OX40 and 4-1BB delineate distinct immune profiles in sarcoma.

Systemic relapse after radiotherapy and surgery is the major cause of disease-related mortality in sarcoma patients. Combining radiotherapy and immunotherapy is under investigation as a means to improve response rates. However, the immune contexture of sarcoma is understudied. Here, we use a retrospective cohort of sarcoma patients, treated with neoadjuvant radiotherapy, and TCGA data. We explore therapeutic targets of relevance to sarcoma, using genomics and multispectral immunohistochemistry to provide insights into the tumor immune microenvironment across sarcoma subtypes. Differential gene expression between radioresponsive myxoid liposarcoma (MLPS) and more radioresistant undifferentiated pleomorphic sarcoma (UPS) indicated UPS contained higher transcript levels of a number of immunotherapy targets (CD73/NT5E, CD39/ENTPD1, CD25/IL2RA, and 4-1BB/TNFRSF9). We focused on 4-1BB/TNFRSF9 and other costimulatory molecules. In TCGA data, 4-1BB correlated to an inflamed and exhausted phenotype. OX40/TNFRSF4 and 4-1BB/TNFRSF9 were highly expressed in sarcoma subtypes versus other cancers. Despite OX40 and 4-1BB being described as Treg markers, we identified that they delineate distinct tumor immune profiles. This was true for sarcoma and other cancers. While only a limited number of samples could be analyzed, spatial analysis of OX40 expression identified two diverse phenotypes of OX40+ Tregs, one associated with and one independent of tertiary lymphoid structures (TLSs). Patient stratification is of intense interest for immunotherapies. We provide data supporting the viewpoint that a cohort of sarcoma patients, appropriately selected, are promising candidates for immunotherapies. Spatial profiling of OX40+ Tregs, in relation to TLSs, could be an additional metric to improve future patient stratification

Android malware detection through generative adversarial networks

© 2019 John Wiley & Sons, Ltd. Mobile and cell devices have empowered end users to tweak their cell phones more than ever and introduce applications just as we used to with personal computers. Android likewise portrays an uprise in mobile devices and personal digital assistants. It is an open-source versatile platform fueling incalculable hardware units, tablets, televisions, auto amusement frameworks, digital boxes, and so forth. In a generally shorter life cycle, Android also has additionally experienced a mammoth development in application malware. In this context, a toweringly large measure of strategies has been proposed in theory for the examination and detection of these harmful applications for the Android platform. These strategies attempt to both statically reverse engineer the application and elicit meaningful information as features manually or dynamically endeavor to quantify the runtime behavior of the application to identify malevolence. The overgrowing nature of Android malware has enormously debilitated the support of protective measures, which leaves the platforms such as Android feeble for novel and mysterious malware. Machine learning is being utilized for malware diagnosis in mobile phones as a common practice and in Android distinctively. It is important to specify here that these systems, however, utilize and adapt the learning-based techniques, yet the overhead of hand-created features limits ease of use of such methods in reality by an end user. As a solution to this issue, we mean to make utilization of deep learning–based algorithms as the fundamental arrangement for malware examination on Android. Deep learning turns up as another way of research that has bid the scientific community in the fields of vision, speech, and natural language processing. Of late, models set up on deep convolution networks outmatched techniques utilizing handmade descriptive features at various undertakings. Likewise, our proposed technique to cater malware detection is by design a deep learning model making use of generative adversarial networks, which is responsible to detect the Android malware via famous two-player game theory for a rock-paper-scissor problem. We have used three state-of-the-art datasets and augmented a large-scale dataset of opcodes extracted from the Android Package Kit bytecode and used in our experiments. Our technique achieves F1 score of 99% with a receiver operating characteristic of 99% on the bytecode dataset. This proves the usefulness of our technique and that it can generally be adopted in real life

Development of a volumetric projection technique for the digital evaluation of field of view

This article was published in the journal, Ergonomics [© Taylor & Francis] and the definitive version is available at: http://dx.doi.org/10.1080/00140139.2013.815805Current regulations for field of view requirements in road vehicles are defined by 2D areas projected on the ground plane. This paper discusses the development of a new software-based volumetric field of view projection tool and its implementation within an existing digital human modelling system. In addition, the exploitation of this new tool is highlighted through its use in a UK Department for Transport funded research project exploring the current concerns with driver vision. Focusing specifically on rearwards visibility in small and medium passenger vehicles, the volumetric approach is shown to provide a number of distinct advantages. The ability to explore multiple projections of both direct vision (through windows) and indirect vision (through mirrors) provides a greater understanding of the field of view environment afforded to the driver whilst still maintaining compatibility with the 2D projections of the regulatory standards. Practitioner Summary: Field of view requirements for drivers of road vehicles are defined by simplified 2D areas projected onto the ground plane. However, driver vision is a complex 3D problem. This paper presents the development of a new software-based 3D volumetric projection technique and its implementation in the evaluation of driver vision in small- and medium-sized passenger vehicles

First Dating of a Recombination Event in Mammalian Tick-Borne Flaviviruses

The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination

HIF-Independent Regulation of Thioredoxin Reductase 1 Contributes to the High Levels of Reactive Oxygen Species Induced by Hypoxia

Cellular adaptation to hypoxic conditions mainly involves transcriptional changes in which hypoxia inducible factors (HIFs) play a critical role. Under hypoxic conditions, HIF protein is stabilized due to inhibition of the activity of prolyl hydroxylases (EGLNs). Because the reaction carried out by these enzymes uses oxygen as a co-substrate it is generally accepted that the hypoxic inhibition of EGLNs is due to the reduction in oxygen levels. However, several studies have reported that hypoxic generation of mitochondrial reactive oxygen species (ROS) is required for HIF stabilization. Here, we show that hypoxia downregulates thioredoxin reductase 1 (TR1) mRNA and protein levels. This hypoxic TR1 regulation is HIF independent, as HIF stabilization by EGLNs inhibitors does not affect TR1 expression and HIF deficiency does not block TR1 hypoxic-regulation, and it has an effect on TR1 function, as hypoxic conditions also reduce TR1 activity. We found that, when cultured under hypoxic conditions, TR1 deficient cells showed a larger accumulation of ROS compared to control cells, whereas TR1 over-expression was able to block the hypoxic generation of ROS. Furthermore, the changes in ROS levels observed in TR1 deficient or TR1 over-expressing cells did not affect HIF stabilization or function. These results indicate that hypoxic TR1 down-regulation is important in maintaining high levels of ROS under hypoxic conditions and that HIF stabilization and activity do not require hypoxic generation of ROS

Sick leave among home-care personnel: a longitudinal study of risk factors

BACKGROUND: Sick leave due to neck, shoulder and back disorders (NSBD) is higher among health-care workers, especially nursing aides/assistant nurses, compared with employees in other occupations. More information is needed about predictors of sick leave among health care workers. The aim of the study was to assess whether self-reported factors related to health, work and leisure time could predict: 1) future certified sick leave due to any cause, in nursing aides/assistant nurses (Study group I) and 2) future self-reported sick leave due to NSBD in nursing aides/assistant nurses (Study group II). METHODS: Study group I, comprised 443 female nursing aides/assistant nurses, not on sick leave at baseline when a questionnaire was completed. Data on certified sick leave were collected after 18 months. Study group II comprised 274 of the women, who at baseline reported no sick leave during the preceding year due to NSBD and who participated at the 18 month follow-up. Data on sick leave due to NSBD were collected from the questionnaire at 18 months. The associations between future sick leave and factors related to health, work and leisure time were tested by logistic regression analyses. RESULTS: Health-related factors such as previous low back disorders (OR: 1.89; 95% CI 1.20–2.97) and previous sick leave (OR 6.40; 95%CI 3.97–10.31), were associated with a higher risk of future sick leave due to any cause. Factors related to health, work and leisure time, i.e. previous low back disorders (OR: 4.45; 95% CI 1.27–15.77) previous sick leave, not due to NSBD (OR 3.30; 95%CI 1.33–8.17), high strain work (OR 2.34; 95%CI 1.05–5.23) and high perceived physical exertion in domestic work (OR 2.56; 95%CI 1.12–5.86) were associated with a higher risk of future sick leave due to NSBD. In the final analyses, previous low back disorders and previous sick leave remained significant in both study groups. CONCLUSION: The results suggest a focus on previous low back disorders and previous sick leave for the design of early prevention programmes aiming at reducing future sick leave due to any cause, as well as due to NSBD, among nursing aides/assistant nurses. A multifactorial approach may be of importance in the early prevention of sick leave due to NSBD

Persistence of immune responses after heterologous and homologous third COVID-19 vaccine dose schedules in the UK: eight-month analyses of the COV-BOOST trial

Background: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose in June 2021. Monovalent messenger RNA (mRNA) COVID-19 vaccines were subsequently widely used for the third and fourth-dose vaccination campaigns in high-income countries. Real-world vaccine effectiveness against symptomatic infections following third doses declined during the Omicron wave. This report compares the immunogenicity and kinetics of responses to third doses of vaccines from day (D) 28 to D242 following third doses in seven study arms. Methods: The trial initially included ten experimental vaccine arms (seven full-dose, three half-dose) delivered at three groups of six sites. Participants in each site group were randomised to three or four experimental vaccines, or MenACWY control. The trial was stratified such that half of participants had previously received two primary doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) and half had received two doses of BNT162b2 (Pfizer–BioNtech, hereafter referred to as BNT). The D242 follow-up was done in seven arms (five full-dose, two half-dose). The BNT vaccine was used as the reference as it was the most commonly deployed third-dose vaccine in clinical practice in high-income countries. The primary analysis was conducted using all randomised and baseline seronegative participants who were SARS-CoV-2 naïve during the study and who had not received a further COVID-19 vaccine for any reason since third dose randomisation. Results: Among the 817 participants included in this report, the median age was 72 years (IQR: 55–78) with 50.7% being female. The decay rates of anti-spike IgG between vaccines are different among both populations who received initial doses of ChAd/ChAd and BNT/BNT. In the population that previously received ChAd/ChAd, mRNA vaccines had the highest titre at D242 following their vaccine dose although Ad26. COV2. S (Janssen; hereafter referred to as Ad26) showed slower decay. For people who received BNT/BNT as their initial doses, a slower decay was also seen in the Ad26 and ChAd arms. The anti-spike IgG became significantly higher in the Ad26 arm compared to the BNT arm as early as 3 months following vaccination. Similar decay rates were seen between BNT and half-BNT; the geometric mean ratios ranged from 0.76 to 0.94 at different time points. The difference in decay rates between vaccines was similar for wild-type live virus-neutralising antibodies and that seen for anti-spike IgG. For cellular responses, the persistence was similar between study arms. Conclusions: Heterologous third doses with viral vector vaccines following two doses of mRNA achieve more durable humoral responses compared with three doses of mRNA vaccines. Lower doses of mRNA vaccines could be considered for future booster campaigns

Knotted vs. Unknotted Proteins: Evidence of Knot-Promoting Loops

Knotted proteins, because of their ability to fold reversibly in the same topologically entangled conformation, are the object of an increasing number of experimental and theoretical studies. The aim of the present investigation is to assess, on the basis of presently available structural data, the extent to which knotted proteins are isolated instances in sequence or structure space, and to use comparative schemes to understand whether specific protein segments can be associated to the occurrence of a knot in the native state. A significant sequence homology is found among a sizeable group of knotted and unknotted proteins. In this family, knotted members occupy a primary sub-branch of the phylogenetic tree and differ from unknotted ones only by additional loop segments. These "knot-promoting" loops, whose virtual bridging eliminates the knot, are found in various types of knotted proteins. Valuable insight into how knots form, or are encoded, in proteins could be obtained by targeting these regions in future computational studies or excision experiments

CO-INFECTION OF DENGUE VIRUS BY SEROTYPES 1 AND 4 IN PATIENT FROM MEDIUM SIZED CITY FROM BRAZIL

SUMMARY The natural co-infection with dengue virus can occur in highly endemic areas where different serotypes have been observed for many years. We report one case of DENV-1/DENV-4 co-infection in human serum detected by molecular tests. Phylogenetic analysis of the sequences obtained indicated the presence of genotype V and II for DENV-1 and DENV-4, respectively