cometadata/datacite-titles-descriptions-related-identifiers huggingface dataset:
DOI: 10.6084/m9.figshare.25516680
title: A novel <i>LTBP2</i> gene variant in a Turkish family with juvenile-onset open-angle glaucoma

description: Juvenile-onset open-angle glaucoma (JOAG) is a rare form of primary open-angle glaucoma (POAG) with an early age of onset before 40 years. Latent transforming growth factor-beta binding protein 2 (LTBP-2) is an extracellular matrix protein with a multi-domain structure and homology to fibrillins. LTBP2 gene variants have been associated with JOAG in a small number of patients. Herein, we report a novel missense variant in the LTBP2 gene in a Turkish family with JOAG. Blood samples were obtained from three siblings (a 20-year-old woman with JOAG, 26-year-old man with JOAG, and 15-year-old girl with posterior embryotoxon) for genetic analysis. Their father had moderate-severe POAG and the 24-year-old brother had JOAG. The mother and 32-year-old sister were healthy. Although the parents reported no consanguinity, they come from the same village. Clinical exome sequencing analysis of the two siblings with JOAG revealed a novel c.607C&gt;T p.(R203C) (rs777450651) homozygous LTBP2 variant, while the variant was heterozygous in their 15-year-old sister. There were no mutations in the MYOC, CYP1B1, or FBN1 genes. We documented a novel missense mutation in the LTBP2 gene leading to a severe form of JOAG with refractory IOP and progressive optic nerve damage, which seems to show autosomal recessive inheritance.
DOI: 10.6084/m9.figshare.25516680.v1
title: A novel <i>LTBP2</i> gene variant in a Turkish family with juvenile-onset open-angle glaucoma

description: Juvenile-onset open-angle glaucoma (JOAG) is a rare form of primary open-angle glaucoma (POAG) with an early age of onset before 40 years. Latent transforming growth factor-beta binding protein 2 (LTBP-2) is an extracellular matrix protein with a multi-domain structure and homology to fibrillins. LTBP2 gene variants have been associated with JOAG in a small number of patients. Herein, we report a novel missense variant in the LTBP2 gene in a Turkish family with JOAG. Blood samples were obtained from three siblings (a 20-year-old woman with JOAG, 26-year-old man with JOAG, and 15-year-old girl with posterior embryotoxon) for genetic analysis. Their father had moderate-severe POAG and the 24-year-old brother had JOAG. The mother and 32-year-old sister were healthy. Although the parents reported no consanguinity, they come from the same village. Clinical exome sequencing analysis of the two siblings with JOAG revealed a novel c.607C&gt;T p.(R203C) (rs777450651) homozygous LTBP2 variant, while the variant was heterozygous in their 15-year-old sister. There were no mutations in the MYOC, CYP1B1, or FBN1 genes. We documented a novel missense mutation in the LTBP2 gene leading to a severe form of JOAG with refractory IOP and progressive optic nerve damage, which seems to show autosomal recessive inheritance.
DOI: 10.6084/m9.figshare.25525969
title: Variant in EZR leads to defects in lens development

description: Congenital cataract is a common cause of blindness. Genetic factors always play important role. This study identified a novel missense variant (c.1412C&gt;T (p.P471L)) in the EZR gene in a four-generation Chinese family with nuclear cataract by linkage analysis and whole-exome sequencing. A knockout study in zebrafish using transcription activator-like effector nucleases was carried out to gain insight into candidate gene function. Conservative and functional prediction suggests that the P-to-L substitution may impair the function of the human ezrin protein. Histology showed developmental delays in the ezrin-mutated zebrafish, manifesting as multilayered lens epithelial cells. Immunohistochemistry revealed abnormal proliferation patterns in mutant fish. The study suggests that ezrin may be involved in the enucleation and differentiation of lens epithelial cells.
DOI: 10.6084/m9.figshare.25525969.v1
title: Variant in EZR leads to defects in lens development

description: Congenital cataract is a common cause of blindness. Genetic factors always play important role. This study identified a novel missense variant (c.1412C&gt;T (p.P471L)) in the EZR gene in a four-generation Chinese family with nuclear cataract by linkage analysis and whole-exome sequencing. A knockout study in zebrafish using transcription activator-like effector nucleases was carried out to gain insight into candidate gene function. Conservative and functional prediction suggests that the P-to-L substitution may impair the function of the human ezrin protein. Histology showed developmental delays in the ezrin-mutated zebrafish, manifesting as multilayered lens epithelial cells. Immunohistochemistry revealed abnormal proliferation patterns in mutant fish. The study suggests that ezrin may be involved in the enucleation and differentiation of lens epithelial cells.
DOI: 10.6084/m9.figshare.25697884
title: Systematic study of ophthalmological findings in 10 patients with <i>PEX1</i>-mediated Zellweger spectrum disorder

description: This cross-sectional study describes the ophthalmological and general phenotype of 10 patients from six different families with a comparatively mild form of Zellweger spectrum disorder (ZSD), a rare peroxisomal disorder. Ophthalmological assessment included best-corrected visual acuity (BCVA), perimetry, microperimetry, ophthalmoscopy, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Medical records were reviewed for medical history and systemic manifestations of ZSD. Nine patients were homozygous for c.2528 G &gt; A (p.Gly843Asp) variants in <i>PEX1</i> and one patient was compound heterozygous for c.2528 G&gt;A (p.Gly843Asp) and c.2097_2098insT (p.Ile700TyrfsTer42) in <i>PEX1</i>. Median age was 22.6 years (interquartile range (IQR): 15.9 – 29.9 years) at the most recent examination, with a median symptom duration of 22.1 years. Symptom onset was variable with presentations of hearing loss (<i>n</i> = 7) or nyctalopia/reduced visual acuity (<i>n</i> = 3) at a median age of 6 months (IQR: 1.9–8.3 months). BCVA (median of 0.8 logMAR; IQR: 0.6–0.9 logMAR) remained stable over 10.8 years and all patients were hyperopic. Fundus examination revealed a variable retinitis pigmentosa (RP)-like phenotype with rounded hyperpigmentations as most prominent feature in six out of nine patients. Electroretinography, visual field measurements, and microperimetry further established the RP-like phenotype. Multimodal imaging revealed significant intraretinal fluid cavities on SD-OCT and a remarkable pattern of hyperautofluorescent abnormalities on FAF in all patients. This study highlights the ophthalmological phenotype resembling RP with moderate to severe visual impairment in patients with mild ZSD. These findings can aid ophthalmologists in diagnosing, counselling, and managing patients with mild ZSD.
DOI: 10.6084/m9.figshare.25697884.v1
title: Systematic study of ophthalmological findings in 10 patients with <i>PEX1</i>-mediated Zellweger spectrum disorder

description: This cross-sectional study describes the ophthalmological and general phenotype of 10 patients from six different families with a comparatively mild form of Zellweger spectrum disorder (ZSD), a rare peroxisomal disorder. Ophthalmological assessment included best-corrected visual acuity (BCVA), perimetry, microperimetry, ophthalmoscopy, fundus photography, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) imaging. Medical records were reviewed for medical history and systemic manifestations of ZSD. Nine patients were homozygous for c.2528 G &gt; A (p.Gly843Asp) variants in <i>PEX1</i> and one patient was compound heterozygous for c.2528 G&gt;A (p.Gly843Asp) and c.2097_2098insT (p.Ile700TyrfsTer42) in <i>PEX1</i>. Median age was 22.6 years (interquartile range (IQR): 15.9 – 29.9 years) at the most recent examination, with a median symptom duration of 22.1 years. Symptom onset was variable with presentations of hearing loss (<i>n</i> = 7) or nyctalopia/reduced visual acuity (<i>n</i> = 3) at a median age of 6 months (IQR: 1.9–8.3 months). BCVA (median of 0.8 logMAR; IQR: 0.6–0.9 logMAR) remained stable over 10.8 years and all patients were hyperopic. Fundus examination revealed a variable retinitis pigmentosa (RP)-like phenotype with rounded hyperpigmentations as most prominent feature in six out of nine patients. Electroretinography, visual field measurements, and microperimetry further established the RP-like phenotype. Multimodal imaging revealed significant intraretinal fluid cavities on SD-OCT and a remarkable pattern of hyperautofluorescent abnormalities on FAF in all patients. This study highlights the ophthalmological phenotype resembling RP with moderate to severe visual impairment in patients with mild ZSD. These findings can aid ophthalmologists in diagnosing, counselling, and managing patients with mild ZSD.
DOI: 10.6084/m9.figshare.23911785.v1
title: <i>In-silico</i> investigation of E8 surface protein of the monkeypox virus to identify potential therapeutic agents

description: The re-emergence of the monkeypox virus (MPXV) in 2022 has become a global issue. The virus was first found in Denmark in 1958. The first human MPXV disease was reported in 1980 in Congo, caused by a rare zoonotic virus belonging to the genus Orthopoxvirus and the family Poxviridae. Like SARS-CoV, there are no specific drugs to treat this infection. Taking cues from the successful implementation of drug repositioning for the Covid-19 pandemic using in silico drug discovery. We employed structure-based drug design in the study to repurpose the existing drug and natural product derivatives libraries against MPXV. The E8 protein was chosen as a therapeutic target because it is a surface membrane protein involved in viral entry and adhesion to the host cell surface membrane. Our study was bifurcated into the following steps; determining and analyzing the structure of the E8, followed by structure-based virtual screening of different datasets (natural products obtained from bacteria and fungi and FDA-approved drugs) to identify the hits. Based on the best binding affinities and protein-ligand interactions, we further proceeded for molecular dynamic (MD) studies of the identified hits, which revealed Gabosine D (docking score = −8.469 kcal/mol, MM/GBSA dG bind = −41.6729 kcal/mol) and Edoxudine (docking score = −6.372 kcal/mol, MM/GBSA dG bind = −35.8291 kcal/mol) as the best lead molecules. MD simulation for 100 ns was performed in triplicate, and post MM/GBSA analysis was conducted, which proves the stability of the identified leads. In addition, their ADME profiles also confirmed their suitability as therapeutic options for the treatment of monkeypox. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23911785
title: <i>In-silico</i> investigation of E8 surface protein of the monkeypox virus to identify potential therapeutic agents

description: The re-emergence of the monkeypox virus (MPXV) in 2022 has become a global issue. The virus was first found in Denmark in 1958. The first human MPXV disease was reported in 1980 in Congo, caused by a rare zoonotic virus belonging to the genus Orthopoxvirus and the family Poxviridae. Like SARS-CoV, there are no specific drugs to treat this infection. Taking cues from the successful implementation of drug repositioning for the Covid-19 pandemic using in silico drug discovery. We employed structure-based drug design in the study to repurpose the existing drug and natural product derivatives libraries against MPXV. The E8 protein was chosen as a therapeutic target because it is a surface membrane protein involved in viral entry and adhesion to the host cell surface membrane. Our study was bifurcated into the following steps; determining and analyzing the structure of the E8, followed by structure-based virtual screening of different datasets (natural products obtained from bacteria and fungi and FDA-approved drugs) to identify the hits. Based on the best binding affinities and protein-ligand interactions, we further proceeded for molecular dynamic (MD) studies of the identified hits, which revealed Gabosine D (docking score = −8.469 kcal/mol, MM/GBSA dG bind = −41.6729 kcal/mol) and Edoxudine (docking score = −6.372 kcal/mol, MM/GBSA dG bind = −35.8291 kcal/mol) as the best lead molecules. MD simulation for 100 ns was performed in triplicate, and post MM/GBSA analysis was conducted, which proves the stability of the identified leads. In addition, their ADME profiles also confirmed their suitability as therapeutic options for the treatment of monkeypox. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23943237
title: A therapeutic epitopes-based vaccine engineering against <i>Salmonella enterica</i> XDR strains for typhoid fever: a Pan-vaccinomics approach

description: A prevalent food-borne pathogen, <i>Salmonella enterica serotypes Typhi,</i> is responsible for gastrointestinal and systemic infections globally. <i>Salmonella</i> vaccines are the most effective, however, producing a broad-spectrum vaccine remains challenging due to <i>Salmonella’s</i> many serotypes. Efforts are urgently required to develop a novel vaccine candidate that can tackle all <i>S. Typhi</i> strains because of their high resistance to multiple kinds of antibiotics (particularly the XDR H58 strain). In this work, we used a computational pangenome-based vaccine design technique on all available (<i>n</i> = 119) <i>S. Typhi</i> reference genomes and identified one TonB-dependent siderophore receptor (WP_001034967.1) as highly conserved and prospective vaccine candidates from the predicted core genome (<i>n</i> = 3,351). The applied pan-proteomics and Immunoinformatic approaches help in the identification of four epitopes that may trigger adequate host body immune responses. Furthermore, the proposed vaccine ensemble demonstrates a stable binding conformation with the examined immunological receptor (HLAs and TRL2/4) and has large interaction energy determined <i>via</i> molecular docking and molecular dynamics simulation techniques. Eventually, an expression vector for the <i>Escherichia. coli</i> K12 strain was constructed from the vaccine sequence. Additional analysis revealed that the vaccine may help to elicit strong immune responses for typhoid infections, however, experimental analysis is required to verify the vaccine’s effectiveness based on these results. Moreover, the applied computer-assisted vaccine design may considerably decrease vaccine development costs and speed up the process. The study’s findings are intriguing, but they must be evaluated in the experimental labs to confirm the developed vaccine’s biological efficiency against XDR <i>S. Typhi</i>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23943237.v1
title: A therapeutic epitopes-based vaccine engineering against <i>Salmonella enterica</i> XDR strains for typhoid fever: a Pan-vaccinomics approach

description: A prevalent food-borne pathogen, <i>Salmonella enterica serotypes Typhi,</i> is responsible for gastrointestinal and systemic infections globally. <i>Salmonella</i> vaccines are the most effective, however, producing a broad-spectrum vaccine remains challenging due to <i>Salmonella’s</i> many serotypes. Efforts are urgently required to develop a novel vaccine candidate that can tackle all <i>S. Typhi</i> strains because of their high resistance to multiple kinds of antibiotics (particularly the XDR H58 strain). In this work, we used a computational pangenome-based vaccine design technique on all available (<i>n</i> = 119) <i>S. Typhi</i> reference genomes and identified one TonB-dependent siderophore receptor (WP_001034967.1) as highly conserved and prospective vaccine candidates from the predicted core genome (<i>n</i> = 3,351). The applied pan-proteomics and Immunoinformatic approaches help in the identification of four epitopes that may trigger adequate host body immune responses. Furthermore, the proposed vaccine ensemble demonstrates a stable binding conformation with the examined immunological receptor (HLAs and TRL2/4) and has large interaction energy determined <i>via</i> molecular docking and molecular dynamics simulation techniques. Eventually, an expression vector for the <i>Escherichia. coli</i> K12 strain was constructed from the vaccine sequence. Additional analysis revealed that the vaccine may help to elicit strong immune responses for typhoid infections, however, experimental analysis is required to verify the vaccine’s effectiveness based on these results. Moreover, the applied computer-assisted vaccine design may considerably decrease vaccine development costs and speed up the process. The study’s findings are intriguing, but they must be evaluated in the experimental labs to confirm the developed vaccine’s biological efficiency against XDR <i>S. Typhi</i>. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.24278631
title: Phytochemicals-based β-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer’s disease: molecular simulations-based predictions

description: Alzheimer’s disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.24278631.v1
title: Phytochemicals-based β-amyloid cleaving enzyme-1 and MAO-B inhibitors for the treatment of Alzheimer’s disease: molecular simulations-based predictions

description: Alzheimer’s disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23984010
title: Identification of CXCR4 inhibitors as a key therapeutic small molecule in renal fibrosis

description: The final stage of almost all chronic kidney diseases is renal fibrosis. Simple wounds or persistent inflammation can cause tissue inflammation, which, in the case of the kidney, results in scarring. Vascular sclerosis, tubulointerstitial fibrosis and glomerular fibrosis are all types of kidney fibrosis. Renal damage and fibrosis are caused by elevated expression of CXCR4. This study aimed to identify possible pharmacological agents which could bind to and inhibit isoform I of CXCR4 and determine their strength of interactions. The I-TASSER, Galaxyweb and Robetta were used to predict and refine the structure of the CXCR4 protein. ModBase was used to improve the loops, and then the quality was evaluated by using the ERRAT value (92.15) and Ramachandran plot. The improved 3D structure was subjected to small molecule database docking using Maestro (from Schrodinger) and the glide module. GROMACS was used to simulate molecules with the three top low glide scores and the best ADME properties. The best glide score was achieved by ligand ID 4990 (-11.5). Simulations, free energy landscape and residue decomposition analysis revealed that 4990 interacted more consistently with CXCR4 than the other two small molecules. Communicated by Ramaswamy H. Sarma
DOI: 10.6084/m9.figshare.23984010.v1
title: Identification of CXCR4 inhibitors as a key therapeutic small molecule in renal fibrosis

description: The final stage of almost all chronic kidney diseases is renal fibrosis. Simple wounds or persistent inflammation can cause tissue inflammation, which, in the case of the kidney, results in scarring. Vascular sclerosis, tubulointerstitial fibrosis and glomerular fibrosis are all types of kidney fibrosis. Renal damage and fibrosis are caused by elevated expression of CXCR4. This study aimed to identify possible pharmacological agents which could bind to and inhibit isoform I of CXCR4 and determine their strength of interactions. The I-TASSER, Galaxyweb and Robetta were used to predict and refine the structure of the CXCR4 protein. ModBase was used to improve the loops, and then the quality was evaluated by using the ERRAT value (92.15) and Ramachandran plot. The improved 3D structure was subjected to small molecule database docking using Maestro (from Schrodinger) and the glide module. GROMACS was used to simulate molecules with the three top low glide scores and the best ADME properties. The best glide score was achieved by ligand ID 4990 (-11.5). Simulations, free energy landscape and residue decomposition analysis revealed that 4990 interacted more consistently with CXCR4 than the other two small molecules. Communicated by Ramaswamy H. Sarma