Oligonucleotide and complementary DNA microarrays are being used to subclassify histologically similar tumours, monitor disease progress, and individualize treatment regimens. However, extracting new biological insight from high-throughput genomic studies of human diseases is a challenge, limited by difficulties in recognizing and evaluating relevant biological processes from huge quantities of experimental data. Here we present a structured network knowledge-base approach to analyse genome-wide transcriptional responses in the context of known functional interrelationships among proteins, small molecules and phenotypes. This approach was used to analyse changes in blood leukocyte gene expression patterns in human subjects receiving an inflammatory stimulus (bacterial endotoxin). We explore the known genome-wide interaction network to identify significant functional modules perturbed in response to this stimulus. Our analysis reveals that the human blood leukocyte response to acute systemic inflammation includes the transient dysregulation of leukocyte bioenergetics and modulation of translational machinery. These findings provide insight into the regulation of global leukocyte activities as they relate to innate immune system tolerance and increased susceptibility to infection in humans.

Trust pervades human societies. Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics. In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country's institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success. Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions. We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks. On the contrary, oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. These results concur with animal research suggesting an essential role for oxytocin as a biological basis of prosocial approach behaviour.

Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained through sleep. Sleep consolidates recent memories and, concomitantly, could allow insight by changing their representational structure. Here we show a facilitating role of sleep in a process of insight. Subjects performed a cognitive task requiring the learning of stimulus-response sequences, in which they improved gradually by increasing response speed across task blocks. However, they could also improve abruptly after gaining insight into a hidden abstract rule underlying all sequences. Initial training establishing a task representation was followed by 8 h of nocturnal sleep, nocturnal wakefulness, or daytime wakefulness. At subsequent retesting, more than twice as many subjects gained insight into the hidden rule after sleep as after wakefulness, regardless of time of day. Sleep did not enhance insight in the absence of initial training. A characteristic antecedent of sleep-related insight was revealed in a slowing of reaction times across sleep. We conclude that sleep, by restructuring new memory representations, facilitates extraction of explicit knowledge and insightful behaviour.

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.

Historically, the term 'memory consolidation' refers to a process whereby a memory becomes increasingly resistant to interference from competing or disrupting factors with the continued passage of time. Recent findings regarding the learning of skilled sensory and motor tasks ('procedural learning') have refined this definition, suggesting that consolidation can be more strictly determined by time spent in specific brain states such as wake, sleep or certain stages of sleep. There is also renewed interest in the possibility that recalling or 'reactivating' a previously consolidated memory renders it once again fragile and susceptible to interference, therefore requiring periods of reconsolidation. Using a motor skill finger-tapping task, here we provide evidence for at least three different stages of human motor memory processing after initial acquisition. We describe the unique contributions of wake and sleep in the development of different forms of consolidation, and show that waking reactivation can turn a previously consolidated memory back into a labile state requiring subsequent reconsolidation.

Memory consolidation resulting from sleep has been seen broadly: in verbal list learning, spatial learning, and skill acquisition in visual and motor tasks. These tasks do not generalize across spatial locations or motor sequences, or to different stimuli in the same location. Although episodic rote learning constitutes a large part of any organism's learning, generalization is a hallmark of adaptive behaviour. In speech, the same phoneme often has different acoustic patterns depending on context. Training on a small set of words improves performance on novel words using the same phonemes but with different acoustic patterns, demonstrating perceptual generalization. Here we show a role of sleep in the consolidation of a naturalistic spoken-language learning task that produces generalization of phonological categories across different acoustic patterns. Recognition performance immediately after training showed a significant improvement that subsequently degraded over the span of a day's retention interval, but completely recovered following sleep. Thus, sleep facilitates the recovery and subsequent retention of material learned opportunistically at any time throughout the day. Performance recovery indicates that representations and mappings associated with generalization are refined and stabilized during sleep.

As video-game playing has become a ubiquitous activity in today's society, it is worth considering its potential consequences on perceptual and motor skills. It is well known that exposing an organism to an altered visual environment often results in modification of the visual system of the organism. The field of perceptual learning provides many examples of training-induced increases in performance. But perceptual learning, when it occurs, tends to be specific to the trained task; that is, generalization to new tasks is rarely found. Here we show, by contrast, that action-video-game playing is capable of altering a range of visual skills. Four experiments establish changes in different aspects of visual attention in habitual video-game players as compared with non-video-game players. In a fifth experiment, non-players trained on an action video game show marked improvement from their pre-training abilities, thereby establishing the role of playing in this effect.

Prostate cancer is a leading cause of cancer-related death in males and is second only to lung cancer. Although effective surgical and radiation treatments exist for clinically localized prostate cancer, metastatic prostate cancer remains essentially incurable. Here we show, through gene expression profiling, that the polycomb group protein enhancer of zeste homolog 2 (EZH2) is overexpressed in hormone-refractory, metastatic prostate cancer. Small interfering RNA (siRNA) duplexes targeted against EZH2 reduce the amounts of EZH2 protein present in prostate cells and also inhibit cell proliferation in vitro. Ectopic expression of EZH2 in prostate cells induces transcriptional repression of a specific cohort of genes. Gene silencing mediated by EZH2 requires the SET domain and is attenuated by inhibiting histone deacetylase activity. Amounts of both EZH2 messenger RNA and EZH2 protein are increased in metastatic prostate cancer; in addition, clinically localized prostate cancers that express higher concentrations of EZH2 show a poorer prognosis. Thus, dysregulated expression of EZH2 may be involved in the progression of prostate cancer, as well as being a marker that distinguishes indolent prostate cancer from those at risk of lethal progression.

Behavioural studies indicate that a newly acquired motor skill is rapidly consolidated from an initially unstable state to a more stable state, whereas neuroimaging studies demonstrate that the brain engages new regions for performance of the task as a result of this consolidation. However, it is not known where a new skill is retained and processed before it is firmly consolidated. Some early aspects of motor skill acquisition involve the primary motor cortex (M1), but the nature of that involvement is unclear. We tested the possibility that the human M1 is essential to early motor consolidation. We monitored changes in elementary motor behaviour while subjects practised fast finger movements that rapidly improved in movement acceleration and muscle force generation. Here we show that low-frequency, repetitive transcranial magnetic stimulation of M1 but not other brain areas specifically disrupted the retention of the behavioural improvement, but did not affect basal motor behaviour, task performance, motor learning by subsequent practice, or recall of the newly acquired motor skill. These findings indicate that the human M1 is specifically engaged during the early stage of motor consolidation.

We have developed a high-definition thermal-imaging technique that can detect attempted deceit by recording the thermal patterns from people's faces. This technique has an accuracy comparable to that of polygraph examination by experts and has potential for application in remote and rapid security screening, without the need for skilled staff or physical contact.

Virus-specific T-helper cells are considered critical for the control of chronic viral infections. Successful treatment of acute HIV-1 infection leads to augmentation of these responses, but whether this enhances immune control has not been determined. We administered one or two supervised treatment interruptions to eight subjects with treated acute infection, with the plan to restart therapy if viral load exceeded 5,000 copies of HIV-1 RNA per millilitre of plasma (the level at which therapy has been typically recommended) for three consecutive weeks, or 50,000 RNA copies per ml at one time. Here we show that, despite rebound in viraemia, all subjects were able to achieve at least a transient steady state off therapy with viral load below 5,000 RNA copies per ml. At present, five out of eight subjects remain off therapy with viral loads of less than 500 RNA copies per ml plasma after a median 6.5 months (range 5-8.7 months). We observed increased virus-specific cytotoxic T lymphocytes and maintained T-helper-cell responses in all. Our data indicate that functional immune responses can be augmented in a chronic viral infection, and provide rationale for immunotherapy in HIV-1 infection.

Asthma is a chronic inflammatory disease of the airways and lung mucosa with a strong correlation to atopy and acquired (IgE) immunity. However, many features of bronchial asthma, such as smooth muscle contraction, mucus secretion and recruitment of inflammatory cells, are consistent with the actions of complement anaphylatoxins, in particular C3a and C5a. Complement activation forms a central core of innate immune defence against mucosal bacteria, viruses, fungi, helminths and other pathogens. As a system of 'pattern-recognition molecules', foreign surface antigens and immune complexes lead to a proteolytic cascade culminating in a lytic membrane attack. The anaphylatoxins C3a and C5a are liberated as activation byproducts and are potent pro-inflammatory mediators that bind to specific cell surface receptors and cause leukocyte activation, smooth muscle contraction and vascular permeability. Here we show that in a murine model of allergic airway disease, genetic deletion of the C3a receptor protects against the changes in lung physiology seen after allergen challenge. Furthermore, human asthmatics develop significant levels of ligand C3a following intra-pulmonary deposition of allergen, but not saline. We propose that, in addition to acquired immune responses, the innate immune system and complement (C3a in particular) are involved in the pathogenesis of asthma.

By using the (14C)2-deoxyglucose method, inhibition has been shown to be a metabolically active process at the level of the synapse. This is supported by recent results from magnetic resonance spectroscopy that related the changes in neuroenergetics occurring with functional activation to neurotransmitter cycling. However, inhibitory synapses are less numerous and strategically better located than excitatory synapses, indicating that inhibition may be more efficient, and therefore less energy-consuming, than excitation. Here we test this hypothesis using event-related functional magnetic resonance imaging in volunteers whose motor cortex was inhibited during the no-go condition of a go/no-go task, as demonstrated by transcranial magnetic stimulation. Unlike excitation, inhibition evoked no measurable change in the blood-oxygenation-level-dependent signal in the motor cortex, indicating that inhibition is less metabolically demanding. Therefore, the 'activation' seen in functional imaging studies probably results from excitation rather than inhibition.