Analysis of the Behavior of Deep Eutectic Solvents upon Addition of Water: Its Effects over a Catalytic Reaction.

This study presents the potential role of deep eutectic solvents (DESs) in a lipase-catalyzed hydrolysis reaction as a co-solvent in an aqueous solution given by a phosphate buffer. Ammonium salts, such as choline chloride, were paired with hydrogen bond donors, such as urea, 1,2,3-propanetriol, and 1,2 propanediol. The hydrolysis of p-nitrophenyl laureate was carried out with the lipase Candida antarctica Lipase B (CALB) as a reaction model to evaluate the solvent effect and tested in different DES/buffer phosphate mixtures at different % w/w. The results showed that two mixtures of different DES at 25 % w/w were the most promising solvents, as this percentage enhanced the activities of CALB, as evidenced by its higher catalytic efficiency (kcatKM). The solvent analysis shows that the enzymatic reaction requires a reaction media rich in water molecules to enable hydrogen-bond formation from the reaction media toward the enzymatic reaction, suggesting a better interaction between the substrate and the enzyme-active site. This interaction could be attributed to high degrees of freedom influencing the enzyme conformation given by the reaction media, suggesting that CALB acquires a more restrictive structure in the presence of DES or the stabilized network given by the hydrogen bond from water molecules in the mixture improves the enzymatic activity, conferring conformational stability by solvent effects. This study offers a promising approach for applications and further perspectives on genuinely green industrial solvents.

Thiophene Stability in Photodynamic Therapy: A Mathematical Model Approach.

Thiophene-containing photosensitizers are gaining recognition for their role in photodynamic therapy (PDT). However, the inherent reactivity of the thiophene moiety toward singlet oxygen threatens the stability and efficiency of these photosensitizers. This study presents a novel mathematical model capable of predicting the reactivity of thiophene toward singlet oxygen in PDT, using Conceptual Density Functional Theory (CDFT) and genetic programming. The research combines advanced computational methods, including various DFT techniques and symbolic regression, and is validated with experimental data. The findings underscore the capacity of the model to classify photosensitizers based on their photodynamic efficiency and safety, particularly noting that photosensitizers with a constant rate 1000 times lower than that of unmodified thiophene retain their photodynamic performance without substantial singlet oxygen quenching. Additionally, the research offers insights into the impact of electronic effects on thiophene reactivity. Finally, this study significantly advances thiophene-based photosensitizer design, paving the way for therapeutic agents that achieve a desirable balance between efficiency and safety in PDT.

Exploring the behavior of Candida antarctica lipase B in aqueous mixtures of an imidazolium ionic liquid and its surfactant analogue.

The performance of Candida antarctica lipase B (CALB) has been evaluated in 1-butyl-3-methylimidazolium tetrafluoroborate (BMIMBF4)/water mixtures in a wide range of molar fractions (χBMIMBF4) with and without 1-dodecyl-3-methylimidazolium tetrafluoroborate (C12-MIMBF4), a surfactant derived from BMIMBF4. The main aim of this work is to evaluate the influence of χBMIMBF4 over micellar aggregates to assess the activity of enzymatic reactions. The investigated reaction corresponds to the hydrolysis of the substrate p-nitrophenyl laureate in each χBMIMBF4. The kinetic study for χBMIMBF4 at around 0.2 proved to be a border point in enzymatic activity. At χBMIMBF4 = 0.1, the lipase activity increases in the presence of C12-MIMBF4. However, at higher concentrations, BMIMBF4 has a negligible effect over the lipase activity. These results suggest specific interactions between water and BMIMBF4 molecules in relation to CALB. This research highlights the superactivity phenomenon driven by the reaction media and the micelle interface. In this interfacial interaction, BMIMBF4 acts directly on the changes induced on the enzyme upon its interaction with the micellar interface. This study opens a green perspective toward the biocatalysis field.

Changes in Protonation Sites of 3-Styryl Derivatives of 7-(dialkylamino)-aza-coumarin Dyes Induced by Cucurbit[7]uril.

The incorporation of a guest, with different basic sites, into an organized system (host), such as macrocycles, could stabilize, detect, or promote the formation of a certain protomer. In this context, this work aimed to study the influence of cucurbit[7]uril (CB7) on dyes such as 7-(dimethylamino)-aza-coumarins, which have more than one basic site along their molecular structure. For this, three 3-styryl derivatives of 7-(dialkylamino)-aza-coumarin dyes (SAC1-3) were synthesized and characterized by NMR, ESI-HRMS and IR. The spectral behaviour of the SACs in the absence and presence of CB7 was studied. The results showed large shifts in the UV-vis spectrum in acid medium: a hypsochromic shift of ≈5400 cm-1 (SAC1-2) and ≈3500 cm-1 (SAC3) in the absence of CB7 and a bathochromic shift of ≈4500 cm-1 (SAC1-3) in the presence of CB7. The new absorptions at long and short wavelengths were assigned to the corresponding protomers by computational calculations at the density functional theory (DFT) level. Additionally, the binding mode was corroborated by molecular dynamics simulations. Findings revealed that in the presence of CB7 the heterocyclic nitrogen was preferably protonated instead of the dialkylamino group. Namely, CB7 induces a change in the protonation preference at the basic sites of the SACs, as consequence of the molecular recognition by the macrocycle.

The Southern Ocean Exchange: porous boundaries between humpback whale breeding populations in southern polar waters.

Humpback whales (Megaptera novaeangliae) are a cosmopolitan species and perform long annual migrations between low-latitude breeding areas and high-latitude feeding areas. Their breeding populations appear to be spatially and genetically segregated due to long-term, maternally inherited fidelity to natal breeding areas. In the Southern Hemisphere, some humpback whale breeding populations mix in Southern Ocean waters in summer, but very little movement between Pacific and Atlantic waters has been identified to date, suggesting these waters constituted an oceanic boundary between genetically distinct populations. Here, we present new evidence of summer co-occurrence in the West Antarctic Peninsula feeding area of two recovering humpback whale breeding populations from the Atlantic (Brazil) and Pacific (Central and South America). As humpback whale populations recover, observations like this point to the need to revise our perceptions of boundaries between stocks, particularly on high latitude feeding grounds. We suggest that this "Southern Ocean Exchange" may become more frequent as populations recover from commercial whaling and climate change modifies environmental dynamics and humpback whale prey availability.

Predicting the Adsorption of Amoxicillin and Ibuprofen on Chitosan and Graphene Oxide Materials: A Density Functional Theory Study.

The occurrence, persistence, and accumulation of antibiotics and non-steroidal anti-inflammatory drugs (NSAIDs) represent a new environmental problem due to their harmful effects on human and aquatic life. A suitable absorbent for a particular type of pollutant does not necessarily absorb other types of compounds, so knowing the compatibility between a particular pollutant and a potential absorbent before experimentation seems to be fundamental. In this work, the molecular interactions between some pharmaceuticals (amoxicillin, ibuprofen, and tetracycline derivatives) with two potential absorbers, chitosan and graphene oxide models (pyrene, GO-1, and coronene, GO-2), were studied using the ωB97X-D/6-311G(2d,p) level of theory. The energetic interaction order found was amoxicillin/chitosan > amoxicillin/GO-1 > amoxicillin/GO-2 > ibuprofen/chitosan > ibuprofen/GO-2 > ibuprofen/GO-1, the negative sign for the interaction energy in all complex formations confirms good compatibility, while the size of Eint between 24-34 kcal/mol indicates physisorption processes. Moreover, the free energies of complex formation were negative, confirming the spontaneity of the processes. The larger interaction of amoxicillin Gos, compared to ibuprofen Gos, is consistent with previously reported experimental results, demonstrating the exceptional predictability of these methods. The second-order perturbation theory analysis shows that the amoxicillin complexes are mainly driven by hydrogen bonds, while van der Waals interactions with chitosan and hydrophobic interactions with graphene oxides are modelled for the ibuprofen complexes. Energy decomposition analysis (EDA) shows that electrostatic energy is a major contributor to the stabilization energy in all cases. The results obtained in this work promote the use of graphene oxides and chitosan as potential adsorbents for the removal of these emerging pollutants from water.

Supramolecular Control of Reactivity toward Hydrolysis of 7-Diethylaminocoumarin Schiff Bases by Cucurbit[7]uril Encapsulation.

A series of aromatic Schiff bases, featuring 7-diethylamino-coumarin and with five different substituents at an adjacent phenyl ring, were synthesized and characterized. With the aim of assessing the stability of these dyes in acidic medium, their hydrolysis reactions were kinetically studied in the absence and presence of the macrocycle cucurbit[7]uril (CB[7]). Our results are consistent with a model containing three different forms of substrates (un-, mono-, and diprotonated) and three parallel reaction pathways. The pK a values and the rate constants were estimated and discussed in terms of the presence of a hydroxyl group at the ortho position and electron-releasing groups on the phenyl ring of the dyes. The kinetic study in the presence of CB[7] led to two different behaviors. Promotion of the reaction by CB[7] was observed for the hydrolysis of the Schiff bases containing only one coordination site toward the macrocycle. Conversely, an inhibitor effect was observed for the hydrolysis of a Schiff base with two coordination sites toward CB[7]. The latter effect could be explained with a model as a function of a prototropic tautomeric equilibrium and the formation of a 2:1 host/guest complex, which prevents the attack of water. Therefore, the kinetic results demonstrated a supramolecular control of the macrocycle toward the reactivity and stability of 7-diethylaminocoumarin Schiff bases in acidic medium.

Cucurbit[7]uril as a Supramolecular Catalyst in Base-Catalyzed Reactions. Experimental and Theoretical Studies on Carbonate and Thiocarbonate Hydrolysis Reactions.

Cucurbit[7]uril (CB7) catalyzes the hydrolysis reaction of bis(4-nitrophenyl)carbonate (1) but inhibits that of bis(4-nitrophenyl)thiocarbonate (2). Two relevant CB7 effects are proposed, a base-catalyst mediated by the CB7 portal and an inhibitory role attributed to the lower interaction of the thiocarbonyl group with the solvent in the host cavity, respectively.

Knowledge deficits and barriers to performing soft-tissue coverage procedures: An analysis of participants in an orthopaedic surgical skills training course in Mexico.

BACKGROUND: An increasing number of traumatic injuries in low- and low-middle-income countries (LICs/LMICs) have coexisting injuries requiring soft-tissue coverage (flaps). Yet, there is a lack of subspecialty care and flap training in Latin America. This study assesses the effectiveness of a surgical skills training course in improving rotational and free flap knowledge and identifies barriers to performing these types of flaps. METHODS: Participants attending a surgical skills training course in Guadalajara, Mexico completed a pre/postcourse flaps knowledge survey consisting of 15 questions from the plastic surgery in-training examination and also completed a 7-point Likert survey regarding perceived barriers to performing flaps at their institution. RESULTS: Of the course participants, 17 (44.7%) completed the precourse knowledge survey, 24 (63.2%) completed the postcourse survey, and 37 (97.4%) completed the barriers survey. Scores improved from pre- to postcourse knowledge surveys (39.6% to 53.6%, P = .005). Plastic surgery subsection scores also improved (39.0% to 60.4%, P = .003). Twenty-five percent of attendees received prior flap training and had plastic surgeons available to perform flaps. Few participants (38.9%) reported flap procedures being commonly completed at their hospitals. Participants stating that flaps were uncommon in their hospital reported more institutional barriers and less access to dermatomes. These participants also reported lack of operating room and surgical personnel availability. CONCLUSION: A surgical skills training course may be useful in improving knowledge of soft-tissue coverage procedures. There are also modifiable physician and institutional barriers that can improve the ability to perform rotational and free flaps as identified by the course participants.

Classical QSAR and Docking Simulation of 4-Pyridone Derivatives for Their Antimalarial Activity.

In this work, the minimum energy structures of 22 4-pyridone derivatives have been optimized at Density Functional Theory level, and several quantum molecular, including electronic and thermodynamic descriptors, were computed for these substrates in order to obtain a statistical and meaningful QSAR equation. In this sense, by using multiple linear regressions, five mathematical models have been obtained. The best model with only four descriptors (r² = 0.86, Q² = 0.92, S.E.P = 0.38) was validated by the leave-one-out cross-validation method. The antimalarial activity can be explained by the combination of the four mentioned descriptors e.g., electronic potential, dipolar momentum, partition coefficient and molar refractivity. The statistical parameters of this model suggest that it is robust enough to predict the antimalarial activity of new possible compounds; consequently, three small chemical modifications into the structural core of these compounds were performed specifically on the most active compound of the series (compound 13). These three new suggested compounds were leveled as 13A, 13B and 13C, and the predicted biological antimalarial activity is 0.02 µM, 0.03 µM, and 0.07 µM, respectively. In order to complement these results focused on the possible action mechanism of the substrates, a docking simulation was included for these new structures as well as for the compound 13 and the docking scores (binding affinity) obtained for the interaction of these substrates with the cytochrome bc1, were -7.5, -7.2, -6.9 and -7.5 kcal/mol for 13A, 13B, 13C and compound 13, respectively, which suggests that these compounds are good candidates for its biological application in this illness.

Early Recurrences During the Blanking Period after Atrial Fibrillation Ablation.

Early recurrences of atrial arrhythmias (ERAA) after ablation are common and predict late recurrences and ablation failure.However,becausea proportion of patients with ERAA will have no subsequent arrhythmias after the blanking period, consensus guidelines recommend against immediate repeat ablation for ERAA episodes occurring during the first 3 months post-ablation. In this review, we summarize the predictors, significance, and treatment of ERAA after AF ablation.

Impact of timing of recurrence following catheter ablation of scar-related ventricular tachycardia on subsequent mortality.

BACKGROUND: Catheter ablation (CA) has an established role in scar-related ventricular tachycardia (VT), but the risk of recurrences is substantial and the appropriate intensity of postablation monitoring unknown. The implication of timing of postablation VT recurrence has not been adequately investigated. METHODS: We studied 120 consecutive patients with scar-related VT (age 60 ± 15 years, left ventricular ejection fraction 39 ± 16%, 52% ischemic etiology) with at least 2 years of follow-up. Timing of VT recurrence was classified as very early (<1 month), early (1-6 months), or late (>6 months). RESULTS: At 24 months follow-up, 53 (44%) patients had recurrent VT, with eight (15%) having very early recurrence, 17 (32%) early recurrence, and 28 (53%) late recurrence. Mortality rates at 2 years were significantly higher in patients with very early VT recurrence (38%) compared to those with early (12%), late (7%), and no (3%) recurrences (log-rank P < 0.001). Very early VT recurrence was associated with an increased risk of death (odds ratio = 5.68, 95% confidence interval = 1.06-30.62, P = 0.04), while recurrent VT beyond 6 months was not associated with increased risk of mortality (P = 0.94). CONCLUSIONS: Timing of VT recurrence following CA of scar-related VT impacts subsequent risk of mortality. Patients experiencing VT recurrence within 1-6 months from the procedure are at particularly high risk. These data support the importance of intense postablation monitoring for at least 6 months after the procedure to identify patients with early VT recurrence who may benefit from additional therapeutic interventions to improve outcomes.

Electrical Storm in Patients with Implantable Cardioverter-defibrillators: A Practical Overview.

Electrical storm (ES) is an increasingly common medical emergency characterized by clustered episodes of sustained ventricular arrhythmias (VAs) that lead to repeated appropriate implantable cardioverter-defibrillator (ICD) therapies. A diagnosis of ES can be made with the occurrence of three or more sustained episodes of VAs, or of three or more appropriate ICD therapies within 24 hours in patients with implanted devices. ES is associated with poor outcomes in patients with structural heart disease, particularly those with severe left ventricular dysfunction. In large clinical trials involving patients with ICDs for primary and secondary prevention, ES appears to be a predictor of cardiac death, with notably higher rates of mortality soon after the event. ES management is challenging and requires special medical attention with accurate patient risk stratification and a multidisciplinary approach that includes the use of pharmacologic therapies such as antiarrhythmic drugs (AADs) and interventional approaches like catheter ablation, surgical ablation, or sympathetic neuromodulation. Initial management involves determining and addressing the underlying ischemia, any electrolyte imbalances, and/or other causative factors. Hemodynamic support needs to be considered in high-risk patients with unstable VAs or those with severe comorbidities such as low left ventricular ejection fraction, advanced New York Heart Association class, and/or chronic pulmonary disease. Following the acute phase of ES, treatment should shift towards maximizing therapeutic efforts to address heart failure, performing revascularization, and preventing subsequent VAs. In the present manuscript, we offer an overview of the most relevant clinical aspects of ES with regard to novel therapeutic strategies.

Dynamics and genetics of a disease-driven species decline to near extinction: lessons for conservation.

Amphibian chytridiomycosis has caused precipitous declines in hundreds of species worldwide. By tracking mountain chicken (Leptodactylus fallax) populations before, during and after the emergence of chytridiomycosis, we quantified the real-time species level impacts of this disease. We report a range-wide species decline amongst the fastest ever recorded, with a loss of over 85% of the population in fewer than 18 months on Dominica and near extinction on Montserrat. Genetic diversity declined in the wild, but emergency measures to establish a captive assurance population captured a representative sample of genetic diversity from Montserrat. If the Convention on Biological Diversity's targets are to be met, it is important to evaluate the reasons why they appear consistently unattainable. The emergence of chytridiomycosis in the mountain chicken was predictable, but the decline could not be prevented. There is an urgent need to build mitigation capacity where amphibians are at risk from chytridiomycosis.

Mechanistic insights into mitral regurgitation due to atrial fibrillation: "Atrial functional mitral regurgitation".

Mitral regurgitation (MR) is common, and definitive management of significant MR often requires percutaneous or surgical correction. Lone atrial fibrillation has been proposed to result in "atrial functional mitral regurgitation (AFMR)" via left atrial enlargement and mitral annular dilation. Patients with AFMR may represent a subgroup in which a rhythm control strategy may be preferred and catheter ablation is a promising nonsurgical therapy. This review discusses the anatomy of the mitral valve apparatus and MR classification schemes. Potential mechanisms in the pathogenesis of AFMR the implications for treatment will be discussed in detail.

Effects on performance and carcass and meat quality attributes following immunocastration with the gonadotropin releasing factor vaccine Bopriva or surgical castration of Bos indicus bulls raised on pasture in Brazil.

Bos indicus bulls 20 months of age grazed on pasture in Minas Gerais, Brazil either received 2 doses of the GnRF vaccine Bopriva at d0 and d91 (group IC, n=144) or were surgically castrated on d91 (group SC, n=144). Slaughter on d280, was 27 weeks after castration. Adverse safety issues in 8% of group SC bulls following surgery contrasted with 0% in group IC bulls. At d105 testosterone levels were suppressed to similar levels in both groups. Importantly, group IC bulls had higher live weight, hot carcass weight, ADG (P<0.005) and dressing percentage (P<0.0001) compared to group SC animals. There were no negative effects on carcass or meat quality traits, thus immunocastration was concluded to offer a safe and effective method that provides production gains, and improves animal welfare in Bos indicus beef bulls without impacting meat and carcass quality.

Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate

There is a strong advocacy movement for large doses of vitamin C. Some authors argue that the biological half-life for vitamin C at high plasma levels is about 30 minutes, but these reports are the subject of some controversy. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. The dynamic flow model refutes the current low-dose recommendations for dietary intakes and links Pauling's mega-dose suggestions with other reported effects of massive doses of ascorbate for the treatment of disease. Although, a couple of controlled clinical studies conducted at The Mayo Clinic did not support a significant benefit for terminal cancer patients after 10 grams of once-a-day oral vitamin C, other clinical trials have demonstrated that ascorbate may indeed be effective against tumors when administered intravenously. Recent studies confirmed that plasma vitamin C concentrations vary substantially with the route of administration. Only by intravenous administration, the necessary ascorbate levels to kill cancer cells are reached in both plasma and urine. Because the efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated. One limitation of current studies is that pharmacokinetic data at high intravenous doses of vitamin C are sparse, particularly in cancer patients. This fact needs prompt attention to understand the significance of intravenous vitamin C administration. This review describes the current state-of-the-art in oral and intravenous vitamin C pharmacokinetics. In addition, the governmental recommendations of dose and frequency of vitamin C intake will also be addressed.

A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients

Case studies suggest that vitamin C, given intravenously at doses of 10-100 grams/day can improve patient well being and in some cases, reduce tumor size. While ascorbate is generally considered safe, clinical data on high intravenous doses is limited. Twenty-four late stage terminal cancer patients were given continuous infusions of 150 to 710 mg/kg/day for up to eight weeks. Blood chemistry and blood count profiles were obtained at roughly one-week intervals while patient health, adverse events and tumor progression were monitored. The majority of patients were vitamin C deficient prior to treatment. Intravenous infusions increased plasma ascorbate concentrations to a mean of 1.1 mM. The most common adverse events reported were nausea, edema, and dry mouth or skin; and these were generally minor. Two Grade 3 adverse events 'possibly related' to the agent were reported: one patient with a history of renal calculi developed a kidney stone after thirteen days of treatment and another patient experienced hypokalemia after six weeks of treatment. White blood cell counts were stable while hemoglobin and hematocrit levels dropped slightly during treatment, consistent with trends observed prior to therapy. Blood creatinine, BUN, glucose, and uric acid concentrations decreased or remained stable during therapy, suggesting that ascorbate infusions did not adversely affect renal function. One patient had stable disease and continued the treatment for forty-eight weeks. These data suggest that intravenous vitamin C therapy for cancer is relatively safe, provided the patient does not have a history of kidney stone formation.