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Stepping of an intact animal was characterized by a fast rise to maxima, maintenance on this level and fast decay of limbs' loading in the stance phase. In deafferentated rats a slow rise without maintenance in that phase was found. The role of afferent input intensity in reflex control of movements is discussed.
The transition from G1 to S phase, sister chromatid separation in anaphase, and the exit from mitosis are driven by the destruction of cell cycle regulatory proteins by distinct ubiquitin-dependent proteolytic pathways. The components and targets of these key degradation pathways are now becoming clear. Genetic and biochemical dissections of these extremely specific and well regulated destruction pathways are providing fundamental insights into the mechanisms of control of the cell division cycle.
Regulator of G-protein-signaling (RGS) proteins play a key role in the regulation of G-protein-coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved approximately 120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for G(alpha) proteins. Most RGS proteins can serve as GAPs for multiple isoforms of G(alpha) and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners. Many RGS proteins have GAP-independent functions that influence GPCR and non-GPCR-mediated signaling, such as effector regulation or action as an effector. Hence, RGS proteins should be considered multifunctional signaling regulators. GPCR-mediated signaling is critical for normal function in the cardiovascular system and is currently the primary target for the pharmacological treatment of disease. Alterations in RGS protein levels, in particular RGS2 and RGS4, produce cardiovascular phenotypes. Thus, because of the importance of GPCR-signaling pathways and the profound influence of RGS proteins on these pathways, RGS proteins are regulators of cardiovascular physiology and potentially novel drug targets as well.
Primulina, a genus of >200 species specialized to extreme soils, provides a model for edaphic adaptation. We assemble seven genomes and construct a pan-genome spanning nine species from karst, Danxia, and acidic soils. Comparative analyses reveal that karst-adapted species have smaller genomes. Two lineage-specific whole-genome duplications (WGDs) exhibit biased duplicate loss in large gene families but preferential retention of transcription factors, indicating combined adaptive and nonadaptive forces. Pan-genome analyses identify ion channel and transporter genes enriched in variant hotspots and under positive selection in karst lineages. Candidate genes for drought and salt stress tolerance include ABC transporters and ion channels. Notably, an ABC transporter shows positive selection in karst species and unique structural variation in non-karst species. Together, our findings show that genome downsizing, biased post-WGD retention, and evolution of ion-transport pathways shape adaptation to extreme soils. The Primulina pan-genome provides a resource for dissecting mechanisms underlying edaphic specialization.
Clinical pathways are similar to the production algorithms developed by industry. They are being adapted for use in healthcare to reduce resource utilization, decrease variability, and control expenditures. At Boston Medical Center we identified four trauma diagnoses that we believed to be amenable to the design and implementation of clinical pathways: closed head injury, penetrating wound to the abdomen, penetrating wound to the chest, and penetrating wound to an extremity. Upon implementation of these pathways, appropriate nonoperative, single-system, short-stay trauma patients were enrolled in them. This article details the process by which the four diagnoses were identified and the pathways designed, implemented, and evaluated. Preliminary data demonstrate a significant decrease in resource utilization following implementation of the pathways, without an adverse impact on readmission rates, length of stay, or mortality.
Deletions at 22q11.1-q11.2 present with variable manifestations usually referred to as DiGeorge or velo-cardio-facial syndrome. We previously reported that deletions observed in patients with the syndrome can be subgrouped into three types (common large deletion, proximal deletion, and distal deletion) and demonstrated the presence of a second critical region for the syndrome. In order to characterize further the second critical region, a 22q11 deletion map was constructed from the data of 100 patients, using 12 DNA markers scattered in the common large deletion, and then a phenotype-genotype correlation was analyzed. The second critical region was found to correspond to the distal deletion encompassing the HCF2, cHKAD26, and D22S935 loci, and the proximal and distal deletions do not overlap each other. Although it seems that this condition is a contiguous gene syndrome, the phenotype of patients with these two types of deletion was indistinguishable from that of patients with the common large deletion. Thus, it is plausible that several genes located in the two segments corresponding to the two deleted regions are involved in the same developmental pathway or in an extremely long-range position effect.
The projection patterns of morphologically and functionally identified auditory and auditory-vibratory receptor cells of receptor organs (the crista acustica and the intermediate organ) in the foreleg of the tettigoniid Psorodonotus illyricus, were investigated with combined recording and staining techniques, and subsequent histological examination and morphometric measurements. With the application of a computer program (AutoCAD), three-dimensional reconstructions of the axon end branches of receptor cells within the neuropile of the anterior Ring Tract (aRT) were made, in order to determine, the entire shape of each, the pattern and density of the end branches, and the positions of the target areas within the auditory neuropile. Clear differences for different functional types of receptors were found.
We present a case of an extremely rare portosystemic collateral pathway which arose from the right intrahepatic portal vein, passed through the liver parenchyma, and terminated into the inferior vena cava. We demonstrate the findings of diagnostic imaging and discuss the etiology of the collateral circulation in this unusual case.
Ralstonia eutropha JMP134 (pJP4) harbors two functional gene clusters for the degradation of chlorocatechols, i.e. tfdCDEF (in short: tfd (I)) and tfdD (II) C (II) E (II) F (II) (in short: tfd (II)), which are both present on the catabolic plasmid pJP4. In this study, we compared the function of both gene clusters for degradation of chlorocatechols by constructing isolated and hybrid tfd (I)- tfd (II) clusters on plasmids in R. eutropha, by activity assays of Tfd enzymes, and by HPLC/MS of individual enzymatic catalytic steps in chlorocatechol conversion. R. eutropha containing the tfd (II) cluster alone or hybrid tfd-clusters with tfdD (II) as sole gene for chloromuconate cycloisomerase were impaired in growth on 3-chlorobenzoate, in contrast to R. eutrophaharboring the complete tfd (I) cluster. Enzyme activities for TfdD(II) and for TfdE(II) were very low in R. eutropha when induced with 3-chlorobenzoate. By contrast, a relatively high enzyme activity was found for TfdF(II). Spectral conversion assays with extracts from R. eutropha strains expressing tfdD (II) all showed accumulation of a compound with a similar UV spectrum as 2-chloro- cis,cis-muconate from 3-chlorocatechol. HPLC analysis of in vitro assays in which each individual step in 3-chlorocatechol conversion was reproduced by sequentially adding cell extracts of an Escherichia coli expressing one Tfd enzyme only demonstrated that TfdD(II) was unable to cause conversion of 2-chloro- cis,cis-muconate. No accumulation of intermediates was observed with 4-chlorocatechol. From these results, we conclude that at least TfdD(II) is a bottleneck in conversion of 3-chlorocatechol and, therefore, in efficient metabolism of 3-chlorobenzoate. This study showed the subtle functional and expression differences between similar enzymes of the tfd-encoded pathway and demonstrated that extreme care has to be taken when inferring functionality from sequence data alone.
1. The GABAergic neurotransmission has been implicated in the modulation of many neural networks in forebrain, midbrain and hindbrain, as well as, in several neurological disorders. 2. The complete comprehension of GABA system neurochemical properties and the search for approaches in identifying new targets for the treatment of neural diseases related to GABAergic pathway are of the extreme relevance. 3. The present review will be focused on the pharmacology and biochemistry of the GABA metabolism, GABA receptors and transporters. In addition, the pathological and psychobiological implications related to GABAergic neurotransmission will be considered.
In this study in the rat, we evaluated the effect of unilateral, multiple cervical dorsal rhizotomy (C5-T1) on nociceptive thresholds in the unoperated limbs. This was tested by measuring the vocalization threshold to paw pressure. We report that deafferentation by dorsal rhizotomy results in a delayed, but transient increase in mechanical nociceptive thresholds in the 3 innervated limbs.
Electrophysiological studies, including electrooculogram (EOG), and simultaneously recorded flash and pattern evoked electroretinograms (FERG and PERG) and visually evoked potentials (FVEP and PVEP) were made in 1988 on 10 newly diagnosed untreated Parkinson's patients at Stage 1 of the Hoehn and Yahr scale. Follow up studies were made on five out of the 10 patients when their disease had progressed to Stage 2 during 1993. The earliest and only sign of abnormality detected in the Stage 1 of Parkinson's patients in 1988 was a delay in the time to reach the peak light rise in the EOG. When the disease had progressed to Stage 2, not only a delay in the time to reach the peak light rise but also a reduction in the amplitude of the peak light rise in the EOG, together with changes in PERG, FERG and PVEPs were demonstrable. These changes observed in PERG, FERG and PVEPs were generally consistent with those reported by previous studies. It is suggested that the reason for the susceptibility of pigment epithelial function to dopamine deficiency in Parkinson's disease may be due to the pigment epithelium being at the extremity of the diffusion pathway from dopamine release sites at the inner plexiform layer.
The ease with which we perform tasks such as opening the lid of a jar, in which the two hands execute quite different actions, belies the fact that there is a strong tendency for the movements of the upper limbs to be drawn systematically towards one another. Mirror movements, involuntary contractions during intended unilateral engagement of the opposite limb, are considered pathological, as they occur in association with specific disorders of the CNS. Yet they are also observed frequently in normally developing children, and motor irradiation, an increase in the excitability of the (opposite) homologous motor pathways when unimanual movements are performed, is a robust feature of the mature motor system. The systematic nature of the interactions that occur between the upper limbs has also given rise to the expectation that functional improvements in the control of a paretic limb may occur when movements are performed in a bimanual context. In spite of the ubiquitous nature of these phenomena, there is remarkably little consensus concerning the neural basis of their mediation. In the present review, consideration is given to the putative roles of uncrossed corticofugal fibers, branched bilateral corticomotoroneuronal projections, and segmental networks. The potential for bilateral interactions to occur in various brain regions including the primary motor cortex, the supplementary motor area, non-primary motor areas, the basal ganglia, and the cerebellum is also explored. This information may provide principled bases upon which to evaluate and develop task and deficit-specific programs of movement rehabilitation and therapy.
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In Cnidarians, cnidoblast cells contain organelles called cnidocysts, which are believed to be the product of an extremely complex regulated secretory pathway. When matured, these stinging organelles are capable of storing and delivering toxins. We hypothesized that translated nematocyst proteins might comprise specific sequences serving as signals in sorting to the organelle. A sodium channel neurotoxin from the sea anemone Actinia equina was cloned and the toxin precursor sequence was compared to those of nematocyst collagens, pore-forming toxins and ion channel neurotoxins. It was found that all the analyzed sequences possess a highly conserved stretch of nine amino acid residues ending with Lys-Arg N-terminally of the mature region.
During the translocation of the band 3 transport site between the inward- and outward-facing orientations, the Cl- transport site complex passes through a transition state lying on the reaction pathway between the two extreme orientations. Niflumic acid, 2-[(7-nitrobenzofurazan-4-yl)amino]ethanesulfonate, and 2,4,6-trichlorobenzenesulfonate each are translocation blockers that can bind to both the inward- and outward-facing conformations of band 3. The principal mechanism of these inhibitors is a reduction in the translocation rate, since they have essentially no effect on the apparent KD for Cl- binding to the transport site and the migration of Cl- between the transport site and solution. Instead, these inhibitors raise the free energy of formation of the transition state during translocation and thereby can lock the transport site into either the inward- or outward-facing orientation. In contrast, 2,4-dinitrofluorobenzene (DNFB) appears to restrict the accessibility of the transport site to solution Cl-; also, the DNFB reaction rate is increased by Cl-, suggesting that DNFB modification may occur during translocation. Thus DNFB is proposed to trap the Cl--transport site complex site during translocation to yield a conformation intermediate to the inward- and outward-facing orientations. A model is presented for the molecular mechanism of transport across biological membranes. The transport machinery is proposed to contain greater than or equal to 6 transmembrane helices that surround a central channel containing a sliding hydrophobic barrier. The transport site lies between two of the channel-forming helices and remains stationary while the hydrophobic barrier slides from one end of the channel to the other, thereby exposing the transport site to the opposite solution compartment.
Based largely upon analysis of ribosomal RNA, a third domain of life, called archaea, had been proposed in addition to bacteria and eukaryotes. However, quantitative analysis of 73 whole genomes shows only a two-domain division of life: into eukaryotes and prokaryotes. Thousands of orthologous genes in archaea and bacteria show an essentially unimodal distribution of sequence identities. Thus, whole genome analyses indicate that archaea are a phylum of bacteria rather than a separate domain of life. In contrast, archaeal rRNA and that of hyperthermophilic bacteria differ from the rRNA of mesophilic bacteria. Thus, there is a bimodal distribution of rRNA sequence identities which differ by 12%. This discrepancy in rRNA and gene content based analyses of whole genomes is likely due to a 15% elevated C:G content of the rRNA of archaea and hyperthermophilic bacteria. The elevated C:G content is consistent with stabilization against thermal denaturation caused by additional hydrogen bonding (3 bonds) in C:G pairs compared to A:U pairs (2 bonds). Based upon this premise, there is no reliable way to correct rRNA for such differences in base composition and it is not possible to quantitatively compare hyperthermophiles with mesophiles by the rRNA method. Furthermore, quantitative study of whole genomes shows that the extent of change in both bacterial and archaeal genes, including rRNA, has reached a limit. Thus, direct sequence comparisons work with closely related genomes, but it is not possible to differentiate the most divergent prokaryotic species, which are currently designated as separate phyla. We believe that the differences in characteristics of archaeal species is based primarily upon selection of genes and pathways compatible with the extreme environmental lifestyle, i.e., hyperthermophily.
Theoretical calculations and gas-phase mass spectrometric studies were performed for the reaction of the naked (NO2+) and monosolvated (CH3NO2.NO2+) nitronium ion with several monosubstituted aromatic compounds. From these studies, we propose a general model for regioselectivity based on the single-electron transfer (SET) mechanism and an alternative mechanistic scheme for electrophilic aromatic nitration. This scheme considers the SET and the polar (Ingold-Hughes) mechanisms as extremes in a continuum pathway, the occurrence and extents of both mechanisms being governed mainly by the ability, or lack of ability, of the aromatic compound to transfer an electron to NO2+.