Contrast Gain Control in Auditory Cortex Rabinowitz, Neil C.; Willmore, Ben D.B.; Schnupp, Jan W.H. ...
Neuron (Cambridge, Mass.),
06/2011, Letnik:
70, Številka:
6
Journal Article
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The auditory system must represent sounds with a wide range of statistical properties. One important property is the spectrotemporal contrast in the acoustic environment: the variation in sound ...pressure in each frequency band, relative to the mean pressure. We show that neurons in ferret auditory cortex rescale their gain to partially compensate for the spectrotemporal contrast of recent stimulation. When contrast is low, neurons increase their gain, becoming more sensitive to small changes in the stimulus, although the effectiveness of contrast gain control is reduced at low mean levels. Gain is primarily determined by contrast near each neuron's preferred frequency, but there is also a contribution from contrast in more distant frequency bands. Neural responses are modulated by contrast over timescales of ∼100 ms. By using contrast gain control to expand or compress the representation of its inputs, the auditory system may be seeking an efficient coding of natural sounds.
► We find evidence for spectrotemporal contrast gain control in auditory cortex ► Gain is determined by a combination of spectrally local and global contrast ► Within a limited range, mean stimulus level also affects neural gain ► Contrast gain control is fast (∼100 ms); gain decreases are faster than increases
Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of ...cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).
Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific
-inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated
depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.
Tumour-infiltrating CD11b
CD33
HLA-DR
MDSCs from patients with HCC potently inhibited autologous CD8
T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b
CD33
HLA-DR
MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to
promoter. Hepatic
induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous
or hepatic IL-6 increased interferon γ
tumour necrosis factor-α
CD8
T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous
depletion upregulated PD-L1 expression and increased intratumorous CD8
T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.
Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
Cortical sensory neurons are commonly characterized using the receptive field, the linear dependence of their response on the stimulus. In primary auditory cortex neurons can be characterized by ...their spectrotemporal receptive fields, the spectral and temporal features of a sound that linearly drive a neuron. However, receptive fields do not capture the fact that the response of a cortical neuron results from the complex nonlinear network in which it is embedded. By fitting a nonlinear feedforward network model (a network receptive field) to cortical responses to natural sounds, we reveal that primary auditory cortical neurons are sensitive over a substantially larger spectrotemporal domain than is seen in their standard spectrotemporal receptive fields. Furthermore, the network receptive field, a parsimonious network consisting of 1-7 sub-receptive fields that interact nonlinearly, consistently better predicts neural responses to auditory stimuli than the standard receptive fields. The network receptive field reveals separate excitatory and inhibitory sub-fields with different nonlinear properties, and interaction of the sub-fields gives rise to important operations such as gain control and conjunctive feature detection. The conjunctive effects, where neurons respond only if several specific features are present together, enable increased selectivity for particular complex spectrotemporal structures, and may constitute an important stage in sound recognition. In conclusion, we demonstrate that fitting auditory cortical neural responses with feedforward network models expands on simple linear receptive field models in a manner that yields substantially improved predictive power and reveals key nonlinear aspects of cortical processing, while remaining easy to interpret in a physiological context.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ ...T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (
i.e.
Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3
+
T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either
ex vivo
expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.
Existing studies on health-related quality of life (HRQoL) mainly covered single growth stages of childhood or adolescence and did not report on the trends in the relationships of HRQoL with sleep ...duration, physical activity, and screen time. This study aimed to establish the population norm of HRQoL in children and adolescents aged 6-17 years and examine the associations of screen time, sleep duration, and physical activity with HRQoL in this population.
We conducted a large-scale cross-sectional population-based survey study of Hong Kong children and adolescents aged 6 to 17 years. A representative sample of students were interviewed to assess their HRQoL using PedsQL and EQ-5D-Y-5L. Multivariable homoscedastic Tobit regression with linear form or restricted cubic spline of predictors was used to analyze the associations between screen time, sleep duration, and HRQoL. Multiple imputation by chained equations was performed to deal with missing data.
A total of 7555 respondents (mean age 11.5, SD 3.2; 55.1% female) were sampled. Their EQ VAS scores, PedsQL physical summary scores, and psychosocial summary scores were positively correlated with sleep duration and moderate/vigorous activity but was negatively correlated with screen time.
Children and adolescents who had longer exposure to screen, shorter sleep duration, and lower physical activity levels appeared to have poorer HRQoL as assessed by PedsQL and EQ-5D-Y-5L. Advice and guidance on screen time allocation for children and adolescents should be provided at the levels of school, community, and family.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell ...cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G
csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
Analysis of delta 18O in igneous zircons of known age traces the evolution of intracrustal recycling and crust-mantle interaction through time. This record is especially sensitive because oxygen ...isotope ratios of igneous rocks are strongly affected by incorporation of supracrustal materials into melts, which commonly have delta 18O values higher than in primitive mantle magmas. This study summarizes data for delta 18O in zircons that have been analyzed from 1,200 dated rocks ranging over 96% of the age of Earth. Uniformly primitive to mildly evolved magmatic delta 18O values are found from the first half of Earth history, but much more varied values are seen for younger magmas. The similarity of values throughout the Archean, and comparison to the composition of the "modern" mantle indicate that delta 18O of primitive mantle melts have remained constant (+-0.2 0/00) for the past 4.4 billion years. The range and variability of delta 18O in all Archean zircon samples is subdued (delta 18O(Zrc)=5-7.5 0/00) ranging from values in high temperature equilibrium with the mantle (5.3+- 0.3 0/00) to slightly higher, more evolved compositions (6.5-7.5 0/00) including samples from: the Jack Hills (4.4-3.3 Ga), the Beartooth Mountains (4.0-2.9 Ga), Barberton (3.5-2.7 Ga), the Superior and Slave Provinces (3.0 to 2.7 Ga), and the Lewisian (2.7 Ga). No zircons from the Archean have been analyzed with magmatic delta 18O above 7.5 0/00. The mildly evolved, higher Archean values (6.5-7.5 0/00) are interpreted to result from exchange of protoliths with surface waters at low temperature followed by melting or contamination to create mildly elevated magmas that host the zircons. During the Proterozoic, the range of delta 18O(Zrc) and the highest values gradually increased in a secular change that documents maturation of the crust. After delta 1.5 Ga, high delta 18O zircons (8 to >10 0/00) became common in many Proterozoic and Phanerozoic terranes reflecting delta 18O(whole rock) values from 9 to over 12 0/00. The appearance of high delta 18O magmas on Earth reflects nonuniformitarian changes in the composition of sediments, and rate and style of recycling of surface-derived material into magmas within the crust. PUBLICATION ABSTRACT
Sound localization requires the integration in the brain of auditory spatial cues generated by interactions with the external ears, head and body. Perceptual learning studies have shown that the ...relative weighting of these cues can change in a context-dependent fashion if their relative reliability is altered. One factor that may influence this process is vision, which tends to dominate localization judgments when both modalities are present and induces a recalibration of auditory space if they become misaligned. It is not known, however, whether vision can alter the weighting of individual auditory localization cues. Using virtual acoustic space stimuli, we measured changes in subjects’ sound localization biases and binaural localization cue weights after ~50 minutes of training on audiovisual tasks in which visual stimuli were either informative or not about the location of broadband sounds. Four different spatial configurations were used in which we varied the relative reliability of the binaural cues (interaural time differences (ITDs) and frequency-dependent interaural level differences (ILDs). In most subjects and experiments, ILDs were weighted more highly than ITDs before training. When visual cues were spatially uninformative, some subjects showed a reduction in auditory localization bias and the relative weighting of ILDs increased only after training with congruent binaural cues. ILDs were also upweighted if they were paired with spatially-congruent visual cues, and the largest group-level improvements in sound localization accuracy occurred when both binaural cues were matched to visual stimuli. These data suggest that binaural cue reweighting reflects baseline differences in the relative weights of ILDs and ITDs, but is also shaped by the availability of congruent visual stimuli. Training subjects with consistently misaligned binaural and visual cues produced the ventriloquism aftereffect, i.e., a corresponding shift in auditory localization bias, without affecting the inter-subject variability in sound localization judgments or their in binaural cue weights. These data show that the relative weighting of different auditory localization cues can be changed by training in ways that depend on their reliability as well as the availability of visual spatial information, with the largest improvements in sound localization likely to result from training with fully congruent audiovisual information.
Identifying behaviorally relevant sounds in the presence of background noise is one of the most important and poorly understood challenges faced by the auditory system. An elegant solution to this ...problem would be for the auditory system to represent sounds in a noise-invariant fashion. Since a major effect of background noise is to alter the statistics of the sounds reaching the ear, noise-invariant representations could be promoted by neurons adapting to stimulus statistics. Here we investigated the extent of neuronal adaptation to the mean and contrast of auditory stimulation as one ascends the auditory pathway. We measured these forms of adaptation by presenting complex synthetic and natural sounds, recording neuronal responses in the inferior colliculus and primary fields of the auditory cortex of anaesthetized ferrets, and comparing these responses with a sophisticated model of the auditory nerve. We find that the strength of both forms of adaptation increases as one ascends the auditory pathway. To investigate whether this adaptation to stimulus statistics contributes to the construction of noise-invariant sound representations, we also presented complex, natural sounds embedded in stationary noise, and used a decoding approach to assess the noise tolerance of the neuronal population code. We find that the code for complex sounds in the periphery is affected more by the addition of noise than the cortical code. We also find that noise tolerance is correlated with adaptation to stimulus statistics, so that populations that show the strongest adaptation to stimulus statistics are also the most noise-tolerant. This suggests that the increase in adaptation to sound statistics from auditory nerve to midbrain to cortex is an important stage in the construction of noise-invariant sound representations in the higher auditory brain.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion gene has been identified as a potent oncogenic driver in non–small-cell lung cancer, in particular ...adenocarcinoma (ADC). It defines a unique subgroup of lung ADC, which may be responsive to ALK inhibitors. Detection of ALK rearrangement by fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction (RT-PCR) is considered to be the standard procedure, but each with its own limitation. We evaluated the practical usefulness of immunohistochemistry (IHC) to detect ALK expression as a reliable detection method of ALK rearrangement in lung ADC.
We tested 373 lung ADCs for ALK rearrangement by IHC and FISH. Multiplex RT-PCR was performed to confirm the fusion variants.
Twenty-two of 373 lung ACs (5.9%) were positive for ALK immunoreactivity. ALK-positive tumor cells demonstrated strong and diffused granular staining in the cytoplasm. All the ALK IHC-positive cases were confirmed to harbor ALK rearrangement, either by FISH, or RT-PCR. Two cases with positive ALK protein expression, but negative for breakapart FISH signal were shown to harbor EML4-ALK variant 1 by RT-PCR. None of the ALK IHC-negative cases were FISH-positive. In addition, we identified a novel EML4-ALK fusion variant (E3:ins53A20), and its potent transformation potential has been confirmed by in vivo tumorigenicity assay.
IHC can effectively detect ALK rearrangement in lung cancer. It might provide a reliable and cost-effective diagnostic approach in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy.
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