Comparative Analysis of the Intrinsic Disorder Within the Layers of the Human Cornea.

PURPOSE: The human cornea is essential for vision, providing structural integrity and refractive power to the eye. Recent advancements have deepened our understanding of the corneal molecular composition, yet the role of intrinsically disordered proteins within the cornea is unexplored. METHODS: We analyzed 3,250 corneal proteins identified by Dyrlund et al, focusing on the epithelium, stroma, and endothelium layers. We performed a bioinformatics analysis to characterize the amino acid composition, the propensity for intrinsic protein disorder, and the distribution of protein types in 3 corneal layer proteome. RESULTS: Our study demonstrates that each corneal layer exhibited unique patterns in amino acid composition related to protein disorder. Order-promoting amino acids were generally depleted except for leucine, whereas disorder-promoting amino acids like arginine and glutamic acid were enriched across all layers. Significant variations were observed in the levels of intrinsic disorder among the different corneal layers, with substantial proportions of highly disordered proteins present in each. Analysis of protein class type in each layers revealed that no significant differences were detected in the distribution of protein classifications across the layers, suggesting a consistent population of the protein types across all corneal layers. CONCLUSIONS: Our findings reveal a sophisticated landscape of protein structures where intrinsic disorder varies across layers, suggesting an adaptation of the corneal proteome to the unique physiological demands of each layer. These structural variations may reflect the intricate requirements for corneal transparency, biomechanical stability, and environmental responsiveness.

APPLICATIONS OF MULTIMODAL GENERATIVE ARTIFICIAL INTELLIGENCE IN A REAL-WORLD RETINA CLINIC SETTING.

PURPOSE: This study evaluates a large language model, Generative Pre-trained Transformer 4 with vision, for diagnosing vitreoretinal diseases in real-world ophthalmology settings. METHODS: A retrospective cross-sectional study at Bascom Palmer Eye Clinic, analyzing patient data from January 2010 to March 2023, assesses Generative Pre-trained Transformer 4 with vision's performance on retinal image analysis and International Classification of Diseases 10th revision coding across 2 patient groups: simpler cases (Group A) and complex cases (Group B) requiring more in-depth analysis. Diagnostic accuracy was assessed through open-ended questions and multiple-choice questions independently verified by three retina specialists. RESULTS: In 256 eyes from 143 patients, Generative Pre-trained Transformer 4-V demonstrated a 13.7% accuracy for open-ended questions and 31.3% for multiple-choice questions, with International Classification of Diseases 10th revision code accuracies at 5.5% and 31.3%, respectively. Accurately diagnosed posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment. International Classification of Diseases 10th revision coding was most accurate for nonexudative age-related macular degeneration, central retinal vein occlusion, and macular hole in OEQs, and for posterior vitreous detachment, nonexudative age-related macular degeneration, and retinal detachment in multiple-choice questions. No significant difference in diagnostic or coding accuracy was found in Groups A and B. CONCLUSION: Generative Pre-trained Transformer 4 with vision has potential in clinical care and record keeping, particularly with standardized questions. Its effectiveness in open-ended scenarios is limited, indicating a significant limitation in providing complex medical advice.

Effects of Aging on Intrinsic Protein Disorder in Human Lenses and Zonules.

This study aims to compare the levels of intrinsic protein disorder within the human lens and zonule proteomes and investigate the role of aging as a potential influencing factor on disorder levels. A cross-sectional proteomic analysis was employed, utilizing a dataset of 1466 proteins derived from the lens and zonule proteomes previously published by Wang et al. and De Maria et al. Bioinformatics tools, including a composition profiler and a rapid intrinsic disorder analysis online tool, were used to conduct a comparative analysis of protein disorder. Statistical tests such as ANOVA, Tukey's HSD, and chi-squared tests were applied to evaluate differences between groups. The study revealed distinct amino acid compositions for each proteome, showing a direct correlation between aging and increased protein disorder in the zonular proteomes, whereas the lens proteomes exhibited the opposite trend. Findings suggest that age-related changes in intrinsic protein disorder within the lens and zonule proteomes may be linked to structural transformations in these tissues. Understanding how protein disorder evolves with age could enhance knowledge of the molecular basis for age-related conditions such as cataracts and pseudoexfoliation, potentially leading to better therapeutic strategies.

Intrinsic disorder in the human vitreous proteome.

The vitreous is a vital component of the eye, occupying a substantial portion of its volume and maintaining its structure. This study delves into the presence and significance of intrinsically disordered proteins (IDPs) within the vitreous, utilizing a dataset of 1240 vitreous proteins previously discovered in the vitreous proteome by Murthy et al.in five healthy subjects. The results indicate that 26.9 % of vitreous proteins are highly disordered, 68.8 % possess moderate disorder, and only 4.3 % are highly ordered. A complex interaction network among these proteins suggests their biological importance, and approximately 25 % may undergo liquid-liquid phase separation (LLPS). These findings offer new perspectives on the vitreous' molecular composition and behavior, potentially impacting our understanding of eye-related diseases, physiological changes such as vitreous syneresis. Further research is needed to translate these insights into clinical applications, although the intrinsic protein disorder and its association with LLPS appears to play a role in vitreous proteome function.

Does foreign aid affect innovation and institutional quality in middle-income countries?

In this study, we explore the dynamics between innovation, institutional quality, and foreign-aid flows in middle-income countries. Using an appropriate econometric model, we investigate the links between these variables in 79 middle-income countries (MICs) over 2005-2020. The results from our study show that foreign aid, institutional quality, and innovation have strong endogenous relationships. The short-run outcomes show that innovation Granger-causes institutional quality; foreign aid Granger-causes innovation; and quality of institutions Granger-causes foreign aid. The long-run outcomes indicate that institutional quality and innovation significantly affect the flow of foreign aid to the MICs. These results indicate that policy-makers in both foreign aid donor and recipient countries should pursue appropriate policies on foreign aid, quality of institutions, and innovation. For instance, in the short run, planners and evaluators in donor countries can direct their aid to MICs that have persistent challenges in improving their institutions and enhancing their innovative capabilities. In the long run, recipient countries ought to recognize that their institutional quality and innovation have a considerable impact on the inflows of foreign aid to their countries.

Correlation Between Altmetric Scores and Citation Count in 4 High-Impact Plastic Surgery Journals.

BACKGROUND: The Altmetric Attention Score (AAS) aims to determine the impact of research articles throughout the internet and social media outlets. The AAS is a weighted average of the interaction on platforms including Twitter, Facebook, Reddit, and more. OBJECTIVES: The aim of this study was to investigate the relationship between the AAS and traditional bibliometrics across plastic surgery journals. METHODS: Articles, number of citations (NOC), and H-index information in Annals of Plastic Surgery (APS), Plastic and Reconstructive Surgery (PRS), Plastic and Reconstructive Surgery Global Open (PRS GO), and Aesthetic Surgery Journal (ASJ) from 2017, 2018, and 2019 were queried with the Scopus Online Tool. AAS metrics were collected with the Altmetric Score Calculator Bookmarklet. Descriptive statistics, Spearman rank-correlation analyses, and analyses of variance were performed to measure associations between NOC and AAS. RESULTS: A total of 3612 articles were analyzed. NOC was weakly correlated with AAS in APS, PRS GO, and ASJ, and moderately correlated with AAS in PRS. NOC was weakly correlated with Twitter mentions in APS, PRS GO, and ASJ, and moderately correlated in PRS. NOC was weakly correlated with news outlet reporting. The H-index of the first author showed more significant correlations with the AAS than the H-index of the last author. CONCLUSIONS: NOC and H-index of the first author correlated with AAS in the plastic surgery literature, suggesting AAS may be a useful adjunct to traditional bibliometrics when evaluating the impact and reach of peer-reviewed articles.

Intrinsic Disorder in BAP1 and Its Association with Uveal Melanoma.

Background: Specific subvariants of uveal melanoma (UM) are associated with increased rates of metastasis compared to other subvariants. BRCA1 (BReast CAncer gene 1)-associated protein-1 (BAP1) is encoded by a gene that has been linked to aggressive behavior in UM. Methods: We evaluated BAP1 for the presence of intrinsically disordered protein regions (IDPRs) and its protein−protein interactions (PPI). We evaluated specific sequence-based features of the BAP1 protein using a set of bioinformatic databases, predictors, and algorithms. Results: We show that BAP1's structure contains extensive IDPRs as it is highly enriched in proline residues (the most disordered amino acid; p-value < 0.05), the average percent of predicted disordered residues (PPDR) was 57.34%, and contains 9 disorder-based binding sites (ie. molecular recognition features (MoRFs)). BAP1's intrinsic disorder allows it to engage in a complex PPI network with at least 49 partners (p-value < 1.0 × 10−16). Conclusion: These findings show that BAP1 contains IDPRs and an intricate PPI network. Mutations in UM that are associated with the BAP1 gene may alter the function of the IDPRs embedded into its structure. These findings develop the understanding of UM and may provide a target for potential novel therapies to treat this aggressive neoplasm.

Functional impact of titin (TTN) mutations in ocular surface squamous neoplasia.

Mutations in the titin (TTN) gene are among the most common genomic aberrations in ocular surface squamous neoplasia (OSSN), the most common cancer of the external eye. Further, TTN mutations are associated with resistance to standard therapy with topical interferon alpha-2b (IFN-α2b). However, it remains unclear how TTN mutations drive OSSN pathogenesis and treatment resistance. TTN encodes the largest protein in the human body and its best understood function is as a myofibril scaffold in striated muscle. However, recent evidence indicates that TTN has additional functions in non-muscle cells and in cancer. Here, we performed a disorder-based bioinformatics analysis which revealed that intrinsically disordered protein regions are abundant in TTN and provide mechanistic insights into its function as a nuclear protein in epithelial cells. Specific mutations found in OSSN are predicted to affect its intrinsically disordered protein regions (IDPRs), promoting chromosomal instability, oncogenesis, and altered response to IFN-α2b treatment.

Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma.

In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10-16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.

Expanding the understanding of the heterogeneous nature of melanoma with bioinformatics and disorder-based proteomics.

The past few decades show that incidences of melanoma are on the rise. The risk associated with this disease is an interplay between genetic and host factors and sun exposure. While scientific progress in the treatment of melanoma is remarkable, additional research is needed to improve patient outcomes and to better understand the heterogenous nature of this disease. Fortunately, as the clinical community enters the era of "big data" and personalized medicine, the rise of bioinformatics that stems from recent advances in high throughout profiling of biological information offers potential for innovative treatment options. This study aims to provide an example of the usefulness of bioinformatics and disorder-based proteomics to identify the molecular pathway in melanoma, garner information on selected proteins from this pathway and uncover their intrinsically disordered proteins regions (IDPRs) and investigate functionality implicated in these IDPRs. The present study provides a new look at the melanoma heterogeneity and suggests that, in addition to the well-established genetic heterogeneity of melanoma, there is another level of heterogeneity that lies within the conformational ensembles that stem from intrinsic disorder in melanoma-related proteins. The hope is that these insights will inspire future drug discovery campaigns.

Ferroptosis - An iron- and disorder-dependent programmed cell death.

Programmed cell death (PCD) is an integral component of both developmental and pathological features of an organism. Recently, ferroptosis, a new form of PCD that is dependent on reactive oxygen species and iron, has been described. As with apoptosis, necroptosis, and autophagy, ferroptosis is associated with a large set of proteins assembled in protein-protein interaction (PPI) networks, interactability of which is driven by the presence of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs). Previous investigations have identified the prevalence and functionality of IDPs/IDPRs in non-ferroptosis PCD. The intrinsic disorder in protein structures is used to increase the regulatory powers of these processes. As uncontrolled PCD is associated with the onset of various pathological traits, uncovering the association between intrinsic disorder and ferroptosis-related proteins is crucial. To understand this association, 31 human ferroptosis-related proteins were analyzed via a multi-dimensional array of bioinformatics and computational techniques. In addition, a disorder meta-predictor (PONDR® FIT) was implored to look at the evolutionary conservation of intrinsic disorder in these proteins. This study presents evidence that IDPs and IDPRs are prevalent in ferroptosis. The intrinsic disorder found in ferroptosis has far-reaching functional implications related to ferroptosis-related PPIs and molecular interactions.

Outcome of a Knowledge Contact-based Anti-stigma Programme in Adolescents and Adults in the Chinese Population.

A lack of knowledge about mental health and stigma of the mentally ill are barriers to the treatment of mental disorders. To reduce these barriers, anti-stigma campaigns using a knowledge contact approach were launched to raise public mental health knowledge by education and to reduce stigma by encouraging contact with individuals with mental disorders. The current study attempted to investigate the outcome of a knowledge contact-based programme in adolescents and adults in the Hong Kong Chinese population. Matched background individuals served as controls. Results from the 149 adolescents and 98 adults who participated in our programme showed that they had superior mental health literacy to the control group. Although both adolescents and adults showed a positive outcome on most measures of stigma, the former showed positive outcome on more measures of stigma than the latter. Our results support the initiative of using a knowledge contact-based anti-stigma campaign in Chinese societies. The results of this study provide preliminary data that will help inform and guide future research and development of effective mental health awareness programmes specific to people of various age-groups in the Chinese community.

Utility of the Health Belief Model in predicting compliance of screening in patients with chronic hepatitis B.

BACKGROUND: Regular surveillance is recommended for patients with chronic hepatitis B, to select candidates for anti-viral therapy and detect early complications. However, factors that determine compliance are not well studied. AIM: To determine the utility of the Health Belief Model in explaining non-compliance, among a group of chronic hepatitis B patients for screening. METHODS: A total of 192 chronic hepatitis B patients who responded to advertisement for free screening took part in a telephonic interview study. Subjects were asked about the five constructs of the Health Belief Model, and factors associated with recent screening were analysed. RESULTS: The mean age of the subjects was 42.1 +/- 0.7 years; 77% white male, and 97% Chinese. About 108 patients (56%) had recent screening. At multivariate analysis, only the ability to remember date of follow-up (OR: 4.37; 95% CI: 2.07-9.17) and the perception of having to wait a long time for venepuncture (OR: 0.38; 95% CI: 0.19-0.79) were significantly associated with recent screening. CONCLUSION: Future public health measures should include improving the logistics of follow-up procedures and providing reminders for screening to improve compliance.

The majority of hepatitis B carriers are not on regular surveillance in Singapore.

INTRODUCTION: Carriers of hepatitis B virus (HBV) are at risk of developing long-term complications. Regular surveillance helps detect treatable chronic hepatitis, cirrhosis and liver cancer, and is recommended by practice guidelines in the United States, Europe and Singapore. However, there have been few studies evaluating the follow-up of HBV carriers. This study seeks to determine the proportion of HBV carriers on regular follow-up in Singapore and the impact on hepatitis B disease. METHODS: An advertisement was taken in local newspapers advertising for free screening to HBV carriers. 387 persons answered the advertisement. The screening comprised history-taking, physical examination, blood tests (liver panel, alphafoetoprotein, hepatitis B surface antigen (Ag) and hepatitis B eAg) and ultrasonography of liver. Further evaluation was conducted if the screening results were abnormal. RESULTS: Of the 387 HBV carriers, 346 (89 percent) were male and 375 (97 percent) were Chinese. Their mean age was 39 years (range 20-60 years) and 36 percent were positive for HBeAg. 247 (64 percent) were not on regular screening over the past 12 months. 19 (5.4 percent) patients were diagnosed to have complications, namely: 13 had HBeAg-positive chronic hepatitis, two had HBeAg-negative chronic hepatitis, one had early liver cancer who recovered well after a curative resection and three had compensated cirrhosis. CONCLUSION: Our screening programme diagnosed 5.4 percent of complications among 387 asymptomatic HBV carriers. However, 64 percent of the study subjects were not screened regularly and may pose an important public health threat if they develop long-term complications. Further studies are needed to evaluate and improve patient compliance for screening.

A novel mutation in neonatal isolated sulphite oxidase deficiency.

Isolated sulphite oxidase deficiency (ISOD) is a very rare hereditary metabolic disorder. Imaging findings of the neonatal form of ISOD, including multicystic leukoencephalopathy with brain atrophy, resemble those of severe ischemic changes of the brain. We report the case of a ten-month-old boy who exhibited neonatal seizures on the 24th day after birth. Excessive quantities of sulphite and S-sulphocysteine in the urine and normal blood uric acid were noted. These findings were consistent with those of ISOD. Point mutations were found in two alleles of the sulphite oxidase (SUOX) gene. One of the mutations was a 1029 C > G mutation, which resulted in an amino acid substitution of tyrosine to a stop code (Y343 X); and the other was a 479 G > A mutation, which resulted in an amino acid substitution of arginine to glutamine (R160 Q). Y343 X is a novel SUOX gene mutation. A review of the literature, including data from this report, showed that 3 of 6 cases had typical imaging findings characterized by initial cerebral edema followed by dramatic multicystic leukoencephalopathy. We emphasize that neonatal ISOD should be included in the differential diagnosis of neonates with unexplained hypoxic-ischemic changes on neuroimaging studies.

Paclitaxel (Taxol) attenuates clinical disease in a spontaneously demyelinating transgenic mouse and induces remyelination.

Treatment with paclitaxel by four intraperitoneal injections (20 mg/kg) 1 week apart attenuated clinical signs in a spontaneously demyelinating model, if given with onset of clinical signs. If given at 2 months of age (1 month prior to clinical signs), disease was almost completely prevented The astrogliosis, prominent in our model, was reversed by paditaxel as determined by astrocyte counts and quantitation of GFAP. Electron microscopic examination of affected regions at 2.5 months demonstrated that the myelin was generally normal. By 4 months of age, demyelination was common in the superior cerebellar peduncle, maximal at 6 months, but continued to 8 months. In addition to myelin vacuolation and nude axons, the presence of many thin myelin sheaths suggested remyelination or partial demyelination. Although no evidence of oligodendrocyte loss was seen, nuclear changes were observed. To substantiate that remyelination was occurring, we measured MBP (18.5 kDa), MBP-exon II, Golli-MBP, TP8, Golli-MBP-J37, platelet-derived growth factor alpha (PDGFR alpha) and sonic hedgehog (SHH). Of these TP8, PDGFR alpha and SHH were up-regulated in the untreated transgenic. After paditaxel treatment, MBP-Exon II, TP8, PDGFR alpha and SHH were further up-regulated. We concluded that some of the effects of paditaxel were to stimulate proteins involved in early myelinating events possibly via a signal transduction mechanism.

New mutations of the HPRT gene in Lesch-Nyhan syndrome.

Lesch-Nyhan syndrome is an X-linked recessive disorder involving the purine metabolism, with resultant hyperuricemia, choreoathetosis, self-mutilation, and profound neurologic dysfunction. A deficiency of the enzyme hypoxanthine guanine phosphoribosyl-transferase is responsible for the disease. The human HPRT gene is located at Xq26-27 and consists of 57 base pairs. At least 2,000 mutations throughout the HPRT gene coding region from exon 1-9 have been reported. Four patients from three Chinese families were diagnosed with Lesch-Nyhan syndrome according to the clinical and laboratory findings. DNA studies revealed the first family (Patients 1 and 2) had a missense mutation in exon 3 of the HPRT encoding region. This novel mutation occurs in the hot spot of the HPRT gene. The second family (Patient 3) was found to have a missense mutation in exon 8 of the HPRT gene. The third family (Patient 4) carried a mutation in the splicing region of intron 4 of the HPRT gene. All three mutations were de novo.

The role of motion in children's categorization of objects.

Perceptual cues play a fundamental role in early categorization of objects. What is meant by perceptual cues in the literature, however, is not always clear. It is fair to say that they are typically understood to be static shape cues. A number of recent studies have suggested that dynamic perceptual cues, such as motion, may also be important in early categorization. The study presented here explored the role that motion plays in children's categorization of animal and non-animal kinds, such as geometric figures. Motion was directly pitted against shape as a cue for categorization. Results showed that 4-year-old children, confronted with a choice between shape and motion, significantly used motion cues over shape cues to categorize objects, regardless of whether they were animals or geometric figures. Seven-year-olds also tended to use motion more often to categorize animals but not when dealing with geometric figures. Older children, who have been found to have a clearer natural kind/artifact distinction, seem to appreciate the uniqueness of movement to animals and see motion as more relevant to their categorization but relatively less so to categorize geometric figures. This developmental shift in the categorization of animals and geometric figures based on motion was further confirmed by testing adults on the same tasks. Adults were found to base their judgements significantly more often on motion for animals but not for geometric figures. These findings support the view that children are initially guided by motion in object categorization, suggesting that motion plays an overriding role that is central in the process of concept acquisition and in the mechanisms by which concepts are later structured.

Mechanism of demyelination in DM20 transgenic mice involves increased fatty acylation.

Transgenic mice (ND4) containing 70 copies of the transgene encoding DM20 were clinically normal up to 3 months of age, spontaneously demyelinated there-after and died in 8-10 months. Whereas the myelin fraction from normal mice increased in amount from 1-4 months as expected, the corresponding fraction in ND4 mice remained constant over this period. In order to study the mechanism by which decreased myelin synthesis was manifest in the ND4 mouse, we investigated the amounts of proteolipids at various ages. The amount of proteolipid protein (PLP) was greatly decreased after 1-2 months in the ND4 mice. Although the message for DM20 was increased (transgene mRNA), very little DM20 was found in myelin at 1 month. It subsequently increased so that at 3-4 months the amount of DM20 in myelin isolated from transgenic animals was much higher than in normal mice. Characterization of the DM20 and PLP at 1 month of age showed that the amount of fatty acid (stearate and palmitate) was increased and the N-terminal glycine was methylated. These data suggested that high copy numbers of the cDNA for DM20 affected post translational events which we postulate affected the proper insertion of both DM20 and PLP in the myelin bilayer.