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Biomedical subjects

R D Johnson

Publications and source records attributed to R D Johnson.

At least 37 records · Page 2Linked to original sources

Spontaneous loss of a conditionally dispensable chromosome from the Alternaria alternata apple pathotype leads to loss of toxin production and pathogenicity.

The Alternaria alternata apple pathotype causes Alternaria blotch of susceptible apple cultivars through the production of a cyclic peptide, host-specific toxin, AM-toxin. We recently cloned a cyclic peptide synthetase gene, AMT, whose product catalyzes the production of AM-toxin and showed that it resides on chromosomes of 1.8 Mb or less, depending on the A. alternata apple pathotype strain. Reverse transcriptase (RT)-PCR, using primers specific to AMT, on laboratory sub-cultured strains previously shown to produce AM-toxin, identified one isolate that did not express the gene. A leaf necrosis bioassay confirmed an AM-toxin-minus phenotype. However, an original isolate of this strain which had not undergone sub-culture gave a positive result by both RTPCR and bioassay. Contour-clamped homogeneous electric field electrophoresis and Southern hybridization demonstrated the loss of a 1.1-Mb chromosome in the non-toxin-producing isolate. Since this chromosome can be entirely lost without affecting growth, but is necessary for pathogenicity, we propose it is a conditionally dispensable chromosome.

Alternaria↗

Double-strand-break-induced homologous recombination in mammalian cells.

In mammalian cells, the repair of DNA double-strand breaks (DSBs) occurs by both homologous and non-homologous mechanisms. Indirect evidence, including that from gene targeting and random integration experiments, had suggested that non-homologous mechanisms were significantly more frequent than homologous ones. However, more recent experiments indicate that homologous recombination is also a prominent DSB repair pathway. These experiments show that mammalian cells use homologous sequences located at multiple positions throughout the genome to repair a DSB. However, template preference appears to be biased, with the sister chromatid being preferred by 2-3 orders of magnitude over a homologous or heterologous chromosome. The outcome of homologous recombination in mammalian cells is predominantly gene conversion that is not associated with crossing-over. The preference for the sister chromatid and the bias against crossing-over seen in mitotic mammalian cells may have developed in order to reduce the potential for genome alterations that could occur when other homologous repair templates are utilized. In attempts to understand further the mechanism of homologous recombination, the proteins that promote this process are beginning to be identified. To date, four mammalian proteins have been demonstrated conclusively to be involved in DSB repair by homologous recombination: Rad54, XRCC2, XRCC3 and BRCA1. This paper summarizes results from a number of recent studies.

Animals↗

Influence of equine herpesvirus type 2 infection on monocyte chemoattractant protein 1 gene transcription in equine blood mononuclear cells.

Representational difference analysis (RDA) was used to compare gene expression in equine mononuclear cells either infected with equine herpesvirus-2 (EHV-2) or adsorbed with inactivated EHV-2. Seven clones identified in non-infected cells after three rounds of selective subtraction and enrichment for differentially expressed genes contained sequences homologous to equine monocyte chemoattractant protein 1 (MCP-1). This suggested that EHV-2 may down-regulate MCP-1 transcription in infected cells. These findings correlate well with similar findings described for human cytomegalovirus and support the view that EHV-2 may have the ability to modify the chemokine environment of infected cells. This may constitute an important feature of EHV-2 biology, because such an ability has the potential to compromise host defence mechanisms and predispose to infection with other pathogens.

Animals↗

P2X1 receptor subunit immunoreactivity and ATP-evoked fast currents in adult rat dorsal root ganglion neurons.

Triple fluorescent staining for P2X1 and P2X3 subunits and isolectin I-B4 (IB4) were performed on acutely dissociated rat DRG neurons. Immunoreactivity for P2X1 and P2X3 subunits was present separately or together in DRG neurons. P2X1 immunoreactivity was present in both IB4-positive and IB4-negative cells. When combining patch-clamp recordings with immunostaining for the P2X1 and P2X3 subunits on single recorded cells, ATP-evoked fast currents were shown to be present on DRG neurons that have immunoreactivity for the P2X3 subunit only, the P2X1 subunit only, or both P2X1 and P2X3 subunits. These results raised a possibility that, in addition to the P2X3 receptor subunit, the P2X1 subunit may also contribute to functional P2X receptors with fast kinetics in DRG neurons.

Adenosine Triphosphate↗

A selective optical sensor based on [9]mercuracarborand-3, a new type of ionophore with a chloride complexing cavity.

A highly selective optical sensor for chloride, based on the multidentate Lewis acid ionophore [9]mercuracarborand-3, is described herein. This sensor is constructed by embedding the mercuracarborand ionophore, a suitable pH-sensitive lipophilic dye, and lipophilic cationic sites in a plasticized polymeric membrane. The multiple complementary interactions offered by the preorganized complexing cavity of [9]mercuracarborand-3 is shown to control the anion selectivity pattern of the optical film. The film exhibits a significantly enhanced selectivity for chloride over a variety of lipophilic anions such as perchlorate, nitrate, salicylate, and thiocyanate. Furthermore, the optical selectivity coefficients obtained for chloride over other biologically relevant anions are shown to meet the selectivity requirements for the determination of chloride in physiological fluids, unlike previously reported chloride optical sensors. In addition, the optical film responds to chloride reversibly over a wide dynamic range (16 microM-136 mM) with fast response and recovery times.

Algorithms↗

Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells.

In mammalian cells, repair of DNA double-strand breaks (DSBs) occurs by both homologous and non-homologous mechanisms. By definition, homologous recombination requires a template with sufficient sequence identity to the damaged molecule in order to direct repair. We now show that the sister chromatid acts as a repair template in a substantial proportion of DSB repair events. The outcome of sister chromatid repair is primarily gene conversion unassociated with reciprocal exchange. This contrasts with expectations from the classical DSB repair model originally proposed for yeast meiotic recombination, but is consistent with models in which recombination is coupled intimately with replication. These results may explain why cytologically observable sister chromatid exchanges are induced only weakly by DNA-damaging agents that cause strand breaks, since most homologous repair events would not be observed. A preference for non-crossover events between sister chromatids suggests that crossovers, although genetically silent, may be disfavored for other reasons. Possibly, a general bias against crossing over in mitotic cells exists to reduce the potential for genome alterations when other homologous repair templates are utilized.

Animals↗

Brainstem microstimulation activates sympathetic fibers in pudendal nerve motor branch.

A bilateral spino-bulbo-spinal circuit conveys information from/to the male urogenital tract and perineal muscles. This is the first electrophysiological report of another descending pathway, one which conveys output from the medullary reticular formation (MRF) to activate postganglionic sympathetic fibers contained within the motor branch of the pudendal nerve (PudM). In anesthetized rats, long latency (> 150 ms) discharges were elicited in the PudM following ipsilateral or contralateral microstimulation of the MRF. These firing bursts were not observed in rats after sectioning the lower lumbar sympathetic trunk. The most robust activation was observed when neurons in or near the lateral paragigantocellular reticular nucleus were microstimulated bilaterally. Urogenital dysfunction that occurs following severe spinal cord injury probably results from disrupting these and other supraspinal circuits.

Action Potentials↗

Distribution patterns of different P2x receptor phenotypes in acutely dissociated dorsal root ganglion neurons of adult rats.

P2x receptors may be used to detect ATP release from tissues during physiological and pathological conditions. We used whole-cell patch clamp recordings to study the expression of P2x receptor phenotypes, their distribution patterns, and their sensitivity to alphabetamATP and suramin in dorsal root ganglion (DRG) neurons acutely dissociated from adult rats. Based on the onset and decay rates of 10 microM ATP-evoked currents, we showed three types of P2x currents: fast, slow, and mixed. Each of these P2x receptor phenotypes had a distinct distribution pattern among DRG neurons. The fast P2x currents were predominantly expressed in small-diameter, isolectin-B4 (IB4)-positive, and capsaicin-sensitive DRG neurons. The slow P2x currents were expressed in both small and medium DRG neurons, and about half of them were IB4 positive. The mixed P2x currents were also expressed in both small and medium-sized DRG neurons, and most of these neurons were IB4-positive neurons. The slow and mixed P2x current groups had both capsaicin-sensitive and -insensitive DRG neurons. All phenotypes revealed with 10 microM ATP could be inhibited by 30 microM suramin. All DRG neurons with fast or mixed P2x currents were also sensitive to 10 microM alphabetamATP, and alphabetamATP evoked currents similar to those induced by ATP. The group expressing slow P2x currents could be further divided into alphabetamATP-sensitive and -insensitive groups. Thus, the relationships among P2x receptor phenotypes, cell sizes, IB4 positivity, and capsaicin sensitivity are more complicated than previously thought, and different P2x receptors may be involved in both nociceptive and non-nociceptive functions.

Adenosine Triphosphate↗

Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer.

PURPOSE: To evaluate the population pharmacokinetics of pemetrexed disodium in cancer patients enrolled in four different open-label, multicenter, nonrandomized phase II studies. METHODS: Pemetrexed disodium was administered as a 10-min intravenous infusion (600 mg/m2) every 21 days. A total of four blood samples were to be collected each cycle per patient (n= 103 patients) during cycles 1 and 3. Plasma concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM to estimate pemetrexed disodium pharmacokinetic parameters (mean, and between- and within-patient variability) as well as relationships between the pharmacokinetic parameters and various patient-specific factors (demographic and physiologic data). RESULTS/CONCLUSIONS: The pharmacokinetics of pemetrexed disodium were best characterized by a two-compartment model with initial distribution and terminal elimination half-lives of 0.63 h and 2.73 h, respectively. The typical value of systemic clearance (CL) in liters per hour included a relationship to creatinine clearance (CrCL) with a slope of 0.0292. Typical values of central volume (V(c)), distributional CL (Q), and peripheral volume (V(p)) were 11.3 1, 3.21 l/h, and 5.20 l, respectively. Between-patient variability was 19.6%, 15.6%, and 21.7% for CL, V(c), and V(p), respectively. A combined additive/proportional error model was used to describe residual variability, with a coefficient of variation of 23.7% for the proportional component and a standard deviation of 0.0410 microg/ml for the additive component. Significant patient-specific factors on CL were calculated CrCL, body weight, and to a lesser extent alanine transaminase and folate deficiency. Gender and body weight were significant factors on V(c) while both body surface area and albumin were significant factors on V(p). In conclusion, population pharmacokinetic modeling revealed relationships between pharmacokinetic parameters and various patient specific factors.

Adult↗

Distribution of P2X1, P2X2, and P2X3 receptor subunits in rat primary afferents: relation to population markers and specific cell types.

We determined the co-expression of immunoreactivity (IR) for ATP-receptor subunits (P2X1, P2X2, and P2X3), neuropeptides, neurofilament (NF), and binding of the isolectin B(4) from Griffonia simplicifolia type one (GS-I-B(4)) in adult dorsal root ganglion neurons. P2X1-IR was expressed primarily in small DRG neurons. Most P2X1-IR neurons expressed neuropeptides and/or GS-I-B(4)-binding, but lacked NF-IR. P2X1-IR overlapped with P2X3-IR, though each was also found alone. P2X2-IR was expressed in many P2X3-IR small neurons, as well as a group of medium to large neurons that lacked either P2X3-IR or GS-I-B(4)-binding. A novel visible four-channel fluorescence technique revealed a unique population of P2X2/3-IR neurons that lacked GS-I-B(4)-binding but expressed NF-IR. Co-expression of P2X1, and P2X3 in individual neurons was also demonstrated. We examined P2X subunit-IR on individual recorded neurons that had been classified by current signature in vitro. Types 1, 2, 4 5, and 7 expressed distinct patterns of P2X-IR that corresponded to patterns identified in DRG sections, and had distinct responses to ATP. Types with rapid ATP currents (types 2, 5, and 7) displayed P2X3-IR and/or P2X1-IR. Types with slow ATP currents (types 1 and 4) displayed P2X2/3-IR. Type 1 neurons also displayed P2X1-IR. This study demonstrates that the correlation between physiological responses to ATP and the expression of particular P2X receptor subunits derived from expression systems is also present in native neurons, and also suggests that novel functional subunit combinations likely exist.

Adenosine Triphosphate↗

Reliability of cervical range of motion using the OSI CA 6000 spine motion analyser on asymptomatic and symptomatic subjects.

Cervical range of motion (ROM) is evaluated in both clinical and research settings. This study's purpose was to determine if ROM data obtained with the OSI CA 6000 Spine Motion Analyser (SMA) from asymptomatic and symptomatic cervical subjects were reliable within and between testers. Cervical ROM was measured in all three planes in 30 adult asymptomatic and 20 adult symptomatic subjects. A standardized protocol was used to fit each subject with the OSI SMA cervical hardware. Subjects were tested in a seated position with the trunk stabilized. Subjects performed four trials of each pain-free cervical motion during testing. The hardware was completely removed and replaced by the same tester and ROM trials in all three planes were repeated for intratester asymptomatic and symptomatic reliability. The same procedure was completed by a second tester for asymptomatic intratester and intertester reliability. Repeated measures analysis of variance and intraclass correlation coefficients (ICC [2,1 and 2 k]) were used to analyse intra- and intertester reliability data. Intratester ICCs were 0.85 or higher (except for flexion 0.76) for asymptomatic subjects and 0. 87 or higher (except for flexion 0.68) for symptomatic subjects for all motions. Intertester ICCs were 0.88 or higher for all motions. Standard error of measurements were less than 3.92 degrees for all motions. Measures of cervical spinal ROM obtained with the OSI SMA showed good intertester reliablity for all motions, and good intratester reliability for all motions with the exception of the motion of flexion for one of the examiners, which showed moderate reliability.

Adult↗

Cloning and characterization of a cyclic peptide synthetase gene from Alternaria alternata apple pathotype whose product is involved in AM-toxin synthesis and pathogenicity.

Afternaria afternata apple pathotype causes Alternaria blotch of susceptible apple cultivars through the production of a cyclic peptide host-specific toxin, AM-toxin. PCR (polymerase chain reaction), with primers designed to conserved domains of peptide synthetase genes, amplified several products from A. alternata apple pathotype that showed high similarity to other fungal peptide synthetases and were specific to the apple pathotype. Screening of a Lambda Zap genomic library with these PCR-generated probes identified overlapping clones containing a complete cyclic peptide synthetase gene of 13.1 kb in length with no introns. Disruption of this gene, designated AM-toxin synthetase (AMT), by transformation of wild-type A. afternata apple pathotype with disruption vectors resulted in toxin-minus mutants, which were also unable to cause disease symptoms on susceptible apple cultivars. AM-toxin synthetase is therefore a primary determinant of virulence and specificity in the A. alternata apple pathotype/apple interaction.

Alternaria↗

Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange.

Cells can achieve error-free repair of DNA double-strand breaks (DSBs) by homologous recombination through gene conversion with or without crossover. In contrast, an alternative homology-dependent DSB repair pathway, single-strand annealing (SSA), results in deletions. In this study, we analyzed the effect of mRAD54, a gene involved in homologous recombination, on the repair of a site-specific I-SceI-induced DSB located in a repeated DNA sequence in the genome of mouse embryonic stem cells. We used six isogenic cell lines differing solely in the orientation of the repeats. The combination of the three recombination-test substrates used discriminated among SSA, intrachromatid gene conversion, and sister chromatid gene conversion. DSB repair was most efficient for the substrate that allowed recovery of SSA events. Gene conversion with crossover, indistinguishable from long tract gene conversion, preferentially involved the sister chromatid rather than the repeat on the same chromatid. Comparing DSB repair in mRAD54 wild-type and knockout cells revealed direct evidence for a role of mRAD54 in DSB repair. The substrate measuring SSA showed an increased efficiency of DSB repair in the absence of mRAD54. The substrate measuring sister chromatid gene conversion showed a decrease in gene conversion with and without crossover. Consistent with this observation, DNA damage-induced sister chromatid exchange was reduced in mRAD54-deficient cells. Our results suggest that mRAD54 promotes gene conversion with predominant use of the sister chromatid as the repair template at the expense of error-prone SSA.

Animals↗

Effects of acute and chronic midthoracic spinal cord injury on neural circuits for male sexual function. II. Descending pathways.

In normal animals, microstimulation of the medullary reticular formation (MRF) has two effects on efferent neurons in the motor branch of the pudendal nerve (PudM). MRF microstimulation depresses motoneuron reflex discharges (RD) elicited by dorsal nerve of the penis (DNP) stimulation and produces long latency sympathetic fiber responses (SFR). The midthoracic spinal location of these descending MRF-PudM projections was studied electrophysiologically using a variety of acute and chronic lesions. Chronic lesions, in 27 mature male rats, included dorsal (DHx) or lateral (LHx) hemisections or moderate/severe contusions (Cx) at spinal level T(8). Behavioral data (sexual reflex latency, bladder voiding) obtained throughout the recovery period revealed a significant impairment of urogenital function for the DHx and severe Cx groups of animals. Microstimulation-induced PudM-RDs and PudM-SFRs, obtained in terminal electrophysiological experiments 30 days postinjury in the same 27 rats (urethan-anesthetized), were tested for a combined total of 1,404 bilateral MRF sites. PudM-RD was obtained for LHx and moderate Cx groups of animals but not for DHx or severe Cx groups. PudM-SFRs were obtained for LHx, DHx (although significantly weakened) and moderate Cx groups but not for those having received either an over-DHx or a severe Cx injury. PudM responses also were tested for 6 MRF sites in six intact control rats both before and after various select acute spinal cord lesions. For MRF sites producing a robust PudM-RD and PudM-SFR, acute bilateral lesions confined to the dorsolateral quadrant (DLQ) eliminated the PudM-RD but failed to eliminate PudM-SFRs. A deeper lesion encompassing additional white matter located dorsally in the ventrolateral quadrant (VLQ) was necessary to eliminate PudM-SFRs. Overall, these electrophysiological results provide evidence for descending projections conveying information between MRF and the lower thoracic/lumbosacral male urogenital circuitry within the DLQ and the dorsal-most aspect of VLQ at the midthoracic level of spinal cord. The alterations of supraspinal projections observed after chronic injury are likely of important clinical significance for functional recovery in cases of clinically incomplete spinal cord injury at midthoracic spinal cord.

Acute Disease↗

Subclassified acutely dissociated cells of rat DRG: histochemistry and patterns of capsaicin-, proton-, and ATP-activated currents.

We used a "current signature" method to subclassify acutely dissociated dorsal root ganglion (DRG) cells into nine subgroups. Cells subclassified by current signature had uniform properties. The type 1 cell had moderate capsaicin sensitivity (25.9 pA/pF), powerful, slowly desensitizing (tau = 2,300 ms), ATP-activated current (13.3 pA/pF), and small nondesensitizing responses to acidic solutions (5.6 pA/pF). Type 1 cells expressed calcitonin gene-related peptide immunoreactivity (CGRP-IR), manifested a wide action potential (7.3 ms), long duration afterhyperpolarization (57.0 ms), and were IB4 positive. The type 2 cell exhibited large capsaicin activated currents (134.9 pA/pF) but weak nondesensitizing responses to protons (15.3 pA/pF). Currents activated by ATP and alphabeta-m-ATP (51.7 and 44.6 pA/pF, respectively) had fast desensitization kinetics (tau = 214 ms) that were distinct from all other cell types. Type 2 cells were IB4 positive but did not contain either substance P (SP) or CGRP-IR. Similar to capsaicin-sensitive nociceptors in vivo, the afterhyperpolarization of the type 2 cell was prolonged (54.7 ms). The type 3 cell expressed, amiloride-sensitive, rapidly desensitizing (tau = 683 ms) proton-activated currents (127.0 pA/pF), and was insensitive to ATP or capsaicin. The type 3 cell was IB4 negative and contained neither CGRP nor SP-IR. The afterhyperpolarization (17.5 ms) suggested nonnociceptive function. The type 4 cell had powerful ATP-activated currents (17.4 pA/pF) with slow desensitization kinetics (tau = 2, 813 ms). The afterhyperpolarization was prolonged (46.5 ms), suggesting that this cell type might belong to a capsaicin-insensitive nociceptor population. The type 4 cell did not contain peptides. The type 7 cell manifested amiloride-sensitive, proton-activated currents (45.8 pA/pF) with very fast desensitization kinetics (tau = 255 ms) and was further distinct from the type 3 cell by virtue of a nondesensitizing amiloride-insensitive component (6.0 pA/pF). Capsaicin and ATP sensitivity were relatively weak (4.3 and 2.9 pA/pF, respectively). Type 7 cells were IB4 positive and contained both SP and CGRP-IR. They exhibited an exceptionally long afterhyperpolarization (110 ms) that was suggestive of a silent (mechanically insensitive) nociceptor. We concluded that presorting of DRG cells by current signatures separated them into internally homogenous subpopulations that were distinct from other subclassified cell types.

Action Potentials↗

Atrial fibrillation occurring in a patient taking etanercept plus methotrexate for rheumatoid arthritis.

A 57-year-old man with nodular rheumatoid arthritis was started on a combination of etanercept and methotrexate. After treatment for five months on this therapy, he presented with new-onset atrial fibrillation. While this report is anecdotal, any new drug warrants intense monitoring for unexpected toxicities in the post-marketing period. Etanercept is being tried in patients with congestive heart failure, where TNF-a seems to be increased. Further surveillance and caution are suggested in patients with known coronary artery disease or atrial dysrhythmia.

Antirheumatic Agents↗

XRCC3 promotes homology-directed repair of DNA damage in mammalian cells.

Homology-directed repair of DNA damage has recently emerged as a major mechanism for the maintenance of genomic integrity in mammalian cells. The highly conserved strand transferase, Rad51, is expected to be critical for this process. XRCC3 possesses a limited sequence similarity to Rad51 and interacts with it. Using a novel fluorescence-based assay, we demonstrate here that error-free homology-directed repair of DNA double-strand breaks is decreased 25-fold in an XRCC3-deficient hamster cell line and can be restored to wild-type levels through XRCC3 expression. These results establish that XRCC3-mediated homologous recombination can reverse DNA damage that would otherwise be mutagenic or lethal.

Animals↗