VNS in the treatment of major depression VNS was recently demonstrated to have an antidepressant effect in a rat model, significantly better than sham treatment, and similar to other antidepressant treatments (desipramine or ECS).190 During the past 5 years, Sackeim, Rush, and colleagues have published results of open and randomized controlled studies of VNS in the treatment of major depression. A preliminary open study of VNS in 60 patients with treatment-resistant

Inhibitors,research,lifescience,medical nonpsychotic major depressive episode revealed a response rate of 30% to 38% by 10 weeks of treatment.191 A 2-year Gefitinib chemical structure follow-up of this open study found a response rate of 40% to 44% after 1 year and 42% after 2 years, and Inhibitors,research,lifescience,medical a remission rate of 27% after 1 year and 22% after 2 years.192,193 A randomized controlled study of VNS in over 200 patients with treatment-resistant, nonpsychotic, major depressive episode showed that acute treatment (10 weeks) yielded a response rate of 15% that was similar to the response rate with sham treatment (10%). 194 After the acute treatment, all patients (VNS and sham groups) received

long-term treatment with VNS for another 12 months. This was associated with a response rate of 27% and a remission rate of 16%. 195 The response rate in the group of patients who were receiving VNS plus medication or ECT for a year (27%) was significantly Inhibitors,research,lifescience,medical better than the response rate of a similar Inhibitors,research,lifescience,medical but nonrandomized group of patients with treatment-resistant

depression who were receiving only medication or ECT for a year (response rate was only 13 %).196 Adverse effects The most common side effects of VNS are voice alteration or hoarseness (55%), coughing (17%), shortness of breath (15%), headache Inhibitors,research,lifescience,medical (22%), neck pain (17%), dysphagia (20%), and pain (15%). Although most side effects usually resolve within a few weeks, voice alteration and dyspnea might persist for long periods. Reduction in current intensity decreases the severity of these symptoms.191 Mechanism of action VNS most probably alters synaptic activities at vagal afferent terminations, stimulates deep brain areas, and thus modulates antidepressant neuronal circuits in multiple limbic system structures. Brain imaging studies reveal some of these suspected brain changes. Metalloexopeptidase PET measurements of cerebral blood flow in 10 patients with epilepsy before and during acute VNS treatment (both low- and high- stimulation VNS) demonstrated increased blood flow in the rostral, dorsal-central medulla, the right postcentral gyrus, bilaterally in the hypothalami, thalami, and insular cortices, and in the cerebellar hemispheres inferiorly Decreased blood flow was demonstrated bilaterally in hippocampus, amygdala, and posterior cingulate gyri.184 Similar changes in cerebral blood flow were also demonstrated during prolonged VNS treatment.

5, which is responsible for the ultra-rapid component of the delayed rectifier potassium current (IKur). The KCNA5 E375X nonsense mutation resulted in a truncated protein lacking the S4-S6 voltage sensor, the pore region, and the C-terminus. Functional studies revealed that this truncated form of KCNA5 was unable to conduct current, which is consistent with a loss-of-function effect.28 In vitro studies using human atrial myocytes and in vivo studies with a murine model found that administration of 4-aminopyridine, a known blocker of IKur, dramatically increased the incidence of early Inhibitors,research,lifescience,medical afterdepolarizations. The authors hypothesized that increased early afterdepolarizations associated with a prolonged

atrial action potential duration could trigger AF akin to that seen in torsade de pointes within the ventricles, which occurs with loss-of-function potassium channels in long QT syndrome. The importance of loss-of-function KCNA5 Inhibitors,research,lifescience,medical mutations in the pathogenesis of AF has been reaffirmed by subsequent reports.29, 30 Loss-of-Function Sodium Channel Mutations The SCN5A gene had been implicated in numerous arrhythmic disorders including the Brugada syndrome, congenital long QT syndrome type 3, and sick sinus syndrome.31-33 A study involving Inhibitors,research,lifescience,medical 375 patients with

a mixture of lone (118) and structural AF (257) identified 8 novel mutations in 10 different subjects that were absent from 360 healthy controls.34 The variants involved highly conserved residues within SCN5A and segregated with disease in all six of the familial cases. This report provided strong evidence that mutations within SCN5A represented an important Inhibitors,research,lifescience,medical cause of AF in patients with and without heart disease. The first SCN5A mutation associated with AF that was selleck inhibitor functionally Inhibitors,research,lifescience,medical characterized was found after screening 57 patients with lone AF or AF with hypertension and a confirmed family history of AF.35 A single novel mutation was found, Asn1986Lys, which was

absent from 300 ethnically matched controls. The affected father of the proband also carried the mutation; however, further genetic profiling of the family was not possible due to lack of consent. Expression of the mutant gene within Xenopus all laevis oocytes suggested a loss-of-function effect as evidenced by a significant hyperpolarizing shift in the midpoint of steady-state inactivation. This alteration was predicted to prolong the atrial action potential duration, and therefore the SCN5A Asn1986Lys was hypothesized to predispose to AF through a manner akin to the aforementioned atrial torsade. Mechanistic Subtype of AF 3: Gap Junction Impairment and Conduction Velocity Heterogeneity Connexins Connexin proteins form specialized channels, termed gap junctions, at the intercellular junction between adjacent cells that permit the flow of charged ions between the cytoplasmic compartments of neighbouring cells.

Activation extent was slightly higher for the right cerebrum than the left. In

both sides of the cerebrum, the occipital lobe demonstrated the greatest activation, followed by the frontal and parietal lobes. In both sides of the occipital lobe, the cuneus demonstrated the highest activation, followed by the lingual gyrus and middle occipital gyrus. Activation in the right frontal lobe was Inhibitors,research,lifescience,medical concentrated in the middle frontal gyrus, an area housing a large portion of the dorsolateral prefrontal cortex. In the cerebellum, activity was greatest in the posterior lobe, with the declive being the gyrus of highest activation on both sides. Table 1 Extent and mean z-statistic for the ROIs of greatest activation. Table ​Table22 shows the results of the quantitative analysis for the 30 ROIs of greatest deactivation extent. Inhibitors,research,lifescience,medical Deactivation extent was higher by nearly a factor of 2 in the left cerebrum compared with the right. In both sides of the cerebrum the frontal lobe demonstrated the greatest deactivation, followed by the parietal, temporal, and limbic lobes. The foci

of deactivation within the lobes were not as homogeneous between hemispheres as compared with the activation foci, although the limbic lobe did demonstrate a focus in the cingulate gyrus on both sides. Table 2 Extent and mean z-statistic for the ROIs of greatest deactivation. Volume Inhibitors,research,lifescience,medical renderings of the

group activation (orange) and deactivation (blue) results are shown in Figure ​Figure3.3. On the left, highly homogenous activation of the occipital lobe Inhibitors,research,lifescience,medical is evident, as is activation in the cerebellum. Deactivation is also evident on both sides of the parietal lobe in the angular gyrus, inferior parietal lobule, and precuneus, and extending down Inhibitors,research,lifescience,medical into the temporal lobe in the superior temporal gyrus and middle temporal gyrus. On the right, additional activation can be seen in the frontal lobe at the AG14699 precentral gyrus and medial central gyrus, and transitioning into the cingulate gyrus. Additional deactivation is present throughout the medial frontal gyrus and superior frontal gyrus. Figure ​Figure44 also shows activation results in the middle frontal gyrus of the right cerebrum. Figure 3 Results of the group maps showing activation (light) and deactivation (dark) for the occipital however and cerebellum views (left) and parietal and frontal views (right). Full anatomical surface renderings are shown in the top row, and serve as references for … Figure 4 Results of the group map showing activation (light) and deactivation (dark) from the front of the brain. The spatial distributions of the COMs for the three lobes of greatest extent for both contrasts were plotted using the Brainmap Slueth 2.0 program (Fox and Lancaster 2002; Fox et al. 2005; Laird et al. 2005).

80 A strong correlation exists between plasma and brain levels of DOC. The temporal and regional associations found in these studies suggest that the steroids originate in the adrenals and are transported to the brain. Upon entering the brain the steroids are metabolized by 5α-reductase and 3α-dehydrogenase enzymes. These enzymes display

brain region and cell specific expression81 that may be responsible for the regional distribution of steroid levels following acute ethanol administration. Furthermore, DOC levels measured in the Khisti et al study Inhibitors,research,lifescience,medical are comparable to 3α,5αselleck products -THDOC levels measured in plasma and brain,21 suggesting that DOC formed after acute ethanol administration may be largely converted to the GABAergic neurosteroid 3α,5α-THDOC. Studies of ethanoPs effects on neurosteroid precursors are important not only to determine the sources and Inhibitors,research,lifescience,medical synthesis of potent metabolites, but

also to establish their role in physiological functions. Effects of neuroactive steroids on drinking behavior in rodents The GABAergic system is important in regulating ethanol consumption, and neurosteroids can also alter drinking behavior through their actions on GABAA receptors. 3α,5α-THP Inhibitors,research,lifescience,medical dose-dependently increased ethanol self-administration in nondependent ethanolpref erring P rats, while decreasing ethanol administration in ethanol-dependent P rats.4 This suggests a complex relationship whereby neurosteroids may promote drinking in nondependent animals consuming small amounts of ethanol, while protecting against excessive drinking in dependent animals. This Inhibitors,research,lifescience,medical possibility is supported by data in

male C57BL/6J mice where 3α,5α-THP dose-dependently Inhibitors,research,lifescience,medical modulated ethanol intake in a 2-hour session, with low doses (3.2 mg/kg) increasing ethanol consumption and high doses (24 mg/kg) decreasing ethanol consumption.82 In addition, at doses of 10 and 17 mg/kg, 3α,5αTHP has been shown to have rewarding properties in mice.83 However, other studies in nondependent rats have shown that pretreatment with a 3 mg/kg dose aminophylline of 3α,5αTHP, but not a 1- or 10-mg/kg dose, increases oral selfadministration of ethanol84 This result suggests that 3α,5α-THP dose-dependently mediates some of the reinforcing effects of ethanol, and its concentration in brain may have an important influence on drinking behavior. Indeed, Sardinian alcohol-preferring rats have larger 3α,5α-THP and 3α,5α-THDOC elevations after ethanol administration than their non-alcohol-preferring counterparts.21 Other studies have shown that increased ethanol intake after 3α,5α-THP administration is selective for ethanol-reinforced responding, and cannot be attributed to palatability or increased motor activity during the experimental sessions.

1). The tube task thus appears less appropriate than the bimanual Brinkman board task and the questionnaire to determine the hand preference in human subjects. This raises then the question whether this task is adequate to assess hand preference in monkeys. The results related to hand preference in monkeys were highly disparate. Only two animals showed similar results (Mk-DI and Mk-AN) and, for each monkey, Inhibitors,research,lifescience,medical there was no systematic hand preference among all the tasks

performed. Considering the questionable suitability of the tube task in human subjects (see above), it was tried to eliminate the tube test from the monkey data: omitting the tube task data did not modify substantially the results, except for Mk-LO, which Inhibitors,research,lifescience,medical was a right-hander for each task except the tube one. Two conclusions maybe drawn from these results: either the tasks used here are not fully appropriate to determine the hand preference in monkeys, or the M. fascicularis monkeys do not show a stable and systematic hand preference for the present panel of tasks. In human subjects, the bimanual Brinkman board appears to be an adequate test, but is it also the case for the Zosuquidar in vitro nonhuman primates? This question highlights Inhibitors,research,lifescience,medical the limits of our experiment. On the one hand, we compare for the first time handedness in human subjects and in nonhuman primates for the same

Inhibitors,research,lifescience,medical tasks directly but, on the other hand, these manual tasks may not be equally relevant in both species. The complexity and the representation of the different tasks may well be different for nonhuman primates and for human subjects. A difference is already present at the level of training. Clearly, Inhibitors,research,lifescience,medical human subjects reached more rapidly plateau values than monkeys, especially for the modified Brinkman board task. Human subjects are obviously more often engaged in bimanual coordination tasks in their everyday life than monkeys, a difference which may bias the comparison between the two groups performing the same manual tasks. At onset time of

behavioral testing, the human subjects were already strongly lateralized, whereas this was most likely not the case in the nonhuman subjects. In the monkeys, the present data demonstrate that hand preference is more prominently revealed by a more challenging task (horizontal Bumetanide slots) than an easier task (vertical slots in the modified Brinkman board task, executed with both hands simultaneously; see Table ​Table1).1). In the comparison between monkeys and humans, it has to be emphasized that reinforcement is not of the same nature (food in monkeys, a bolt in human) and therefore the motivational context is different. Furthermore, human subjects were asked to perform the task as rapidly as possible, whereas there was no such time constraint in monkeys.

Loh et al. [31] electrospun thermosensitive poly(PEG/PPG/PCL urethane) hydrogel NFs encapsulating a model protein BSA. BSA release was regulated

by adjusting temperature in the range of 25°C to 37°C. When temperature increased, hydrophilic fiber mats expelled water and became hydrophobic. The model suggests both the rate constants of diffusion/convection Inhibitors,research,lifescience,medical (kS) and disassociation (koff) increase with temperature (Table 3). Likely, the thermally induced expelling of water enhances the disassociation of and expels BSA from the hydrogels fibers. As a comparison, temperature increase has little effect on BSA release from PCL NFs: kS and koff remain the same when temperature increases from 25 to 37°C, while a moderate increase in ΔG explains a lightly enhanced burst release. In contrast to the two-phase release of BSA from PCL NFs, hydrogel NFs release BSA in three phases: initial burst release, sustained release, and second burst release. Inhibitors,research,lifescience,medical The second burst release of BSA is due to the erosion of hydrogel fibers [31]. The current model captures the first two phases of BSA release from hydrogels fibers, but not the second burst release, because the model does not consider the volume change of drug carriers and its influences on drug release. 3.5. Statistical Analysis for Nonlinear Regression To validate

the model and evaluate the selleck screening library robustness of the parameter determination process, bootstrap sampling is used to study the properties Inhibitors,research,lifescience,medical of each model parameter, such as mean and standard deviation. In this

process, we assume that the observations in each case are independent. This assumption is satisfied for most cases through testing autocorrelation between observations. Using this method, Inhibitors,research,lifescience,medical all the 60 cases are studied, except a few cases (e.g., Figures 3(b), 3(c), 3(e), and 4(a)) whose sample sizes are too small. Results from the statistical analysis show that all parameters are significant. Parameter estimates for two selected cases are presented in Tables ​Tables44 and ​and5.5. Inhibitors,research,lifescience,medical At the significant level of 0.05, small P values of the F-statistic show that the nonlinear model of (4) is significantly different from a simple linear model. Additionally, small P values (<0.05) from the bootstrap results show that all the parameters in (4) are significant and should be kept. Nevertheless, the comparable results between bootstrap method and our parameter estimates in Tables ​Tables1,1, ​,2,2, and ​and33 suggest that the nonlinear model is very robust. Table 4 Properties of the model Linifanib (ABT-869) parameters for Figure 3(a). Table 5 Properties of the model parameters for Figure 4(d). 4. Conclusion We evaluated the ability of a simple, three-parameter model to capture the release of bioactive molecules from various nanocarriers. Specifically, the model considers reversible drug-carrier interaction, leading to a closed-form analytical solution. A parameter study illustrated the dependence of release kinetics on each model parameter.

Our interest in this area stemmed from clinical observations that estrogen acts beyond its traditional targets in the hypothalamus and pituitary, and influences other facets of brain function involved in memory and

neurodegeneration. Since neurodegenerative events occur frequently in elderly women who are chronically hypoestrogenic, the results of these studies carry profound implications in the clinical setting. Thus, it is important, to determine Inhibitors,research,lifescience,medical whether and how ERT can ameliorate neural dysfunction. Estrogen and cognition Clinical studies demonstrate that estrogen influences memory and cognition,6,17-22 and can protect against neurodegenerative diseases such as AD.10,11,23-30 These findings, however, are not without Inhibitors,research,lifescience,medical controversy. As the results of more clinical studies become available, we are beginning to appreciate that, the protective actions of estrogen do not apply in all situations.31-33 Many studies have examined whether ERT

improves cognitive function. The majority of data show that estrogen can enhance cognitive function in both young22 and Inhibitors,research,lifescience,medical older women.19,21,34 It appears that by maintaining normal cognitive function, estrogen may further act to decrease the risk and delay the onset, of AD.10,26,28-35 Importantly, estrogen docs not exert actions on all aspects of memory. It is critical to consider that memory is a broad term describing several distinct neural functions, many Inhibitors,research,lifescience,medical of which originate in EVP4593 in vitro different and overlapping regions of the brain. Thus, it is not surprising that estrogen may influence specific subtypes of memory. For example, some,17,19,34 but not all,36 studies show that ERT appears to specifically enhance immediate and delayed recall of verbal information. Other reports indicate that the beneficial actions of ERT on cognition include improvement of visuospatial memory.37,38

Estrogen and Alzheimer’s disease Several studies have examined whether ERT decreases the risk, delays the onset, or stops the progression of neurodegeneration caused by AD. Estrogen has been shown to decrease Inhibitors,research,lifescience,medical the risk for AD10 or induce a modest improvement, in cognitive function in individuals with AD.11,35,39,40 However, other studies have reported no difference in cognitive function Electron transport chain between estrogen- and placebo-treated individuals.41-43 A recent cohort, study43 failed to detect slowing of AD progression or improvement of cognitive and functional outcomes in women with mild-to-modcratc AD treated with Premarin®. The results of this study and those of other studies31-33 strongly suggest, that estrogen may fail to reverse or even halt a disease process that has already been initiated. Therefore, while it is clear that estrogen can influence certain aspects of cognitive function and decrease the risk for AD, it remains controversial whether it can act against an existing neurodegenerative condition. Taken together, the findings of these studies indicate that estrogen may protect the brain through primary prevention.

Associations were investigated in a well-characterized sample of adults with bipolar disorder, major depressive disorder, or healthy controls. Candidate polymorphisms were expected to show only modest associations with

mood disorder symptoms and diagnoses. However, genetic variation was expected to be significantly associated with individual differences in cognitive processing (global ability, impulsivity, memory) and fronto-limbic volumes. Fronto-limbic volumes Inhibitors,research,lifescience,medical were expected to mediate the relationships between genetic variation and cognitive vulnerability to mood disorder. Materials and Methods Participants The present sample represents a subgroup of individuals accrued through multiple diagnostic clinics and recruited into overlapping NIMH-funded research studies evaluating FHPI neuroimaging findings in adults with mood disorders at the University of Texas Health Science Center at San Antonio. In these studies, adult participants Inhibitors,research,lifescience,medical were recruited using advertisements broadcast on the radio and flyers placed

Inhibitors,research,lifescience,medical in the community and at hospitals and clinics in the South Texas Medical Center area. Age, gender, handedness, and race/ethnicity (coded as white/non-Hispanic and other race/ethnicity) were obtained via clinical interview. Participants received a physical examination and laboratory tests to rule out physical illnesses and substance use. Any participant with endocrinological disease, head trauma, neurological disease, family history of hereditary Inhibitors,research,lifescience,medical neurological disorder, or a

medical condition such as hypertension, diabetes, active liver disease, kidney problems, respiratory problems, or current alcohol /drug abuse dependence was excluded. Left handed and ambidextrous participants were excluded from this sample to reduce heterogeneity of neuroimaging. The Institutional Review Board of the University of the Texas Health Science Center at Houston and Baylor College of Medicine approved this study. Written informed Inhibitors,research,lifescience,medical consent was obtained from all the participants after a complete Thalidomide description of the study was provided. Procedures Diagnostic and symptom assessment Participants were evaluated for DSM-IV-TR Axis I disorders using the Structured Clinical Interview for DSM-IV (SCID) Axis I disorders, research version, patient edition (First et al. 2002). A senior psychiatrist (JCS) reviewed all clinical information, including history of medical and neurological conditions, and confirmed that all subjects met DSM-IV-TR diagnostic criteria for bipolar disorder (BD) or for Major Depressive Disorder. Clinical symptom ratings were completed using the Hamilton Rating Scale for Depression (HAM-D; Hamilton 1960) and the Young Mania Rating Scale (YMRS; Young et al. 1978).

The meeting focused on the following main areas: 1) the biology of the nucleus and the nuclear envelope and the biological pathways affected in laminopathies; 2) the epidemiology of muscle laminopathies, lipodystrophies and progeroid syndromes; 3) the Emery- Dreifuss Muscular dystrophy (EDMD) from a clinical point of view; 4) Dilated cardiomyopathy with conduction defects (CMD-CD) from diagnosis to therapy; 5) Familial partial lipodystrophy of the Dunningan type (FPLD): diagnosis and therapy; 6) Progeroid laminopathies, including

mandibuloacral displasia (MADA) Inhibitors,research,lifescience,medical and Hutchinson-Gilford progeria (HGPS): diagnosis and therapeutic trials. Biology of the cell nucleus and pathogenetic pathways in laminopathies The first day of the meeting was devoted to an introduction to the biology of the cell nucleus (2). New insights

Inhibitors,research,lifescience,medical into the understanding of nuclear functionality have been presented. The nucleus is now considered a complex interaction platform, where proteins regulate nucleo-cytoskeleton interplay in view of chromatin organization and transcriptional activity (Nadir M. Maraldi, Bologna). The main pathogenetic pathways in lamina A/Clinked disorders have been reviewed. Altered mechanosignaling transduction, chromatin modulation and differentiation-related gene transcription Inhibitors,research,lifescience,medical (3, 4) have been highlighted as the key events at the basis of laminopathic diseases. Prelamin A accumulation (5) has been reported as the main molecular defect in systemic and adipose tissue laminopathies (Cristina Capanni, Inhibitors,research,lifescience,medical Bologna). Epidemiology of lamin-linked diseases Muscle laminopathies, including EDMD, LGMD1B and CMD-DC, are transmitted by dominant inheritance or may occur due to spontaneous mutations. The clinical phenotype (6)

is characterized by joint contractures, muscle weakness and wasting and cardiac conduction defects, most of them Inhibitors,research,lifescience,medical evolving to pictures of dilated cardiomyopathy. The epidemiology of muscle laminopathies is complex and as yet not well defined. The incidence of autosomal dominant EDMD caused by mutations in lamin A/C gene (Enrico Bertini, Rome) has been reported as extremely variable, ranging from 1 to 3:100.000. Lipodystrophies may be caused by mutations in several genes including PPARgamma, LMNA, AKT and seipin gene or also acquired, ADP ribosylation factor such as it happens in 40 percent of HIV infected patients undergoing anti-retroviral therapy. An overview of these disorders has been presented, with particular emphasis on LMNA-associated familial partial lipodystrophy, the most reSB216763 cell line presented form of the disease (Renato Pasquali, Bologna). Progeroid syndromes linked to mutations in several genes including LMNA have been reviewed (Claudio Franceschi, Bologna).

Mapping the network structure of the human brain Due to the invasive nature of most classical anatomical methods like tract tracing, these methods cannot be applied to large samples of individual brains and they cannot be deployed in vivo, hence rendering tract tracing studies in human populations and relating structural network features to brain dynamics or behavior virtually impossible. Tract tracing has an Rapamycin important role to play for

the study of anatomical Inhibitors,research,lifescience,medical connections in animal models, particularly in non-human primates,43 and it is of vital importance for validating anatomical data derived from noninvasive imaging technology.44 To the extent that such validation has been carried out, indications are that most projections identified by noninvasive imaging have counterparts in white matter fascicles described by classical anatomy. Most studies on human brain connectomics have been

carried out by charting structural connections on the basis of data coming from diffusion MRI and tractography (Figure 4). 45-48 Diffusion MRI and traclography infer the spatial orientations and trajectories Inhibitors,research,lifescience,medical of bundles of myelinated axons traversing the brain’s white matter, on the basis of measurements of the diffusion anisotropy of water or other small molecules within biological tissue. Importantly, diffusion imaging and tractography deliver inferential and statistical models Inhibitors,research,lifescience,medical of fiber anatomy but cannot directly trace or visualize anatomical connections. Methods for signal acquisition and fiber reconstruction

are under continual development, with important recent advances in imaging complex (eg, intersecting) fiber architecture,49,50 and new algorithms for improved accuracy Inhibitors,research,lifescience,medical in inferring fiber pathways, including estimates of their uncertainty and evidence.51,52 Figure 4. From imaging structural brain connectivity to network metrics. The three plots show three different ways to represent structural connections in anatomical space. (A) A set of tractography streamlines. Red, green and blue indicate fibers running along … Another Inhibitors,research,lifescience,medical area of important methodological development concerns the biological interpretation of connection weights resulting from aggregating fiber counts or probabilities into a connection matrix.53,54 New approaches for obtaining additional measures of white matter microstructure, eg, axonal diameters and packing densities,55 will likely help to refine estimates of the weight, strength, and conduction velocity of individual long-distance projections. The node degree (the number of connections Carnitine palmitoyltransferase II attached at each node) is one of the most easily accessible graph measures and it is also highly informative, as is the distribution of node degrees across the whole network. Most, if not all, complex networks found in natural, especially biological, systems have been shown to have a broad degree distribution, with a small but important admixture of nodes that maintain considerably higher numbers of connections than most other nodes.