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PubMed1995

Expression of LTP by AMPA and/or NMDA receptors is determined by the extent of NMDA receptors activation during the tetanus.

1. We have tested, in CA1 hippocampal slices, the hypothesis that the expression of long-term potentiation (LTP) by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and/or N-methyl-D-aspartate (NMDA) receptors depends on the degree of NMDA receptors activation during the tetanus. 2. Slices were perfused in an artificial cerebrospinal fluid (ACSF) containing glycine (1 microM), bicuculline (5 microM) and a low Mg2+ concentration (0.3 mM). To measure the AMPA and NMDA receptor-mediated field excitatory postsynaptic potential (fEPSPA and fEPSPN, respectively), we have used the following procedure: control fEPSPA was first measured, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 microM) was then added, and fEPSPN was evoked. CNQX was washed, and once control fEPSPA was recorded, the Schaffer collaterals were tetanized at a weak or a strong intensity. The slope of fEPSPA was measured for 30-45 min followed by that of fEPSPN after the application of CNQX. 3. At a weak intensity (TW, which corresponds to a fEPSPA of approximately 0.3 mV of amplitude and no fEPSPN), the tetanic stimulation generated LTP of fEPSPA (58.7 +/- 8.1% mean +/- SE, n = 9) but no significant potentiation of the fEPSPN (11.2 +/- 2.2%, n = 9). These values were significantly different (P < 0.05, analysis of variance, Fisher test). 4. In 9 of 13 slices, tetanic stimulation of strong intensity (Ts, intensity corresponding to a fEPSPN of approximately 0.3 mV of amplitude) generated LTP of fEPSPN (89.1 +/- 17.2%) but not of fEPSPA (9.44 +/- 2.8%). In the four remaining slices the tetani induce LTP of both fEPSPA and fEPSPN (81.7 +/- 14.7% and 101 +/- 35.6%, respectively, both values were not significantly different). 5. We then examined the effects of decreasing fEPSPN by 50% in LTP generated by Ts and Tw. In the presence of 7-Chlorokynurenate (7Cl(-)-Kyn; 6 microM; n = 6), an antagonist of the allosteric glycine site of the NMDA receptors, Ts generated LTP of fEPSPA (63.2 +/- 8.2%) but not of fEPSPN (12.6 +/- 4.0%). Both values were significantly different. Tw still evoked LTP of fEPSPA but of smaller magnitude (29.8 +/- 6.3%, n = 8) than the one obtained in the absence of the antagonist (58.7 +/- 8.1%). Both values were significantly different. 6. The present observation suggests that l) LTP of fEPSPA has a lower threshold than that of fEPSPN, i.e., stronger activation of NMDA receptors during the tetani is required to induce LTP of fEPSPN than the one required for inducing LTP of fEPSPA; and 2) there is a bell-shaped relationship between the degree of activation of NMDA receptors during the tetani and the magnitude of LTP of the fEPSPA: tetani that generate LTP of fEPSPN have a low probability to induce LTP of fEPSPA. We suggest that AMPA and NMDA components are potentiated through two different presumably postsynaptic processes.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Transition modes in Ising networks: an approximate theory for macromolecular recognition.

For a statistical lattice, or Ising network, composed of N identical units existing in two possible states, 0 and 1, and interacting according to a given geometry, a set of values can be found for the mean free energy of the 0-->1 transition of a single unit. Each value defines a transition mode in an ensemble of nu N = 3N - 2N possible values and reflects the role played by intermediate states in shaping the energetics of the system as a whole. The distribution of transition modes has a number of intriguing properties. Some of them apply quite generally to any Ising network, regardless of its dimension, while others are specific for each interaction geometry and dimensional embedding and bear on fundamental aspects of analytical number theory. The landscape of transition modes encapsulates all of the important thermodynamic properties of the network. The free energy terms defining the partition function of the system can be derived from the modes by simple transformations. Classical mean-field expressions can be obtained from consideration of the properties of transition modes in a rather straightforward way. The results obtained in the analysis of the transition mode distributions have been used to develop an approximate treatment of the problem of macromolecular recognition. This phenomenon is modeled as a cooperative process that involves a number of recognition subsites across an interface generated by the binding of two macromolecular components. The distribution of allowed binding free energies for the system is shown to be a superposition of Gaussian terms with mean and variance determined a priori by the theory. Application to the analysis of the biologically interaction of thrombin with hirudin has provided some useful information on basic aspects of the interaction, such as the number of recognition subsites involved and the energy balance for binding and cooperative coupling among them. Our results agree quite well with information derived independently from analysis of the crystal structure of the thrombin-hirudin complex.

Binding Sites↗

PubMed1983

Systematic management and analysis of fatty acid data from multiple tissue samples.

A systematic approach has been developed for the collection and analysis of gas chromatographic (GC) data from multiple fatty acid profiles. The approach was applied to a series of polar and nonpolar tissue lipids generated in animal feeding studies to allow a comparison of mean fatty acid profiles as a function of either dietary regimen or tissue location. The magnitude of the studies, sufficiently large to minimize error from animal variabilities, mandated the use of computer assistance. Nevertheless, manual input was essential due to the complexity of the GC patterns, and was invoked for peak assignment and report editing. The approach discussed here allowed for the consolidation and statistical analysis of data from over 30,000 GC peaks, and generated results in both tabular and graphic formats. It should be extendable to other chromatographic studies of lipid components.

Adipose Tissue↗

PubMed2003

Inter simple sequence repeat (ISSR) analysis of genetic diversity in tef [Eragrostis tef (Zucc.) Trotter].

The DNA polymorphism among 92 selected tef genotypes belonging to eight origin groups was assessed using eight inter simple sequence repeat (ISSR) primers. The objectives were to examine the possibility of using ISSR markers for unravelling genetic diversity in tef, and to assess the extent and pattern of genetic diversity in the test germplasm with respect to origin groups. The eight primers were able to separate or distinguish all of the 92 tef genotypes based on a total of 110 polymorphic bands among the test lines. The Jaccard similarity coefficient among the test genotypes ranged from 0.26 to 0.86, and at about 60 % similarity level the clustering of this matrix using the unweighted pair-group method based on arithmetic average (UPGMA) resulted in the formation of six major clusters of 2 to 37 lines with further eight lines remaining ungrouped. The standardized Nei genetic distance among the eight groups of origin ranged between 0.03 and 0.32. The UPGMA clustering using the standardized genetic distance matrix resulted in the identification of three clusters of the eight groups of origin with bootstrap values ranging from 56 to 97. The overall mean Shannon Weaver diversity index of the test lines was 0.73, indicating better resolution of genetic diversity in tef with ISSR markers than with phenotypic (morphological) traits used in previous studies. This can be attributed mainly to the larger number of loci generated for evaluation with ISSR analysis as compared to the few number of phenotypic traits amenable for assessment and which are further greatly affected by environment and genotype x environment interaction. Analysis of variance of mean Shannon Weaver diversity indices revealed substantial (P < or = 0.05) variation in the level of diversity among the eight groups of origin. In conclusion, our results indicate that ISSR can be useful as DNA-based molecular markers for studying genetic diversity and phylogenetic relationships, DNA fingerprinting for the identification of varieties or cultivars, and also for genome mapping in tef.

Electrophoresis, Polyacrylamide Gel↗

PubMed2005

A software tool for 2D/3D visualization and analysis of phase-space data generated by Monte Carlo modelling of medical linear accelerators.

A computer program has been developed for novel 2D/3D visualization and analysis of the phase-space parameters of Monte Carlo simulations of medical accelerator radiation beams. The software is written in the IDL language and reads the phase-space data generated in the BEAMnrc/BEAM Monte Carlo code format. Contour and colour-wash plots of the fluence, mean energy, energy fluence, mean angle, spectra distribution, energy fluence distribution, angular distribution, and slices and projections of the 3D ZLAST distribution can be calculated and displayed. Based on our experience of using it at Massachusetts General Hospital, the software has proven to be a useful tool for analysis and verification of the Monte Carlo generated phase-space files. The software is in the public domain.

Computer Graphics↗

PubMed1995

Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility.

OBJECTIVE: To assess a non-invasive test for endothelial dysfunction, an important early event in the atherogenic process. METHODS: Using high resolution ultrasound, the accuracy of detecting small changes in vessel diameter was assessed using phantom "arteries", and the same equipment was then used to measure flow mediated dilatation in the brachial artery of 40 healthy adults aged 22-51 years, studied on four occasions; intervals between scans were 1-2 days, 1-2 weeks, and 2-4 months. RESULTS: Differences between pairs of phantom "arteries" with diameters 0.1-0.2 mm apart were correctly estimated in 162 of 264 cases (61%); no measurement by any of four independent observers was > 0.1 mm in error, and the mean error was 0.04 mm. For in vivo scans, the overall coefficient of variation for flow mediated dilatation was 1.8% (1.6% for women, 1.9% for men, P = 0.18). In 34/40 subjects (85%), all values for flow mediated dilatation were within 2.5% of the overall mean for each subject. A nested analysis of variance showed the expected between patient variability, and also significant day to day variation, but little between weeks or months. Using these data to generate power function analyses, we calculated that for individuals, an improvement in flow mediated dilatation of 4-8% is significantly greater than natural variability. In clinical trials, a mean improvement in flow mediated dilatation of at least 2% would usually be required to detect a treatment benefit, with much larger subject numbers needed for a parallel group compared to a crossover trial design. CONCLUSIONS: Vascular responses to endothelium dependent and independent stimuli in systemic arteries can be studied non-invasively in man. Subjects should be studied on at least two occasions before and after any intervention, to optimise the chance of showing a significant effect from any potentially beneficial therapy.

Adult↗

PubMed1987

Successful selection for increased longevity in Drosophila: analysis of the survival data and presentation of a hypothesis on the genetic regulation of longevity.

Long lived strains of Drosophila melanogaster have been generated via 25 generations of artificial selection. The mean and the maximum lifespans have been increased both absolutely as well as relative to the controls. The mean lifespan of the selected line now exceeds the maximum lifespan of the controls. The data shows that this increase is entirely accounted for by a genetically based delay in the onset of senescence. Identification and analysis of biomarker data involving reproductive functions supports this interpretation and leads to a suggestion of the processes involved in the lifespan extension. This increase in the duration of the pre-senescent period is under both genetic and environmental control. Senescence itself is not under genetic control and appears to occur stochastically. Selection for decreased longevity was unsuccessful, supporting the concept of a minimum species specific lifespan. A testable hypothesis regarding the biphasic mode of gene regulation of senescence is presented in which a gene-environment interaction takes place in larval life that results in a temporal reprogramming of other, presumably structural, genes which act in adult life at a time prior to the onset of senescence.

Aging↗

PubMed1996

Neutrophil activation in jugular venous blood during carotid endarterectomy.

OBJECTIVES: Neutrophils may play an important role in cerebral ischaemia. We investigated whether neutrophil activation can be detected in cerebral venous blood during the mild cerebral hypoxia and reperfusion that occurs during carotid cross clamping and declamping for endarterectomy. DESIGN, SETTING AND MATERIALS: The ipsilateral jugular bulb was cannulated at operation in 16 patients undergoing carotid endarterectomy. Blood was taken immediately prior to and 30 seconds following internal carotid cross clamping; then immediately prior to, 30 s and 2 m following declamping. Blood was also taken from a peripheral vein in the foot. Intracerebral oxygen saturation (CsO2) was measured continuously by near infrared cerebral spectroscopy. Neutrophil activation was measured by flow cytometric detection of fluorescence to hydrogen peroxide in unstimulated cells and phorbol myristate acetate stimulated cells, and expressed as mean fluorescent intensity (MFI). OUTCOME MEASURES: Neutrophil activation and cerebral oxygenation. MAIN RESULTS: CsO2 fell from 68% (95% Confidence interval 64%-72%) to 63% (59%-68%) following carotid cross clamping (p < 0.05, repeated measures analysis of variance). This recovered slightly during the cross clamp period to 64% but only returned to preclamp levels following declamping (p > 0.05). Neutrophil hydrogen peroxide generation by stimulated neutrophils rose significantly from 0.79 mean fluorescent intensity (0.53-1.19) to 1.46 (0.98-2.20) but no there was no further rise following cross clamp release. There was no significant neutrophil activation in the peripheral samples. CONCLUSIONS: These results indicate that even mild cerebral hypoxia is associated with priming of neutrophils in cerebral venous blood.

Aged↗

PubMed2006

CyberKnife stereotactic radiotherapy for patients with malignant glioma.

OBJECTIVE: The CyberKnife is a new frameless image-guided radiosurgical modality. The authors report on their experience using the CyberKnife in 25 patients with malignant gliomas. METHODS: Twenty-five patients with histologically proven malignant gliomas (18 glioblastoma: GB, 7 anaplastic astrocytoma: AA) were treated with the CyberKnife at Konan St. Hill Hospital between June 1998 and November 2002. CyberKnife therapy was performed on 44 lesions (31 GB lesions, 13 AA lesions) in the 25 patients. The median target volume was 19.1 mL (range: 0.3 - 90.2). The median prescribed dose was 20.3 Gy (range: 13.9 - 26.4). Patient-, tumor-, and treatment-related variables were analyzed by univariate analysis, and survival curves were generated by the Kaplan-Meier product limit. RESULTS: In the 18 GB patients, the median survival after diagnosis was 20.7 months (82.6 weeks) with a mean follow-up of 85.7 weeks. Of the 7 AA patients, 6 were alive at the time of analysis with follow-up periods ranging from 11.4 to 52.8 months. Patients younger than 70 years had a median survival after diagnosis of 37.1 months, compared to 12.4 months for older patients (p = 0.003). Similarly, patients with well-controlled lesions had a median survival after diagnosis of 39.8 months compared to 16.0 months for those with uncontrolled lesions (p = 0.031). Late delayed radiation necrosis was seen in 1 GB patient. No other patient suffered acute or delayed neurological morbidity after CyberKnife therapy. CONCLUSION: This is the first report of CyberKnife stereotactic radiotherapy applied to the treatment of malignant gliomas. The frameless and painless CyberKnife stereotactic radiotherapy has the potential to be as useful for treatment of malignant glioma as other radiosurgical modalities.

Adult↗

PubMed1983

Clinical experience with a bradycardia indicating pacemaker.

The beneficial effect of permanent pacing is controversial in certain patient groups. Once pacing has been instituted it is seldom terminated and an evaluation of pacemaker dependence is therefore not possible. An implantable pulse generator, detecting bradycardia below 30 bpm has been developed in order to broaden our knowledge about the natural history of bradyarrhythmias treated by permanent pacing. This pacemaker has been implanted in 38 patients who did not have clear-cut indications for permanent pacing. They have been followed for a mean of 13 months. Bradycardia was detected in 33 patients 1 to 21 months (4.6 mean) after implantation. Twenty-one patients did not have a detected bradycardia for long periods (months-years). Minor symptoms of lightheadedness attributable to bradycardia were reported by 15 patients during periods when the pacemaker had been activated. Holter monitoring for at least 24 hours was carried out in all patients and electronic analysis of explanted generators was performed in eleven cases. No technical failure related to the bradycardia-detecting facility was observed. The combination of diagnostic and therapeutic properties in the bradycardia-indicating pacemaker provides means for safe evaluation of pacemaker dependency over long time periods in patient groups with controversial indications for permanent pacing.

Aged↗

PubMed1990

Paleodemography of the Carlston Annis (Bt-5) Late Archaic skeletal population.

The study presents a demographic assessment of the Carlston Annis (Bt-5) Late Archaic hunting and gathering population recovered from the banks of the Green River in west-central Kentucky. The shell midden habitation and cemetery site originally yielded the remains of 390 individuals. Radiocarbon dates place site occupation between 3,000 and 4,500 y.b.p. The skeletal sample consisted of 354 individuals ranging in age from 7 months in utero to 70 + years. Subadults were aged by seriation of dental and skeletal developmental criteria. Adult ages were determined by the multifactorial summary age method that employed 1) five indicators of adult skeletal age at death, 2) the procedure of age indicator seriation, and 3) differential weighting of age assessments as determined by principal components analysis. Adult sex diagnoses were based on qualitative assessment of pelvic and cranial morphological criteria. The Bt-5 life table analysis yields an E0 of 22.4 years, crude birth of 45, mean family size of 3.3, gross reproductive rate of 2.7, generation length of 26.6 years, and B of .076, indicating a healthy population with a substantial capability to replace succeeding generations. Survivorship profiles and demographic parameters that compare the Carlston Annis (Bt-5) and Indian Knoll (Oh-2) skeletal series are presented. Both populations display type II survivorship curves, with high infant mortality and early onset of elevated mortality rates in adults. Major differences between Bt-5 and Oh-2 demographic parameters concern adult sex ratio and adult age distribution over 30 years. These differences are interpreted to reflect census errors in the Oh-2 demographic reconstruction that were possibly introduced by selective methodological biases and/or taphonomic factors.

Age Determination by Skeleton↗

PubMed2001

Autosomal dominant inherited hearing impairment caused by a missense mutation in COL11A2 (DFNA13).

OBJECTIVE: To analyze the phenotype in a 5-generation DFNA13 family with a missense mutation in the COL11A2 gene that causes autosomal dominant, presumably prelingual, nonsyndromic sensorineural hearing impairment. DESIGN: Family study. SETTING: University hospital department. PATIENTS: Twenty mutation carriers from a large American kindred. METHODS: Cross-sectional analysis using pure-tone threshold measurements at 0.25, 0.5, 1, 2, 4, and 8 kHz. The audiometric configuration was evaluated according to an existing consensus protocol. The significance of features relating to audiometric configuration was tested using 1-way analysis of variance. Progression was evaluated with linear regression analyses of threshold-on-age. RESULTS: Most individuals showed midfrequency (U-shaped) characteristics. The mean threshold in generations IV and V was 44 dB at 1, 2, and 4 kHz (midfrequencies); it was 29 dB at the other frequencies (0.25, 0.5, and 8 kHz). There was no significant progression beyond presbyacusis. CONCLUSION: The trait in this family can be characterized as autosomal dominant, nonprogressive, presumably prelingual, midfrequency sensorineural hearing impairment.

Adolescent↗

PubMedDate not supplied

Solution structure and energy calculation of bis-intercalation of homodimeric thiazole orange dye derivatives in DNA: effects of modifying the linker.

We have used two-dimensional (1)H NMR spectroscopy obtained at 750 MHz to determine a high-resolution solution structure of the double-stranded DNA oligonucleotide d(5'-CGCTAGCG-3')(2) complexed with the bis-intercalating dye 1,1'-(5,5,9,9-tetramethyl-5, 9-diazatridecamethylene)-bis-4-[3-ethyl-2,3-dihydro(benzo-1, 3-thiazolyl)-2-methylidene]quino-linium tetraiodide (TOTO11Et). The determination of the structure was based on a complete relaxation matrix analysis of the NOESY cross-peaks followed by restrained molecular dynamics calculations. Forty final structures were generated for the TOTO11Et complex from A-form and B-form dsDNA starting structures. The root-mean-square (rms) deviation of the coordinates for the 40 structures of the complex was 0.52 A. A conformational analysis of the deoxyribose rings based on coupling constants obtained from selective DQF-COSY spectra revealed that all ring conformations were almost pure S-type. The structure of the TOTO11Et complex was compared with the structure of a similar DNA complex with a dye containing a shorter linker (TOTOEt). Substantial differences were observed between the two structures because of the difference in the length of the linker. Most prominent was a large difference in the degree of unwinding of the dsDNA part in the two complexes. Unwinding of 73 degrees and 22 degrees relative to the free dsDNA was observed for the complexes with TOTOEt and TOTO11Et, respectively. The AMBER94 force field together with the GB/SA solvation model was used for energy calculations on both of the two complexes. In the calculations, the complex formation was divided into two steps: (i) unwinding of the free oligonucleotide and (ii) association of the bis-intercalators to the unwound oligonucleotide. The complex formation was in favor of TOTO11Et, mainly because the dsDNA is distorted less in the complex with TOTO11Et than in the complex with TOTOEt.

DNA↗

PubMed2000

Informatics for mutagenesis: the design of mutabase--a distributed data recording system for animal husbandry, mutagenesis, and phenotypic analysis.

The increasing use of high-throughput methods for the production of biologically important information and the increasing diversity of that information pose considerable bioinformatics challenges. These challenges will be met by implementing electronic data management systems not only to capture the data, but increasingly to provide a platform for data integration and mining as we enter the post-genomic era. We discuss the design and implementation of such a data capture system, 'Mutabase', as a model of how such electronic systems might be designed and implemented. Mutabase was created in support of a large-scale, phenotype-driven mouse mutagenesis program at MRC Mammalian Genetics Unit, Harwell, in collaboration with SmithKline Beecham Pharmaceuticals, Queen Mary and Westfield College, London, and Imperial College of Science, Technology and Medicine, London. The aim of this mutagenesis project is to make a significant contribution to the existing mouse mutant resource, closing the phenotype gap and providing many more models for fundamental research and disease modeling. Mutabase records experimental details at the 'point of generation' and provides a number of dissemination and analysis tools for the experimental data, as well as providing a means of assessing various aspects of progress of the program. Mutabase uses a hypertext-based interface to provide interaction between a number of intranet-based client workstations and a central industrial strength database. Mutabase utilizes a variety of techniques in order to implement the user interface system including Perl/CGI, Java Servlets, and an experimental CORBA server. We discuss the relative merits of these methods in the context of the need to provide sound informatics approaches for the support of systematic mutagenesis programs.

Animal Husbandry↗

PubMed2005

Commentary: creating research capacity in complementary medicine.

A House of Lords Report recently recommended the creation of 'centres of excellence' for research into complementary medicine. The UK government decided not to follow this advice but to sponsor nine research fellowships each supervising a PhD student. An analysis of past researchers at the unit in Exeter suggest that 'centres of excellence' are an effective means of generating research capacity in this area. It is suggested that this approach is likely to be more productive than the present governmental strategy.

Complementary Therapies↗

PubMed1997

Analysis of phosphorescence in heterogeneous systems using distributions of quencher concentration.

A continuous distribution approach, instead of the traditional mono- and multiexponential analysis, for determining quencher concentration in a heterogeneous system has been developed. A mathematical model of phosphorescence decay inside a volume with homogeneous concentration of phosphor and heterogeneous concentration of quencher was formulated to obtain pulse-response fitting functions for four different distributions of quencher concentration: rectangular, normal (Gaussian), gamma, and multimodal. The analysis was applied to parameter estimates of a heterogeneous distribution of oxygen tension (PO2) within a volume. Simulated phosphorescence decay data were randomly generated for different distributions and heterogeneity of PO2 inside the excitation/emission volume, consisting of 200 domains, and then fit with equations developed for the four models. Analysis using a monoexponential fit yielded a systematic error (underestimate) in mean PO2 that increased with the degree of heterogeneity. The fitting procedures based on the continuous distribution approach returned more accurate values for parameters of the generated PO2 distribution than did the monoexponential fit. The parameters of the fit (M = mean; sigma = standard deviation) were investigated as a function of signal-to-noise ratio (SNR = maximum signal amplitude/peak-to-peak noise). The best-fit parameter values were stable when SNR > or = 20. All four fitting models returned accurate values of M and sigma for different PO2 distributions. The ability of our procedures to resolve two different heterogeneous compartments was also demonstrated using a bimodal fitting model. An approximate scheme was formulated to allow calculation of the first moments of a spatial distribution of quencher without specifying the distribution. In addition, a procedure for the recovery of a histogram, representing the quencher concentration distribution, was developed and successfully tested.

Light↗

PubMed1993

Synergies and strategies underlying normal and vestibulary deficient control of balance: implication for neuroprosthetic control.

Future developments of neuroprosthetic control will probably permit locomotion and posture to be maintained without the aid of crutches and will therefore require some form of balance control. Three fundamental questions will arise. First, the question of the location of imbalance-sensing transducers must be assessed. Secondly, the synergy, which is the relative amplitude and timing of muscle activity, and/or the strategy of joint torques required to re-establish a stable posture for different types of balance disturbances must be addressed. Thirdly, the control laws that map either trunk muscle activity or imbalance-sensing transducer outputs into multi-joint postural control of standing by paraplegic individuals must be generated. The most appropriate means of gathering the relevant information applicable to neuroprosthetic control systems is through the detailed analysis of normal and non-normal human models. In order to gain such detailed insights into normal balance control and its dependence on head angular and linear accelerations, the synergy and strategy of balance corrections in normal subjects or patients with vestibular deficits were investigated for two types of support surface perturbation, a dorsiflexion rotation (ROT) and a rearward translation (TRANS). These experimentally induced perturbations to upright stance were adjusted to cause equal amplitudes of ankle dorsiflexion, thus providing additional information about the role of lower leg proprioception on balance control. Synergies defined on the basis of peak cross-correlations of each recorded muscle's EMG to that of the largest muscle response were significantly different for TRANS and ROT. Translation synergies consisted of a sequential coactivation at several levels (soleus and abdominals some 30 msec before hamstrings, and trapezius some 15 msec before paraspinals), whereas the sequential activation of paraspinals and tibialis anterior dominated the balance synergy to ROT. Likewise, response strategies, defined using cross-correlations of joint torques, differed. That for TRANS was organised as a multi-link strategy with neck torques leading those of all other joints by 40 msec or more; hip joint lead ankle torques by 30 msec. That for ROT was organised around hip and ankle torques without a major correlation to neck torques. Vestibulary deficient subjects developed weaker synergies with respect to subjects with normal balance systems under eyes-open conditions and there was no clear synergy with eyes closed. Consequently, hip torques were delayed some 180 msec with respect to ankle torques, and correlations to neck torques were completely out of phase under eyes-closed conditions. Fundamental changes in TRANS synergies and strategies also occurred in vestibulary deficient subjects for eyes-open and eyes-closed conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Ankle↗

PubMed2022

Genome-scale metabolic modeling reveals increased reliance on valine catabolism in clinical isolates of Klebsiella pneumoniae.

Infections due to carbapenem-resistant Enterobacteriaceae have recently emerged as one of the most urgent threats to hospitalized patients within the United States and Europe. By far the most common etiological agent of these infections is Klebsiella pneumoniae, frequently manifesting in hospital-acquired pneumonia with a mortality rate of ~50% even with antimicrobial intervention. We performed transcriptomic analysis of data collected previously from in vitro characterization of both laboratory and clinical isolates which revealed shifts in expression of multiple master metabolic regulators across isolate types. Metabolism has been previously shown to be an effective target for antibacterial therapy, and genome-scale metabolic network reconstructions (GENREs) have provided a powerful means to accelerate identification of potential targets in silico. Combining these techniques with the transcriptome meta-analysis, we generated context-specific models of metabolism utilizing a well-curated GENRE of K. pneumoniae (iYL1228) to identify novel therapeutic targets. Functional metabolic analyses revealed that both composition and metabolic activity of clinical isolate-associated context-specific models significantly differs from laboratory isolate-associated models of the bacterium. Additionally, we identified increased catabolism of L-valine in clinical isolate-specific growth simulations. These findings warrant future studies for potential efficacy of valine transaminase inhibition as a target against K. pneumoniae infection.

Humans↗