The substrate specificity of cruzipain 2, a cysteine protease isoform from Trypanosoma cruzi

Papain-like cysteine proteases are important for the survival of the flagellated protozoa Trypanosoma cruzi, the causative agent of Chagas' Disease. the lysosomal cysteine protease designated as cruzipain or cruzain, is the archetype of a multigene family of related isoforms. We investigated the substrate specificity of the cruzipain 2 isoform using internally quenched fluorogenic substrates. We found that cruzipain 2 and cruzain differ substantially regarding the specificity in the S-2, S-1(') and S-2(') pockets. Our study indicates that cruzipain 2 has a more restricted specificity than cruzain, suggesting that these isoforms might act on distinct natural substrates.Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21949900 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilWeb of Scienc

White matter integrity as a predictor of response to treatment in first episode psychosis

The integrity of brain white matter connections is central to a patient's ability to respond to pharmacological interventions. This study tested this hypothesis using a specific measure of white matter integrity, and examining its relationship to treatment response using a prospective design in patients within their first episode of psychosis. Diffusion tensor imaging data were acquired in 63 patients with first episode psychosis and 52 healthy control subjects (baseline). Response was assessed after 12 weeks and patients were classified as responders or non-responders according to treatment outcome. At this second time-point, they also underwent a second diffusion tensor imaging scan. Tract-based spatial statistics were used to assess fractional anisotropy as a marker of white matter integrity. At baseline, non-responders showed lower fractional anisotropy than both responders and healthy control subjects (P < 0.05; family-wise error-corrected), mainly in the uncinate, cingulum and corpus callosum, whereas responders were indistinguishable from healthy control subjects. After 12 weeks, there was an increase in fractional anisotropy in both responders and non-responders, positively correlated with antipsychotic exposure. This represents one of the largest, controlled investigations of white matter integrity and response to antipsychotic treatment early in psychosis. These data, together with earlier findings on cortical grey matter, suggest that grey and white matter integrity at the start of treatment is an important moderator of response to antipsychotics. These findings can inform patient stratification to anticipate care needs, and raise the possibility that antipsychotics may restore white matter integrity as part of the therapeutic response

Unexpected drop of dynamical heterogeneities in colloidal suspensions approaching the jamming transition

As the glass (in molecular fluids\cite{Donth}) or the jamming (in colloids and grains\cite{LiuNature1998}) transitions are approached, the dynamics slow down dramatically with no marked structural changes. Dynamical heterogeneity (DH) plays a crucial role: structural relaxation occurs through correlated rearrangements of particle ``blobs'' of size $\xi$\cite{WeeksScience2000,DauchotPRL2005,Glotzer,Ediger}. On approaching these transitions, $\xi$ grows in glass-formers\cite{Glotzer,Ediger}, colloids\cite{WeeksScience2000,BerthierScience2005}, and driven granular materials\cite{KeysNaturePhys2007} alike, strengthening the analogies between the glass and the jamming transitions. However, little is known yet on the behavior of DH very close to dynamical arrest. Here, we measure in colloids the maximum of a ``dynamical susceptibility'', $\chi^*$, whose growth is usually associated to that of $\xi$\cite{LacevicPRE}. $\chi^*$ initially increases with volume fraction $\phi$, as in\cite{KeysNaturePhys2007}, but strikingly drops dramatically very close to jamming. We show that this unexpected behavior results from the competition between the growth of $\xi$ and the reduced particle displacements associated with rearrangements in very dense suspensions, unveiling a richer-than-expected scenario.Comment: 1st version originally submitted to Nature Physics. See the Nature Physics website fro the final, published versio

Cerebrospinal fluid in the diagnosis of spinal schistosomiasis

Cerebrospinal fluid (CSF) changes in spinal shistosomiasis have been described. Its characteristic features are mild to moderate pleocytosis, presence of eosinophils, slight to moderate protein increase, elevated gamma globulin concentration and a positive immune assay. Nevertheless, these abnormalities are not always present together and therefore difficulties may arise in the assessment of the diagnosis. The purpose of this paper is to evaluate the importance of each CSF alteration concerning the diagnosis in 22 cases of spinal shistosomiasis. According to the results, only 20% of the cases had all the five feature that are considered to be characteristic of spinal shistomiasis. Abnormal cell count was present in 86%, protein increase in 77.3%, immunoglobulin G increase in 60,8%, eosinophils were present in 36.8% and indirect fluorescent antibody test was positive in 68.2%. In three cases all CSF parameters studied were within the normal limits. As the most specific test among those described was the indirect fluorescent antibody test, it should be regarded for the diagnosis.As três espécies de esquistossoma podem comprometer o sistema nervoso. O S. mansoni é responsável pela esquistossomose no Brasil, sendo a mielopatia uma forma grave desta helmintose. O propósito deste trabalho é analisar as alterações do líquido cefalorraquidiano (LCR) para dar mais subsídios para o diagnóstico da esquistossomose raquimedular. Fizeram parte deste estudo 22 amostras de LCR de pacientes com esquistossomose espinal. Os resultados das análises destas amostras mostraram que a associação de alterações do LCR com quadro inflamatório e RIFI-IgM positiva ocorreu em 88% dos pacientes, que o eosinófilo esteve presente em apenas 7 amostras (36,8%), e que 3 dos 22 pacientes estudados apresentaram LCR normal. Conclui-se que o exame de LCR é coadjuvante muito útil para o diagnóstico da neuroesquistossomose.Universidade Estadual de Londrina Centro de Ciências da SaúdeUniversidade Federal de São Paulo (UNIFESP)Universidade de São Paulo Faculdade de Ciências Farmacêuticas Departamento de Análises ClínicasUNIFESPSciEL

Pharmacogenomics, CYP2D6, and tamoxifen: A survey of the reasons sustaining european clinical practice paradigms

Tamoxifen is a drug that is often used in the clinical management of breast cancer. CYP2D6 is a key metabolizing enzyme that is involved in the conversion of tamoxifen to its active drug metabolites. CYP2D6 has several alleles that metabolize tamoxifen and other drugs at different rates that can alter therapeutic impact, a characteristic that renders it one of the most studied enzymes in the field of pharmacogenetics. Background and objectives: Portugal has no implemented measures based on pharmacogenomics analysis prior to therapy that might function as a cultural sample control when analyzing the individual and economic factors present in clinical practice paradigms. Therefore, we aim to investigate the impact of CYP2D6 genotyping of the tamoxifen metabolizing enzymes in the clinical management of breast cancer patients. Materials and Methods: Qualitative/quantitative studies regarding the impact of pharmacogenomics in breast cancer; personal interviews in different Portuguese laboratories within hospital setting using a survey. Analysis of data through interviews to management board and/or decision makers from major oncological centers. Results: Reasons for common adoption of pharmacogenomics practice are contradictory and based both in economic factors and cultural/clinical bias. Conclusions: This research study identifies specific cultural and/or clinical bias that act as obstacles to pharmacogenomic implementation and proposes viable courses of action that might bring about change in cultural/medical habits.This research was partially support by UID/BIM/04293/2013 and UID/EQU/0470/2019

Detection of ALK fusion transcripts in FFPE lung cancer samples by NanoString technology

Background: ALK-rearranged lung cancers exhibit specific pathologic and clinical features and are responsive to anti-ALK therapies. Therefore, the detection of ALK-rearrangement is fundamental for personalized lung cancer therapy. Recently, new molecular techniques, such as NanoString nCounter, have been developed to detect ALK fusions with more accuracy and sensitivity. Methods: In the present study, we intended to validate a NanoString nCounter ALK-fusion panel in routine biopsies of FFPE lung cancer patients. A total of 43 samples were analyzed, 13 ALK-positive and 30 ALK-negative, as previously detected by FISH and/or immunohistochemistry. Results: The NanoString panel detected the presence of the EML4-ALK, KIF5B-ALK and TFG-ALK fusion variants. We observed that all the 13 ALK-positive cases exhibited genetic aberrations by the NanoString methodology. Namely, six cases (46.15%) presented EML-ALK variant 1, two (15.38%) presented EML-ALK variant 2, two (15.38%) presented EML-ALK variant 3a, and three (23.07%) exhibited no variant but presented unbalanced expression between 5'/3' exons, similar to other positive samples. Importantly, for all these analyses, the initial input of RNA was 100 ng, and some cases displayed poor RNA quality measurements. Conclusions: In this study, we reported the great utility of NanoString technology in the assessment of ALK fusions in routine lung biopsies of FFPE specimens.This study was partially funded by FINEP (MCTI/FINEP/MS/SCTIE/DECIT), Brazil. BIOPLAT (1302/13).info:eu-repo/semantics/publishedVersio

The secreted triose phosphate isomerase of Brugia malayi is required to sustain microfilaria production in vivo

Human lymphatic filariasis is a major tropical disease transmitted through mosquito vectors which take up microfilarial larvae from the blood of infected subjects. Microfilariae are produced by long-lived adult parasites, which also release a suite of excretory-secretory products that have recently been subject to in-depth proteomic analysis. Surprisingly, the most abundant secreted protein of adult Brugia malayi is triose phosphate isomerase (TPI), a glycolytic enzyme usually associated with the cytosol. We now show that while TPI is a prominent target of the antibody response to infection, there is little antibody-mediated inhibition of catalytic activity by polyclonal sera. We generated a panel of twenty-three anti-TPI monoclonal antibodies and found only two were able to block TPI enzymatic activity. Immunisation of jirds with B. malayi TPI, or mice with the homologous protein from the rodent filaria Litomosoides sigmodontis, failed to induce neutralising antibodies or protective immunity. In contrast, passive transfer of neutralising monoclonal antibody to mice prior to implantation with adult B. malayi resulted in 60–70% reductions in microfilarial levels in vivo and both oocyte and microfilarial production by individual adult females. The loss of fecundity was accompanied by reduced IFNγ expression by CD4+ T cells and a higher proportion of macrophages at the site of infection. Thus, enzymatically active TPI plays an important role in the transmission cycle of B. malayi filarial parasites and is identified as a potential target for immunological and pharmacological intervention against filarial infections

Climate change and anthropogenic intervention impact on the hydrologic anomalies in a semi-arid area : lower Zab river basin, Iraq

Climate change impact, drought phenomena and anthropogenic stress are of increasing apprehension for water resource managers and strategists, particularly in arid regions. The current study proposes a generic methodology to evaluate the potential impact of such changes at a basin scale. The Lower Zab River Basin located in the north of Iraq has been selected for illustration purposes. The method has been developed through evaluating changes during normal hydrological years to separate the effects of climate change and estimate the hydrologic abnormalities utilising Indicators of Hydrologic Alteration. The meteorological parameters were perturbed by applying adequate delta perturbation climatic scenarios. Thereafter, a calibrated rainfall-runoff model was used for streamflow simulations. Findings proved that climate change has a more extensive impact on the hydrological characteristics of the streamflow than anthropogenic intervention (i.e. the construction of a large dam in the catchment). The isolated baseflow is more sensitive to the precipitation variations than to the variations of the potential evapotranspiration. The current hydrological anomalies are expected to continue. This comprehensive basin study demonstrates how climate change impact, anthropogenic intervention as well as hydro-climatic drought and hydrological anomalies can be evaluated with a new methodology

What Has Changed During the COVID-19 Pandemic? - The Effect on an Academic Breast Department in Portugal

Introduction: One year ago, Portugal entered its first lockdown because of the coronavirus disease-2019 (COVID-19) pandemic. The impact of this on delays in cancer diagnosis and treatment is a major concern, which may negatively affect the outcomes of these patients. Materials and methods: This retrospective, single-center analysis compared the clinical and pathological characteristics of breast cancer (BC) patients referred to a medical oncology first appointment between March 2020 and 2021, with the same period in the previous year. Results: Strikingly, there was a 40% reduction in the number of BC patients during lockdown. However, there was a statistically significant increase in the proportion of metastatic BC patients admitted for the first time for systemic therapy (13.6% vs. 28.9%, p = 0.003). Additionally, a statistically significant increase in the number of patients with bilateral early BC at diagnosis after March 2020 was found (7.2% vs. 1.9%, p = 0.043). Conclusion: These findings support international recommendations for an accelerated restoration of BC screening, to reduce incidence of advanced breast cancer at diagnosis and mitigate the expected impact of the COVID-19 pandemic on patients with cancer. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.info:eu-repo/semantics/publishedVersio

The conservation value of human-modified landscapes for the world's primates

Land-use change pushes biodiversity into human-modified landscapes, where native ecosystems are surrounded by anthropic land covers (ALCs). Yet, the ability of species to use these emerging covers remains poorly understood. We quantified the use of ALCs by primates worldwide, and analyzed species' attributes that predict such use. Most species use secondary forests and tree plantations, while only few use human settlements. ALCs are used for foraging by at least 86 species with an important conservation outcome: those that tolerate heavily modified ALCs are 26% more likely to have stable or increasing populations than the global average for all primates. There is no phylogenetic signal in ALCs use. Compared to all primates on Earth, species using ALCs are less often threatened with extinction, but more often diurnal, medium or large-bodied, not strictly arboreal, and habitat generalists. These findings provide valuable quantitative information for improving management practices for primate conservation worldwide