During object manipulation tasks, the brain selects and implements action-phase controllers that use sensory predictions and afferent signals to tailor motor output to the physical properties of the ...objects involved. Analysis of signals in tactile afferent neurons and central processes in humans reveals how contact events are encoded and used to monitor and update task performance.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A fundamental feature of first-order neurons in the tactile system is that their distal axon branches in the skin and forms many transduction sites, yielding complex receptive fields with many highly ...sensitive zones. We found that this arrangement constitutes a peripheral neural mechanism that allows individual neurons to signal geometric features of touched objects. Specifically, we observed that two types of first-order tactile neurons that densely innervate the glabrous skin of the human fingertips signaled edge orientation via both the intensity and the temporal structure of their responses. Moreover, we found that the spatial layout of a neuron's highly sensitive zones predicted its sensitivity to particular edge orientations. We submit that peripheral neurons in the touch-processing pathway, as with peripheral neurons in the visual-processing pathway, perform feature extraction computations that are typically attributed to neurons in the cerebral cortex.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary Almost every disorder of the CNS is said to have an inflammatory component, but the precise nature of inflammation in the CNS is often imprecisely defined, and the role of CNS-resident cells ...is uncertain compared with that of cells that invade the tissue from the systemic immune compartment. To understand inflammation in the CNS, the term must be better defined, and the response of tissue to disturbances in homoeostasis (eg, neurodegenerative processes) should be distinguished from disorders in which aberrant immune responses lead to CNS dysfunction and tissue destruction (eg, autoimmunity). Whether the inflammatory tissue response to injury is reparative or degenerative seems to be dependent on context and timing, as are the windows of opportunity for therapeutic intervention in inflammatory CNS diseases.
Zebrafish is a powerful model for forward genetics. Reverse genetic approaches are limited by the time required to generate stable mutant lines. We describe a system for gene knockout that ...consistently produces null phenotypes in G0 zebrafish. Yolk injection of sets of four CRISPR/Cas9 ribonucleoprotein complexes redundantly targeting a single gene recapitulated germline-transmitted knockout phenotypes in >90% of G0 embryos for each of 8 test genes. Early embryonic (6 hpf) and stable adult phenotypes were produced. Simultaneous multi-gene knockout was feasible but associated with toxicity in some cases. To facilitate use, we generated a lookup table of four-guide sets for 21,386 zebrafish genes and validated several. Using this resource, we targeted 50 cardiomyocyte transcriptional regulators and uncovered a role of zbtb16a in cardiac development. This system provides a platform for rapid screening of genes of interest in development, physiology, and disease models in zebrafish.
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•Redundant targeting of single genes generates nearly complete gene disruption•Effects are early and durable, complementing morpholino-based approaches•A genome-scale guide set provides a resource to aid automated experimental design•A transcription factor screen uncovers a role for zbtb16a in heart development
Wu et al. describe a pipeline for CRISPR/Cas9 genetic screening with optimized, redundant gene targeting to produce penetrant gene disruption in zebrafish. The authors evaluate this system on several genes and apply this strategy to 50 empirically identified zebrafish cardiomyocyte transcription factors, uncovering a role for zbtb16a in cardiac development.
Summary The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement ...sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.
The sleep disorder narcolepsy is linked to immune-system genes and is caused by the loss of neurons that express the protein hypocretin. Hypocretin-targeting immune cells have now been found in ...people with narcolepsy.
Immune cells impede repair of old neurons Gaudenzio, Nicolas; Liblau, Roland S
Science (American Association for the Advancement of Science),
05/2022, Letnik:
376, Številka:
6594
Journal Article
Recenzirano
Interfering with age-related neuroimmune interactions promotes nerve regeneration.
The aim of this systematic review was to evaluate the longitudinal evolution of midterm to long-term results of reverse total shoulder arthroplasty (RTSA) for patients with massive irreparable ...rotator cuff tears (miRCT).
Databases were scanned for studies of RTSA for miRCT. Studies with a minimum Level IV of evidence were considered eligible. Studies were included if they reported a minimum of 5 years of follow-up and excluded if they reported RTSA combined with tendon transfers or as revision arthroplasty. Data were grouped based on results after 5 to 7 years, 7 to 10 years, and 10 to 20 years of follow-up.
Eight studies with a total of 365 shoulders were included. After a mean follow-up of 9.5 years (range, 5-20 years), the preoperative absolute and relative Constant scores were significantly improved from 24 to 59 points (P = .004) and from 33% to 74% (P = .009). The preoperative Subjective Shoulder Value improved from 23% to 72% (P = .049). Active anterior elevation and abduction also improved significantly (P = .004 and P = .014, respectively), but active external rotation remained unchanged (P = .855). None of the clinical scores or active ranges of motion significantly deteriorated up to 20 years after the operation (P > .05). After 10 years, 42% of the RTSAs showed grade III or IV inferior scapular notching.
Pooled long-term results of RTSA for miRCT show significant improvement of overhead function and of objective and subjective outcome scores up to 20 years after surgery. Shoulder function and outcome scores also showed no significant deterioration between 5 and 20 years of follow-up. Longer follow-up will be needed to determine ultimate longevity.
The diversity and complexity of proteins and peptides in biological systems requires powerful liquid chromatography-based separations to optimize resolution and detection of components. Proteomics ...strategies often combine two orthogonal separation modes to meet this challenge. In nearly all cases, the second dimension is a reverse phase separation interfaced directly to a mass spectrometer. Here we report on the use of hydrophilic interaction chromatography (HILIC) as part of a multidimensional chromatography strategy for proteomics. Tryptic peptides are separated on TSKgel Amide-80 columns using a shallow inverse organic gradient. Under these conditions, peptide retention is based on overall hydrophilicity, and a separation truly orthogonal to reverse phase is produced. Analysis of tryptic digests from HeLa cells yielded numbers of protein identifications comparable to that obtained using strong cation exchange. We also demonstrate that HILIC represents a significant advance in phosphoproteomics analysis. We exploited the strong hydrophilicity of the phosphate group to selectively enrich and fractionate phosphopeptides based on their increased retention under HILIC conditions. Subsequent IMAC enrichment of phosphopeptides from HILIC fractions showed better than 99% selectivity. This was achieved without the use of derivatization or chemical modifiers. In a 300-μg equivalent of HeLa cell lysate we identified over 1000 unique phosphorylation sites. More than 700 novel sites were added to the HeLa phosphoproteome.
Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2+Ly6Chi monocytes. However, the mechanisms driving tumor cell ...extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2+ endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2−/− mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.
► Tumor-cell derived CCL2 controls vascular permeability, extravasation, and metastasis ► Endothelial CCR2 expression is necessary and sufficient for extravasation/ metastasis ► Activation of JAK2-Stat5 and p38MAPK signaling via CCR2 induce vascular permeability ► CCL2 expression levels correlate with metastatic potential of UICC IV colon carcinoma
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