A refined physical map of chromosome 17q21.31 uncovered a 900-kb inversion polymorphism. Chromosomes with the inverted segment in different orientations represent two distinct lineages, H1 and H2, that have diverged for as much as 3 million years and show no evidence of having recombined. The H2 lineage is rare in Africans, almost absent in East Asians but found at a frequency of 20% in Europeans, in whom the haplotype structure is indicative of a history of positive selection. Here we show that the H2 lineage is undergoing positive selection in the Icelandic population, such that carrier females have more children and have higher recombination rates than noncarriers.

Multiple methicillin-resistant Staphylococcus aureus (MRSA) clones carrying type IV staphylococcal cassette chromosome mec were identified in the community-acquired MRSA strains of both the United States and Australia. They multiplied much faster than health-care-associated MRSA and were resistant to fewer non-beta-lactam antibiotics. They seem to have been derived from more diverse S. aureus populations than health-care-associated MRSA strains.

Discovered in nematodes in 1993, microRNAs (miRNAs) are non-coding RNAs that are related to small interfering RNAs (siRNAs), the small RNAs that guide RNA interference (RNAi). miRNAs sculpt gene expression profiles during plant and animal development. In fact, miRNAs may regulate as many as one-third of human genes. miRNAs are found only in plants and animals, and in the viruses that infect them. miRNAs function very much like siRNAs, but these two types of small RNAs can be distinguished by their distinct pathways for maturation and by the logic by which they regulate gene expression.

This article describes a meta-analysis of published associations between depression and heart failure (HF) in regard to 3 questions: 1) What is the prevalence of depression among patients with HF? 2) What is the magnitude of the relationship between depression and clinical outcomes in the HF population? 3) What is the evidence for treatment effectiveness in reducing depression in HF patients? Key word searches of the Medline and PsycInfo databases, as well as reference searches in published HF and depression articles, identified 36 publications meeting our criteria. Clinically significant depression was present in 21.5% of HF patients, and varied by the use of questionnaires versus diagnostic interview (33.6% and 19.3%, respectively) and New York Heart Association-defined HF severity (11% in class I vs. 42% in class IV), among other factors. Combined results suggested higher rates of death and secondary events (risk ratio = 2.1, 95% confidence interval 1.7 to 2.6), trends toward increased health care use, and higher rates of hospitalization and emergency room visits among depressed patients. Treatment studies generally relied on small samples, but also suggested depression symptom reductions from a variety of interventions. In sum, clinically significant depression is present in at least 1 in 5 patients with HF; however, depression rates can be much higher among patients screened with questionnaires or with more advanced HF. The relationship between depression and poorer HF outcomes is consistent and strong across multiple end points. These findings reinforce the importance of psychosocial research in HF populations and identify a number of areas for future study.

Inability to replicate many results has led to increasing scepticism about the value of simple association study designs for detection of genetic variants contributing to common complex traits. Much attention has been drawn to the problems that might, in theory, bedevil this approach, including confounding from population structure, misclassification of outcome, and allelic heterogeneity. Other researchers have argued that absence of replication may indicate true heterogeneity in gene-disease associations. We suggest that the most important factors underlying inability to replicate these associations are publication bias, failure to attribute results to chance, and inadequate sample sizes, problems that are all rectifiable. Without changes to present practice, we risk wastage of scientific effort and rejection of a potentially useful research strategy.

Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: Reconsolidation blockade typically requires potentially toxic drugs, and extinction is not permanent. Here, we describe a behavioral design in which a fear memory in rats is destabilized and reinterpreted as safe by presenting an isolated retrieval trial before an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.

Word frequency is the most important variable in research on word processing and memory. Yet, the main criterion for selecting word frequency norms has been the availability of the measure, rather than its quality. As a result, much research is still based on the old Kucera and Francis frequency norms. By using the lexical decision times of recently published megastudies, we show how bad this measure is and what must be done to improve it. In particular, we investigated the size of the corpus, the language register on which the corpus is based, and the definition of the frequency measure. We observed that corpus size is of practical importance for small sizes (depending on the frequency of the word), but not for sizes above 16-30 million words. As for the language register, we found that frequencies based on television and film subtitles are better than frequencies based on written sources, certainly for the monosyllabic and bisyllabic words used in psycholinguistic research. Finally, we found that lemma frequencies are not superior to word form frequencies in English and that a measure of contextual diversity is better than a measure based on raw frequency of occurrence. Part of the superiority of the latter is due to the words that are frequently used as names. Assembling a new frequency norm on the basis of these considerations turned out to predict word processing times much better than did the existing norms (including Kucera & Francis and Celex). The new SUBTL frequency norms from the SUBTLEX(US) corpus are freely available for research purposes from http://brm.psychonomic-journals.org/content/supplemental, as well as from the University of Ghent and Lexique Web sites.

Human hepcidin, a 25-amino acid peptide made by hepatocytes, may be a new mediator of innate immunity and the long-sought iron-regulatory hormone. The synthesis of hepcidin is greatly stimulated by inflammation or by iron overload. Evidence from transgenic mouse models indicates that hepcidin is the predominant negative regulator of iron absorption in the small intestine, iron transport across the placenta, and iron release from macrophages. The key role of hepcidin is confirmed by the presence of nonsense mutations in the hepcidin gene, homozygous in the affected members, in 2 families with severe juvenile hemochromatosis. Recent evidence shows that deficient hepcidin response to iron loading may contribute to iron overload even in the much milder common form of hemochromatosis, from mutations in the HFE gene. In anemia of inflammation, hepcidin production is increased up to 100-fold and this may account for the defining feature of this condition, sequestration of iron in macrophages. The discovery of hepcidin and its role in iron metabolism could lead to new therapies for hemochromatosis and anemia of inflammation.

Significantly more carbon is stored in the world's soils--including peatlands, wetlands and permafrost--than is present in the atmosphere. Disagreement exists, however, regarding the effects of climate change on global soil carbon stocks. If carbon stored belowground is transferred to the atmosphere by a warming-induced acceleration of its decomposition, a positive feedback to climate change would occur. Conversely, if increases of plant-derived carbon inputs to soils exceed increases in decomposition, the feedback would be negative. Despite much research, a consensus has not yet emerged on the temperature sensitivity of soil carbon decomposition. Unravelling the feedback effect is particularly difficult, because the diverse soil organic compounds exhibit a wide range of kinetic properties, which determine the intrinsic temperature sensitivity of their decomposition. Moreover, several environmental constraints obscure the intrinsic temperature sensitivity of substrate decomposition, causing lower observed 'apparent' temperature sensitivity, and these constraints may, themselves, be sensitive to climate.

1. Exchangeable Ca in guinea-pig auricles and ventricular trabeculae of sheep and calf hearts was labelled with (45)Ca and the loss of radioactivity into inactive rinsing solutions of different ion composition was measured for periods up to 6 hr. At no time did the decrease of radioactivity in the muscle follow a single exponential course, while the rate coefficient k (= fraction of (45)Ca lost per minute from muscle into rinsing solution) decreased slightly with time.2. On the basis of the temperature-sensitivity of Ca efflux from auricles the activation energy has been calculated to have a value of 5900 cal/mole, corresponding to a Q(10) of 1.35. 2,4-Dinitrophenol (5.5 x 10(-5) - 5.5 x 10(-4)M) had either no effect on Ca efflux or increased it slightly.3. Compared to control efflux in 1.8 mM [Ca](o) Ca efflux decreased to 70% in Ca-free solution, to 20% in Ca-free, Na-free solution and to 65% in Ca-containing, Na-free solution, NaCl being replaced by either sucrose or LiCl. Quantitatively, Ca efflux from auricles has been shown to depend to a large extent on the ratio [Ca(2+)](o)/[Na(+)](o) (2). The affinity for Na of the activation site for Ca efflux (carrier) is much less than for Ca.4. The efflux from muscles soaked for about 2 hr in Ca-free solution was not linearly related to Ca-concentration in the tissue but followed a square law.5. While Ca content in auricles increased in Ca-containing, Na-poor solution it decreased again when Tyrode solution was readmitted indicating a Na-sensitive Ca net transport in cardiac muscle.6. The results are interpreted in terms of a modified exchange diffusion mechanism (Ussing, 1947) which is responsible for Ca extrusion from mammalian cardiac muscle.

OBJECTIVE

The heterosexual spread of HIV-1 is occurring at different rates in different parts of the world. The transmission probability of HIV-1 per sexual contact is low, but may be greatly enhanced by several cofactors. Sexually transmitted diseases (STD), especially genital ulcers, may be such factors. So far, epidemiological evidence that other STD facilitate HIV-1 transmission is weak. The objective of this study was to determine whether treatable STD enhanced sexual transmission of HIV-1 in a cohort of female prostitutes in Kinshasa, Zaire.

METHODS

We conducted a nested case-control study of 431 initially HIV-1-negative women followed prospectively for a mean duration of 2 years (with monthly STD check-ups and 3-monthly HIV-1 serology). Cases (seroconverters, n = 68) were compared with controls (women who remained HIV-1-negative, n = 126) for incidence of STD and sexual exposure during the presumed period of HIV-1 acquisition.

RESULTS

The annual incidence of HIV-1 in this cohort was 9.8%. Seroconverters were younger than HIV-1-negative women (mean age, 24.6 versus 26.8 years; P = 0.04). During the period of HIV-1 acquisition, cases had a much higher incidence of gonorrhoea, chlamydial infection and trichomoniasis, and engaged in unprotected sex with clients and partners more frequently than controls. After controlling for sexual exposure by multivariate analysis, adjusted odds ratios for seroconversion were 4.8 [95% confidence interval (CI), 2.4-9.8] for gonorrhoea, 3.6 (95% CI, 1.4-9.1) for chlamydial infection and 1.9 (95% CI, 0.9-4.1) for trichomoniasis. Genital ulcers were more frequent in cases than controls, but much less common than other STD.

CONCLUSIONS

Non-ulcerative STD were risk factors for sexual transmission of HIV-1 in women, after controlling for sexual exposure. Because of their high prevalence in some populations, non-ulcerative STD may represent a considerable population-attributable risk in the transmission of HIV-1 worldwide. The identification of treatable STD as risk factors for HIV-1 transmission offers an important additional strategy for the prevention of HIV/AIDS.

This review describes the contribution of noncytolytic mechanisms to the control of viral infections with a particular emphasis on the role of cytokines in these processes. It has long been known that most cell types in the body respond to an incoming viral infection by rapidly secreting antiviral cytokines such as interferon alpha/beta (IFN-alpha/beta). After binding to specific receptors on the surface of infected cells, IFN-alpha/beta has the potential to trigger the activation of multiple noncytolytic intracellular antiviral pathways that can target many steps in the viral life cycle, thereby limiting the amplification and spread of the virus and attenuating the infection. Clearance of established viral infections, however, requires additional functions of the immune response. The accepted dogma is that complete clearance of intracellular viruses by the immune response depends on the destruction of infected cells by the effector cells of the innate and adaptive immune system [natural killer (NK) cells and cytotoxic T cells (CTLs)]. This notion, however, has been recently challenged by experimental evidence showing that much of the antiviral potential of these cells reflects their ability to produce antiviral cytokines such as IFN-gamma and tumor necrosis factor (TNF)-alpha at the site of the infection. Indeed, these cytokines can purge viruses from infected cells noncytopathically as long as the cell is able to activate antiviral mechanisms and the virus is sensitive to them. Importantly, the same cytokines also control viral infections indirectly, by modulating the induction, amplification, recruitment, and effector functions of the immune response and by upregulating antigen processing and display of viral epitopes at the surface of infected cells. In keeping with these concepts, it is not surprising that a number of viruses encode proteins that have the potential to inhibit the antiviral activity of cytokines.

Deficits in a wide array of functional outcome areas (eg, social functioning, social skills, independent living skills, etc) are marked in schizophrenia. Consequently, much recent research has attempted to identify factors that may contribute to functional outcome; social cognition is one such domain. The purpose of this article is to review research examining the relationship between social cognition and functional outcome. Comprehensive searches of PsycINFO and MEDLINE/PUBMED were conducted to identify relevant published manuscripts to include in the current review. It is concluded that the relationship between social cognition and functional outcome depends on the specific domains of each construct examined; however, it can generally be concluded that there are clear and consistent relationships between aspects of functional outcome and social cognition. These findings are discussed in light of treatment implications for schizophrenia.

The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid beta peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N- and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of "structure correctors" to convert apoE4 to an "apoE3-like" molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and "mitochondrial protectors" to prevent cellular energy disruption.

Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome--attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene--the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of approximately 3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is approximately 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member; 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABA(A) receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.

The Krüppel-like factor (KLF) family of transcription factors regulates diverse biological processes that include proliferation, differentiation, growth, development, survival, and responses to external stress. Seventeen mammalian KLFs have been identified, and numerous studies have been published that describe their basic biology and contribution to human diseases. KLF proteins have received much attention because of their involvement in the development and homeostasis of numerous organ systems. KLFs are critical regulators of physiological systems that include the cardiovascular, digestive, respiratory, hematological, and immune systems and are involved in disorders such as obesity, cardiovascular disease, cancer, and inflammatory conditions. Furthermore, KLFs play an important role in reprogramming somatic cells into induced pluripotent stem (iPS) cells and maintaining the pluripotent state of embryonic stem cells. As research on KLF proteins progresses, additional KLF functions and associations with disease are likely to be discovered. Here, we review the current knowledge of KLF proteins and describe common attributes of their biochemical and physiological functions and their pathophysiological roles.

The retina, like many other central nervous system structures, contains a huge diversity of neuronal types. Mammalian retinas contain approximately 55 distinct cell types, each with a different function. The census of cell types is nearing completion, as the development of quantitative methods makes it possible to be reasonably confident that few additional types exist. Although much remains to be learned, the fundamental structural principles are now becoming clear. They give a bottom-up view of the strategies used in the retina's processing of visual information and suggest new questions for physiological experiments and modeling.

To assess the age-related loss of muscle mass and to determine the mechanisms behind this aging atrophy, the muscle structure and fiber type composition have been estimated, using invasive and noninvasive techniques. Limb muscles from older men and women are 25-35% smaller and have significantly more fat and connective tissue than limb muscles from younger individuals. Comparisons of muscle biopsies from younger and older individuals reveal that type 2 (fast-twitch) fibers are smaller in the old, while the size of type 1 (slow-twitch) fibers is much less affected. Studies of whole muscle cross sections also show a significantly smaller number of muscle fibers, a significantly lower relative type 2 fiber area, and a significant increase in fiber type grouping with increasing age. These results indicate a gradual decrease in size/volume with advancing age, accompanied by a replacement by fat and connective tissue. This aging atrophy seems to be due to a reduction in both number and size of muscle fibers, mainly of type 2, and is to some extent caused by a slowly progressive neurogenic process.

BACKGROUND

About 13 million people are classified as refugees worldwide, and many more former refugees have been granted citizenship in their new countries. However, the prevalence of post-traumatic stress disorder, major depression, or psychotic illnesses in these individuals is not known. We did a systematic review of surveys about these disorders in general refugee populations in western countries.

METHODS

We searched for psychiatric surveys that were based on interviews of unselected refugee populations and that included current diagnoses of post-traumatic stress disorder, major depression, psychotic illnesses, or generalised anxiety disorder. We did computer-assisted searches, scanned reference lists, searched journals, and corresponded with authors to determine prevalence rates of these mental disorders and to explore potential sources of heterogeneity, such as diagnostic criteria, sampling methods, and other characteristics.

RESULTS

20 eligible surveys provided results for 6743 adult refugees from seven countries, with substantial variation in assessment and sampling methods. In the larger studies, 9% (99% CI 8-10%) were diagnosed with post-traumatic stress disorder and 5% (4-6%) with major depression, with evidence of much psychiatric comorbidity. Five surveys of 260 refugee children from three countries yielded a prevalence of 11% (7-17%) for post-traumatic stress disorder. Larger and more rigorous surveys reported lower prevalence rates than did studies with less optimum designs, but heterogeneity persisted even in findings from the larger studies.

CONCLUSIONS

Refugees resettled in western countries could be about ten times more likely to have post-traumatic stress disorder than age-matched general populations in those countries. Worldwide, tens of thousands of refugees and former refugees resettled in western countries probably have post-traumatic stress disorder.

BACKGROUND

In patients undergoing percutaneous coronary intervention (PCI) in the modern era, the incidence and prognostic implications of acute renal failure (ARF) are unknown.

RESULTS

With a retrospective analysis of the Mayo Clinic PCI registry, we determined the incidence of, risk factors for, and prognostic implications of ARF (defined as an increase in serum creatinine [Cr] >0.5 mg/dL from baseline) after PCI. Of 7586 patients, 254 (3.3%) experienced ARF. Among patients with baseline Cr <2.0, the risk of ARF was higher among diabetic than nondiabetic patients, whereas among those with a baseline Cr >2.0, all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum Cr, acute myocardial infarction, shock, and volume of contrast medium administered. Twenty-two percent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF (P<0.0001). After adjustment, ARF remained strongly associated with death. Among hospital survivors with ARF, 1- and 5-year estimated mortality rates were 12.1% and 44.6%, respectively, much greater than the 3.7% and 14.5% mortality rates in patients without ARF (P<0.0001).

CONCLUSIONS

The overall incidence of ARF after PCI is low. Diabetic patients with baseline Cr values <2.0 mg/dL are at higher risk than nondiabetic patients, whereas all patients with a serum Cr >2.0 are at high risk for ARF. ARF was highly correlated with death during the index hospitalization and after dismissal.

Transcranial direct current stimulation (tDCS) of the human motor cortex results in polarity-specific shifts of cortical excitability during and after stimulation. Anodal tDCS enhances and cathodal stimulation reduces excitability. Animal experiments have demonstrated that the effect of anodal tDCS is caused by neuronal depolarisation, while cathodal tDCS hyperpolarises cortical neurones. However, not much is known about the ion channels and receptors involved in these effects. Thus, the impact of the sodium channel blocker carbamazepine, the calcium channel blocker flunarizine and the NMDA receptor antagonist dextromethorphane on tDCS-elicited motor cortical excitability changes of healthy human subjects were tested. tDCS-protocols inducing excitability alterations (1) only during tDCS and (2) eliciting long-lasting after-effects were applied after drug administration. Carbamazepine selectively eliminated the excitability enhancement induced by anodal stimulation during and after tDCS. Flunarizine resulted in similar changes. Antagonising NMDA receptors did not alter current-generated excitability changes during a short stimulation, which elicits no after-effects, but prevented the induction of long-lasting after-effects independent of their direction. These results suggest that, like in other animals, cortical excitability shifts induced during tDCS in humans also depend on membrane polarisation, thus modulating the conductance of sodium and calcium channels. Moreover, they suggest that the after-effects may be NMDA receptor dependent. Since NMDA receptors are involved in neuroplastic changes, the results suggest a possible application of tDCS in the modulation or induction of these processes in a clinical setting. The selective elimination of tDCS-driven excitability enhancements by carbamazepine proposes a role for this drug in focussing the effects of cathodal tDCS, which may have important future clinical applications.

Following pioneering work, solution-processable organic-inorganic hybrid perovskites-such as CH3NH3PbX3 (X = Cl, Br, I)-have attracted attention as light-harvesting materials for mesoscopic solar cells. So far, the perovskite pigment has been deposited in a single step onto mesoporous metal oxide films using a mixture of PbX2 and CH3NH3X in a common solvent. However, the uncontrolled precipitation of the perovskite produces large morphological variations, resulting in a wide spread of photovoltaic performance in the resulting devices, which hampers the prospects for practical applications. Here we describe a sequential deposition method for the formation of the perovskite pigment within the porous metal oxide film. PbI2 is first introduced from solution into a nanoporous titanium dioxide film and subsequently transformed into the perovskite by exposing it to a solution of CH3NH3I. We find that the conversion occurs within the nanoporous host as soon as the two components come into contact, permitting much better control over the perovskite morphology than is possible with the previously employed route. Using this technique for the fabrication of solid-state mesoscopic solar cells greatly increases the reproducibility of their performance and allows us to achieve a power conversion efficiency of approximately 15 per cent (measured under standard AM1.5G test conditions on solar zenith angle, solar light intensity and cell temperature). This two-step method should provide new opportunities for the fabrication of solution-processed photovoltaic cells with unprecedented power conversion efficiencies and high stability equal to or even greater than those of today's best thin-film photovoltaic devices.

Population genomics has the potential to improve studies of evolutionary genetics, molecular ecology and conservation biology, by facilitating the identification of adaptive molecular variation and by improving the estimation of important parameters such as population size, migration rates and phylogenetic relationships. There has been much excitement in the recent literature about the identification of adaptive molecular variation using the population-genomic approach. However, the most useful contribution of the genomics model to population genetics will be improving inferences about population demography and evolutionary history.

One of the defining features of plants is a body plan based on the physical properties of cell walls. Structural analyses of the polysaccharide components, combined with high-resolution imaging, have provided the basis for much of the current understanding of cell walls. The application of genetic methods has begun to provide new insights into how walls are made, how they are controlled, and how they function. However, progress in integrating biophysical, developmental, and genetic information into a useful model will require a system-based approach.