Convergent input from brainstem coincidence detectors onto delay-sensitive neurons in the inferior colliculus.

Responses of low-frequency neurons in the inferior colliculus (IC) of anesthetized guinea pigs were studied with binaural beats to assess their mean best interaural phase (BP) to a range of stimulating frequencies. Phase plots (stimulating frequency vs BP) were produced, from which measures of characteristic delay (CD) and characteristic phase (CP) for each neuron were obtained. The CD provides an estimate of the difference in travel time from each ear to coincidence-detector neurons in the brainstem. The CP indicates the mechanism underpinning the coincidence detector responses. A linear phase plot indicates a single, constant delay between the coincidencedetector inputs from the two ears. In more than half (54 of 90) of the neurons, the phase plot was not linear. We hypothesized that neurons with nonlinear phase plots received convergent input from brainstem coincidence detectors with different CDs. Presentation of a second tone with a fixed, unfavorable delay suppressed the response of one input, linearizing the phase plot and revealing other inputs to be relatively simple coincidence detectors. For some neurons with highly complex phase plots, the suppressor tone altered BP values, but did not resolve the nature of the inputs. For neurons with linear phase plots, the suppressor tone either completely abolished their responses or reduced their discharge rate with no change in BP. By selectively suppressing inputs with a second tone, we are able to reveal the nature of underlying binaural inputs to IC neurons, confirming the hypothesis that the complex phase plots of many IC neurons are a result of convergence from simple brainstem coincidence detectors

Spatial ecology of jaguars, pumas, and ocelots: a review of the state of knowledge

Knowledge of the spatial ecology of mammalian carnivores is critical for understanding species’ biology and designing effective conservation and management interventions. We reviewed the available information about the spatial ecology of jaguars Panthera onca, pumas Puma concolor, and ocelots Leopardus pardalis, and we examined how sex and extrinsic variables affect their spatial behaviour. Sixty-one articles addressing home range, home range overlap, daily net displacement (straight-line distance between two locations on consecutive days), and/or distance of dispersal of the three species were included. Meta-analysis, ANOVA, ANCOVA, and beta regression tests were run to analyse differences among species and sexes and to elucidate the influence of other variables, such as latitude and ecoregion, on spatial behaviour. Pumas had on average larger home ranges (mean ± SE: 281.87 ± 35.76 km) than jaguars (128.61 ± 49.5 km) and ocelots (12.46 ± 3.39 km). Intersexual range overlap was higher than intrasexual range overlap in jaguars and pumas. Sex affected the home range size of all three species, but only influenced daily net displacement in ocelots. Ecoregion affected the home range size of all three species but did not significantly affect either the daily net displacement or the dispersal distance of pumas. Latitude affected the home range size of jaguars and pumas. It did not affect daily net displacement or dispersal distance in jaguars and pumas, but did affect daily net displacement in ocelots. Although there was a lack of studies in most countries for the three species, information was particularly lacking in the Neotropics for jaguars and pumas and in North America for ocelots. Researchers usually presented low sample sizes and used different methods to examine the ecological issues considered here. Homogenisation of methods is needed to clarify the ecology of these species and to allow a better understanding of the threats to their populations.Peer Reviewe

Cancer stem cell heterogeneity in hereditary breast cancer

The cancer stem cell hypothesis proposes that tumors arise in stem or progenitor cells generating in tumors driven by a subcomponent that retains cancer stem cell properties. Recent evidence supports the hypothesis that the BRCA1 gene involved in hereditary breast cancer plays a role in breast stem cell function. Furthermore, studies using mouse BRCA1 knockout models provide evidence for the existence of heterogeneous cancer stem cell populations in tumors generated in these mice. Although these populations may arise from different stem/progenitor cells, they share the expression of a common set of stem cell regulatory genes and show similar characteristics in in vitro mammosphere assays and xenograft models. Furthermore, these 'cancer stem cells' display resistance to chemotherapeutic agents. These studies suggest that breast tumors may display intertumor stem cell heterogeneity. Despite this heterogeneity, cancer stem cells may share common characteristics that can be used for their identification and for therapeutic targeting

Efficient tumour formation by single human melanoma cells

A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells ( 0.1 - 0.0001%) form tumours when transplanted into non- obese diabetic/ severe combined immunodeficiency ( NOD/ SCID) mice. However, the extent to which NOD/ SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/ SCID interleukin- 2 receptor gamma chain null (Il2rg(-/-)) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single- cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.Howard Hughes Medical Institute ; Allen H. Blondy Research Fellowship ; Lewis and Lillian Becker ; University of Michigan Comprehensive Cancer Center ; National Institutes of Health [CA46592]; University of Michigan Flow Cytometry Core Facility ; N. McAnsh and the University of Michigan Cancer Centre Histology Core ; National Institute of Diabetes, Digestive, and Kidney Diseases [NIH5P60- DK20572]; Michigan Diabetes Research and Training Center ; Spanish Ministry of Education ; Marie Curie Outgoing International Fellowship from the European Commission ; Australian National Health and Medical Research Council ; Human Frontiers Science Program and Australia PostThis work was supported by the Howard Hughes Medical Institute and by the Allen H. Blondy Research Fellowship. The University of Michigan Melanoma Bank was supported by a gift from Lewis and Lillian Becker. Flow cytometry was partly supported by the University of Michigan Comprehensive Cancer Center grant from the National Institutes of Health CA46592. We thank: D. Adams, M. White and the University of Michigan Flow Cytometry Core Facility for support; N. McAnsh and the University of Michigan Cancer Centre Histology Core for histological studies; G. K. Smyth for assistance with statistics; and Z. Azizan for support with tissue collection. Antibody production was supported in part by the National Institute of Diabetes, Digestive, and Kidney Diseases, grant NIH5P60- DK20572 to the Michigan Diabetes Research and Training Center. Some antibodies were provided by Caltag or by eBioscience to screen for cancer stem- cell markers. Human primary melanocyte cultures were provided by M. Soengas. Human mesenchymal stem cells were provided by Z. Wang and P. Krebsbach. E. Q. was supported by the Spanish Ministry of Education and the Marie Curie Outgoing International Fellowship from the European Commission. M. S. was supported by the Australian National Health and Medical Research Council, the Human Frontiers Science Program and Australia Post.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62970/1/nature07567.pd

Long-Term Sphere Culture Cannot Maintain a High Ratio of Cancer Stem Cells: A Mathematical Model and Experiment

Acquiring abundant and high-purity cancer stem cells (CSCs) is an important prerequisite for CSC research. At present, researchers usually gain high-purity CSCs through flow cytometry sorting and expand them by short-term sphere culture. However, it is still uncertain whether we can amplify high-purity CSCs through long-term sphere culture. We have proposed a mathematical model using ordinary differential equations to derive the continuous variation of the CSC ratio in long-term sphere culture and estimated the model parameters based on a long-term sphere culture of MCF-7 stem cells. We found that the CSC ratio in long-term sphere culture presented as gradually decreased drift and might be stable at a lower level. Furthermore, we found that fitted model parameters could explain the main growth pattern of CSCs and differentiated cancer cells in long-term sphere culture

Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells could be the origin of BRCA1 related breast cancer. Since ALDH1 is a marker of both mammary stem cells and breast cancer stem cells, we compared ALDH1 expression in malignant tissue of BRCA1 mutation carriers to non-carriers. Methods Forty-one BRCA1 related breast cancers and 41 age-matched sporadic breast cancers were immunohistochemically stained for ALDH1. Expression in epithelium and stroma was scored and compared. Results Epithelial (P=0.001) and peritumoral (P=0.001) ALDH1 expression was significantly higher in invasive BRCA1 related carcinomas compared to sporadic carcinomas. Intratumoral stromal ALDH1 expression was similarly high in both groups. ALDH1 tumor cell expression was an independent predictor of BRCA1 mutation status. Conclusion BRCA1 related breast cancers showed significantly more frequent epithelial ALDH1 expression, indicating that these hereditary tumors have an enlarged cancer stem cell component. Besides, (peritumoral) stromal ALDH1 expression was also more frequent in BRCA1 mutation carriers. ALDH1 may therefore be a diagnostic marker and a therapeutic target of BRCA1 related breast cancer

Reversed flow of Atlantic deep water during the Last Glacial Maximum

The meridional overturning circulation (MOC) of the Atlantic Ocean is considered to be one of the most important components of the climate system. This is because its warm surface currents, such as the Gulf Stream, redistribute huge amounts of energy from tropical to high latitudes and influence regional weather and climate patterns, whereas its lower limb ventilates the deep ocean and affects the storage of carbon in the abyss, away from the atmosphere. Despite its significance for future climate, the operation of the MOC under contrasting climates of the past remains controversial. Nutrient-based proxies1, 2 and recent model simulations3 indicate that during the Last Glacial Maximum the convective activity in the North Atlantic Ocean was much weaker than at present. In contrast, rate-sensitive radiogenic 231Pa/230Th isotope ratios from the North Atlantic have been interpreted to indicate only minor changes in MOC strength4, 5, 6. Here we show that the basin-scale abyssal circulation of the Atlantic Ocean was probably reversed during the Last Glacial Maximum and was dominated by northward water flow from the Southern Ocean. These conclusions are based on new high-resolution data from the South Atlantic Ocean that establish the basin-scale north to south gradient in 231Pa/230Th, and thus the direction of the deep ocean circulation. Our findings are consistent with nutrient-based proxies and argue that further analysis of 231Pa/230Th outside the North Atlantic basin will enhance our understanding of past ocean circulation, provided that spatial gradients are carefully considered. This broader perspective suggests that the modern pattern of the Atlantic MOC—with a prominent southerly flow of deep waters originating in the North Atlantic—arose only during the Holocene epoch

Frequency-Invariant Representation of Interaural Time Differences in Mammals

Interaural time differences (ITDs) are the major cue for localizing low-frequency sounds. The activity of neuronal populations in the brainstem encodes ITDs with an exquisite temporal acuity of about . The response of single neurons, however, also changes with other stimulus properties like the spectral composition of sound. The influence of stimulus frequency is very different across neurons and thus it is unclear how ITDs are encoded independently of stimulus frequency by populations of neurons. Here we fitted a statistical model to single-cell rate responses of the dorsal nucleus of the lateral lemniscus. The model was used to evaluate the impact of single-cell response characteristics on the frequency-invariant mutual information between rate response and ITD. We found a rough correspondence between the measured cell characteristics and those predicted by computing mutual information. Furthermore, we studied two readout mechanisms, a linear classifier and a two-channel rate difference decoder. The latter turned out to be better suited to decode the population patterns obtained from the fitted model

Responses to Diotic, Dichotic, and Alternating Phase Harmonic Stimuli in the Inferior Colliculus of Guinea Pigs

Humans perceive a harmonic series as a single auditory object with a pitch equivalent to the fundamental frequency (F0) of the series. When harmonics are presented to alternate ears, the repetition rate of the waveform at each ear doubles. If the harmonics are resolved, then the pitch perceived is still equivalent to F0, suggesting the stimulus is binaurally integrated before pitch is processed. However, unresolved harmonics give rise to the doubling of pitch which would be expected from monaural processing (Bernstein and Oxenham, J. Acoust. Soc. Am., 113:3323–3334, 2003). We used similar stimuli to record responses of multi-unit clusters in the central nucleus of the inferior colliculus (IC) of anesthetized guinea pigs (urethane supplemented by fentanyl/fluanisone) to determine the nature of the representation of harmonic stimuli and to what extent there was binaural integration. We examined both the temporal and rate-tuning of IC clusters and found no evidence for binaural integration. Stimuli comprised all harmonics below 10 kHz with fundamental frequencies (F0) from 50 to 400 Hz in half-octave steps. In diotic conditions, all the harmonics were presented to both ears. In dichotic conditions, odd harmonics were presented to one ear and even harmonics to the other. Neural characteristic frequencies (CF, n = 85) were from 0.2 to 14.7 kHz; 29 had CFs below 1 kHz. The majority of clusters responded predominantly to the contralateral ear, with the dominance of the contralateral ear increasing with CF. With diotic stimuli, over half of the clusters (58%) had peaked firing rate vs. F0 functions. The most common peak F0 was 141 Hz. Almost all (98%) clusters phase locked diotically to an F0 of 50 Hz, and approximately 40% of clusters still phase locked significantly (Rayleigh coefficient >13.8) at the highest F0 tested (400 Hz). These results are consistent with the previous reports of responses to amplitude-modulated stimuli. Clusters phase locked significantly at a frequency equal to F0 for contralateral and diotic stimuli but at 2F0 for dichotic stimuli. We interpret these data as responses following the envelope periodicity in monaural channels rather than as a binaurally integrated representation

Pitch Comparisons between Electrical Stimulation of a Cochlear Implant and Acoustic Stimuli Presented to a Normal-hearing Contralateral Ear

Four cochlear implant users, having normal hearing in the unimplanted ear, compared the pitches of electrical and acoustic stimuli presented to the two ears. Comparisons were between 1,031-pps pulse trains and pure tones or between 12 and 25-pps electric pulse trains and bandpass-filtered acoustic pulse trains of the same rate. Three methods—pitch adjustment, constant stimuli, and interleaved adaptive procedures—were used. For all methods, we showed that the results can be strongly influenced by non-sensory biases arising from the range of acoustic stimuli presented, and proposed a series of checks that should be made to alert the experimenter to those biases. We then showed that the results of comparisons that survived these checks do not deviate consistently from the predictions of a widely-used cochlear frequency-to-place formula or of a computational cochlear model. We also demonstrate that substantial range effects occur with other widely used experimental methods, even for normal-hearing listeners