Young Joo Sun

There is a growing number of articles about conversational AI (i.e., ChatGPT) for generating scientific literature reviews and summaries. Yet, comparative evidence lags its wide adoption by many clinicians and researchers. We explored ChatGPT’s utility for literature search from an end-user perspective through the lens of clinicians and biomedical researchers. We quantitatively compared basic versions of ChatGPT’s utility against conventional search methods such as Google and PubMed. We further tested whether ChatGPT user-support tools (i.e., plugins, web-browsing function, prompt-engineering, and custom-GPTs) could improve its response across four common and practical literature search scenarios: (1) high-interest topics with an abundance of information, (2) niche topics with limited information, (3) scientific hypothesis generation, and (4) for newly emerging clinical practices questions. Our results demonstrated that basic ChatGPT functions had limitations in consistency, accuracy, and relevancy. User-support tools showed improvements, but the limitations persisted. Interestingly, each literature search scenario posed different challenges: an abundance of secondary information sources in high interest topics, and uncompelling literatures for new/niche topics. This study tested practical examples highlighting both the potential and the pitfalls of integrating conversational AI into literature search processes, and underscores the necessity for rigorous comparative assessments of AI tools in scientific research.

Purpose: To determine the prevalence of SARS-CoV-2 in tear samples and to investigate whether it correlates with ocular findings and patients’ prognosis in Brazil. Methods: Tears were collected using Schirmer strips (SS) and conjunctival swabs (CS) from patients hospitalized with laboratory-confirmed SARS-CoV-2 infection. Samples were analyzed using qRT-PCR. Demographic and clinical data, ocular symptoms, and Schirmer tests (ST) were collected from patients. Charlson Comorbidity Index (CCI) was used to rate comorbidities, and patients were monitored until hospital discharge or death. Results: There were 61 hospitalized patients, 33 of which were diagnosed with COVID-19. Within the confirmed COVID-19 patients, SARS-CoV-2 was detected in 18.2% (n = 6) of CS and 12.1% (n = 4) of SS samples. Subjective and objective parameters for dry eye syndrome (e.g., ST COVID-19: 8.3 ± 6.4mm, non-COVID-19: 8.9 ± 6.6mm, p > 0.05) were comparable between COVID-19 (n = 33) and non-COVID-19 patients (n = 28). Among the 16 COVID-19 patients exhibiting ocular symptoms, only tearing was reported significantly more frequently when tear samples were positive for SARS-CoV-2 (p < 0.05). Strikingly, patients whose tears tested positive for SARS-CoV-2 had significantly inferior CCI (pos.: 34.0 ± 31.8%, neg.: 67.6 ± 36.4%, p < 0.05) and higher mortality rates (pos.: 50.0%, neg.: 7.4%, p < 0.01). Conclusions: SARS-CoV-2 was detected with a prevalence of 18.2% on the ocular surface. Decreased CCI and increased mortality rate in the positive tear group suggests that viral detection may relate to prognosis and highlight the need of personal protective measures for healthcare professionals. Most of the patients, regardless of COVID-19 diagnosis, had low tear production and eye discomfort, possibly pointing to the need for artificial tear use during hospitalization.

Postsynaptic density-95, disks-large, and zonula occludens-1 (PDZ) domain interactions with cognate linear binding motifs (i.e., PDZ-binding motifs or PBMs) are important for many biological processes and can be pathological when disrupted. There are hundreds of PDZ–PBM interactions reported but few have been quantitatively determined. Moreover, PDZ–PBM interactions have been identified as potential therapeutic targets. To thoroughly understand PDZ–PBM binding energetics and their specificity, we have developed a sensitive and quantitative equilibrium binding assay. Here, we describe a protocol for determining PDZ–PBM binding energetics using fluorescence anisotropy-based methodology.

Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS coronavirus 2 (SARS-CoV-2) viral entry and may represent such a target. We hypothesized that drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool named 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo. Several candidate compounds, avoralstat, PCI-27483, antipain, and soybean trypsin inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested kallikrein-related B1 inhibitor, inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, avoralstat significantly reduced lung tissue titers and mitigated weight loss when administered prophylactically to mice susceptible to SARS-CoV-2, indicating its potential to be repositioned for coronavirus disease 2019 (COVID-19) prophylaxis in humans.

Ocular disorders originating in the retina can result in a partial or total loss of vision, making drug delivery to the retina of vital importance. However, effectively delivering drugs to the retina remains a challenge for ophthalmologists due to various anatomical and physicochemical barriers in the eye. This review introduces diverse administration routes and the accordant pharmacokinetic profiles of ocular drugs to aid in the development of safe and efficient drug delivery systems to the retina with a focus on peptidomimetics as a growing class of retinal drugs, which have great therapeutic potential and a high degree of specificity. We also discuss the pharmacokinetic profiles of small molecule drugs due to their structural similarity to small peptidomimetics. Lastly, various formulation strategies are suggested to overcome pharmacokinetic hurdles such as solubility, retention time, enzymatic degradation, tissue targeting, and membrane permeability. This knowledge can be used to help design ocular delivery platforms for peptidomimetics, not only for the treatment of various retinal diseases, but also for the selection of potential peptidomimetic drug targets.

Summary: Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals and vaccination. Transmembrane serine protease 2 (TMPRSS2) is a human protease required for SARS-CoV-2 viral entry and may represent such a target. ^1–3 We hypothesized drugs selected from proteins related by their tertiary structure, rather than their primary structure, were likely to interact with TMPRSS2. We created a structure-based phylogenetic computational tool 3DPhyloFold to systematically identify structurally similar serine proteases with known therapeutic inhibitors and demonstrated effective inhibition of SARS-CoV-2 infection in vitro and in vivo . ^4,5 Several candidate compounds, Avoralstat, PCI-27483, Antipain, and Soybean-Trypsin-Inhibitor, inhibited TMPRSS2 in biochemical and cell infection assays. Avoralstat, a clinically tested Kallikrein-related B1 inhibitor, ⁶ inhibited SARS-CoV-2 entry and replication in human airway epithelial cells. In an in vivo proof of principle, ⁵ Avoralstat significantly reduced lung tissue titers and mitigated weight-loss when administered prophylactically to SARS-CoV-2 susceptible mice indicating its potential to be repositioned for COVID-19 prophylaxis in humans.

Background: Mutations in the Kelch-like protein 7 (KLHL7) represent a recently described and, to date, poorly characterized etiology of inherited retinal dystrophy. Dominant mutations in KLHL7 are a cause of isolated, non-syndromic retinitis pigmentosa (RP). In contrast, recessive loss-of-function mutations are known to cause Crisponi or Bohring-Opitz like cold induced sweating syndrome-3 (BOS-3). In this study, the phenotype and progression of five unrelated patients with KLHL7 mediated autosomal dominant RP (adRP) are characterized. Clinical evaluation of these patients involved a complete ophthalmic exam, full-field electroretinography (ffERG), and imaging, including fundus photography, spectral domain optical coherence tomography (SD-OCT), short wavelength fundus autofluorescence (SW-AF), and near-infrared fundus autofluorescence (NIR-AF). Molecular diagnoses were performed using whole-exome sequencing or gene panel testing. Disease progression was monitored in three patients with available data for a mean follow up time of 4.5 ± 2.9 years. Protein modeling was performed for all variants found in this study in addition to those documented in the literature for recessive loss-of-function alleles causing Crisponi or Bohring-Opitz like cold-induced sweating syndrome. Results: Genetic testing in three patients identified two novel variants within the 3-box motif of the BACK domain: c.472 T > C:p.(Cys158Arg) and c.433A > T:p.(Asn145Tyr). Clinical imaging demonstrated hyperautofluorescent ring formation on both SW-AF and NIR-AF in three patients, with diffuse peripheral and peripapillary atrophy seen in all but one case. SD-OCT demonstrated a phenotypic spectrum, from parafoveal atrophy of the outer retina with foveal sparing to widespread retinal thinning and loss of photoreceptors. Incidence of cystoid macular edema was high with four of five patients affected. Protein modeling of dominant alleles versus recessive loss-of-function alleles showed dominant alleles localized to the BTB and BACK domains while recessive alleles were found in the Kelch domain. Conclusions: We report the phenotype in five patients with KLHL7 mediated adRP, two novel coding variants, and imaging biomarkers using SW-AF and NIR-AF. These findings may influence future gene-based therapies for adRP and pave the way for mechanistic studies that elucidate the pathogenesis of KLHL7-mediated RP.

A powerful approach to understand protein structure and evolution is to perform computer simulations that mimic aspects of evolution. In particular, structure-based computational protein design (CPD) can address the inverse folding problem, exploring a large space of amino acid sequences and selecting ones predicted to adopt a given fold. Previously, CPD has been used to entirely redesign several proteins: all or most of the protein sequence was allowed to mutate freely; among sampled sequences, those with low computed folding energy were selected, and a few percent of them did indeed adopt the correct fold. Those studies used an energy function that was partly or largely knowledge-based, with several empirical terms. Here, we show that a PDZ domain can be entirely redesigned using a "physics-based" energy function that combines standard molecular mechanics and a recent, continuum electrostatic solvent model. Many thousands of sequences were generated by Monte Carlo simulation. Among the lowest-energy sequences, three were chosen for experimental testing. All three could be overexpressed and had native-like circular dichroism and 1D NMR spectra. Two exhibited an upshift of their thermal denaturation curves when a peptide ligand was present, indicating they were able to bind and were most likely correctly folded. Evidently, the physical principles that govern molecular mechanics and continuum electrostatics are sufficient to perform whole-protein redesign. This is encouraging, since these methods provide physical insights, can be systematically improved, and are transferable to other biopolymers and ligands of medical or technological interest.