Ritscher-Schinzel syndrome can be characterized as an endosomal recyclinopathy

Ritscher-Schinzel syndrome (RSS) is a congenital malformation syndrome characterized by cerebellar, cardiac, and craniofacial malformations and phenotypes associated with liver, skeletal, and kidney dysfunction. The genetic cause of RSS remains to be fully defined, and limited information is available regarding the root cause of the multiple tissue phenotypes. Causative mutations in the Commander multiprotein assembly are an emerging feature of this syndrome. Commander organizes the sorting nexin-17 (SNX17)-dependent recycling of hundreds of integral membrane proteins through the endosomal network. Here, we identify previously unrecognized cohorts of patients with RSS that we genetically and clinically analyzed to identify causative genes in the copper metabolic murr1 domain-containing (COMMD) proteins COMMD4, COMMD9, and coiled-coil domain containing 93 (CCDC93) subunits of the Commander complex. Using interactome analysis, we determined that these mutations disrupted Commander assembly and, through cell surface proteomics, that this reduces tissue-specific presentation of cell surface integral membrane proteins essential for kidney, bone, and brain development. We established that these integral proteins contained ΦxNPxY/F or ΦxNxxY/F sorting motifs in their cytoplasmic-facing domains (where Φ is a hydrophobic residue and x is any residue) that are recognized by SNX17 to drive their Commander-dependent endosomal recycling. Last, through generation of mouse models of RSS, we show replication of RSS-associated clinical phenotypes including proteinuria, skeletal malformation, and neurological impairment. Our data establish RSS as a "recyclinopathy" that arises from a dysfunction in the Commander endosomal recycling pathway

Advances in exosome therapies in ophthalmology–From bench to clinical trial

During the last decade, the fields of advanced and personalized therapeutics have been constantly evolving, utilizing novel techniques such as gene editing and RNA therapeutic approaches. However, the method of delivery and tissue specificity remain the main hurdles of these approaches. Exosomes are natural carriers of functional small RNAs and proteins, representing an area of increasing interest in the field of drug delivery. It has been demonstrated that the exosome cargo, especially miRNAs, is at least partially responsible for the therapeutic effects of exosomes. Exosomes deliver their luminal content to the recipient cells and can be used as vesicles for the therapeutic delivery of RNAs and proteins. Synthetic therapeutic drugs can also be encapsulated into exosomes as they have a hydrophilic core, which makes them suitable to carry water-soluble drugs. In addition, engineered exosomes can display a variety of surface molecules, such as peptides, to target specific cells in tissues. The exosome properties present an added advantage to the targeted delivery of therapeutics, leading to increased efficacy and minimizing the adverse side effects. Furthermore, exosomes are natural nanoparticles found in all cell types and as a result, they do not elicit an immune response when administered. Exosomes have also demonstrated decreased long-term accumulation in tissues and organs and thus carry a low risk of systemic toxicity. This review aims to discuss all the advances in exosome therapies in ophthalmology and to give insight into the challenges that would need to be overcome before exosome therapies can be translated into clinical practice

Burden of Mendelian disorders in a large Middle Eastern biobank

Background: Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. Methods: Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. Results: We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. Conclusions: This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.This study was, in part, financially supported by QGP, Qatar National Research Fund (QNRF award, QF-QBB-RES-PUB-003, NPRP10-1219-160035, NPRP10-0202-170320, and NPRP11S-0110-180250), as well as Sidra internal funds

Multidisciplinary Approach to Delayed Treatment of Traumatic Teeth Injuries Involving Extrusive Luxation, Avulsion and Crown Fracture

SUMMARY A 12-year-old boy with extrusion of the maxillary right central incisor, uncomplicated fracture of the left central incisor, avulsion of the mandibular right and left central incisors, and crown fracture of the mandibular right lateral incisor presented to the Kocaeli University Department of Pediatric Dentistry 20 days after sustaining the traumatic injuries. Orthodontic repositioning of the extrusive maxillary right central incisor was planned. Additionally, this tooth was necrotic and needed root canal treatment. The maxillary left central incisor and right mandibular lateral incisor were necrotic and needed root canal treatment. The orthodontic and endodontic treatments were successfully performed simultaneously. Restoration of the fractured mandibular right lateral incisor and maxillary left central incisor was completed with resin composite. Subsequent to orthodontic and endodontic treatment, prosthodontic rehabilitation was performed. At the two-year followup, the teeth appeared normal and the patient had no complaints.</jats:p

Clinical and biological correlates of optical coherence tomography findings in schizophrenia

There is a growing body of evidence indicating retinal layer thinning in schizophrenia. However, neuropathological processes underlying these retinal structural changes and its clinical correlates are yet to be known. Here, we aim to investigate the clinical and biological correlates of OCT findings in schizophrenia. 50 schizophrenia patients and 40 healthy controls were recruited. Retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and macular and choroidal thicknesses were recorded. A comprehensive battery of neuropsychological tests was applied. Fasting glucose, triglycerides and HDL-cholesterol levels, TNF-alpha, IL-1 beta and IL-6 levels were measured. Right IPL was significantly thinner in patients than the controls after controlling for various confounders (F = 5.42, p = .02). Higher IL-6, IL-1 beta, and TNF-alpha levels were associated with decreased left macular thickness (r = - 0.26, p = .027, r = - 0.30, p = 0.012, and r = - 0.24, p = .046, respectively) and higher IL-6 was associated with thinning of right IPL (r = - 0.27, p = 0.023) and left choroid (r = - 0.23, p = .044) in the overall sample. Thinning of right IPL and left macula were also associated with worse executive functioning (r = 0.37, p = 0.004 and r = 0.33, p = 0.009) and attention (r = 0.31, p = 0.018 and r = 0.30, p = 0.025). In patients with schizophrenia, IPL thinning was associated with increased BMI (r = - 0.44, p = 0.009) and decreased HDL levels (r = 0.43, p = 0.021). Decreased TNF-alpha level was related to IPL thinning, especially in the left eye (r = 0.40, p = 0.022). These findings support the hypothesis that OCT might provide the opportunity to establish an accessible and non-invasive probe of brain pathology in schizophrenia and related disorders. However, future studies investigating retinal structural changes as a biological marker for schizophrenia should also consider the metabolic state of the subjects

Evaluation of the relationship between corneal biomechanic and HbA1C levels in type 2 diabetes patients

Serpil Yazgan,1 Ugur Celik,2 Havva Kaldirim,3 Orhan Ayar,1 Ahmet Elbay,4 Veysel Aykut,2 Burcu Celik,5 Mehmet Taş6 1Department of Ophthalmology, Zonguldak Karaelmas University, Zonguldak, Turkey; 2Department of Ophthalmology, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey; 3Department of Ophthalmology, Bagcilar Training and Research Hospital, Istanbul, Turkey; 4Department of Ophthalmology, Pendik Government Hospital, Istanbul, Turkey; 5Department of Ophthalmology, Beyoglu Eye Training and Research Hospital, Istanbul, Turkey; 6Department of Ophthalmology, Malatya State Hospital, Malatya, Turkey Purpose: To evaluate the corneal biomechanical properties due to the glycosylated hemoglobin (HbA1C) levels using the ocular response analyzer (ORA) in the patients with type 2 diabetes mellitus (DM). Methods: ORA values were obtained from 156 eyes of subjects with type 2 DM and 74 eyes of healthy control subjects with similar age and sex. Subjects were divided into three groups: Group 1, healthy control subjects; Group 2, diabetes patients with HbA1C &ge;7%; and Group 3, diabetes patients with HbA1C &lt;7%. Corneal biomechanical parameters: corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann-correlated pressure (IOPg), and corneal-compensated intraocular pressure (IOPcc) measurements were obtained using ORA. Ultrasound pachymetry was used for measurement of central corneal thickness (CCT). Results: CH and CRF were significantly different in each of the three groups (P-values for CH respectively; Groups 1 and 2=0.008, Groups 1 and 3, and Groups 2 and 3, &lt;0.001, and for CRF respectively; =0.002, &lt;0.001, &lt;0.001). CCT was significantly different between Groups 1 and 3 and Groups 2 and 3 (P&lt;0.001) but was insignificant between Groups 1 and 2 (P=0.965). IOPcc was not different between Groups 1 and 2 (P=0.524), and Groups 2 and 3 (P=0.115), but was significantly different between Groups 1 and 3 (P=0.003). IOPg was statistically different between each of the three groups (respectively; Groups 1 and 2, P=0.015, Groups 1 and 3, and Groups 2 and 3, P&lt;0.001). Conclusion: Both diabetes groups were affected in terms of corneal biomechanical properties when compared to healthy subjects, there was also a positive correlation between HbA1C level and intraocular pressure. Keywords: type 2 diabetes mellitus, HbA1C, ocular response analyzer, intraocular pressure, corneal biomechanical parameter

WOOD COMPONENTS AS SOURCES OF PENTO-CONTAINING RAW MATERIALS FOR SYNTHESIS OF USEFUL COMPOUNDS, PRODUCTS AND REAGENTS

The paper considers the main components and products of wood processing, agricultural waste, pulp and paper industry waste and qualifies them as sources of pentose-containing resource-renewable domestic raw materials. The article describes in detail the structural components of wood as a natural polymer, which contains aromatic and carbohydrate parts. It is noted that these poly-mers are promising as raw materials for the production of useful chemical products. The role of lignin, cellolose and hemicellulose in the design of mechanical and structural properties of wood is considered. The article considers the features of the sulfonation reactions of the lignin monomer unit depending on the pH of the medium: acidic, neutral and alkaline. There are three main reac-tions that occur simultaneously with lignin in the process of wood delignification during sulfite cooking, such as the sulfonation reaction, the hydrolytic destruction reaction, and the condensation reaction. It is shown that the lignin-hemicellulose matrix contains three types of interconnected mesh structures: the lignin itself; a network of covalent bonds of lignin with hemicelluloses, and a network whose structure is obtained due to the hydrogen bond and the forces of the physical inter-action of lignin and hemicelluloses. The features of chemical transformations of the monomeric aromatic link of lignosulfonate – phenylpropane unit in the processes of wood delignification, the main chemical reactions of wood raw material delignification under the conditions of sulfite and neutral-sulfite brews are shown. The method of quantitative determination of monosaccharides in the composition of the carbohydrate part is proposed.</jats:p

Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era

AbstractType 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The type 1 diabetes patient cohort is highly heterogeneous, with individuals presenting with disease at different stages and severities, arising from distinct etiologies, and overlaying varied genetic backgrounds. At present, the “one-size-fits-all” treatment for type 1 diabetes is exogenic insulin substitution therapy, but this approach fails to achieve optimal blood glucose control in many individuals. With advances in our understanding of early-stage diabetes development, diabetes stratification, and the role of genetics, type 1 diabetes is a promising candidate for a personalized medicine approach, which aims to apply “the right therapy at the right time, to the right patient”. In the case of type 1 diabetes, great efforts are now being focused on risk stratification for diabetes development to enable pre-clinical detection, and the application of treatments such as gene therapy, to prevent pancreatic destruction in a sub-set of patients. Alongside this, breakthroughs in stem cell therapies hold great promise for the regeneration of pancreatic tissues in some individuals. Here we review the recent initiatives in the field of personalized medicine for type 1 diabetes, including the latest discoveries in stem cell and gene therapy for the disease, and current obstacles that must be overcome before the dream of personalized medicine for all type 1 diabetes patients can be realized.</jats:p

A USE OF PENTOSAN-CONTAINING FRACTION OF NEUTRAL LIGNOSULFONATES FOR OBTAINING FURANE DERIVATIVES

The article describes the technological possibility and gives a conditional scheme of obtaining, based on the carbohydrate part of neutral lignosulfonate, useful products such as furfurol, furan, tetrahydrofuran, properties which have a number of significant physicochemical differences from the properties of lignosulfonate obtained as a result of sulphite brews. The article discusses features of aromatic and carbohydrate constituents of neutral lignosulfonates, monomeric units of aromatic part, structure of polysaccharide components of carbohydrate part, as well as lignocarboxylic matrix characterizing their combination in macromolecule of lignosulfonate. On this basis, the possibility of using neutral LSTs as pentose-containing raw materials was studied and experimentally realized. The experimental part of the article proposes a method of fractionation of lignosulfonates, in our case lignosulfonates of the neutral-sulfite method of delignification of wood raw materials. Samples of the neutral lignosulfonate that was the subject of the study were subjected to alkaline hydrolysis, after which fractionation was carried out by exclusive chromatography or gel filtration on Sephadex grade 100. Water was used as eluent. Fractions were taken by volume, the composition of fractions, both aromatic and carbohydrate, was determined by UV spectroscopy. The criterion for the composition of the fraction was the presence or absence of peaks on the spectrogram in the wavelength region characteristic of the hydroxyl phenolic groups of the aromatic part of neutral lignosulfonates and monosaccharides of the pentose class. The combined polysaccharide fractions represented mainly by xylanes (pentosans) were extracted into an organic solvent, followed by distillation and boiling of the furan-containing compounds. Material balance of the process of producing furan derivatives based on pentose-containing component of neutral lignosulfonates is drawn up.</jats:p