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3 In the authors' experience, this border tends to vary with species, breed, respiratory effort and underlying lung lesions. 3 It is also the authors' experience that it can be difficult to determine the caudal extent of the lung margin on a lateral radiograph, particularly given this border changes during the respiratory cycle. [...]it is interesting to note that as VetBLUE increases the sites assessed from a single intercostal space to multiple intercostal spaces, it more closely aligns with earlier studies published by Dr Armenise 6 and the protocol used in the current study. An abstract in dogs suggests LUS protocols that examine larger lung surface area can detect pathology otherwise missed with protocols that scan less lung surface area, although this is a small study and prospective veterinary studies are needed to know how many sites need to be scanned to maximize sensitivity and specificity at finding underlying pleural and lung pathology. 8 The duration of time to perform lung ultrasound will likely need to be balanced against the speed with which a diagnosis needs to be made.

Fourteen of 16 patients with metastatic, castration-resistant prostate cancer and genetic defects in repair of DNA damage had a response to the PARP inhibitor olaparib. Anemia and fatigue were the major toxic effects. Prostate cancer is the most common cancer in men and the sixth leading cause of death from cancer among men throughout the world. 1 The interpatient molecular heterogeneity of this disease is well recognized; however, treatment to date has not been molecularly stratified. 2 , 3 It would be useful to identify predictive biomarkers in order to provide more precise treatment for this disease. 4 Metastatic, castration-resistant prostate cancer can have genomic aberrations that interfere with DNA repair. 3 , 5 Some of these aberrations have been associated with sensitivity to platinum and poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibitors, suggesting that treatment with a PARP inhibitor . . .

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease where liver biopsy remains the gold standard for diagnosis. Here we aimed to evaluate the role of circulating adiponectin, leptin, and insulin-like growth factor 1 (IGF-1) levels as non-invasive NAFLD biomarkers and assess their correlation with the metabolome. Materials and Methods: Leptin, adiponectin, and IGF-1 serum levels were measured by ELISA in two independent cohorts of biopsy-proven obese NAFLD patients and healthy-liver controls (discovery: 38 NAFLD, 13 controls; validation: 194 NAFLD, 31 controls) and correlated with clinical data, histology, genetic parameters, and serum metabolomics. Results: In both cohorts, leptin increased in NAFLD vs. controls (discovery: AUROC 0.88; validation: AUROC 0.83; p < 0.0001). The leptin levels were similar between obese and non-obese healthy controls, suggesting that obesity is not a confounding factor. In the discovery cohort, adiponectin was lower in non-alcoholic steatohepatitis (NASH) vs. non-alcoholic fatty liver (AUROC 0.87; p < 0.0001). For the validation cohort, significance was attained for homozygous for PNPLA3 allele c.444C (AUROC 0.63; p < 0.05). Combining adiponectin with specific serum lipids improved the assay performance (AUROC 0.80; p < 0.0001). For the validation cohort, IGF-1 was lower with advanced fibrosis (AUROC 0.67, p < 0.05), but combination with international normalized ratio (INR) and ferritin increased the assay performance (AUROC 0.81; p < 0.01). Conclusion: Serum leptin discriminates NAFLD, and adiponectin combined with specific lipids stratifies NASH. IGF-1, INR, and ferritin distinguish advanced fibrosis.

Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules.

K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro , is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives. Artemisinin-resistant Plasmodium is an increasing problem. Here, using a medicinal chemistry programme, the authors identify a tetraoxane-based drug candidate that shows no cross-resistance with an artemisinin-resistant strain (PfK13-C580Y) and is efficient in Plasmodium mouse models.

Tropical forests face increasing climate risk 1 , 2 , yet our ability to predict their response to climate change is limited by poor understanding of their resistance to water stress. Although xylem embolism resistance thresholds (for example, Ψ 50 ) and hydraulic safety margins (for example, HSM 50 ) are important predictors of drought-induced mortality risk 3 – 5 , little is known about how these vary across Earth’s largest tropical forest. Here, we present a pan-Amazon, fully standardized hydraulic traits dataset and use it to assess regional variation in drought sensitivity and hydraulic trait ability to predict species distributions and long-term forest biomass accumulation. Parameters Ψ 50 and HSM 50 vary markedly across the Amazon and are related to average long-term rainfall characteristics. Both Ψ 50 and HSM 50 influence the biogeographical distribution of Amazon tree species. However, HSM 50 was the only significant predictor of observed decadal-scale changes in forest biomass. Old-growth forests with wide HSM 50 are gaining more biomass than are low HSM 50 forests. We propose that this may be associated with a growth–mortality trade-off whereby trees in forests consisting of fast-growing species take greater hydraulic risks and face greater mortality risk. Moreover, in regions of more pronounced climatic change, we find evidence that forests are losing biomass, suggesting that species in these regions may be operating beyond their hydraulic limits. Continued climate change is likely to further reduce HSM 50 in the Amazon 6 , 7 , with strong implications for the Amazon carbon sink. A pan-Amazon study of forests shows large variations in drought tolerance traits and finds that forests in regions of pronounced climate change are losing biomass and may be operating beyond their hydraulic limits.

Antimicrobial peptides have been developed based on plant-derived molecular scaffolds for the treatment of infectious diseases. Chenopodin is an abundant seed storage protein in quinoa, an Andean plant with high nutritional and therapeutic properties. Here, we used computer- and physicochemical-based strategies and designed four peptides derived from the primary structure of Chenopodin. Two peptides reproduce natural fragments of 14 amino acids from Chenopodin, named Chen1 and Chen2, and two engineered peptides of the same length were designed based on the Chen1 sequence. The two amino acids of Chen1 containing amide side chains were replaced by arginine (ChenR) or tryptophan (ChenW) to generate engineered cationic and hydrophobic peptides. The evaluation of these 14-mer peptides on Staphylococcus aureus and Escherichia coli showed that Chen1 does not have antibacterial activity up to 512 µM against these strains, while other peptides exhibited antibacterial effects at lower concentrations. The chemical substitutions of glutamine and asparagine by amino acids with cationic or aromatic side chains significantly favoured their antibacterial effects. These peptides did not show significant hemolytic activity. The fluorescence microscopy analysis highlighted the membranolytic nature of Chenopodin-derived peptides. Using molecular dynamic simulations, we found that a pore is formed when multiple peptides are assembled in the membrane. Whereas, some of them form secondary structures when interacting with the membrane, allowing water translocations during the simulations. Finally, Chen2 and ChenR significantly reduced SARS-CoV-2 infection. These findings demonstrate that Chenopodin is a highly useful template for the design, engineering, and manufacturing of non-toxic, antibacterial, and antiviral peptides.

Human papillomavirus (HPV) infection is implicated in causing several types of cancer, including cervical cancer. In Brazil, the quadrivalent HPV vaccine is provided free of charge for children between the ages of 9 and 14. Nevertheless, the vaccination coverage rate has remained below 60% since its implementation in 2014. This study aimed (i) to assess the knowledge of parents/guardians on HPV infection and vaccine prophylaxis and (ii) to test the association between having a “higher degree of knowledge” (HDK) and the sociodemographic characteristics. A total of 388 parents/guardians of children of vaccination age were enrolled. Questions assessing sociodemographic characteristics, knowledge, and attitudes toward HPV infection and vaccination were administered to participants via a self-answered questionnaire. Questionnaires of 343 participants were considered for analysis. Participants who answered at least 70% of the questions correctly were classified as presenting HDK. Multivariate logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the associations between population characteristics and HDK. This study occurred prior to the COVID-19 pandemic; thus, the pandemic was not considered in our analysis. A total of 212 (61.8%) participants showed HDK. Participants who were male (OR = 0.39; 95% CI = 0.22, 0.70) and lived in larger households (OR = 0.48; 95% CI = 0.25, 0.95) were less likely to present HDK. Participants who reported having an acquaintance with prior/concurrent HPV infection were more likely to have HDK (OR = 3.78; 95% CI = 2.02, 7.05). These findings suggest the importance of developing novel strategies for raising parental awareness of HPV, particularly targeting males.

CD161 is a C-type lectin-like receptor expressed on the majority of natural killer (NK) cells; however, the significance of CD161 expression on NK cells has not been comprehensively investigated. Recently, we found that CD161 expression identifies a transcriptional and innate functional phenotype that is shared across various T cell populations. Using mass cytometry and microarray experiments, we demonstrate that this functional phenotype extends to NK cells. CD161 marks NK cells that have retained the ability to respond to innate cytokines during their differentiation, and is lost upon cytomegalovirus-induced maturation in both healthy and human immunodeficiency virus (HIV)-infected patients. These pro-inflammatory NK cells are present in the inflamed lamina propria where they are enriched for integrin CD103 expression. Thus, CD161 expression identifies NK cells that may contribute to inflammatory disease pathogenesis and correlates with an innate responsiveness to cytokines in both T and NK cells.