Novel Dihydropteridinone Derivatives As Potent Inhibitors of the Understudied Human Kinases Vaccinia-Related Kinase 1 and Casein Kinase 1δ/ε.

Vaccinia-related kinase 1 (VRK1) and the δ and ε isoforms of casein kinase 1 (CK1) are linked to various disease-relevant pathways. However, the lack of tool compounds for these kinases has significantly hampered our understanding of their cellular functions and therapeutic potential. Here, we describe the structure-based development of potent inhibitors of VRK1, a kinase highly expressed in various tumor types and crucial for cell proliferation and genome integrity. Kinome-wide profiling revealed that our compounds also inhibit CK1δ and CK1ε. We demonstrate that dihydropteridinones 35 and 36 mimic the cellular outcomes of VRK1 depletion. Complementary studies with existing CK1δ and CK1ε inhibitors suggest that these kinases may play overlapping roles in cell proliferation and genome instability. Together, our findings highlight the potential of VRK1 inhibition in treating p53-deficient tumors and possibly enhancing the efficacy of existing cancer therapies that target DNA stability or cell division.

Formulation and characterization of amiodarone-methyl-beta-cyclodextrin inclusion complexes: A molecular modelling perspective.

This study aimed to develop immediate-release tablets containing amiodarone hydrochloride (AM). AM is a BCS class II compound, i.e., high permeable, and poorly soluble. The interactions between amiodarone and methyl-ß-cyclodextrin were DFT-based, theoretically measured, supporting the complexation of AM with cyclodextrin by using methyl-ß-cyclodextrin through a spray-drying process. Thus, increasing substantially the drug solubility to 93.31% and 87.14%, respectively. Solubility studies demonstrated the formation of the Drug-Methyl-ß-cyclodextrin inclusion complex with 1:1 stoichiometry. The complex formation was characterized by SBET, XRD, DSC, SEM, FTIR, and 1H NMR. Complementing, immediate-release tablets containing the inclusion complex were developed by direct compression, and in vitro dissolution studies were performed in gastrointestinal fluids using USP Pharmacopeia standard dissolution rate testing equipment. The dissolution rate of immediate-release tablets was substantially higher than the pristine drug in all mediums evaluated. These results confirm the application of methyl-ß-cyclodextrin as an effective excipient for incorporation in novel dosage forms to increase the solubility of poorly soluble drugs.

The importance of integrating morphological attributes of microplastics: a theoretical discussion to assess environmental impacts.

Most scientific studies on microplastic (MP) pollution report their results as number of particles (e.g., particles/m2, particles/m3, particles/kg dw). An important limitation of this expression is to consider all MP particles as environmentally equivalent, regardless of their size, volume, mass, or specific surface area. Using a theoretical approach, we advocate that including such morphological attributes reveals significant differences in results of supposedly equivalent samples that consider only the number of particles. Our goal is to present how particle size and shape produce different results for hypothetical samples with the same number of particles. Therefore, from these examples we expect to stimulate the debate and contribute to improve accuracy and comparability of studies on MP pollution.

Adsorption and Photocatalytic Degradation of Pesticides into Nanocomposites: A Review.

The extensive use of pesticides in agriculture has significantly impacted the environment and human health, as these pollutants are inadequately disposed of into water bodies. In addition, pesticides can cause adverse effects on humans and aquatic animals due to their incomplete removal from the aqueous medium by conventional wastewater treatments. Therefore, processes such as heterogeneous photocatalysis and adsorption by nanocomposites have received special attention in the scientific community due to their unique properties and ability to degrade and remove several organic pollutants, including pesticides. This report reviews the use of nanocomposites in pesticide adsorption and photocatalytic degradation from aqueous solutions. A bibliographic search was performed using the ScienceDirect, American Chemical Society (ACS), and Royal Society of Chemistry (RSC) indexes, using Boolean logic and the following descriptors: "pesticide degradation" AND "photocatalysis" AND "nanocomposites"; "nanocomposites" AND "pesticides" AND "adsorption". The search was limited to research article documents in the last ten years (from January 2012 to June 2022). The results made it possible to verify that the most dangerous pesticides are not the most commonly degraded/removed from wastewater. At the same time, the potential of the supported nanocatalysts and nanoadsorbents in the decontamination of wastewater-containing pesticides is confirmed once they present reduced bandgap energy, which occurs over a wide range of wavelengths. Moreover, due to the great affinity of the supported nanocatalysts with pesticides, better charge separation, high removal, and degradation values are reported for these organic compounds. Thus, the class of the nanocomposites investigated in this work, magnetic or not, can be characterized as suitable nanomaterials with potential and unique properties useful in heterogeneous photocatalysts and the adsorption of pesticides.

Efficacy and Safety of Granulocyte-Colony Stimulating Factor Therapy in Chagas Cardiomyopathy: A Phase II Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

Aim: Previous studies showed that granulocyte-colony stimulating factor (G-CSF) improved heart function in a mice model of Chronic Chagas Cardiomyopathy (CCC). Herein, we report the interim results of the safety and efficacy of G-CSF therapy vs. placebo in adults with Chagas cardiomyopathy. Methods: Patients with CCC, New York Heart Association (NYHA) functional class II to IV and left ventricular ejection fraction (LVEF) 50% or below were included. A randomization list using blocks of 2 and 4 and an allocation rate of 1:1 was generated by R software which was stratified by functional class. Double blinding was done to both arms and assessors were masked to allocations. All patients received standard heart failure treatment for 2 months before 1:1 randomization to either the G-CSF (10 mcg/kg/day subcutaneously) or placebo group (1 mL of 0.9% saline subcutaneously). The primary endpoint was either maintenance or improvement of NYHA class from baseline to 6-12 months after treatment, and intention-to-treat analysis was used. Results: We screened 535 patients with CCC in Salvador, Brazil, of whom 37 were randomized. Overall, baseline characteristics were well-balanced between groups. Most patients had NYHA class II heart failure (86.4%); low mean LVEF was 32 ± 7% in the G-CSF group and 33 ± 10% in the placebo group. Frequency of primary endpoint was 78% (95% CI 0.60-0.97) vs. 66% (95% CI 0.40-0.86), p = 0.47, at 6 months and 68% (95% CI 0.43-0.87) vs. 72% (95% CI 0.46-0.90), p = 0.80, at 12 months in placebo and G-CSF groups, respectively. G-CSF treatment was safe, without any related serious adverse events. There was no difference in mortality between both arms, with five deaths (18.5%) in treatment vs. four (12.5%) in the placebo arm. Exploratory analysis demonstrated that the maximum rate of oxygen consumption during exercise (VO2 max) showed an improving trend in the G-CSF group. Conclusion: G-CSF therapy was safe and well-tolerated in 12 months of follow-up. Although prevention of symptom progression could not be demonstrated in the present study, our results support further investigation of G-CSF therapy in Chagas cardiomyopathy patients. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT02154269].

Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B.

The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.

Insights on the intestinal absorption of chlorophyll series from microalgae.

The bioaccessibility and subsequent uptake by Caco-2 human intestinal cells of chlorophyll pigments from Scenedesmus obliquus were determined for the first time. In order to evaluate the impact of different types of the matrix on bioaccessibility of chlorophyll from microalgae, three different products were evaluated: isolated chlorophyll extract (ICE); wet ultrasonicated biomass (WUB); and whole dried biomass (WDB). The samples were submitted to in vitro digestion model according to the INFOGEST protocol, and Caco-2 cells determined the intestinal uptake. Chlorophyll pigments were determined by HPLC-PDA-MS/MS. A total of ten chlorophyll pigments (8,318.48 µg g-1) were separated in S. obliquus biomass, with chlorophyll a (3,507.76 µg g-1) and pheophytin a' (1,598.09 µg g-1) the major ones. After in vitro digestion, all tested products showed bioaccessible chlorophylls. However, the total bioaccessibility results were as follows: ICE (33.45%), WUB (2.65%), WDB (0.33%). Five compounds were bioaccessible in ICE, three in WUB, and one in WDB. The hydroxypheophytin a showed the highest bioaccessibility (212%) in ICE, while pheophytin a' in WUB (11%) and WDB (2%). As a result, bioavailability estimates of ICE using the Caco-2 cell showed hydroxypheophytin a (102.53%), followed by pheophytin a' (64.69%) as the chlorophyll pigments most abundant in intestinal cells. In summary, from a nutritional perspective, these three types of the matrix (WDB, WUB, and ICE) influence the promotion of chlorophyll bioaccessibility. In this way, the data suggest that chlorophylls bioaccessibility from ICE is greater than that in WDB and WUB. Therefore, ICE should be considered a product that provides bioavailable chlorophyll and could be the best choice, such as ingredients in the development of functional foods chlorophyll-based.

Resource availability and disturbance shape maximum tree height across the Amazon.

Tall trees are key drivers of ecosystem processes in tropical forest, but the controls on the distribution of the very tallest trees remain poorly understood. The recent discovery of grove of giant trees over 80 meters tall in the Amazon forest requires a reevaluation of current thinking. We used high-resolution airborne laser surveys to measure canopy height across 282,750 ha of old-growth and second-growth forests randomly sampling the entire Brazilian Amazon. We investigated how resources and disturbances shape the maximum height distribution across the Brazilian Amazon through the relations between the occurrence of giant trees and environmental factors. Common drivers of height development are fundamentally different from those influencing the occurrence of giant trees. We found that changes in wind and light availability drive giant tree distribution as much as precipitation and temperature, together shaping the forest structure of the Brazilian Amazon. The location of giant trees should be carefully considered by policymakers when identifying important hot spots for the conservation of biodiversity in the Amazon.

Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways.

(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan® arrays in paired tumor and normal lung tissues (n = 38) from treatment-naïve patients with lung adenocarcinoma (AD; n = 23) and lung squamous cell carcinoma (SCC; n = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD (n = 561) and lung SCC (n = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and p < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate EGFR and TGFß signaling, among other known pathways relevant to lung tumorigenesis.

Carbon dioxide capture and use in photobioreactors: The role of the carbon dioxide loads in the carbon footprint.

This research evaluated the carbon dioxide capture and use by Scenedesmus obliquus in a photobioreactor under different CO2 loads. Performance indicators, carbon and energy balances, sustainability indicators, and carbon credits on the photobioreactor were assessed. The results expressed that the CO2 loads of 384.9 kg/m3/d (15% CO2) provide the best trade-off for the process. For this condition, maximum biomass productivities of 0.36 kg/m3/d, carbon dioxide conversion rates of 0.44 kgCO2/m3/d, and oxygen release rates of 0.33 kgO2/m3/d were observed, reaching maximum CO2 removal efficiencies of 30.76%. Volatile organic compounds were the major products generated (>80%). However, only <3% was fixed in biomass. From the environmental and economic point of view, the net energy ratio was 3.44, while the potential carbon credit was of 0.04 USD per m3 of culture. Finally, the use of adequate CO2 loads was also proven to be determinant to improve the global performance of the system.

The true identity of Bryconops cyrtogaster (Norman), and description of a new species of Bryconops Kner (Characiformes: Iguanodectidae) from the Rio Jari, lower Amazon basin.

Bryconops cyrtogaster, a poorly known species endemic from the Oyapock River at the border between French Guyana and Brazil, is redescribed herein based on examination of available type material, as well as newly collected material. Additionally, a new rheophilic species from the rio Jari rapids, lower Amazon basin, Brazil, is described. The two species belong to the subgenus Creatochanes and are unique among the congeneres for possessing a posteriorly positioned humeral blotch at the level of the sixth and seventh lateral line scales. They differ from each other by meristic and morphometric characters. The list of endemic species in the rio Jari basin is revised.

Author Correction: Superconductor to resistive state switching by multiple fluctuation events in NbTiN nanostrips.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2.

Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (26) displayed an IC50 value of 150 nM and was fairly selective in a panel of 48 human kinases (selectivity score S(50%) of 0.04). Differences in compound binding mode and substituent preferences between the two VRKs were identified by the structure-activity relationship combined with the crystallographic analysis of key compounds. We expect our results to serve as a starting point for the design of more specific and potent inhibitors against each of the two VRKs.

Superconductor to resistive state switching by multiple fluctuation events in NbTiN nanostrips.

We report on measurements of the switching current distributions on two-dimensional superconducting NbTiN strips that are 5 nm thick and 80 nm wide. We observe that the width of the switching current distributions has a non-monotonous temperature dependence, where it is constant at the lowest temperatures up to about 1.5 K, after which it increases with temperature until 2.2 K. Above 2.5 K any increase in temperature decreases the distribution width which at 4.0 K is smaller than half the width observed at 0.3 K. By using a careful analysis of the higher order moments of the switching distribution, we show that this temperature dependence is caused by switching due to multiple fluctuations. We also find that the onset of switching by multiple events causes the current dependence of the switching rate to develop a characteristic deviation from a pure exponential increase, that becomes more pronounced at higher temperatures, due to the inclusion of higher order terms.

Poor taxonomic sampling undermines nomenclatural stability: A reply to Roxo et al. (2019).

A recent study based on genomic data by Roxo et al. (2019) provided a phylogeny of the Loricariidae, the largest catfish family and second largest Neotropical fish family with approximately 1,000 species. The study represents a valuable and innovative contribution for understanding higher-level relationships within the family. The phylogenetic tree inferred by Roxo et al. (2019) thoroughly corroborates the monophyly and relationships of most currently accepted subfamilies of Loricariidae, based on a fair taxon sampling (nearly 14% of the species in the family) representing most genera of each but one of the subfamilies, the Lithogeninae, the sister-group of the remaining members of the family (Pereira & Reis, 2017; Reis et al., 2017). In addition to a hypothesis of relationships, Roxo et al. (2019) also proposed a series of lower-level taxonomic changes, which are deemed premature considering that the taxonomic sampling of the study targeted higher-level clades, and go against one of the pillars of biological classification: nomenclatural stability (e.g., Heterick & Majer, 2018; Beninger & Backeljau, 2019). Here we (1) discuss implications of inadequate taxonomic sampling as a basis for changes in classification of species; (2) explain why the taxonomic sampling design of Roxo et al. (2019) is inadequate for the proposed nomenclatural changes; and (3) advocate that changes to classifications must be grounded on phylogenies with dense sampling of taxa at the relevant level.

Poecilia (Pamphorichthys) akroa, a new poeciliid species (Cyprinodontiformes: Poeciliidae) from the Rio Tocantins basin, Brazil.

A new species, Poecilia (Pamphorichthys) akroa, is described from the Rio Tocantins drainage, Brazil. The new species differs from the remaining species of the genus by the possession of 10 or 11 pectoral-fin rays, entire preopercular ramus and posterior portion of the supraorbital ramus of the cephalic sensory system enclosed in canals, a faint longitudinal band along the body, a single gonapophysis, a homogeneous reticulate color pattern on sides of body, urogenital region of females heavily pigmented, distalmost segments of the anterior branch (4a) of the fourth gonopodial ray fused into an elongated segment turned anteriorly, subdistal segments of anterior branch (5a) of fifth gonopodial ray simple, without anterior (ventral) projections, dorsal fin with pigmentation at its distal portion and with a basal black blotch, and chromatophores more concentrated on the posterior margin of the mid-ventral scale series of the caudal peduncle and ventrolateral margin of the adjacent scales forming a series of rhombi posterior to anal fin.

Current advances of pharmacological properties of 7-chloro-4-(phenylselanyl) quinoline: Prevention of cognitive deficit and anxiety in Alzheimer's disease model.

This study investigated the effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) at a dose of 1 mg/kg in memory impairment and anxiety in an Alzheimer's disease (AD) model induced by amyloid ß-peptide (Aß) (fragment 25-35) in mice. The involvement of acetylcholinesterase (AChE) activity and lipid peroxidation in hippocampus and cerebral cortex was evaluated. Male Swiss mice were pretreated with 4-PSQ (1 mg/kg, intragastrically (i.g.), daily) for fourteen days. Thirty minutes after the first treatment with 4-PSQ, the animals received a single injection of Aß (3 nmol/3 µl/per site, intracerebroventricular (i.c.v.)). Mice were submitted to the behavioral tasks (open-field, elevated plus maze, Barnes maze, object recognition and location, and step-down inhibitory avoidance tests) from the fifth day onwards. On the fifteenth day, blood was removed for analysis of biochemical markers (glucose, triglycerides, urea, aspartate (AST) and alanine (ALT) aminotrasferases), and cerebral cortex and hippocampus for determination of AChE activity and thiobarbituric acid reactive species (TBARS) levels. Aß caused memory impairment, anxiogenic behavior, increased AChE activity in the cerebral structures and TBARS levels in the cerebral cortex. 4-PSQ was effective to protect against behavioral changes, AChE activity and TBARS levels. In conclusion, 4-PSQ protected against learning and memory impairment and anxiety in a mouse model of AD induced by Aß, and anticholinesterase and antioxidant actions are involved in the pharmacological effect of the compound.

New species of Creagrutus (Ostariophysi; Characiformes; Characidae) from the Rio Xingu drainage, Brazil.

Creagrutus yudja is described from the Rio Xingu basin, Brazil. It is distinguished from its congeners by the lack of infraorbital 6, the shallower body (13.7-19.2% of SL), the presence of 34-36 perforated lateral line scales, and the presence of 4-6 post-anal scales. The inclusion of the new species on the available, morphology-based phylogenetic study of Creagrutus placed C. yudja as the sister-species of C. nigrotaeniatus, but the clade including those species is not recovered as sister to the pair C. cracentis + C. maxillaris, suggesting independent modifications of the dentition pattern typical of Creagrutus to a condition similar to the plesiomorphic characid condition within the genus.

Green and fast determination of the alcoholic content of wines using thermal infrared enthalpimetry.

An innovative use of thermal infrared enthalpimetry (TIE) is proposed for the determination of alcoholic content of red and white wines. Notwithstanding the presence of ethanol in beverages, absolute ethanol was added directly to wines, and the temperature rise caused by the heat of dilution was monitored using an infrared camera. Analytical signals were obtained in only 10 s for four samples simultaneously, and a calibration curve was constructed with hydroalcoholic reference solutions. A linear calibration curve was obtained from 3.0 to 18.0% (v/v) ethanol (R2 = 0.9987). The results showed agreement ranging from 98.2 to 104.0% with 942.06 and 969.12 methods of AOAC. Organic compounds (e.g., sugar) did not interfere in the determinations. The proposed method provided fast results, with a throughput of 480 samples per hour and negligible energy consumption (0.001 kWh). In addition, the consumption of reagents was reduced when compared with conventional method fulfilling green analytical chemistry requirements.

2-Aminopyridine-Based Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Inhibitors: Assessment of Mechanism-Based Safety.

Studies have linked the serine-threonine kinase MAP4K4 to the regulation of a number of biological processes and/or diseases, including diabetes, cancer, inflammation, and angiogenesis. With a majority of the members of our lead series (e.g., 1) suffering from time-dependent inhibition (TDI) of CYP3A4, we sought design avenues that would eliminate this risk. One such approach arose from the observation that carboxylic acid-based intermediates employed in our discovery efforts retained high MAP4K4 inhibitory potency and were devoid of the TDI risk. The medicinal chemistry effort that led to the discovery of this central nervous system-impaired inhibitor together with its preclinical safety profile is described.