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Background: Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). TB treatment is based on the administration of three major antibiotics: isoniazid, rifampicin, and pyrazinamide. However, multi-drug resistant (MDR) Mtb strains are increasing around the world, thus, allowing TB to spread around the world. The stringent response is demonstrated by Mtb strains in order to survive under hostile circumstances, even including exposure to antibiotics. The stringent response is mediated by alarmones, which regulate bacterial replication, transcription and translation. Moreover, the Mtb cell wall contributes to the mechanism of antibiotic resistance along with efflux pump activation and biofilm formation. Immunity over the course of TB is managed by M1-macrophages and M2-macrophages, which regulate the immune response against Mtb infection, with the former exerting inflammatory reactions and the latter promoting an anti-inflammatory profile. T helper 1 cells via secretion of interferon (IFN)-gamma, play a protective role in the course of TB, while T regulatory cells secreting interleukin 10, are anti-inflammatory. Alternative therapeutic options against TB require further discussion. In view of the increasing number of MDR Mtb strains, attempts to replace antibiotics with natural and biological products have been object of intensive investigation. Therefore, in this review the anti-Mtb effects exerted by probiotics, polyphenols, antimicrobial peptides and IFN-gamma will be discussed. All the above cited compounds are endowed either with direct antibacterial activity or with anti-inflammatory and immunomodulating characteristics.

Introduction Distal radius is the most common site of fracture in children, comprising 23%–31% of all paediatric fractures. Approximately one-fifth of these fractures are displaced. Completely displaced distal metaphyseal radius fractures in children have traditionally been treated with closed reduction. Recent evidence suggests that correcting the shortening in over-riding distal metaphyseal radius fractures is not necessary in prepubertal children. To date, no published randomised controlled trial (RCT) has compared treatment of these fractures in children by casting the fracture in bayonet position to reduction and pin fixation.Methods and analysis We will conduct an RCT to compare the outcomes of casting the fracture in bayonet position in children under 11 years of age to reduction and percutaneous pin fixation. 60 patients will be randomly assigned to casting or surgery groups. We have two primary outcomes. The first is ratio (injured side/non-injured side) in the total active forearm rotation and the second is ratio (injured side/non-injured side) in total active range of motion of the wrist in the flexion–extension plane at 6 months. The secondary outcomes will include axial radiographic alignment, passive extension of the wrists, grip strength and length of forearms and hands, patient-reported outcome QuickDASH and pain questionnaire PedsQL. Patients not willing to participate in the RCT will be asked to participate in a prospective cohort. Patients not eligible for randomisation will be asked to participate in a non-eligible cohort. These cohorts are included to enhance the external validity of the results of the RCT. Our null hypothesis is that the results of the primary outcome measures in the casting group are non-inferior to surgery group.Ethics and dissemination The institutional review board of the Helsinki and Uusimaa Hospital District has approved the protocol. We will disseminate the findings through peer-reviewed publications.Trial registration number NCT04323410.Protocol V.1.1, 29 September 2020.

Research‐based knowledge is essential for effective conservation and restoration of threatened aquatic species and habitats. Here, our aim was to gather this knowledge on the lake‐dwelling grayling (Thymallus thymallus), typically a riverine fish. Such atypical populations are particularly vulnerable to anthropogenic impacts, including fishing pressure, climate change, eutrophication and waterway construction, some of which affect especially the early life stages. However, there is little information available to guide management and conservation of grayling in lakes. Accordingly, we assessed characteristics of the nursery areas in the threatened grayling population of Lake Puruvesi (eastern Finland). In particular, we used beach seines in two consecutive years to sample lakeshore sites (including islands) that were a priori presumed suitable for grayling. We assessed the occurrence of grayling fry (larvae and post‐larvae <40 mm in length) regarding depth, year, the site's exposure (fetch), bottom shear stress, substrate coarseness and shoreline's north–south orientation. Overall, we found grayling fry in low numbers at every fourth site, with the sites' exposure and dominant substrate coarseness being most relevant variables. In particular, more exposed sites (i.e. with higher fetch values) and fine‐grained substrates dominated by sand or gravel had more grayling fry. Average depth, bottom shear stress or shoreline orientation along the north–south axis did not have a significant effect. Together, the results suggest that the most important nursery areas for lake‐dwelling grayling are lakeshore zones that are barren and exposed. Hence, the sites share characteristics with those used for reproduction by the more common riverine grayling. We hope that these findings will facilitate lake‐dwelling grayling's management and conservation efforts. [ABSTRACT FROM AUTHOR]

In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in colon carcinomas, the ERα/β ratio is often increased, an observation that prompted us to further investigate ERα's role in colorectal cancer (CRC). Here, we assessed ERα nuclear expression in 351 CRC patients. Among them, 119 exhibited positive ERα nuclear expression, which was significantly higher in cancer tissues than in matched normal tissues. Importantly, patients with positive nuclear ERα expression had a poor prognosis. Furthermore, positive ERα expression correlated with increased levels of the G-protein coupled cysteinyl leukotriene receptor 1 (CysLT1R) and nuclear β-catenin, both known tumour promoters. In mouse models, ERα expression was decreased in Cysltr1−/− CAC (colitis-associated colon cancer) mice but increased in ApcMin/+ mice with wild-type Cysltr1. In cell experiments, an ERα-specific agonist (PPT) increased cell survival via WNT/β-catenin signalling. ERα activation also promoted metastasis in a zebrafish xenograft model by affecting the tight junction proteins ZO-1 and Occludin. Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis. [ABSTRACT FROM AUTHOR]

Glycoside hydrolase family 7 (GH7) cellulases are key enzymes responsible for carbon cycling on earth through their role in cellulose degradation and constitute highly important industrial enzymes as well. Although these enzymes are found in a wide variety of evolutionarily distant organisms across eukaryotes, they exhibit remarkably conserved features within two groups: exo‐acting cellobiohydrolases and endoglucanases. However, recently reports have emerged of a separate clade of GH7 endoglucanases from protist symbionts of termites that are 60–80 amino acids shorter. In this work, we describe the first crystal structure of a short GH7 endoglucanase, RsSymEG1, from a symbiont of the lower termite Reticulitermes speratus. A more open flat surface and shorter loops around the non‐reducing end of the cellulose‐binding cleft indicate enhanced access to cellulose chains on the surface of cellulose microfibrils. Additionally, when comparing activities on polysaccharides to a typical fungal GH7 endoglucanase (Trichoderma longibrachiatum Cel7B), RsSymEG1 showed significantly faster initial hydrolytic activity. We also examine the prevalence and diversity of GH7 enzymes that the symbionts provide to the termite host, compare overall structures and substrate binding between cellobiohydrolase and long and short endoglucanase, and highlight the presence of similar short GH7s in other organisms. [ABSTRACT FROM AUTHOR]

Several immunization products are currently being developed against respiratory syncytial virus (RSV) for children, pregnant females, and older adults, and some products have already received authorization. Therefore, studies to monitor the effectiveness of these products are needed in the following years. To assist researchers to conduct postmarketing studies, we developed a generic protocol for register-based cohort studies to evaluate immunization product effectiveness against RSV-specific and nonspecific outcomes. To conduct a study on the basis of this generic protocol, the researchers can use any relevant databases or healthcare registers that are available at the study site. [ABSTRACT FROM AUTHOR]

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI. [ABSTRACT FROM AUTHOR]

Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras‐MAPK pathway, and, downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as the hepatocyte growth factor (HGF) and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of the gene encoding hepsin (Hpn) in a WAP‐Myc model of aggressive MYC‐driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in epidermal growth factor receptor (EGFR) protein levels. We further demonstrate in 3D cultures of patient‐derived breast cancer explants that both basal TGFβ signaling and EGFR protein expression are inhibited by neutralizing antibodies or small‐molecule inhibitors of hepsin. The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer. [ABSTRACT FROM AUTHOR]

Background: Today, mycotoxins are considered critical contaminants in foodstuffs produced by fungi, highlighting the importance of food safety to human health. The toxigenic fungi invasion and mycotoxin production are highly variable and depend on climate, plant, and agronomic practices. Among these, Aflatoxins (AFs) are considered the most potent toxins. This study investigated the fungi presence and AFB1 contamination in corn and wheat grown in Albania during the 2022 harvesting year. Methods: Wheat samples were collected during the summer, while corn during the autumn, and further analyzed. Mycological contamination assessment applied the Verband Deutscher Landëirtschaftlicher Untersuchungs-- und Forschungsanstalten (VDLUFA) procedures. The AFB1 levels were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. The MATLAB R2016b software was applied to perform statistical analysis. The Estimated Daily Intake on AFB1 was calculated to evaluate human exposure. Results: The genera Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium were isolated, with higher rates of contamination in corn and the highest frequency Penicillium genus (77.89%). The Korça region presented a higher fungal load, 104 Colony Forming Unit (CFU)/g in corn. The AFB1 incidence (88.23%) in corn, was significantly higher than in wheat (4.91%). Additionally, the maximum level in corn was found 69.120 μg/kg, while in wheat, only 0.402 μg/kg. None of the wheat samples, in contrast to the 41.18% of corn samples, exceeded the threshold when referring to the respective Maximum Residue Levels. Conclusions: Our observation indicates a higher rate of AFB1 contamination in corn than in wheat. The high concentration levels and contamination incidence in corn require targeted interventions to reduce the AFB1 amounts. Strengthened regulation based on scientific evidence can reduce contamination outbreaks, economic implications, and potential benefits, such as increased consumer trust. Our study indicates that the exposure to AFB1 originates from corn consumption among the adult population. [ABSTRACT FROM AUTHOR]

Determining the sensitivity of the posterior to perturbations of the prior and likelihood is an important part of the Bayesian workflow. We introduce a practical and computationally efficient sensitivity analysis approach using importance sampling to estimate properties of posteriors resulting from power-scaling the prior or likelihood. On this basis, we suggest a diagnostic that can indicate the presence of prior-data conflict or likelihood noninformativity and discuss limitations to this power-scaling approach. The approach can be easily included in Bayesian workflows with minimal effort by the model builder and we present an implementation in our new R package priorsense. We further demonstrate the workflow on case studies of real data using models varying in complexity from simple linear models to Gaussian process models. [ABSTRACT FROM AUTHOR]

Based on a review of diff erent analytical frameworks, it is suggested to run a table top cyber wargame when trying to analyse the eff ects of closed national networks being imposed in the near future. Th e scope of the wargame is to extract results to show how the resilience of an open national network diff ers from a closed national network. It is self-evident that the formation process of resilience is diff erent between the diverse systems. Th e proposed wargame is a two-sided cyber table top wargame. Th e wargame is based on at least two blue teams, at least one red team and a control team (namely a white team). One blue team is located in the closed national networks and its system relies on closed national network infrastructure. Th e other blue team operates its system within open network society. By designing, constructing and executing the proposed cyber wargame we argue it is possible to fi nd these diff erences and similarities as well. Current research improves cyber situation awareness and proposes a direction to be followed when trying to understand the changing circumstances of the cyber space. It also suggests how the research resources could be directed when trying to improve the situation awareness of the closing process.

Abstract Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant‐based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years—vegans, vegetarians, or omnivores from same daycare centers—for a cross‐sectional study. They enjoyed nutritionist‐planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border‐line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n‐3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant‐onset vegan diets are warranted.