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Abstract T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.

Abstract Earth observation (EO) technologies, such as very high-resolution optical satellite data available from Maxar, can enhance economic consequence modeling of disasters by capturing the fine-grained and real-time behavioral responses of businesses and the public. We investigated this unique approach to economic consequence modeling to determine whether crowd-sourced interpretations of EO data can be used to illuminate key economic behavioral responses that could be used for computable general equilibrium modeling of supply chain repercussions and resilience effects. We applied our methodology to the COVID-19 pandemic experience in Los Angeles County, California as a case study. We also proposed a dynamic adjustment approach to account for the changing character of EO through longer-term disasters in the economic modeling context. We found that despite limitations, EO data can increase sectoral and temporal resolution, which leads to significant differences from other data sources in terms of direct and total impact results. The findings from this analytical approach have important implications for economic consequence modeling of disasters, as well as providing useful information to policymakers and emergency managers, whose goal is to reduce disaster costs and to improve economic resilience.

Flooding is a frequent extreme weather event that causes significant financial and societal losses. According to the International Disaster Database (EM-DAT), during January through July 2023, 87 flooding events caused about 2000 deaths and ${\$}$13 billions in damages globally. Among the impacted, low- and medium-income countries with resource scarcity tend to experience high mortality, displacement of people, unmitigated damages, and long-term recovery. Currently, several hydrologic models and Earth observation (EO) datasets are used to forecast flood severity and impacts. However, not all of these models are globally operational or publicly available. The variability in outputs in terms of accuracy, scale, and content also limits their usage for emergency response activities. The Model of Models (MoM), an ensemble approach, integrates hydrologic models and EO datasets 1) to forecast flood risk (probability of occurrence) globally every 24 h at a subwatershed level and 2) to disseminate alert messages and potential impact information to at-risk communities using the Pacific Disaster Center's DisasterAWARE platform. MoM is operational and designed to assist countries with flood risk management and mitigation by providing early warning and situational awareness information. An accuracy assessment of MoM from user-perspective across nine different flood types revealed that 1) the model reliably generated early warning for 100% of the flooded subwatersheds in seven events, and 2) during 2022 flooding, 61% and 89% of the flooded subwatersheds that were identified to be in Watch and Warning categories in Pakistan and Chad, respectively, were detected to be flooding by the Copernicus Global Flood Monitoring system.

Antimicrobial resistance is a global threat, leading to an alarming increase in the prevalence of bacterial infections that can no longer be treated with available antibiotics. The World Health Organization estimates that by 2050 up to 10 million deaths per year could be associated with antimicrobial resistance, which would equal the annual number of cancer deaths worldwide. To overcome this emerging crisis, novel anti-bacterial compounds are urgently needed. There are two possible approaches in the fight against bacterial infections: a) targeting structures within bacterial cells, similar to existing antibiotics; and/or b) targeting virulence factors rather than bacterial growth. Here, for the first time, we provide a comprehensive overview of the key steps in the evaluation of potential new anti-bacterial and/or anti-virulence compounds. The methods described in this review include: a) in silico methods for the evaluation of novel compounds; b) anti-bacterial assays (MIC, MBC, Time-kill); b) anti-virulence assays (anti-biofilm, anti-quorum sensing, anti-adhesion); and c) evaluation of safety aspects (cytotoxicity assay and Ames test). Overall, we provide a detailed description of the methods that are an essential tool for chemists, computational chemists, microbiologists, and toxicologists in the evaluation of potential novel antimicrobial compounds. These methods are cost-effective and have high predictive value. They are widely used in preclinical studies to identify new molecular candidates, for further investigation in animal and human trials.

Considering the sporadic number of scientific studies on vermicomposting apple pomace waste, this research conducts a comparative analysis of vermicomposting processes using Eisenia fetida, focusing on apple pomace both independently and in combination with wheat straw and/or manure (experiment 1: 60% apple pomace and 40% cattle manure; experiment 2: 60% wheat straw and 40% cattle manure; experiment 3: 80% apple pomace, 10% wheat straw, and 10% cattle manure; and experiment 4: 100% apple pomace). After a 240-day substrate transformation period, all four variations of vermicompost produced demonstrated favorable sensory properties, along with high microbiological and physicochemical quality. Throughout the vermicomposting process, the pH of all vermicomposting mixtures changed, converging towards approximately neutral values by the process’s conclusion. There was an increase in dry matter content, as well as total N, P, K, Ca, and Mg, along with organic matter. Notably, the levels of heavy metals (Zn, Cu, Cd, and Pb) in both the vermicomposting materials and resulting vermicomposts remained significantly below the maximum permissible levels stipulated by Republic of Serbia and European Union legislation, which is directly linked to the ecological origin of the raw materials used. The microbiological quality of the final vermicomposts was deemed satisfactory. Over time, there was a decrease in the counts of aerobic mesophilic bacteria as well as Escherichia coli. The counts of sulfite-reducing clostridia in all substrates remained below 102 CFU/g, while Salmonella spp. and Listeria monocytogenes were not detected in either the composting materials or the resulting composts. The vermiculture of apple pulp exhibited advantageous characteristics, notably a shortened vermicomposting period (150 days) compared to other agricultural waste. This reduction in processing time contributes an additional layer of advantage to the overall quality and efficiency of the resulting vermicompost.

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC50 17.8 to 35.9 µM) and no relevant cytotoxicity to mammalian cells (CC50 > 200 µM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antiparasitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.

Summary: Background: Cardiovascular disease (CVD) and cancer are leading causes of death and people with cancer are at higher risk of developing CVD than the general population. Many cancer medicines have cardiotoxic effects but the size of the population exposed to these potentially cardiotoxic medicines is not known. We aimed to determine the prevalence of exposure to potentially cardiotoxic cancer medicines in Australia. Methods: We identified potentially cardiotoxic systemic cancer medicines through searching the literature and registered product information documents. We conducted a retrospective cohort study of Australians dispensed potentially cardiotoxic cancer medicines between 2005 and 2021, calculating age-standardised annual prevalence rates of people alive with exposure to a potentially cardiotoxic medicine during or prior to each year of the study period. Findings: We identified 108,175 people dispensed at least one potentially cardiotoxic cancer medicine; median age, 64 (IQR: 52–74); 57% female. Overall prevalence increased from 49 (95%CI: 48.7–49.3)/10,000 to 232 (95%CI: 231.4–232.6)/10,000 over the study period; 61 (95%CI: 60.5–61.5)/10,000 to 293 (95%CI: 292.1–293.9)/10,000 for females; and 39 (95%CI: 38.6–39.4)/10,000 to 169 (95%CI: 168.3–169.7)/10,000 for males. People alive five years following first exposure increased from 29 (95%CI: 28.8–29.2)/10,000 to 134 (95%CI: 133.6–134.4)/10,000; and from 22 (95%CI: 21.8–22.2)/10,000 to 76 (95%CI: 75.7–76.3)/10,000 for those alive at least 10 years following first exposure. Most people were exposed to only one potentially cardiotoxic medicine, rates of which increased from 39 (95%CI: 38.7–39.3)/10,000 in 2005 to 131 (95%CI: 130.6–131.4)/10,000 in 2021. Interpretation: The number of people exposed to efficacious yet potentially cardiotoxic cancer medicines in Australia is growing. Our findings can support the development of service planning and create awareness about the magnitude of cancer treatment-related cardiotoxicities. Funding: NHMRC Centre for Research Excellence in Medicines Intelligence, Cancer Institute NSW Early Career Fellowship.

Circular RNAs can contribute to tumour progression. Here the authors show that two circular RNAs, circCsnk1g3 and circAnkib1 promote sarcoma growth by controlling the expression of interferon related genes and pro-inflammatory factors in sarcoma cells

Abstract Multiple myeloma (MM) is the second most common hematological cancer and causes significant mortality and morbidity. Knowledge regarding modifiable risk factors for MM remains limited. This analysis of an Australian population‐based case–control family study investigates whether smoking or alcohol consumption is associated with risk of MM and related diseases. Incident cases (n = 789) of MM were recruited via cancer registries in Victoria and New South Wales. Controls (n = 1,113) were either family members of cases (n = 696) or controls recruited for a similarly designed study of renal cancers (n = 417). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional multivariable logistic regression. Heavy intake (>20 g ethanol/day) of alcohol had a lower risk of MM compared with nondrinkers (OR = 0.68, 95% CI: 0.50–0.93), and there was an inverse dose–response relationship for average daily alcohol intake (OR per 10 g ethanol per day = 0.92, 95% CI: 0.86–0.99); there was no evidence of an interaction with sex. There was no evidence of an association with MM risk for smoking‐related exposures (p > 0.18). The associations between smoking and alcohol with MM are similar to those with non‐Hodgkin lymphoma. Further research into potential underlying mechanisms is warranted.

Abstract Background Clinical trials report systemic hypertension is an adverse effect of vascular signalling pathway inhibitor (VSPi) use. There are limited data from routine clinical practice. We aimed to estimate the real-world incidence and risk factors of new-onset and aggravated hypertension for cancer patients dispensed VSPi in whole-of-population Australian setting. Methods We used dispensing records for a 10% random sample of Australians to identify treatment with subsidised VSPi from 2013 to 2018. We further identified dispensings of oral antihypertensive medicines 6 months before and 12 months after VSPi therapy. We defined (i) new-onset hypertension in people first dispensed antihypertensives after VSPi and (ii) aggravated hypertension in people with prior antihypertensive use dispensed an additional, or higher strength, antihypertensive after VSPi. We applied the Fine-Gray cumulative incidence function and Cox proportional hazard regression. Results 1802 patients were dispensed at least one VSPi. The mean age of the cohort was 65 years and 57% were male. The incidence of new-onset treated hypertension was 24.3% (95%CI: 21.2–27.8); age ≥ 60 years (HR 1.74; 95%CI: 1.32–2.31) and treatment with oral tyrosine kinase inhibitors compared to bevacizumab (HR 1.96; 95%CI: 1.16–3.31) were risk factors. The incidence of aggravated hypertension was 25.2% (95%CI: 22.0–28.7) and risk was elevated for patients with renal cancer (HR 2.84; 95%CI: 1.49–5.41) and cancers other than colorectal (HR 1.85; 95%CI: 1.12–3.03). Conclusions Our real-world estimates of incident hypertension appear comparable to those observed in clinical trials (21.6–23.6%). Our population-based study provides some insight into the burden of hypertension in patients commencing VSPi in routine practice.

BackgroundThe association between dietary intake of foods of animal origin and follicular lymphoma (FL) risk and survival is uncertain. In this study, we examined the relationship between dietary intake of dairy foods and fats, meat, fish and seafoods, and the likelihood of FL and survival.MethodsWe conducted a population-based family case-control study in Australia between 2011 and 2016 and included 710 cases, 303 siblings and 186 spouse/partner controls. We assessed dietary intake of animal products prior to diagnosis (the year before last) using a structured food frequency questionnaire and followed-up cases over a median of 6.9 years using record linkage to national death data. We examined associations with the likelihood of FL using logistic regression and used Cox regression to assess association with all-cause and FL-specific mortality among cases.ResultsWe observed an increased likelihood of FL with increasing daily quantity of oily fish consumption in the year before last (highest category OR = 1.96, CI = 1.02–3.77; p-trend 0.06) among cases and sibling controls, but no associations with spouse/partner controls. We found no association between the likelihood of FL and the consumption of other types of fish or seafood, meats or dairy foods and fats. In FL cases, we found no association between meat or oily fish intake and all-cause or FL-specific mortality.ConclusionOur study showed suggestive evidence of a positive association between oily fish intake and the likelihood of FL, but findings varied by control type. Further investigation of the potential role of environmental contaminants in oily fish on FL etiology is warranted.

Aromatic plants and essential oils have many applications in medicine, pharmaceuticals, cosmetics, and the food industry. The essential oil of the flowering aerial parts of Achillea grandifolia, obtained by hydrodistillation, was analyzed for its constituents and investigated for antimicrobial and radical scavenging activity. The essential oil was characterized by a high amount of oxygenated monoterpenes (72.7%) with 1,8-cineole (29.2%) and camphor (23.4%) being the most abundant. Sesquiterpenes were present in smaller quantities (4.8%). Antimicrobial activity was tested against eight ATCC bacterial strains and two ATCC strains of Candida albicans. The essential oil exhibited highly pronounced antimicrobial activity against Micrococcus luteus with a MIC value of 3.50 μg/mL, as well as significant antimicrobial activity (

Interest in the research topic arose as a result of studying the texts of folklore prose of the Yakuts and Telengits. Used method, i.e. reliance on scientific works, collection of facts, comparative analysis of lexical-semantic parallels led to interesting results. The identified samples from the folklore of peoples separated by a huge distance and an independent history of development indicate the presence of common roots. Legends reflect the peculiarities of the ideological ideas of ethnic groups, spiritual and moral values, religious views; at the same time, commonality is found not only in the lexico-semantic plan, but also in the compositional structure of the presentation of the material and the syntax of texts. The changes are quite insignificant, for example, in the Yakut version of the legend «Dispute» the image of a large animal is transformed in accordance with the realities of the Arctic nature, for example, a camel turns into an elk. The thematic approach to the consideration of examples allows us to come to the conclusion that most of the coincidences fall on the texts of religious and everyday content. Some examples from onomastics also speak of ancient linguistic contacts or testify to migration processes among the Turkic-speaking ethnic groups, which have not yet received proper coverage in historical science. In the conclusion of the article, it is said about the need to attract more extensive material to the comparative historical study of the phenomenon. Based on the comprehension of the collected material, an assumption is made about the stability of individual lexemes and lexical-semantic constructions in the translation of the traditional beliefs of the people.

Abstract Backgrounds The present study explored the viability of bovine milk macrophages, their intracellular production of reactive oxygen and nitrogen species (RONS), and their phagocytosis of Staphylococcus aureus, as well as the profile of lymphocytes, from healthy udder quarters and udder quarters infected by Corynebacterium bovis. The study included 28 healthy udder quarters from 12 dairy cows and 20 udder quarters infected by C. bovis from 10 dairy cows. The percentages of macrophages and lymphocytes were identified by flow cytometry using monoclonal antibodies. Macrophage viability, RONS production, and S. aureus phagocytosis were evaluated by flow cytometry. Results Milk samples from quarters infected with C. bovis showed a lower percentage of macrophages but an increased number of milk macrophages per mL and a higher percentage of macrophages that produced intracellular RONS and phagocytosed S. aureus. No effect of C. bovis infection on macrophage viability was found. Udder quarters infected by C. bovis showed a higher percentage of T cells and CD4+ T lymphocytes, but no effect was found on the percentage of CD8+ CD4− T, CD8− CD4− T, or B lymphocytes. Conclusions Thus, our results corroborate, at least in part, the finding that intramammary infections by C. bovis may offer protection against intramammary infections by major pathogens.

Chagas disease is an endemic tropical disease caused by the protozoan Trypanosoma cruzi, which affects around 7 million people worldwide, mostly in development countries. The treatment relies on only two available drugs, with severe adverse effects and a limited efficacy. Therefore, the search for new therapies is a legitimate need. Within this context, our group reported the anti-Trypanosoma cruzi activity of gibbilimbol B, a natural alkylphenol isolated from the plant Piper malacophyllum. Two synthetic derivatives, LINS03018 (1) and LINS03024 (2), demonstrated a higher antiparasitic potency and were selected for mechanism of action investigations. Our studies revealed no alterations in the plasma membrane potential, but a rapid alkalinization of the acidocalcisomes. Nevertheless, compound 1 exhibit a pronounced effect in the bioenergetics metabolism, with a mitochondrial impairment and consequent decrease in ATP and reactive oxygen species (ROS) levels. Compound 2 only depolarized the mitochondrial membrane potential, with no interferences in the respiratory chain. Additionally, no macrophages response of nitric oxide (NO) was observed in both compounds. Noteworthy, simple structure modifications in these derivatives induced significant differences in their lethal effects. Thus, this work reinforces the importance of the mechanism of action investigations at the early phases of drug discovery and support further developments of the series.

Previous studies reported that p-coumaric acid modulates melanoma growth. Because the esterification of p-coumaric acid (p-CA) enhanced its activity as an antimelanogenic agent, we aimed to determine the antitumor potential of two derivatives, the ethyl and butyl esters, against the murine B16-F10 and the human SK-MEL-25 melanoma cells. Cell viability was determined in vitro by the lactate dehydrogenase release and violet crystal absorption assays. The cell proliferation rate and cell cycle behavior were determined by the colony formation assay and flow cytometry analysis. Although p-CA, at the concentration of 1 mM, failed to exert a significant antitumor activity, the ethyl and butyl ester derivatives caused substantial tumor cell death at doses < 1 mM. Despite a reduction in their direct cytotoxicity at minor doses, both products controlled the melanoma growth by arresting the cell cycle at the G0/G1 (B16-F10) or S/G2 (SK-MEL-25). Furthermore, the in vivo experiments showed that the butyl ester derivative suppressed the lung B16-F10 burden, compared to the p-CA-treated mice. Thus, the esterification of p-coumaric acid improved the control over the proliferation of murine and human melanoma cells and can be considered an approach for designing novel anticancer agents.

Although selenium nanoparticles (SeNPs) have gained attention in the scientific community mostly through investigation of their anticancer activity, a great potential of this nanomaterial was recognized recently regarding its antimicrobial activity. The particle form, size, and surface chemistry have been recognized as crucial parameters determining the interaction of nanomaterials with biological entities. Furthermore, considering a narrow boundary between beneficial and toxic effects for selenium per se, it is clear that investigations of biomedical applications of SeNPs are very demanding and must be done with great precautions. The goal of this work is to evaluate the effects of SeNPs surface chemistry and structure on antimicrobial activity against several common bacterial strains, including Staphylococcus aureus (ATCC 6538), Enterococcus faecalis (ATCC 29212), Bacillus subtilis (ATCC 6633), and Kocuria rhizophila (ATCC 9341), as well as Escherichia coli (ATCC 8739), Salmonella Abony (NCTC 6017), Klebsiella pneumoniae (NCIMB 9111) and Pseudomonas aeruginosa (ATCC 9027), and the standard yeast strain Candida albicans (ATCC 10231). Three types of SeNPs were synthesized by chemical reduction approach using different stabilizers and reducing agents: (i) bovine serum albumin (BSA) + ascorbic acid, (ii) chitosan + ascorbic acid, and (iii) with glucose. A thorough physicochemical characterization of the obtained SeNPs was performed to determine the effects of varying synthesis parameters on their morphology, size, structure, and surface chemistry. All SeNPs were amorphous, with spherical morphology and size in the range 70–300 nm. However, the SeNPs obtained under different synthesis conditions, i.e. by using different stabilizers as well as reducing agents, exhibited different antimicrobial activity as well as cytotoxicity which are crucial for their applications. In this paper, the antimicrobial screening of the selected systems is presented, which was determined by the broth microdilution method, and inhibitory influence on the production of monomicrobial and dual-species biofilm was evaluated. The potential mechanism of action of different systems is proposed. Additionally, the cytotoxicity of SeNPs was examined on the MRC-5 cell line, in the same concentration interval as for antimicrobial testing. It was shown that formulation SeNPs-BSA expressed a significantly lower cytotoxic effect than the other two formulations.

This study aimed to investigate outbreak with high mortality in cultured juvenile cobia occurred in Southeast Brazil in 2011. Fish displayed retarded growth rates, lethargy, fin ulceration, skin depigmentation, corneal opacity, and physical deformities. Internally, livers were increased in volume and pale in different degrees. Firm whitish nodules were disseminated in the liver, kidney and spleen. A moderate number of parasites identified as Neobenedenia melleni were recovered from the body surface. Microscopically, severe hepatic steatosis and extensive granulomatous lesion were identified in all fish sampled. Microbiological analysis of moribund fish revealed the presence in pure culture of a Gram-negative bacterium identified as Photobacterium damselae subsp. piscicida using biochemical and molecular characteristics. Analysis of the partial 16S rRNA sequences confirmed the results demonstrating high identity (98%). The isolates were sensitive to chloramphenicol and enrofloxacin and resistant to ciprofloxacin, florfenicol, doxycycline hydrochloride, norfloxacin, oxytetracycline, and tetracycline. Chronic pasteurellosis was considered as the main problem in the farm, while hepatic steatosis and parasitic infestation may have contributed to the development of the process.

The continental shelf of Brazil is home to a wide range of lobster species, with varying body size, color, habitat preference, and geographic and bathymetric distribution. Spiny lobsters (Panulirus) and slipper lobsters (Scyllaridae) are exploited for export and for the domestic market. Deep sea lobsters (Nephropidae and Polychelidae) have no commercial potential, and little is known about their biology. In this review, we identified 24 lobster species from benthic ecosystems off Brazil (Palinuridae 25%, Scyllaridae 29%, Nephropidae 25%, Polychelidae 17%, Enoplometopidae 4%). We designed a simplified theoretical scheme to understand the role of lobsters in the ecosystem, based on available evidence of distribution, biodiversity, life cycle, connectivity, and abundance. Finally, we propose a theoretical scheme of trophic top-down control, with interactions between a large decapod (spiny lobster), a demersal predator (red snapper), an apex predator (small tuna), benthic invertebrates and fishing exploitation.

Abstract Every year around 300 Gl of vinasse, a by-product of ethanol distillation in sugarcane mills, are flushed into more than 9 Mha of sugarcane cropland in Brazil. This practice links fermentation waste management to fertilization for plant biomass production, and it is known as fertirrigation. Here we evaluate public datasets of soil metagenomes mining for changes in antibiotic resistance genes (ARGs) of soils from sugarcane mesocosms repeatedly amended with vinasse. The metagenomes were annotated using the ResFam database. We found that the abundance of open read frames (ORFs) annotated as ARGs changed significantly across 43 different families (p-value

Objective: Adipose tissue relies on lipid droplet (LD) proteins in its role as a lipid-storing endocrine organ that controls whole body metabolism. Hypoxia-inducible Gene 2 (Hig2) is a recently identified LD-associated protein in hepatocytes that promotes hepatic lipid storage, but its role in the adipocyte had not been investigated. Here we tested the hypothesis that Hig2 localization to LDs in adipocytes promotes adipose tissue lipid deposition and systemic glucose homeostasis. Method: White and brown adipocyte-deficient (Hig2fl/fl × Adiponection cre+) and selective brown/beige adipocyte-deficient (Hig2fl/fl × Ucp1 cre+) mice were generated to investigate the role of Hig2 in adipose depots. Additionally, we used multiple housing temperatures to investigate the role of active brown/beige adipocytes in this process. Results: Hig2 localized to LDs in SGBS cells, a human adipocyte cell strain. Mice with adipocyte-specific Hig2 deficiency in all adipose depots demonstrated reduced visceral adipose tissue weight and increased glucose tolerance. This metabolic effect could be attributed to brown/beige adipocyte-specific Hig2 deficiency since Hig2fl/fl × Ucp1 cre+ mice displayed the same phenotype. Furthermore, when adipocyte-deficient Hig2 mice were moved to thermoneutral conditions in which non-shivering thermogenesis is deactivated, these improvements were abrogated and glucose intolerance ensued. Adipocyte-specific Hig2 deficient animals displayed no detectable changes in adipocyte lipolysis or energy expenditure, suggesting that Hig2 may not mediate these metabolic effects by restraining lipolysis in adipocytes. Conclusions: We conclude that Hig2 localizes to LDs in adipocytes, promoting adipose tissue lipid deposition and that its selective deficiency in active brown/beige adipose tissue mediates improved glucose tolerance at 23 °C. Reversal of this phenotype at thermoneutrality in the absence of detectable changes in energy expenditure, adipose mass, or liver triglyceride suggests that Hig2 deficiency triggers a deleterious endocrine or neuroendocrine pathway emanating from brown/beige fat cells. Keywords: Obesity, Adipocyte, Lipid droplet, Lipolysis, Hypoxia-inducible gene 2 (Hig2)

The ichthyotoxic dinoflagellate Karlodinium veneficum has a worldwide distribution and produces highly potent lytic toxins (karlotoxins) that have been associated with massive fish kill events in coastal environments. The capacity of K. veneficum to gain energy from photosynthesis as well as phagotrophy enables cellular maintenance, growth and dispersal under a broad range of environmental conditions. Coastal ecosystems are highly dynamic in light of the prevailing physicochemical conditions, such as seawater carbonate speciation (CO2, HCO3−, and CO32−) and pH. Here, we monitored the growth rate and ichthyotoxicity of K. veneficum in response to a seawater pH gradient. K. veneficum exhibited a significant linear reduction in growth rate with elevated seawater acidity [pH(totalscale) from 8.05 to 7.50]. Ichthyotoxicity was assessed by exposing fish gill cells to K. veneficum extracts and subsequent quantification of gill cell viability via resorufin fluorescence. Extracts of K. veneficum indicated increased toxicity when derived from elevated pH treatments. The variation in growth rate and toxin production per cell in regard to seawater pH implies that (1) future alteration of seawater carbonate speciation, due to anthropogenic ocean acidification, may negatively influence physiological performance and ecosystem interactions of K. veneficum and (2) elevated seawater pH values (>8.0) represent favorable conditions for K. veneficum growth and toxicity. This suggests that prey of K. veneficum may be exposed to increased karlotoxin concentrations at conditions when nutrients are scarce and seawater pH has been elevated due to high photosynthetic activity from prior autotrophic phytoplankton blooms.

Background: Effective assessments programs are a challenge in problem-based learning (PBL). One of the main principles of this educational setting is the Formative Assessment (FA). We hypothesized that students’ performance assessed by FA in tutorial sessions in a PBL curriculum is related to other summative assessments. Objective: To investigate the correlation among FA in tutorial sessions with grades obtained in Objective Structured Clinical Evaluation (OSCE) and Progress Testing (PT) to better understand the assessment process in PBL medical teaching approach and to predict student’s future performance. Design: An observational cross-sectional study was conducted comparing FA, OSCE and PT scores from 4th to 8th semester medical students. Correlation analyses were performed using pooled and separate data from the 4th and 8th semesters. Results: From the 5th to 8th semester, OSCE scores were smaller compared to the FA, while PT scores were lower in all stages. In the pooled data, the correlation analysis showed a significant positive relationship between grades on FA and OSCE, FA and PT and OSCE and PT. A significant correlation among the three assessments strategies was also detected in the 8th semester, but not in the 4th semester. Conclusions: Assessment strategies in PBL approach, including FA, OSCE and PT, have positive correlations, which increases as the medical course becomes more complex.

TiO2/SiO2 nanoparticles with 3, 5, and 10 molar percent of silica, were synthesized by hydrothermal method and characterized by SEM, TEM, N2 adsorption-desorption isotherms, X-ray diffraction, and Raman and UV-Vis spectroscopy. While pristine TiO2 thermally treated at 500°C presents a surface area of 36 m2 g-1 (±10 m2 g-1), TiO2/SiO2 containing 3, 5, and 10 molar percent of silica present surface areas of 93, 124, and 150 m2 g-1 (±10 m2 g-1), respectively. SiO2 is found to form very small amorphous domains well dispersed in the TiO2 matrix. X-ray diffraction and Raman spectroscopy data show that anatase-to-rutile phase transition temperature is delayed by the presence of SiO2, enabling single-anatase phase photoanodes for DSSCs. According to the I×V measurements, photoanodes with 3% of SiO2 result in improved efficiency, which is mainly related to increased surface area and dye loading. In addition, the results suggest a gain in photocurrent related to the passivation of defects by SiO2.

Pr3+-doped Y2O3 nanocrystals (NCs) have been obtained via five wet-chemistry synthesis methods which were optimized in order to achieve superior optical properties. To this end, a systematic study on the influence of different reaction parameters was performed for each procedure. Specifically, precursor concentration, reaction temperature, calcination temperature, and time, among others, were analyzed. The synthesized Y2O3: Pr3+ NCs were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), powder X-ray diffraction (PXRD), transmission electron microscopy (TEM), and reflectance and Raman spectroscopy. In addition, the optical properties of such NCs were investigated by excitation, emission, and luminescence decay measurements. Concretely, emission from the 1D2 level was detected in all samples, while emission from 3PJ was absent. Finally, the effect of the synthesis methods and the reaction conditions on the luminescence decay has been discussed, and a comparative study of the different methods using the fluorescence lifetime of so-obtained Y2O3: Pr3+ NCs as a figure of merit has been carried out.

Abstract Objective: To examine the validity and impact of record linkage using name code compared to full name records. Methods: A registry of 45,419 opioid substitution clients (1985–2007) was linked with national population‐based death and cancer registries using registrant's name, date of birth, sex, state, postcode and date of death. Records were linked using full name and then using the first two letters of the given and surname (2×2 name code). Sensitivity and specificity were computed and regression analysis used to identify factors related to linkage accuracy. Standardised mortality ratios (SMR) and standardised cancer incidence ratios (SIR) were estimated. Results: The sensitivity and specificity of name code compared to full name linkage were 65.31% and 99.91% for death records and 76.81% and 99.89% for cancer records. Registrants' age and sex and accuracy of the registries were associated with risk of false linkages. Death and cancer risks (SMR 6.98, 95%CI 6.77–7.19; SIR 1.16, 95%CI 1.08–1.24) were significantly under‐estimated using name code linkage (SMR 4.39, 95%CI 4.23–4.56; SIR 0.92, 95%CI 0.85–0.99). Conclusion: Record linkage using 2×2 name code has low sensitivity but high specificity, resulting in conservative estimates of death and cancer risk. This may translate to meaningful differences in outcomes.

Objective. The study aimed to investigate the effectiveness of glyceryl guaiacolate ether (GGE) and compare the times of induction, recovery, hematological changes, total protein and glycaemia among anesthetics in Nile tilapia, Oreochromis niloticus. Materials and methods. A total of 60 tilapia distributed in 3 aquariums (N=20) were used, which formed the group benzocaine (100 mg/L), eugenol (50 mg/L) and guaiacol glyceryl ether (9.000 mg/L). After the induction of anesthesia fish blood samples were collected to determine the complete hemogram and glycemia. Then the animals were placed in aquariums with running water for assessing the anesthesia recovery. Results. It was verified that GGE showed longer induction and recovery times as well a significant increase (p0.05). An increase in the number of monocytes in the group treated with benzocaine (p

UVA affects epidermal cell physiology in a complex manner, but the harmful effects have been studied mainly in terms of DNA damage, mutagenesis and carcinogenesis. We investigated UVA effects on membrane integrity and antioxidant defense of dysplastic keratinocytes after one and two hours of irradiation, both immediately after exposure, and 24 h post-irradiation. To determine the UVA oxidative stress on cell membrane, lipid peroxidation was correlated with changes in fatty acid levels. Membrane permeability and integrity were assessed by propidium iodide staining and lactate dehydrogenase release. The effects on keratinocyte antioxidant protection were investigated in terms of catalase activity and expression. Lipid peroxidation increased in an exposure time-dependent manner. UVA exposure decreased the level of polyunsaturated fatty acids, which gradually returned to its initial value. Lactate dehydrogenase release showed a dramatic loss in membrane integrity after 2 h minimum of exposure. The cell ability to restore membrane permeability was noted at 24 h post-irradiation (for one hour exposure). Catalase activity decreased in an exposure time-dependent manner. UVA-irradiated dysplastic keratinocytes developed mechanisms leading to cell protection and survival, following a non-lethal exposure. The surviving cells gained an increased resistance to apoptosis, suggesting that their pre-malignant status harbors an abnormal ability to control their fate.

O tamanho do corpo dos organismos representa um parâmetro importante, podendo gerar consequências na sua ecologia, atividades reprodutivas, evolução e desenvolvimento. Relação alométrica é o estudo do tamanho (ou do crescimento) de uma parte do corpo relacionado com o tamanho (ou crescimento) total do corpo do organismo. Este estudo analisou a relação alométrica entre as fêmeas de Podocnemis unifilis (Troschel, 1848) e seus ovos e filhotes e entre as características dos ninhos e a ninhada em uma área de várzea do baixo rio Amazonas, estado do Pará, Brasil. As ninhadas de P. unifilis foram monitoradas no Tabuleiro da Água Preta durante o período reprodutivo de 2009. As fêmeas encontradas desovando foram medidas e seus respectivos ninhos marcados com estacas numeradas e as características físicas mensuradas. Os ovos e filhotes destes ninhos foram retirados e contados, e tiveram seus dados biométricos tomados. Os parâmetros das fêmeas analisados (comprimento retilíneo da carapaça e massa) correlacionaram-se fortemente às variáveis dos ovos (variável x) e filhotes (variável y), exceto com o comprimento do ovo e com a massa do filhote. Estudos futuros direcionados para melhor compreensão de como as características ambientais influenciam nas ninhadas podem ser aplicados, sendo úteis no manejo da espécie.

Six β-hydroxy-β-aryl propanoic acids were synthesised using a modification of Reformatsky reaction which has already been reported. These acids belong to the aryl propanoic acid class of compounds, structurally similar to the NSAIDs, such as ibuprofen, and an anti-inflammatory activity is thus expected. The aim of this work was to determine anti-inflammatory activity, examine gastric tolerability, and to carry out molecular docking experiments to identify potential COX-2 inhibitors among the β-hydroxy-β-aryl propanoic acids, and to elucidate the effect α-methyl substitution on the anti-inflammatory activity. Anti-inflammatory activity and gastric tolerability were determined on rats using carragenan induced paw oedema method, and docking studies were carried out using Autodock v4.0.1. The range of ED50 values is between 127 µmol/kg and 15 µmol/kg, while the result for ibuprofen is 51.7 µmol/kg. Only slight hyperaemia or few petechiae were spotted on rat’s stomach. The results indicate that all compounds possess significant anti-inflammatory activity after oral administration, and that 2-methyl-3-hydroxy-3,3-diphenyl-propanoic acid has greatest activity, surpassing that of ibuprofen, a standard NSAID. Another compound, 3-hydroxy-3,3-diphenylpropanoic acid, shows activity matching that of ibuprofen, and is non-chiral and is proven to be non-toxic. The most of investigated compounds have interactions with P3 anchor site like COX-2 selective inhibitors. No tested substances or ibuprofen produced any significant gastric lesions.

UVA radiation induces multiple and complex changes in the skin, affecting epidermal cell behavior. This study reports the effects of UVA exposure on normal (HaCaT) and dysplastic (DOK) keratinocytes. The adherence, spreading and proliferation were investigated by time-lapse measurement of cell layer impedance on different matrix proteins. Prior to UVA exposure, the time required for adherence and spreading did not differ significantly for HaCaT and DOK cells, while spreading areas were larger for HaCaT cells. Under UVA exposure, HaCaT and DOK cells behavior differed in terms of movement and proliferation. The cells’ ability to cover the denuded surface and individual cell trajectories were recorded by time-lapse videomicroscopy, during wound healing experiments. Dysplastic keratinocytes showed more sensitivity to UVA, exhibiting transient deficiencies in directionality of movement and a delay in re-coating the denuded area. The actin cytoskeleton displayed a cortical organization immediately after irradiation, in both cell lines, similar to mock-irradiated cells. Post-irradiation, DOK cells displayed a better organization of stress fibers, persistent filopodia, and new, stronger focal contacts. In conclusion, after UVA exposure HaCaT and DOK cells showed a different behavior in terms of adherence, spreading, motility, proliferation, and actin cytoskeleton dynamics, with the dyplastic keratinocytes being more sensitive.

The largest diasporic exodus fanning out of mainland China took place in the context of the immense turmoil, turbulence, suffering, and pauperization of the masses from late 19th to early 20th centuries. Today, over 24 million diasporic Chinese and ethnic Chinese are spread across Southeast Asia in Philippines, Malaysia, Brunei, Singapore, Thailand, Vietnam, Cambodia, Myanmar and Laos, Indonesia, and Timor-Lester.  The first generation (G1) diasporic Chinese came to Southeast Asia with the mentality of sojourners because their emigration was self-imposed and for survival, fueled by the astounding historical, social, political, and economic circumstances of the times. Giving and generosity naturally follows back to motherland; it was focused on “giving back to China and loyalty to motherland”. The longstanding heritage in these cultures holds strength in the ethos of the “heart” when it comes to beneficence and philanthropy. The next generation (G2 now born outside of China) began to recognize that the success of their family businesses was dependent on resources, access to networks, and social norms of these local communities, outside of China. We begin to see flexibility in identifying with local communities since their stakes as Nationals are now becoming evident.  After WWII, and the realities of a closed-door policy in China from 1949-1978, their vision of retiring back in China became less and less viable. It forced many already outside of China to shed their sojourner mentality. Impulses of the “heart” are soon quickly checked by rational prudence of the “head”. In the lands they have just adopted as their new homes, they quickly assimilate, advocate, and find resources for their own survival – including continued re-migration until families found the most suitable location to settle. Naturally, this leads to multiple loyalties over a lifetime. To assimilate and optically appear to be “local”, their philanthropy is often used as a platform to affirm their identity as Nationals. Without the “motherland memory” to fall back on, future generations will likely reduce their giving to their parents’ country of origin.More recently, globalization, information/digital age, social media have all converged to redefine human connectivity, ease of travel, social-political dynamics, and more. Entities in the diasporic world are now hybridized – thriving on flexible identities and multiple loyalties. Current generations from the original diasporic Chinese are now more “transnational” Chinese than diasporic. However, this hybridity is contextual or versatile in different social settings. As they become westernized or secular in lifestyle, education, ethos, and religion, there will come the time when they cease to “give back” to their parents’ or grandparents’ homeland.  Their choices in philanthropy follows the contextual mutation of their own Chineseness and evolution of flexible identities and multiple loyalties through religion, lifestyles, ethics, worldviews, and localized social norms.