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Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.

A large number of individuals are using to purchase their necessary goods. When going to buy an item, the customer takes into account the time you spend in the aisles, between product shelves, at the checkout counter and at checkout lines. The customers usually face some problems and difficulties while purchasing. These issues include worrying that the money they brought in will not be enough for all the items purchased as well as standing in a long line to get to the billing counter, which is a waste of time. In some cases, customers have problems with insufficient data about a particular product. We can end this problem by replacing the normal shopping cart with a smart shopping experience using the customer’s mobile phone and the shops’ smart carts with a recommender system. The user will scan an items using the provided mobile application. The application will show the items you have purchased and after the completion of the purchase, the invoice will appear as a QR code that can be scanned by the self checkout kiosk .This project aims to develop and improve the shopping cart into a smart shopping cart with a QR code that can be scanned with a mobile application, so that the smart shopping cart application can be accessed. The application will display the items you have purchased, the number of items and the invoice for your cart, and after completing the purchase, the invoice will appear as a QR code that the accountant can scan, after which the consumer pays the invoice value easily, either Visa or Cash. Therefore, the entire system will use encryption methods for data transmitted to and from the server to monitor all purchases. &nbsp

Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8+ T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

Climate change is one of the most important environmental issues affecting our society today and we need to educate the citizens about the impact on human lives. An attempt was made to integrate experiential-based climate change education into the teaching and learning of secondary school Biology lessons on the topic of Endangered Ecosystem to improve students’ knowledge on climate change and increase motivation towards caring for the environment. Two classes from a school were randomly assigned to experimental (N = 30) and control groups (N = 32). Following the intervention, a one-way analysis of covariance (ANCOVA) with pre-test data as covariate showed statistically significant differences in knowledge and motivation. Experiential-based climate change activities enabled students to construct the knowledge socially and also satisfied the three basic human needs: competence, autonomy and relatedness, which have subsequently promoted motivation. The findings described in this study are similar wit...

The acceleration of average temperature of lands and oceans, rising sea level, frequent extreme weather events and ocean acidification denote that climate change is a contemporary pressing dilemma facing the world. Everyday human activities such as open burning, deforestation, burning of fossil fuels and agricultural activities significantly contribute to Earth warming. Preventing the aforementioned activities reduce the greenhouse gas emission to the atmosphere and subsequently slows the changes in climate. Thus, climate change education is integral to educate people on the destructive consequences of their actions to the climate. Past studies revealed that well-established theories and models guided the designing of education to deliver behavioral change in many countries and reportedly improved participants&rsquo, knowledge, attitude and motivation. However, these theories and models exist as an after effect of the education and the long-term impact of the initiative frequently not found and less information available on the sustainability of such education. Additionally, effective climate change education is typically context-based and designed based on factors related to local students&rsquo, behavior. Hence, this study examined how knowledge and psychological factors such as belief and motivation explain the formation of climate conserving behavior among secondary school students. A total of 221 questionnaires was distributed to 14 years old Malaysian secondary school students to measure knowledge, motivation and belief. The data obtained were later analyzed using the partial least squares structural equation modelling (PLS-SEM) approach. The findings revealed that knowledge (&beta, = 0.259, p &lt, 0.05), belief (&beta, = 0.295, p &lt, 0.05) and motivation (&beta, = 0.546, p &lt, 0.05) positively affects the behavior. These findings reflected that knowledge, belief and motivation collectively explain a total of 65.5% of variances in the formation of climate conserving behavior among Malaysian secondary school students.

The bacterial chromosome is under varying levels of mechanical stress due to a high degree of crowding and dynamic protein–DNA interactions experienced within the nucleoid. DNA tension is difficult to measure in cells and its functional significance remains unclear although in vitro experiments have implicated a range of biomechanical phenomena. Using single-molecule tools, we have uncovered a novel protein–DNA interaction that responds to fluctuations in mechanical tension by condensing DNA. We combined tethered particle motion (TPM) and optical tweezers experiments to probe the effects of tension on DNA in the presence of the Hha/H-NS complex. The nucleoid structuring protein H-NS is a key regulator of DNA condensation and gene expression in enterobacteria and its activity in vivo is affected by the accessory factor Hha. We find that tension, induced by optical tweezers, causes the rapid compaction of DNA in the presence of the Hha/H-NS complex, but not in the presence of H-NS alone. Our results imply that H-NS requires Hha to condense bacterial DNA and that this condensation could be triggered by the level of mechanical tension experienced along different regions of the chromosome.

Hha facilitates H-NS-mediated silencing of foreign genes in bacteria.Two Hha monomers bind opposing faces of the H-NS N-terminal dimerization domain.Hha binds the dimerization domain of H-NS and may contact DNA via positively charged surface residues.The structure of Hha and H-NS in complex provides a mechanistic model of how Hha may affect gene regulation. The bacterial nucleoid-associated proteins Hha and H-NS jointly repress horizontally acquired genes in Salmonella, including essential virulence loci encoded within Salmonella pathogenicity islands. Hha is known to interact with the N-terminal dimerization domain of H-NS; however, the manner in which this interaction enhances transcriptional silencing is not understood. To further understand this process, we solved the x-ray crystal structure of Hha in complex with the N-terminal dimerization domain of H-NS (H-NS(1-46)) to 3.2 Å resolution. Two monomers of Hha bind to symmetrical sites on either side of the H-NS(1-46) dimer. Disruption of the Hha/H-NS interaction by the H-NS site-specific mutation I11A results in increased expression of the Hha/H-NS co-regulated gene hilA without affecting the expression levels of proV, a target gene repressed by H-NS in an Hha-independent fashion. Examination of the structure revealed a cluster of conserved basic amino acids that protrude from the surface of Hha on the opposite side of the Hha/H-NS(1-46) interface. Hha mutants with a diminished positively charged surface maintain the ability to interact with H-NS but can no longer regulate hilA. Increased expression of the hilA locus did not correspond to significant depletion of H-NS at the promoter region in chromatin immunoprecipitation assays. However, in vitro, we find Hha improves H-NS binding to target DNA fragments. Taken together, our results show for the first time how Hha and H-NS interact to direct transcriptional repression and reveal that a positively charged surface of Hha enhances the silencing activity of H-NS nucleoprotein filaments.

The 5.5 protein (T7p32) of coliphage T7 (5.5 T7 ) was shown to bind and inhibit gene silencing by the nucleoid-associated protein H-NS, but the mechanism by which it acts was not understood. The 5.5 T7 protein is insoluble when expressed in Escherichia coli , but we find that 5.5 T7 can be isolated in a soluble form when coexpressed with a truncated version of H-NS followed by subsequent disruption of the complex during anion-exchange chromatography. Association studies reveal that 5.5 T7 binds a region of H-NS (residues 60 to 80) recently found to contain a distinct domain necessary for higher-order H-NS oligomerization. Accordingly, we find that purified 5.5 T7 can disrupt higher-order H-NS-DNA complexes in vitro but does not abolish DNA binding by H-NS per se . Homologues of the 5.5 T7 protein are found exclusively among members of the Autographivirinae that infect enteric bacteria, and despite fairly low sequence conservation, the H-NS binding properties of these proteins are largely conserved. Unexpectedly, we find that the 5.5 T7 protein copurifies with heterogeneous low-molecular-weight RNA, likely tRNA, through several chromatography steps and that this interaction does not require the DNA binding domain of H-NS. The 5.5 proteins utilize a previously undescribed mechanism of H-NS antagonism that further highlights the critical importance that higher-order oligomerization plays in H-NS-mediated gene repression.

The bacterial H-NS protein silences expression from sequences with higher AT-content than the host genome and is believed to buffer the fitness consequences associated with foreign gene acquisition. Loss of H-NS results in severe growth defects in Salmonella, but the underlying reasons were unclear. An experimental evolution approach was employed to determine which secondary mutations could compensate for the loss of H-NS in Salmonella. Six independently derived S. Typhimurium hns mutant strains were serially passaged for 300 generations prior to whole genome sequencing. Growth rates of all lineages dramatically improved during the course of the experiment. Each of the hns mutant lineages acquired missense mutations in the gene encoding the H-NS paralog StpA encoding a poorly understood H-NS paralog, while 5 of the mutant lineages acquired deletions in the genes encoding the Salmonella Pathogenicity Island-1 (SPI-1) Type 3 secretion system critical to invoke inflammation. We further demonstrate that SPI-1 misregulation is a primary contributor to the decreased fitness in Salmonella hns mutants. Three of the lineages acquired additional loss of function mutations in the PhoPQ virulence regulatory system. Similarly passaged wild type Salmonella lineages did not acquire these mutations. The stpA missense mutations arose in the oligomerization domain and generated proteins that could compensate for the loss of H-NS to varying degrees. StpA variants most able to functionally substitute for H-NS displayed altered DNA binding and oligomerization properties that resembled those of H-NS. These findings indicate that H-NS was central to the evolution of the Salmonellae by buffering the negative fitness consequences caused by the secretion system that is the defining characteristic of the species., Author Summary H-NS is an abundant DNA-binding protein found in enteric bacteria including the important pathogens Escherichia, Salmonella, Vibrio, and Yersinia, that plays a primary role in defending the bacterial genome by silencing AT-rich foreign genes. H-NS has been hypothesized to facilitate the evolution of bacterial species by acting as a buffer against the negative consequences that can occur when new genes are incorporated into pre-existing genetic landscapes. Here experimental evolution and whole-genome sequencing were employed to determine the factors underlying the severe growth defects displayed by Salmonella strains lacking H-NS. Through tracking the evolution of several independently derived mutant lineages, we find that compensatory mutations arise quickly and that they occur in loci related to virulence. A frequent outcome was loss of the Salmonella Pathogenicity Island-1, the defining genetic island of the genus Salmonella. Among other things these findings demonstrate that H-NS has enabled the birth of a new and important bacterial pathogen by buffering the fitness consequences caused by overexpression of SPI-1. These findings are likely generalizable to pathogens such as E. coli, Yersinia, Shigella, and Vibrio cholerae, all of which maintain a pool of “expensive” AT-rich virulence genes that are repressed by H-NS.