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. Academia excels in the discovery of fundamental scientific concepts and biological processes, while industry excels in translational science and product development. Potential for collaboration exists at every step of the drug discovery and development continuum. This perspective walks through such collaborative activities, provides examples, and offers tips for potential collaborations.

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

ß-lactams are a chemically diverse group of molecules with a wide range of biological activities. Having recently observed curious trends in 2JHH coupling values in studies on this structural class, we sought to obtain a more comprehensive understanding of these diagnostic NMR parameters, specifically interrogating 1JCH, 2JCH, and 2JHH, to differentiate 3- and 4-monosubstituted ß-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. The utility of computational linguistic analyses, as an efficient tool for capturing pragmatic abilities, was also explored. Methods: Pragmatic skills of boys with idiopathic ASD (ASD-O, n = 43), FXS with and without ASD (FXS-ASD, n = 57; FXS-O, n = 14), Down syndrome (DS, n = 22), and typical development (TD, n = 24) were compared using variables obtained from a standardized measure, narrative, and semi-naturalistic conversation at up to three time points. Results: Pragmatic language was most significantly impacted among males with ASD-O and FXS-ASD across all three contexts, with more difficulties in the least structured context (conversation), and also some differences based on FXS comorbidity. Patterns of group differences were more nuanced for boys with FXS-O and DS, with context having less of an impact. Clinical groups demonstrated minimal changes in pragmatic skills with age, with some exceptions. Computational language measurement tools showed some utility for measuring pragmatic skills, but were not as successful as traditional methods at capturing differences between clinical groups. Conclusion: Overlap and differences between ASD and other forms of neurodevelopmental disability in general, and between idiopathic and syndromic ASD in particular, have important implications for developing precisely tailored assessment and intervention approaches, consistent with a personalized medicine approach to clinical study and care in ASD.

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). Experimental utility was demonstrated at the sub-milligram / nanomole scale with only a few hours of acquisition time required for structure elucidation of several complex proton-deficient natural products, which could not be fully elucidated by conventional 2D NMR experiments. Because i-HMBC overcomes the key limitation of HMBC without significant reduction in sensitivity or performance, i-HMBC can be used as a complement to HMBC when unambiguous identifications of two-bond correlations are needed.

DELTA50: A Highly Accurate Database of Experimental 1H and 13C NMR Chemical Shifts Applied to DFT Benchmarking.

Density functional theory (DFT) benchmark studies of 1H and 13C 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 1H and 13C 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. The best performing DFT methodologies for 1H and 13C NMR chemical shift predictions were WP04/6-311++G(2d,p) and ωB97X-D/def2-SVP, respectively, when combined with the polarizable continuum solvent model (PCM) and gauge-independent atomic orbital (GIAO) method. Geometries should be optimized at the B3LYP-D3/6-311G(d,p) level including the PCM solvent model for the best accuracy. Predictions of 20 organic compounds and natural products from a separate probe set had root-mean-square deviations (RMSD) of 0.07 to 0.19 for 1H and 0.5 to 2.9 for 13C. Maximum deviations were less than 0.5 and 6.5 ppm for 1H and 13C, respectively.

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. STING activation, particularly within cells of the innate immune system, triggers potent type I interferon and proinflammatory cytokine production. We thus hypothesized that generalized expression of a constitutively active STING mutant in mice would lead to hypercytokinemia. To test this, a Cre-loxP-based system was used to cause the inducible expression of a constitutively active hSTING mutant (hSTING-N154S) in any tissue or cell type. Herein, we employed a tamoxifen-inducible ubiquitin C-CreERT2 transgenic to obtain generalized expression of the hSTING-N154S protein, thereby triggering the production of IFN-ß and multiple proinflammatory cytokines. This required euthanizing the mice within 3 to 4 d after tamoxifen administration. This preclinical model will allow for the rapid identification of compounds aimed at either preventing or ameliorating the lethal effects of hypercytokinemia.

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 13 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 1 H and 13 C NMR chemical shift assignments for [1]benzothieno[2,3-c]naphtho[1,2-f]quinoline that confirms these suspicions.

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. Evidence suggests that differences in prosody may be evident among first-degree relatives of autistic individuals, indicating that genetic liability to ASD is expressed through prosodic variation, along with subclinical traits referred to as the broad autism phenotype (BAP). This study aimed to further characterize prosodic profiles associated with ASD and the BAP to better understand the clinical and etiologic significance of prosodic differences. METHOD: Autistic individuals, their parents, and respective control groups completed the Profiling Elements of Prosody in Speech-Communication (PEPS-C), an assessment of receptive and expressive prosody. Responses to expressive subtests were further examined using acoustic analyses. Relationships between PEPS-C performance, acoustic measurements, and pragmatic language ability in conversation were assessed to understand how differences in prosody might contribute to broader ASD-related pragmatic profiles. RESULTS: In ASD, receptive prosody deficits were observed in contrastive stress. With regard to expressive prosody, both the ASD and ASD Parent groups exhibited reduced accuracy in imitation, lexical stress, and contrastive stress expression compared to respective control groups, though no acoustic differences were noted. In ASD and Control groups, lower accuracy across several PEPS-C subtests and acoustic measurements related to increased pragmatic language violations. In parents, acoustic measurements were tied to broader pragmatic language and personality traits of the BAP. CONCLUSION: Overlapping areas of expressive prosody differences were identified in ASD and parents, providing evidence that prosody is an important language-related ability that may be impacted by genetic risk of ASD.

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). Lower performance in language-related skills among siblings mirrored previously-reported patterns among parents, which were also associated with greater subclinical ASD-related traits in themselves and their parents, and with greater symptom severity in their sibling with ASD. Findings demonstrated specific phenotypes, derived from standardized academic testing, that may represent childhood indicators of genetic liability to ASD in first-degree relatives.

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. Associations between neural processing of speech sounds and language-related abilities were evident in both groups. Parent-child associations were also detected in neural pitch processing. Together, results suggest that atypical neural processing of speech sounds is a heritable ingredient contributing to the ASD language phenotype.

J-modulated 19 F- and 1 H-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE: A universal ADEQUATE experiment.

The recently reported 19 F-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE experiment and the previously reported 1 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 1 JCC and n JCC 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.

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. Powdered α-lactose monohydrate was stable under all conditions, whereas ß-lactose stored at 40 °C and 75 % RH suffered epimerisation, falling to 3.9 ± 0.3 ß-content after 6-months. Zero-order kinetics observed by NMR, indicated a shelf-life (5 % degradation) of 4.55-days for ß-lactose containing powders. Thermal analysis revealed monohydrate formation as ß-lactose epimerised, seen as tomahawk shaped α-lactose monohydrate crystals by SEM. Therefore, it is recommended ß-rich lactose containing powders, e.g., infant formula or direct compression tablet formulations, are stored hermetically in tropical zones.

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. The electrochemical oxidation of MK-8133 and MK-6096 was conducted in aqueous media and found to produce the corresponding α-piperidinols with exclusive regio- and stereoselectivity, as confirmed by high-resolution nuclear magnetic resonance (NMR) characterization of products. Based on density functional theory (DFT) calculations, the exceptional regio- and stereoselectivity for this electrochemical oxidation are governed by more favorable energetics of the transition state, leading to the preferred secondary carbon radical α to the amide group and subsequent steric hindrance associated with the U-shaped conformation of the cation derived from the secondary α-carbon radical, respectively.

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. The shapes and order parameters of these local landscapes are determined via fitting that maximizes the congruence between experimentally determined anisotropic NMR measurables and their predicted counterparts, thus avoiding the need for an a priori knowledge of the global medium morphology. This method achieves substantial improvements in the accuracy of predicted anisotropic NMR values compared to current methods, as demonstrated herein with sixteen natural products. Furthermore, because this formalism extracts structural commonalities of the medium by combining anisotropic NMR data from different compounds, its robustness and accuracy are expected to improve as more experimental data become available for further re-optimization of fitting parameters.

Application of 1,1-ADEQUATE and DFT to correct 13 C misassignments of carbonyl chemical shifts for carbapenem antibiotics.

Prior to the development of sensitive proton-detected 2D NMR experiments, assigning 13 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 13 C chemical shifts for the ß-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 13 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. Our models revealed successful classification of ASD diagnosis using rhythm-relative features within and across both languages. Classification with intonation-relevant features was significant for English but not Cantonese. Results highlight differences in rhythm as a key prosodic feature impacted in ASD, and also demonstrate important variability in other prosodic properties that appear to be modulated by language-specific differences, such as intonation.

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. Results: Among 15,111 eligible patients, mean age was 68.4 (SD = 10.8), 68.7% were male, and 79.4% were non-Hispanic White. At follow-up, 87.8% of patients were prescribed a statin, 9.7% were on ezetimibe, and 0.5% were on a PCSK9 inhibitor. Mean LDL-C at follow-up was 75.6 mg/dL and 45.5% of patients were on high-intensity treatment. Higher LDL-C values were associated with female sex, younger patients, non-Hispanic Black patients, high poverty or out of state zip code, Medicaid, or angina as the qualifying diagnosis. For 332 clinicians with >10 patients in the cohort, mean last recorded LDL-C values ranged from 47 to 102 mg/dL. Conclusions: There were important variations in LDL-C control between patients in our health system with the same indication for treatment. Variation in treatment among physicians is an area ripe for quality improvement interventions. This study may be easily reproduced by other medical centers and used for highlighting both patient and physician opportunities for improvement.

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. Using molecular dynamics (MD) simulations, we assessed the binding site and affinity of GE11 for EGFR. The GE11-modified micelles, tagged with a near-infrared fluorophore, showed enhanced internalization by EGFR-overexpressing CRC cells in vitro and a trend toward increased primary tumor homing in an orthotopic CRC xenograft in vivo. In line with these observations, the GE11 modification of polymeric micelles was shown to positively contribute to the improved therapeutic activity of encapsulated A83B4C63 against HCT116-PTEN-/- cells in vitro and that of orthotopic CRC xenograft in vivo. In conclusion, our results provided proof of principle evidence for the potential benefit of EGFR targeted polymeric micellar formulations of A83B4C63 as monotherapeutics for aggressive and metastatic CRC tumors but at the same time highlighted the need for the development of EGFR ligands with improved physiological stability and EGFR binding.

19 F-detected dual-optimized inverted 1 JCC 1,n-ADEQUATE.

Modification of the recently reported 19 F-detected 1,1-ADEQUATE experiment that incorporates dual-optimization to selectively invert a wide range of 1 JCC 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 1 JCC homonuclear coupling constants of poly- and perfluorinated molecules relative to protonated molecules to allow broadband inversion of the 1 JCC correlations. The observation and utility of isotope shifts are reported for the first time for 1,1- and 1,n-ADEQUATE correlations.

Which plants matter? A comparison of academic and community assessments of plant value and conservation status in the Moroccan High Atlas.

As interest in including local communities and their knowledge in biodiversity conservation increases, challenges to do so become clear. One of them is to harmonize local and academic assessments of conservation status. Here, we document the culturally valuable flora of two Amazigh communities in the Moroccan High Atlas Mountains and contrast local conservation observations with IUCN and other red-listing assessments. Our study reveals two levels of mismatch. Unsurprisingly, the species of interest of these two knowledge systems differ considerably. Moreover, species' availability and populations' trends of change and the conservation evaluations often diverge between local and academic assessments. Locally valuable species are rarely threatened, but a focus on locally prioritized species is essential to ensure the active participation of local communities in conservation initiatives. Given the salient role of IUCN Red Lists in guiding conservation action, a better understanding of the differences in plant value and conservation assessments between the two knowledge systems can help harmonize biodiversity conservation and community wellbeing goals.