Pax7 is requisite for maintenance of a subpopulation of superior collicular neurons and shows a diverging expression pattern to Pax3 during superior collicular development

<p>Abstract</p> <p>Background</p> <p><it>Pax7 </it>encodes a transcription factor well-established as an important determinant of mesencephalic identity and superior collicular development. <it>Pax7 </it>mutant mice, however, present with no obvious morphological impairments to the superior colliculus. This finding is paradoxical and has been attributed to functional redundancy afforded by its paralogue <it>Pax3</it>. Here we utilise <it>Pax7 </it>mutant mice to investigate the precise role of this important developmental regulator during superior collicular development and neuronal specification/differentiation. We also assess its spatiotemporal relationship with <it>Pax3 </it>during embryonic development.</p> <p>Results</p> <p>Analysis of the superior colliculus of <it>Pax7 </it>mutant and wildtype mice at a variety of developmental timepoints revealed that whilst correct initial specification is maintained, a subpopulation of dorsal mesencephalic neurons is lost at early postnatal stages. Moreover, a comparative analysis of embryonic <it>Pax3 </it>and <it>Pax7 </it>expression profiles indicate that <it>Pax3 </it>expression overlaps extensively with that of <it>Pax7 </it>initially, but their expression domains increasingly diverge as development progresses, coinciding spatiotemporally with neuronal differentiation and maturation of the tissue. Furthermore, <it>Pax3 </it>expression is perturbed within the CNS of embryonic <it>Pax7 </it>mutant mice.</p> <p>Conclusion</p> <p>In summary, these results demonstrate that during superior collicular development, <it>Pax7 </it>is required to maintain a subpopulation of dorsal, mesencephalic neurons and partially regulates, spatiotemporally, <it>Pax3 </it>expression within the CNS. The differential nature of <it>Pax7 </it>and <it>Pax3 </it>with respect to neuronal differentiation may have implications for future stem cell therapies aimed at exploiting their developmental capabilities.</p

Neurohypophysial dysmorphogenesis in mice lacking the homeobox gene Uncx4·1

Abstract A number of transcription factors have been implicated in the development of the hypothalamo-neurohypophysial system (HNS). Null mutations for these factors caused severe defects in proliferation, migration and survival during early embryogenesis. While they have informed about early events of HNS developments no insights in mechanisms of late development and maturation of this major peptidergic system have been obtained as yet. In a screen for adult-expressed homeobox genes we identified Uncx4.1 as a gene expressed in adult and embryonic magnocellular neurons of the (HNS). Null mutation of Uncx4.1 left these neurons viable and able to express neuropeptides. However, the connectivity of magnocellular neurons with posterior pituitary elements was compromised. As a consequence neuronal fibres traversed to the adenohypophysis. The penetrance of this phenotype was about 50%. The data show a selective role of Uncx4.1 in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and to deliver hormones for control of peripheral functions

RNF40 regulates gene expression in an epigenetic context-dependent manner

Background Monoubiquitination of H2B (H2Bub1) is a largely enigmatic histone modification that has been linked to transcriptional elongation. Because of this association, it has been commonly assumed that H2Bub1 is an exclusively positively acting histone modification and that increased H2Bub1 occupancy correlates with increased gene expression. In contrast, depletion of the H2B ubiquitin ligases RNF20 or RNF40 alters the expression of only a subset of genes. Results Using conditional Rnf40 knockout mouse embryo fibroblasts, we show that genes occupied by low to moderate amounts of H2Bub1 are selectively regulated in response to Rnf40 deletion, whereas genes marked by high levels of H2Bub1 are mostly unaffected by Rnf40 loss. Furthermore, we find that decreased expression of RNF40-dependent genes is highly associated with widespread narrowing of H3K4me3 peaks. H2Bub1 promotes the broadening of H3K4me3 to increase transcriptional elongation, which together lead to increased tissue-specific gene transcription. Notably, genes upregulated following Rnf40 deletion, including Foxl2, are enriched for H3K27me3, which is decreased following Rnf40 deletion due to decreased expression of the Ezh2 gene. As a consequence, increased expression of some RNF40-“suppressed” genes is associated with enhancer activation via FOXL2. Conclusion Together these findings reveal the complexity and context-dependency whereby one histone modification can have divergent effects on gene transcription. Furthermore, we show that these effects are dependent upon the activity of other epigenetic regulatory proteins and histone modifications

The fate and behaviour of gunshot residue: recreational shooter distribution

Despite continued improvements in gunshot residue (GSR) detection and analysis, there are still challenges in the interpretation of GSR evidence. The level and distribution of GSR present on an individual can be influenced by many factors, dependent upon the context of any given case. Due and diligent attention must therefore be placed upon fate and behaviour processes in relation to GSR when assessing and interpreting any case findings. The distribution of GSR upon the body of a recreational shooter was assessed. Samples were taken from 17 positions across a shooter’s body immediately after the discharge of one round of ammunition. The shooting hand prevailed as the most GSR-contaminated area, with as many as 351 characteristic GSR particles identified. The face and supporting hand also exhibited high levels of GSR contamination. This level of contamination raises questions concerning the fate and behaviour of GSR particles within the general environment, specifically with regard to transfer processes

Assessment of treatment burden and its impact on quality of life in dialysis-dependent and pre-dialysis chronic kidney disease patients

Background The management of chronic kidney disease (CKD) and its complications places a significant burden on patients, resulting in impairment of their health-related quality of life (HR-QOL). Little is known about treatment-related burden in pre-dialysis and hemodialysis (HD) CKD patients. Objective This study aimed to investigate the magnitude of treatment-related burden and its impact on HR-QOL among patients with CKD. Methods This was a prospective, cross-sectional study to assess treatment-related burden and HR-QOL among patients with CKD in Qatar. Treatment-related burden and HR-QOL were assessed quantitatively using the Treatment Burden Questionnaire (TBQ) and the Kidney Disease Quality of Life (KDQOL™) questionnaire, respectively. The total TBQ score ranges from 0 to 150, with a higher score indicating higher treatment burden, while the range of total possible scores for the KDQOL™ are from 0 to 3600 with higher transformed score indicating better QOL. Pre-dialysis and hemodialysis (HD) CKD patients who had regular follow-up appointments at Fahad Bin Jassim Kidney Center in Qatar were enrolled. Data were analyzed descriptively and inferentially using SPSS version-24. Results Two hundred-eighty CKD patients (HD = 223 and pre-dialysis = 57) were included in the analyses (response rate 60.9%). Approximately 35% of the participants reported moderate to high treatment-related burden (TBQ global score 51–150). HD patients experienced significantly higher treatment burden compared to pre-dialysis patients with a median (IQR) score of 45 (36) versus 25 (33), respectively (p < 0.001). Medication burden and lifestyle changes burden were the highest perceived treatment-related burden. Overall, the perceived median (IQR) HR-QOL measured using the KDQOL-36™ among the participants was 2280.6 (1096.2) compared to the maximum global score of 3600. Similarly, the HD patients demonstrated significantly lower HR-QOL compared to the pre-dialysis patients [median (IQR) score of 2140 (1100) vs. 2930 (995), respectively; p < 0.001). There was a strong negative correlation between TBQ score and KDQOL-36™ score [rs (251) = −0.616, p < 0.001], signifying that HR-QOL decreases as treatment burden increases. Conclusions This study suggests that a considerable proportion of CKD patients suffered from treatment-related burden and deterioration in HR-QOL at a varying degree of seriousness. HD patients experienced significantly higher burden of treatment and lower HR-QOL compared to pre-dialysis patients and that HR-QOL declines as treatment burden increases. Therefore, treatment-related burden should be considered in CKD management and factors that increase it should be considered when designing healthcare interventions directed to CKD patients.This research was funded by Qatar University under Student Grant number QUST-CPH-SPR/2017-19 [Approved amount QAR 20,000.00 (~US$ 5,480)]. The funders had no role in the design, planning, and implementation of the study. The content is the sole responsibility of the authors.Scopu

A Review of One-Way and Two-Way Experiments to Test the Isotropy of the Speed of Light

As we approach the 125th anniversary of the Michelson-Morley experiment in 2012, we review experiments that test the isotropy of the speed of light. Previous measurements are categorized into one-way (single-trip) and two-way (round-trip averaged or over closed paths) approaches and the level of experimental verification that these experiments provide is discussed. The isotropy of the speed of light is one of the postulates of the Special Theory of Relativity (STR) and, consequently, this phenomenon has been subject to considerable experimental scrutiny. Here, we tabulate significant experiments performed since 1881 and attempt to indicate a direction for future investigation.Comment: Updated Fig. 7 and references; Revised sections 3.2 and 4. Accepted in the Indian Journal of Physics on March 30, 201

Robotic-assisted surgery for left sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study

Introduction: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. Methods: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. Results: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p &lt; 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p &lt; 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p &lt; 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). Conclusions: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation