RNA-directed peptide synthesis across a nicked loop.

Ribosomal translation at the origin of life requires controlled aminoacylation to produce mono-aminoacyl esters of tRNAs. Herein, we show that transient annealing of short RNA oligo:amino acid mixed anhydrides to an acceptor strand enables the sequential transfer of aminoacyl residues to the diol of an overhang, first forming aminoacyl esters then peptidyl esters. Using N-protected aminoacyl esters prevents unwanted peptidyl ester formation in this manner. However, N-acyl-aminoacyl transfer is not stereoselective.

The Central Dogma dominates our understanding of modern biology. However, the mechanisms of how RNA directed peptide synthesis (translation) developed at the dawn of life remain a puzzle. In this study, we demonstrate that short peptides can spontaneously form at the end of a duplex RNA with an overhang. Contemporary proteins are composed exclusively of L-amino acids and our research reveals that L-amino acids with free amino groups are also more likely to participate in this prebiotic peptide synthesis mechanism. Conversely, when one of the amino acids is protected as it is in modern bacteria, this preference disappears. We demonstrate this chemistry can afford a variety of peptide sequences in a sequence-dependent manner.

The Association of Ethnicity and Oncologic Outcomes for Oral Cavity Squamous Cell Carcinoma (OSCC).

(1) Background: To compare oncologic outcomes of South Asian (SA) patients treated for oral squamous cell carcinoma (OSCC) to the general population. (2) Methods: Adult patients who underwent surgical resection of OSCC +/- adjuvant treatment between 2009 and 2022 (N = 697) at a regional cancer centre in Canada were included. SA patients, identified using a validated method, were compared to non-SA patients. Kaplan-Meier methods were used to compare the primary outcomes, disease-specific survival (DSS) and recurrence-free survival (RFS) across baseline univariate characteristics, including betel nut consumption. Median follow-up time was 36.4 months. Cox proportional hazard models were used to identify independent predictors of survival with significance set at p < 0.05. (3) Results: SA patients (9% of cohort, N = 64) were significantly younger and had lower rates of smoking and alcohol consumption compared to non-SA patients (p < 0.05). SA patients had a two-fold higher risk of recurrence and significantly worse disease-specific survival, even after adjusting for stage and high-risk features [RFS: HR 2.01 (1.28-3.14), DSS: HR 1.79 (1.12-2.88)]. The consumption of betel nut was not associated with outcomes. (4) Conclusions: SA patients had significantly worse oncologic outcomes, even after controlling for known predictors of poor prognosis. These findings are novel and can inform personalized treatment decisions and influence public health policies when managing patients with different ethnic backgrounds.

Initial Amino Acid:Codon Assignments and Strength of Codon:Anticodon Binding.

The ribosome brings 3'-aminoacyl-tRNA and 3'-peptidyl-tRNAs together to enable peptidyl transfer by binding them in two major ways. First, their anticodon loops are bound to mRNA, itself anchored at the ribosomal subunit interface, by contiguous anticodon:codon pairing augmented by interactions with the decoding center of the small ribosomal subunit. Second, their acceptor stems are bound by the peptidyl transferase center, which aligns the 3'-aminoacyl- and 3'-peptidyl-termini for optimal interaction of the nucleophilic amino group and electrophilic ester carbonyl group. Reasoning that intrinsic codon:anticodon binding might have been a major contributor to bringing tRNA 3'-termini into proximity at an early stage of ribosomal peptide synthesis, we wondered if primordial amino acids might have been assigned to those codons that bind the corresponding anticodon loops most tightly. By measuring the binding of anticodon stem loops to short oligonucleotides, we determined that family-box codon:anticodon pairings are typically tighter than split-box codon:anticodon pairings. Furthermore, we find that two family-box anticodon stem loops can tightly bind a pair of contiguous codons simultaneously, whereas two split-box anticodon stem loops cannot. The amino acids assigned to family boxes correspond to those accessible by what has been termed cyanosulfidic chemistry, supporting the contention that these limited amino acids might have been the first used in primordial coded peptide synthesis.

The impact of racism on Black American mental health.

Black individuals in the USA experience disparities in mental health that lead to unfavorable health outcomes and increased morbidity from mental illness due to centuries of racism. We emphasize the need to understand the roots of racial injustice to achieve racial equity. Historical factors such as European imperialism, enslavement, the myth of Black inferiority, and scientific racial classification have all perpetuated disparities, leading to the current underestimation, misdiagnosis, and inadequate treatment of mental illness in Black populations. Many of the issues discussed herein apply to Black people globally; however, our focus is on Black Americans and the inequities that result from the current US mental health system. We discuss the limitations of using the DSM-5 classification system and common epidemiological surveys, which do not capture or call for a comprehensive analysis of the systems producing mental health issues, to understand mental illness among Black Americans.

A simple formula to control posterior tibial slope during proximal tibial osteotomies.

BACKGROUND: High tibial osteotomy surgery is a widely successful joint-preserving procedure which alters the hip-knee-ankle axis which can delay the progression of osteoarthritis; however, conventional osteotomy surgical procedures do not adequately control the posterior tibial slope. This study aimed to determine the key variables influencing posterior tibial slope during high tibial osteotomy and provide a simple means of implementing the findings during pre-operative planning. METHODS: A virtual cohort of twenty-eight proximal tibia geometries of knee osteoarthritis patients was used in the study. Firstly, absolute posterior tibial slope values were contrasted using anatomical and posterior mechanical axis measurement approaches. Secondly, the influence of variables affecting posterior tibial slope change during osteotomy surgery was investigated using 3D preoperative planning surgical simulation and analytical modelling. FINDINGS: There was a poor correlation (R2 = 0.38) between the different clinical measurements of posterior tibial slope; with an average of 7.0 ± 1.3° and 14.8 ± 2.2° respectively. An analytical solution for the change in posterior tibial slope was derived based on the hinge axis angle and the osteotomy opening angle. For three different opening angles (6°, 9° and 12°) and seven different hinge axis orientations (-30° to +30°), the results obtained were identical for the analytical model and the 3D preoperative planning. INTERPRETATION: This study determined that the key variables affecting posterior tibial slope during high tibial osteotomy are the osteotomy opening angle and the hinge axis orientation. The derived formula provides a simple means of determining the change in posterior tibial slope resulting from a particular surgical approach.

Simultaneous cochlear implantation during resection of a cerebellopontine angle meningioma: case report.

Cerebellopontine angle (CPA) meningiomas commonly involve the internal auditory canal (IAC). We report a case of a 68-year-old lady with idiopathic profound bilateral deafness with a meningioma which was discovered on workup for cochlear implantation. We performed simultaneous excision of her CPA and IAC meningioma with insertion of a cochlear implant (CI). She regained functional hearing with marked improvement in quality of life. Intraoperative electrophysiological testing can be used to confirm preservation of the cochlear nerve enabling simultaneous implantation which is preferable for clinical and logistical reasons. This creates an option for hearing rehabilitation at the time of IAC/CPA tumour surgery in appropriate patients.

Degeneracy in Intercalated Pb Phases under Buffer-Layer Graphene on SiC(0001) and Diffuse Moiré Spots in Surface Diffraction.

First-principles density functional theory (DFT) is used to analyze the stability of Pb intercalated phases under buffer layer graphene on SiC(0001) as a function of the supercell size, Pb coverage, and degree of Pb ordering. By comparing the chemical potentials of such two-dimensional Pb structures, we find that there is a family of structurally distinct thermodynamically preferred Pb subsurface configurations with minute stability differences. These differences are comparable to the thermal energies at about 450 °C, where the Pb intercalated phases are grown. High-resolution surface-diffraction experiments using Spot Profile Analysis Low-Energy Electron Diffraction (SPA-LEED) confirm this high degree of degeneracy of the Pb intercalated phases from broad, low-intensity moiré spots observed exclusively from intercalated Pb. The low intensity of the moiré spots implies the coexistence of structurally different subsurface Pb phases.

Triplet-Encoded Prebiotic RNA Aminoacylation.

The encoding step of translation involves attachment of amino acids to cognate tRNAs by aminoacyl-tRNA synthetases, themselves the product of coded peptide synthesis. So, the question arises─before these enzymes evolved, how were primordial tRNAs selectively aminoacylated? Here, we demonstrate enzyme-free, sequence-dependent, chemoselective aminoacylation of RNA. We investigated two potentially prebiotic routes to aminoacyl-tRNA acceptor stem-overhang mimics and analyzed those oligonucleotides undergoing the most efficient aminoacylation. Overhang sequences do not significantly influence the chemoselectivity of aminoacylation by either route. For aminoacyl-transfer from a mixed anhydride donor strand, the chemoselectivity and stereoselectivity of aminoacylation depend on the terminal three base pairs of the stem. The results support early suggestions of a second genetic code in the acceptor stem.

Photochemistry of 2-thiooxazole: a plausible prebiotic precursor to RNA nucleotides.

Potentially prebiotic chemical reactions leading to RNA nucleotides involve periods of UV irradiation, which are necessary to promote selectivity and destroy biologially irrelevant side products. Nevertheless, UV light has only been applied to promote specific stages of prebiotic reactions and its effect on complete prebiotic reaction sequences has not been extensively studied. Here, we report on an experimental and computational investigation of the photostability of 2-thiooxazole (2-TO), a potential precursor of pyrimidine and 8-oxopurine nucleotides on early Earth. Our UV-irradiation experiments resulted in rapid decomposition of 2-TO into unidentified small molecule photoproducts. We further clarify the underlying photochemistry by means of accurate ab initio calculations and surface hopping molecular dynamics simulations. Overall, the computational results show efficient rupture of the aromatic ring upon the photoexcitation of 2-TO via breaking of the C-O bond. Consequently, the initial stage of the divergent prebiotic synthesis of pyrimidine and 8-oxopurine nucleotides would require periodic shielding from UV light either with sun screening chromophores or through a planetary scenario that would protect 2-TO until it is transformed into a more stable intermediate compound, e.g. oxazolidinone thione.

Mechanism of gelation in high nickel content cathode slurries for sodium-ion batteries.

Sodium-ion batteries are a prospective sustainable alternative to the ubiquitous lithium-ion batteries due to the abundancy of sodium, and their cobalt free cathodes. The high nickel O3-type oxides show promising energy densities, however, a time dependency in the rheological properties of the composite electrode slurries is observed, which leads to inhomogeneous coatings being produced. A combination of electron microscopy and infra-red spectroscopy were used to monitor the O3-oxide surface changes upon exposure to air, and the effect upon the rheology and stability of the inks was investigated. Upon exposure to air, NaOH rather than Na2CO3 was observed on the surfaces of the powder through FTIR and EDS. The subsequent gelation of the slurry was initiated by the NaOH and dehydrofluorination with crosslinking of PVDF was observed through the reaction product, NaF. Approximately 15% of the CF bonds in PVDF undergo this dehydrofluorination to form NaF. As observed in the relaxation time of fitted rheological data, the gelation undergoes a three-stage process: a dehydrofluorination stage, creating saturated structures, a crosslinking stage, resulting in the highest rate of gelation, and a final crosslinking stage. This work shows the mechanism for instability of high nickel containing powders and electrode slurries, and presents a new time dependent oscillatory rheology test that can be used to determine the process window for these unstable slurry systems.

Template-Free Assembly of Functional RNAs by Loop-Closing Ligation.

The first ribozymes are thought to have emerged at a time when RNA replication proceeded via nonenzymatic template copying processes. However, functional RNAs have stable folded structures, and such structures are much more difficult to copy than short unstructured RNAs. How can these conflicting requirements be reconciled? Also, how can the inhibition of ribozyme function by complementary template strands be avoided or minimized? Here, we show that short RNA duplexes with single-stranded overhangs can be converted into RNA stem loops by nonenzymatic cross-strand ligation. We then show that loop-closing ligation reactions enable the assembly of full-length functional ribozymes without any external template. Thus, one can envisage a potential pathway whereby structurally complex functional RNAs could have formed at an early stage of evolution when protocell genomes might have consisted only of collections of short replicating oligonucleotides.

Potentially Prebiotic Synthesis of Aminoacyl-RNA via a Bridging Phosphoramidate-Ester Intermediate.

Translation according to the genetic code is made possible by selectivity both in aminoacylation of tRNA and in anticodon/codon recognition. In extant biology, tRNAs are selectively aminoacylated by enzymes using high-energy intermediates, but how this might have been achieved prior to the advent of protein synthesis has been a largely unanswered question in prebiotic chemistry. We have now elucidated a novel, prebiotically plausible stereoselective aminoacyl-RNA synthesis, which starts from RNA-amino acid phosphoramidates and proceeds via phosphoramidate-ester intermediates that subsequently undergo conversion to aminoacyl-esters by mild acid hydrolysis. The chemistry avoids the intermediacy of high-energy mixed carboxy-phosphate anhydrides and is greatly favored under eutectic conditions, which also potentially allow for the requisite pH fluctuation through the variable solubility of CO2 in solid/liquid water.

Eficacia de la cánula nasal de alto flujo en patologías respiratorias / Efficiency of high flow nasal cannula in pediatric respiratory pathologies

Introducción: En la edad pediátrica hay factores predisponentes importantes que hacen a los niños ser más vulnerables a presentar insuficiencia respiratoria aguda (IRA). Objetivo: Demostrar los beneficios del uso de la cánula nasal de alto flujo (CNAF) en pacientes menores de 5 años con IRA secundaria a enfermedades respiratorias y admitidos a la unidad de cuidados intensivos pediátricos (UCIP). Sujetos y Métodos: Estudio analítico observacional de cohortes mixtas, donde una cohorte esta formada por un grupo expuesto a la CNAF evaluada de manera prospectiva, mientras se comparo con una cohorte histórica. Resultados: 138 pacientes fueron admitidos al estudio de los cuales 69 fueron casos manejados con CNAF y 69 fueron controles que no estuvieron expuestos al uso de la CNAF pero sí a otros modos de ventilación mecánica invasiva. Los días de oxigenoterapia fueron estadísticamente menores en el grupo de casos de 13 (DE 8.01) días a 22 (DE 20.7) días en el grupo control (P = <0.05). Al igual los días de UCIP y los días totales de hospitalización fueron menores en el grupo manejado con CNAF (P = 0.011 y P = 0.001, respectivamente), con una media de tiempo de 10 (DE 7.8) días en UCIP y 17 (DE 9.25) días intrahospitalarios para el grupo de casos versus 14 (DE 10.1) días en UCIP y 28 (DE 23.9) días intrahospitalarios para el grupo control. Conclusión: La CNAF es un método de soporte respiratorio no invasivo, efectivo y fácil de usar en la población pediátrica con IRA secundario a diversas patologías respiratorias.

Introduction: During pediatric ages there are important predisposing factors that make children more vulnerable to present acute respiratory failure (ARF). Objective: Determine the benefits of the use of high flow nasal cannula (HFNC) in patients younger than 5 years with ARF, secondary to respiratory diseases and admitted to the pediatric intensive care unit (PICU). Subjects and Method: Analytical observational study of mixed type cohorts, where a cohort is formed by the group exposed to HFNC and evaluated prospectively, while it was compared with a historical cohort. Results: 138 patients were admitted to the study of which 69 were cases handled with HFNC and 69 were controls who were not exposed to the use of HFNC but to other types of invasive mechanical ventilation. Oxygen therapy days were statistically shorter in the case group from 13 (SD 8.01) days to 22 (SD 20.7) days in the control group (P = <0.05). The length of stay in PICU and the total inpatient days were lower in the group managed with HFNC (P = 0.011, P = 0.001), with a mean time of 10 (SD 7.8) days in PICU and 17 (SD 9.25) inpatient days for the case group versus 14 (SD 10.1) days in PICU and 28 (SD 23.9) inpatient days for the control group. Conclusion: HFNC system is a non-invasive respiratory support method, simple, effective and easy to use in the pediatric population less than 5 years of age with ARF due to various respiratory diseases.

On the Solubility and Stability of Polyvinylidene Fluoride.

This literature review covers the solubility and processability of fluoropolymer polyvinylidine fluoride (PVDF). Fluoropolymers consist of a carbon backbone chain with multiple connected C-F bonds; they are typically nonreactive and nontoxic and have good thermal stability. Their processing, recycling and reuse are rapidly becoming more important to the circular economy as fluoropolymers find widespread application in diverse sectors including construction, automotive engineering and electronics. The partially fluorinated polymer PVDF is in strong demand in all of these areas; in addition to its desirable inertness, which is typical of most fluoropolymers, it also has a high dielectric constant and can be ferroelectric in some of its crystal phases. However, processing and reusing PVDF is a challenging task, and this is partly due to its limited solubility. This review begins with a discussion on the useful properties and applications of PVDF, followed by a discussion on the known solvents and diluents of PVDF and how it can be formed into membranes. Finally, we explore the limitations of PVDF's chemical and thermal stability, with a discussion on conditions under which it can degrade. Our aim is to provide a condensed overview that will be of use to both chemists and engineers who need to work with PVDF.

A Case of Focal Dermal Hypoplasia (Goltze Syndrome) Masquerading as Lingual Tonsillar Hypertrophy.

Focal dermal hypoplasia is a rare condition affecting organ systems of mesodermal origin. We present a rare case of this condition presenting with apparent palatine tonsillar regrowth and outline our management. Airway management should always be a consideration in this rare condition.

Photostability of oxazoline RNA-precursors in UV-rich prebiotic environments.

Pentose aminooxazolines and oxazolidinone thiones are considered as the key precursors which could have enabled the formation of RNA nucleotides under the conditions of early Earth. UV-irradiation experiments and quantum-chemical calculations demonstrate that these compounds are remarkably photostable and could accumulate over long periods of time in UV-rich prebiotic environments to undergo stereoisomeric purification.