(C) 2008 Elsevier Ltd All rights reserved “
“Extracellular

(C) 2008 Elsevier Ltd. All rights reserved.”
“Extracellular signal-regulated kinase (ERK) is highly sensitive to regulation by neuronal activity and is critically involved in several forms of synaptic plasticity. These features suggested that alterations in ERK signaling might occur in epilepsy. Previous studies have described

increased ERK phosphorylation immediately after the induction of severe seizures, but patterns of ERK activation in epileptic animals during the chronic period have not been determined. Thus, the localization and abundance of phosphorylated extracellular signal-regulated kinase (pERK) were examined in a pilocarpine model of recurrent seizures in C57BL/6 mice during the seizure-free period and at short intervals after spontaneous seizures. Immunolabeling of pERK in control animals revealed an abundance of distinctly-labeled neurons within the hippocampal Pexidartinib formation. However, in pilocarpine-treated mice during the seizure-free period, the numbers of pERK-labeled neurons were substantially decreased throughout much of the hippocampal formation. Double labeling with a general neuronal marker suggested that the decrease in pERK-labeled neurons was not due primarily to cell loss. The decreased ERK phosphorylation in seizure-prone animals was interpreted

Tideglusib in vitro as a compensatory response to increased neuronal excitability within the network. Nevertheless, striking increases in pERK labeling occurred at the time of spontaneous seizures and were evident in large populations of neurons at very short intervals (as early as 2 min) after detection of a behavioral seizure. These findings suggest that increased selleck chemical pERK labeling could be one of the earliest immunohistochemical indicators

of neurons that are activated at the time of a spontaneous seizure. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.”
“It is still unclear how information is actually stored in biological neural networks. We propose here that information could be first orthogonalized and then stored. This could happen in a manner similar to how a set of vectors is transformed into a set of orthogonalized (i.e. mutually perpendicular) vectors. Orthogonalization may overcome the limits of conventional artificial networks, particularly the catastrophic interference caused by interference between stored inputs. The features needed to allow orthogonalization are common to biological networks, suggesting that it may be a common network mechanism. To illustrate this hypothesis, we characterize the underlying features that an archetypal biological network must have in order to perform orthogonalization, and point out that a number of actual networks show this archetypal network organization. (C) 2008 Elsevier Ltd. All rights reserved.

Carers’ CC at follow-Lip was not significantly predicted by eithe

Carers’ CC at follow-Lip was not significantly predicted by either baseline family stress, burden of care or patient-related variables. Conversely, baseline EOI predicted both family stress and burden of care at 7 months follow-up. Finally, family burden of care at follow-up was a function of baseline EOI and patients’ depressive symptoms. C

onclusions. This buy Veliparib study provides preliminary Support to the postulate that EOI and CC may be influenced by separate factors early in the course of psychosis and warrant future research and therapeutic interventions

as separate constructs. Implications for family interventions in the early phase of psychosis and the prevention of CC and EOI are discussed.”
“Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with

depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal check details behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in

the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic Calpain or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects. Neuropsychopharmacology (2013), 476-484; doi:10.1038/npp.2012.205; published online 17 October 2012″
“We investigate invasions from a biological reservoir to an initially empty, heterogeneous habitat in the presence of advection. The habitat consists of a periodic alternation of favorable and unfavorable patches. In the latter the population dies at fixed rate. In the former it grows either with the logistic or with an Allee effect type dynamics, where the population has to overcome a threshold to glow.

(C) 2011 IBRO Published by Elsevier Ltd All rights reserved “

(C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.”
“Producing and maintaining distinct (orthogonal) neural representations for similar events is critical to avoiding interference in long-term memory. Recently, our laboratory provided the first evidence for separation-like signals in the human CA3/dentate. Here, we extended this by parametrically varying the change in input (similarity) while monitoring CA1 and CA3/dentate for separation and completion-like signals using high-resolution fMRI. In the

CA1, activity varied in a graded fashion in response to increases in the change in input. In contrast, the CA3/dentate Volasertib order showed a stepwise transfer function that was highly sensitive to small changes in input.”
“Expectations about

a food can impact on its taste, but this may represent a perceptual change or a bias in response at the decision-making stage. We hypothesised that CH5183284 manufacturer expectation of taste intensity should be underpinned by modulation of activity in primary taste cortex. Using functional magnetic resonance imaging, we found that expecting a very sweet drink, but receiving a less sweet drink, enhanced the reported sweetness and bolstered activity in taste cortex, relative to a less sweet drink without this expectation. The activation overlapped with primary taste cortex activation found in 11 recent taste studies. Our findings provide evidence that taste expectation modulates activity in an area consistently reported as primary taste cortex, implying that expectation effects do indeed impact on taste perception. NeuroReport 22:365-369 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.”
“We investigated the involvement of PKA and PKC signaling in a negatively reinforced operant learning paradigm in Aplysia, learning that food is

inedible (LFI). In vivo injection of PKA or PKC inhibitors blocked long-term LFI memory formation. Moreover, a persistent phase of PKA activity, although not PKC activity, was necessary for long-term memory. Surprisingly, neither PKA nor PKC activity was required for associative Regorafenib in vitro short-term LFI memory. Additionally, PKA and PKC were not required for the retrieval of short- or long-term memory (STM and LTM, respectively). These studies have identified key differences between the mechanisms underlying nonassociative sensitization, operant reward learning, and LFI memory in Aplysia.”
“The capacity of human adipose-derived stem cells (hADSCs) to differentiate into motor neurons and the identity of molecular factors that confer hADSCs with the competence of motor neurons have yet to be elucidated. Here, retinoic acid and sonic hedgehog were applied to examine whether hADSCs could be differentiated into motor neurons. As early as 6 h after induction, hADSCs were changed toward neuronal morphology. After induction, hADSCs showed positive immunocytochemical staining for beta-III-tubulin, choline acetyltransferase, and neuron-specific enolase.

Here, we investigate the role of M-5 receptors in the effects of

Here, we investigate the role of M-5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M (5) (-/-) mice backcrossed to the C57BL/6NTac strain.

Sensitization of the locomotor response is considered a model for chronic adaptations

to repeated substance exposure, which might be related CX-6258 nmr to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M (5) (-/-) mice, while the effects of cocaine were similar in M (5) (-/-) and wild-type mice.

Consistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M (5) (-/-) mice.

The different effects of amphetamine and cocaine in M (5) (-/-) mice may be due to the divergent pharmacological profile

of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M-5 receptor. These results support the concept that the M-5 receptor modulates effects of addictive drugs.”
“The genetic code is the triplet code based on the three-letter codons, which determines the specific amino acid sequences in proteins synthesis. Choosing an appropriate selleck chemical model for processing these codons is a useful method to study genetic processes in Molecular Biology. As an effective modeling tool of discrete event dynamic systems (DEDS), colored petri net (CPN) has been used for modeling several biological systems, such as metabolic pathways and genetic regulatory networks. According to the genetic code table, CPN is employed to model the process of genetic information transmission. In this paper, we propose a CPN model of amino acids classification, and further present the improved CPN model. Based on the model mentioned above, we give another new CPN model to classify the

type of gene mutations via contrasting the bases of DNA strands and the codons of amino acids along the polypeptide chain. This model is helpful in determining whether a certain gene mutation will cause the changes of the structures and functions of protein molecules. The effectiveness and accuracy of the presented model are illustrated by the examples in this paper. (C) 2012 Elsevier Ltd. All rights reserved.”
“The developmental anatomy of the brain is largely directed by neural-based cues. Despite this knowledge, the developmental trajectory of the primate brain has not yet been fully characterized. To realize this goal, the advance in noninvasive imaging methods and new brain atlases are essential. The common marmoset (Callithrix jacchus), a small New World primate, is widely used in neuroscience research.

Several studies have reported inferior results with CAS in the el

Several studies have reported inferior results with CAS in the elderly. The objective of this study was to evaluate national outcomes of CAS and CEA and to compare utilization and outcomes of these procedures in different age groups.

Methods: We evaluated the 2005

Nationwide Inpatient Sample for hospitalizations with a procedure of CAS or CEA within 2 days after admission at age 60 years and above. Procedures were analyzed with respect to patient demographics and associated complications.

Results. A total of 80,498 carotid interventions (73,929 CEA and 6,569 CAS) were identified. The overall incidence of stroke was 4.16% after CAS and 2.66% after CEA (P<.0001). CAS was more often utilized in octogenarians than in younger patients (8.55% in 80+ vs selleck JNJ-64619178 purchase 7.92% in 60-69 years; P<.0002). Increased age was not associated with greater stroke rates after CAS or CEA (P=.19 and.06, respectively). Octogenarians, compared to younger patients, had greater cardiac, pulmonary, and renal complications after CEA (3.0% vs 1.9%, 1.9% vs 1.0%, and 1.4% vs 0.54%, respectively; P<.0001). When adjusted by age, gender,

complications, and Elixhauser coniorbidities, patients after CAS were 1.6 times as likely to have a stroke (confidence interval [CI] = 1.37-1.78) when compared to CEA. Significant predictors of postoperative hospital mortality were stroke (odds ratio [OR] = 29.0; 95% CI = 21.5-39.1), cardiac complications (OR = 6.4; 95% CI = 4.4-9.1), pulmonary complications (OR = 3.5; 95% CI = 2.31-5.19), and renal failure (OR = 2.5; 95% CI = 1.6-3.8). With increasing age, overall mortality steadily increased after CAS (from 0.23% to 0.67%; P=.0409) but remained stable after CEA.

Conclusion: Octogenarians did not have a higher risk of stroke after CAS when compared to younger patients. Stroke was the strongest predictor of hospital mortality. The increased utilization of CAS in the aged, which had significantly higher stroke rates in all age groups studied, may account for the greater hospital mortality seen after CAS in the elderly.

Further studies focused on the aged are needed check details to define the best management strategies in the elderly. (J Vase Surg 2009;49: 325-30.)”
“We previously reported that BT-11, the extract of dried roots of Polygala tenuifolia Willdenow, had neuroprotective effects and improved scopolamine- and stress-induced amnesia in rats. It also blocked the activity of acetylcholinesterase and enhanced glucose utilization in the rat brain. Therefore, we examined whether BT-11 could enhance memory in healthy humans. This study was a randomized, double-blind, placebo-controlled, parallel-group study of BT-11 in healthy adults. The participants were given capsules of BT-11 or placebo 3 times daily for 4 weeks.


“Purpose: Kidney stones in children are increasing in inci


“Purpose: Kidney stones in children are increasing in incidence. The continued evolution of stone treatment modalities, including shock wave lithotripsy, makes the assessment of continuous outcomes essential. We describe contemporary shock wave lithotripsy outcomes in pediatric patients.

Materials and Methods: A medical record review was performed of all patients younger than 20 years who underwent shock

wave lithotripsy in 1998 to 2007. Patients were treated using a Dornier Compact Delta (R) lithotriptor with ultrasound and fluoroscopic imaging. Subjects were defined as stone-free if imaging within 12 months showed no evidence of stones with no additional treatment. Patient and treatment factors associated with successful outcomes were analyzed.

Results: In 101 buy AZD1080 children a total of 114 treatment sequences Ilomastat cell line were performed at a total of 150 shock wave lithotripsy sessions. Mean patient age was 10.5 years and 53% of the patients were girls. Mean stone diameter was 8 mm.

Treatment was done for a solitary stone in 76% of cases, for 2 stones in 17% and for 3 or more in 7% with a mean shock count of 2,247. One, 2 and 3 or more treatment sessions were done in 78%, 16% and 6% of patients, respectively. The overall stone-free rate was 58.6%. However, the stone-free rate was only 12.5% after treatment sequences in 20 children with a history of anatomical urological conditions or surgery, while the stone-free rate in children without urological conditions was 67% (p < 0.0001). Another

factor associated with a decreased stone-free rate was stone size greater than 10 mm (25% vs 63%, p = 0.01). Complications included requiring acute reevaluation or treatment after 7% of shock wave lithotripsy isometheptene sessions and 3.4% of patients required readmission.

Conclusions: Extracorporeal shock wave lithotripsy is effective in many children with urolithiasis and it is well tolerated. However, in some children, particularly those with a history of urological surgery or congenital genitourinary conditions, success rates are low. These children may be best treated with other modalities.”
“Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 mu g) via an intrathecal catheter (n = 8 each).

We also found color-related activities in

We also found color-related activities in mTOR inhibitor the anterior portion of the superior temporal sulcus (STS), suggesting its involvement in the color vision. The present results revealed that aITC is involved in the color vision of macaque monkeys by a functional imaging technique. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“The discovery of a novel coronavirus (CoV) as the causative agent of severe acute respiratory syndrome (SARS) has highlighted the need for a better understanding of CoV replication. The replication of SARS-CoV

is highly dependent on host cell factors. However, relatively little is known about the cellular proteome changes that occur during SARS-CoV replication. Recently, we developed a cell line expressing a SARS-CoV sub-genomic replicon and used it to screen inhibitors of SARS-CoV replication. To identify host proteins important for SARS-CoV RNA replication, the protein profiles of the SARS-CoV replicon cells and parental BHK21 cells were compared using a quantitative proteomic

strategy termed “”stable-isotope labeling by amino acids in cell culture-mass spectrometry”" (SILAC-MS). Our results revealed that, among the 1,081 host proteins quantified in both forward and reverse SILAC measurements, 74 had significantly altered levels of expression. Of these, significantly upregulated BCL2-associated athanogene secondly 3 (BAG3) was selected for further functional studies. BAG3 is involved in a wide variety of cellular processes, including selleck cell survival, cellular stress response, proliferation, migration, and apoptosis. Our results show that inhibition of BAG3 expression by RNA interference led to significant suppression of SARS-CoV replication, suggesting the possibility that upregulation of BAG3 may be part of the machinery that SARS-CoV relies on for replication. By correlating the proteomic data with these functional studies, the findings of this study provide important information for understanding SARS-CoV replication.”
“Although dynorphins

are widely involved in the control of not only nociceptive neurotransmission but also a variety of brain functions such as memory and emotion, no natural regulator for inducing the mRNA expression of prodynorphin (Pdyn), a precursor protein of dynorphins, is known. Using primary cultures of rat cortical neurons, we found that pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon neuropeptide family, markedly induces Pdyn mRNA expression. PACAP was much more effective than VIP, indicating a major role for PAC1 in the PACAP-induced Pdyn mRNA expression. The increase in Pdyn mRNA expression was independent of de novo protein synthesis.

We analyzed urea-solubilized proteins by 2-DE/MS (data set 2-DE)

We analyzed urea-solubilized proteins by 2-DE/MS (data set 2-DE) and by 1-DE-LC/MS (Supprot); proteins insoluble in 9 M urea but solubilized by SDS (Pellet); proteins precipitating in the Sephadex layer at the application side of IEF (Sephadex) by 1-DE-LC/MS; and proteins precipitating close to the application side within the IEF gel by LC/MS (Startline). The experimental proteomics data of H. pylori comprising 567 proteins (protein coverage: 36.6%) were stored in the Proteome Database A-1331852 in vitro System for Microbial Research (http://www.mpiib-berlin.mpg.de/2D-PAGE/), which gives access to

raw mass spectra (MALDI-TOF/TOF) in T2D format, as well as to text files of peak lists. For data mining the protein mapping and comparison tool PROMPT (http://webclu.bio.wzw.tum.de/prompt/) was used. The percentage of proteins with transmembrane regions, relative to all proteins detected, was 0, 0.2, 0, 0.5, 3.8 and 6.3% for 2-DE, Supprot, Startline, Sephadex, Pellet, and Etalon, respectively. Z-DEVD-FMK in vivo 2-DE does not separate membrane proteins because they are insoluble in 9 M urea/70 mM DTT and 2% CHAPS. SDS solubilizes a considerable portion of the urea-insoluble proteins and makes them accessible for separation by SDS-PAGE and LC. The 2-DE/MS analysis with urea-solubilized proteins and the 1-DE-LC/MS analysis with the urea-insoluble protein fraction (Pellet)

are complementary procedures in the pursuit Selleck Cisplatin of a complete proteome analysis. Access to the PROMPT-generated diagrams in the Proteome Database allows the

mining of experimental data with respect to other functional aspects.”
“Introduction: Longitudinal changes of 4′-[methyl-C-11]thiothymidine ([C-11]DST) uptake were evaluated in turpentine-induced inflammation.

Methods: Turpentine (0.1 ml) was injected intramuscularly into the right hind leg of male Wistar rats. Longitudinal [C-11]4DST uptake was evaluated by the tissue dissection method at 1, 2, 4, 7, and 14 days after turpentine injection (n=5). The tumor selectivity index was calculated using the previously published biodistribution data in C6 glioma-bearing rats. Dynamic PET scan was performed on day 4 when maximum [C-11]4DST uptake was observed during the longitudinal study. Histopathological analysis and Ki-67 immunostaining were also performed.

Results: The uptake of [C-11]4DST in inflammatory tissue was significantly increased on days 2-4 after turpentine injection, and then decreased. On day 14, tracer uptake returned to the day 1 level. The maximum SUV of inflamed muscle was 0.6 and was 3 times higher than that of the contralateral healthy muscle on days 2-4 after turpentine injection. However, tumor selectivity index remains very high (>10) because of the low inflammation uptake.

Eighty-seven patients with first-ever, unilateral, ischemic strok

Eighty-seven patients with first-ever, unilateral, ischemic stroke who had been active smokers at stroke onset were examined during hospitalization and at 3-month follow-up. No association was found between

any specific lesion localization (the insula, operculum, striatum, thalamus, internal capsule, brainstem) and smoking status at the 3-month follow-up visit. Patients with lacunar circulation strokes (LACS) were more likely to be non-smokers at the follow-up examination. No sudden disruption of nicotine addition was observed in patients with insular or other stroke locations. Selleckchem R788 Concluding, post-stroke smoking cessation may not be associated with insular lesions. (c) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Genetic bottlenecks facilitate the fixation and extinction of variants in populations, and viral populations are no exception to this theory. To examine the existence of genetic bottlenecks in cell-to-cell movement of plant RNA viruses, we prepared constructs for Soil-borne wheat mosaic virus RNA2 vectors carrying two different fluorescent proteins, yellow fluorescent protein (YFP) and cyan fluorescent protein (CFP).

Coinoculation of host plant leaves with the two RNA2 vectors and the wild-type RNA1 showed separation of the two vector RNA2s, mostly within seven to nine cell-to-cell movements from individual initially coinfected cells. Our statistical analysis showed that the number of viral RNA genomes establishing infection see more in adjacent cells after the first cell-to-cell movement from an initially infected cell was 5.97 +/- 0.22 on average and 5.02 +/- 0.29 after the second cell-to-cell movement. These results indicate that plant

RNA viruses may generally face narrow genetic bottlenecks in every cell-to-cell movement. Furthermore, our model suggests that, rather than suffering from fitness losses caused by the bottlenecks, the plant RNA viruses are utilizing the repeated genetic bottlenecks as an essential element of rapid selection Obatoclax Mesylate (GX15-070) of their adaptive variants in trans-acting genes or elements to respond to host shifting and changes in the growth conditions of the hosts.”
“Divergent Toll-like receptor 7 (TLR7) and TLR9 signaling has been proposed to distinguish pathogenic from nonpathogenic simian immunodeficiency virus infection in primate models. We demonstrate here that increased expression of type I interferon in pathogenic rhesus macaques compared to nonpathogenic African green monkeys was associated with the recruitment of plasmacytoid dendritic cells in the lymph nodes and the presence of an inflammatory environment early after infection, instead of a difference in the TLR7/9 response.

In Fura-2 Ca2+

In Fura-2 Ca2+ 8-Bromo-cAMP datasheet imaging analysis, ghrelin administration increased the intracellular Ca2+ concentration in approximately 50% of total isolated anterior pituitary cells, and 20% of these cells strongly responded to ghrelin. Immunocytochemical analysis revealed that 82.9 +/- 1.3% of cells that responded to ghrelin stimulation were GH-immunopositive. On the other hand, PRL-, LH-, and ACTH-immunopositive cells constituted 2.0 +/- 0.3%, 12.6 +/- 0.3%, and 2.5 +/- 0.8% of ghrelin-responding pituitary cells, respectively. TSH-immunopositive

cells did not respond to ghrelin treatment. These results suggest that ghrelin directly acts not only on somatotrophs, but also on mammotrophs, gonadotrophs, Torin 2 in vivo and corticotrophs in the rat pituitary gland. (C) 2012 Elsevier Ireland Ltd. All rights reserved.”
“Purpose: Prostate cancer progression from androgen dependence to castration resistance results at least in part from oxidative stress induced by androgen deprivation therapy. We elucidated the state

and the role of oxidative stress induced by androgen deprivation therapy and the possibility of antioxidant therapy in human prostate cancer.

Materials and Methods: We investigated 4-HNE (4-hydroxy-2-nonenal histidine adduct) staining, and Twist1, YB-1 and androgen receptor expression by immunohistochemistry in prostate cancer samples treated with or without neoadjuvant androgen deprivation therapy. Intracellular reactive oxygen species and protein expression were examined by CM-H2DCFDA and Western blot analysis, respectively.

A cell proliferation assay and a mouse xenograft model were Vildagliptin used to assess tumor growth.

Results: Androgen deprivation therapy increased oxidative stress, as shown by 4-HNE staining in human prostate cancer tissue. Twist1 and YB-1 expression was up-regulated by androgen deprivation, resulting in androgen receptor over expression. In LNCaP and 22Rv1 cells androgen deprivation increased intracellular reactive oxygen species and evoked Twist1, YB-1 and androgen receptor over expression, resulting in cell growth in a castration resistant manner. Growth was alleviated by N-acetyl-cysteine, an electrophile that supports glutathione production. N-acetyl-cysteine also decreased LNCaP and 22Rv1 tumor growth in castrated and noncastrated mice.

Conclusions: Androgen deprivation therapy induced oxidative stress in in vitro and human prostate cancer. Antioxidant therapy using N-acetyl-cysteine appears to be a promising therapeutic modality for prostate cancer.”
“Neural networks provide candidate substrates for the spread of proteinopathies causing neurodegeneration, and emerging data suggest that macroscopic signatures of network disintegration differentiate diseases.