Exoerythrocytic Plasmodium Parasites Secrete a Cysteine Protease Inhibitor Involved in Sporozoite Invasion and Capable of Blocking Cell Death of Host Hepatocytes

Plasmodium parasites must control cysteine protease activity that is critical for hepatocyte invasion by sporozoites, liver stage development, host cell survival and merozoite liberation. Here we show that exoerythrocytic P. berghei parasites express a potent cysteine protease inhibitor (PbICP, P. berghei inhibitor of cysteine proteases). We provide evidence that it has an important function in sporozoite invasion and is capable of blocking hepatocyte cell death. Pre-incubation with specific anti-PbICP antiserum significantly decreased the ability of sporozoites to infect hepatocytes and expression of PbICP in mammalian cells protects them against peroxide- and camptothecin-induced cell death. PbICP is secreted by sporozoites prior to and after hepatocyte invasion, localizes to the parasitophorous vacuole as well as to the parasite cytoplasm in the schizont stage and is released into the host cell cytoplasm at the end of the liver stage. Like its homolog falstatin/PfICP in P. falciparum, PbICP consists of a classical N-terminal signal peptide, a long N-terminal extension region and a chagasin-like C-terminal domain. In exoerythrocytic parasites, PbICP is posttranslationally processed, leading to liberation of the C-terminal chagasin-like domain. Biochemical analysis has revealed that both full-length PbICP and the truncated C-terminal domain are very potent inhibitors of cathepsin L-like host and parasite cysteine proteases. The results presented in this study suggest that the inhibitor plays an important role in sporozoite invasion of host cells and in parasite survival during liver stage development by inhibiting host cell proteases involved in programmed cell death

Efeitos do treinamento muscular inspiratório em universitários tabagistas e não tabagistas

O hábito de fumar pode reduzir a capacidade aeróbica, aumentar a resistência ao fluxo aéreo e afetar a função dos músculos respiratórios. O objetivo deste estudo foi comparar os efeitos do Treinamento Muscular Inspiratório (TMI) entre dois grupos: tabagistas e não tabagistas. Participaram 44 voluntários universitários, divididos em dois grupos: tabagistas (GT), composto por 20 indivíduos (25,60±7,01 anos) e não tabagistas, constituindo o Grupo Controle (GC), composto por 24 voluntários (24,08±7,52 anos). Ambos os grupos foram submetidos ao TMI, por meio do uso do manovacuômetro aneroide, com duração de 6 semanas, sendo 3 sessões semanais, totalizando 18 sessões. Os resultados mostraram diferença estatisticamente significativa (p<0,05) pós-TMI no GC para as variáveis: Pressão Inspiratória Máxima (PImáx), Pico de Fluxo Expiratório (PFE), Pressão Arterial Média ao repouso (PAM pré-TC6) e Teste de Caminhada de Seis Minutos (TC6). No GT, houve diferença estatisticamente significativa pós-TMI para as variáveis: PImáx, PFE, TC6 e saturação periférica de oxigênio após o TC6 (SpO2 pós-imediata). A comparação das médias das variáveis entre GT e GC mostrou diferença estatisticamente significativa no pós-TMI para as variáveis PImáx e PFE. A variável TC6 não apresentou diferença estatisticamente significativa. Conclui-se que o TMI proporcionou um aumento significativo da força muscular inspiratória, melhora da função pulmonar e melhora do desempenho físico nos indivíduos estudados

Conformation-regulated mechanosensory control via titin domains in cardiac muscle

The giant filamentous protein titin is ideally positioned in the muscle sarcomere to sense mechanical stimuli and transform them into biochemical signals, such as those triggering cardiac hypertrophy. In this review, we ponder the evidence for signaling hotspots along the titin filament involved in mechanosensory control mechanisms. On the way, we distinguish between stress and strain as triggers of mechanical signaling events at the cardiac sarcomere. Whereas the Z-disk and M-band regions of titin may be prominently involved in sensing mechanical stress, signaling hotspots within the elastic I-band titin segment may respond primarily to mechanical strain. Common to both stress and strain sensor elements is their regulation by conformational changes in protein domains

Reconnecting with nature for sustainability

Calls for humanity to ‘reconnect to nature’ have grown increasingly louder from both scholars and civil society. Yet, there is relatively little coherence about what reconnecting to nature means, why it should happen and how it can be achieved. We present a conceptual framework to organise existing literature and direct future research on human–nature connections. Five types of connections to nature are identified: material, experiential, cognitive, emotional, and philosophical. These various types have been presented as causes, consequences, or treatments of social and environmental problems. From this conceptual base, we discuss how reconnecting people with nature can function as a treatment for the global environmental crisis. Adopting a social–ecological systems perspective, we draw upon the emerging concept of ‘leverage points’—places in complex systems to intervene to generate change—and explore examples of how actions to reconnect people with nature can help transform society towards sustainability

Abnormal Reorganization of Functional Cortical Small-World Networks in Focal Hand Dystonia

We investigated the large-scale functional cortical connectivity network in focal hand dystonia (FHD) patients using graph theoretic measures to assess efficiency. High-resolution EEGs were recorded in 15 FHD patients and 15 healthy volunteers at rest and during a simple sequential finger tapping task. Mutual information (MI) values of wavelet coefficients were estimated to create an association matrix between EEG electrodes, and to produce a series of adjacency matrices or graphs, G, by thresholding with network cost. Efficiency measures of small-world networks were assessed. As a result, we found that FHD patients have economical small-world properties in their brain functional networks in the alpha and beta bands. During a motor task, in the beta band network, FHD patients have decreased efficiency of small-world networks, whereas healthy volunteers increase efficiency. Reduced efficient beta band network in FHD patients during the task was consistently observed in global efficiency, cost-efficiency, and maximum cost-efficiency. This suggests that the beta band functional cortical network of FHD patients is reorganized even during a task that does not induce dystonic symptoms, representing a loss of long-range communication and abnormal functional integration in large-scale brain functional cortical networks. Moreover, negative correlations between efficiency measures and duration of disease were found, indicating that the longer duration of disease, the less efficient the beta band network in FHD patients. In regional efficiency analysis, FHD patients at rest have high regional efficiency at supplementary motor cortex (SMA) compared with healthy volunteers; however, it is diminished during the motor task, possibly reflecting abnormal inhibition in FHD patients. The present study provides the first evidence with graph theory for abnormal reconfiguration of brain functional networks in FHD during motor task

Don't Fall Off the Adaptation Cliff: When Asymmetrical Fitness Selects for Suboptimal Traits

The cliff-edge hypothesis introduces the counterintuitive idea that the trait value associated with the maximum of an asymmetrical fitness function is not necessarily the value that is selected for if the trait shows variability in its phenotypic expression. We develop a model of population dynamics to show that, in such a system, the evolutionary stable strategy depends on both the shape of the fitness function around its maximum and the amount of phenotypic variance. The model provides quantitative predictions of the expected trait value distribution and provides an alternative quantity that should be maximized (“genotype fitness”) instead of the classical fitness function (“phenotype fitness”). We test the model's predictions on three examples: (1) litter size in guinea pigs, (2) sexual selection in damselflies, and (3) the geometry of the human lung. In all three cases, the model's predictions give a closer match to empirical data than traditional optimization theory models. Our model can be extended to most ecological situations, and the evolutionary conditions for its application are expected to be common in nature

Once bitten, not necessarily shy? Determinants of foreign market re-entry commitment strategies

We investigate foreign market re-entry commitment strategies, namely the changes in the modes of operation (commitment) undertaken by multinational enterprises (MNEs) as they return to foreign markets from which they had previously exited. We combine organisational learning theory with the institutional change literature to examine the antecedents of re-entry commitment strategies. From an analysis of 1,020 re-entry events between 1980 and 2016, we find that operation mode prior to exit is a strong predictor of subsequent re-entry mode. Contrary to the predictions of learning theory, we did not find support for the effect of experience accumulated during the initial market endeavour on the re-entry commitment strategies of MNEs. In turn, exit motives significantly impact on the re-entrants' decision to re-enter via a different mode of operation, by either increasing or decreasing their commitment to the market. We show that re-entrants do not replicate unsuccessful operation mode strategies if they had previously underperformed in the market. When favourable host institutional changes occur during the time-out period re-entrants tend to increase commitment in the host market irrespective of the degree of prior experience accumulated in the market

Mantle Pb paradoxes : the sulfide solution

Author Posting. © Springer, 2006. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 152 (2006): 295-308, doi:10.1007/s00410-006-0108-1.There is growing evidence that the budget of Pb in mantle peridotites is largely contained in sulfide, and that Pb partitions strongly into sulfide relative to silicate melt. In addition, there is evidence to suggest that diffusion rates of Pb in sulfide (solid or melt) are very fast. Given the possibility that sulfide melt ‘wets’ sub-solidus mantle silicates, and has very low viscosity, the implications for Pb behavior during mantle melting are profound. There is only sparse experimental data relating to Pb partitioning between sulfide and silicate, and no data on Pb diffusion rates in sulfides. A full understanding of Pb behavior in sulfide may hold the key to several long-standing and important Pb paradoxes and enigmas. The classical Pb isotope paradox arises from the fact that all known mantle reservoirs lie to the right of the Geochron, with no consensus as to the identity of the “balancing” reservoir. We propose that long-term segregation of sulfide (containing Pb) to the core may resolve this paradox. Another Pb paradox arises from the fact that the Ce/Pb ratio of both OIB and MORB is greater than bulk earth, and constant at a value of 25. The constancy of this “canonical ratio” implies similar partition coefficients for Ce and Pb during magmatic processes (Hofmann et al. 1986), whereas most experimental studies show that Pb is more incompatible in silicates than Ce. Retention of Pb in residual mantle sulfide during melting has the potential to bring the bulk partitioning of Ce into equality with Pb if the sulfide melt/silicate melt partition coefficient for Pb has a value of ~ 14. Modeling shows that the Ce/Pb (or Nd/Pb) of such melts will still accurately reflect that of the source, thus enforcing the paradox that OIB and MORB mantles have markedly higher Ce/Pb (and Nd/Pb) than the bulk silicate earth. This implies large deficiencies of Pb in the mantle sources for these basalts. Sulfide may play other important roles during magmagenesis: 1). advective/diffusive sulfide networks may form potent metasomatic agents (in both introducing and obliterating Pb isotopic heterogeneities in the mantle); 2). silicate melt networks may easily exchange Pb with ambient mantle sulfides (by diffusion or assimilation), thus ‘sampling’ Pb in isotopically heterogeneous mantle domains differently from the silicate-controlled isotope tracer systems (Sr, Nd, Hf), with an apparent ‘de-coupling’ of these systems.Our intemperance should not be blamed on the support we gratefully acknowledge from NSF: EAR- 0125917 to SRH and OCE-0118198 to GAG

A systematic review on the effectiveness of complementary and alternative medicine for chronic non-specific low-back pain

The purpose of this systematic review was to assess the effects of spinal manipulative therapy (SMT), acupuncture and herbal medicine for chronic non-specific LBP. A comprehensive search was conducted by an experienced librarian from the Cochrane Back Review Group (CBRG) in multiple databases up to December 22, 2008. Randomised controlled trials (RCTs) of adults with chronic non-specific LBP, which evaluated at least one clinically relevant, patient-centred outcome measure were included. Two authors working independently from one another assessed the risk of bias using the criteria recommended by the CBRG and extracted the data. The data were pooled when clinically homogeneous and statistically possible or were otherwise qualitatively described. GRADE was used to determine the quality of the evidence. In total, 35 RCTs (8 SMT, 20 acupuncture, 7 herbal medicine), which examined 8,298 patients, fulfilled the inclusion criteria. Approximately half of these (2 SMT, 8 acupuncture, 7 herbal medicine) were thought to have a low risk of bias. In general, the pooled effects for the studied interventions demonstrated short-term relief or improvement only. The lack of studies with a low-risk of bias, especially in regard to SMT precludes any strong conclusions; however, the principal findings, which are based upon low- to very-low-quality evidence, suggest that SMT does not provide a more clinically beneficial effect compared with sham, passive modalities or any other intervention for treatment of chronic low-back pain. There is evidence, however, that acupuncture provides a short-term clinically relevant effect when compared with a waiting list control or when acupuncture is added to another intervention. Although there are some good results for individual herbal medicines in short-term individual trials, the lack of homogeneity across studies did not allow for a pooled estimate of the effect. In general, these results are in agreement with other recent systematic reviews on SMT, but in contrast with others. These results are also in agreement with recent reviews on acupuncture and herbal medicine. Randomized trials with a low risk of bias and adequate sample sizes are direly needed

Genome-wide Association Study of Borderline Personality Disorder Reveals Genetic Overlap with Bipolar Disorder, Major Depression and Schizophrenia

Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case–control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10−7) and PKP4 (P=8.67 × 10−7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10−3]), SCZ (rg=0.34 [P=4.37 × 10−5]) and MDD (rg=0.57 [P=1.04 × 10−3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies