Signaling Pathways Governing the Caspofungin Paradoxical Effect in Aspergillus fumigatus.

Aspergillus fumigatus is responsible for a wide range of diseases affecting several million people worldwide. Currently, a few families of antifungals are available to fight aspergillosis, and we are facing a worrisome increase in resistance to azoles, the drugs used for both first-line treatment and prophylaxis of invasive aspergillosis. In this context, some of the latest antifungals, i.e., echinocandins, have gained attention. Even though acquired resistance to echinocandins is yet uncommon in A. fumigatus clinical isolates, some strains exhibit another characteristic that relies on their capacity to grow at suprainhibitory echinocandin concentrations in vitro This intriguing phenomenon, especially observed with caspofungin and now referred to as the caspofungin paradoxical effect (CPE), relies on molecular mechanisms that were hitherto little understood. Here, we discuss the recent key findings of Valero and colleagues published in mBio (C. Valero, A. C. Colabardini, J. Chiaratto, L. Pardeshi, et al., mBio 11:e00816-20, 2020, https://doi.org/10.1128/mBio.00816-20) that will allow a better understanding of the complex regulatory pathway involved in governing the response of A. fumigatus to caspofungin

TEORI PERMINTAAN DALAM PERSPEKTIF EKONOMI ISLAM DAN KONVENSIONAL

ABSTRACTMicroeconomic theory is one of the branches of science that is very important insociety, where people to meet their needs will create demand. Studying from an Islamicand conventional perspective on demand, in general, is almost the same. This studyaims to find out how the theory of demand in Islamic and conventional viewpoints.Using a descriptive qualitative method, collecting data by combining from severalsources and discussions with students of Islamic economics majoring in SiliwangiUniversity. So, from the results of research on legal sources that are used by Islamicboundaries in view of demand, from the existence of different views about commoditiesand objectives to be achieved. The main source of the theory of Islamic demand is theQur'an, al-hadith, and as-sunnah of the Prophet Muhammad. Meanwhile, inconventional theory, human reason is sometimes not even rational when buying anumber of commodities for goods or services

Automating the measurement of physiological parameters: a case study in the image analysis of cilia motion

International audienceAs image processing and analysis techniques improve, an increasing number of procedures in bio-medical analyses can be automated. This brings many benefits, e.g improved speed and accuracy, leading to more reliable diagnoses and follow-up, ultimately improving patients outcome. Many automated procedures in bio-medical imaging are well established and typically consist of detecting and counting various types of cells (e.g. blood cells, abnormal cells in Pap smears, and so on). In this article we propose to automate a different and difficult set of measurements, which is conducted on the cilia of people suffering from a variety of respiratory tract diseases. Cilia are slender, microscopic, hair-like structures or organelles that extend from the surface of nearly all mammalian cells. Motile cilia, such as those found in the lungs and respiratory tract, present a periodic beating motion that keep the airways clear of mucus and dirt. In this paper, we propose a fully automated method that computes various measurements regarding the motion of cilia, taken with high-speed video-microscopy. The advantage of our approach is its capacity to automatically compute robust, adaptive and regionalized measurements, i.e. associated with different regions in the image. We validate the robustness of our approach, and illustrate its performance in comparison to the state-of-the-art

Promising pre-clinical validation of targeted radionuclide therapy using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment

Targeted internal radionuclide therapy (TRT) would be an effective alternative to current therapies for dissemi- nated melanoma treatment. At our institution, a class of iodobenzamides has been developed as potent melanoma- seeking agents. This review described the preclinical vali- dations of a quinoxaline derivative molecule (ICF01012) as tracer for TRT application. It was selected for its high, specific and long-lasting uptake in tumour with rapid clear- ance from non-target organs providing suitable dosimetry parameters for TRT. Extended in vivo study of metabolic profiles confirmed durable tumoural concentration of the unchanged molecule form. Moreover melanin specificity of ICF01012 was determined by binding assay with syn- thetic melanin and in vivo by SIMS imaging. Then, we showed in vivo that [131I] ICF01012 treatment drastically inhibited growth of B16F0, B16Bl6 and M4Beu tumours whereas [131I] NaI or unlabelled ICF01012 treatment was without significant effect. Histological analysis showed that residual tumour cells exhibit a significant loss of aggres- siveness after treatment. This anti-tumoural effect was associated with a lengthening of the treated-mice survival time and an inhibition of lung dissemination for B16Bl6 model. Results presented here support the concept of TRT using a [131I] labelled iodoquinoxaline derivative for an effective melanoma treatment.<br /

The injury epidemiology of cyclists based on a road trauma registry

<p>Abstract</p> <p>Background</p> <p>Bicycle use has increased in some of France's major cities, mainly as a means of transport. Bicycle crashes need to be studied, preferably by type of cycling. Here we conduct a descriptive analysis.</p> <p>Method</p> <p>A road trauma registry has been in use in France since 1996, in a large county around Lyon (the Rhône, population 1.6 million). It covers outpatients, inpatients and fatalities. All injuries are coded using the Abbreviated Injury Scale (AIS). Proxies were used to identify three types of cycling: learning = children (0-10 years old); sports cycling = teenagers and adults injured outside towns; cycling as means of transport = teenagers and adults injured in towns. The study is based on 13,684 cyclist casualties (1996-2008).</p> <p>Results</p> <p>The percentage of cyclists injured in a collision with a motor vehicle was 8% among children, 17% among teenagers and adults injured outside towns, and 31% among those injured in towns. The percentage of serious casualties (MAIS 3+) was 4.5% among children, 10.9% among adults injured outside towns and 7.2% among those injured in towns. Collisions with motor-vehicles lead to more internal injuries than bicycle-only crashes.</p> <p>Conclusion</p> <p>The description indicates that cyclist type is associated with different crash and injury patterns. In particular, cyclists injured in towns (where cycling is increasing) are generally less severely injured than those injured outside towns for both types of crash (bicycle-only crashes and collisions with a motor vehicle). This is probably due to lower speeds in towns, for both cyclists and motor vehicles.</p

Ultra-structural cell distribution of the melanoma marker iodobenzamide: improved potentiality of SIMS imaging in life sciences

BACKGROUND: Analytical imaging by secondary ion mass spectrometry (SIMS) provides images representative of the distribution of a specific ion within a sample surface. For the last fifteen years, concerted collaborative research to design a new ion microprobe with high technical standards in both mass and lateral resolution as well as in sensitivity has led to the CAMECA NanoSims 50, recently introduced onto the market. This instrument has decisive capabilities, which allow biological applications of SIMS microscopy at a level previously inaccessible. Its potential is illustrated here by the demonstration of the specific affinity of a melanoma marker for melanin. This finding is of great importance for the diagnosis and/or treatment of malignant melanoma, a tumour whose worldwide incidence is continuously growing. METHODS: The characteristics of the instrument are briefly described and an example of application is given. This example deals with the intracellular localization of an iodo-benzamide used as a diagnostic tool for the scintigraphic detection of melanic cells (e.g. metastasis of malignant melanoma). B16 melanoma cells were injected intravenously to C(57)BL(6)/J(1)/co mice. Multiple B16 melanoma colonies developed in the lungs of treated animals within three weeks. Iodobenzamide was injected intravenously in tumour bearing mice six hours before sacrifice. Small pieces of lung were prepared for SIMS analysis. RESULTS: Mouse lung B16 melanoma colonies were observed with high lateral resolution. Cyanide ions gave "histological" images of the cell, representative of the distribution of C and N containing molecules (e.g. proteins, nucleic acids, melanin, etc.) while phosphorus ions are mainly produced by nucleic acids. Iodine was detected only in melanosomes, confirming the specific affinity of the drug for melanin. No drug was found in normal lung tissue. CONCLUSION: This study demonstrates the potential of SIMS microscopy, which allows the study of ultra structural distribution of a drug within a cell. On the basis of our observations, drug internalization via membrane sigma receptors can be excluded

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigate relationships have been unsuitable for rare diseases. / Methods: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, twelve clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. / Results: Disease severity at diagnosis measured by FEV1 z-score was (i) significantly worse in individuals with CCDC39 mutations compared to other gene mutations and (ii) better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. / Conclusions: This large scale multi-national study presents PCD as a syndrome with overlapping symptoms and variation in phenotype, according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutations), and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations

Ultrastructural pathology of primary ciliary dyskinesia: report about 125 cases in Germany

<p>Abstract</p> <p>Background</p> <p>Primary ciliary dyskinesia (PCD) is a rare genetically induced disorder of cilia inducing mainly respiratory diseases. Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for diagnosis. We report our experience of TEM investigations in a large series of patients.</p> <p>Methods</p> <p>TEM analysis performed of 742 biopsies from patients with suspected PCD was reviewed retrospectively. Ultrastructural defects were analysized further in 125 cases with changes typical for PCD.</p> <p>Results</p> <p>In 18.1% of patients diagnosis of PCD was made because of morphological alterations, in 68.2% secondary changes were seen. In 13.7% material was not feasible for analysis. Mostly defects of dynein arms were detected in PCD (96.8%). In particular defects of the inner arms (51.2%) and combined dynein defects (37.6%) were found. Total loss of dynein arms was dominant. Only in 3.2% deficiencies of central structures were found alone. Associated situs inversus or dextracardia was reported clinically in 21.4%.</p> <p>Conclusions</p> <p>TEM analysis is possible in most patients and a useful tool for diagnosis of PCD. Functional and genetic analysis should be done additionally. Registers should be installed to collect all available informations and push further research.</p