Essentiality of mmpL3 and impact of its silencing on Mycobacterium tuberculosis gene expression

MmpL3 is an inner membrane transporter of Mycobacterium tuberculosis responsible for the export of trehalose momomycolate, a precursor of the mycobacterial outer membrane component trehalose dimycolate (TDM), as well as mycolic acids bound to arabinogalactan. MmpL3 represents an emerging target for tuberculosis therapy. In this paper, we describe the construction and characterization of an mmpL3 knockdown strain of M. tuberculosis. Downregulation of mmpL3 led to a stop in bacterial division and rapid cell death, preceded by the accumulation of TDM precursors. MmpL3 was also shown to be essential for growth in monocyte-derived human macrophages. Using RNA-seq we also found that MmpL3 depletion caused up-regulation of 47 genes and down-regulation of 23 genes (at least 3-fold change and false discovery rate <= 1%). Several genes related to osmoprotection and metal homeostasis were induced, while several genes related to energy production and mycolic acids biosynthesis were repressed suggesting that inability to synthesize a correct outer membrane leads to changes in cellular permeability and a metabolic downshift

Lansoprazole is an antituberculous prodrug targeting cytochrome bc1

Better antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc(1) complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc(1) inhibitors is highly active against drug-resistant clinical isolates and spares the human H+K+-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens

Red squirrels in the British Isles are infected with leprosy bacilli

Leprosy, caused by infection with Mycobacterium leprae or the recently discovered Mycobacterium lepromatosis, was once endemic in humans in the British Isles. Red squirrels in Great Britain (Sciurus vulgaris) have increasingly been observed with leprosy-like lesions on the head and limbs. Using genomics, histopathology, and serology, we found M. lepromatosis in squirrels from England, Ireland, and Scotland, and M. leprae in squirrels from Brownsea Island, England. Infection was detected in overtly diseased and seemingly healthy animals. Phylogenetic comparisons of British and Irish M. lepromatosis with two Mexican strains from humans show that they diverged from a common ancestor around 27,000 years ago, whereas the M. leprae strain is closest to one that circulated in Medieval England. Red squirrels are thus a reservoir for leprosy in the British Isles

Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide

Accessing parental perspectives to inform the development of parent training in autism in south-eastern Europe

Parent training has been shown to be an important means of supporting families living with autism – but such services are not universally accessible. A multinational project funded by the European Commission has been developed in order to establish such parent training in three south-eastern European countries. To ensure that the training was relevant and appropriate, a survey was carried out in autumn 2015 to ascertain the attitudes of parents of children with autism in Croatia, Cyprus and the Former Yugoslav Republic of Macedonia regarding this issue, and to identify the areas of training that they felt most important. Two hundred and fifty-three surveys were distributed, and 148 were returned, a response rate of 58%. Respondents in the three counties were overwhelmingly positive about parent training, with almost 90% stating that they would like to attend such training. Weekend training sessions were preferred by the majority of respondents. There was wide variation between the three countries with regard to what content was felt important to be included, with parents in the FYR of Macedonia seeking information in the greatest number of areas. Five topics were prioritised by parents across all three countries. These were: • Strategies for enhancing my child’s communication • Strategies on facilitating my child’s interaction with other children • Sensory integration and development • General information on behavioural management strategies • Identifying and/or developing socialisation opportunitie

Navika tjelesne aktivnosti kod autora koji su objavljivali u Hrvatskom časopisu za javno zdravstvo

Navike se mogu definirati kao stečeni oblik ponašanja. Navike nastaju višestrukim, višegodišnjim, ponavljanjem odgovarajućih pokreta ili radnji. Postoje razne vrste navika npr. navike ponašanja, higijenske navike, radne navike itd. Neke od njih su pozitivne, a neke negativne. Tjelesna aktivnost je primjer pozitivne navike, koja pridonosi poboljšanju psiho-fizičkog stanja čovjeka, te je stog vrlo važna u primarnoj prevenciji niza kroničnih i akutnih bolesti. Da bi se stvorila navika redovitog tjelesnog vježbanja potrebno je, unatoč fizičkom zamoru koji proizlazi iz same aktivnosti, ponavljati odgovarajuće vježbe ili aktivnosti iz dana u dan, iz godine u godinu. Kada organizam počne prepoznavati umor u vrijeme treninga, a pogotovo nakon treninga, kao vrhunac ugode, tada možete biti sigurni da ste ovisnik o jednoj pozitivnoj navici- tjelesnoj aktivnosti.

Ancient genomes reveal a high diversity of Mycobacterium leprae in medieval Europe.

Studying ancient DNA allows us to retrace the evolutionary history of human pathogens, such as Mycobacterium leprae, the main causative agent of leprosy. Leprosy is one of the oldest recorded and most stigmatizing diseases in human history. The disease was prevalent in Europe until the 16th century and is still endemic in many countries with over 200,000 new cases reported annually. Previous worldwide studies on modern and European medieval M. leprae genomes revealed that they cluster into several distinct branches of which two were present in medieval Northwestern Europe. In this study, we analyzed 10 new medieval M. leprae genomes including the so far oldest M. leprae genome from one of the earliest known cases of leprosy in the United Kingdom-a skeleton from the Great Chesterford cemetery with a calibrated age of 415-545 C.E. This dataset provides a genetic time transect of M. leprae diversity in Europe over the past 1500 years. We find M. leprae strains from four distinct branches to be present in the Early Medieval Period, and strains from three different branches were detected within a single cemetery from the High Medieval Period. Altogether these findings suggest a higher genetic diversity of M. leprae strains in medieval Europe at various time points than previously assumed. The resulting more complex picture of the past phylogeography of leprosy in Europe impacts current phylogeographical models of M. leprae dissemination. It suggests alternative models for the past spread of leprosy such as a wide spread prevalence of strains from different branches in Eurasia already in Antiquity or maybe even an origin in Western Eurasia. Furthermore, these results highlight how studying ancient M. leprae strains improves understanding the history of leprosy worldwide

Genome-Wide Analysis of the “Cut-and-Paste” Transposons of Grapevine

Background: The grapevine is a widely cultivated crop and a high number of different varieties have been selected since its domestication in the Neolithic period. Although sexual crossing has been a major driver of grapevine evolution, its vegetative propagation enhanced the impact of somatic mutations and has been important for grapevine diversity. Transposable elements are known to be major contributors to genome variability and, in particular, to somatic mutations. Thus, transposable elements have probably played a major role in grapevine domestication and evolution. The recent publication of the complete grapevine genome opens the possibility for an in deep analysis of its transposon content. Principal Findings: We present here a detailed analysis of the ‘‘cut-and-paste’ ’ class II transposons present in the genome of grapevine. We characterized 1160 potentially complete grapevine transposons as well as 2086 defective copies. We report on the structure of each element, their potentiality to encode a functional transposase, and the existence of matching ESTs that could suggest their transcription. Conclusions: Our results show that these elements have transduplicated and amplified cellular sequences and some of them have been domesticated and probably fulfill cellular functions. In addition, we provide evidences that the mobility o

Navika tjelesne aktivnosti kod autora koji su objavljivali u Hrvatskom časopisu za javno zdravstvo

Navike se mogu definirati kao stečeni oblik ponašanja. Navike nastaju višestrukim, višegodišnjim, ponavljanjem odgovarajućih pokreta ili radnji. Postoje razne vrste navika npr. navike ponašanja, higijenske navike, radne navike itd. Neke od njih su pozitivne, a neke negativne. Tjelesna aktivnost je primjer pozitivne navike, koja pridonosi poboljšanju psiho-fizičkog stanja čovjeka, te je stog vrlo važna u primarnoj prevenciji niza kroničnih i akutnih bolesti. Da bi se stvorila navika redovitog tjelesnog vježbanja potrebno je, unatoč fizičkom zamoru koji proizlazi iz same aktivnosti, ponavljati odgovarajuće vježbe ili aktivnosti iz dana u dan, iz godine u godinu. Kada organizam počne prepoznavati umor u vrijeme treninga, a pogotovo nakon treninga, kao vrhunac ugode, tada možete biti sigurni da ste ovisnik o jednoj pozitivnoj navici- tjelesnoj aktivnosti.