Matched increases in cerebral artery shear stress, irrespective of stimulus, induce similar changes in extra-cranial arterial diameter in humans.

The mechanistic role of arterial shear stress in the regulation of cerebrovascular responses to physiological stimuli (exercise and hypercapnia) is poorly understood. We hypothesised that, if shear stress is a key regulator of arterial dilation, then matched increases in shear, induced by distinct physiological stimuli, would trigger similar dilation of the large extra-cranial arteries. Participants ( n = 10) participated in three 30-min experimental interventions, each separated by ≥48 h: (1) mild-hypercapnia (FICO2:∼0.045); (2) submaximal cycling (EX; 60%HRreserve); or (3) resting (time-matched control, CTRL). Blood flow, diameter, and shear rate were assessed (via Duplex ultrasound) in the internal carotid and vertebral arteries (ICA, VA) at baseline, during and following the interventions. Hypercapnia and EX produced similar elevations in blood flow and shear rate through the ICA and VA ( p < 0.001), which were both greater than CTRL. Vasodilation of ICA and VA diameter in response to hypercapnia (5.3 ± 0.8 and 4.4 ± 2.0%) and EX (4.7 ± 0.7 and 4.7 ± 2.2%) were similar, and greater than CTRL ( p < 0.001). Our findings indicate that matched levels of shear, irrespective of their driving stimulus, induce similar extra-cranial artery dilation. We demonstrate, for the first time in humans, an important mechanistic role for the endothelium in regulating cerebrovascular response to common physiological stimuli in vivo

Phenotypes of lung mononuclear phagocytes in HIV seronegative tuberculosis patients: evidence for new recruitment and cell activation

Mycobacterium tuberculosis preferentially resides in mononuclear phagocytes. The mechanisms by which mononuclear phagocytes keep M. tuberculosis in check or by which the microbe evades control to cause disease remain poorly understood. As an initial effort to delineate these mechanisms, we examined by immunostaining the phenotype of mononuclear phagocytes obtained from lungs of patients with active tuberculosis. From August 1994 to March 1995, consecutive patients who had an abnormal chest X-ray, no demostrable acid-fast bacilli in sputum specimens and required a diagnostic bronchoalveolar lavage (BAL) were enrolled. Of the 39 patients enrolled, 21 had microbiologically diagnosed tuberculosis. Thirteen of the 21 tuberculosis patients were either HIV seronegative (n = 12) or had no risk factor for HIV and constituted the tuberculosis group. For comparison, M. tuberculosis negative patients who had BAL samples taken during this time (n = 9) or normal healthy volunteers (n = 3) served as control group. Compared to the control group, the tuberculosis group had significantly higher proportion of cells expressing markers of young monocytes (UCHM1) and RFD7, a marker for phagocytic cells, and increased expression of HLA-DR, a marker of cell activation. In addition, tuberculosis group had significantly higher proportion of cells expressing dendritic cell marker (RFD1) and epithelioid cell marker (RFD9). These data suggest that despite recruitment of monocytes probably from the peripheral blood and local cell activation, host defense of the resident lung cells is insufficient to control M. tuberculosis

Structure-Based Predictive Models for Allosteric Hot Spots

In allostery, a binding event at one site in a protein modulates the behavior of a distant site. Identifying residues that relay the signal between sites remains a challenge. We have developed predictive models using support-vector machines, a widely used machine-learning method. The training data set consisted of residues classified as either hotspots or non-hotspots based on experimental characterization of point mutations from a diverse set of allosteric proteins. Each residue had an associated set of calculated features. Two sets of features were used, one consisting of dynamical, structural, network, and informatic measures, and another of structural measures defined by Daily and Gray [1]. The resulting models performed well on an independent data set consisting of hotspots and non-hotspots from five allosteric proteins. For the independent data set, our top 10 models using Feature Set 1 recalled 68–81% of known hotspots, and among total hotspot predictions, 58–67% were actual hotspots. Hence, these models have precision P = 58–67% and recall R = 68–81%. The corresponding models for Feature Set 2 had P = 55–59% and R = 81–92%. We combined the features from each set that produced models with optimal predictive performance. The top 10 models using this hybrid feature set had R = 73–81% and P = 64–71%, the best overall performance of any of the sets of models. Our methods identified hotspots in structural regions of known allosteric significance. Moreover, our predicted hotspots form a network of contiguous residues in the interior of the structures, in agreement with previous work. In conclusion, we have developed models that discriminate between known allosteric hotspots and non-hotspots with high accuracy and sensitivity. Moreover, the pattern of predicted hotspots corresponds to known functional motifs implicated in allostery, and is consistent with previous work describing sparse networks of allosterically important residues

Addiction in the Light of African Values: Undermining Vitality and Community

In this article I address the question of what makes addiction morally problematic, and seek to answer it by drawing on values salient in the sub-Saharan African philosophical tradition. Specifically, I appeal to life-force and communal relationship, each of which African philosophers have at times advanced as a foundational value, and spell out how addiction, or at least salient instances of it, could be viewed as unethical for flouting them. I do not seek to defend either vitality or community as the best explanation of when and why addiction is immoral, instead arguing that each of these characteristically African values grounds an independent and plausible account of that. I conclude that both vitalism and communalism merit consideration as rivals to accounts that Western ethicists would typically make, according to which addiction is immoral insofar as it degrades rationality or autonomy, as per Kantianism, or causes pain or dissatisfaction, à la utilitarianism