The concept of hematopoietic stem cell (HSC) niche was formulated in 1978, but HSC niches remained unidentified for the following two decades largely owing to technical limitations. Sophisticated ...live microscopy techniques and genetic manipulations have identified the endosteal region of the bone marrow (BM) as a preferential site of residence for the most potent HSC - able to reconstitute in serial transplants - with osteoblasts and their progenitors as critical cellular elements of these endosteal niches. This article reviews the path to the discovery of these endosteal niches (often called 'osteoblastic' niches) for HSC, what cell types contribute to these niches with their known physical and biochemical features. In the past decade, a first wave of research uncovered many mechanisms responsible for HSC homing to, and mobilization from, the whole BM tissue. However, the recent discovery of endosteal HSC niches has initiated a second wave of research focusing on the mechanisms by which most primitive HSC lodge into and migrate out of their endosteal niches. The second part of this article reviews the current knowledge of the mechanisms of HSC lodgment into, retention in and mobilization from osteoblastic niches.
The CXCR4 antagonist AMD3100 is progressively replacing cyclophosphamide (CYP) as adjuvant to granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) for autologous ...transplants in patients who failed prior mobilization with G-CSF alone. It has recently emerged that G-CSF mediates HSC mobilization and inhibits bone formation via specific bone marrow (BM) macrophages. We compared the effect of these three mobilizing agents on BM macrophages, bone formation, osteoblasts, HSC niches and HSC reconstitution potential. Both G-CSF and CYP suppressed niche-supportive macrophages and osteoblasts, and inhibited expression of endosteal cytokines resulting in major impairment of HSC reconstitution potential remaining in the mobilized BM. In sharp contrast, although AMD3100 was effective at mobilizing HSC, it did not suppress osteoblasts, endosteal cytokine expression or reconstitution potential of HSC remaining in the mobilized BM. In conclusion, although G-CSF, CYP and AMD3100 efficiently mobilize HSC into the blood, their effects on HSC niches and bone formation are distinct with both G-CSF and CYP targeting HSC niche function and bone formation, whereas AMD3100 directly targets HSC without altering niche function or bone formation.
•We recorded mismatch responses (MMRs) to vowel changes in a variable speech stream.•Newborns extracted relevant phonetic information from the stream, evidenced by MMRs.•High dyslexia risk infants ...had diminished MMRs to vowel changes.•MMR amplitudes and hemispheric lateralization correlated with later language skills.•Poor phoneme extraction may compromise phonological and language development.
A crucial skill in infant language acquisition is learning of the native language phonemes. This requires the ability to group complex sounds into distinct auditory categories based on their shared features. Problems in phonetic learning have been suggested to underlie language learning difficulties in dyslexia, a developmental reading-skill deficit. We investigated auditory abilities important for language acquisition in newborns with or without a familial risk for dyslexia with electrophysiological mismatch responses (MMRs). We presented vowel changes in a sequence of acoustically varying vowels, requiring grouping of the stimuli to two phoneme categories. The vowel changes elicited an MMR which was significantly diminished in infants whose parents had the most severe dyslexia in our sample. Phoneme-MMR amplitude and its hemispheric lateralization were associated with language test outcomes assessed at 28 months, an age at which it becomes possible to behaviourally test children and several standardized tests are available. In addition, statistically significant MMRs to violations of a complex sound-order rule were only found in infants without dyslexia risk, but these results are very preliminary due to small sample size. The results demonstrate the relevance of the newborn infants’ readiness for phonetic learning for their emerging language skills. Phoneme extraction difficulties in infants at familial risk may contribute to the phonological deficits observed in dyslexia.
Sounds provide us with useful information about our environment which complements that provided by other senses, but also poses specific processing problems. How does the auditory system distentangle ...sounds from different sound sources? And what is it that allows intermittent sound events from the same source to be associated with each other? Here we review findings from a wide range of studies using the auditory streaming paradigm in order to formulate a unified account of the processes underlying auditory perceptual organization. We present new computational modelling results which replicate responses in primary auditory cortex Fishman, Y.I., Arezzo, J.C., Steinschneider, M., 2004. Auditory stream segregation in monkey auditory cortex: effects of frequency separation, presentation rate, and tone duration. J. Acoust. Soc. Am. 116, 1656–1670; Fishman, Y. I., Reser, D. H., Arezzo, J.C., Steinschneider, M., 2001. Neural correlates of auditory stream segregation in primary auditory cortex of the awake monkey. Hear. Res. 151, 167–187 to tone sequences. We also present the results of a perceptual experiment which confirm the bi-stable nature of auditory streaming, and the proposal that the gradual build-up of streaming may be an artefact of averaging across many subjects Pressnitzer, D., Hupé, J. M., 2006. Temporal dynamics of auditory and visual bi-stability reveal common principles of perceptual organization. Curr. Biol. 16(13), 1351–1357.. Finally we argue that in order to account for all of the experimental findings, computational models of auditory stream segregation require four basic processing elements; segregation, predictive modelling, competition and adaptation, and that it is the formation of effective predictive models which allows the system to keep track of different sound sources in a complex auditory environment.
We tested the effects of predictability on involuntary attention switching to task-irrelevant sound changes (distraction). Behavioral and neurophysiological evidence are provided, showing that the ...predictability of task-irrelevant sound changes eliminates effects of distraction even though the automatic auditory change detection system remains responsive. Two indices of distraction, slower task performance and cortical brain responses associated with attention switching, were seen only in the unpredictable condition, in which the irrelevant acoustic changes were unexpected. Attention was not involuntarily drawn away from the primary task when the subjects had foreknowledge of when the irrelevant changes would occur. These results demonstrate attentional control over orienting to sound changes and suggest that involuntary attention switching occurs mainly when an irrelevant stimulus change is unexpected. The present data allowed observation of the temporal dynamics of attention switching in the human brain.
We present a statistical analysis on the plasmaspheric mass density derived from the field line resonance (FLR) observations by the Mid‐continent MAgnetoseismic Chain (McMAC). McMAC consists of nine ...stations in the United States and Mexico along the 330° magnetic longitude, spanning L‐values between 1.5 and 3.4. Using the gradient method and an automated procedure for FLR detection, we studied a full year of McMAC observations between July 2006 and June 2007. We find that the rate of FLR detection can reach as high as 56% around local noon at L = 2.7, and the detection rates at higher and lower L‐values decline due to the occasional presence of the plasmapause and weaker FLR signals, respectively. At L‐values between 1.8 and 3.1, the inferred equatorial plasma mass density follows the L‐dependence of L−4. By comparing the mass density with the electron density, we found that the ion mass gradually decreased from 1.7 amu at L = 1.8 to 1 amu at L = 3.1. The plasma mass density exhibits an annual variation that maximizes in January, and at L = 2.4 the ratio between January and July densities is 1.6. Our observations also show a local time dependence of plasmaspheric mass density that stays steady in the morning and rises postnoon, a phenomenon that may be attributed to the equatorial ionization anomaly as a part of the plasma neutral coupling at low latitude.
Key Points
Ground observations reveal statistical properties of plasmaspheric density.
Plasmaspheric mass density exhibits an annual variation that peaks in winter.
Plasmaspheric mass density stays steady in the morning and rises post‐noon.
•First-impressions have a lasting impact on auditory relevance filtering.•First-impressions bias modulation of auditory mismatch negativity (MMN) amplitude.•The auditory system forms a hierarchy of ...prediction models over multiple timescales.•The auditory system modifies confidence in first-impressions but does not drop them.
Although first-impressions are known to impact decision-making and to have prolonged effects on reasoning, it is less well known that the same type of rapidly formed assumptions can explain biases in automatic relevance filtering outside of deliberate behavior. This paper features two studies in which participants have been asked to ignore sequences of sound while focusing attention on a silent movie. The sequences consisted of blocks, each with a high-probability repetition interrupted by rare acoustic deviations (i.e., a sound of different pitch or duration). The probabilities of the two different sounds alternated across the concatenated blocks within the sequence (i.e., short-to-long and long-to-short). The sound probabilities are rapidly and automatically learned for each block and a perceptual inference is formed predicting the most likely characteristics of the upcoming sound. Deviations elicit a prediction-error signal known as mismatch negativity (MMN). Computational models of MMN generally assume that its elicitation is governed by transition statistics that define what sound attributes are most likely to follow the current sound. MMN amplitude reflects prediction confidence, which is derived from the stability of the current transition statistics. However, our prior research showed that MMN amplitude is modulated by a strong first-impression bias that outweighs transition statistics. Here we test the hypothesis that this bias can be attributed to assumptions about predictable vs. unpredictable nature of each tone within the first encountered context, which is weighted by the stability of that context. The results of Study 1 show that this bias is initially prevented if there is no 1:1 mapping between sound attributes and probability, but it returns once the auditory system determines which properties provide the highest predictive value. The results of Study 2 show that confidence in the first-impression bias drops if assumptions about the temporal stability of the transition-statistics are violated. Both studies provide compelling evidence that the auditory system extrapolates patterns on multiple timescales to adjust its response to prediction-errors, while profoundly distorting the effects of transition-statistics by the assumptions formed on the basis of first-impressions.
Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent ...autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic.
Hypoxia-inducible factor (HIF)-1α accumulation promotes hematopoietic stem cells' quiescence and is necessary to maintain their self-renewal. However, the role of HIF-2α in hematopoietic cells is ...less clear. We investigated the role of HIF-2α in leukemia and lymphoma cells. HIF-2α expression was high in subsets of human and mouse leukemia and lymphoma cells, whereas it was low in normal bone marrow leukocytes. To investigate the role of HIF-2α, we transduced human HIF-2α cDNA in mouse syngeneic models of myeloid preleukemia and a transgenic model of B lymphoma. Ectopic expression of HIF-2α accelerated leukemia cell proliferation in vitro. Mice transplanted with cells transduced with HIF-2α died significantly faster of leukemia or B lymphoma than control mice transplanted with empty vector-transduced cells. Conversely, HIF-2α knockdown in human myeloid leukemia HL60 cells decreased proliferation in vitro and significantly prolonged animal survival following transplantation. In human acute myeloid leukemia (AML), HIF-2α mRNA was significantly elevated in several subsets such as the t(15;17), inv(16), complex karyotype and favorable cytogenetic groups. However, patients with high HIF-2α expression had a trend to higher disease-free survival in univariate analysis. The different effects of HIF-2α overexpression in mouse models of leukemia and human AML illustrates the complexity of this mutliclonal disease.
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•Monophagy exhibited by presumptive Fergusonina gall flies was 73%.•Genetic variation did not vary with sample size or geographic distance within species.•Oligophagous species ...possessed greater genetic variation than monophagous species.•Evolutionary history of host plant use and gall type showed moderate constraint.
This study investigated host-specificity and phylogenetic relationships in Australian galling flies, Fergusonina Malloch (Diptera: Fergusoninidae), in order to assess diversity and explore the evolutionary history of host plant affiliation and gall morphology. A DNA barcoding approach using COI data from 203 Fergusonina specimens from 5gall types on 56 host plant species indicated 85 presumptive fly species. These exhibited a high degree of host specificity; of the 40 species with multiple representatives, each fed only on a single host genus, 29 (72.5%) were strictly monophagous, and 11 (27.5%) were reared from multiple closely related hosts. COI variation within species was not correlated with either sample size or geographic distance. However variation was greater within oligophagous species, consistent with expectations of the initial stages of host-associated divergence during speciation. Phylogenetic analysis using both nuclear and mitochondrial genes revealed host genus-restricted clades but also clear evidence of multiple colonizations of both host plant genus and host species. With the exception of unilocular peagalls, evolution of gall type was somewhat constrained, but to a lesser degree than host plant association. Unilocular peagalls arose more often than any other gall type, were primarily located at the tips of the phylogeny, and did not form clades comprising more than a few species. For ecological reasons, species of this gall type are predicted to harbor substantially less genetic variation than others, possibly reducing evolutionary flexibility resulting in reduced diversification in unilocular gallers.
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