A geometric network model of intrinsic grey-matter connectivity of the human brain

Network science provides a general framework for analysing the large-scale brain networks that naturally arise from modern neuroimaging studies, and a key goal in theoretical neuro- science is to understand the extent to which these neural architectures influence the dynamical processes they sustain. To date, brain network modelling has largely been conducted at the macroscale level (i.e. white-matter tracts), despite growing evidence of the role that local grey matter architecture plays in a variety of brain disorders. Here, we present a new model of intrinsic grey matter connectivity of the human connectome. Importantly, the new model incorporates detailed information on cortical geometry to construct ‘shortcuts’ through the thickness of the cortex, thus enabling spatially distant brain regions, as measured along the cortical surface, to communicate. Our study indicates that structures based on human brain surface information differ significantly, both in terms of their topological network characteristics and activity propagation properties, when compared against a variety of alternative geometries and generative algorithms. In particular, this might help explain histological patterns of grey matter connectivity, highlighting that observed connection distances may have arisen to maximise information processing ability, and that such gains are consistent with (and enhanced by) the presence of short-cut connections

Lentiviral Vector-Mediated Correction of a Mouse Model of Leukocyte Adhesion Deficiency Type I

Leukocyte adhesion deficiency type I (LAD-I) is a primary immunodeficiency caused by mutations in the ITGB2 gene and is characterized by recurrent and life-threatening bacterial infections. These mutations lead to defective or absent expression of β2 integrins on the leukocyte surface, compromising adhesion and extravasation at sites of infection. Three different lentiviral vectors (LVs) conferring ubiquitous or preferential expression of CD18 in myeloid cells were constructed and tested in human and mouse LAD-I cells. All three hCD18-LVs restored CD18 and CD11a membrane expression in LAD-I patient-derived lymphoblastoid cells. Corrected cells recovered the ability to aggregate and bind to sICAM-1 after stimulation. All vectors induced stable hCD18 expression in hematopoietic cells from mice with a hypomorphic Itgb2 mutation (CD18(HYP)), both in vitro and in vivo after transplantation of corrected cells into primary and secondary CD18(HYP) recipients. hCD18(+) hematopoietic cells from transplanted CD18(HYP) mice also showed restoration of mCD11a surface co-expression. The analysis of in vivo neutrophil migration in CD18(HYP) mice subjected to two different inflammation models demonstrated that the LV-mediated gene therapy completely restored neutrophil extravasation in response to inflammatory stimuli. Finally, these vectors were able to correct the phenotype of human myeloid cells derived from CD34(+) progenitors defective in ITGB2 expression. These results support for the first time the use of hCD18-LVs for the treatment of LAD-I patients in clinical trials

Primary and secondary agonists can use P2X1 receptors as a major pathway to increase intracellular Ca2+ in the human platelet

See also Nurden AT. Does ATP act through P2X1 receptors to regulate platelet activation and thrombus formation? This issue, pp 907–9

Enhanced Motor Function by Training in Spinal Cord Contused Rats Following Radiation Therapy

Weight-bearing stepping, without supraspinal re-connectivity, can be attained by treadmill training in an animal whose spinal cord has been completely transected at the lower thoracic level. Repair of damaged tissue and of supraspinal connectivity/circuitry following spinal cord injury in rat can be achieved by specific cell elimination with radiation therapy of the lesion site delivered within a critical time window, 2-3 weeks postinjury. Here we examined the effects of training in the repaired spinal cord following clinical radiation therapy. Studies were performed in a severe rat spinal cord contusion injury model, one similar to fracture/crush injuries in humans; the injury was at the lower thoracic level and the training was a combined hindlimb standing and stepping protocol. Radiotherapy, in a similar manner to that reported previously, resulted in a significant level of tissue repair/preservation at the lesion site. Training in the irradiated group, as determined by limb kinematics tests, resulted in functional improvements that were significant for standing and stepping capacity, and yielded a significant direct correlation between standing and stepping performance. In contrast, the training in the unirradiated group resulted in no apparent beneficial effects, and yielded an inverse correlation between standing and stepping performance, e.g., subject with good standing showed poor stepping capacity. Further, without any training, a differential functional change was observed in the irradiated group; standing capacity was significantly inhibited while stepping showed a slight trend of improvement compared with the unirradiated group. These data suggest that following repair by radiation therapy the spinal circuitries which control posture and locomotor were modified, and that the beneficial functional modulation of these circuitries is use dependent. Further, for restoring beneficial motor function following radiotherapy, training seems to be crucial

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Integrated plasmonic circuitry on a vertical-cavity surface-emitting semiconductor laser platform

Integrated plasmonic sources and detectors are imperative in the practical development of plasmonic circuitry for bio- and chemical sensing, nanoscale optical information processing, as well as transducers for high-density optical data storage. Here we show that vertical-cavity surface-emitting lasers (VCSELs) can be employed as an on-chip, electrically pumped source or detector of plasmonic signals, when operated in forward or reverse bias, respectively. To this end, we experimentally demonstrate surface plasmon polariton excitation, waveguiding, frequency conversion and detection on a VCSEL-based plasmonic platform. The coupling efficiency of the VCSEL emission to waveguided surface plasmon polariton modes has been optimized using asymmetric plasmonic nanostructures. The plasmonic VCSEL platform validated here is a viable solution for practical realizations of plasmonic functionalities for various applications, such as those requiring sub-wavelength field confinement, refractive index sensitivity or optical near-field transduction with electrically driven sources, thus enabling the realization of on-chip optical communication and lab-on-a-chip devices

Rural to Urban Migration and Changes in Cardiovascular risk Factors in Tanzania: A Prospective Cohort Study.

High levels of rural to urban migration are a feature of most African countries. Our aim was to investigate changes, and their determinants, in cardiovascular risk factors on rural to urban migration in Tanzania. Men and women (15 to 59 years) intending to migrate from Morogoro rural region to Dar es Salaam for at least 6 months were identified. Measurements were made at least one week but no more than one month prior to migration, and 1 to 3 monthly after migration. Outcome measures included body mass index, blood pressure, fasting lipids, and self reported physical activity and diet. One hundred and three men, 106 women, mean age 29 years, were recruited and 132 (63.2%) followed to 12 months. All the figures presented here refer to the difference between baseline and 12 months in these 132 individuals. Vigorous physical activity declined (79.4% to 26.5% in men, 37.8% to 15.6% in women, p < 0.001), and weight increased (2.30 kg men, 2.35 kg women, p < 0.001). Intake of red meat increased, but so did the intake of fresh fruit and vegetables. HDL cholesterol increased in men and women (0.24, 0.25 mmoll-1 respectively, p < 0.001); and in men, not women, total cholesterol increased (0.42 mmoll-1, p = 0.01), and triglycerides fell (0.31 mmoll-1, p = 0.034). Blood pressure appeared to fall in both men and women. For example, in men systolic blood pressure fell by 5.4 mmHg, p = 0.007, and in women by 8.6 mmHg, p = 0.001. The lower level of physical activity and increasing weight will increase the risk of diabetes and cardiovascular disease. However, changes in diet were mixed, and may have contributed to mixed changes in lipid profiles and a lack of rise in blood pressure. A better understanding of the changes occurring on rural to urban migration is needed to guide preventive measures

Sex and the city: Differences in disease- and disability-free life years, and active community participation of elderly men and women in 7 cities in Latin America and the Caribbean

<p>Abstract</p> <p>Background</p> <p>The world's population is ageing, and four of the top 10 most rapidly ageing developing nations are from the region of Latin America and the Caribbean (LAC).</p> <p>Although an ageing population heralds likely increases in chronic disease, disability-related dependence, and economic burden, the societal contribution of the chronically ill or those with disability is not often measured.</p> <p>Methods</p> <p>We calculated country-specific prevalences of 'disability' (difficulty with at least one activity of daily living), 'disease' and 'co-morbidity' (presence of at least one, and at least two, of seven chronic diseases/conditions, respectively), and 'active community engagement' (using five levels of community participation, from less than weekly community contact to voluntary or paid work) in seven LAC cities. We estimated remaining life expectancy (LE) with and without disability, disease and co-morbidity, and investigated age, sex, and regional variations in disability-free LE. Finally, we modeled the association of disease, co-morbidity and disability with active community participation using an ordinal regression model, adjusted for depression.</p> <p>Results</p> <p>Overall, 77% of the LAC elderly had at least one chronic disease/condition, 44% had co-morbidity and 19% had a disability. The proportion of disability-free LE declined between the youngest (60–64 years) and the eldest (90 years and over) age-groups for both men (from 85% to 55%) and women (from 75% to 45%). Disease-free and co-morbidity-free LE, however, remained at approximately 30% and 62%, respectively, for men (20% and 48% for women), until 80–84 years of age, then increased. Only Bridgetown's participants had statistically significantly longer disability-free LE than the regional average (IRR = 1.08; 95%CI 1.05–1.10; p < 0.001). Only Santiago's participants had disability-free LE which was shorter than the regional average (IRR = 0.94; 95%CI 0.92–0.97; p < 0.001). There was 75% active community participation overall, with more women than men involved in active help (49% vs 32%, respectively) and more men involved in voluntary/paid work (46% vs 25%, respectively). There was either no, or borderline significance in the association between having one or more diseases/conditions and active community engagement for both sexes. These associations were limited by depression (odds ratio [OR] reduced by 15–17% for men, and by 8–11% for women), and only remained statistically significant in men. However, disability remained statistically significantly associated with less community engagement after adjusting for depression (OR = 0.58, 95%CI 0.49–0.69, p < 0.001 for women and OR = 0.50, 95%CI 0.47–0.65, p < 0.001 for men).</p> <p>Conclusion</p> <p>There is an increasing burden of disease and disability with older age across the LAC region. As these nations cope with resulting social and economic demands, governments and civic societies must continue to develop and maintain opportunities for community participation by this increasingly frail, but actively engaged group.</p

The phase difference between neural drives to antagonist muscles in essential tremor is associated with the relative strength of supraspinal and afferent input

The pathophysiology of essential tremor (ET), the most common movement disorder, is not fully understood. We investigated which factors determine the variability in the phase difference between neural drives to antagonist muscles, a long-standing observation yet unexplained. We used a computational model to simulate the effects of different levels of voluntary and tremulous synaptic input to antagonistic motoneuron pools on the tremor. We compared these simulations to data from 11 human ET patients. In both analyses, the neural drive to muscle was represented as the pooled spike trains of several motor units, which provides an accurate representation of the common synaptic input to motoneurons. The simulations showed that, for each voluntary input level, the phase difference between neural drives to antagonist muscles is determined by the relative strength of the supraspinal tremor input to the motoneuron pools. In addition, when the supraspinal tremor input to one muscle was weak or absent, Ia afferents provided significant common tremor input due to passive stretch. The simulations predicted that without a voluntary drive (rest tremor) the neural drives would be more likely in phase, while a concurrent voluntary input (postural tremor) would lead more frequently to an out-of-phase pattern. The experimental results matched these predictions, showing a significant change in phase difference between postural and rest tremor. They also indicated that the common tremor input is always shared by the antagonistic motoneuron pools, in agreement with the simulations. Our results highlight that the interplay between supraspinal input and spinal afferents is relevant for tremor generation