Mycobacterium tuberculosis Virulence Is Mediated by PtpA Dephosphorylation of Human Vacuolar Protein Sorting 33B

SummaryEntry into host macrophages and evasion of intracellular destruction mechanisms, including phagosome-lysosome fusion, are critical elements of Mycobacterium tuberculosis (Mtb) pathogenesis. To achieve this, the Mtb genome encodes several proteins that modify host signaling pathways. PtpA, a low-molecular weight tyrosine phosphatase, is a secreted Mtb protein of unknown function. The lack of tyrosine kinases in the Mtb genome suggests that PtpA may modulate host tyrosine phosphorylated protein(s). We report that a genetic deletion of ptpA attenuates Mtb growth in human macrophages, and expression of PtpA-neutralizing antibodies simulated this effect. We identify VPS33B, a regulator of membrane fusion, as a PtpA substrate. VPS33B and PtpA colocalize in Mtb-infected human macrophages. PtpA secretion combined with active-phosphorylated VPS33B inhibited phagosome-lysosome fusion, a process arrested in Mtb infections. These results demonstrate that PtpA is essential for Mtb intracellular persistence and identify a key host regulatory pathway that is inactivated by Mtb

Teeth as lithic raw material: Experiments and use-wear analysis

This paper explores the archaeological and ethnographic evidence for use of rodent teeth as instruments, without direct modification (without manufacturing), in replacement of lithic raw materials. There are ethnographic records that describe the use of teeth, extracted from the jaw by direct manual grip or use of handles, and also used inside the jaw, which functions as a handle. Most of the teeth that appear in archaeological contexts have been studied within the framework of zooarchaeological analysis, however, there is the possibility that the dental pieces have been used as instruments, although this has rarely been considered. The objective of this work is to present the results of a comparative study of experimental work, which we carried out with beaver (Castor canadensis) and capybara (Hydrochoerus hydrochaeris), and to discuss their similarities and differences with the traces of use of lithic material. Through macro- and microscopic analysis (Stereomicroscope and metallographic microscope), we were able to characterize and explain the natural use signs of the teeth and differentiate them from the anthropic use signs produced when they are used as instruments. These traces on a macro- and microscopic scale, have different characteristics depending on the material worked and the kinematics used, and at the same time show similarities with the traces that occur on certain lithic materials. Consequently, we believe that it is possible to develop functional analyses on teeth of different animal species, and that these analyses will contribute to our knowledge about the life forms of past societies.Este trabajo explora la evidencia arqueológica y etnográfica sobre el uso de dientes de roedores, sin modificación directa (sin manufactura) como instrumentos, en reemplazo de materias primas líticas. Existen publicaciones que muestran su uso, extraídos de la mandíbula, en prehensión manual directa o enmangados, pero también usados dentro de la mandíbula que funcional como mango. Sin embargo hasta ahora, la mayoría de los dientes que aparecen en contextos arqueológicos han sido estudiados en el marco del análisis zooarqueológico. La posibilidad de que hayan sido utilizados como instrumentos es rara vez tenida en cuenta, en parte debido a que se pensaba que no era posible identificarlos entre los restos faunísticos. En  investigaciones previas desarrollamos un trabajo experimental preliminar utilizando dientes de dos grupos de roedores, castor (Castor canadensis) y capybara (Hydrochoerus hydrochaeris), para procesar otros materiales. Observamos que  era posible identificar rastros de uso, que permitirían reconocer tales instrumentos en sitios arqueológicos. Para hacerlo, utilizamos el mismo equipamiento y metodología que se emplea habitualmente para el análisis de rastros de uso en material lítico. A lo largo de los años hemos desarrollado numerosas líneas experimentales sobre diferentes tipos de materias primas líticas. En este trabajo, efectuamos un estudio comparativo de ambas especies y discutimos sus similitudes y diferencias con el material lítico. De manera comparativa mostramos las huellas de uso desarrolladas en riolita, una materia prima lítica común de Tierra del Fuego. Los resultados muestran que los dientes utilizados como instrumentos son eficientes para trabajar diferentes materiales y con diferentes modos de uso. Mediante análisis macro y microscópico (lupa binocular y microscopio metalográfico), pudimos caracterizar y explicar los rastros de uso naturales de los dientes y diferenciarlos de los rastros de uso antrópicos producidos cuando se los utiliza como instrumentos. También observamos que el comportamiento de las dos partes del diente, la dentina y el esmalte, es diferente, ya que su composición es ligeramente diferente. Finalmente, pudimos caracterizar estos rastros de uso a escala macro y microscópica; tienen características diferentes según el material trabajado y cinemática, y al mismo tiempo muestran similitudes con los rastros que se producen sobre ciertos materiales líticos. Las huellas producidas en los dientes al ser utilizados sobre diferentes materiales son muy similares a las producidas sobre materias primas líticas. La razón de ello es la composición química de los dientes.  Las piezas dentales de todos los animales, incluido el ser humano, están formadas por bioapatita, un mineral producido por fenómenos biológicos, mientras que el esmalte dental está formado principalmente por fluoroapatita (Ca5(PO4)3F). La presencia de este mineral provoca la formación de microtrazas de desgaste similares a las de los minerales en cualquier materia prima lítica. Al mismo tiempo, pudimos comprobar que los dientes utilizados como herramientas son eficientes para trabajar diferentes materiales y con diversas cinemáticas. Esta observación confirma la eficacia de los dientes tal y como se informa en los registros etnográficos. En consecuencia, creemos que es posible desarrollar análisis funcional sobre dientes de diferentes especies animales, y que estos análisis contribuirán a nuestro conocimiento sobre las formas de vida de las sociedades pasadas

Sociocultural Interaction and Symbolism in Prehistoric South America: Quartz Crystal Manuports from Tierra del Fuego

The use of mineral elements with special characteristics, such as quartz crystals, in ornamental or ceremonial contexts, is not uncommon in archaeology. Their appearance in different archaeological sites is the basis to discuss their significance for past societies. However, while these objects are loaded with symbolic value, it is difficult to identify them in hunter-gatherer sites. In this chapter, we discuss this subject from the case of a series of crystals discovered in the central area of the Big Island of Tierra del Fuego, and we outline their interpretation based on technofunctional analysis confronted with the ethnographic information for the region. Tierra del Fuego is located at the southern tip of South America. It was inhabited by hunter-gatherer societies since the end of last glaciation until the beginning of the twentieth century. In historical times, the central-northern sector of the Big Island was occupied by the Selknam society, in which there is an extensive ethnographic and ethnohistorical bibliography. Archaeological research in the central area of Tierra del Fuego has revealed a continuous occupation of hunter-gatherer societies. The analysis of provenience of raw materials lets us to propose hypothesis about mobility and interaction networks that can be confronted with the ethnographic information

Antimicrobial, Anti-Inflammatory, Antiparasitic, and Cytotoxic Activities of Laennecia confusa

The current paper investigated the potential benefit of the traditional Mexican medicinal plant Laennecia confusa (Cronquist) G. L. Nesom (Asteraceae). Fractions from the hexane, chloroform, methanol, and aqueous extracts were analyzed for antibacterial, antifungal, anti-inflammatory, and antiparasitic activities. The antimicrobial activity of the extracts and fractions was assessed on bacterial and fungal strains, in addition to the protozoa Leishmania donovani, using a microdilution assay. The propensity of the plant's compounds to produce adverse effects on human health was also evaluated using propidium iodine to identify damage to human macrophages. The anti-inflammatory activity of the extracts and fractions was investigated by measuring the secretion of interleukin-6. Chemical analyses demonstrated the presence of flavonoids, cyanogenic and cardiotonic glycosides, saponins, sesquiterpene lactones, and triterpenes in the chloroform extract. A number of extracts and fractions show antibacterial activity. Of particular interest is antibacterial activity against Staphylococcus aureus and its relative methicillin-resistant strain, MRSA. Hexanic and chloroformic fractions also exhibit antifungal activity and two extracts and the fraction CE 2 antiparasitic activity against Leishmania donovani. All bioactive extracts and fractions assayed were also found to be cytotoxic to macrophages. In addition, the hexane and methane extracts show anti-inflammatory activity by suppressing the secretion of interleukine-6

Disruption of the serine/threonine protein kinase H affects phthiocerol dimycocerosates synthesis in Mycobacterium tuberculosis

Mycobacterium tuberculosis possesses a complex cell wall that is unique and essential for interaction of the pathogen with its human host. Emerging evidence suggests that the biosynthesis of complex cell-wall lipids is mediated by serine/threonine protein kinases (STPKs). Herein, we show, using in vivo radiolabelling, MS and immunostaining analyses, that targeted deletion of one of the STPKs, pknH, attenuates the production of phthiocerol dimycocerosates (PDIMs), a major M. tuberculosis virulence lipid. Comparative protein expression analysis revealed that proteins in the PDIM biosynthetic pathway are differentially expressed in a deleted pknH strain. Furthermore, we analysed the composition of the major lipoglycans, lipoarabinomannan (LAM) and lipomannan (LM), and found a twofold higher LAM/LM ratio in the mutant strain. Thus, we provide experimental evidence that PknH contributes to the production and synthesis of M. tuberculosis cell-wall components

The forest as a fuel source: Anthracological analysis on sites of central strip of Isla Grande de Tierra del Fuego

El objetivo de este trabajo es presentar el análisis antracológico de dos sitios de la faja central de la Isla Grande de Tierra del Fuego (Cabo San Pablo 2017 y Kami 7) y discutir la utilización de recursos leñosos por parte de los grupos que habitaron el área durante el Holoceno tardío. Se aplicó una metodología de análisis antracológico estándar, que incluyó la identificación taxonómica, la evaluación de alteraciones en la estructura de los carbones y estimación del calibre original de los leños utilizados. Los resultados demuestran un énfasis en el uso combustible de taxa de la clase fitosociológica Nothofagetea pumilionis-antarcticae, siendo Nothofagus pumilio y N. antartica/betuloides los más abundantes. Se registra una preponderancia de carbones de grandes calibres, de madera colectada en buen estado y alteraciones que reflejan eventos de altas temperaturas de fogón. De los resultados se deduce un aprovechamiento intenso y variado de los bosques cercanos a los sitios.The objective of this paper is to present the anthracological analysis of two sites of the central strip of the Isla Grande de Tierra del Fuego (Cabo San Pablo 2017 y Kami 7) and to discuss the use of woody resources by the groups that inhabited the area during the Late Holocene. A standard methodology was applied, focusing on taxonomical identification, evaluation of structural alterations on charcoal and calliper estimations of the original collected wood. Results demonstrated an emphasis on the use as fuel of taxa of the phytosociological class Nothofagetea pumilionis-antarcticae, where Nothofagus pumilio and N. antartica/betuloides are the most abundant. Thick wood calliper, good wood conditions and alterations reflecting events of high temperatures in hearths were registered. From the results an intense and varied use of the forests near the sites was recognized.Fil: Franch Bach, Anna. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Mansur, Maria Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; Argentina. Universidad Nacional de Tierra del Fuego. Instituto de Desarrollo Economico E Innovacion; ArgentinaFil: Parmigiani, Vanesa Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: de Angelis, Hernan Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Alvarez Soncini, Maria Celina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Ciampagna, María Laura. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Arqueología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Capparelli, Aylen. Universidad Nacional de La Plata. Facultad de Ciencias Naturales y Museo. División Arqueología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Chemical and antimicrobial profiling of propolis from different regions within Libya.

Extracts from twelve samples of propolis collected from different regions of Libya were tested for their activity against Trypanosoma brucei, Leishmania donovani, Plasmodium falciparum, Crithidia fasciculata and Mycobacterium marinum and the cytotoxicity of the extracts was tested against mammalian cells. All the extracts were active to some degree against all of the protozoa and the mycobacterium, exhibiting a range of EC50 values between 1.65 and 53.6 μg/ml. The toxicity against mammalian cell lines was only moderate; the most active extract against the protozoan species, P2, displayed an IC50 value of 53.2 μg/ml. The extracts were profiled by using liquid chromatography coupled to high resolution mass spectrometry. The data sets were extracted using m/z Mine and the accurate masses of the features extracted were searched against the Dictionary of Natural Products (DNP). A principal component analysis (PCA) model was constructed which, in combination with hierarchical cluster analysis (HCA), divided the samples into five groups. The outlying groups had different sets of dominant compounds in the extracts, which could be characterised by their elemental composition. Orthogonal partial least squares (OPLS) analysis was used to link the activity of each extract against the different micro-organisms to particular components in the extracts

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing