“
“Paleolithic stone tools provide concrete evidence of major developments in human buy GSK458 behavioural and cognitive evolution. Of particular interest are evolving cognitive mechanisms

implied by the cultural transmission of increasingly complex prehistoric technologies, hypothetically including motor resonance, causal reasoning and mentalizing. To test the relevance of these mechanisms to specific Paleolithic technologies, we conducted a functional magnetic resonance imaging study of Naïve, Trained and Expert subjects observing two toolmaking methods of differing complexity and antiquity: the simple ‘Oldowan’ method documented by the earliest tools 2.5 million years ago; and the more complex ‘Acheulean’ method used to produce

refined tools 0.5 million years ago. Subjects observed 20-s video clips of an expert demonstrator, followed by behavioural GDC-0449 clinical trial tasks designed to maintain attention. Results show that observational understanding of Acheulean toolmaking involves increased demands for the recognition of abstract technological intentions. Across subject groups, Acheulean compared with Oldowan toolmaking was associated with activation of left anterior intraparietal and inferior frontal sulci, indicating the relevance of resonance mechanisms. Between groups, Naïve subjects relied on bottom-up kinematic simulation in the premotor cortex to reconstruct unfamiliar intentions, and Experts employed a combination of familiarity-based sensorimotor matching in the posterior parietal cortex and top-down mentalizing involving the medial Phosphatidylethanolamine N-methyltransferase prefrontal cortex. While no specific differences between toolmaking technologies were found for Trained subjects, both produced frontal activation relative to Control, suggesting focused engagement with toolmaking stimuli. These findings support motor resonance hypotheses for the evolutionary origins of human social cognition and cumulative culture, directly linking these hypotheses with archaeologically observable behaviours in prehistory. Neither toolmaking (Beck, 1980) nor cultural transmission (Whiten et al., 2007) is unique to humans. Yet there is

a vast gulf between the accumulated (Tennie et al., 2009) complexity of human technology and that of any other living species. This disparity has been attributed to uniquely human physical (Johnson-Frey, 2003) or social (Tomasello et al., 2005) cognition, or both (Passingham, 2008). Motor hypotheses of action understanding (Gallese & Goldman, 1998; Blakemore & Decety, 2001) suggest a possible unification of these explanations. The ‘Motor Cognition Hypothesis’ (Gallese et al., 2009) proposes that human social cognition has its phylogenetic and ontogenetic origins in ‘motor resonance’. Distinctive human capacities for technology, language and intersubjectivity might thus have a single origin in evolutionary modifications of a primate ‘mirror neuron system’ (Rizzolatti & Craighero, 2004).

Each plate contained the test strain with the plasmid pET26b+ or with the plasmid pETSN as a control. The selected transformants were cultured in LB medium containing 30 μg mL−1 kanamycin at 37 °C. IPTG was added to the medium at a final concentration of 0.7 mM to induce bacteria when the OD600 nm reached approximately 0.8 (Liang et al., 2007). After further induction overnight at 20 °C, cells were harvested by centrifugation, resuspended and then disrupted by sonication on ice. The supernatant of the whole-cell extracts was purified using the Ni-NTA column (Invitrogen) and DEAE Sepharose Fast Flow column

(Amersham Biosciences) according to the manufacturers’ instructions. The purification was performed at 0–4 °C. After the purification, the molecular mass of the purified enzymes was analyzed by SDS-PAGE using DAPT cell line a 12.5% (w/v) polyacrylamide separating gel. The protein concentration was determined

using the BCA protein assay reagent kit (Pierce). For immunoblotting, the proteins separated by SDS-PAGE were electrically transferred onto a polyvinylidene difluoride membrane. The membrane was blocked overnight at 4 °C in the blocking buffer (5% skim milk) and then incubated for 2 h at 37 °C with 1 : 3000 diluted mouse anti-His-tag monoclonal antibody, followed by incubation for 1 h at 37 °C with 1 : 6000 diluted HRP-Goat anti-mouse IgG (H + L) (Genscript, Nanjing, China). Finally, bands were visualized using enhanced chemiluminescence Apoptosis inhibitor Western blotting detection reagents (Millipore). Fibrinolytic activity was determined by measuring the areas of the lysed zone on the fibrin plate (Astrup & Mullertz, 1952; Liang et al., 2007). In brief, the fibrin plate was made up of 0.4% fibrinogen, 0.6% agarose and 0.5 U mL−1 thrombin, which were dissolved in 50 mM barbitol buffer (pH 7.8) beforehand and mixed in a petri dish (9 cm in diameter). Purified enzymes were also diluted using the 50 mM barbitol buffer, and 20 μL of the samples were placed into holes which had been made previously on the fibrin plate. After measuring the dimension of the clear zone and Bacterial neuraminidase incubating

the plate at 37 °C for 18 h, the fibrinolytic activity was estimated using urokinase as a standard. The specific activity of the enzyme to hydrolyze fibrin was defined as urokinase units of fibrinolytic activity in each milligram of enzyme. Enzymatic kinetics were determined by measuring the release of p-nitroaniline from the chromogenic substrate suc-AAPF-pNA in 100 mM phosphate buffer (pH 8.0) containing 4% (v/v) DMSO at (37 °C ± 0.2) (Sumi et al., 1987). After incubation for 10 min at 37 ± 0.2 °C, the concentration of liberated p-nitroaniline was measured at an absorbance of 405 nm using an automatic microplate reader (Thermo Lab systems, Multiskan MK3). Kinetic parameters (Vmax and Km) were determined from initial rate measurements at different substrate concentrations ranging from 0.098 to 0.392 mM.

pAZI8952 was transformed into E. coli murG(Ts) using heat shock (Sambrook et al., 1989) but resuscitation was at 30 °C for 2 h. Cells were plated on LB-amp agar containing 0%, 0.02% and find protocol 0.2% arabinose. Two sets of plates were incubated at 30 and 42 °C. The transformants are referred as E. coli murG(Ts);pAZI8952. For studying the growth kinetics, E. coli murG(Ts); pAZI8952 was grown overnight in LB-amp, 0.2% arabinose (LB-amp-ara) at 42 °C. The cells were washed twice and used to inoculate fresh prewarmed LB-amp (initial A600 nm ~ 0.1)

containing different concentrations of arabinose or glucose; growth at 42 °C was monitored by the A600 nm. pAZI8952 was transformed into E. coli murG(Ts), and transformants were selected on LB-amp-ara plates at 42 °C. Freshly grown transformants were inoculated into LB-amp-ara (A600 0.01) and grown on a shaker till A600 of 1.6. Membranes were isolated (Chandrakala et al., 2001) and will be referred to as Eco(Ts) ΔMurG. Escherichia coli murG was PCR-amplified using forward (5′-GCC GGA TCC ATG AGT GGT CAA CGA AA- 3′) and reverse (5′-GTC AAGC TTA CGCCCG GGC AAC CCG G-3′) primers and

cloned into vector pRSETA between the BamHI and HindIII sites. The resulting plasmid, pARC0359, encoded E. coli MurG with an N-terminal His-tag, which, along with other epitopes, contributed an see more extra 35 amino acids compared with the native sequence, giving a calculated molecular weight of 42 kDa. Escherichia coli BL21(DE3) transformed with pARC0359 was inoculated into LB-amp (A600 nm 0.01) and grown at 37 °C on a shaker till A600 nm 0.6. IPTG (1 mM) was added and the cells were harvested after 3 h. All further processing was carried out at 4 °C. The cells were washed in 20 mM Amisulpride Tris–HCl pH 7.5, 0.1 mM MgCl2, resuspended in the same buffer and lysed in a French Press. The lysate was centrifuged at 6000 g for 10 min, and the supernatant was centrifuged at 200 000 g for 40 min. This membrane pellet was

resuspended in 50 mM Tris–HCl, pH 7.5, 0.1 mM MgCl2 and 1% CHAPS for solubilization. After 1 h, the solubilized material was centrifuged at 200 000 g. The supernatant was filtered through a 0.45-μm syringe filter, and the filtrate was stirred overnight with 1 mL Ni-NTA-agarose. Stepwise batch elution was carried out in a column with 1 mL of 50 mM Tris–HCl, pH 7.5 containing 100, 300 and 400 mM imidazole. The purified fractions were dialysed and concentrated for further analysis. All enzyme assays were performed in duplicate in flexible 96-well microplates (1450-401) from Wallac, Finland, and the radioactivity was read in a Microbeta Trilux. For paper chromatography analysis, 2 μCi UDP-[3H]GlcNAc was used, and reactions were stopped by the addition of 5 μL of 90 mM EDTA instead of the SPA beads (Chandrakala et al., 2001). This was performed as earlier described (Solapure et al., 2005). Briefly, E. coli membranes (source of MraY) were incubated with UDP-[3H]MurNAc(pp).

Factors contributing to a MRHA identified in this study are all important considerations for medicines optimisation in this vulnerable patient Trametinib group. Direct referral to pharmacists from GPs and practice nurses within the primary healthcare setting is one way by which this patient group can be supported to optimise their medicines use. A limitation to this study is the small sample size of patients recruited and thus further investigation would be required to substantiate this finding. 1. Hallas J, Harvald B, Gram LF, Grodum E, Brosen K, Haghfelt T et al. Drug related hospital admissions: the role of definitions and intensity of data collection, and the possibility of prevention.

Journal of Internal Medicine 1990; 228: 83–90. 2. Gordon K., Smith F, Dhillon S. The development and validation of a screening tool for the identification of patients experiencing medication-related problems. IJPP 2005; 13: 187–193. J. Desborough, D. Somally, selleck products on behalf of the CAREMED management group University of East Anglia, Norwich, UK Multi-professional medication reviews have the potential to improve the quality of prescribing in care home residents Nearly all care home residents (91%) had at least one intervention with an average of four interventions per resident following the review Residents

identified as needing a further review or with medication changes were more likely to be admitted to hospital in the 6 months following the multi-professional medication review More responsive models of care are needed to support GPs to prevent hospital admissions in complex care home residents. With a growing population of older people residing in care homes and recognised sub optimal medicines management, there is a need to develop services to better support residents. The CAREMED study was an RCT of a multi-professional medication review service in 30 care homes for older people(1). The aims of this study were to explore the interventions made during the first medication review in

the intervention arm of the CAREMED trial and identify any relationships with patient outcomes Tyrosine-protein kinase BLK of falls and hospital admissions. The CAREMED study was a cluster randomised controlled trial in 30 care homes for older people. This sub-analysis extracted data from all intervention residents’ first medication review including demographics, medication and medical conditions. Details of the interventions made during the review were extracted and categorised. Regression analysis was used to identify any relationships between the individual intervention categories and the outcomes of falls and emergency hospital admissions in the 6 months following the review. Ethical approval was granted from NHS research ethics. Three hundred twenty (90%) residents had at least one medication where the multidisciplinary team recommended an intervention.

Clinical improvements have been achieved by applying inhibitory

rTMS patterns to either the unaffected hemisphere (Oliveri et al., 2001; Brighina et al., 2003; Mansur et al., 2005; Fregni et al., 2005; Shindo et al., 2006; Takeuchi et al., 2005, 2008) or excitatory rTMS patterns to the injured hemisphere (Khedr et al., 2005; Kim et al., 2006; Yozbatiran et al., 2009). Transcranial DCS has also provided evidence of recovery in several neurological conditions using similar principles (Boggio et al., 2007; Hesse et al., 2007; Reis et al., 2009; Sparing et al., 2009). The insights provided by rTMS and tDCS studies have unequivocally elevated the scientific and clinical drive to alleviate functional impairments in the brain-injured population. However, despite promising results obtained in small-scale studies, limitations in clinical RO4929097 mouse outcomes remain, and neurostimulation has often been considered inconsistent in delivering significant and long-lasting ameliorations when applied to larger populations of

patients. Factors such as lesion size, degree of spontaneous recovery, lesion chronicity, and influence of tissue characteristics are among the variables thought to contribute to behavioral discrepancies in large patient populations receiving neurostimulation treatment (Wagner et al., 2007; Plow RG7204 cost et al., 2009). Furthermore, in order to preserve patient safety, the number of consecutive TMS sessions are restricted, yet research performed in healthy subjects has demonstrated that the accumulation of sessions might be key to enhancing rTMS efficacy (Maeda et al., 2002; Bäumer et al., 2003; Valero-Cabré et al.,

2008). Suppressive rTMS sessions not exceeding ten applications on the intact hemisphere have yielded enhancements in function which are Rapamycin purchase probably still present weeks after the end of the treatment (Avenanti et al., 2012; Koch et al., 2012). However, the therapeutic potential of high-frequency perilesional rTMS in repeated sessions has yet to be consistently assessed in detail. We hereby hypothesized that a very high number of consecutive rTMS sessions applied to lesion-adjacent cortex could maximize functional recovery well beyond spontaneous recovery levels in the chronic phase following focal brain damage. To freely address our hypothesis, we turned to a well-established animal model of visuospatial disorders. We induced focal unilateral lesions in a subregion of the feline posterior parietal cortex, specifically known as the posterior middle suprasylvian area (pMS), leading to enduring visuospatial deficits in the contralesional hemispace (Huxlin & Pasternak, 2004; Rushmore et al., 2010; Das et al., 2012). Subjects were followed for ~2.5 months post-lesion, which was the time required to consistently reach plateau levels of spontaneous recovery. Animals were then treated for 3.

The number of colonies was counted after an overnight incubation at 37 °C. Methanol (0.2%) alone was also added in a control study to determine its effect on bacterial growth and CT production. All experiments were performed in triplicate and the mean values with SD were calculated. Among V. cholerae strains, an El Tor variant CRC41 strain was selected for elaborative study. A dose-dependent assay using 0.1, 1.0, 10, 50 and 100 μg mL−1 of capsaicin

was performed against the strain CRC41. The El Tor variant strain CRC41 was grown in AKI medium at 37 °C up to the late logarithmic phase (∼2 × 108 CFU mL−1) with and without red chilli methanol extract or capsaicin (100 μg mL−1). Total RNA was extracted and purified using Trizol reagent (Gibco-BRL, NY) selleck products according to the manufacturer’s instructions. The qRT-PCR assay was carried out selleck with ctxA,

tcpA, toxT, toxR, toxS, tcpP, tcpH and hns gene-specific primers and probes (Table 2) following the TaqMan probe method. Each probe was labeled with FAM as a 5′-reporter dye and with TAMRA as a 3′-quencher dye. A housekeeping recA gene was used as an internal control. The reverse transcription was carried out using the quick RNA-cDNA kit (Applied Biosystems Inc., CA) according to the manufacturer’s instruction. Briefly, cDNA was synthesized with 1 μg of RNA at 37 °C for 60 min, followed by incubation at 95 °C for 5 min using GeneAmp PCR system 9700 (Applied Biosystems Inc.). Real-time PCR was carried out using the prepared cDNA (100 ng) with each set of primer and probe and TaqMan Gene Expression master mix (Applied Biosystems Inc.). PCR conditions were 50 °C for 2 min, 95 °C for 10 min and 40 cycles, each having 95 °C for 15 s and Atezolizumab in vitro 60 °C for 1 min in an ABI PRISM 7000 sequence detection system (Applied Biosystems Inc.). The RNA and cDNA were quantified at A260 nm using a spectrophotometer (DU530, Beckman

Coulter, CA). The recA gene transcription was used as an internal control and compared with that of the bacterial culture not treated with red chilli methanol extract or capsaicin. The relative transcription in comparison with the internal control was analyzed according to Hagihara et al. (2004). Student’s two-sample t-test was used in excel to analyze the significant differences. A P-value of <0.05 was considered as significant. Initially, four El Tor variant strains (CO533, CRC27, CRC41 and CRC87) were selected to determine the effect of red chilli methanol extract on CT production. We observed that 100 μg mL−1 of red chilli methanol extract was the highest concentration that did not affect the bacterial growth (data not shown); however, CT production of these strains was significantly inhibited (≥90%) at this concentration. Methanol (0.2%) alone, used as a control, did not show any inhibitory effect on the growth or CT production (data not shown).

The origin of index cases was highly consistent with population migration routes and countries most frequently visited by French tourists as shown by a nationwide study.[6] This fact justifies screening and presumptive isolation with contact precautions of patients transferred from or previously hospitalized abroad.[10] Although returned travelers who have neither been ill nor hospitalized during travel can acquire resistant bacteria, at present, the risk does

not seem high enough to justify routinely screening all hospitalized patients with history of recent travel. If the number of CPE events

increased between 2004 and 2011, the number of outbreaks GDC-0941 in vitro remained low, eg, only three outbreaks occurred in 2011, contrasting with 40 reported events during the same period. This fact emphasizes the efficacy of the specific control measures of the AP-HP “emergent MDR” program[7, 9] and specially screening and isolating patients transferred from foreign hospitals. The AP-HP program has been subsequently extended at the national level by health authorities.[10] Importantly, intensive care units are the first wards concerned by repatriation of CPE carriers patients in our study and physicians must be

alerted of this risk. In conclusion, proactive strategy Fulvestrant in vivo to control spread of antibiotic resistance such as CPE should include systematic screening and isolation of patients transferred from or previously hospitalized abroad. The authors state that they have no conflicts of interest to declare. Antoine Andremont, Frédéric Barbut, Edouard Bingen, Christine Bcl-w Bonnal, Emmanuelle Cambau, Anne Carbonne, Anne Casetta, Jacques Chemardin, Jean-Winoc Decousser, Catherine Doit, Florence Doucet-Populaire, Laurence Drieux-Rouzet, Florence Espinasse, Nicolas Fortineau, Jean-Louis Gaillard, Jean-Michel Guérin, Laurent Gutmann, Béate Heym, Guillaume Kac, Christine Lawrence, Patrick Legrand, Jean-Christophe Lucet, Simone Nerome, Marie-Hélène Nicolas-Chanoine, Patrice Nordmann, Jean-Claude Petit, Bertrand Picard, Claire Poyart, Laurent Raskine, Jérôme Robert, Martine Rouveau, Delphine Seytre, and Isabelle Simon. “
“Background. Increasing air travel has resulted in a significant increase in aeromedical evacuation (AE) over the past decade. However, there are limited epidemiological data available on the diagnosis, costs, and transport characteristics of AE cases. Methods.

edisan.fr). Edisan® is a commercially available software updated every 6 weeks, used to help physicians for travel advice in general selleck kinase inhibitor and for malaria prophylaxis and vaccine prescriptions in particular. Updated specific recommendations are provided for each country, and within each country for specific areas at risk. Physicians can also use folders with updated recommendations and prefilled prescriptions for malaria prophylaxis, mosquito repellents, and mosquito nets. During the visit,

patients receive individualized travel health advice according to their medical condition, and general advice on vector-borne diseases, water-borne diseases, animal bites, as well as sexually transmitted diseases, high altitude sickness, and trauma. Patients are prescribed vaccines and malaria chemoprophylaxis when appropriate. Finally, AZD2014 ic50 they are encouraged to update their routine vaccination (hepatitis B, Diphtheria-Tetanus-Poliomyelitis, measles, and pertussis). Vaccinations are then performed by one of the three nurses in the center on the same day. The objective of the study was to assess the adequacy of malaria prophylaxis, yellow fever, and hepatitis A vaccination prescriptions to French recommendations. For

that purpose we used the questionnaires available in our center that were designed to assess our current practice and to ensure traceability of the advice and prescriptions

given to travelers. The questionnaire is first filled by the traveler while he/she is waiting for the physician and the Carbohydrate data are then checked and completed by the physician. The questionnaires covered the following areas: age, sex, medical condition and past medical history of each traveler, ongoing treatment, pregnancy status, and vaccine status. The trip characteristics are also recorded: destinations and itineraries, duration, and type of travel (rural or urban, for tourism or visiting friends and relatives, or professional). On the same questionnaire, the physician prescribes the vaccines to be administered by the nurse and treatments recommended during the visit (chemoprophylaxis for malaria, anti-diarrheal agents or antibiotics for travelers’ diarrhea or any other specific treatment). The reasons for the choice of malaria prophylaxis prescribed are also provided by the physician. The majority of questions could be answered by “yes” or “no,” some questions provided answer choices, and a few others allowed free text entries. All physicians were informed of the study goals and time lines of implementation. At the end of the study period, all questionnaires were reviewed by two investigators who assessed the adequacy of the prescriptions to the French recommendations for malaria chemoprophylaxis and yellow fever and hepatitis A vaccines.

1). The sequencing of the QRDR of the gyrA (GenBank accession no. GQ495079) gene indicated a mutation in codon 83, which resulted in the substitution of serine to isoleucine. The sequencing of the QRDR of the parC (GenBank accession no. GQ495081) gene revealed a mutation in codon 85, which resulted in the substitution of serine to leucine. However, no mutations were detected in QRDR of gyrB and parE genes. Tetracycline, ciprofloxacin and co-trimoxazole are the most important drugs considered for the treatment of cholera (Amita et al., 2003; Khan et al., 2003; Sack et al., 2004). Furazolidone was found to be effective clinically in treating cholera in children (Rabbani CYC202 et al.,

1991). The MCV09 showed resistance to 10 antibiotics including the common drugs used for the treatment of diarrhoeal diseases. All O1 strains examined from Kerala since 1999 were resistant to co-trimoxazole, streptomycin, nalidixic acid and polymixin B and furazolidone (Sabeena et al., 2001; Sabu et al., 2007). When compared with these data, the test strain showed additional resistance to ampicillin, furazolidone, tetracycline and ciprofloxacin. Hence, the Selleckchem BMS-734016 emergence of resistance to potent

antibiotics among toxigenic strains is a cause of great concern and it may create major problems in treating severe cases of diarrhoea when an antibiotic intervention is necessary. Since 1992, the majority of O1 and O139 strains isolated from India have exhibited uniform resistance to trimethoprim–sulphamethoxazole and streptomycin and a harboured SXT element (Waldor et al., 1996; Amita et al., 2003; Ramachandran

et al., 2007). The SXT element was also identified in NADPH-cytochrome-c2 reductase non-O1/non-O139 strains of both environmental and clinical origin (Thungapathra et al., 2002; Mohapatra et al., 2008). Hence, it becomes highly relevant to examine the SXT and associated drug resistance genes in MCV09. The Int is required for integration and excision of SXT from chromosome and the C-terminal half (232–254 and 342–377 residues) is highly conserved (Hochhut & Waldor, 1999). The substitutions observed in the present investigation were not in conserved domains and therefore may not interfere with the function of Int. Ahmed et al. (2005) described a variant of SXT with typical antibiotic resistance genes from V. fluvialis isolated from Calcutta. They further compared the attP sites of V. fluvialis and MO10 and explained that the attP in the former is shorter and there is deletion of 144 bp and addition of 95 bp. When analysed, the sequence of attP from MCV09 also exhibited similar addition and deletion (data not shown). However, the 17-bp core sequences of MCV09 and all O1 strains differed from that of V. fluvialis and MO10 in a single nucleotide position (Fig. 3). No such changes in the attP attachment site and the 17-bp core site have been reported from SXT previously.

, 2009). When taken together, these considerations have supported the conceptualisation of ascending systems as exerting powerful modulatory, but primarily nonspecific, functions such as ‘arousal’, ‘activation’, ‘information gating’, or ‘increasing the signal-to-noise ratio’. The intuitive allure of these traditional views persists in the contemporary

literature (e.g. Hornung, 2003; Eggermann & Feldmeyer, 2009; Lee & Dan, 2012; Sara & Bouret, 2012; Moran et al., 2013; Varela, 2013). The usefulness of such poorly-defined functional concepts for guiding research on the functions of ascending systems has been questioned PD-L1 inhibitor (Robbins & Everitt, 1995). Moreover, newer evidence concerning the basal forebrain system indicates a highly structured and topographic organisation of efferent projections and the presence of clusters of cholinergic terminals in the cortical innervation space (e.g., Zaborszky, 2002; Zaborszky et al., 2008, 2013). The presence of phasic actions of ascending neurotransmitter systems (Dayan & Yu, 2006; Parikh et al., 2007; Howells et al., 2012) further challenges the classification of the neurotransmitters of

ascending projection systems as strictly neuromodulators (Parikh & Sarter, 2008; Dayan, 2012; Marder, 2012; Picciotto et al., 2012; Sun et al., 2013). Below we review Talazoparib solubility dmso the available evidence in support of the hypothesis that basal forebrain cholinergic Resveratrol projections to the cortex form an integral part of cortical circuitry, capable of mediating, as opposed to modulating, discrete cognitive and behavioral functions. In other words, cortical and subcortical projections employ cholinergic

inputs to contribute to cortical information processing (Fig. 1). Furthermore, these cholinergic inputs themselves are subject to neuromodulation by cortical and subcortical input (Fig. 1; below). This review does not cover the basic organisation of the cholinergic system and evidence indicating neuromodulatory functions (Wenk, 1997; Deco & Thiele, 2008; Schliebs & Arendt, 2011; Picciotto et al., 2012). Rather, we will focus specifically on the evidence in support of the idea that cortical circuitry integrates a component of the ascending systems to support cortical information processing and therefore has deterministic functions. By reviewing the evidence in support of this hypothesis we are not rejecting the importance or presence of a neuromodulatory component of ascending systems, including a component of the cortically-projecting basal forebrain cholinergic system (St Peters et al., 2011; see also further below for a conceptualisation of cholinergic neuromodulation). Rather, we propose that separate from and in addition to their role as a neuromodulator, these ascending projections take part in highly specialised cortical information processing (Aston-Jones & Cohen, 2005; Zaborszky et al.