the final output of the HPA axis, following occlusal disharmony in rats injected with 6-hydroxydopamine (6-OHDA), a specific catecholamine neurotoxin. 6-OHDA microinjection into the V-NAB reduced the magnitude of the responses of extracellular NA in the PVN and the plasma corticosterone to occlusal disharmony. Our results suggest that V-NAB to the PVN are involved in occlusal disharmony-induced activation of the HPA axis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.”
“The Rabusertib chemical structure act of drilling a tooth belongs to the most feared situations of patients suffering from dental phobia. We presented

25 female patients and 24 nonphobic women with the sound of a dental drill, pleasant and neutral sounds. Brain activation was recorded via near infrared spectroscopy in fronto-parietal and premotor areas. The groups differed in supplementary motor area (SMA) recruitment. Relative to controls, the phobics displayed increased oxy hemoglobin while presented with the phobia-relevant sound, but showed comparable activation in the other conditions. As the SMA is engaged in the preparation of motor actions, the increased response in patients might mirror the priming of flight behavior during VX-770 clinical trial exposure. We found no indication of an emotional modulation of parietal and dorsomedial prefrontal cortex activation. (C) 2011 Elsevier Ireland Ltd. All

rights reserved.”
“Recent morphological and physiological studies support the assumption that the extrageniculate ascending tectofugal pathways send visual projection to the caudate nucleus (CN)

in amniotes. In the present study we investigate the anatomical connection between the visual associative cortex along the anterior ectosylvian sulcus (AES) and the CN in adult domestic cats. An anterograde tracer – fluoro-dextraneamine – was injected into the AES cortex. The distribution of labeled axons was not uniform in the CN. The majority of labeled axons and Celecoxib terminal like puncta was found only in a limited area in the dorsal part of the CN between the coordinates anterior 12-15. Furthermore, a retrograde tracer – choleratoxin-B – was injected into the dorsal part of the CN between anterior 12 and 13. We detected a large number of labeled neurons in the fundus and the dorsal part of the AES between the coordinates anterior 12-14. Based upon our recent results we argue that there is a direct monosynaptic connection between the visual associative cortex along the AES and the CN. Beside the posterior thalamus, the AES cortex should also participate in the transmission of the tectal visual information to the CN. This pathway is likely to convey complex information containing both sensory and motor components toward the basal ganglia, which supports their integrative function in visuomotor actions such as motion and novelty detection and saccade generation. (C) 2011 Elsevier Ireland Ltd.

(c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Objective: This

clinical study evaluated prospectively adverse events immediately following ultrasound-guided foam sclerotherapy (UGFS) for the treatment of lower extremity venous valvular insufficiency. Incidence of side effects associated with carbon dioxide (CO(2)) foam was compared with a historical control using air-based foam. The literature on the subject was reviewed.

Methods: Vital signs were monitored during and immediately after UGFS, and adverse events were learn more recorded for 24 hours following the procedure. The air-based foam group had 49 patients: 44 women and 5 men. The CO(2)-based foam group had 128 patients: 115 women and 13 men. CEAP class https://www.selleckchem.com/products/nec-1s-7-cl-o-nec1.html was C2EpAsPr, describing varicose veins, primary etiology, and saphenous reflux. UGFS followed thermal ablation of the great saphenous vein. Foam was prepared using the three-way tap technique to mix gas with 1% polidocanol in a 4:1 ratio. Segments of the great and small saphenous veins and their tributaries were treated with UGFS. Foam volumes injected were 27 +/- 10 (SD) (6-46 range) and 25 +/- 12 (6-57 range) mL for air- and CO(2)-based foams respectively (P =.39). Incidence of adverse events

was compared by chi(2) statistics. Vital signs were compared by paired t test.

Results. During the procedure, the average heart rate decreased by less than 5 bpm for both groups (P <.001), and blood pressure decreased by less Erythromycin than 3 turn Hg in the CO(2) group (P <.02). Respiratory rate, electrocardiogram, and pulse oxymetry did not change significantly in both air- and CO(2)-foarn

series (P >.05). Visual disturbances were experienced by 3.1% (4/128) and 8.2% (4/49) patients in the CO(2) and air groups respectively (P =.15). Respiratory difficulties or circumoral paresthesia each occurred in 0.8% (n = 1) of the CO(2) patients. Incidence of chest tightness (3.1% vs 18%), dry cough (1.6% vs 16%), or dizziness (3.1% vs 12%) were significantly lower in the CO(2) vs air groups (P <.02). Nausea occurred in 2% and 4% of the CO(2) and air-based foam groups (P =.53). Overall, the proportion of patients describing side effects decreased from 39% (19/49) to 11% (14/128) as CO(2) replaced air for foam preparation (P <.001). Similar findings were described in the literature of air-based foam but data on the use of physiological gas were rare.

Conclusions. Side effects decreased significantly if CO(2) rather than air was employed to make the sclerosing foam for chemical ablation of superficial veins of the lower extremity.”
“Large conductance Ca2+-activated potassium channels (BKCa channels) are expressed in the plasma membrane of various cell types. Interestingly, recent studies provided evidence for the existence of BKCa channels also in mitochondria.

Both P2X3 receptor antagonists, Selleck STI571 A317491 and octoxynol-9, which attenuate endothelial cell function, eliminated SIEH without affecting epinephrine hyperalgesia. We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache, whose receptors are present in endothelial cells – the triptans and beta blockers – have a vascular component to their anti-hyperalgesic action. For this, we tested the effect of ICI-118,551, a beta(2)-adrenergic receptor

antagonist and sumatriptan, an agonist at 5-HT1B and 5-HT1D receptors, on nociceptive effects of endothelin and epinephrine. ICI-118,551 inhibited endothelin SIEH, and attenuated epinephrine hyperalgesia and SIEH. Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH, while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct-acting inflammatory mediator, prostaglandin E-2. These results support the suggestion that triptans and beta-blockers interact with the endothelial cell component of the blood vessel to produce anti-hyperalgesia. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.”
“The synaptic Ras/Rap-GTPase-activating SGC-CBP30 order protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D-aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts

NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional 4-Aminobutyrate aminotransferase significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters,

many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity.

No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity.

Conclusions: Schizophrenia

CP-868596 in vitro is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.”
“Introduction: This study evaluated the readability, accessibility, usability, and reliability of vascular surgery information on the Internet in the English language.

Methods: The Google, Yahoo, and MSN/Bing search engines were searched for “”carotid endarterectomy,”" “”EVAR or endovascular aneurysm repair,”" and “”varicose veins or varicose veins surgery.”" The first 50 Web sites from each search engine for each topic were analyzed. GSI-IX concentration The Flesch Reading Ease Score and Gunning Fog Index were calculated to assess readability. The LIDA tool (Minervation Ltd, Oxford, UK) was used to assess accessibility, usability, and reliability.

Results: The Web sites were difficult to

read and comprehend. The mean Flesch Reading Ease scores were 53.53 for carotid endarterectomy, 50.53 for endovascular aneurysm repair, and 58.59 for varicose veins. The mean Gunning Fog Index scores were 12.3 for carotid endarterectomy, 12.12 for endovascular aneurysm repair, and 10.69 for varicose veins. The

LIDA values for accessibility were good, but the results for usability and reliability were poor.

Conclusions: Internet information on vascular surgical conditions and procedures is poorly written and unreliable. We suggest that health professionals should recommend Web sites that are easy to read and contain high-quality surgical information. Medical information on the Internet must be readable, accessible, usable, and reliable. (J Vasc Surg 2012;56:1461-7.)”
“Site-saturation libraries of the Pseudomonas fluorescens esterase were created targeting three surface BCKDHA positions to increase its thermostability on the basis of the B-factor iterative test principle. All three positions were saturated simultaneously using our recently developed protocol for the design of ‘small, but smart’ mutant libraries bearing only consensus-like mutations. Hence, the library size could be significantly reduced while ensuring a high hit rate. Variants could be identified that showed significantly improved stability (8 degrees C higher compared with the wild type) without compromising specific activity. Subsequent iterative saturation mutagenesis gave an esterase mutant with a 9 degrees C increased melting point, but unchanged catalytic properties.

6 vs 12.5 mm (p<0.0001) and 7.1 vs 7.3 mm. (p = 0.6), respectively. The stone-free rate in nonstented vs; stented renal and ureteral stone cases was 76.3% vs 77.3% and 91.4% vs 93.5%, respectively (each p>0.99). The total energy applied per stone was 110 +/- 83 vs 150 +/- 89 J (p<0.0001) and 183 +/- 131 vs 209 +/- 125 J (p = 0.1), respectively. Auxiliary measures were required after shock wave lithotripsy for renal and ureteral stones in 5.4% and 10.8% of nonstented, and in 1.3% and 4.3% of stented cases, respectively. No complications were detected in stented renal and ureteral stone cases compared to 2.9% and 6.9% in nonstented. cases,

respectively.

Conclusions: A high success rate and a low complication rate were achieved in renal and ureteral stone cases with and without prior ureteral stent placement. Total energy needed to achieve a stone-free state did not differ between Nirogacestat cell line stented and nonstented ureteral cases, suggesting the absence of a significant influence of the stent. Overall stents decreased complications necessitating hospitalization and auxiliary invasive measures.”
“OBJECTIVE:The placement of thoracic pedicle screws, particularly EPZ 6438 in the deformed spine, poses unique challenges, and a learning curve. We measured the in vivo accuracy of placement of thoracic

pedicle screws by computed tomography in the deformed spine by a single surgeon over time.

METHODS: After obtaining institutional review board approval, we retrospectively selected the first 30 consecutive patients who had undergone

a posterior spinal fusion using a pedicle screw construct for adolescent idiopathic scoliosis by a single surgeon. The average patient age was 14 years, and their preoperative thoracic Cobb angle was, on average, 62.6 degrees. Patients were divided into 3 groups: group A, patients I to 10; group 13, patients 11 to 20; and group C, patients 21 to 30. Intraoperative evaluation of all pedicle screws included probing of the pedicle screw tract, neurophysiologic monitoring, and fluoroscopic confirmation. Postoperative computed tomographic scans Plasmin were evaluated by 2 spine surgeons, and a consensus read was established, as previously described (Kim YJ, Lenke LG, Bridwell KH, Cho YS, Riew KD. Free hand pedicle screw placement in the thoracic spine: is it safe? Spine. 2004;29(3):333-342), as (1) “”in,”" axis of pedicle screw within the confines of the pedicle; or (2) “”out,”" axis of pedicle screw outside the confines of the pedicle.

RESULTS: A total of 553 thoracic pedicle screws were studied (group A, n = 181; group B, n = 189; group C, n = 183) with 64 graded as out (medial, 35; lateral, 29), for an overall breach rate of 11.6%. When the breach rates were stratified by the surgeon’s evolving experience, there was a temporal decrease in the breach rate (group A, 15.5%; group 13, 10.6%; group C, 8.7%; P < .05).

The primary outcome was the patient-reported score on the Menorrhagia Multi-Attribute Scale (MMAS) (ranging from 0 to 100, with lower scores indicating greater severity), assessed over a 2-year period. Secondary outcomes included general quality-of-life and sexual-activity scores and surgical intervention.

RESULTS

MMAS scores improved from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group (mean increase, 32.7 and 21.4 points, respectively; P<0.001 for both comparisons). The improvements were maintained over a 2-year period but PD-0332991 ic50 were significantly greater in the levonorgestrel-IUS

group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9 to 16.9; P<0.001). Improvements in all

MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health) were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group, and this was also true for seven of the eight quality-of-life domains. At 2 years, more of the women were still using the levonorgestrel-IUS than were undergoing the Selleck ZVADFMK usual medical treatment (64% vs. 38%, P<0.001). There were no significant between-group differences in the rates of surgical intervention or sexual-activity scores. There were no significant differences in serious adverse events between groups.

CONCLUSIONS

In women with menorrhagia

who presented to primary care providers, the levonorgestrel-IUS was more effective than usual medical treatment in reducing the effect of heavy menstrual bleeding on quality of life. (Funded by the National Institute of Health Research Health Technology Assessment Programme; Rho ECLIPSE Controlled-Trials.com number, ISRCTN86566246.)”
“The monoclonal antibody (MAb) VRC01 was isolated from a slowly progressing HIV-1-infected donor and was shown to neutralize diverse HIV-1 strains by binding to the conserved CD4 binding site (CD4bs) of gp120. To better understand the virologic factors associated with such antibody development, we characterized HIV-1 envelope (Env) variants from this donor and five other donors who developed broadly neutralizing antibodies. A total of 473 env sequences were obtained by single-genome amplification, and 100 representative env clones were expressed and tested for entry and neutralization sensitivity. While VRC01 neutralizes about 90% of the genetically diverse heterologous HIV-1 strains tested, only selective archival Env variants from the VRC01 donor were sensitive to VRC01 and all of the Env variants derived from the donor plasma were resistant, indicating strong antibody-based selection pressure. Despite their resistance to this broadly reactive MAb that partially mimics CD4, all Env variants required CD4 for entry.

History of language acquisition is a potentially valuable marker to refine our search for causes and treatments in autism spectrum.”
“Lithium is the mainstay for the treatment of bipolar disorder

Selleckchem 3-deazaneplanocin A (BD) and inhibits glycogen synthase kinase 3-beta (GSK3-beta). The less active GSK3-beta promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-beta gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-beta promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-beta

rs334558*C gene-promoter variants, and the long-term administration of the GSK3-beta inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-beta inhibition and mafosfamide lithium could counteract the detrimental influences of BD on WM structure, with specific benefits p53 activator resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections. Neuropsychopharmacology (2013) 38, 313-327; doi:10.1038/npp.2012.172; published online 19 September 2012″
“Background. Children with attention deficit/hyperactivity disorder (ADHD) are at risk of negative academic outcomes. However, relatively few studies in this area have been based

on long-term longitudinal designs and community-based settings. This study examined the link between childhood hyperactivity-inattention symptoms (HI-s) and Subsequent academic achievement in a community setting, controlling for other behavioural symptoms, socio-economic status (SES) and environmental factors at baseline.

Method. The sample consisted of 1264 subjects (aged 12 to 26 years at follow-up) recruited from the longitudinal GAZEL Youth study. Psychopathology, environmental variables and academic outcomes were measured through self-reports. Multivariate modelling was performed to evaluate the effects of childhood HI-s and other risk factors oil academic achievement 8 years later.

Results. HI-s independently predicted grade retention [adjusted odds ratio (OR) 3.

2009, PNAS 106 5406-5411], the model predicts that exposing the cell to extracellular 1.5% CO2/10 mM HCO3- (pH 7.50) causes pH(i) to fall and pH(S) to rise rapidly to a peak and then decay. Moreover, the model provides insights into the competition between diffusion and reaction processes when we

change the width of the EUF, membrane permeability to CO2, native extra- and intracellular carbonic anhydrase-like activities, the non-CO2/HCO3- (intrinsic) intracellular buffering power, or mobility of intrinsic intracellular buffers. (C) 2012 Elsevier Ltd. All rights reserved.”
“Alzheimer’s disease (AD) is a chronic neurodegenerative disease that causes a progressive loss in selleck kinase inhibitor learning and memory capabilities and eventually results in dementia. The non-renewable nature of neurons in the central nervous system leads to the basic pathological changes that are related to the various behavioral and psychological symptoms of AD. Oligodendrocyte- and myelin-related neurite outgrowth inhibitors (NOIs) tend to hinder the regeneration of neurons. We designed a recombinant DNA vaccine composed of multiple specific inhibitory domains of NOIs: Vaccination induced effective antibodies against the specific domains in the sera of mice treated with a DNA primed-vaccinia

virus boost regimen. The vaccine attenuated neuronal degeneration in the mouse brain and protected the model mice from behavioral deficits. Vaccination also decreased the formation of soluble A beta oligomer and amyloid plaques PF-4708671 in the co-transgenic mice brain. What’s more, astrocytosis in brains of APP/PS1 co-transgenic mice was also relieved. The results suggested that immunotherapy with multiple specific domains of myelin- and oligodendrocyte-related NOIs may be a promising approach for Alzheimer’s disease and other degenerative central nervous system diseases. (C) 2012 Published by Elsevier Ltd.”
“Objective:

Neuropsychological studies comparing cognitive performance in patients suffering from Obsessive-Compulsive Disorder (OCD) or Major Depressive Disorder (MDD) revealed deficits in the domains of verbal fluency and viso-motor speed/set shifting in both groups. Spatial working memory deficits, however, have been identified as specific markers of OCD. As yet, it has not been substantiated whether deficits in visual organization and complex visual memory are also specific to OCD and are not Amrubicin shared by MDD.

Method: Test performance in seven cognitive domains was assessed in 40 OCD patients, 20 MDD patients, and 40 healthy controls. Patient groups were matched according to severity of depressive symptoms.

Results: Deficits shared by both patient groups, as compared to controls, were found in delayed spatial recall and verbal fluency while verbal memory was normal in both patient groups. Only patients with OCD, but not MDD patients were impaired in the domains visual memory, viso-motor speed/set shifting, visual organization, and problem solving.

A less severe impairment was observed with the tone CS. The results suggest that CS information from the LGNv and light CSs is relayed to the cerebellum through the MPN. Retrograde tracing with fluoro-gold (FG) showed that the LGNv and nucleus of the optic tract have ipsilateral projections to the MPN. Unilateral inputs to the MPN from the LGNv and nucleus of the optic tract may be part of the visual CS pathway that is necessary for visual eyeblink conditioning.”
“In the context of probabilistic AZD1480 mouse learning, previous functional magnetic resonance imaging studies have shown decreasing uncertainty

accompanying decreasing neuronal activation in task-relevant networks. Moreover, initial evidence points to a relationship between white matter structure and cognitive performance. Little is known, however, about the structural correlates underlying individual differences in activation and performance in the context of probabilistic learning. This combined functional magnetic resonance imaging diffusion tensor imaging study aimed at investigating the individual ability to reduce processing resources with decreasing uncertainty in direct relation to individual characteristics in white matter brain structure. Results showed that more successful learners, as compared with less successful learners, exhibited stronger activation decreases with decreasing selleck chemicals llc uncertainty. An increased

mean and axial diffusivity in, among others, the inferior and superior longitudinal fasciculus, the posterior part of the cingulum bundle, and the corpus callosum were detectable in less successful learners compared with more successful learners. Most importantly, there was a negative correlation between uncertainty-related activation and diffusivity in a fronto-parieto-striatal network in

less successful learners only, indicating a direct relation between diffusivity and the PLEKHM2 ability to reduce processing resources with decreasing uncertainty. These findings indicate that interindividual variations in white matter characteristics within the normal population might be linked to neuronal activation and critically influence individual learning performance. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Four experiments used rats to study the role of the basolateral amygdala (BLA) in the reinstatement and extinction of fear responses (freezing) to a previously extinguished conditioned stimulus (CS). In Experiment 1, BLA inactivation before pairing the extinguished CS with the shock unconditioned stimulus (US) or before US-alone exposure impaired the restoration and the reinstatement of fear responses to the extinguished CS. In Experiment 2, BLA inactivation before extinction impaired long-term inhibition of fear responses, but its inactivation before extinction of fear responses restored by CS-US pairing did not impair long-term inhibition.

“”Old persons”" were evaluated differently in the various life domains, and age thresholds for ascriptions of being old differed between domains. Furthermore, the positivity of domain-specific age stereotypes of a person predicted individual life satisfaction for the respective life domain. The strength of the relationship between age stereotypes and life satisfaction increased with participants’ age.

Discussion. Our results indicate the existence of domain-specific age stereotypes that become internalized into older persons’ self-views.”
“High-efficiency Selleckchem PSI-7977 prefractionation of complex protein mixtures is critical for top-down proteomics, i.e., the analysis of intact proteins by

M S. Free-flow electrophoresis (FFE) can be used for IEF to separate proteins within a pH gradient according to their pIs. In an FFE system, this separation is performed entirely in the VX-765 order liquid phase, without the need for particulate

chromatographic media, gels, or membranes. Herein, we demonstrated the compatibility of IEF-FFE with ESI-Fourier transform ICR MS (ESI-FTICR-MS) for top-down experiments. We demonstrated that IEF-FFE of intact proteins were highly reproducible between FFE instruments, between laboratories, and between analyses. Applying native (0.2% hydroxypropylmethyl cellulose) IEF-FFE to an enzyme resulted in no decrease in enzyme activity; applying either native or denaturing (8 M urea) IEF-FFE to a four-protein mixture with different pIs resulted in isolation of each protein into separate fractions in a 96-well plate. After desalting, each protein was sequenced by top-down MS/MS. As an application of this technique, either chicken erythrocyte histone H2A-IV and its major modified forms were enriched by IEF-FFE. Top-down analysis revealed Lys-5 to be a major acetylation site, in addition to N-terminal acetylation.”
“Regulatory regions with similar transcriptional output often have little overt sequence similarity, both within and between genomes. Although cis- and trans-regulatory changes can contribute to sequence divergence without dramatically altering gene expression outputs, heterologous DNA often functions similarly in organisms that share little regulatory sequence similarities

(e.g. human DNA in fish), indicating that trans-regulatory mechanisms tend to diverge more slowly and can accommodate a variety of cis-regulatory configurations. This capacity to ‘tinker’ with regulatory DNA probably relates to the complexity, robustness and evolvability of regulatory systems, but cause-and-effect relationships among evolutionary processes and properties of regulatory systems remain a topic of debate. The challenge of understanding the concrete mechanisms underlying cis-regulatory evolution-including the conservation of function without the conservation of sequence-relates to the challenge of understanding the function of regulatory systems in general. Currently, we are largely unable to recognize functionally similar regulatory DNA.