Use of an Artificial Intelligence-Generated Vascular Severity Score Improved Plus Disease Diagnosis in Retinopathy of Prematurity.

PURPOSE: To evaluate whether providing clinicians with an artificial intelligence (AI)-based vascular severity score (VSS) improves consistency in the diagnosis of plus disease in retinopathy of prematurity (ROP). DESIGN: Multireader diagnostic accuracy imaging study. PARTICIPANTS: Eleven ROP experts, 9 of whom had been in practice for 10 years or more. METHODS: RetCam (Natus Medical Incorporated) fundus images were obtained from premature infants during routine ROP screening as part of the Imaging and Informatics in ROP study between January 2012 and July 2020. From all available examinations, a subset of 150 eye examinations from 110 infants were selected for grading. An AI-based VSS was assigned to each set of images using the i-ROP DL system (Siloam Vision). The clinicians were asked to diagnose plus disease for each examination and to assign an estimated VSS (range, 1-9) at baseline, and then again 1 month later with AI-based VSS assistance. A reference standard diagnosis (RSD) was assigned to each eye examination from the Imaging and Informatics in ROP study based on 3 masked expert labels and the ophthalmoscopic diagnosis. MAIN OUTCOME MEASURES: Mean linearly weighted κ value for plus disease diagnosis compared with RSD. Area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPR) for labels 1 through 9 compared with RSD for plus disease. RESULTS: Expert agreement improved significantly, from substantial (κ value, 0.69 [0.59, 0.75]) to near perfect (κ value, 0.81 [0.71, 0.86]), when AI-based VSS was integrated. Additionally, a significant improvement in plus disease discrimination was achieved as measured by mean AUC (from 0.94 [95% confidence interval (CI), 0.92-0.96] to 0.98 [95% CI, 0.96-0.99]; difference, 0.04 [95% CI, 0.01-0.06]) and AUPR (from 0.86 [95% CI, 0.81-0.90] to 0.95 [95% CI, 0.91-0.97]; difference, 0.09 [95% CI, 0.03-0.14]). CONCLUSIONS: Providing ROP clinicians with an AI-based measurement of vascular severity in ROP was associated with both improved plus disease diagnosis and improved continuous severity labeling as compared with an RSD for plus disease. If implemented in practice, AI-based VSS could reduce interobserver variability and could standardize treatment for infants with ROP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy and safety of Artemisinin Combination Therapy for the treatment of uncomplicated Plasmodium falciparum malaria across international borders of India.

BACKGROUND OBJECTIVES: Malaria due to Plasmodium falciparum (Pf) remains a major public threat in India. Artemisinin-based combination therapy (ACT) has been the country's first-line drug for uncomplicated Pf malaria. In 2013-2014, Artesunate plus sulfadoxine (AS+SP) was replaced by Artemether Lumefantrine (AL) as the first- line antimalarial in North East (NE) states of the country which are endemic for Pf malaria. Regular monitoring of antimalarial drugs is of utmost importance to achieve the goal of elimination. This study aimed to assess the efficacy and safety of ACT for treating uncomplicated Pf malaria in the NE states of India. METHODS: A prospective study of 28-day follow-up was conducted to monitor the efficacy and safety of AL from 2018-2019 in four districts, Udalgiri, Meghalaya, Lawngtlai, and Dhalai of NE, India. The clinical and parasitological response and the polymorphism analysis of the Pfdhps, P/dhfr, and Pfkelch 13 gene were evaluated. RESULTS: A total of 234 patients were enrolled in the study out of 216 patients who completed the follow-up to 28 days. One-hundred percent adequate clinical and parasitological responses (ACPR) were observed with polymerase chain reaction (PCR) correction. The genotype results suggest no recrudescence in the treatment-failure patients. The classical single nucleotide polymorphisms (SNP) in the Pfdhfr gene was S108N (94.9%), followed by C59R (91.5%), whereas, in the Pfdhps gene, the common SNP was A437G (79.6%), followed by S3436A. No associated or validated mutations were found in the propeller region of the PfKelch13 gene. INTERPRETATION CONCLUSION: AL was efficacious and safe in uncomplicated P. falciparum malaria in North East India. In contrast, mutations in the genes responsible for sulfadoxine and pyrimethamine resistance have been fixed in northeast India's population.

Comparison of Cardiovascular Response to Lower Body and Whole Body Exercise Among Sedentary Young Adults.

Background Cardiovascular responses to exercise are essential indicators of cardiovascular health and fitness. Understanding how different types of exercise, such as lower-body and whole-body exercises, impact these responses is crucial for designing effective fitness programs and assessing cardiovascular function. Aim This study aimed to compare the cardiovascular response of young adults during lower-body exercise using a bicycle ergometer and whole-body exercise on a treadmill. Methods Thirty-two healthy young adults participated in this study. Each participant completed two exercise sessions on separate days: lower-body exercise on a bicycle ergometer with a fixed cadence of 60 rpm with a breaking resistance of 1.75 kg and whole-body exercise on a treadmill with a speed of 1.7 mph and a 10% grade. Heart rate (HR), systolic blood pressure (BP), and diastolic BP were measured at rest and immediately after a three-minute exercise. Data were analyzed using paired t-tests to compare the cardiovascular responses between the two exercise modalities. Results A total of 17 male and 15 female young adults with a mean age of 20.87±1.43 years participated in the study. The male and female participants had similar ages (p =0.56) and body mass indexes (p = 0.1). There was a higher HR (129.16±2.67 versus 150.87±3.23, p<0.0001) and systolic BP (127.29±2.34 versus 144.9±4.16, p<0.0001) and lower diastolic BP (68.97±2.41 versus 62.97±2.31, p<0.0001) in whole body exercise on treadmill compared to lower body exercise in bicycle ergometer. The effect size was large enough as Cohen's d was 7.33, 5.13, and 2.54 for HR, systolic BP, and diastolic BP, respectively. Conclusion In sedentary young adults, treadmill exercise led to higher HR, systolic BP, and lower diastolic BP than bicycle ergometer exercise. Increased muscle recruitment might result in higher energy expenditure, increasing the HR and systolic BP to deliver oxygen and nutrients to the working muscles. Further research is needed to understand the mechanisms and long-term implications for precise exercise recommendations and better cardiovascular health management.

Characterization of tumor microenvironment in glioblastoma multiforme identifies ITGB2 as a key immune and stromal related regulator in glial cell types.

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor characterized by inter and intra-tumor heterogeneity and complex tumor microenvironment. To uncover the molecular targets in this milieu, we systematically identified immune and stromal interactions at the glial cell type level that leverages on RNA-sequencing data of GBM patients from The Cancer Genome Atlas. The perturbed genes between the high vs low immune and stromal scored patients were subjected to weighted gene co-expression network analysis to identify the glial cell type specific networks in immune and stromal infiltrated patients. The intramodular connectivity analysis identified the highly connected genes in each module. Combining it with univariable and multivariable prognostic analysis revealed common vital gene ITGB2, between the immune and stromal infiltrated patients enriched in microglia and newly formed oligodendrocytes. We found following unique hub genes in immune infiltrated patients; COL6A3 (microglia), ITGAM (oligodendrocyte precursor cells), TNFSF9 (microglia), and in stromal infiltrated patients, SERPINE1 (microglia) and THBS1 (newly formed oligodendrocytes, oligodendrocyte precursor cells). To validate these hub genes, we used external GBM patient single cell RNA-sequencing dataset and this identified ITGB2 to be significantly enriched in microglia, newly formed oligodendrocytes, T-cells, macrophages and adipocyte cell types in both immune and stromal datasets. The tumor infiltration analysis of ITGB2 showed that it is correlated with myeloid dendritic cells, macrophages, monocytes, neutrophils, B-cells, fibroblasts and adipocytes. Overall, the systematic screening of tumor microenvironment components at glial cell types uncovered ITGB2 as a potential target in primary GBM.

Did the early full genome sequencing of yeast boost gene function discovery?

BACKGROUND: Although the genome of Saccharomyces cerevisiae (S. cerevisiae) was the first one of a eukaryote organism that was fully sequenced (in 1996), a complete understanding of the potential of encoded biomolecular mechanisms has not yet been achieved. Here, we wish to quantify how far the goal of a full list of S. cerevisiae gene functions still is. RESULTS: The scientific literature about S. cerevisiae protein-coding genes has been mapped onto the yeast genome via the mentioning of names for genomic regions in scientific publications. The match was quantified with the ratio of a given gene name's occurrences to those of any gene names in the article. We find that ~ 230 elite genes with ≥ 75 full publication equivalents (FPEs, FPE = 1 is an idealized publication referring to just a single gene) command ~ 45% of all literature. At the same time, about two thirds of the genes (each with less than 10 FPEs) are described in just 12% of the literature (in average each such gene has just ~ 1.5% of the literature of an elite gene). About 600 genes have not been mentioned in any dedicated article. Compared with other groups of genes, the literature growth rates were highest for uncharacterized or understudied genes until late nineties of the twentieth century. Yet, these growth rates deteriorated and became negative thereafter. Thus, yeast function discovery for previously uncharacterized genes has returned to the level of ~ 1980. At the same time, literature for anyhow well-studied genes (with a threshold T10 (≥ 10 FPEs) and higher) remains steadily growing. CONCLUSIONS: Did the early full genome sequencing of yeast boost gene function discovery? The data proves that the moment of publishing the full genome in reality coincides with the onset of decline of gene function discovery for previously uncharacterized genes. If the current status of literature about yeast molecular mechanisms can be extrapolated into the future, it will take about another ~ 50 years to complete the yeast gene function list. We found that a small group of scientific journals contributed extraordinarily to publishing early reports relevant to yeast gene function discoveries.

Design and validation of multiplex polymerase chain reaction as a diagnostic tool for Plasmodium species.

BACKGROUND & OBJECTIVES: The highly sensitive method for a true understanding of malaria prevalence is of utmost importance for India's elimination strategy. The PCR reaction type with rapid detection, cost-effectiveness, and less workforce should be preferable. Multiplex PCR type accomplishes the present requirement by saving time and resources to find true surveillance data for malaria, especially in low-parasitemia/asymptomatic groups or populations. METHODS: The present study focuses on designing multiplex PCR (mPCR) to detect simultaneously Plasmodium genus (PAN) and two common Plasmodium species found in India. It is compared to standard nested PCR on 195 clinical samples to diagnose malaria. The mPCR was designed with a minimum number of primers, leading to less clogging and effective and enhanced detection. It contains one common reverse primer and three forward primers amplifying three targeted genes corresponding to P. falciparum, P. vivax, and Plasmodium genus. RESULTS: The sensitivity and specificity for mPCR were 94.06 and 95.74, respectively. The limit of detection for mPCR was 0.1 parasites/µl. The study has shown a ROC curve area for the mPCR of 0.949 for Plasmodium genus and P. falciparum and 0.897 for P. vivax with standard nPCR. INTERPRETATION & CONCLUSION: The mPCR is rapid in detecting species together, cost-effective, and requires fewer human resources than the standard nPCR. Therefore, the mPCR can be used as an alternative technique for the higher sensitive detection of the malaria parasite. It could also become a vital tool for determining malaria prevalence, facilitating the application of the most effective measures.

Quality assurance of malaria rapid diagnostic tests: An aid in malaria elimination.

Background & objectives: India targets malaria elimination by 2030 in a phased manner, so malaria's assured diagnosis is crucial. Introduction of rapid diagnostic kits in India in 2010 has revolutionized malaria surveillance. The storage temperature of rapid diagnostic tests (RDTs), kit components and handling in transportations impact the results of RDTs. Therefore, quality assurance (QA) is required before it reaches end-users. The Indian Council of Medical Research-National Institute of Malaria Research (ICMR-NIMR) has a World Health Organization (WHO) recognized lot-testing laboratory facility to assure the quality of RDTs. Methods: The ICMR-NIMR receives RDTs from different manufacturing companies as well as various agencies such as National and State Programmes and Central Medical Services Society. The WHO standard protocol is followed to conduct all the tests, including long-term and post-dispatch testing. Results: A total of 323 lots tested during January 2014-March 2021 were received from different agencies. Amongst them, 299 lots passed the quality of test and 24 failed. In long-term testing, 179 lots were tested and only nine failed. A total of 7741 RDTs were received from end-users for post-dispatch testing of which 7540 qualified the QA test with a score of 97.4 per cent. Interpretation & conclusions: RDTs received for quality testing showed compliance with QA evaluation of malaria RDTs based on the protocol recommended by the WHO. However, continuous monitoring of the quality of RDTs is required under QA programme. Quality-assured RDTs have a major role, especially in areas where low parasitaemia of parasites persists.

About the dark corners in the gene function space of Escherichia coli remaining without illumination by scientific literature.

BACKGROUND: Although Escherichia coli (E. coli) is the most studied prokaryote organism in the history of life sciences, many molecular mechanisms and gene functions encoded in its genome remain to be discovered. This work aims at quantifying the illumination of the E. coli gene function space by the scientific literature and how close we are towards the goal of a complete list of E. coli gene functions. RESULTS: The scientific literature about E. coli protein-coding genes has been mapped onto the genome via the mentioning of names for genomic regions in scientific articles both for the case of the strain K-12 MG1655 as well as for the 95%-threshold softcore genome of 1324 E. coli strains with known complete genome. The article match was quantified with the ratio of a given gene name's occurrence to the mentioning of any gene names in the paper. The various genome regions have an extremely uneven literature coverage. A group of elite genes with ≥ 100 full publication equivalents (FPEs, FPE = 1 is an idealized publication devoted to just a single gene) attracts the lion share of the papers. For K-12, ~ 65% of the literature covers just 342 elite genes; for the softcore genome, ~ 68% of the FPEs is about only 342 elite gene families (GFs). We also find that most genes/GFs have at least one mentioning in a dedicated scientific article (with the exception of at least 137 protein-coding transcripts for K-12 and 26 GFs from the softcore genome). Whereas the literature growth rates were highest for uncharacterized or understudied genes until 2005-2010 compared with other groups of genes, they became negative thereafter. At the same time, literature for anyhow well-studied genes started to grow explosively with threshold T10 (≥ 10 FPEs). Typically, a body of ~ 20 actual articles generated over ~ 15 years of research effort was necessary to reach T10. Lineage-specific co-occurrence analysis of genes belonging to the accessory genome of E. coli together with genomic co-localization and sequence-analytic exploration hints previously completely uncharacterized genes yahV and yddL being associated with osmotic stress response/motility mechanisms. CONCLUSION: If the numbers of scientific articles about uncharacterized and understudied genes remain at least at present levels, full gene function lists for the strain K-12 MG1655 and the E. coli softcore genome are in reach within the next 25-30 years. Once the literature body for a gene crosses 10 FPEs, most of the critical fundamental research risk appears overcome and steady incremental research becomes possible.

Computed Analysis of Retinal Vascular Growth After Bevacizumab Treatment of Retinopathy of Prematurity Until Age 3 Years.

PURPOSE: Premature infants, after anti-vascular endothelial growth factor injections for retinopathy of prematurity, have persistent peripheral avascular retina (PAR). PAR is ablated with laser; however, physiologic growth of the retinal vasculature in the long term has not been measured. The purposes of this study were to measure retinal vessel growth after treatment with intravitreal bevacizumab (IVB) for retinopathy of prematurity, using serial fluorescein angiography (FA), until age 3 years, and to assess the timing for providing laser ablation in PAR. METHODS: Data from an observational, longitudinal clinical study were collected. Angiographic images of eyes treated with IVB were included; imaging data from laser photocoagulation were excluded. All eyes underwent initial examination under general anesthesia with FA and photographic imaging. The retinal vessel length was measured from the temporal margin of the optic disc passing through the foveal center, and the lengths at subsequent FA were compared. To compare the changes in retinal vessel length over time in individual eyes, a paired-sample t test was performed. FINDINGS: FA images from 70 eyes (35 infants) treated with IVB were available. A total of 150 FA images were available for review; data from 125 images of good quality were used for analysis. The mean postmenstrual ages (PMAs) at first, second, third, and fourth FA were 66.2, 100.9, 135.1, and 180.7 weeks, respectively. The mean retinal vessel length was 14.177 mm at first FA and 13.199 mm at fourth FA (PMA range, 42...234 weeks). Retinal vascular lengths of individual eyes compared over time showed no statistically significant growth from the first FA to age 3 years. The changes in retinal vessel length from first to second FA were -0.117 ± 0.79 mm (p = 0.42; n = 30); from first to third FA, +0.060 ± 0.85 mm (p = 0.79; n = 15); and first to fourth FA, -0.404 ± 1.32 mm (p = 0.45; n = 7). IMPLICATIONS: Beyond 65 weeks' PMA, no meaningful retinal vascular growth occurred after IVB up to age 3 years, guiding the timing for physicians if laser photocoagulation is being considered. Future studies are needed to address retinal growth changes in the growing eyes of infants.

Comparative Assessment of Diagnostic Performance of Cytochrome Oxidase Multiplex PCR and 18S rRNA Nested PCR.

Malaria elimination and control require prompt and accurate diagnosis for treatment plan. Since microscopy and rapid diagnostic test (RDT) are not sensitive particularly for diagnosing low parasitemia, highly sensitive diagnostic tools are required for accurate treatment. Molecular diagnosis of malaria is commonly carried out by nested polymerase chain reaction (PCR) targeting 18S rRNA gene, while this technique involves long turnaround time and multiple steps leading to false positive results. To overcome these drawbacks, we compared highly sensitive cytochrome oxidase gene-based single-step multiplex reaction with 18S rRNA nested PCR. Cytochrome oxidase (cox) genes of P. falciparum (cox-III) and P. vivax (cox-I) were compared with 18S rRNA gene nested PCR and microscopy. Cox gene multiplex PCR was found to be highly specific and sensitive, enhancing the detection limit of mixed infections. Cox gene multiplex PCR showed a sensitivity of 100% and a specificity of 97%. This approach can be used as an alternative diagnostic method as it offers higher diagnostic performance and is amenable to high throughput scaling up for a larger sample size at low cost.

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules.

Colorectal cancer (CRC) is a significant contributor to cancer-related deaths caused by an unhealthy lifestyle. Multiple studies reveal that viruses are involved in colorectal tumorigenesis. The viruses such as Human Cytomegalovirus (HCMV), Human papillomaviruses (HPV16 & HPV18), and John Cunningham virus (JCV) are known to cause colorectal cancer. The molecular mechanisms of cancer genesis and maintenance shared by these viruses remain unclear. We analysed the virus-host networks and connected them with colorectal cancer proteome datasets and extracted the core shared interactions in the virus-host CRC network. Our network topology analysis identified prominent virus proteins RL6 (HCMV), VE6 (HPV16 and HPV18), and Large T antigen (JCV). Sequence analysis uncovered short linear motifs (SLiMs) in each viral target. We used these targets to identify the antiviral drugs through a structure-based virtual screening approach. This analysis highlighted that temsavir, pimodivir, famotine, and bictegravir bind to each virus protein target, respectively. We also assessed the effect of drug binding using molecular dynamic simulations, which shed light on the modulatory effect of drug molecules on SLiM regions in viral targets. Hence, our systematic screening of virus-host networks revealed viral targets, which could be crucial for cancer therapy.

Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure.

Objective: The monocyte-macrophage system is central to the host's innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes' functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF. Design: Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration. Results: Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals. Conclusion: Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

Functional characterization of α-Gal producing lactic acid bacteria with potential probiotic properties.

The possibility of exploiting the human immune response to glycan α-Gal for the control of multiple infectious diseases has been the objective of recent investigations. In this field of research, the strain of Escherichia coli O86:B7 has been at the forefront, but this Gram-negative microorganism presents a safety concern and therefore cannot be considered as a probiotic. To address this challenge, this study explored the identification of novel lactic acid bacteria with a safe history of use, producing α-Gal and having probiotic potential. The lactic acid bacteria were isolated from different traditionally fermented foods (kununn-zaki, kindirmo, and pulque) and were screened for the production of α-Gal and some specific probiotic potential indicators. The results showed that Ten (10) out of forty (40) [25%] of the tested lactic acid bacteria (LAB) produced α-Gal and were identified as Limosilactobacillus fermentum, Levilactobacillus brevis, Agrilactobacillus composti, Lacticaseibacillus paracasei, Leuconostoc mesenteroides and Weissella confusa. Four (4) LAB strains with highest levels of α-Gal were further selected for in vivo study using a mouse model (α1,3GT KO mice) to elucidate the immunological response to α-Gal. The level of anti-α-Gal IgG observed were not significant while the level of anti-α-Gal IgM was lower in comparison to the level elicited by E. coli O86:B7. We concluded that the lactic acid bacteria in this study producing α-Gal have potential probiotic capacity and can be further explored in α-Gal-focused research for both the prevention and treatment of various infectious diseases and probiotic development.

Partial CHARGE syndrome with bilateral retinochoroidal colobomas associated with 7q11.23 duplication syndrome: case report.

BACKGROUND: CHARGE syndrome is a relatively common cause of deafness and blindness resulting from failure to form the primordia of specific organs due to deficient contribution of neural crest cell derivatives. The majority of CHARGE syndrome cases are caused by heterozygous mutations in CHD7 on chromosome 8q21. Those with CHARGE syndrome without CHD7 mutation typically do not have an identified genetic defect. 7q11.23 duplication syndrome is associated with mild facial dysmorphism, heart defects, language delay, and autism spectrum disorder. In the current literature, 7q11.23 duplication has not been associated with CHARGE syndrome, retinochoroidal colobomas, or significant ear abnormalities. CASE PRESENTATION: We describe a patient with 7q11.23 duplication syndrome and clinical CHARGE syndrome with no variant in CHARGE-associated genes. CONCLUSIONS: This case highlights the still incomplete understanding of the pathogenesis of CHARGE syndrome and raises the possibility of a dose-sensitive effect of genes in the 7q11.23 critical region on neural crest differentiation and fate.

Unraveling unique and common cell type-specific mechanisms in glioblastoma multiforme.

Glioblastoma multiforme persists to be an enigmatic distress in neuro-oncology. Its untethering capacity to thrive in a confined microenvironment, metastasize intracranially, and remain resistant to the systemic treatments, renders this tumour incurable. The glial cell type specificity in GBM remains exploratory. In our study, we aimed to address this problem by studying the GBM at the cell type level in the brain. The cellular makeup of this tumour is composed of genetically altered glial cells which include astrocyte, microglia, oligodendrocyte precursor cell, newly formed oligodendrocyte and myelinating oligodendrocyte. We extracted cell type-specific solid tumour as well as recurrent solid tumour glioma genes, and studied their functional networks and contribution towards gliomagenesis. We identified the principal transcription factors that are found to be regulating vital tumorigenic processes. We also assessed the protein-protein interaction networks at their domain level to get a more microscopic view of the structural and functional operations that transpire in these cells. This yielded the eminent protein regulators exhibiting their regulation in signaling pathways. Overall, our study unveiled regulatory mechanisms in glioma cell types that can be targeted for a more efficient glioma therapy.

Angiographic Review of Choroidal Involution in Eyes with Retinopathy of Prematurity Treated with Bevacizumab.

PURPOSE: Retinopathy of prematurity (ROP) is considered a disease of the inner retina; however, there is increasing evidence that demonstrates choroidal vasculature loss in ROP, leading to degeneration of outer retinal function and visual deterioration. Central choroidal thinning is noted in children with history of ROP using optical coherence tomography imaging. This study characterizes the presence and persistence of choroidal loss angiographically in eyes of infants treated with intravitreal bevacizumab (IVB) for stage 3 ROP. METHODS: The fluorescein angiography (FA) images of 62 eyes of 31 infants treated with IVB monotherapy were retrospectively reviewed. The eyes with good quality early-, mid-, and late-phase imaging were included in this study. The presence of choroidal hypofluoresence involving the central and or peripheral retina was noted. In infants with multiple FAs, serial FAs were analyzed for persistence of choroidal hypofluorescence. RESULTS: The mean age and birth weight of infants was 24.4 weeks post-menstrual age and 683 g, respectively. All infants received IVB monotherapy. Twenty-four of 62 angiography images of sufficient quality reviewed showed the presence of choroidal hypofluorescence involving central and peripheral lobular loss in the early phase and its persistence into mid- and late phases. Twelve eyes demonstrated persistent choroidal loss on sequential FA until 3 years chronological age. CONCLUSIONS: The study demonstrates the presence of choroidal vascular loss angiographically both central and peripheral fundus in infants with ROP. It highlights the critical role of choroidal involution in outer retinal function that could affect visual outcomes.

Bilateral anterior segment dysgenesis and persistent fetal vasculature associated with terminal 10q26 deletion.

Deletion of the 26q position on chromosome 10 results in a syndrome with well-documented systemic phenotypes. There are few reports of ophthalmic manifestations in terminal 10q26 deletion. We report a 4-week-old boy with terminal 10q26 deletion who had extensive ophthalmic abnormalities, including bilateral anterior segment dysgenesis and bilateral persistent fetal vasculature, with microphthalmia, microcornea, iris corectopia, congenital cataracts, and posterior embryotoxon.

Network Analysis Identifies Drug Targets and Small Molecules to Modulate Apoptosis Resistant Cancers.

Programed cell death or apoptosis fails to induce cell death in many recalcitrant cancers. Thus, there is an emerging need to activate the alternate cell death pathways in such cancers. In this study, we analyzed the apoptosis-resistant colon adenocarcinoma, glioblastoma multiforme, and small cell lung cancers transcriptome profiles. We extracted clusters of non-apoptotic cell death genes from each cancer to understand functional networks affected by these genes and their role in the induction of cell death when apoptosis fails. We identified transcription factors regulating cell death genes and protein-protein interaction networks to understand their role in regulating cell death mechanisms. Topological analysis of networks yielded FANCD2 (ferroptosis, negative regulator, down), NCOA4 (ferroptosis, up), IKBKB (alkaliptosis, down), and RHOA (entotic cell death, down) as potential drug targets in colon adenocarcinoma, glioblastoma multiforme, small cell lung cancer phenotypes respectively. We also assessed the miRNA association with the drug targets. We identified tumor growth-related interacting partners based on the pathway information of drug-target interaction networks. The protein-protein interaction binding site between the drug targets and their interacting proteins provided an opportunity to identify small molecules that can modulate the activity of functional cell death interactions in each cancer. Overall, our systematic screening of non-apoptotic cell death-related genes uncovered targets helpful for cancer therapy.

Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites.

BACKGROUND: The human proteins TMTC1, TMTC2, TMTC3 and TMTC4 have been experimentally shown to be components of a new O-mannosylation pathway. Their own mannosyl-transferase activity has been suspected but their actual enzymatic potential has not been demonstrated yet. So far, sequence analysis of TMTCs has been compromised by evolutionary sequence divergence within their membrane-embedded N-terminal region, sequence inaccuracies in the protein databases and the difficulty to interpret the large functional variety of known homologous proteins (mostly sugar transferases and some with known 3D structure). RESULTS: Evolutionary conserved molecular function among TMTCs is only possible with conserved membrane topology within their membrane-embedded N-terminal regions leading to the placement of homologous long intermittent loops at the same membrane side. Using this criterion, we demonstrate that all TMTCs have 11 transmembrane regions. The sequence segment homologous to Pfam model DUF1736 is actually just a loop between TM7 and TM8 that is located in the ER lumen and that contains a small hydrophobic, but not membrane-embedded helix. Not only do the membrane-embedded N-terminal regions of TMTCs share a common fold and 3D structural similarity with subgroups of GT-C sugar transferases. The conservation of residues critical for catalysis, for binding of a divalent metal ion and of the phosphate group of a lipid-linked sugar moiety throughout enzymatically and structurally well-studied GT-Cs and sequences of TMTCs indicates that TMTCs are actually sugar-transferring enzymes. We present credible 3D structural models of all four TMTCs (derived from their closest known homologues 5ezm/5f15) and find observed conserved sequence motifs rationalized as binding sites for a metal ion and for a dolichyl-phosphate-mannose moiety. CONCLUSIONS: With the results from both careful sequence analysis and structural modelling, we can conclusively say that the TMTCs are enzymatically active sugar transferases belonging to the GT-C/PMT superfamily. The DUF1736 segment, the loop between TM7 and TM8, is critical for catalysis and lipid-linked sugar moiety binding. Together with the available indirect experimental data, we conclude that the TMTCs are not only part of an O-mannosylation pathway in the endoplasmic reticulum of upper eukaryotes but, actually, they are the sought mannosyl-transferases.

Correlation of central corneal thickness and associated factors in premature infants with and without retinopathy of prematurity.

OBJECTIVE: Central corneal thickness (CCT) in premature infants is described in racially homogenous populations, and factors affecting CCT in infants are relatively unknown. This study describes CCT in premature infants and its association of steroid and oxygen requirements, gestational age (GA), birth weight (BW), race, and their relationship with CCT and corneal haze. METHODS: CCT measurements of 87 infants/174 eyes screened for retinopathy of prematurity were taken between 30 and 44 weeks of GA. CCT was analyzed using a mixed model for its relationship with BW, GA, race, corneal clarity, steroid, and oxygen use. RESULTS: Average CCT decreased at a rate of 12.3 µm/week. Caucasians had the thickest corneas and Hispanics the thinnest (p < 0.01) at baseline, but the rate of CCT decline varied based on racial/ethnic group (p = 0.079). Infants with BW <1000 g had a higher CCT at baseline, but CCT decreased at a faster rate than infants with higher BW (-13. 4 µm/week vs -9.9 µm/week, p = 0.020). Infants born <27 weeks of GA had higher CCT at baseline, but CCT decreased at faster rate compared with patients born later (-13.3 µm/week vs -10.1 µm/week, p = 0.029). Steroid and oxygen use were not statistically significantly associated with CCT or corneal haze (p > 0.05) CONCLUSIONS: CCT varies by racial group in premature infants. Lower BW and GA are associated with increased CCT at baseline but thin at a faster rate. Average, CCT decreases at a rate of 12.3 µm/week between 30 and 44 weeks GA and averages to 550 µm by 44 weeks GA.