Intracellular growth of Mycobacterium tuberculosis after macrophage cell death leads to serial killing of host cells

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states. DOI: http://dx.doi.org/10.7554/eLife.22028.00

A highly potent anti-VISTA antibody KVA12123 - a new immune checkpoint inhibitor and a promising therapy against poorly immunogenic tumors

BackgroundImmune checkpoint therapies have led to significant breakthroughs in cancer patient treatment in recent years. However, their efficiency is variable, and resistance to immunotherapies is common. VISTA is an immune-suppressive checkpoint inhibitor of T cell response belonging to the B7 family and a promising novel therapeutic target. VISTA is expressed in the immuno-suppressive tumor microenvironment, primarily by myeloid lineage cells, and its genetic knockout or antibody blockade restores an efficient antitumor immune response.MethodsFully human monoclonal antibodies directed against VISTA were produced after immunizing humanized Trianni mice and sorting and sequencing natively-linked B cell scFv repertoires. Anti-VISTA antibodies were evaluated for specificity, cross-reactivity, monocyte and T cell activation, Fc-effector functions, and antitumor efficacy using in vitro and in vivo models to select the KVA12123 antibody lead candidate. The pharmacokinetics and safety profiles of KVA12123 were evaluated in cynomolgus monkeys.ResultsHere, we report the development of a clinical candidate anti-VISTA monoclonal antibody, KVA12123. KVA12123 showed high affinity binding to VISTA through a unique epitope distinct from other clinical-stage anti-VISTA monoclonal antibodies. This clinical candidate demonstrated high specificity against VISTA with no cross-reactivity detected against other members of the B7 family. KVA12123 blocked VISTA binding to its binding partners. KVA12123 induced T cell activation and demonstrated NK-mediated monocyte activation. KVA12123 treatment mediated strong single-agent antitumor activity in several syngeneic tumor models and showed enhanced efficacy in combination with anti-PD-1 treatment. This clinical candidate was engineered to improve its pharmacokinetic characteristics and reduce Fc-effector functions. It was well-tolerated in preclinical toxicology studies in cynomolgus monkeys, where hematology, clinical chemistry evaluations, and clinical observations revealed no indicators of toxicity. No cytokines associated with cytokine release syndrome were elevated.ConclusionThese results establish that KVA12123 is a promising drug candidate with a distinct but complementary mechanism of action of the first generation of immune checkpoint inhibitors. This antibody is currently evaluated alone and in combination with pembrolizumab in a Phase 1/2 open-label clinical trial in patients with advanced solid tumors

The Internally Truncated LRP5 Receptor Presents a Therapeutic Target in Breast Cancer

BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth. METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer

Specialist laboratory networks as preparedness and response tool - The emerging viral diseases-expert laboratory network and the chikungunya outbreak, Thailand, 2019

We illustrate the potential for specialist laboratory networks to be used as preparedness and response tool through rapid collection and sharing of data. Here, the Emerging Viral Diseases-Expert Laboratory Network (EVD-LabNet) and a laboratory assessment of chikungunya virus (CHIKV) in returning European travellers related to an ongoing outbreak in Thailand was used for this purpose. EVD-LabNet rapidly collected data on laboratory requests, diagnosed CHIKV imported cases and sequences generated, and shared among its members and with the European Centre for Disease Prevention and Control. Data across the network showed an increase in CHIKV imported cases during 1 October 2018-30 April 2019 vs the same period in 2018 (172 vs 50), particularly an increase in cases known to be related to travel to Thailand (72 vs 1). Moreover, EVD-LabNet showed that strains were imported from Thailand that cluster with strains of the ECSA-IOL E1 A226 variant emerging in Pakistan in 2016 and involved in the 2017 outbreaks in Italy. CHIKV diagnostic requests increased by 23.6% between the two periods. The impact of using EVD-LabNet or similar networks as preparedness and response tool could be improved by standardisation of the collection, quality and mining of data in routine laboratory management systems

Crash risk in currency markets

Abstract Since the Fall of 2008, out-of-the money puts on high interest rate currencies have become significantly more expensive than out-of-the-money calls, suggesting a large crash risk of those currencies. To evaluate crash risk precisely, we propose a parsimonious structural model that includes both Gaussian and disaster risks and can be estimated even in samples that do not contain disasters. Estimating the model for the 1996 to 2014 sample period using monthly exchange rate spot, forward, and option data, we obtain a real-time index of the compensation for global disaster risk exposure. We find that disaster risk accounts for more than a third of the carry trade risk premium in advanced countries over the period examined. The measure of disaster risk that we uncover in currencies proves to be an important factor in the cross-sectional and time-series variation of exchange rates, interest rates, and equity tail risk

Identification of carbon dioxide in an exoplanet atmosphere

Carbon dioxide (CO2) is a key chemical species that is found in a wide range of planetary atmospheres. In the context of exoplanets, CO2 is an indicator of the metal enrichment (that is, elements heavier than helium, also called ‘metallicity’), and thus the formation processes of the primary atmospheres of hot gas giants. It is also one of the most promising species to detect in the secondary atmospheres of terrestrial exoplanets. Previous photometric measurements of transiting planets with the Spitzer Space Telescope have given hints of the presence of CO2, but have not yielded definitive detections owing to the lack of unambiguous spectroscopic identification. Here we present the detection of CO2 in the atmosphere of the gas giant exoplanet WASP-39b from transmission spectroscopy observations obtained with JWST as part of the Early Release Science programme. The data used in this study span 3.0–5.5 micrometres in wavelength and show a prominent CO2 absorption feature at 4.3 micrometres (26-sigma significance). The overall spectrum is well matched by one-dimensional, ten-times solar metallicity models that assume radiative–convective–thermochemical equilibrium and have moderate cloud opacity. These models predict that the atmosphere should have water, carbon monoxide and hydrogen sulfide in addition to CO2, but little methane. Furthermore, we also tentatively detect a small absorption feature near 4.0 micrometres that is not reproduced by these models

Service quality as a part of a customer stisfaction. Case The Flying Pig Beach Hostel.

Tämän tutkimuksen tarkoituksena oli ymmärtää, miten asiakastyytyväisyys syntyy Flying Pig Beach Hostelissa ja miten palvelun laatu tukee asiakastyytyväisyyttä. Tutkimus oli kehittämistutkimus, ja tarkoituksena oli selvittää hostellin realistiset kehittämiskohteet. Flying Pig Beach Hostel on tämän tutkimuksen toimeksiantaja, ja se sijaitsee Noordwijkissa, Alankomaissa. Hostelli tarjoaa majoitus- ja baaripalveluja.   Tutkimuksen tavoitteena oli lisätä tietoa siitä, miten hostelli täyttää palvelun laatustandardit ja -ulottuvuudet. Tutkimus perustuu kirjallisuuteen, artikkeleihin, internetlähteisiin ja tilastoihin. Tutkimus toteutettiin hostellin majoituspalveluja käyttäviltä asiakkailta kerätyn esitutkimuksen avulla. Esitutkimus oli kyselytutkimus, jossa käytettiin sekä laadullisia, että määrällisiä menetelmiä. Esitutkimuksella pyrittiin selvittämään, millaisia odotuksia asiakkailla oli palvelua kohtaan ja miten palvelu koettiin. Tutkimuksessa käytettiin myös kvalitatiivista menetelmää haastattelemalla organisaation henkilökuntaa. Haastattelut toteutettiin teemahaastattelumenetelmää käyttäen. Haastattelujen tavoitteena oli selvittää, miten henkilökunta näkee palvelun laadun ja miten se mahdollistetaan ja ylläpidetään hostellissa.   Hostellin nykyinen palvelun laatu määriteltiin tutkimustulosten avulla. Palvelun laadun nykyinen taso muodostettiin vastausten perusteella, joissa käsiteltiin asiakastyytyväisyyttä. Tulokset osoittivat, että palvelun laatu on kohdeorganisaatiossa korkealla tasolla, asiakkaat ovat tyytyväisiä, sekä kehuivat erityisesti hyvää ja ystävällistä asiakaspalvelua sekä hostellin viihtyisää ja kodikasta ilmapiiriä.   Tuloksista muodostui kehittämisideoita, joiden mukaan hostellissa voitaisiin järjestää enemmän toimintaa, jotta asiakkaiden vuorovaikutus keskenään olisi helpompaa ja asiakaskokemukseen saataisiin lisää arvoa, mikä taas parantaa asiakastyytyväisyyttä entisestään. Toinen esiin noussut asia oli, että varausalustat voisivat tuoda majoituspalvelua koskevan informaation näkyvämmin esiin mahdollisten väärinkäsitysten välttämiseksi, joka vaikuttaa positiivisesti asiakastyytyväisyyteen.The purpose of this research was to understand how customer satisfaction is created in the Flying Pig Beach Hostel and how the service quality supports customer satisfaction. The research was development research, and the purpose was to find out realistic targets for development in the hostel. Flying Pig Beach Hostel is the commissioner in this research, and it is located Noordwijk, the Netherlands. The hostel offers accommodation and bar services.   The goal of the research was to increase knowledge about how the hostel meets up with the service quality standards and dimensions. The research is based on literature, articles, internet sources, and statistics. The research was implemented through a feasible study gathered from the hostel’s customers using the accommodation services. The feasibility study was a survey using a mix of qualitative and quantitative methods. The feasibility study was to find out what the customer’s expectations of the service were and how the service was experienced. The research also used qualitative methods by interviewing the organization’s staff members. The interviews were implemented using theme interview method. The goals of the interviews were to find out how staff members view the service quality and how it is enabled and maintained in the hostel.   The hostel’s current service quality was defined using the results of the research. The current level of service quality was built from the answers that dealt with customer satisfaction. The results showed that the service quality is high in the target organization, customers are satisfied, and they praised a good, friendly customer service and the cozy, homelike atmosphere in the hostel.   Development ideas formed from the results were that more activities could be arranged to make it easier for customers to interact with each other and add more value to the customer experience, which again improves the customer satisfaction even more. Another matter that arose was that the booking platforms could point out the house rules more visibly to avoid possible misunderstandings, which makes customers more satisfied

P2–280: Disruption of default mode correlations in aging and Alzheimer’s disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152976/1/alzjjalz2006051119.pd