Metagenomic functional profiling: to sketch or not to sketch?

MOTIVATION: Functional profiling of metagenomic samples is essential to decipher the functional capabilities of microbial communities. Traditional and more widely used functional profilers in the context of metagenomics rely on aligning reads against a known reference database. However, aligning sequencing reads against a large and fast-growing database is computationally expensive. In general, k-mer-based sketching techniques have been successfully used in metagenomics to address this bottleneck, notably in taxonomic profiling. In this work, we describe leveraging FracMinHash (implemented in sourmash, a publicly available software), a k-mer-sketching algorithm, to obtain functional profiles of metagenome samples. RESULTS: We show how pieces of the sourmash software (and the resulting FracMinHash sketches) can be put together in a pipeline to functionally profile a metagenomic sample. We named our pipeline fmh-funprofiler. We report that the functional profiles obtained using this pipeline demonstrate comparable completeness and better purity compared to the profiles obtained using other alignment-based methods when applied to simulated metagenomic data. We also report that fmh-funprofiler is 39-99× faster in wall-clock time, and consumes up to 40-55× less memory. Coupled with the KEGG database, this method not only replicates fundamental biological insights but also highlights novel signals from the Human Microbiome Project datasets. AVAILABILITY AND IMPLEMENTATION: This fast and lightweight metagenomic functional profiler is freely available and can be accessed here: https://github.com/KoslickiLab/fmh-funprofiler. All scripts of the analyses we present in this manuscript can be found on GitHub.

Patterned PVA Hydrogels with 3D Petri Dish® Micro-Molds of Varying Topography for Spheroid Formation of HeLa Cancer Cells: In Vitro Assessment.

Cell spheroids are an important three-dimensional (3D) model for in vitro testing and are gaining interest for their use in clinical applications. More natural 3D cell culture environments that support cell-cell interactions have been created for cancer drug discovery and therapy applications, such as the scaffold-free 3D Petri Dish® technology. This technology uses reusable and autoclavable silicone micro-molds with different topographies, and it conventionally uses gelled agarose for hydrogel formation to preserve the topography of the selected micro-mold. The present study investigated the feasibility of using a patterned Poly(vinyl alcohol) hydrogel using the circular topography 12-81 (9 × 9 wells) micro-mold to form HeLa cancer cell spheroids and compare them with the formed spheroids using agarose hydrogels. PVA hydrogels showed a slightly softer, springier, and stickier texture than agarose hydrogels. After preparation, Fourier transform infrared (FTIR) spectra showed chemical interactions through hydrogen bonding in the PVA and agarose hydrogels. Both types of hydrogels favor the formation of large HeLa spheroids with an average diameter of around 700-800 µm after 72 h. However, the PVA spheroids are more compact than those from agarose, suggesting a potential influence of micro-mold surface chemistry on cell behavior and spheroid formation. This was additionally confirmed by evaluating the spheroid size, morphology, integrity, as well as E-cadherin and Ki67 expression. The results suggest that PVA promotes stronger cell-to-cell interactions in the spheroids. Even the integrity of PVA spheroids was maintained after exposure to the drug cisplatin. In conclusion, the patterned PVA hydrogels were successfully prepared using the 3D Petri Dish® micro-molds, and they could be used as suitable platforms for studying cell-cell interactions in cancer drug therapy.

Effect of Crude Extract from the Sea Anemone Bunodeopsis globulifera on Voltage-Gated Ion Channels from Central and Peripheral Murine Nervous Systems.

Sea anemones are an important source of bioactive compounds with potential pharmacological applications. Their toxins are produced and stored in organelles called nematocysts and act on specific targets, including voltage-gated ion channels. To date, sea anemone toxins have demonstrated effects on voltage-gated sodium and potassium channels, facilitating investigations into the structure and function of these proteins. In this study, we evaluated the effect of Bunodeopsis globulifera sea anemone crude extract, and of a low molecular weight fraction, on voltage-gated sodium and calcium channels within the murine nervous system. Notably, the crude extract led to a significant reduction in total sodium current, while also triggering calcium-dependent glutamate release. Furthermore, the low molecular weight fraction, in particular, enhanced total calcium currents and current density. These findings underscore the existence of sea anemone toxins with diverse mechanisms of action beyond those previously documented.

Low Energy Intake Leads to Body Composition and Performance Decrements in a Highly-Trained, Female Athlete: The WANDER (Woman's Activity and Nutrition during an Extensive Hiking Route) Case Study.

OBJECTIVE: This case study's purpose was to quantify energy intake vs energy expenditure during a thru-hiker's trek and assess its relationship to performance and health. METHODS: A highly trained, female thru-hiker (Age (yrs): 62, Ht (cm): 157, Wt (kg): 53.5, BMI (kg/m2): 21.7, %BF: 26.0) embarked on a 4-month journey through the Pacific Crest Trail, USA. The athlete's body composition and 3-day diet record were assessed before (PRE) and after the hike (POST). During the hike, she tracked her diet and performance daily and completed a wellness survey each time she reached a town-check point. Data were analyzed for descriptive (weekly averages, means ± SD) and frequency statistics. RESULTS: She spent 10 wk (∼70 days) on the trail and hiked 1,506.35 km (26.1 ± 3.2 km/day) with an estimated energy expenditure of ∼2334 ± 351 kcal/day. During the hike, she under consumed calories (1285.3 ± 103 kcal) and dietary carbohydrate (169.5 ± 19.5g), fat (49.7 ± 5.8g), protein (41.9 ± 4.8g; 0.8 g/kg), fiber (11.8 ± 2.1g) and sodium (1642.4 ± 298.6 mg) when compared to ultra-endurance nutrition recommendations. She was unable to complete the trail due to fatigue and anthropometric changes. By POST, she had decreased total mass (PRE: 53.5 kg vs POST: 48.4 kg), BMI (PRE 21.6 vs POST: 19.5), fat-free mass (PRE: 39.6 vs POST: 38.8), and body fat (PRE: 26% vs POST: 19.6%) when compared to PRE. CONCLUSION: Trail-related challenges combined with high energy expenditures led to low nutrient intake which contributed to trail-ending injuries and performance decrements. Research aimed at addressing the barriers associated with thru-hike fueling is needed to identify nutritional opportunities to support hikers' performance and reduce injury risks.

Light-Driven Energy and Charge Transfer Processes between Additives within Electrospun Nanofibres.

Electrospinning is a cost-effective and efficient method of producing polymeric nanofibre films. The resulting nanofibres can be produced in a variety of structures, including monoaxial, coaxial (core@shell), and Janus (side-by-side). The resulting fibres can also act as a matrix for various light-harvesting components such as dye molecules, nanoparticles, and quantum dots. The addition of these light-harvesting materials allows for various photo-driven processes to occur within the films. This review discusses the process of electrospinning as well as the effect of spinning parameters on resulting fibres. Building on this, we discuss energy transfer processes that have been explored in nanofibre films, such as Förster resonance energy transfer (FRET), metal-enhanced fluorescence (MEF), and upconversion. A charge transfer process, photoinduced electron transfer (PET), is also discussed. This review highlights various candidate molecules that have been used for photo-responsive processes in electrospun films.

Pirfenidone Protects from UVB-Induced Photodamage in Hairless Mice.

BACKGROUND: Ultraviolet radiation (UV) is the main environmental factor that causes histological degenerative changes of the skin giving rise to a chronic process called photodamage. Non-melanoma skin cancer induced by UVB radiation is a result of a cascade of molecular events caused by DNA damage in epidermis cells, including persistent inflammation, oxidative stress, and suppression of T cell-mediated immunity. Retinoids such as tretinoin have been widely used in skin to treat photoaging and photodamage, though its secondary adverse effects have been recognized. Pirfenidone (PFD) has emerged as an antifibrogenic, anti-inflammatory and antioxidant agent, and in this work its efficacy was evaluated in a model of UVB-induced photodamage. METHODS: Epidermal, dermal, and inflammatory changes were measured by histomorphometric parameters. In addition, gene, and protein expression of key molecules in these processes were evaluated. RESULTS: Our results revealed an anti-photodamage effect of topical PFD with absence of inflammatory skin lesions determined by dermoscopy. In addition, PFD reduced elastosis, improved organization, arrangement, and deposition of dermal collagens, downregulated several pro-inflammatory markers such as NF-kB, IL-1, IL-6 and TNFα, and decreased keratinocyte damage. CONCLUSION: Topical pirfenidone represents a promising agent for the treatment of cell photodamage in humans. Clinical trials need to be carried out to explore this premise.

Application of a New Carbohydrate Food Quality Scoring System: An Expert Panel Report.

Carbohydrate foods (≥40% energy from carbohydrates) are the main source of energy in the US diet. In contrast to national-level dietary guidance, many regularly consumed carbohydrate foods are low in fiber and whole grains but high in added sugar, sodium, and/or saturated fat. Given the important contribution of higher-quality carbohydrate foods to affordable healthy diets, new metrics are needed to convey the concept of carbohydrate quality to policymakers, food industry stakeholders, health professionals, and consumers. The recently developed Carbohydrate Food Quality Scoring System is well aligned with multiple key healthy messages on nutrients of public health concern from the 2020-2025 Dietary Guidelines for Americans. Two models are described in a previously published paper: one for all non-grain carbohydrate-rich foods (e.g., fruits, vegetables, legumes) known as the Carbohydrate Food Quality Score-4 (CFQS-4), and one for grain foods only known as the Carbohydrate Food Quality Score-5 (CFQS-5). These CFQS models provide a new tool that can guide policy, programs, and people towards improved carbohydrate food choices. Specifically, the CFQS models represent a way to unify and reconcile diverse ways to describe different types of carbohydrate-rich foods (e.g., refined vs. whole, starchy vs. non-starchy, dark green vs. red/orange) and make for more useful and informative messaging that better aligns with a food's nutritional and/or health contributions. The present paper's aims are to show that the CFQS models can inform future dietary guidelines and help support carbohydrate food recommendations with other health messages aimed at promoting foods that are nutrient-dense, fiber-rich, and low in added sugar.

Neighborhood infrastructure-related risk factors and non-communicable diseases: a systematic meta-review.

BACKGROUND: With rapid urbanization, the urban environment, especially the neighborhood environment, has received increasing global attention. However, a comprehensive overview of the association between neighborhood risk factors and human health remains unclear due to the large number of neighborhood risk factor-human health outcome pairs. METHOD: On the basis of a whole year of panel discussions, we first obtained a list of 5 neighborhood domains, containing 33 uniformly defined neighborhood risk factors. We only focused on neighborhood infrastructure-related risk factors with the potential for spatial interventions through urban design tools. Subsequently, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic meta-review of 17 infrastructure-related risk factors of the 33 neighborhood risk factors (e.g., green and blue spaces, proximity to major roads, and proximity to landfills) was conducted using four databases, Web of Science, PubMed, OVID, and Cochrane Library, from January 2000 to May 2021, and corresponding evidence for non-communicable diseases (NCDs) was synthesized. The review quality was assessed according to the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) standard. RESULTS: Thirty-three moderate-and high-quality reviews were included in the analysis. Thirteen major NCD outcomes were found to be associated with neighborhood infrastructure-related risk factors. Green and blue spaces or walkability had protective effects on human health. In contrast, proximity to major roads, industry, and landfills posed serious threats to human health. Inconsistent results were obtained for four neighborhood risk factors: facilities for physical and leisure activities, accessibility to infrastructure providing unhealthy food, proximity to industry, and proximity to major roads. CONCLUSIONS: This meta-review presents a comprehensive overview of the effects of neighborhood infrastructure-related risk factors on NCDs. Findings on the risk factors with strong evidence can help improve healthy city guidelines and promote urban sustainability. In addition, the unknown or uncertain association between many neighborhood risk factors and certain types of NCDs requires further research.

Development of a multidimensional housing and environmental quality index (HEQI): application to the American Housing Survey.

BACKGROUND: Substandard housing conditions and hazardous indoor environmental exposures contribute to significant morbidity and mortality worldwide. Housing indices that capture the multiple dimensions of healthy housing are important for tracking conditions and identifying vulnerable households. However, most indices focus on physical deficiencies and repair costs and omit indoor environmental exposures, as few national data sources routinely collect this information. METHODS: We developed a multidimensional Housing and Environmental Quality Index (HEQI) based on the World Health Organization's Housing and Health Guidelines and applied it to the 2019 American Housing Survey (AHS). The HEQI consisted of ten domains associated with poor health: household fuel combustion, dampness and mold, pests and allergens, lead paint risk, high indoor temperatures, low indoor temperatures, household crowding, injury hazards, inadequate water and sanitation, and ventilation. We evaluated the validity and performance of the HEQI against three housing characteristics (i.e., year built, monthly rent costs, unit satisfaction rating) and two established indices (i.e., Adequacy Index, Poor Quality Index). RESULTS: Approximately 79% (92 million) of U.S. households reported at least one HEQI domain associated with poor health (mean per household: 1.3; range: 0,8). Prevalent domains included household fuel combustion (61.4%), dampness and mold (15.9%), inadequate water and sanitation (14.3%), and injury hazards (11.9%). Pests and allergens, low indoor temperatures, and injury hazards were consistently associated with older homes, lower rent costs, and lower unit satisfaction. Compared to established housing indices, the HEQI captured four new environmental domains which enabled the identification of 57.7 million (63%) more households with environmental risk factors like mold, cockroaches, crowding, household fuel combustion, and higher building leakage. CONCLUSIONS: Indoor environmental exposures are prevalent in U.S. households and not well-captured by existing housing indices. The HEQI is a multidimensional tool that can be used to monitor indoor environmental exposures and housing quality trends in the U.S. Some domains, including radon, pesticides, asbestos, noise, and housing accessibility could not be assessed due to the lack of available data in the AHS. The mounting evidence linking residential environmental exposures with adverse health outcomes underscore the need for this data in the AHS and other national surveys.

A Sea Anemone Lebrunia neglecta Venom Fraction Decreases Boar Sperm Cells Capacitation: Possible Involvement of HVA Calcium Channels.

Sea anemones produce venoms characterized by a complex mixture of low molecular weight compounds, proteins and peptides acting on voltage-gated ion channels. Mammal sperm cells, like neurons, are characterized by their ion channels. Calcium channels seem to be implicated in pivotal roles such as motility and capacitation. In this study, we evaluated the effect of a low molecular weight fraction from the venom of the sea anemone Lebrunia neglecta on boar sperm cells and in HVA calcium channels from rat chromaffin cells. Spermatozoa viability seemed unaffected by the fraction whereas motility and sperm capacitation were notoriously impaired. The sea anemone fraction inhibited the HVA calcium current with partial recovery and no changes in chromaffin cells' current kinetics and current-voltage relationship. These findings might be relevant to the pharmacological characterization of cnidarian venoms and toxins on voltage-gated calcium channels.

A New Carbohydrate Food Quality Scoring System to Reflect Dietary Guidelines: An Expert Panel Report.

Existing metrics of carbohydrate food quality have been based, for the most part, on favorable fiber- and free sugar-to-carbohydrate ratios. In these metrics, higher nutritional quality carbohydrate foods are defined as those with >10% fiber and <10% free sugar per 100 g carbohydrate. Although fiber- and sugar-based metrics may help to differentiate the nutritional quality of various types of grain products, they may not aptly capture the nutritional quality of other healthy carbohydrate foods, including beans, legumes, vegetables, and fruits. Carbohydrate food quality metrics need to be applicable across these diverse food groups. This report introduces a new carbohydrate food scoring system known as a Carbohydrate Food Quality Score (CFQS), which supplements the fiber and free sugar components of previous metrics with additional dietary components of public health concern (e.g., sodium, potassium, and whole grains) as identified by the Dietary Guidelines for Americans. Two CFQS models are developed and tested in this study: one that includes four dietary components (CFQS-4: fiber, free sugars, sodium, potassium) and one that considers five dietary components (CFQS-5: fiber, free sugars, sodium, potassium, and whole grains). These models are applied to 2596 carbohydrate foods in the Food and Nutrient Database for Dietary Studies (FNDDS) 2017−2018. Consistent with past studies, the new carbohydrate food scoring system places large percentages of beans, vegetables, and fruits among the top scoring carbohydrate foods. The whole grain component, which only applies to grain foods (N = 1561), identifies ready-to-eat cereals, oatmeal, other cooked cereals, and selected whole grain breads and crackers as higher-quality carbohydrate foods. The new carbohydrate food scoring system shows a high correlation with the Nutrient Rich Food (NRF9.3) index and the Nutri-Score. Metrics of carbohydrate food quality that incorporate whole grains, potassium, and sodium, in addition to sugar and fiber, are strategically aligned with multiple 2020−2025 dietary recommendations and may therefore help with the implementation of present and future dietary guidelines.

Association of fruit and vegetable color with incident diabetes and cardiometabolic risk biomarkers in the United States Hispanic/Latino population.

BACKGROUND: Color groups of fruits and vegetables (FV) are part of a healthy diet, but evidence for an association with cardiometabolic outcomes is inconsistent. OBJECTIVE: To examine the association between intake of FV of different colors with incident diabetes and cardiometabolic risk biomarkers among U.S. Hispanics/Latinos. SUBJECTS/METHODS: We used data from 9206 adults ages 18-74 years who were free of diabetes at baseline (2008-2011) and had follow-up data at visit 2 (2014-2017) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a multicenter, prospective cohort study of self-identified Hispanics/Latinos. Dietary intake was assessed using two 24 h recalls at baseline. FV were categorized into five color groups: green, white, yellow/orange, red/purple, and uncategorized. Diabetes was defined based on laboratory measures and self-reported antihyperglycemic medication. We used survey logistic regression models to evaluate the association between FV color groups and incident diabetes and survey linear regression models to evaluate the association of FV color groups with cardiometabolic risk biomarkers at visit 2. RESULTS: During ~6 years of follow-up, 970 incident cases of diabetes were documented. The red/purple FV color group was the least consumed (0.21 servings/day), whereas white FV were the most consumed (0.92 servings/day). For each serving of total FV intake, body mass index (BMI) was lower by 0.24% (p = 0.03) and insulin by 0.69% (p = 0.03). For each serving of red/purple FV intake, HDL was 1.59% higher (p = 0.04). For each serving of white FV intake (with potato), post-OGTT was 0.83% lower (p = 0.04) and triglycerides 1.43% lower (p = 0.04). There was no association between FV intake and incident diabetes. CONCLUSIONS: Specific FV colors were associated with cardiometabolic benefits though the associations were of relatively small magnitudes. Dietary recommendations could consider varying colors of FV intake, especially white and red/purple color groups, for a healthy diet.

Assessment of elevated CO2 concentrations and heat stress episodes in soybean cultivars growing in heavy metal polluted soils: Crop nutritional quality and food safety.

The present study evaluated the interactive effects of global change and heavy metals on the growth and development of three soybean [Glycine max (L.) Merrill] cultivars and the consequences on yield and food safety. Soybean cultivars (Alim 3.14 from Argentina, and ES Mentor and Sigalia, from Germany) were grown until maturity in heavy metals polluted soils from the Rhine Valley, Germany, at two CO2 concentrations (400 and 550 ppm) and heat stress (HS) episodes (9 days with 10 °C higher than maximum regular temperature) during the critical growth period in controlled environmental chambers. Different morpho-physiological parameters, heavy metal concentration in aerial organs, seed quality parameters, and toxicological index were recorded. The results showed that no morphological differences were observed related to CO2. Moreover, Alim 3.14 showed the highest yield under control conditions, but it was more sensitive to climatic conditions than the German cultivars, especially to heat stress which strongly reduces the biomass of the fruits. Heavy metals concentration in soil exceeds the legislation limits for agricultural soils for Cd and Pb, with 1.6 and 487 mg kg-1 respectively. In all cultivars, soybeans accumulated Cd in its aerial organs, and it could be translocated to fruits. Cd concentration in seeds ranged between 0.6 and 2.4 mg kg-1, which exceed legislation limits and with toxicological risk to potential Chinese consumers. Pb levels were lower than Cd in seeds (0.03-0.17 mg kg-1), and the accumulation were concentrated in the vegetative organs, with 93% of the Pb incorporated. Moreover, pods accumulated 11 times more Pb than seeds, which suggests that they act as a barrier to the passage of Pb to their offspring. These results evidence that soybean can easily translocate Cd, but not Pb, to reproductive organs. No regular patterns were observed in relation to climatic influence on heavy metal uptake.

Sea anemone Bartholomea annulata venom inhibits voltage-gated Na+ channels and activates GABAA receptors from mammals.

Toxin production in nematocysts by Cnidaria phylum represents an important source of bioactive compounds. Using electrophysiology and, heterologous expression of mammalian ion channels in the Xenopus oocyte membrane, we identified two main effects produced by the sea anemone Bartholomea annulata venom. Nematocysts isolation and controlled discharge of their content, revealed that venom had potent effects on both voltage-dependent Na+ (Nav) channels and GABA type A channel receptors (GABAAR), two essential proteins in central nervous system signaling. Unlike many others sea anemone toxins, which slow the inactivation rate of Nav channels, B. annulata venom potently inhibited the neuronal action potential and the Na+ currents generated by distinct Nav channels opening, including human TTX-sensitive (hNav1.6) and TTX-insensitive Nav channels (hNav1.5). A second effect of B. annulata venom was an agonistic action on GABAAR that activated distinct receptors conformed by either α1ß2γ2, α3ß2γ1 or, ρ1 homomeric receptors. Since GABA was detected in venom samples by ELISA assay at low nanomolar range, it was excluded that GABA from nematocysts directly activated the GABAARs. This revealed that substances in B. annulata nematocysts generated at least two potent and novel effects on mammalian ion channels that are crucial for nervous system signaling.

Synthesizing the links between secure housing tenure and health for more equitable cities.

Millions of households in rich and poor countries alike are at risk of being unwilfully displaced from their homes or the land on which they live (i.e., lack secure tenure), and the urban poor are most vulnerable. Improving housing tenure security may be an intervention to improve housing and environmental conditions and reduce urban health inequalities. Building on stakeholder workshops and a narrative review of the literature, we developed a conceptual model that infers the mechanisms through which more secure housing tenure can improve housing, environmental quality, and health. Empirical studies show that more secure urban housing tenure can boost economic mobility, improve housing and environmental conditions including reduced exposure to pollution, create safer and more resourced communities, and improve physical and mental health. These links are shared across tenure renters and owners and different economic settings. Broader support is needed for context-appropriate policies and actions to improve tenure security as a catalyst for cultivating healthier homes and neighbourhoods and reducing urban health inequalities in cities.

Neighbourhood, Built Environment and Children's Outdoor Play Spaces in Urban Ghana: Review of Policies and Challenges.

Although a great deal of research work has been done by social scientists on walkability and playability, the focus to a large extent has been on the global north. Research work on the urban built environment and children's play has not engaged Africa in general and Ghana in particular. More importantly, there is limited evidence of policies in terms of community-based practices and governmental policies and programmes for the promotion of play. The limited effort in promoting physical activities have to a large extent focused on walkability, yet evidence to date indicates that walking only constitutes a small proportion of the physical activities of children. This is against the backdrop of growing urbanization and the increasing reported incidence of sedentary lifestyles, less physical activity and obesity among children and the youth. Our main objective in this paper is to contribute to the literature on Ghana, and by extension Sub-Saharan Africa, by examining the extent to which playability features in city and national policies and strategies in urban Ghana. We conclude that while there is dearth of public policies on children's play, with the situation in communities compounded by weak city government capacity to plan, implement and enforce development control to protect open spaces for children's play and recreational purposes. The paper recommends a change in policy and practice on creating spaces in urban built-environments for children's play in urban Ghana.

Effect of Pb-Polluted Soil on Soybean Growth and Associated Toxicological Risk.

Glycine max (L.) Merr. (soybean) has been mentioned as a potential accumulator of hazardous metals, such as Pb. The main route of human exposure to heavy metals is consumption. This study evaluates Pb accumulation in soybean at different growth stages. The aim was to determine the period of the crop development when absorption and distribution mostly occur. Soybean plants were grown in control and Pb-polluted soils in a greenhouse experiment. Morpho-physiological parameters and Pb content in organs were analyzed. Results showed that Pb affected the biomass of roots and plant height, with the highest Pb accumulation occurring in the roots and with low translocation to aerial organs. Moreover, Pb accumulation and distribution occurred before grain filling, the crop critical period. Soybean seeds accumulated Pb above permissible values, but with no associated toxicological risk. Furthermore, pods showed higher Pb values ​​than seeds, suggesting a protective effect.

A novel series of pyrazole derivatives toward biological applications: experimental and conceptual DFT characterization.

A new series of 13 pyrazole-derivative compounds with potential antifungal activity were synthetized with good yields. The series have the (E)-2-((1-(R)-3,5-dimethyl-1H-pyrazol-4-yl)diazenyl)phenol general structure and were characterized by means of X-ray diffraction, UV-Vis, FTIR, 1H-NMR, 13C-NMR, and two-dimensional NMR experiments. This experimental characterization was complemented by DFT simulations. A deep insight regarding molecular reactivity was accomplished employing a conceptual DFT approach. In this sense, dual descriptors were calculated at HF and DFT level of theory and GGV spin-density Fukui functions. The main reactive region within the molecules was mapped through isosurface and condensed representations. Finally, chemical descriptors that have previously shown to be close related to biological activity were compared within the series. Thus, higher values of chemical potential ω and electrophilicity χ obtained for compounds 10, 9, 8, 6 and 7, in this order, suggest that these molecules are the better candidates as biological agents.

Ribosome Elongation Kinetics of Consecutively Charged Residues Are Coupled to Electrostatic Force.

The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multiscale simulations, that positively charged residues generate large forces that move the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but move the A- and P-sites closer together. These conformational changes, respectively, increase and decrease the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome-nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation and provide a framework for interpreting experimental results on translation speed.