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Traumatic brain injury (TBI) impairs autoregulation of cerebral blood flow, which contributes to the development of secondary brain injury, increasing mortality of patients. Impairment of pressure-induced myogenic constriction of cerebral arteries plays a critical role in autoregulatory dysfunction; however, the underlying cellular and molecular mechanisms are not well understood. To determine the role of mitochondria-derived H O and large-conductance calcium-activated potassium channels (BK ) in myogenic autoregulatory dysfunction, middle cerebral arteries (MCAs) were isolated from rats with severe weight drop-impact acceleration brain injury. We found that 24 h post-TBI MCAs exhibited impaired myogenic constriction, which was restored by treatment with a mitochondria-targeted antioxidant (mitoTEMPO), by scavenging of H O (polyethylene glycol [PEG]-catalase) and by blocking both BK channels (paxilline) and transient receptor potential cation channel subfamily V member 4 (TRPV4) channels (HC 067047). Further, exogenous administration of H O elicited significant dilation of MCAs, which was inhibited by blocking either BK or TRPV4 channels. Vasodilation induced by the TRPV4 agonist GSK1016790A was inhibited by paxilline. In cultured vascular smooth muscle cells H O activated BK currents, which were inhibited by blockade of TRPV4 channels. Collectively, our results suggest that after TBI, excessive mitochondria-derived H O activates BK channels via a TRPV4-dependent pathway in the vascular smooth muscle cells, which impairs pressure-induced constriction of cerebral arteries. Future studies should elucidate the therapeutic potential of pharmacological targeting of this pathway in TBI, to restore autoregulatory function in order to prevent secondary brain damage and decrease mortality.

• Legumes form a symbiosis with atmospheric nitrogen (N₂)-fixing soil rhizobia, resulting in new root organs called nodules that enable N₂-fixation. Nodulation is a costly process that is tightly regulated by the host through autoregulation of nodulation (AON) and nitrate-dependent regulation of nodulation. Both pathways require legume-specific CLAVATA/ESR-related (CLE) peptides. • Nitrogen-induced nodulation-suppressing CLE peptides have not previously been investigated in Medicago truncatula, for which only rhizobia-induced MtCLE12 and MtCLE13 have been characterised. Here, we report on novel peptides MtCLE34 and MtCLE35 in nodulation control. • The nodulation-suppressing CLE peptides of five legume species were classified into three clades based on sequence homology and phylogeny. This approached identified MtCLE34 and MtCLE35 and four new CLE peptide orthologues of Pisum sativum. Whereas MtCLE12 and MtCLE13 are induced by rhizobia, MtCLE34 and MtCLE35 respond to both rhizobia and nitrate. MtCLE34 was identified as a pseudogene lacking a functional CLE-domain. MtCLE35 was found to inhibit nodulation in a SUNN- and RDN1-dependent manner via overexpression analysis. • Together, our findings indicate that MtCLE12 and MtCLE13 have a specific role in AON, while MtCLE35 regulates nodule numbers in response to both rhizobia and nitrate. MtCLE34 likely had a similar role to MtCLE35, but its function was lost due to a premature nonsense mutation.

Background Legumes utilize a long-distance signaling feedback pathway, termed Autoregulation of Nodulation (AON), to regulate the establishment and maintenance of their symbiosis with rhizobia. Several proteins key to this pathway have been discovered, but the AON pathway is not completely understood. Results We report a new hypernodulating mutant, defective in autoregulation , with disruption of a gene, DAR ( Medtr2g450550/MtrunA17_Chr2g0304631 ), previously unknown to play a role in AON. The dar-1 mutant produces ten-fold more nodules than wild type, similar to AON mutants with disrupted SUNN gene function. As in sunn mutants, suppression of nodulation by CLE peptides MtCLE12 and MtCLE13 is abolished in dar . Furthermore, dar-1 also shows increased root length colonization by an arbuscular mycorrhizal fungus, suggesting a role for DAR in autoregulation of mycorrhizal symbiosis (AOM). However, unlike SUNN which functions in the shoot to control nodulation, DAR functions in the root. Conclusions DAR encodes a membrane protein that is a member of a small protein family in M. truncatula . Our results suggest that DAR could be involved in the subcellular transport of signals involved in symbiosis regulation, but it is not upregulated during symbiosis. DAR gene family members are also present in Arabidopsis, lycophytes, mosses, and microalgae, suggesting the AON and AOM may use pathway components common to other plants, even those that do not undergo either symbiosis.

MtCLE12 and MtCLE13 encode CLAVATA3/EMBRYO-SURROUNDING REGION RELATED (CLE) peptides which regulate autoregulation of nodulation (AON) in Medicago through the shoot receptor, SUNN (SUPER NUMERIC NODULES). Genetics suggests RDN1 (ROOTDETERMINED NODULATION 1) arabinosylates MtCLE12 to enable SUNN perception. The functional structures of MtCLE12 and MtCLE13 peptides, however, remain elusive. Wecombined genetic and chemical synthesis approaches to determine if glyco-modifications of three nodule-expressed CLE peptides are essential for AON. We also examined how root and shoot applied AON-CLEs inhibit nodulation. MtCLE12, MtCLE13 and MtCLE42 peptides were synthesized with hydroxylation, monoarabinosylation or tri-arabinosylation (TaP) at proline 7. Only MtCLE12-TaP and MtCLE13-TaP peptides induced AON in wild-type (WT) and rdn1-1, but not in sunn-4. The application of MtCLE13-TaP to cotyledons 1 d before rhizobial inoculation completely inhibited both rhizobial infection and nodulation. By contrast, MtCLE12-TaP induced significant AON without abolishing rhizobial infection. The results indicate that key CLE domain amino acids and TaP modifications to MtCLE12 and MtCLE13 are essential for SUNN-dependent AON. We also show evidence that RDN1 does not tri-arabinosylate MtCLE13. Finally, MtCLE13-TaP can induce a strong AON response in shoots that inhibits the entire symbiotic processes in roots. We present a new model for AON in Medicago.

We assess the relationships between various continuous measures of autoregulatory capacity in a cohort of adults with traumatic brain injury (TBI). We assessed relationships between autoregulatory indices derived from intracranial pressure (ICP: PRx, PAx, RAC), transcranial Doppler (TCD: Mx, Sx, Dx), brain tissue-oxygenation (ORx), and spatially resolved near infrared spectroscopy (NIRS resolved: TOx, THx). Relationships between indices were assessed using Pearson correlation coefficient, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC) and k-means cluster analysis (KMCA). All analytic techniques were repeated for a range of temporal resolutions of data, including minute-by-minute averages, moving means of 30 samples, and grand mean for each patient. Thirty-seven patients were studied. The PRx displayed strong association with PAx/RAC across all the analytical techniques: Pearson correlation (r = 0.682/r = 0.677, p < 0.0001), PCA, AHC, and KMCA in the grand mean data sheet. Most TCD-based indices (Mx, Dx) were correlated and co-clustered on PCA, AHC, and KMCA. The Sx was found to be more closely associated with ICP-derived indices on Pearson correlation, PCA, AHC, and KMCA. The NIRS indices displayed variable correlation with each other and with indices derived from ICP and TCD signals. Of interest, TOx and THx co-cluster with ICP-based indices on PCA and AHC. The ORx failed to display any meaningful correlations with other indices in neither of the analytical method used. Thirty-minute moving average and minute-by-minute data set displayed similar results across all the methods. The RAC, Mx, and Sx were the strongest predictors of outcome at six months. Continuously updating autoregulatory indices are not all correlated with one another. Caution must be advised when utilizing less commonly described autoregulation indices (i.e., ORx) for the clinical assessment of autoregulatory capacity, because they appear to not be related to commonly measured/establish indices, such as PRx. Further prospective validation is required.

The number of legume root nodules resulting from a symbiosis with rhizobia is tightly controlled by the plant. Certain members of the CLAVATA3/Embryo Surrounding Region (CLE) peptide family, specifically MtCLE12 and MtCLE13 in Medicago truncatula, act in the systemic autoregulation of nodulation (AON) pathway that negatively regulates the number of nodules. Little is known about the molecular pathways that operate downstream of the AON-related CLE peptides. Here, by means of a transcriptome analysis, we show that roots ectopically expressing MtCLE13 deregulate only a limited number of genes, including three down-regulated genes encoding lysin motif receptor-like kinases (LysM-RLKs), among which are the nodulation factor (NF) receptor NF Perception gene (NFP) and two up-regulated genes, MtTML1 and MtTML2, encoding Too Much Love (TML)-related Kelch-repeat containing F-box proteins. The observed deregulation was specific for the ectopic expression of nodulation-related MtCLE genes and depended on the Super Numeric Nodules (SUNN) AON RLK. Moreover, overexpression and silencing of these two MtTML genes demonstrated that they play a role in the negative regulation of nodule numbers. Hence, the identified MtTML genes are the functional counterpart of the Lotus japonicus TML gene shown to be central in the AON pathway. Additionally, we propose that the down-regulation of a subset of LysM-RLK-encoding genes, among which is NFP, might contribute to the restriction of further nodulation once the first nodules have been formed.

The symbiosis between legumes and nitrogen fixing bacteria called rhizobia leads to the formation of root nodules. Nodules are highly organized root organs that form in response to Nod factors produced by rhizobia, and they provide rhizobia with a specialized niche to optimize nutrient exchange and nitrogen fixation. Nodule development and invasion by rhizobia is locally controlled by feedback between rhizobia and the plant host. In addition, the total number of nodules on a root system is controlled by a systemic mechanism termed ’autoregulation of nodulation’. Both the local and the systemic control of nodulation are regulated by phytohormones. There are two mechanisms by which phytohormone signalling is altered during nodulation: through direct synthesis by rhizobia and through indirect manipulation of the phytohormone balance in the plant, triggered by bacterial Nod factors. Recent genetic and physiological evidence points to a crucial role of Nod factor-induced changes in the host phytohormone balance as a prerequisite for successful nodule formation. Phytohormones synthesized by rhizobia enhance symbiosis effectiveness but do not appear to be necessary for nodule formation. This review provides an overview of recent advances in our understanding of the roles and interactions of phytohormones and signalling peptides in the regulation of nodule infection, initiation, positioning, development, and autoregulation. Future challenges remain to unify hormone–related findings across different legumes and to test whether hormone perception, response, or transport differences among different legumes could explain the variety of nodules types and the predisposition for nodule formation in this plant family. In addition, the molecular studies carried out under controlled conditions will need to be extended into the field to test whether and how phytohormone contributions by host and rhizobial partners affect the long term fitness of the host and the survival and competition of rhizobia in the soil. It also will be interesting to explore the interaction of hormonal signalling pathways between rhizobia and plant pathogens.

Failure of cerebral autoregulation has been linked to unfavorable outcome after traumatic brain injury (TBI). Preliminary evidence from a small, retrospective, single-center analysis suggests that autoregulatory dysfunction may be associated with traumatic lesion expansion, particularly for pericontusional edema. The goal of this study was to further explore these associations using prospective, multi-center data from the Collaborative European Neurotrauma Effectiveness Research in TBI (CENTER-TBI) and to further explore the relationship between autoregulatory failure, lesion progression, and patient outcome. A total of 88 subjects from the CENTER-TBI High Resolution ICU Sub-Study cohort were included. All patients had an admission computed tomography (CT) scan and early repeat scan available, as well as high-frequency neurophysiological recordings covering the between-scan interval. Using a novel, semiautomated approach at lesion segmentation, we calculated absolute changes in volume of contusion core, pericontusional edema, and extra-axial hemorrhage between the imaging studies. We then evaluated associations between cerebrovascular reactivity metrics and radiological lesion progression using mixed-model regression. Analyses were adjusted for baseline covariates and non-neurophysiological factors associated with lesion growth using multi-variate methods. Impairment in cerebrovascular reactivity was significantly associated with progression of pericontusional edema and, to a lesser degree, intraparenchymal hemorrhage. In contrast, there were no significant associations with extra-axial hemorrhage. The strongest relationships were observed between RAC-based metrics and edema formation. Pulse amplitude index showed weaker, but consistent, associations with contusion growth. Cerebrovascular reactivity metrics remained strongly associated with lesion progression after taking into account contributions from non-neurophysiological factors and mean cerebral perfusion pressure. Total hemorrhagic core and edema volumes on repeat CT were significantly larger in patients who were deceased at 6 months, and the amount of edema was greater in patients with an unfavourable outcome (Glasgow Outcome Scale-Extended 1–4). Our study suggests associations between autoregulatory failure, traumatic edema progression, and poor outcome. This is in keeping with findings from a single-center retrospective analysis, providing multi-center prospective data to support those results.

Similar to functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS) detects the changes of hemoglobin species inside the brain, but via differences in optical absorption. Within the near-infrared spectrum, light can penetrate biological tissues and be absorbed by chromophores, such as oxyhemoglobin and deoxyhemoglobin. What makes fNIRS more advantageous is its portability and potential for long-term monitoring. This paper reviews the basic mechanisms of fNIRS and its current clinical applications, the limitations toward more widespread clinical usage of fNIRS, and current efforts to improve the temporal and spatial resolution of fNIRS toward robust clinical usage within subjects. Oligochannel fNIRS is adequate for estimating global cerebral function and it has become an important tool in the critical care setting for evaluating cerebral oxygenation and autoregulation in patients with stroke and traumatic brain injury. When it comes to a more sophisticated utilization, spatial and temporal resolution becomes critical. Multichannel NIRS has improved the spatial resolution of fNIRS for brain mapping in certain task modalities, such as language mapping. However, averaging and group analysis are currently required, limiting its clinical use for monitoring and real-time event detection in individual subjects. Advances in signal processing have moved fNIRS toward individual clinical use for detecting certain types of seizures, assessing autonomic function and cortical spreading depression. However, its lack of accuracy and precision has been the major obstacle toward more sophisticated clinical use of fNIRS. The use of high-density whole head optode arrays, precise sensor locations relative to the head, anatomical co-registration, short-distance channels, and multi-dimensional signal processing can be combined to improve the sensitivity of fNIRS and increase its use as a wide-spread clinical tool for the robust assessment of brain function.