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Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second most common cause of cancer related death in both men and women. Although a number of treatments are available to combat this malignancy, the antime tabolite 5-fluorouracil has been the cornerstone of therapy since its synthesis in the 1950s. Unfortunately, the prolonged use of 5-fluorouracil can lead to chemoresistance, which has prompted research into combination regimens to improve efficacy and quality of life and reduce resistance. Here, we evaluated the synergistic potential of two compounds isolated from guayule, and argentatins A and B, alone and in combination with 5-fluorouracil in a panel of colorectal cancer cell lines. Cell viability assays showed that the combination treatment (argentatin A with 5 fluorouracil) significantly enhanced cytotoxicity, especially in RKO, where the analysis using the Bliss independence model indicated a remarkable synergistic effect with the lowest doses of both compounds. In contrast to the combination with argentatin B, in which the additive effect was only found in the HCT-116 cell line. Finally, immunocytometric analysis revealed that combination treatments induced higher rates of apoptosis than single-agent treatments. Collectively, our findings indicate that argentatins A and B may enhance the anti-tumour effects of 5-fluorouracil and may represent a promising strategy to improve the efficacy of anticancer therapies based on this antimetabolite.

Enteroaggregative (EAEC) strains have been linked to several outbreaks of severe diarrhea around the world, and this bacterium is now commonly resistant to antibiotics. As part of the pathophysiology of EAEC, the characteristic pattern of adherence looks like stacked bricks on the intestinal epithelium. This phenotype depends on an aggregative adhesion plasmid (pAA), which codes for a regulatory protein named AggR. The AggR protein is a master regulator that transcriptionally actives the main virulence genes in this pathotype, such as those that encode the aggregative adhesion fimbriae, dispersin and its secretion apparatus, Aar regulatory protein, and type VI secretion system. Several reports have shown that AggR positively affects most EAEC virulence genes, functioning as a classic transcriptional activator in the promoter region of these genes, interacting with the RNA polymerase. This minireview article integrates the information about virulence determinants of EAEC controlled by the AggR regulator.

Complement factor H (fH) is a plasma protein that regulates activation of the alternative pathway, and mutations in fH are associated with a rare form of thrombotic microangiopathy (TMA), known as atypical hemolytic uremic syndrome (aHUS). A more common TMA is thrombotic thrombocytopenic purpura, which is caused by the lack of normal ADAMTS-13-mediated cleavage of von Willebrand factor (VWF). We investigated whether fH interacts with VWF and affects cleavage of VWF. We found that factor H binds to VWF in plasma, to plasma-purified VWF, and to recombinant A1 and A2 domains of VWF as detected by co-immunoprecipitation (co-IP) and surface plasmon resonance assays. Factor H enhanced ADAMTS-13-mediated cleavage of recombinant VWF-A2 as determined by quantifying the cleavage products using Western-blotting, enhanced cleavage of a commercially available fragment of VWF-A2 (FRETS-VWF73) as determined by fluorometric assay, and enhanced cleavage of ultralarge (UL) VWF under flow conditions as determined by cleavage of VWF-platelet strings attached to histamine stimulated endothelial cells. Using recombinant full-length and truncated fH molecules, we found that the presence of the C-terminal half of fH molecule is important for binding to VWF-A2 and for enhancing cleavage of the A2 domain by ADAMTS-13. We conclude that factor H binds to VWF and may modulate cleavage of VWF by ADAMTS-13.

An intricate regulatory network controls the expression of Salmonella virulence genes. The transcriptional regulator HilD plays a central role in this network by controlling the expression of tens of genes mainly required for intestinal colonization. Accordingly, the expression/activity of HilD is highly regulated by multiple factors, such as the SirA/BarA two-component system and the Hcp-like protein HilE. SirA/BarA positively regulates translation of hilD mRNA through a regulatory cascade involving the small RNAs CsrB and CsrC, and the RNA-binding protein CsrA, whereas HilE inhibits HilD activity by protein-protein interaction. In this study, we show that SirA/BarA also positively regulates translation of hilE mRNA through the same mentioned regulatory cascade. Thus, our results reveal a paradoxical regulation exerted by SirA/BarA-Csr on HilD, which involves simultaneous opposite effects, direct positive control and indirect negative control through HilE. This kind of regulation is called an incoherent type-1 feedforward loop (I1-FFL), which is a motif present in certain regulatory networks and represents a complex biological problem to decipher. Interestingly, our results, together with those from a previous study, indicate that HilE, the repressor component of the I1-FFL reported here (I1-FFL SirA/BarA-HilE-HilD ), is required to reduce the growth cost imposed by the expression of the genes regulated by HilD. Moreover, we and others found that HilE is necessary for successful intestinal colonization by Salmonella . Thus, these findings support that I1-FFL SirA/BarA-HilE-HilD cooperates to control the precise amount and activity of HilD, for an appropriate balance between the growth cost and the virulence benefit generated by the expression of the genes induced by this regulator. I1-FFL SirA/BarA-HilE-HilD represents a complex regulatory I1-FFL that involves multiple regulators acting at distinct levels of gene expression, as well as showing different connections to the rest of the regulatory network governing Salmonella virulence.

Arginine is a conditionally essential amino acid that is depleted in critically ill or surgical patients. In pediatric and adult patients, sepsis results in an arginine-deficient state, and the depletion of plasma arginine is associated with greater mortality. However, direct supplementation of arginine can result in the excessive production of nitric oxide (NO), which can contribute to the hypotension and macrovascular hypo-reactivity observed in septic shock. Pegylated arginine deiminase (ADI-PEG20, pegargiminase) reduces plasma arginine and generates citrulline that can be transported intracellularly to generate local arginine and NO, without resulting in hypotension, while maintaining microvascular patency. The objective of this study was to assess the efficacy of ADI-PEG20 with and without supplemental intravenous citrulline in mitigating hypovolemic shock, maintaining tissue levels of arginine, and reducing systemic inflammation in an endotoxemic pediatric pig model. Twenty 3-week-old crossbred piglets were implanted with jugular and carotid catheters as well as telemetry devices in the femoral artery to measure blood pressure, body temperature, heart rate, and respiration rate. The piglets were assigned to one of three treatments before undergoing a 5 h lipopolysaccharide (LPS) infusion protocol. Twenty-four hours before LPS infusion, control pigs (LPS; n=6) received saline, ADI-PEG20 pigs (n=7) received an injection of ADI-PEG20, and seven pigs (ADI-PEG20 + CIT pigs [n=7]) received ADI-PEG20 and 250 mg/kg citrulline intravenously. Pigs were monitored throughout LPS infusion and tissue was harvested at the end of the protocol. Plasma arginine levels decreased and remained low in ADI-PEG20 + CIT and ADI-PEG20 pigs compared with LPS pigs but tissue arginine levels in the liver and kidney were similar across all treatments. Mean arterial pressure in all groups decreased from 90 mmHg to 60 mmHg within 1 h of LPS infusion but there were no significant differences between treatment groups. ADI-PEG20 and ADI-PEG20 + CIT pigs had less CD45+ infiltrate in the liver and lung and lower levels of pro-inflammatory cytokines in the plasma. ADI-PEG20 and citrulline supplementation failed to ameliorate the hypotension associated with acute endotoxic sepsis in pigs but reduced systemic and local inflammation in the lung and liver.

Urbanization involves changes in landscape terrain, hydrology, and vegetation. These changes allow some wildlife species to thrive in cities while inhibiting others. We analyzed how an urbanization gradient (i.e., percentage of impervious surface) in Xalapa, Mexico, affects raptors habitat associations and at what percentage of impervious surface these effects are the most pronounced. We also characterized the spatial distribution of species along this gradient and quantified seasonal effects. We conducted intensive area searches along an urban-to-conserved gradient inside 20, 500-m radius circular plots. Through direct observations and call-broadcast surveys, we estimated relative abundance, richness, and Shannon diversity index of diurnal and nocturnal raptors. From June 2019–February 2020, we visited each site during three seasons (breeding, fall migration, and winter), during two daily cycle periods, from 07:00–12:00 h and 19:00–00:00 h. We obtained 201 individual records of 14 species. Species abundance ranged from 1–45 individuals from 1–10 species (gradient richness), and the Shannon diversity index varied from 1–7.02 along the urban gradient. As expected, better conserved sites along the gradient held the highest diversity. Our results indicate that the transition from the intermediate to the most urbanized sites (> 70% impervious surface) is where the most abrupt filtering occurs, and we observed only four species in the most urbanized areas. According to Detrended Correspondence Analyses and two-way PERMANOVAs, the spatial distribution of the raptor community in Xalapa is significantly affected by the degree of urbanization, with some resident species using urban areas and migratory species using the intermediate and conserved areas. Our findings expand our understanding on how urbanization influences raptor communities in Neotropical cities. However, more research is needed to determine how urbanization filters raptor assemblages in cities worldwide.

This paper presents a general analysis of all the quartic equations with real coefficients and multiple roots; this analysis revealed some unknown formulae to solve each kind of these equations and some precisions about the relation between these ones and the Resolvent Cubic; for example, it is well-known that any quartic equation has multiple roots whenever its Resolvent Cubic also has multiple roots; however, this analysis reveals that any non-biquadratic quartic equation and its Resolvent Cubic always have the same number of multiple roots; additionally, the four roots of any quartic equation with multiple roots are real whenever some specific forms of its Resolvent Cubic have three non-negative real roots. This analysis also proves that any method to solve third-degree equations is unnecessary to solve quartic equations with multiple roots, despite the existence of the Resolvent Cubic; finally, here is developed a generalized variation of the Ferrari Method and the Descartes Method, which help to avoid complex arithmetic operations during the resolution of any quartic equation with real coefficients, even though this equation has non-real roots; and a new, more simplified form of the discriminant of the quartic equations is also featured here.

Information on strategies and practices in the search of missing persons with dementia is inconsistent which creates challenges for first responders, such as police, when they choose appropriate search and rescue approaches. The purpose of this study was to describe current strategies among police services in Ontario. Telephone interviews with police were conducted. Questions included what strategies were used for locating missing persons living with dementia, and what gaps exist in search practices. Participants described they used high- and low-tech solutions in search and rescue. They identified gaps in education and awareness, proactive strategies, resources, and funding. Information collected from the interviews was used to develop a practice guideline for police in partnership with the Alzheimer Society of Ontario.

Disaster epidemiology (i.e., applied epidemiology in disaster settings) presents a source of reliable and actionable information for decision-makers and stakeholders in the disaster management cycle. However, epidemiological methods have yet to be routinely integrated into disaster response and fully communicated to response leaders. We present a framework consisting of rapid needs assessments, health surveillance, tracking and registries, and epidemiological investigations, including risk factor and health outcome studies and evaluation of interventions, which can be practiced throughout the cycle. Applying each method can result in actionable information for planners and decision-makers responsible for preparedness, response, and recovery. Disaster epidemiology, once integrated into the disaster management cycle, can provide the evidence base to inform and enhance response capability within the public health infrastructure.

The nucleoid-associated protein Fis functions as a global regulator that influences various cellular processes in Gram-negative bacteria. In this study, we examined the role of Fis in the transcriptional regulation of type 3 fimbriae in Klebsiella pneumoniae, a notable opportunistic pathogen associated with hospital-acquired infections. Our transcriptional analyses revealed that deleting the fis gene caused a significant upregulation of mrkA and mrkH, the genes responsible for the structure and regulation of type 3 fimbriae, respectively. Additionally, phenotypic assays demonstrated that the Δfis mutant exhibited enhanced biofilm formation and greater adherence to A549 lung epithelial cells compared to the wild-type strain. These effects were restored to wild-type levels in the cis-complemented strain. Electrophoretic mobility shift assays confirmed that Fis directly binds to the regulatory regions upstream of both mrkA and mrkH, indicating that repression occurs through direct interaction with the promoter. In summary, our findings show that Fis acts as a transcriptional repressor of mrkA and mrkH, thereby negatively regulating the expression of type 3 fimbriae, biofilm formation, and adherence. This study highlights Fis as a direct regulator of fimbrial expression and biofilm development in K. pneumoniae, deepening our understanding of its virulence regulatory network.