Linkage and association analysis of candidate genes for TB and TNFα cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes

Tuberculosis (TB) is a growing public health threat globally and several studies suggest a role of host genetic susceptibility in increased TB risk. As part of a household contact study in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB by developing an intermediate phenotype model for TB susceptibility, analyzing levels of tumor necrosis factor-α (TNFα) in response to culture filtrate as the phenotype. In the present study, we analyzed candidate genes related to TNFα regulation and found that interleukin (IL)-10, interferon-gamma receptor 1 (IFNGR1), and TNFα receptor 1 (TNFR1) genes were linked and associated to both TB and TNFα. We also show that these associations are with progression to active disease and not susceptibility to latent infection. This is the first report of an association between TB and TNFR1 in a human population and our findings for IL-10 and IFNGR1 replicate previous findings. By observing pleiotropic effects on both phenotypes, we show construct validity of our intermediate phenotype model, which enables the characterization of the role of these genetic polymorphisms on TB pathogenesis. This study further illustrates the utility of such a model for disentangling complex traits. C. C. Whalen and S. K. Iyengar contributed equally as senior authors of this work.     

Baroreflex control of renal sympathetic nerve activity during air-jet stress in rats

The effects of acute emotional stress on the sympathetic component of the arterial baroreceptor reflex have not yet been described in conscious animals and humans. Arterial pressure (AP) and renal sympathetic nerve activity (RSNA) were simultaneously recorded in 11 conscious rats before and during exposure to a mild environmental stressor (jet of air). Baroreflex function curves relating AP and RSNA were constructed by fitting a sigmoid function to RSNA and AP measured during sequential nitroprusside and phenylephrine administrations. Stress increased mean AP from 112 +/- 2 to 124 +/- 2 mmHg, heart rate from 381 +/- 10 to 438 +/- 18 beats/min, and RSNA from 0.80 +/- 0.14 to 1.49 +/- 0.23 microV. The RSNA-AP relationship was shifted toward higher AP values, and its maximum gain was significantly (P < 0.01) increased from 9.0 +/- 1.3 to 16.2 +/- 2.1 normalized units (NU)/mmHg. The latter effect was secondary to an increase (P < 0.01) in the range of the RSNA variation from 285 +/- 33 to 619 +/- 59 NU. In addition, the operating range of the reflex was increased (P < 0.01) from 34 +/- 2 to 41 +/- 3 mmHg. The present study indicates that in rats, the baroreflex control of RSNA is sensitized and operates over a larger range during emotional stress, which suggests that renal vascular tone, and possibly AP, are very efficiently controlled by the sympathetic nervous system under this condition.     

A transfer function method for the continuous assessment of baroreflex control of renal sympathetic nerve activity in rats

The present study examined whether the gain of the transfer function relating cardiac-related rhythm of renal sympathetic nerve activity (RSNA) to arterial pressure (AP) pulse might serve as a spontaneous index of sympathetic baroreflex sensitivity (BRS). AP and RSNA were simultaneously recorded in conscious rats, either baroreceptor-intact (control, n = 11) or with partial denervation of baroreflex afferents [aortic baroreceptor denervated (ABD; n = 10)] during 1-h periods of spontaneous activity. Transfer gain was calculated over 58 adjacent 61.4-s periods (segmented into 10.2-s periods). Coherence between AP and RSNA was statistically (P < 0.05) significant in 90 +/- 3% and 56 +/- 10% of cases in control and ABD rats, respectively. Transfer gain was higher (P = 0.0049) in control [2.39 +/- 0.13 normalized units (NU)/mmHg] than in ABD (1.48 +/- 0.22 NU/mmHg) rats. In the pooled study sample, transfer gain correlated with sympathetic BRS estimated by the vasoactive drug injection technique (R = 0.75; P < 0.0001) and was inversely related to both time- (standard deviation; R = -0.74; P = 0.0001) and frequency-domain [total spectral power (0.00028-2.5 Hz); R = -0.82; P < 0.0001] indices of AP variability. In control rats, transfer gain exhibited large fluctuations (coefficient of variation: 34 +/- 3%) that were not consistently related to changes in the mean level of AP, heart rate, or RSNA. In conclusion, the transfer function method provides a continuous, functionally relevant index of sympathetic BRS and reveals that the latter fluctuates widely over time.     

Effect of elastin degradation on carotid wall mechanics as assessed by a constituent-based biomechanical model

Arteries display a nonlinear anisotropic behavior dictated by the elastic properties and structural arrangement of its main constituents, elastin, collagen, and vascular smooth muscle. Elastin provides for structural integrity and for the compliance of the vessel at low pressure, whereas collagen gives the tensile resistance required at high pressures. Based on the model of Zulliger et al. (Zulliger MA, Rachev A, Stergiopulos N. Am J Physiol Heart Circ Physiol 287: H1335-H1343, 2004), which considers the contributions of elastin, collagen, and vascular smooth muscle cells (VSM) in an explicit form, we assessed the effects of enzymatic degradation of elastin on biomechanical properties of rabbit carotids. Pressure-diameter curves were obtained for controls and after elastin degradation, from which elastic and structural properties were derived. Data were fitted into the model of Zulliger et al. to assess elastic constants of elastin and collagen as well as the characteristics of the collagen engagement profile. The arterial segments were also prepared for histology to visualize and quantify elastin and collagen. Elastase treatment leads to a diameter enlargement, suggesting the existence of significant compressive prestresses within the wall. The elastic modulus was more ductile in treated arteries at low circumferential stretches and significantly greater at elevated circumferential stretches. Abrupt collagen fiber recruitment in elastase-treated arteries leads to a much stiffer vessel at high extensions. This change in collagen engagement properties results from structural alterations provoked by the degradation of elastin, suggesting a clear interaction between elastin and collagen, often neglected in previous constituent-based models of the arterial wall.     

Coupling between neuronal firing rate, gamma LFP, and BOLD fMRI is related to interneuronal correlations

BACKGROUND: To what extent is activity of individual neurons coupled to the local field potential (LFP) and to blood-oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI)? This issue is of high significance for understanding brain function and for relating animal studies to fMRI, yet it is still under debate. RESULTS: Here we report data from simultaneous recordings of isolated unit activity and LFP by using multiple electrodes in the human auditory cortex. We found a wide range of coupling levels between the activity of individual neurons and gamma LFP. However, this large variability could be predominantly explained (r = 0.66) by the degree of firing-rate correlations between neighboring neurons. Importantly, this phenomenon occurred during both sensory stimulation and spontaneous activity. Concerning the coupling of neuronal activity to BOLD fMRI, we found that gamma LFP was well coupled to BOLD measured across different individuals (r = 0.62). By contrast, the coupling of single units to BOLD was highly variable and, again, tightly related to interneuronal-firing-rate correlations (r = 0.70). CONCLUSIONS: Our results offer a resolution to a central controversy regarding the coupling between neurons, LFP, and BOLD signals by demonstrating, for the first time, that the coupling of single units to the other measures is variable yet it is tightly related to the degree of interneuronal correlations in the human auditory cortex.     

Extra-retinal vision: firing at will

Recent evidence suggests that a key visual motion centre in the brain ignores extra-retinal motor information concerning reflexive eye movement. Instead it seems that neurons sensitive to oculomotor actions in this area fire at will.     

Peptidoglycan recognition proteins of the innate immune system

Peptidoglycan (PGN) is the major component of bacterial cell walls and one of the main microbial products recognized by the innate immune system. PGN recognition is mediated by several families of pattern recognition molecules, including Toll-like receptors, nucleotide-binding oligomerization domain-containing proteins, and peptidoglycan recognition proteins (PGRPs). However, only the interaction of PGN with PGRPs, which are highly conserved from insects to mammals, has so far been characterized at the molecular level. Here, we describe recent structural studies of PGRPs that reveal the basis for PGN recognition and provide insights into the signal transduction and antibacterial activities of these innate immune proteins.     

Wide dynamic range phase-sensitive surface plasmon resonance biosensor based on measuring the modulation harmonics

In this study, a novel phase-sensitive surface plasmon resonance (SPR) setup, based on temporal modulation of a pumping beam by a photoelastic modulator, and subsequent extraction of phase information at the second and the third harmonics of the modulation frequency, has been developed to study biomolecular interactions on SPR-supporting gold. We demonstrated that the design setup provides ultra-high phase sensitivity, together with a wide dynamic range of measurements. In particular, the proposed scheme was used to study real-time interaction of biotin-protein and streptavidin-BSA complexes. We have found that the proposed technique has a detection limit as high as 2.89 x 10(-7) in terms of refractive index units (RIU). In terms of biosensing performance, a detection sensitivity of 1.3 nM from the streptavidin-maleimide/thiolated BSA complex binding reaction has also been demonstrated.     

Government targets for protected area management: will threatened butterflies benefit?

The UK Government has set targets for biodiversity conservation in England based on several indicators, including the status of protected areas [e.g. Sites of Special Scientific Interest (SSSIs)]. Specifically, the Government aims to achieve favourable condition [defined by Common Standards Monitoring (CSM)] on 95% by area of SSSIs by 2010. SSSIs are important for threatened butterflies and management to achieve favourable condition will play a key role in determining future population levels of these high-profile insects. Because only notified features of SSSIs are considered within CSM, we investigated the level of notification for three threatened butterflies. We found that these species were notified at only 15–33% of SSSIs where they occurred; though most site managers did manage for them under broader site conservation objectives. We investigated the relationship between SSSI condition status and population trend for eight butterfly species of conservation concern to assess the benefit to butterflies of sites attaining favourable condition status. The majority (80%) of population trends on SSSIs in favourable condition were positive, suggesting an overall beneficial impact of SSSI management. However, four of the eight species maintained lower populations at favourable condition SSSIs than at sites in one of the unfavourable condition categories. We suggest that current condition assessment based chiefly on notified vegetation communities lacks the sensitivity to identify the complex habitat conditions for these (mosaic) species. As butterflies are good indictors for a wide range of invertebrates, many species requiring fine-scale habitat heterogeneity may be at risk from the Government’s target.