Genetic assessment of the effects of streamscape succession on coho salmon Oncorhynchus kisutch colonization in recently deglaciated streams.

Measures of genetic diversity within and among populations and historical geomorphological data on stream landscapes were used in model simulations based on approximate Bayesian computation (ABC) to examine hypotheses of the relative importance of stream features (geomorphology and age) associated with colonization events and gene flow for coho salmon Oncorhynchus kisutch breeding in recently deglaciated streams (50-240 years b.p.) in Glacier Bay National Park (GBNP), Alaska. Population estimates of genetic diversity including heterozygosity and allelic richness declined significantly and monotonically from the oldest and largest to youngest and smallest GBNP streams. Interpopulation variance in allele frequency increased with increasing distance between streams (r = 0·435, P < 0·01) and was inversely related to stream age (r = -0·281, P < 0·01). The most supported model of colonization involved ongoing or recent (<10 generations before sampling) colonization originating from large populations outside Glacier Bay proper into all other GBNP streams sampled. Results here show that sustained gene flow from large source populations is important to recently established O. kisutch metapopulations. Studies that document how genetic and demographic characteristics of newly founded populations vary associated with successional changes in stream habitat are of particular importance to and have significant implications for, restoration of declining or repatriation of extirpated populations in other regions of the species' native range.

Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer.

BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer.

Reduced relative fitness in hatchery-origin Pink Salmon in two streams in Prince William Sound, Alaska.

Previous studies generally report that hatchery-origin Pacific Salmon (Oncorhynchus spp.) have lower relative reproductive success (RRS) than their natural-origin counterparts. We estimated the RRS of Pink Salmon (O. gorbuscha) in Prince William Sound (PWS), Alaska using incomplete pedigrees. In contrast to other RRS studies, Pink Salmon have a short freshwater life history, freshwater habitats in PWS are largely unaltered by development, and sampling was conducted without the aid of dams or weirs resulting in incomplete sampling of spawning individuals. Pink Salmon released from large-scale hatchery programs in PWS have interacted with wild populations for more than 15 generations. Hatchery populations were established from PWS populations but have subsequently been managed as separate broodstocks. Gene flow is primarily directional, from hatchery strays to wild populations. We used genetic-based parentage analysis to estimate the RRS of a single generation of stray hatchery-origin Pink Salmon in two streams, and across the odd- and even-year lineages. Despite incomplete sampling, we assigned 1745 offspring to at least one parent. Reproductive success (RS), measured as sampled adult offspring that returned to their natal stream, was significantly lower for hatchery- vs. natural-origin parents in both lineages, with RRS ranging from 0.03 to 0.47 for females and 0.05 to 0.86 for males. Generalized linear modeling for the even-year lineage indicated that RRS was lower for hatchery-origin fish, ranging from 0.42 to 0.60, after accounting for sample date (run timing), sample location within the stream, and fish length. Our results strongly suggest that hatchery-origin strays have lower fitness in the wild. The consequences of reduced RRS on wild productivity depend on whether the mechanisms underlying reduced RRS are environmentally driven, and likely ephemeral, or genetically driven, and likely persistent across generations.

Functional role of exercise-induced cortical organization of sensorimotor cortex after spinal transection.

Spinal cord transection silences neuronal activity in the deafferented cortex to cutaneous stimulation of the body and untreated animals show no improvement in functional outcome (weight-supported stepping) with time after lesion. However, adult rats spinalized since neonates that receive exercise therapy exhibit greater functional recovery and exhibit more cortical reorganization. This suggests that the change in the somatotopic organization of the cortex may be functionally relevant. To address this issue, we chronically implanted arrays of microwire electrodes into the infragranular layers of the hindlimb somatosensory cortex of adult rats neonatally transected at T8/T9 that received exercise training (spinalized rats) and of normal adult rats. Multiple, single neuron activity was recorded during passive sensory stimulation, when the animals were anesthetized, and during active sensorimotor stimulation during treadmill-induced locomotion when the animal was awake and free to move. Our results demonstrate that cortical neurons recorded from the spinalized rats that received exercise 1) had higher spontaneous firing rates, 2) were more likely to respond to both sensory and sensorimotor stimulations of the forelimbs, and also 3) responded with more spikes per stimulus than those recorded from normal rats, suggesting expansion of the forelimb map into the hindlimb map. During treadmill locomotion the activity of neurons recorded from neonatally spinalized rats was greater during weight-supported steps on the treadmill compared with the neuronal activity during nonweight supported steps. We hypothesize that this increased activity is related to the ability of the animal to take weight supported steps and that, therefore, these changes in cortical organization after spinal cord injury are relevant for functional recovery.

Modulation of natural killer cell cytotoxicity and cytokine release by the drug glatiramer acetate.

Glatiramer acetate (GA or Copaxone) is a drug used to treat experimental autoimmune encephalomyelitis in mice and multiple sclerosis in human. Here, we describe a new mechanism of action for this drug. GA enhanced the cytolysis of human NK cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells (DCs). This drug reduced the percentages of mature DCs expressing CD80, CD83, HLA-DR or HLA-I. In contrast, it did not modulate the percentages of NK cells expressing NKG2D, NKp30, or NKp44. Nonetheless, anti-NKp30 or anti-CD86 inhibited GA-enhanced human NK cell lysis of immature DCs. Hence, CD86, and NKp30 are important for NK cell lysis of immature DCs, whereas CD80, CD83, HLA-DR and HLA-I are important for the lysis of mature DCs when GA is used as a stimulus. Further, GA inhibited the release of IFN-gamma 24 h but increased the release of TNF-alpha 48 h after incubation with NK cells.

Early auditory experience aligns the auditory map of space in the optic tectum of the barn owl.

Auditory and visual space are mapped in the optic tectum of the barn owl. Normally, these maps of space are in close mutual alignment. Ear plugs inserted unilaterally in young barn owls disrupted the binaural cues that constitute the basis of the auditory map. Yet when recordings were made from the tecta of these birds as adults, the auditory and visual maps were in register. When the ear plugs were removed from these adult birds and binaural balance was restored, the auditory maps were shifted substantially relative to the visual maps and relative to the physical borders of the tecta. These results demonstrate that the neural connectivity that gives rise to the auditory map of space in the optic tectum can be modified by experience in such a way that spatial alignment between sensory modalities is maintained.

Capacity for plasticity in the adult owl auditory system expanded by juvenile experience.

In the process of creating a multimodal map of space, auditory-visual neurons in the optic tectum establish associations between particular values of auditory spatial cues and locations in the visual field. In the barn owl, tectal neurons reveal these associations in the match between their tuning for interaural time differences (ITDs) and the locations of their visual receptive fields (VRFs). In young owls ITD-VRF associations can be adjusted by experience over a wide range, but the range of adjustment normally becomes quite restricted in adults. This normal range of adjustment in adults was greatly expanded in owls that had previously learned abnormal ITD-VRF associations as juveniles. Thus, the act of learning abnormal associations early in life leaves an enduring trace in this pathway that enables unusual functional connections to be reestablished, as needed, in adulthood, even when the associations represented by these connections have not been used for an extended period of time.

Center-surround organization of auditory receptive fields in the owl.

The spinal receptive fields of specialized auditory units in the midbrain of the barn owl (Tyto abla) contain two functionally antagonistic areas: an excitatory center and an inhibitory surround. The response of these units represents the balance of acoustic activation of the two areas, which in turn depends upon the location, intensity, and spectral content of the sound stimulus.

Functional selection of adaptive auditory space map by GABAA-mediated inhibition.

The external nucleus of the inferior colliculus in the barn owl contains an auditory map of space that is based on the tuning of neurons for interaural differences in the timing of sound. In juvenile owls, this region of the brain can acquire alternative maps of interaural time difference as a result of abnormal experience. It has been found that, in an external nucleus that is expressing a learned, abnormal map, the circuitry underlying the normal map still exists but is functionally inactivated by inhibition mediated by gamma-aminobutyric acid type A (GABAA) receptors. This inactivation results from disproportionately strong inhibition of specific input channels to the network. Thus, experience-driven changes in patterns of inhibition, as well as adjustments in patterns of excitation, can contribute critically to adaptive plasticity in the central nervous system.

The oilbird: hearing and echolocation.

Oilbirds can navigate in total darkness by echolocation. The sound energy in their sonar cries is unevenly distributed over the range from about 1 to 15 kilohertz, with a dominant frequency range of 1.5 to 2.5 kilohertz. This corresponds to the most sensitive range of their hearing as determined by neurophysiological methods. Behavioral tests in their home cave indicate that the smallest object avoided by this is a disk 20 centimeters in diameter.

A neural map of auditory space in the owl.

Auditory units that responded to sound only when it originated from a limited area of space were found in the lateral and anterior portions of the midbrain auditory nucleus of the owl (Tyto alba). The areas of space to which these units responded (their receptive fields) were largely independent of the nature and intensity of the sound stimulus. The units were arranged systematically within the midbrain auditory nucleus according to the relative locations of their receptive fields, thus creating a physiological map of auditory space.

Visual instruction of the neural map of auditory space in the developing optic tectum.

Neural maps of visual and auditory space are aligned in the adult optic tectum. In barn owls, this alignment of sensory maps was found to be controlled during ontogeny by visual instruction of the auditory spatial tuning of neurons. Large adaptive changes in auditory spatial tuning were induced by raising owls with displacing prisms mounted in spectacle frames in front of the eyes; neurons became tuned to sound source locations corresponding to their optically displaced, rather than their normal, visual receptive field locations. The results demonstrate that visual experience during development calibrates the tectal auditory space map in a site-specific manner, dictating its topography and alignment with the visual space map.

Receptive fields of auditory neurons in the owl.

The influence of sound location on the responses of auditory neurons in the forebrain of the owl (Tyto alba) was studied directly by using a remotely controlled, movable sound source under free-field, anechoic conditions. Some auditory neurons demonstrated well-defined receptive fields that were (i) restricted both in elevation and in azimuth and (ii) relatively independent of the intensity and the nature of the sound stimulus. The majority of the fields were located frontally and contralateral to the recording site.

Vision guides the adjustment of auditory localization in young barn owls.

Barn owls raised with one ear plugged make systematic errors in auditory localization when the earplug is removed. Young owls correct their localization errors within a few weeks. However, such animals did not correct their auditory localization errors when deprived of vision. Moreover, when prisms were mounted in front of their eyes, they adjusted their auditory localization to match the visual error induced by the prisms, as long as the visual and auditory errors were within the same quadrant of directions. The results demonstrate that, during development, the visual system provides the spatial reference for fine-tuning auditory localization.

Newly learned auditory responses mediated by NMDA receptors in the owl inferior colliculus.

Alignment of auditory and visual receptive fields in the optic tectum of the barn owl (Tyto alba) is maintained through experience-dependent modification of auditory responses in the external nucleus of the inferior colliculus (ICX), which provides auditory input to the tectum. Newly learned tectal auditory responses, induced by altered visual experience, were found to be pharmacologically distinct from normal responses expressed at the same tectal sites. N-methyl-D-aspartate (NMDA) receptor antagonists administered systemically or applied locally in the ICX reduced learned responses more than normal responses. This differential blockade was not observed with non-NMDA or broad-spectrum antagonists. Thus, NMDA receptors preferentially mediate the expression of novel neuronal responses induced by experience during development.

Territory location and quality, together with climate, affect the timing of breeding in the white-throated dipper.

Recent climate change has led to advanced spring phenology in many temperate regions. The phenological response to variation in the local environment, such as the habitat characteristics of the territories birds occupy, is less clear. The aim of this study is to understand how ecological conditions affect breeding time, and its consequences for reproduction, in a white-throated dipper Cinclus cinclus population in a river system in Norway during 34 years (1978-2011). Hatching date advanced almost nine days, indicating a response to higher temperatures and the advanced phenology in the area. Earlier breeding was found in warm springs and at lower altitudes. High population density facilitated earlier breeding close to the coast. Furthermore, when population density was low, breeding was early at territories that were rarely occupied, while in years with high density, breeding was early at territories that were frequently occupied. Also, when population density was low, earlier breeding occurred at territories that on average produced more offspring than other territories, while there was no difference in breeding time in high population years. Selection for early breeding was dependent on spring temperatures and high spring temperatures contributed to higher breeding success during the study period. We found that breeding phenology may have strong effects on fitness in the white-throated dipper, and thus that breeding time is an important ecological factor in a species that feeds mainly on aquatic rather than terrestrial prey.

Loss of the retinoblastoma tumor suppressor: differential action on transcriptional programs related to cell cycle control and immune function.

Functional inactivation of the retinoblastoma tumor suppressor gene product (RB) is a common event in human cancers. Classically, RB functions to constrain cellular proliferation, and loss of RB is proposed to facilitate the hyperplastic proliferation associated with tumorigenesis. To understand the repertoire of regulatory processes governed by RB, two models of RB loss were utilized to perform microarray analysis. In murine embryonic fibroblasts harboring germline loss of RB, there was a striking deregulation of gene expression, wherein distinct biological pathways were altered. Specifically, genes involved in cell cycle control and classically associated with E2F-dependent gene regulation were upregulated via RB loss. In contrast, a program of gene expression associated with immune function and response to pathogens was significantly downregulated with the loss of RB. To determine the specific influence of RB loss during a defined period and without the possibility of developmental compensation as occurs in embryonic fibroblasts, a second system was employed wherein Rb was acutely knocked out in adult fibroblasts. This model confirmed the distinct regulation of cell cycle and immune modulatory genes through RB loss. Analyses of cis-elements supported the hypothesis that the majority of those genes upregulated with RB loss are regulated via the E2F family of transcription factors. In contrast, those genes whose expression was reduced with the loss of RB harbored different promoter elements. Consistent with these analyses, we found that disruption of E2F-binding function of RB was associated with the upregulation of gene expression. In contrast, cells harboring an RB mutant protein (RB-750F) that retains E2F-binding activity, but is specifically deficient in the association with LXCXE-containing proteins, failed to upregulate these same target genes. However, downregulation of genes involved in immune function was readily observed with disruption of the LXCXE-binding function of RB. Thus, these studies demonstrate that RB plays a significant role in both the positive and negative regulations of transcriptional programs and indicate that loss of RB has distinct biological effects related to both cell cycle control and immune function.

Cyclin D1: polymorphism, aberrant splicing and cancer risk.

The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.