The Role of Double Heterozygotes of SLC3A1 and SLC7A9 in the Prevalence of Cystine Stones.

PURPOSE: Cystine stones, an autosomal recessive disorder caused by cystinuria, result from pathogenic variants of SLC3A1 and SLC7A9. Previous publications revealed clinical prevalence is higher than genetically predicted prevalence. Heterozygous carriers in either gene are not stone formers. However, double heterozygotes (DH), individuals with two heterozygous pathogenic variants in both genes, were never evaluated and may explain the gap between clinical and genetic prevalence. METHODS: Due to the rarity of the condition, direct clinical observation is impractical. We perform this population study as a surrogate by identifying the observed DH, deriving the theoretical/expected DH, and testing the null hypothesis (NH) that the observed DH frequency is equal or greater than expected. This NH biologically correlates to DH are asymptomatic and without cystine stone. RESULTS: Using the 1000 Genome Database, we identified 0 DH. We derived the theoretical/expected DH with Hardy-Weinberg Equilibrium and Mendel's law of independent assortment, as 4.94x10-s. Population proportion test revealed Z= -0.353, and p= 0.362, the NH cannot be rejected. CONCLUSION: Statistical testing does not support that DH are symptomatic, i.e. DH of SLC3A1 and SLC7A9 may not present with cystine stone, and other factors responsible for the gap that current genetics knowledge cannot explain.

Development of Biological Coating from Novel Halophilic Exopolysaccharide Exerting Shelf-Life-Prolonging and Biocontrol Actions for Post-Harvest Applications.

The literature presents the preserving effect of biological coatings developed from various microbial sources. However, the presented work exhibits its uniqueness in the utilization of halophilic exopolysaccharides as food coating material. Moreover, such extremophilic exopolysaccharides are more stable and economical production is possible. Consequently, the aim of the presented research was to develop a coating material from marine exopolysaccharide (EPS). The significant EPS producers having antagonistic attributes against selected phytopathogens were screened from different marine water and soil samples. TSIS01 isolate revealed the maximum antagonism well and EPS production was selected further and characterized as Bacillus tequilensis MS01 by 16S rRNA analysis. EPS production was optimized and deproteinized EPS was assessed for biophysical properties. High performance thin layer chromatography (HPTLC) analysis revealed that EPS was a heteropolymer of glucose, galactose, mannose, and glucuronic acid. Fourier transform infrared spectroscopy, X-ray diffraction, and UV-visible spectra validated the presence of determined sugars. It showed high stability at a wide range of temperatures, pH and incubation time, ≈1.63 × 106 Da molecular weight, intermediate solubility index (48.2 ± 3.12%), low water holding capacity (12.4 ± 1.93%), and pseudoplastic rheologic shear-thinning comparable to xanthan gum. It revealed antimicrobial potential against human pathogens and antioxidants as well as anti-inflammatory potential. The biocontrol assay of EPS against phytopathogens revealed the highest activity against Alternaria solani. The EPS-coated and control tomato fruits were treated with A. solani suspension to check the % disease incidence, which revealed a significant (p < 0.001) decline compared to uncoated controls. Moreover, it revealed shelf-life prolonging action on tomatoes comparable to xanthan gum and higher than chitosan. Consequently, the presented marine EPS was elucidated as a potent coating material to mitigate post-harvest losses.

Diversity in Surface Microstructures of Trichomes, Epidermal Cells, and Stomata in Lentil Germplasm.

To develop crops capable of withstanding challenges posed by climate change, breeding strategies must focus on addressing multiple stresses occurring concurrently in plants. Leaf epidermal structures such as trichomes, stomata, and epidermal cells play an important role in mediating plant defense and could be essential traits that impart wide-ranging tolerance to biotic and abiotic stresses. Consequently, it is important to inform on the underlying diversity in these traits in lentil germplasm (Lens spp.). In this study, we characterized foliar microstructures of 12 genotypes belonging to seven wild and cultivated Lens species. We performed scanning electron microscopy on leaflet and pod surfaces for their qualitative characterization. For quantitative characterization, we observed surface imprints via light microscopy and quantified trichome density (TD), trichome length (TL), stomatal density (SD), epidermal cell density (ECD), and stomatal index (SI) on adaxial and abaxial leaflet surfaces for each genotype. We also assessed the heritability of trichome traits by evaluating interspecific recombinant inbred lines (RILs) derived from the cross Lens culinaris CDC Redberry × Lens tomentosus IG 72805. Comparing foliar microstructures, we found that TD and TL varied widely among cultivated and wild lentil genotypes. However, in most lentil genotypes, the adaxial leaflet surface had lower TD and longer trichomes compared to the abaxial surface. Pubescence on pods comprised five major phenotypes: no trichomes or glabrous pods, very short trichomes at low density, short trichomes at high density, medium-length trichomes at high density, and long trichomes at high density. Leaves of all species were amphistomatous, and SI, SD, and ECD were all higher on the adaxial compared to the abaxial surface. Adaxial surfaces had slightly sunken stomata, which might be an adaptive trait to conserve water. Quantifying TD and TL on the leaflets of interspecific RILs revealed transgressive segregation of these traits, suggesting that TD and TL are quantitative in nature. While taxonomic implications of this study are limited, a detailed description of agronomically relevant morphophysiological traits presented in this paper along with the mode of inheritance of trichomes may serve as a resource for scientists developing lentil adapted to concurrent biotic and abiotic stresses of the future.

Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal.

Cellular stress responses serve as crucial decision points balancing persistence or culling of hematopoietic stem cells (HSCs) for lifelong blood production. Although strong stressors cull HSCs, the linkage between stress programs and self-renewal properties that underlie human HSC maintenance remains unknown, particularly at quiescence exit when HSCs must also dynamically shift metabolic state. Here, we demonstrate distinct wiring of the sphingolipidome across the human hematopoietic hierarchy and find that genetic or pharmacologic modulation of the sphingolipid enzyme DEGS1 regulates lineage differentiation. Inhibition of DEGS1 in hematopoietic stem and progenitor cells during the transition from quiescence to cellular activation with N-(4-hydroxyphenyl) retinamide activates coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs to maintain immunophenotypic and functional HSCs. Thus, our work identifies a linkage between sphingolipid metabolism, proteostatic quality control systems, and HSC self-renewal and provides therapeutic targets for improving HSC-based cellular therapeutics.

Evaluation of the first year of the Oxpal Medlink: A web-based partnership designed to address specific challenges facing medical education in the occupied Palestinian territories.

OBJECTIVES: To (1) evaluate educational needs of clinical students at Al-Quds University Medical School in the West Bank; (2) address these needs where possible using synchronous distance learning, with clinicians in Oxford providing case-based tutorials to undergraduates in the West Bank via an online platform (WizIQ) and (3) assess the impact of this education. DESIGN: Review of online OxPal Medlink database for tutorials held between March 2012 and April 2013. Needs assessment and evaluation of student and tutor experiences through online questionnaires, focus groups and semi-structured interviews. SETTING: Oxford University Hospitals, Oxford, UK, and Al-Quds University Medical School, Abu Dies, Palestine. PARTICIPANTS: Doctors at Oxford University Hospitals and fourth-, fifth- and sixth-year medical students and faculty members at Al-Quds Medical School. MAIN OUTCOME MEASURES: Number of tutorials, student participation, student-rated satisfaction and qualitative feedback from tutors and students. RESULTS: Students demonstrated strong theoretical knowledge but struggled to apply this in presentation-based scenarios. Between March 2012 and April 2013, 90 tutorials were delivered to 60 students. Feedback: >95% respondents rated tutorials as 'Excellent' or 'Good' and 'Very' or 'Fairly' relevant to their future practice in Palestine. Students reported the programme had modified their approach to patients but requested better synchronization with concurrent attachments and clarification of learning outcomes. CONCLUSIONS: OxPal Medlink is a novel, web-based distance-learning partnership designed to overcome some of the challenges to local medical education in the occupied Palestinian territories. Evaluation of the first year indicates teaching is relevant to local practice and of high quality. This approach may have the potential to strengthen local capacity for medical education.

Gemcitabine-induced large vessel vasculitis demonstrated by PET CT: a rare, important side effect.

Gemcitabine is a nucleoside analogue used widely across haemato-oncology. Side effects are generally predictable, and typically consist of cytopenia, nausea, and infection. As the present case clearly demonstrates, gemcitabine is in rare cases associated with life-threatening large vessel vasculitis, which can involve the aorta. It is important to consider gemcitabine-induced vasculitis in non-specifically unwell patients with raised inflammatory markers and fever of unknown origin, with or without signs of vascular compromise. Early recognition, cessation of gemcitabine therapy, and high-dose steroids are critical for a good outcome. PET CT is valuable to diagnose large vessel vasculitis and monitor treatment response.

Screening for latent TB in patients with rheumatic disorders prior to biologic agents in a 'high-risk' TB population: comparison of two interferon gamma release assays.

Patients with rheumatic disorders treated with TNF inhibitors are at increased risk of developing TB. There is no 'gold-standard' for the diagnosis of latent TB prior to initiation of biologic agents. We report our own experience of comparing two interferon gamma release assays (IGRAs) in screening for latent TB in a 'high-risk' TB area in patients with rheumatic disorders. The study demonstrated good concordance between the two tests. We believe the additional cost of these assays is justified in high-risk populations prior to biologic agents, with 16% of the current study population with at least one positive IGRA assay.

Update on the classification of vasculitis.

Classification criteria have an important role and practical use in everyday rheumatology. Improvement in therapy and our understanding of the aetiopathogenesis of vasculitis have driven the need to have better descriptors and groupings of diseases. This in turn will allow newer therapy and further understanding to have a greater impact. The American College of Rheumatology (ACR) classification criteria have been an important advance but have limitations. There remains confusion between classification and diagnostic criteria and definitions. We hope to resolve this using evidence-based improvements in classification and diagnostic criteria. Further understanding of the underlying causative mechanisms could lead to diagnostic testing, eliminating the need for classification criteria.

Sarcoidosis presenting as massive splenic infarction.

Sarcoidosis is a multisystem granulomatous disease of unknown aetiology. Granulomatous inflammation involving the spleen is common and associated with splenomegaly. However, massive splenomegaly is a rare occurrence. Infrequently massive splenomegaly can result in splenic infarction. Massive splenic infarction in sarcoidosis has, to our knowledge, not been previously reported. We present a case of a woman presenting with massive splenic infarction and sarcoidosis confirmed by granulomatous inflammation of the liver.