Moisture Transport and Recycling in Central Asia

Stable water isotope (delta(18)O, deltaD) data from a high elevation (5100 masl) ice core recovered from the Tien Shan Mountains, Kyrgyzstan, display a seasonal cycle in deuterium excess (d = deltaD - 8* delta(18)O) related to changes in the regional hydrologic cycle during 1994 - 2000. While there is a strong correlation (r(2) = 0.98) between delta(18)O and dD in the ice core samples, the regression slope (6.9) and mean d value (23.0) are significantly different than the global meteoric water line values. The resulting time-series ice core d profile contains distinct winter maxima and summer minima, with a yearly d amplitude of similar to 15 - 20parts per thousand. Local-scale processes that may affect d values preserved in the ice core are not consistent with the observed seasonal variability. Data from Central Asian monitoring sites in the Global Network of Isotopes in Precipitation (GNIP) have similar seasonal d changes. We suggest that regional-scale hydrological conditions, including seasonal changes in moisture source, transport, and recycling in the Caspian/ Aral Sea region, are responsible for the observed spatial and temporal d variability.

Thermal and Barometric Constraints on the Intrusive and Unroofing History of the Black Mountains: Implications for Timing, Initial Dip, and Kinematics of Detachment Faulting in the Death-Valley Region, California

Unroofing of the Black Mountains, Death Valley, California, has resulted in the exposure of 1.7 Ga crystalline basement, late Precambrian amphibolite facies metasedimentary rocks, and a Tertiary magmatic complex. The Ar-40/Ar-39 cooling ages, obtained from samples collected across the entire length of the range (>55 km), combined with geobarometric results from synextensional intrusions, provide time-depth constraints on the Miocene intrusive history and extensional unroofing of the Black Mountains. Data from the southeastern Black Mountains and adjacent Greenwater Range suggest unroofing from shallow depths between 9 and 10 Ma. To the northwest in the crystalline core of the range, biotite plateau ages from approximately 13 to 6.8 Ma from rocks making up the Death Valley turtlebacks indicate a midcrustal residence (with temperatures >300-degrees-C) prior to extensional unroofing. Biotite Ar-40/Ar-39 ages from both Precambrian basement and Tertiary plutons reveal a diachronous cooling pattern of decreasing ages toward the northwest, subparallel to the regional extension direction. Diachronous cooling was accompanied by dike intrusion which also decreases in age toward the northwest. The cooling age pattern and geobarometric constraints in crystalline rocks of the Black Mountains suggest denudation of 10-15 km along a northwest directed detachment system, consistent with regional reconstructions of Tertiary extension and with unroofing of a northwest deepening crustal section. Mica cooling ages that deviate from the northwest younging trend are consistent with northwestward transport of rocks initially at shallower crustal levels onto deeper levels along splays of the detachment. The well-known Amargosa chaos and perhaps the Badwater turtleback are examples of this "splaying" process. Considering the current distance of the structurally deepest samples away from moderately to steeply east tilted Tertiary strata in the southeastern Black Mountains, these data indicate an average initial dip of the detachment system of the order of 20-degrees, similar to that determined for detachment faults in west central Arizona and southeastern California. Beginning with an initially listric geometry, a pattern of footwall unroofing accompanied by dike intrusion progress northwestward. This pattern may be explained by a model where migration of footwall flexures occur below a scoop-shaped banging wall block. One consequence of this model is that gently dipping ductile fabrics developed in the middle crust steepen in the upper crust during unloading. This process resolves the low initial dips obtained here with mapping which suggests transport of the upper plate on moderately to steeply dipping surfaces in the middle and upper crust.

Oxygen Isotopic and Soluble Ionic Composition of a Shallow Firn Core, Inilchek Glacier, Central Tien Shan

Oxygen isotopic and soluble ionic measurements made on snow-pit (2 in depth) and firn-core (12.4 m depth samples recovered from the accumulation zone 5100 m) of Inilchek glacier 43degrees N, 79degrees E) provide information on recent (1992-98) climatic and environmental conditions in the central Tien Shan region of central Asia. The combined 14.4 m snow-pit/firn-core profile lies within the firn zone, arid contains only one observed melt feature (10 m temperature = - 12 degreesC), Although some post-depositional attenuation of the sub-seasonal delta(18)O record is possible, annual cycles are apparent throughout the isotope profile. We therefore use the preserved delta(18)O record to establish a depth/age scale for the core. Mean delta(18)O values for the entire core and for summer periods are consistent with delta(18)O/temperature observations, and suggest the delta(18)O record provides a means to reconstruct past changes in summer surface temperature at the site. Major-ion (Na(+), K(+), Mg(2+), Ca(2+), NH(4)(+), Cl(-), NO(3)(-), SO(4)(2-)) data from the core demonstrate the dominant influence of dust deposition on the soluble chemistry at the site, arid indicate significant interannual variability in atmospheric-dust loading during the 1900s. Anthropogenic impacts oil NH(4)(+) concentrations are observed at the site, and suggest a summer increase in atmospheric NH(4)(+) that may be related to regional agricultural (nitrogen-rich fertilizer use activities.

Preliminary Results from the Chemical Records of an 80.4 M Ice Core Recovered from East Rongbuk Glacier, Qomolangma (Mount Everest), Himalaya

High-resolution chemical records from an 80.4 m ice core from the central Himalaya demonstrate climatic and environmental changes since 1844. The chronological net accumulation series shows a sharp decrease from the mid-1950s, which is coincident with the widely observed glacier retreat. A negative correlation is found between the ice-core delta(18)O record and the monsoon precipitation for Indian region 7. The temporal variation of the terrestrial ions (Ca2+ and Mg2+) is controlled by both the monsoon precipitation for Indian regions 3,7 and 8, located directly south and west of the Himalaya, and the dust-storm duration and frequency in the northern arid regions, such as the Taklimakan desert, China. The NH4+ profile is fairly flat until the 1940s, then substantially increases until the end of the 1980s, with a slight decrease during the 1990s which may reflect new agricultural practices. The SO42- and NO3- profiles show an apparent increasing trend, especially during the period 1940s-80s. Moreover, SO42- concentrations for the East Rongbuk Glacier core are roughly double that of the nearby Dasuopu core at Xixabangma, Himalaya, due to local human activity including that of climbing teams who use gasoline for cooking, energy and transport.

A 700-Year Record of Atmospheric Circulation Developed from the Law Dome Ice Core, East Antarctica

A 700-year, high-resolution, multivariate ice core record from Dome Summit South (DSS) (66degrees46'S, 112degrees48'E; 1370 m), Law Dome, is used to investigate sea level pressure (SLP) variability in the region of East Antarctica. Empirical orthogonal function (EOF) analysis reveals that the first EOF (LDEOF1) of the combined glaciochemical, oxygen isotope ratio, and accumulation rate record from DSS represents most of the variability in sea salt seen in the record. LDEOF1 is positively correlated (at least 95% confidence level) to instrumental June mean SLP across most of East Antarctica. Over the last 700 years, LDEOF1 levels at Law Dome were the highest during the nineteenth century, suggesting an increase in intensification of winter circulation during this period. The Law Dome DSS oxygen isotope ratio series also indicates that the nineteenth century had the coldest winters of any century in the record. In contrast, LDEOF1 levels were the lowest at Law Dome during the eighteenth century, suggesting a significant shift in the patterns and/or intensity of East Antarctic atmospheric circulation between the eighteenth and the nineteenth centuries. The LDEOF1 sea salt record is characterized by significant decadal-scale variability with a strong 25-year periodic structure.