Dynamic regulatory elements in single-cell multimodal data implicate key immune cell states enriched for autoimmune disease heritability.

In autoimmune diseases such as rheumatoid arthritis, the immune system attacks the body's own cells. Developing a precise understanding of the cell states where noncoding autoimmune risk variants impart causal mechanisms is critical to developing curative therapies. Here, to identify noncoding regions with accessible chromatin that associate with cell-state-defining gene expression patterns, we leveraged multimodal single-nucleus RNA and assay for transposase-accessible chromatin (ATAC) sequencing data across 28,674 cells from the inflamed synovial tissue of 12 donors. Specifically, we used a multivariate Poisson model to predict peak accessibility from single-nucleus RNA sequencing principal components. For 14 autoimmune diseases, we discovered that cell-state-dependent ('dynamic') chromatin accessibility peaks in immune cell types were enriched for heritability, compared with cell-state-invariant ('cs-invariant') peaks. These dynamic peaks marked regulatory elements associated with T peripheral helper, regulatory T, dendritic and STAT1+CXCL10+ myeloid cell states. We argue that dynamic regulatory elements can help identify precise cell states enriched for disease-critical genetic variation.

Inferring gene regulation from stochastic transcriptional variation across single cells at steady state.

Regulatory relationships between transcription factors (TFs) and their target genes lie at the heart of cellular identity and function; however, uncovering these relationships is often labor-intensive and requires perturbations. Here, we propose a principled framework to systematically infer gene regulation for all TFs simultaneously in cells at steady state by leveraging the intrinsic variation in the transcriptional abundance across single cells. Through modeling and simulations, we characterize how transcriptional bursts of a TF gene are propagated to its target genes, including the expected ranges of time delay and magnitude of maximum covariation. We distinguish these temporal trends from the time-invariant covariation arising from cell states, and we delineate the experimental and technical requirements for leveraging these small but meaningful cofluctuations in the presence of measurement noise. While current technology does not yet allow adequate power for definitively detecting regulatory relationships for all TFs simultaneously in cells at steady state, we investigate a small-scale dataset to inform future experimental design. This study supports the potential value of mapping regulatory connections through stochastic variation, and it motivates further technological development to achieve its full potential.

3-Deoxy-D-arabino-heptulosonate 7-phosphate synthase as the gatekeeper of plant aromatic natural product biosynthesis.

The shikimate pathway connects the central carbon metabolism with the biosynthesis of aromatic amino acids-l-tyrosine, l-phenylalanine, and l-tryptophan-which play indispensable roles as precursors of numerous aromatic phytochemicals. Despite the importance of the shikimate pathway-derived products for both plant physiology and human society, the regulatory mechanism of the shikimate pathway remains elusive. This review summarizes the recent progress and current understanding on the plant 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHP synthase or DHS) enzymes that catalyze the committed reaction of the shikimate pathway. We particularly focus on how the DHS activity is regulated in plants in comparison to those of microbes and discuss potential roles of DHS as the critical gatekeeper for the production of plant aromatic compounds.

Therapeutic effects of TP5, a Cdk5/p25 inhibitor, in in vitro and in vivo models of Parkinson's disease.

Parkinson's Disease (PD) is a chronic progressive neurodegenerative disease. Current treatments for PD are symptomatic and only increase striatal dopamine levels. Proactive neuroprotective approaches that slow the progression of PD and maintain appropriate dopamine neuron populations are needed to treat the disease. One suggested mechanism contributing to the pathology of PD involves the binding of cyclin-dependent kinase 5 (Cdk5) to p25, creating a hyperactivated complex to induce cell death. The objective of this study is to investigate the neuroprotective and neurorestorative properties of Truncated Peptide 5 (TP5), a derivative of the p35 activator involved in Cdk5 regulation, via the inhibition of Cdk5/p25 complex function. SH-SY5Y cell line and the nematode Caenorhabditis elegans were exposed to paraquat (PQ), an oxidative stressor, to induce Parkinsonian phenotypes. TP5 was administered prior to PQ exposure to determine its neuroprotective effects and, in further experiments, after PQ exposure to examine its neurorestorative effects. In the SH-SY5Y cell line, TP5 was found to have neuroprotective effects using a cell viability assay and demonstrated neuroprotective and neurorestorative effects in C. elegans by examining dopaminergic neurons and dopamine-dependent behaviour. TP5 decreased elevated Cdk5 activation in worms that were exposed to PQ. TP5's inhibition of Cdk5/p25 hyperactivity led to the protection of dopamine neurons in these PD models. This suggests that TP5 can act as a potential therapeutic drug towards PD.

Comparison of Plusoptix S12R photoscreener with cycloplegic retinoscopy and autorefraction in pediatric age group.

Purpose: To compare refractive measurements of noncycloplegic photoscreener Plusoptix S12R with cycloplegic retinoscopy, noncycloplegic autorefractor, and cycloplegic autorefractor in children. Methods: The study population (200 eyes of 100 children) was divided into two groups: Group 1 (age 3-7 years) and Group 2 (age 8-15 years). In Group 1, Plusoptix was compared with cycloplegic retinoscopy. In Group 2, Plusoptix was compared with cycloplegic retinoscopy and autorefraction. The second group was made because the younger group was found to be uncooperative for autorefraction. Paired t-test and Pearson's correlation were used for statistical analysis. Results: The mean difference in sphere (DS), spherical equivalent (DSE), and cylinder (DC) between cycloplegic retinoscopy and Plusoptix in Group 1 was 0.68 ± 0.55 (P < 0.001), 0.77 ± 0.61 (P < 0.001), and 0.18 ± 0.28 (P < 0.001), respectively. In Group 2, DS, DSE, and DC between cycloplegic retinoscopy and Plusoptix were 0.86 ± 0.49 (P < 0.001), 0.97 ± 0.51 (P < 0.001), and 0.23 ± 0.28 (P < 0.001); between cycloplegic autorefractor and Plusoptix were 0.69 ± 0.47 (P < 0.001), 0.74 ± 0.49 (P < 0.001), and 0.10 ± 0.31 (P = 0.002); and between noncycloplegic autorefractor and Plusoptix were - 0.25 ± 0.39 (P < 0.001), -0.19 ± 0.41 (P < 0.001), and 0.11 ± 0.31 (P < 0.001), respectively. Pearson's correlation coefficients of S, SE, and C between Plusoptix and cycloplegic retinoscopy were 0.948, 0.938, and 0.924 in Group 1 and 0.972, 0.972, and 0.946 in Group 2, and these values were statistically significant. Bland-Altman plots showed good agreement between cycloplegic retinoscopy and Plusoptix in both groups. Plusoptix gave axis values within 10° of cycloplegic retinoscopy in 81.56% of eyes in Group 1 and in 71.44% of eyes in Group 2. Conclusion: Plusoptix photoscreener can be used for prescription of axis of cylinder in children; however, other refractive measurements must be refined by cycloplegic retinoscopy.

Coalitional Game Theory Facilitates Identification of Non-Coding Variants Associated With Autism.

Studies on autism spectrum disorder (ASD) have amassed substantial evidence for the role of genetics in the disease's phenotypic manifestation. A large number of coding and non-coding variants with low penetrance likely act in a combinatorial manner to explain the variable forms of ASD. However, many of these combined interactions, both additive and epistatic, remain undefined. Coalitional game theory (CGT) is an approach that seeks to identify players (individual genetic variants or genes) who tend to improve the performance-association to a disease phenotype of interest-of any coalition (subset of co-occurring genetic variants) they join. This method has been previously applied to boost biologically informative signal from gene expression data and exome sequencing data but remains to be explored in the context of cooperativity among non-coding genomic regions. We describe our extension of previous work, highlighting non-coding chromosomal regions relevant to ASD using CGT on alteration data of 4595 fully sequenced genomes from 756 multiplex families. Genomes were encoded into binary matrices for three types of non-coding regions previously implicated in ASD and separated into ASD (case) and unaffected (control) samples. A player metric, the Shapley value, enabled determination of individual variant contributions in both sets of cohorts. A total of 30 non-coding positions were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Cross-study analyses revealed that a subset of mutated non-coding regions (all of which are in human accelerated regions (HARs)) and related genes are involved in biological pathways or behavioral outcomes known to be affected in autism, suggesting the importance of single nucleotide polymorphisms (SNPs) within HARs in ASD. These findings support the use of CGT in identifying hidden yet influential non-coding players from large-scale genomic data, to better understand the precise underpinnings of complex neurodevelopmental disorders such as autism.

Effect of Cycloplegia on Optical Biometry in Pediatric Eyes.

PURPOSE: To study the effect of cycloplegia on optical biometry parameters in pediatric eyes using the Lenstar LS 900 (Haag-Streit, Koeniz, Switzerland). METHODS: In this observational and comparative study, 56 normal eyes and 20 cataractous eyes in children between 5 and 15 years of age were included. Measurements were taken before and after cycloplegia using 2% homatropine drops. Parameters studied were axial length, central corneal thickness, keratometry, anterior chamber depth, and lens thickness. The Wilcoxon test was used to compare the effects of cycloplegia on all parameters. RESULTS: Cycloplegia resulted in a statistically significant decrease in axial length (P < .05), central corneal thickness (P < .05), and lens thickness (P < .001) and an increase in the anterior chamber depth (P < .001) in normal eyes. In the cataract group, cycloplegia resulted in an increase in anterior chamber depth (P < .001) and decrease in lens thickness (P < .001). CONCLUSIONS: Biometry measurements have to be carefully interpreted in pediatric eyes where cycloplegia is an important part of the examination. [J Pediatr Ophthalmol Strabismus. 2018;55(4):260-265.].

Coalitional game theory as a promising approach to identify candidate autism genes.

Despite mounting evidence for the strong role of genetics in the phenotypic manifestation of Autism Spectrum Disorder (ASD), the specific genes responsible for the variable forms of ASD remain undefined. ASD may be best explained by a combinatorial genetic model with varying epistatic interactions across many small effect mutations. Coalitional or cooperative game theory is a technique that studies the combined effects of groups of players, known as coalitions, seeking to identify players who tend to improve the performance--the relationship to a specific disease phenotype--of any coalition they join. This method has been previously shown to boost biologically informative signal in gene expression data but to-date has not been applied to the search for cooperative mutations among putative ASD genes. We describe our approach to highlight genes relevant to ASD using coalitional game theory on alteration data of 1,965 fully sequenced genomes from 756 multiplex families. Alterations were encoded into binary matrices for ASD (case) and unaffected (control) samples, indicating likely gene-disrupting, inherited mutations in altered genes. To determine individual gene contributions given an ASD phenotype, a "player" metric, referred to as the Shapley value, was calculated for each gene in the case and control cohorts. Sixty seven genes were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Using network and cross-study analysis, we found that these genes are involved in biological pathways known to be affected in the autism cases and that a subset directly interact with several genes known to have strong associations to autism. These findings suggest that coalitional game theory can be applied to large-scale genomic data to identify hidden yet influential players in complex polygenic disorders such as autism.

Foveal neovascularization in a patient with Type 2 diabetes mellitus.

Retinal neovascularization in Diabetes mellitus (DM) is commonly seen at the optic disc and mid-periphery. It is rare at the fovea as the fovea is an avascular zone and there are very few case reports of foveal neovascularization in Type 1 DM. We report a case of unilateral foveal neovascularization in Type 2 DM.

Peripheral retinal ischemia in a young Indian woman with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF-1) is an autosomal dominantly inherited disease characterized by café-au-lait spots, neurofibromas, axillary freckling, Lisch nodules of iris, gliomas and various systemic vascular ischemic manifestations mainly in the aorta, brain and kidney. Retinal vascular manifestations in patients with NF-1 are usually representative of retinal capillary hemangiomatosis. Few cases of NF-1 with retinal vascular occlusive disease have been described. We describe a young Indian woman with NF-1 with unilateral peripheral retinal ischemia but no vascular abnormality at the posterior pole.

Comparison of Goldmann applanation tonometer, Tono-Pen and noncontact tonometer in children.

BACKGROUND: To evaluate the agreement of Goldmann applanation tonometer (GAT) with Tono-Pen and noncontact tonometer (NCT) for measurement of intraocular pressure (IOP) in pediatric age group and to evaluate the correlation between central corneal thickness (CCT) and IOP measured with the tonometers used. MATERIALS AND METHODS: IOP was measured in 200 eyes in a group of Indian children, aged between 8 and 18 years using three different tonometers: NCT, the Tono-Pen and GAT. All IOP readings were made in the office settings by the same examiner. Readings obtained were compared between the instruments and with the CCT for each tonometer. Tonometer inter-method agreement was assessed by the Bland-Altmann method. The relations of CCT with absolute IOP values and inter-tonometer differences were analyzed by linear regression. RESULTS: The mean age was 13.37 ΁ 3.51 years. The mean IOP values recorded with NCT; Tono-Pen and GAT were 14.38, 15.63, and 12.44 mmHg, respectively. Both Tono-Pen and NCT recorded statistically higher IOP values than the GAT (P = 0.00) regardless of the CCT. The percentage increase of IOP measured over GAT was 15.66% for NCT and 25.70% for Tono-Pen which was also statistically significant. A correlation was found between CCT and IOP values obtained with all the three tonometers. CONCLUSION: IOP measurements on children vary significantly between instruments and correlations are affected by the corneal thickness. Further studies on children are needed to determine which instrument is most appropriate and to derive a normative IOP scale for the growing eye.

Comparison of Transcorneal and Pars Plana Routes in Pediatric Cataract Surgery in Infants Using a 25-Gauge Vitrectomy System.

PURPOSE: To demonstrate and compare the performance of the 25-gauge transconjunctival sutureless vitrectomy system via anterior (transcorneal) and posterior (pars plana) routes in congenital cataracts in infants. METHODS: In this prospective interventional study, 12 pediatric patients younger than 1 year with bilateral congenital cataract were included to undergo cataract surgery with posterior vitreorhexis and limited anterior vitrectomy using a 25-gauge vitrectomy system. One eye of each patient was operated on by the anterior (transcorneal) route and the other by the posterior (pars plana) route. All eyes were left aphakic. Intraoperative and postoperative (12 months after surgery) results were compared between the two routes, including visual axis opacification and astigmatism. All eyes were rehabilitated with contact lenses or spectacles. RESULTS: The 25-gauge vitrectomy system allowed excellent intraoperative control in both groups. Postoperatively, there was minimal conjunctival congestion, corneal edema, and inflammatory reaction. No intra-operative or postoperative complications were noted in any eye. All eyes had a clear visual axis 12 months after surgery. Mean spherical equivalent was 15.50 ± 2.28 diopters (D) and mean astigmatism was 0.25 ± 0.45 D in the transcorneal group, whereas in the pars plana group it was 15.46 ± 2.45 D and 0.16 ± 0.39 D, respectively, at 12 months, the difference being statistically insignificant (P > .05). CONCLUSIONS: The 25-gauge vitrectomy system allows sutureless surgery with excellent intraoperative control and minimal postoperative inflammation and astigmatism with clear visual axis by both the transcorneal and pars plana routes.

Intravitreal Diclofenac in the Treatment of Macular Edema Due to Branch Retinal Vein Occlusion.

BACKGROUND AND OBJECTIVE: To evaluate the effect of a single dose of intravitreal diclofenac on macular edema (ME) due to branch retinal vein occlusion (BRVO). PATIENTS AND METHODS: In this prospective, interventional case series, 15 eyes with BRVO and ME with central macular thickness (CMT) greater than 250 µm on spectral-domain optical coherence tomography (SD-OCT) were enrolled. All patients were given 0.05 mg/0.1 mL of intravitreal diclofenac under aseptic conditions and followed up for 3 months with respect to best-corrected visual acuity (BCVA), intraocular pressure (IOP), fundus fluorescein angiography, and CMT measured on OCT. RESULTS: The mean visual acuity improved from 0.115 ± 0.03 preoperatively to 0.356 ± 0.29 at 3 months (P = .002). Mean line improvement was 2.2 ± 1.6. Mean preoperative CMT decreased from 453.2 µm ± 55.3 µm to 340.47 µm ± 101 µm at 3 months postoperatively (P = .001). The mean preoperative IOP was 16.4 mm Hg ± 1.59 mm Hg, whereas the mean postoperative IOP was 16.6 mm Hg ± 1.58 mm Hg (P = .08). None of the 12 phakic eyes showed evidence of cataract progression. CONCLUSION: Intravitreal diclofenac is safe and effective in improving BCVA and decreasing CMT in patients with BRVO and ME.

The Optical Performance of Spherical and Aspheric Intraocular Lenses in Pediatric Eyes: A Comparative Study.

PURPOSE: To compare the optical performance of aspheric intraocular lenses (IOLs) designed to correct the corneal spherical aberration versus spherical IOLs in pediatric eyes after cataract surgery. METHODS: In this prospective study, 40 eyes of patients 6 to 16 years old with developmental cataract were randomly assigned to receive a spherical IOL or an aspheric IOL after pediatric cataract surgery. At 3 months postoperatively, the outcomes compared between the two groups were best-corrected visual acuity, contrast sensitivity, and wavefront aberrometry. RESULTS: The mean best-corrected visual acuity was 0.32 ± 0.19 logMAR in the spherical IOL group and 0.28 ± 0.16 logMAR in the aspheric IOL group (P = .179). The aspheric IOL group showed better contrast sensitivity at 1.5, 3, and 6 cycles per degree than the spherical IOL group (P < .05). Total ocular aberrations, higher-order aberrations, and spherical aberrations were significantly lower in the aspheric IOL group (P < .05). CONCLUSIONS: The results suggest that aspheric IOLs compensate for the spherical aberration of pediatric eyes. In comparison to spherical IOLs, eyes with aspheric IOLs had decreased ocular aberrations, particularly spherical aberration, which contributed to better contrast sensitivity in these eyes. Further studies are required to evaluate the role of aspheric IOLs in children.

Bilateral optic disc pit with maculopathy in a patient with cleft lip and cleft palate.

Optic disc pit (ODP) is small, gray-white, oval depression found at the optic nerve head. It is a congenital defect that occurs due to imperfect closure of superior edge of the embryonic fissure. Cleft lip and palate are also congenital midline abnormalities occurring due to defect in the fusion of frontonasal prominence, maxillary prominence and mandibular prominence. There is only one case report describing the occurrence of ODP in a young patient with cleft lip and palate who also had basal encephalocele. We describe a 52-year-old patient with congenital cleft lip and palate with bilateral ODP with maculopathy but without any other midline abnormality.

Inverted mucoepidermoid papilloma of conjunctiva in a child.

Inverted papillomas are benign epithelial tumors usually arising from the mucous membrane of the sinonasal cavity and the urinary tract. Similar tumors of the conjunctiva are much rarer. We describe a case of juxtalimbal inverted papilloma in an 11-year-old boy who presented with a pigmented lesion that simulated a conjunctival nevus. Excisional biopsy established the diagnosis of inverted papilloma. The patient was carefully followed for 2 years, because the tumor's behavior in the conjunctiva is unknown. There was no recurrence of the lesion.

Ocular findings in a case of periorbital giant congenital melanocytic nevus.

Giant congenital melanocytic nevus (GCMN) is a large melanocytic nevus that rarely occurs in the periorbital region. Various systemic, as well as ophthalmic associations, have been reported with GCMN. However, there is only one case report describing ophthalmic findings in periorbital GCMN. We describe the ocular findings in a case of periorbital GCMN.

Polarity related influence maximization in signed social networks.

Influence maximization in social networks has been widely studied motivated by applications like spread of ideas or innovations in a network and viral marketing of products. Current studies focus almost exclusively on unsigned social networks containing only positive relationships (e.g. friend or trust) between users. Influence maximization in signed social networks containing both positive relationships and negative relationships (e.g. foe or distrust) between users is still a challenging problem that has not been studied. Thus, in this paper, we propose the polarity-related influence maximization (PRIM) problem which aims to find the seed node set with maximum positive influence or maximum negative influence in signed social networks. To address the PRIM problem, we first extend the standard Independent Cascade (IC) model to the signed social networks and propose a Polarity-related Independent Cascade (named IC-P) diffusion model. We prove that the influence function of the PRIM problem under the IC-P model is monotonic and submodular Thus, a greedy algorithm can be used to achieve an approximation ratio of 1-1/e for solving the PRIM problem in signed social networks. Experimental results on two signed social network datasets, Epinions and Slashdot, validate that our approximation algorithm for solving the PRIM problem outperforms state-of-the-art methods.

Parry-Romberg syndrome studied by spectral-domain optical coherence tomography.

Parry-Romberg syndrome is a rare disorder characterized by progressive hemifacial atrophy. Ophthalmic findings are characterized by enophthalmos, strabismus, nerve palsies, anisometropia, glaucoma, and angle abnormalities. Vision loss has also been reported due to retinal changes such as venous dilatation, disc edema, retinal edema, and retinal folds. The authors describe a case of Parry-Romberg syndrome with retinal alterations but a normal macula on spectral-domain optical coherence tomography.

Distribution-based clustering: using ecology to refine the operational taxonomic unit.

16S rRNA sequencing, commonly used to survey microbial communities, begins by grouping individual reads into operational taxonomic units (OTUs). There are two major challenges in calling OTUs: identifying bacterial population boundaries and differentiating true diversity from sequencing errors. Current approaches to identifying taxonomic groups or eliminating sequencing errors rely on sequence data alone, but both of these activities could be informed by the distribution of sequences across samples. Here, we show that using the distribution of sequences across samples can help identify population boundaries even in noisy sequence data. The logic underlying our approach is that bacteria in different populations will often be highly correlated in their abundance across different samples. Conversely, 16S rRNA sequences derived from the same population, whether slightly different copies in the same organism, variation of the 16S rRNA gene within a population, or sequences generated randomly in error, will have the same underlying distribution across sampled environments. We present a simple OTU-calling algorithm (distribution-based clustering) that uses both genetic distance and the distribution of sequences across samples and demonstrate that it is more accurate than other methods at grouping reads into OTUs in a mock community. Distribution-based clustering also performs well on environmental samples: it is sensitive enough to differentiate between OTUs that differ by a single base pair yet predicts fewer overall OTUs than most other methods. The program can decrease the total number of OTUs with redundant information and improve the power of many downstream analyses to describe biologically relevant trends.