Computational NMR Study of Benzothienoquinoline Heterohelicenes.

Early NMR studies of several heterohelicenes containing an annular nitrogen atom and a thiophene ring in their structure suggested the possibility of the lengthening of the carbon-carbon bonds in the interior of the helical turn of the molecule based on the progressive upfield shift of C resonances toward the center of the helical turn. We now report a comprehensive analysis of the optimized geometry and a comparison of the calculated vs. observed H and C NMR chemical shifts of nineteen representative benzothienoquinoline heterohelicenes.

Narrative Ability in Autism and First-Degree Relatives.

Narrative is an important communication skill for sharing personal experiences and connecting with others. Narrative skills are often impacted in autism spectrum disorder (ASD) and have important consequences for social interactions and relationships. Subtle differences in narrative have also been reported among first-degree relatives of autistic individuals, suggesting that narrative may also be an etiologically important language-related skill that is influenced by genes associated with ASD.

History and Prospects of Drug Discovery and Development Collaboration between Industry and Academia.

Research collaborations and licensing deals are critical for the discovery and development of life-saving drugs. This practice has been ongoing since the inception of the pharmaceutical industry. The current process of drug discovery and development is complex, regulated, and highly regimented, having evolved over time.

DFT investigation of coupling constant anomalies in substituted β-lactams.

β-lactams are a chemically diverse group of molecules with a wide range of biological activities. Having recently observed curious trends in J coupling values in studies on this structural class, we sought to obtain a more comprehensive understanding of these diagnostic NMR parameters, specifically interrogating J, J, and J, to differentiate 3- and 4-monosubstituted β-lactams. Further investigation using computational chemistry methods was employed to explore the geometric and electronic origins for the observed and calculated differences between the two substitution patterns.

A longitudinal investigation of pragmatic language across contexts in autism and related neurodevelopmental conditions.

Background: Pragmatic language, or the use of language in social contexts, is a critical skill in daily life, supporting social interactions and the development of meaningful social relationships. Pragmatic language is universally impacted in autism spectrum disorder (ASD) and pragmatic deficits are also common in other neurodevelopmental conditions, particularly those related to ASD, such as fragile X syndrome (FXS). This study used a multi-method, longitudinal approach to characterize potentially unique pragmatic profiles across different neurodevelopmental disabilities, and across contexts that varied in degree of social demand.

Unequivocal identification of two-bond heteronuclear correlations in natural products at nanomole scale by i-HMBC.

HMBC is an essential NMR experiment for determining multiple bond heteronuclear correlations in small to medium-sized organic molecules, including natural products, yet its major limitation is the inability to differentiate two-bond from longer-range correlations. There have been several attempts to address this issue, but all reported approaches suffer various drawbacks, such as restricted utility and poor sensitivity. Here we present a sensitive and universal methodology to identify two-bond HMBC correlations using isotope shifts, referred to as i-HMBC (isotope shift detection HMBC).

DELTA50: A Highly Accurate Database of Experimental H and C NMR Chemical Shifts Applied to DFT Benchmarking.

Density functional theory (DFT) benchmark studies of H and C NMR chemical shifts often yield differing conclusions, likely due to non-optimal test molecules and non-standardized data acquisition. To address this issue, we carefully selected and measured H and C NMR chemical shifts for 50 structurally diverse small organic molecules containing atoms from only the first two rows of the periodic table. Our NMR dataset, DELTA50, was used to calculate linear scaling factors and to evaluate the accuracy of 73 density functionals, 40 basis sets, 3 solvent models, and 3 gauge-referencing schemes.

Inducible generalized activation of hSTING-N154S expression in mice leads to lethal hypercytokinemia: a model for "cytokine storm".

Excessive levels of circulating proinflammatory mediators, known as "hypercytokinemia," that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens.

A profile of prosodic speech differences in individuals with autism spectrum disorder and first-degree relatives.

Background: Impairments in prosody (e.g., intonation, stress) are among the most notable communication characteristics of individuals with autism spectrum disorder (ASD) and can significantly impact communicative interactions.

Computational studies of [1]benzothieno[2,3-c]naphtho[1,2-f]quinoline.

Early NMR studies of several heterohelicenes containing an annular nitrogen atom and a thiophene ring in their structure suggested the possibility of the lengthening of the carbon-carbon bonds in the interior of the helical turn of the molecule based on the progressive more shielded nature of C resonances toward the center of the helical turn. Computational chemistry capabilities when those NMR studies were performed were primitive in comparison to what is now possible. We now report the optimized geometry and a comparison of the calculated versus observed H and C NMR chemical shift assignments for [1]benzothieno[2,3-c]naphtho[1,2-f]quinoline that confirms these suspicions.

J-modulated F- and H-detected dual-optimized inverted J 1,n-ADEQUATE: A universal ADEQUATE experiment.

The recently reported F-detected dual-optimized inverted J 1,n-ADEQUATE experiment and the previously reported H-detected version have been modified to incorporate J-modulation, making it feasible to acquire all 1,1- and 1,n-ADEQUATE correlations as well as J and J homonuclear scalar couplings in a single experiment. The experiments are demonstrated using N,N-dimethylamino-2,5,6-trifluoro-3,4-phthalonitrile and N,N-dimethylamino-3,4-phthalonitrile.

One-Step Regio- and Stereoselective Electrochemical Synthesis of Orexin Receptor Antagonist Oxidative Metabolites.

Synthesis of drug metabolites, which often have complex structures, is an integral step in the evaluation of drug candidate metabolism, pharmacokinetic (PK) properties, and safety profiles. Frequently, such synthetic endeavors entail arduous, multiple-step de novo synthetic routes. Herein, we present the one-step Shono-type electrochemical synthesis of milligrams of chiral α-hydroxyl amide metabolites of two orexin receptor antagonists, MK-8133 and MK-6096, as revealed by a small-scale (pico- to nano-mole level) reaction screening using a lab-built online electrochemistry (EC)/mass spectrometry (MS) (EC/MS) platform.

A study of solid-state epimerisation within lactose powders and implications for milk derived ingredients stored in simulated tropical environmental zones.

Isolated from milk, lactose is a food ingredient and an excipient in medicines. Its chiral forms are known to undergo epimerisation in solution but understanding whether this chemical reaction occurs in lactose powders exposed to tropical environments is of great importance for medicine stability and food quality. Thus, the aim of this study was to investigate epimerisation within lactose powders stored under specified conditions that model hot and humid climates.

Prediction of anisotropic NMR data without knowledge of alignment medium structure by surface decomposition.

Prediction of anisotropic NMR data directly from solute-medium interaction is of significant theoretical and practical interest, particularly for structure elucidation, configurational analysis and conformational studies of complex organic molecules and natural products. Current prediction methods require an explicit structural model of the alignment medium: a requirement either impossible or impractical on a scale necessary for small organic molecules. Here we formulate a comprehensive mathematical framework for a parametrization protocol that deconvolutes an arbitrary surface of the medium into several simple local landscapes that are distributed over the medium's surface by specific orientational order parameters.

Application of 1,1-ADEQUATE and DFT to correct C misassignments of carbonyl chemical shifts for carbapenem antibiotics.

Prior to the development of sensitive proton-detected 2D NMR experiments, assigning C signals could be a significant challenge, and mistakes have occurred even for prominent compound classes. In this study, 1,1-ADEQUATE data were used to unambiguously reassign the C chemical shifts for the β-lactam carbonyl at the C-7 position and the proximal carboxylate at the C-10 position of the carbapenems, meropenem and imipenem. Density functional theory (DFT) was then investigated to provide sufficiently accurate C chemical shift predictions, allowing for the carbonyl signal reassignment of thienamycin.

Cross-linguistic patterns of speech prosodic differences in autism: A machine learning study.

Differences in speech prosody are a widely observed feature of Autism Spectrum Disorder (ASD). However, it is unclear how prosodic differences in ASD manifest across different languages that demonstrate cross-linguistic variability in prosody. Using a supervised machine-learning analytic approach, we examined acoustic features relevant to rhythmic and intonational aspects of prosody derived from narrative samples elicited in English and Cantonese, two typologically and prosodically distinct languages.

Neural Processing of Speech Sounds in ASD and First-Degree Relatives.

Efficient neural encoding of sound plays a critical role in speech and language, and when impaired, may have reverberating effects on communication skills. This study investigated disruptions to neural processing of temporal and spectral properties of speech in individuals with ASD and their parents and found evidence of inefficient temporal encoding of speech sounds in both groups. The ASD group further demonstrated less robust neural representation of spectral properties of speech sounds.

Low-Density Lipoprotein Cholesterol Levels in Coronary Artery Disease Patients: Opportunities for Improvement.

Background: We sought to characterize the level of LDL-C control and identify opportunities for improvement and characteristics of patients who were undertreated.

Methods: Study patients were from a large multihospital system, age <90, with documentation of at least two encounters with a CAD diagnosis or procedure before a first measured LDL-C level and a last recorded LDL-C measurement over a minimum six-month (median = 22 months, IQR = 15-26 months) follow-up from January 2017 to September 2019. Linear regression analysis for last recorded LDL-C level was used to analyze the effects of statin intensity and patient characteristics.

Biodistribution and Activity of EGFR Targeted Polymeric Micelles Delivering a New Inhibitor of DNA Repair to Orthotopic Colorectal Cancer Xenografts with Metastasis.

The disruption of polynucleotide kinase/phosphatase (PNKP) in colorectal cancer (CRC) cells deficient in phosphatase and tensin homolog (PTEN) is expected to lead to the loss of cell viability by a process known as synthetic lethality. In previous studies, we have reported on the encapsulation of a novel inhibitor of PNKP, namely, A83B4C63, in polymeric micelles and its activity in slowing the growth of PTEN-deficient CRC cells as well as subcutaneous xenografts. In this study, to enhance drug delivery and specificity to CRC tumors, the surface of polymeric micelles carrying A83B4C63 was modified with GE11, a peptide targeting epidermal growth factor receptor (EGFR) overexpressed in about 70% of CRC tumors.

Childhood Academic Performance: A Potential Marker of Genetic Liability to Autism.

Autism spectrum disorder (ASD), a heritable neurodevelopmental disorder, confers genetic liability that is often expressed among relatives through subclinical, genetically-meaningful traits, or endophenotypes. For instance, relative to controls, parents of individuals with ASD differ in language-related skills, with differences emerging in childhood. To examine ASD-related endophenotypes, this study investigated developmental academic profiles among clinically unaffected siblings of individuals with ASD (n = 29).

Nano-Delivery of a Novel Inhibitor of Polynucleotide Kinase/Phosphatase (PNKP) for Targeted Sensitization of Colorectal Cancer to Radiation-Induced DNA Damage.

Inhibition of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) increases the sensitivity of cancer cells to DNA damage by ionizing radiation (IR). We have developed a novel inhibitor of PNKP, i.e.

A Longitudinal Study of Parent-Child Interactions and Language Outcomes in Fragile X Syndrome and Other Neurodevelopmental Disorders.

Difficulties with pragmatic language (i.e., language in social contexts, such as conversational ability) are a noted characteristic of the language profiles of both fragile X syndrome (FXS) and autism spectrum disorder (ASD), conditions which show significant phenotypic overlap.

F-detected dual-optimized inverted J 1,n-ADEQUATE.

Modification of the recently reported F-detected 1,1-ADEQUATE experiment that incorporates dual-optimization to selectively invert a wide range of J correlations in a 1,n-ADEQUATE experiment is reported. Parameters for the dual-optimization segment of the pulse sequence were modified to accommodate the increased size of J homonuclear coupling constants of poly- and perfluorinated molecules relative to protonated molecules to allow broadband inversion of the J correlations. The observation and utility of isotope shifts are reported for the first time for 1,1- and 1,n-ADEQUATE correlations.

The Phenotypic Profile Associated With the Premutation in Women: An Investigation of Clinical-Behavioral, Social-Cognitive, and Executive Abilities.

The gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the PM, and associations with -related variability. Participants included 152 female PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome.