Assessment of the Activity of Nitroisoxazole Derivatives against Trypanosoma cruzi.

The development of new compounds to treat Chagas disease is imperative due to the adverse effects of current drugs and their low efficacy in the chronic phase. This study aims to investigate nitroisoxazole derivatives that produce oxidative stress while modifying the compounds' lipophilicity, affecting their ability to fight trypanosomes. The results indicate that these compounds are more effective against the epimastigote form of T. cruzi, with a 52 ± 4% trypanocidal effect for compound 9. However, they are less effective against the trypomastigote form, with a 15 ± 3% trypanocidal effect. Additionally, compound 11 interacts with a higher number of amino acid residues within the active site of the enzyme cruzipain. Furthermore, it was also found that the presence of a nitro group allows for the generation of free radicals; likewise, the large size of the compound enables increased interaction with aminoacidic residues in the active site of cruzipain, contributing to trypanocidal activity. This activity depends on the size and lipophilicity of the compounds. The study recommends exploring new compounds based on the nitroisoxazole skeleton, with larger substituents and lipophilicity to enhance their trypanocidal activity.

Sensitivities of heat-wave mortality projections: Moving towards stochastic model assumptions.

This paper analyses the probabilistic future behaviour of heat-waves (HWs) in the city of Madrid in the twenty-first century, using maximum daily temperatures from twenty-one climate circulation models under two representative concentration pathways (RCP 8.5 & RCP 4.5). HWs are modelled considering three factors: number per annum, duration and intensity, characterised by three stochastic processes: Poisson, Gamma and truncated Gaussian, respectively. Potential correlations between these processes are also considered. The probabilistic temperature behaviour is combined with an epidemiological model with stochastic mortality risk following a generalized extreme value distribution (gev). The objective of this study is to obtain probability distributions of mortality and risk measures such as the mean value of the 5% of worst cases in the 21st century, in particular from 2025 to 2100. Estimates from stochastic models for characterising HWs and epidemiological impacts on human health can vary from one climate model to another, so relying on a single climate model can be problematic. For this reason, the calculations are carried out for 21 models and the average of the results is obtained. A sensitivity adaptation analysis is also performed. Under RCP 8.5 for 2100 for Madrid city a mean excess of 3.6 °C over the 38 °C temperature threshold is expected as the average of all models, with an expected attributable mortality of 1614 people, but these figures may be substantially exceeded in some cases if the highest-risk cases occur.

Polyphenolic Composition and Antioxidant Activity (ORAC, EPR and Cellular) of Different Extracts of Argylia radiata Vitroplants and Natural Roots.

Plant biochemistry studies have increased in recent years due to their potential to improve human health. Argylia radiata is an extremophile plant with an interesting polyphenolic profile. However, its biomass is scarce and occasionally available. Argylia in vitro biomass was obtained from tissue culture and compared with in vivo roots regarding its polyphenolic and flavonoid content. Different solvents were used to prepare extracts from the in vitro tissue of callus and aerial plant organs and in vivo roots. UPLC-MS/MS was used to assess the chemical composition of each extract. ORAC-FL and scavenging of free radicals (DPPH and OH) methods were used to determine the antioxidant capacity of extracts. Furthermore, the biological activity of the extracts was established using the cellular antioxidant activity method. The vitroplants were a good source of polyphenols (25-68 mg GAE/100 g tissue FW), and methanol was the most efficient solvent. Eight polyphenolic compounds were identified, and their antioxidant properties were investigated by different chemical methods with EPR demonstrating its specific scavenging activity against free radicals. All extracts showed cellular dose-dependent antioxidant activity. The methanolic extract of vitroplants showed the highest cellular antioxidant activity (44.6% and 51%) at 1 and 10 µg/mL of extract, respectively. Vitroplants of A. radiata are proposed as a biotechnological product as a source of antioxidant compounds with multiple applications.

Dependence of the Ripeness Stage on the Antioxidant and Antimicrobial Properties of Walnut (Juglans regia L.) Green Husk Extracts from Industrial By-Products.

Walnut green husk (WGH) is a waste generated by the walnut (Juglans regia L.) harvest industry. It represents a natural source of polyphenols, compounds with antioxidant and antimicrobial activities, but their activity could be dependent on the ripeness stage of the raw material. In this study, the effect of the different ripeness stages-open (OH) and closed (CH) husks-on the antioxidant and antimicrobial properties of WGH extracts were analyzed, emphasizing the influence of the extracts in inhibiting Escherichia coli growth. The ripeness stage of WGH significantly affected the antioxidant activity of the extracts. This was attributed to the different polyphenol profiles related to the mechanical stress when the husk opened compared to the closed sample. The antimicrobial activity showed inhibition of E. coli growth. OH-extracts at 96 µg/mL caused the lowest specific growth rate (µmax = 0.003 h-1) and the greatest inhibition percentage (I = 93%) compared to CH-extract (µmax = 0.01 h-1; I = 69%). The obtained results showed the potential of the walnut green husk, principally open husk, as an economical source of antioxidant and antimicrobial agents with potential use in the food industry.

Proangiogenic Effect of Affinin and an Ethanolic Extract from Heliopsis longipes Roots: Ex Vivo and In Vivo Evidence.

Angiogenesis, the formation of new blood vessels, underlies tissue development and repair. Some medicinal plant-derived compounds can modulate the angiogenic response. Heliopsis longipes, a Mexican medicinal plant, is widely used because of its effects on pain and inflammation. The main bioactive phytochemicals from H. longipes roots are alkamides, where affinin is the most abundant. Scientific studies show various medical effects of organic extracts of H. longipes roots and affinin that share some molecular pathways with the angiogenesis process, with the vasodilation mechanism of action being the most recent. This study investigates whether pure affinin and the ethanolic extract from Heliopsis longipes roots (HLEE) promote angiogenesis. Using the aortic ring rat assay (ex vivo method) and the direct in vivo angiogenesis assay, where angioreactors were implanted in CD1 female mice, showed that affinin and the HLEE increased vascular growth in a dose-dependent manner in both bioassays. This is the first study showing the proangiogenic effect of H. longipes. Further studies should focus on the mechanism of action and its possible therapeutic use in diseases characterized by insufficient angiogenesis.

Impact of Receiving Secondary Results from Genomic Research: A 12-Month Longitudinal Study.

The impact of returning secondary results from exome sequencing (ES) on patients/participants is important to understand as ES is increasingly utilized in clinical care and research. Participants were recruited from studies using ES and were separated into two arms: 107 who had ES and were offered the choice to learn secondary results (ES group) and 85 who had not yet had ES (No ES group). Questionnaires were administered at baseline and 1 and 12 months, following results disclosure (ES group) or enrollment (No ES group). While the majority (65%) elected to learn all results following pre-test counseling, it was reduced from the 76% who indicated a desire for all results at baseline. Thirty-seven percent received results associated with an increased personal disease risk. There were no differences in changes in any of the psychological and social measures from baseline to post-results disclosure between the ES and No ES groups. Receiving a wide range of secondary findings appeared to have little measurable impact on most participants. The experience of learning secondary results may be related to participants' previous experiences with genetics, as well as the genetic counseling provided. Future research with a more diverse, genetically naïve group, as well as scalable methods of delivery, is needed.

Synthesis and Properties of Tin Sulfide Thin Films from Nanocolloids Prepared by Pulsed Laser Ablation in Liquid.

Tin sulfide (SnS) nanoparticles were synthesized by pulsed laser ablation in liquid (PLAL) technique using an Nd:YAG laser operated at 532 nm. SnS thin films were deposited by spraying the colloidal suspension onto the heated substrates. The influence of different liquid media (dimethyl formamide and isopropyl alcohol) on the thin film properties were studied. Morphology, crystalline structure, and chemical composition of the nanoparticles were identified using transmission electron microscopy with energy dispersive X-ray analysis. The crystalline structure of the thin films was analyzed by using grazing incidence X-ray diffraction, and the chemical states by X-ray photoelectron spectroscopy. Scanning electron microscopy was employed for the morphological analysis of the thin films. Annealing the films at 380 °C improved the crystallinity of the films exhibiting a layered morphology, which may be useful in optoelectronic and sensing applications. Cyclic voltammetry studies showed that the films have good electrochemical properties.

Research Participants' Preferences for Hypothetical Secondary Results from Genomic Research.

Secondary or incidental results can be identified in genomic research that increasingly uses whole exome/genome sequencing. Understanding research participants' preferences for secondary results and what influences these decisions is important for patient education, counseling, and consent, and for the development of policies regarding return of secondary results. Two hundred nineteen research participants enrolled in genomic studies were surveyed regarding hypothetical preferences for specific types of secondary results, and these preferences were correlated with demographic information and psychosocial data. The majority of research participants (73%) indicated a preference to learn about all results offered, with no clear pattern regarding which results were not desired by the remaining participants. Participants who reported greater interest in genetic privacy were less likely to indicate a preference to learn all results, as were individuals who self-identified as Jewish. Although most research participants preferred to receive all secondary results offered, a significant subset preferred to exclude some results, suggesting that an all-or-none policy would not be ideal for all participants. The correlations between preferences to receive secondary results, religious identification, and privacy concerns demonstrate the need for culturally sensitive counseling and educational materials accessible to all education levels to allow participants to make the best choices for themselves.

Phaseolus acutifolius Lectin Fractions Exhibit Apoptotic Effects on Colon Cancer: Preclinical Studies Using Dimethilhydrazine or Azoxi-Methane as Cancer Induction Agents.

Phaseolus acutifolius (Tepary bean) lectins have been studied as cytotoxic molecules on colon cancer cells. The toxicological profile of a Tepary bean lectin fraction (TBLF) has shown low toxicity in experimental animals; exhibiting anti-nutritional effects such as a reduction in body weight gain and a decrease in food intake when using a dose of 50 mg/kg on alternate days for six weeks. Taking this information into account, the focus of this work was to evaluate the effect of the TBLF on colon cancer using 1,2-dimethylhydrazine (DMH) or azoxy-methane/dextran sodium sulfate (AOM/DSS) as colon cancer inductors. Rats were treated with DMH or AOM/DSS and then administered with TBFL (50 mg/kg) for six weeks. TBLF significantly decreased early tumorigenesis triggered by DMH by 70%, but without any evidence of an apoptotic effect. In an independent experiment, AOM/DSS was used to generate aberrant cryptic foci, which decreased by 50% after TBLF treatment. TBLF exhibited antiproliferative and proapoptotic effects related to a decrease of the signal transduction pathway protein Akt in its activated form and an increase of caspase 3 activity, but not to p53 activation. Further studies will deepen our knowledge of specific apoptosis pathways and cellular stress processes such as oxidative damage.

Researchers' views on informed consent for return of secondary results in genomic research.

PURPOSE: Previous studies have suggested that genomic investigators generally favor offering to return at least some secondary findings to participants and believe that participants' preferences should determine the information they receive. We surveyed investigators to ascertain their views on four models of informed consent for this purpose: traditional consent, staged consent, mandatory return, and outsourced consent. METHODS: We performed an online survey of the views regarding return of secondary results held by 198 US genetic researchers drawn from our subject pool for an earlier study. Potential participants were identified through the National Institutes of Health RePORTER database and abstracts from the 2011 American Society of Human Genetics meeting. RESULTS: Under circumstances in which resource constraints are not an issue, approximately a third of respondents would endorse either staged consent or traditional consent; outsourced consent and mandatory return are favored by only a small minority. However, taking resource constraints into account, roughly half the sample would favor traditional consent, with support for staged consent dropping to 13%. CONCLUSION: Despite their liabilities, traditional approaches to consent are seen as the most viable under current circumstances. However, there is considerable interest in staged consent, assuming the infrastructure to support it can be provided.

Association of Researcher Characteristics with Views on Return of Incidental Findings from Genomic Research.

Whole exome/ genome sequencing (WES/WGS) is now commonly used in research and is increasingly used in clinical care to identify the genetic basis of rare and unknown diseases. The management of incidental findings (IFs) generated through these analyses is debated within the research community. To examine how views regarding genomic research IFs are associated with researcher characteristics and experiences, we surveyed genetic professionals and assessed the effect of professional background and experience on their opinions. Researchers who did not have clinical training, provide clinical care to research participants, or have prior experience returning research results were in general more inclined to offer return of IFs than their colleagues with these characteristics. Understanding this will be important to fully appreciate the impact that policies on return of genetic IFs could have on participants, researchers, and genomic research.

Position-specific anthropometry and throwing velocity of elite female water polo players.

This study was conducted with the following aims: (a) to describe the effect of playing position on anthropometrics and throwing velocity in elite female water polo players and (b) to observe any relationships between anthropometric parameters and throwing velocity. To achieve these aims, we analyzed a total of 46 female elite players (age: 22.5 ± 5.1 years; height: 172.0 ± 6.9 cm, body mass: 67.4 ± 7.5 kg) members of the top 4 teams of the Spanish Honour Division women league (21 offensive wings players, 17 center, and 8 goalkeepers). Wings were significantly shorter and had smaller arm spans than goalkeepers and center players. Goalkeepers demonstrated longer forearm lengths than wing and center players. No other significant differences were evident between positions in terms of anthropometric, strength, or throwing velocity variables The somatotype of the offensive wing players was mesomorphic, whereas centers were endomorph (classified as endomesomorphic). Height, arm span, muscular mass, biepicondylar breadth of the humerus, arm girth (relaxed and tensed), and forearm girth were related to throwing velocity. In conclusion, only a small number of anthropometric differences exist between players of different positions in elite female water polo. Shorter players with smaller arm spans may be better suited to the wings, whereas athletes with longer forearms may be better suited to the goalkeeper position. Taller, more muscular athletes with wider arm spans, broader humeri, and wider arms (relaxed and flexed) tended to throw with increased velocity. Trainers should focus on increasing the modifiable characteristics (muscle mass and arm girths) that contribute to throwing velocity in this population.

Informed consent for return of incidental findings in genomic research.

PURPOSE: Researchers face the dilemma of how to obtain consent for return of incidental findings from genomic research. We surveyed and interviewed investigators and study participants, with the goal of providing suggestions for how to shape the consent process. METHODS: We performed an online survey of 254 US genetic researchers identified through the NIH RePORTER database, abstracts from the 2011 American Society of Human Genetics meeting, and qualitative semi-structured interviews with 28 genomic researchers and 20 research participants. RESULTS: Most researchers and participants endorsed disclosure of a wide range of information about return of incidental findings, including risks, benefits, impact on family members, data security, and procedures, for return of results in the event of death or incapacity and for recontact. However, most researchers were willing to devote 30 min or less to this process and expressed concerns that disclosed information would overwhelm participants, a concern shared by many participants themselves. CONCLUSION: There is a disjunction between the views of investigators and participants about the amount of information that should be disclosed and the practical realities of the research setting, including the time available for consent discussions. This strongly suggests the need for innovative approaches to the informed consent process.

Models of consent to return of incidental findings in genomic research.

Genomic research-including whole genome sequencing and whole exome sequencing-has a growing presence in contemporary biomedical investigation. The capacity of sequencing techniques to generate results that go beyond the primary aims of the research-historically referred to as "incidental findings"-has generated considerable discussion as to how this information should be handled-that is, whether incidental results should be returned, and if so, which ones.Federal regulations governing most human subjects research in the United States require the disclosure of "the procedures to be followed" in the research as part of the informed consent process. It seems reasonable to assume-and indeed, many commentators have concluded-that genomic investigators will be expected to inform participants about, among other procedures, the prospect that incidental findings will become available and the mechanisms for dealing with them. Investigators, most of whom will not have dealt with these issues before, will face considerable challenges in framing meaningful disclosures for research participants.To help in this task, we undertook to identify the elements that should be included in the informed consent process related to incidental findings. We did this by surveying a large number of genomic researchers (n = 241) and by conducting in-depth interviews with a smaller number of researchers (n = 28) and genomic research participants (n = 20). Based on these findings, it seems clear to us that routine approaches to informed consent are not likely to be effective in genomic research in which the prospect of incidental findings exists. Ensuring that participants' decisions are informed and meaningful will require innovative approaches to dealing with the consent issue. We have identified four prototypical models of a consent process for return of incidental findings.

Cardiac Sympathetic Denervation as a Treatment for Ventricular Arrhythmias Refractory to Conventional Treatment: A Case Series.

Background: Ventricular arrhythmias are a leading cause of sudden death. The objective of this study was to characterise the results of patients with ventricular arrhythmias refractory to standard medical management, undergoing Video-assisted thoracoscopic cardiac sympathetic denervation (VAT-CSD) during 2012-2022 in Cali, Colombia. Methods: This was an observational retrospective study, using the Institutional General Thoracic Surgery Database for patient identification and retrospectively reviewing the clinical charts for data description and analysis. Results: Clinical records of 19 patients who underwent VAT-CSD for ventricular arrhythmia were analysed. The patients were predominantly male (73.7%) with an mean age of 62 years. Ischaemic heart disease was the main underlying condition (52.6%); all individuals had a diagnosis of heart failure, with comorbidities such as hypertension (63.1%), acute MI (57.8%) and diabetes (26.3%) also present. The procedure was performed bilaterally in 89.4% of cases and was successful with minimal perioperative complications. Postoperative follow-up showed improvement in symptoms, including a significant reduction in the number of ICD shocks and emergency department visits. Conclusion: VAT-CSD is a viable, safe and palliative therapeutic option for patients with ventricular arrhythmias who have not responded to conventional treatments, achieving a significant decrease in symptoms with low mortality and perioperative complications.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase I Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Researchers' views on return of incidental genomic research results: qualitative and quantitative findings.

PURPOSE: Comprehensive genomic analysis including exome and genome sequencing is increasingly being utilized in research studies, leading to the generation of incidental genetic findings. It is unclear how researchers plan to deal with incidental genetic findings. METHODS: We conducted a survey of the practices and attitudes of 234 members of the US genetic research community and performed qualitative semistructured interviews with 28 genomic researchers to understand their views and experiences with incidental genetic research findings. RESULTS: We found that 12% of the researchers had returned incidental genetic findings, and an additional 28% planned to do so. A large majority of researchers (95%) believe that incidental findings for highly penetrant disorders with immediate medical implications should be offered to research participants. However, there was no consensus on returning incidental results for other conditions varying in penetrance and medical actionability. Researchers raised concerns that the return of incidental findings would impose significant burdens on research and could potentially have deleterious effects on research participants if not performed well. Researchers identified assistance needed to enable effective, accurate return of incidental findings. CONCLUSION: The majority of the researchers believe that research participants should have the option to receive at least some incidental genetic research results.

Moist and warm conditions in Eurasia during the last glacial of the Middle Pleistocene Transition.

The end of the Middle Pleistocene Transition (MPT, ~ 800-670 thousand years before present, ka) was characterised by the emergence of large glacial ice-sheets associated with anomalously warm North Atlantic sea surface temperatures enhancing moisture production. Still, the direction and intensity of moisture transport across Eurasia towards potential ice-sheets is poorly constrained. To reconstruct late MPT moisture production and dispersal, we combine records of upper ocean temperature and pollen-based Mediterranean forest cover, a tracer of westerlies and precipitation, from a subtropical drill-core collected off South-West Iberia, with records of East Asia summer monsoon (EASM) strength and West Pacific surface temperatures, and model simulations. Here we show that south-western European winter precipitation and EASM strength reached high levels during the Marine Isotope Stage 18 glacial. This anomalous situation was caused by nearly-continuous moisture supply from both oceans and its transport to higher latitudes through the westerlies, likely fuelling the accelerated expansion of northern hemisphere ice-sheets during the late MPT.

Capsaicinoids and Their Effects on Cancer: The "Double-Edged Sword" Postulate from the Molecular Scale.

Capsaicinoids are a unique chemical species resulting from a particular biosynthesis pathway of hot chilies (Capsicum spp.) that gives rise to 22 analogous compounds, all of which are TRPV1 agonists and, therefore, responsible for the pungency of Capsicum fruits. In addition to their human consumption, numerous ethnopharmacological uses of chili have emerged throughout history. Today, more than 25 years of basic research accredit a multifaceted bioactivity mainly to capsaicin, highlighting its antitumor properties mediated by cytotoxicity and immunological adjuvancy against at least 74 varieties of cancer, while non-cancer cells tend to have greater tolerance. However, despite the progress regarding the understanding of its mechanisms of action, the benefit and safety of capsaicinoids' pharmacological use remain subjects of discussion, since CAP also promotes epithelial-mesenchymal transition, in an ambivalence that has been referred to as "the double-edge sword". Here, we update the comparative discussion of relevant reports about capsaicinoids' bioactivity in a plethora of experimental models of cancer in terms of selectivity, efficacy, and safety. Through an integration of the underlying mechanisms, as well as inherent aspects of cancer biology, we propose mechanistic models regarding the dichotomy of their effects. Finally, we discuss a selection of in vivo evidence concerning capsaicinoids' immunomodulatory properties against cancer.

Last glacial hydroclimate variability in the Yucatán Peninsula not just driven by ITCZ shifts.

We reconstructed hydroclimate variability in the Yucatán Peninsula (YP) based on stalagmite oxygen and carbon isotope records from a well-studied cave system located in the northeastern YP, a region strongly influenced by Caribbean climate dynamics. The new stalagmite isotopic records span the time interval between 43 and 26.6 ka BP, extending a previously published record from the same cave system covering the interval between 26.5 and 23.2 ka BP. Stalagmite stable isotope records show dominant decadal and multidecadal variability, and weaker variability on millennial timescales. These records suggest significant precipitation declines in the broader Caribbean region during Heinrich events 4 and 3 of ice-rafted discharge into the North Atlantic, in agreement with the antiphase pattern of precipitation variability across the equator suggested by previous studies. On millennial timescales, the stalagmite isotope records do not show the distinctive saw-tooth pattern of climate variability observed in Greenland during Dansgaard-Oeschger (DO) events, but a pattern similar to North Atlantic sea surface temperature (SST) variability. We propose that shifts in the mean position of the Intertropical Convergence Zone (ITCZ), per se, are not the dominant driver of last glacial hydroclimate variability in the YP on millennial timescales but instead that North Atlantic SSTs played a dominant role. Our results support a negative climate feedback mechanism whereby large low latitude precipitation deficits resulting from AMOC slowdown would lead to elevated salinity in the Caribbean and ultimately help reactivate AMOC and Caribbean precipitation. However, because of the unique drivers of future climate in the region, predicted twenty-first century YP precipitation reductions are unlikely to be modulated by this negative feedback mechanism.